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Article Contents

Introduction, literature search, physeal injuries and growth disturbance, residual problems after injury in athletes, outcomes of operative management of common sports injuries, conclusions.

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Sport injuries: a review of outcomes

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Nicola Maffulli, Umile Giuseppe Longo, Nikolaos Gougoulias, Dennis Caine, Vincenzo Denaro, Sport injuries: a review of outcomes, British Medical Bulletin , Volume 97, Issue 1, March 2011, Pages 47–80, https://doi.org/10.1093/bmb/ldq026

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Injuries can counter the beneficial aspects related to sports activities if an athlete is unable to continue to participate because of residual effects of injury. We provide an updated synthesis of existing clinical evidence of long-term follow-up outcome of sports injuries. A systematic computerized literature search was conducted on following databases were accessed: PubMed, Medline, Cochrane, CINAHL and Embase databases. At a young age, injury to the physis can result in limb deformities and leg-length discrepancy. Weight-bearing joints including the hip, knee and ankle are at risk of developing osteoarthritis (OA) in former athletes, after injury or in the presence of malalignment, especially in association with high impact sport. Knee injury is a risk factor for OA. Ankle ligament injuries in athletes result in incomplete recovery (up to 40% at 6 months), and OA in the long term (latency period more than 25 years). Spine pathologies are associated more commonly with certain sports (e.g. wresting, heavy-weight lifting, gymnastics, tennis, soccer). Evolution in arthroscopy allows more accurate assessment of hip, ankle, shoulder, elbow and wrist intra-articular post-traumatic pathologies, and possibly more successful management. Few well-conducted studies are available to establish the long-term follow-up of former athletes. To assess whether benefits from sports participation outweigh the risks, future research should involve questionnaires regarding the health-related quality of life in former athletes, to be compared with the general population.

Participation in sports is widespread all over the world, 1 with well-described physical, psychological and social consequences for involved athletes. 2–5 The benefits associated with physical activity in both youth and elderly are well documented. 2 , 6–8 Regular participation in sports is associated with a better quality of life and reduced risk of several diseases, 1 , 9 allowing people involved to improve cardiovascular health. 10 , 11 Both individual and team sports are associated with favourable physical and physiological changes consisting of decreased percentage of body fat 12 and increased muscular strength, endurance and power. 13 , 14 Moreover, regular participation in high-volume impact-loading and running-based sports (such as basketball, gymnastics, tennis, soccer and distance running) is associated with enhanced whole-body and regional bone mineral content and density, 14 , 15 whereas physical inactivity is associated with obesity and coronary heart disease. 16 Sports are associated with several psychological and emotional benefits. 7 , 17 , 18 First of all, there is a strong relationship between the development of positive self-esteem, due to testing of self in a context of sport competition, 19 reduced stress, anxiety and depression. 20 Physical activities also contribute to social development of athletes, prosocial behaviour, fair play and sportspersonship 21 and personal responsibility. 22

Engaging in sports activities has numerous health benefits, but also carries the risk of injury. 7 , 23 , 24 At every age, competitive and recreational athletes sustain a wide variety of soft tissue, bone, ligament, tendon and nerve injuries, caused by direct trauma or repetitive stress. 25–35 Different sports are associated with different patterns and types of injuries, whereas age, gender and type of activity (e.g. competitive versus practice) influence the prevalence of injuries. 7 , 36 , 37

Injuries in children and adolescents, who often tend to focus on high performance in certain disciplines and sports, 24 include susceptibility to growth plate injury, nonlinearity of growth, limited thermoregulatory capacity and maturity-associated variation. 9 In the immature skeleton, growth plate injury is possible 38 and apophysitis is common. The most common sites are at the knee (Osgood-Schlatter lesion), the heel (Sever's lesion) and the elbow. 39 Certain contact sports, such as rugby, for example, are associated with 5.2 injuries per 1000 total athletic exposures in high school children (usually boys). These were more common during competition compared with training and fractures accounted for 16% of these injuries, whereas concussions (15.8%) and ligament sprains (15.7%) were almost as common. 40

Sports trauma commonly affects joints of the extremities (knee, ankle, hip, shoulder, elbow, wrist) or the spine. Knee injuries are among the most common. Knee trauma can result in meniscal and chondral lesions, sometimes in combination with cruciate ligament injuries. 37 Ankle injuries constitute 21% of all sports injuries. 41 Ankle ligament injuries are more commonly (83%) diagnosed as ligament sprains (incomplete tears), and are common in sports such as basketball and volleyball. Ankle injuries occur usually during competition and in the majority of cases, athletes can return to sports within a week. 42 Hip labral injuries have drawn attention in recent years with the advent of hip arthroscopy. 43 , 44 Upper extremity syndromes caused by a single stress or by repetitive microtrauma occur in a variety of sports. Overhead throwing, long-distance swimming, bowling, golf, gymnastics, basketball, volleyball and field events can repetitively stress the hand, wrist, elbow and shoulder. Shoulder and elbow problems are common in the overhead throwing athlete whereas elbow injuries remain often unrecognized in certain sports. 45 Hand and wrist trauma accounts for 3–9% of all athletic injuries. 46 Wrist trauma can affect the triangular fibrocartilage complex 47 or cause scaphoid fractures, 48 whereas overuse problems (e.g. tenosynovitis) are not uncommon. 49 Spinal problems can range from lumbar disc herniation, 39–42 to fatigue fractures of the pars interarticularis, 50 and ‘catastrophic’ cervical spine injuries. 51

Thus, in addition to the beneficial aspects related to sports activities, injuries can counter these if an athlete is unable to continue to participate because of residual effects of injury. Do injuries in children, adolescents and young adults have long-term consequences? What are the outcomes of the most commonly performed surgical procedures? The aim of this review is to provide an updated synthesis of existing clinical evidence of long-term follow-up outcome of sports injuries.

An initial pilot Pubmed search using the keywords ‘sports’, ‘injury’, ‘injuries’, ‘athletes’, ‘outcome’, ‘long term’, was performed. From 1467 abstracts that were retrieved and scanned we identified the thematic topics (types of injury, management, area of the body involved) of the current review, listed below:

Then a more detailed search of PubMed, Medline, Cochrane, CINAHL and Embase databases followed. We used combinations of the keywords: ‘sport’, ‘sports’, ‘youth sports’, ‘young athletes’, ‘former athletes’, ‘children’, ‘skeletally immature’, ‘adolescent’, ‘paediatric’, ‘pediatric’, ‘physeal’, ‘epiphysis’, ‘epiphyseal injuries’, ‘hip’, ‘knee’, ‘ankle’, ‘spine’, ‘spinal’, ‘shoulder’, ‘elbow’, ‘wrist’, ‘football players’, ‘football’, ‘soccer’, ‘tennis’, ‘swimmers’, ‘swimming’, ‘divers’, ‘wrestlers’, ‘wrestling’, ‘cricket’, ‘gymnastics’, ‘skiers’, ‘baseball’, ‘basketball’, ‘osteoarthritis’, ‘former athletes’, ‘strain’, ‘contusion’, ‘distortion’, ‘injury’, ‘injuries’, ‘trauma’, ‘drop out’, ‘dropping out’, ‘attrition’, ‘young’, ‘ youth’, ‘sprain’, ‘ligament’, ‘ACL’, ‘cruciate ligament’, ‘meniscus’, ‘meniscal’, ‘chondral’, ‘labrum’, ‘labral’, ‘reconstruction’, ‘arthroscopy’, ‘throwing’, ‘overhead’, ‘rotator cuff’, ‘TFCC’, ‘scaphoid’, ‘osteoarthritis’, ‘arthritis’, ‘long term’, ‘follow-up’ and ‘athlete’. The most recent search was performed during the second week of November 2009.

Osteoarthritis (OA) in former athletes

Spine problems in former athletes

Knee injury and OA

Ankle ligament injury and OA

Residual upper limb symptoms in the ‘overhead’ athlete

Meniscectomy and oa, meniscal repair in athletes.

Anterior cruciate ligament (ACL) reconstruction and OA

ACL reconstruction in children

Ankle arthroscopy in athletes, hip arthroscopy in athletes.

Operative management of shoulder injuries in athletes (focusing on surgery for instability and labral tears)

Operative management of wrist injuries in athletes (focusing on triquetral fibrocartilage complex, TFCC, injuries and scaphoid fractures)

Given the different types of sports injuries in terms of location in the body, several searches were carried out. The search was limited to articles published in peer-reviewed journals.

From a total of 2596 abstracts that were scanned, 1247 studies were irrelevant to the subject and were excluded. The remaining studies were categorized in the topics identified earlier. We excluded from our investigation case reports, letter to editors and articles not specifically reporting outcomes, as well as ‘kin’ studies (studies reporting on the same patients' population). The most recent study or the study with the longest follow-up was included. In some topics of particular importance, such as the effect of knee injuries (given their frequency), we included long-term studies reporting not only on athletes, but also on the general population (usually in these studies a very high proportion on sports injuries is included). Regarding knee injuries in adults, we included articles with follow-up more than 10 years.

Given the linguistic capabilities of the research team, we considered publications in English, Italian, French, German, Spanish and Portuguese.

A concern regarding children's participation in sports is that the tolerance limits of the physis may be exceeded by the mechanical stresses of sports such as football and hockey or by the repetitive physical loading required in sports such as baseball, gymnastics and distance running. 52 Unfortunately, what is known about the frequency of acute sport-related physeal injuries is derived primarily from case reports and case series data. In a previous systematic review on the frequency and characteristics of sports-related growth plate injuries affecting children and youth, we found that 38.3% of 2157 acute cases were sport related and among these 14.9% were associated with growth disturbance. 24 These injuries were incurred in a variety of sports, although football is the sport most often reported. 53

There are accumulating reports of stress-related physeal injuries affecting young athletes in a variety of sports, including baseball, basketball, climbing, cricket, distance running, American football, soccer, gymnastics, rugby, swimming, tennis. 24 Although most of these stress-related conditions resolved without growth complication during short-term follow-up, there are several reports of stress-related premature partial or complete distal radius physeal closure of young gymnasts. 25–29 These data indicate that sport training, if of sufficient duration and intensity, may precipitate pathological changes of the growth plate and, in extreme cases, produce growth disturbance. 24 , 32

Disturbed physeal growth as a result of injury can result in length discrepancy, angular deformity or altered joint mechanics and may cause significant long-term disability. 33 However, the incidence of long-term health outcome of physeal injuries in children's and youth sports is largely unknown.

Based on the previously selection criteria, 20 studies 54–73 were retained for analysis (Table  1 ). Injury to the physis can result in limb deformities and leg-length discrepancy, the latter being more common after motor vehicle accidents, rather than sports participation.

Evidence on acute physeal injury with subsequent adverse affects on growth.

OA in former athletes

Two studies investigated former top-level female gymnasts for residual symptoms (back pain) and radiographical changes. 74 , 75 Both studies reported no significant differences in back pain between gymnast and control groups; however, the prevalence of radiographical abnormalities was greater in gymnasts than controls in one study. 74

Lower limb weight-bearing joints such as the hip and the knee are at risk of developing OA after injury or in the presence of malalignment, especially in association with high impact sport. 76 Varus alignment was present in 65 knees (81%) in 81 former professional footballers (age 44–70 years), whereas radiographic OA in 45 (56%). 77 Others showed that prevalence of knee OA in soccer players and weight lifters was 26% (eight athletes) and 31% (nine athletes), respectively, whereas it was only 14% in runners (four athletes). 78 By stepwise logistic regression analysis, the increased risk is explained by knee injuries in soccer players and by high body mass in weight lifters. A survey in English former professional soccer players revealed that 47% retired because of an injury. The knee was most commonly involved (46%), followed by the ankle (21%). Of all respondents, 32% had OA in at least one lower limb joint and 80% reported joint pain. 79 Another study examined the incidence of knee and ankle arthritis in injured and uninjured elite football players. The mean time from injury was 25 years. 80 Arthritis was present in 63% of the injured knees and in 33% of the injured ankles, whereas the incidence of arthritis in uninjured players was 26% in the knee and 18% in the ankle. Obviously, it should be kept in mind that radiographic studies can only ascertain the presence of degenerative joint disease, which is just one of the features of OA. Clinical examination is always necessary to clarify the diagnosis, and formulate a management plan.

Ex-footballers also had high prevalence of hip OA (odds ratio: 10.2), 81 whereas in another study the incidence of hip arthritis was 5.6% among former soccer players (mean age: 55 years) compared with 2.8% in an age-matched control group. In 71 elite players it was higher (14%). Female ex-elite athletes (runners, tennis players) were compared with an age-matched population of women, and were found to have higher rates (2–3 fold increase) of radiographic OA (particularly the presence of osteophytes) of the hip and knee. 82 The risk was similar in ex-elite athletes and in a subgroup from the general population who reported long-term sports activity, suggesting that duration rather than frequency of training is important. An older study 83 is runners associated degenerative changes with genu varum and history of injury. A cohort of 27 Swiss long-distance runners was at increased risk of developing ankle arthritis compared with a control group. 84 Similarly elite tennis players were at risk of developing glenohumeral OA, 85 whereas handball players of developing premature hip OA, 86 and former elite volleyball players had marginally increased risk for ankle OA. 87 Interestingly a study that investigated the health-related quality of life (HRQL) in 284 former professional players in the UK found that medical treatment for football-related injuries was a common feature, as was arthritis, with the knee being most commonly affected. Respondents with arthritis reported poorer outcomes in all aspects of HRQL. 88

In summary, OA is more common among former athletes, compared with the general population. The lower limb joints are commonly affected, in association with high impact and injury.

Evidence from follow-up studies on spine of former athletes

Heavy physical work and activity lead to degenerative changes in the spine. Studies on different athletic disciplines and heavy workers have given variable degenerative changes and abnormalities in the lumbar spine. Even though sporting activity is regarded as an important predisposing factor in the development of spinal pathologies, 89–99 there are few studies on the late spinal sequelae of competitive youth sport. Any comparison in terms of back pain between top athletes and the general population is difficult. Experience of pain may be influenced by factors such as susceptibility, motivation and physical activity. Minor pain may be provoked by vigorous body movements that hamper athletic performance, thereby ascribing the pain a greater impact than in the general population. On the other hand, a well-motivated athlete may ignore even severe pain to maintain or improve his/her athletic performance. Also, varying rate/prevalence of osteophytosis has been reported in players associated with various disciplines of sports.

Efforts should be made to understand the aetiology of injuries to the intervertebral discs during athletic performance and thereby prevent them. 74

Based on the previously selection criteria, seven studies 74 , 89 , 98 , 100–103 were retained for analysis (Table  2 ). In summary, spine pathologies are associated more commonly with certain sports (e.g. wresting, heavy-weight lifting, gymnastics, tennis, soccer). Degenerative changes in the athlete's spine can occur, but they are not necessarily associated with clinically relevant symptoms of OA. Therefore, it cannot be determined whether it threatens the athlete's career, or whether it has a worse impact on athletes compared with the general population.

Evidence from follow-up studies on spine of former athletes.

Knee injury and OA in athletes

A population-based case-control study investigated the risk of knee OA with respect to sports activity and previous knee injuries of 825 athletes competing in different sports. They were matched with 825 controls. After confounding factors were adjusted, the sports-related increase risk of OA was explained by knee injuries. 104 Another study leads to the same conclusion: 23 American football high-school players were compared with 11 age-matched controls, 20 years after high-school competition. No significant increase in OA could be demonstrated clinically or radiographically. However, a significant increase in knee joint OA was found in the subgroup of football players who had sustained a knee injury. 105

A cohort of 286 former soccer players (71 elite, 215 non-elite) with a mean age of 55 years was compared with 572 age-matched controls, regarding the prevalence of radiographic features of knee arthritis. Arthritis in elite players, non-elite players and controls was 15%, 4.2% and 1.6%, respectively. In non-elite players, absence of history of knee injury was associated with arthritis prevalence similar to the controls. 106

An interesting study involved a cohort of 19 high-level athletes of the Olympic program of former East Germany. They sustained an ACL tear between 1963 and 1965. None were reconstructed, and all were able to return to sports within 14 weeks. Subsequent meniscectomies were necessary in 15/19 (79%) athletes at 10 years and 18/19 (95%) at 20 years, when in 18 of the 19 knees, arthroscopy was performed, 13 patients (68%) had a grade four chondral lesion. By year 2000 (more than 35 years after ACL rupture), 10/19 knees required a joint replacement. 107

The incidence of radiographic advanced degeneration (Kellgren–Lawrence grade 2 or higher) was 41% in a cohort of 122 Swedish male soccer players (from a total of 154) who consented to radiographic follow-up, 14 years after an ACL rupture. No difference was found between players treated with or without surgery for their ACL rupture. The prevalence of Kellgren–Lawrence grade 2 or higher knee OA was 4% in the uninjured knees. 108

Similar results were evident among Swedish female soccer players who were injured before the age of 20. The prevalence of radiographic OA was 51%, compared with 8% only in the uninjured knee, 12 years later. The presence of symptoms was documented in 63 of 84 (75%) athletes who answered the questionnaire, and was similar ( P = 0.2) in the two management groups (operative versus non-operative). The presence of symptoms did not necessarily correlate with radiographic OA ( P = 0.4). 109

In summary, knee injury is a recognized risk factor for OA. Injured athletes develop OA more commonly than the general population in the long term. Approximately half of the injured knees could have radiographic changes 10–15 years later. It is not clear whether radiographic changes correspond to presence of symptoms.

Ankle ligament injuries and OA in athletes

Ankle sprains are common sporting injuries generally believed to be benign and self-limiting. However, some studies report a significant proportion of patients with ankle sprains having persistent symptoms for months or even years. Nineteen patients with a mean age of 20 years (range: 13–28), who were referred to a sports medicine clinic after an ankle inversion injury, were followed for 29 months (average), and compared with matched controls. Only five (26%) injured patients had recovered fully, whereas 74% had symptoms 1.5–4 years after the injury. Assessments of quality of life using the short form-36 questionnaires revealed a difference in the general health subscale between the two groups, favouring the controls ( P < 0.05). 110

Similar conclusions were drawn from another study, regarding ankle injuries in a young (age range: 17–24 years) athletic population. 111 There were 104 ankle injuries (96 sprains, 7 fractures and 1 contusion), accounting for 23% of all injuries seen. Of the 96 sprains, 4 were predominately medial injuries, 76 lateral and 16 syndesmosis sprains. Although 95% had returned to sports at 6 weeks, 55% reported pain or loss of function. At 6 months, 40% had not fully recovered, reporting residual symptoms. Syndesmosis injuries were associated with prolonged recovery.

The association between ligamentous ankle injuries has been highlighted in a study that, retrospectively, reviewed data from 30 patients (mean age: 59 years, 33 ankles) with ankle osteoarthritis. 112 They found that 55% had a history of sports injuries (33% from soccer), and 85% had a lateral ankle ligament injury. The mean latency time between injury and OA was 34.3 years. The latency period for acute severe injuries was significantly lower (25.7 years), compared with chronic instability (38 years). Varus malalignment and persistent instability were present in 52% of those patients.

In summary, ankle ligamentous injuries in athletes can result in considerable morbidity, residual symptoms and arthritis 25–30 years later.

Shoulder injuries account for 7% of sports injuries and often limit the athlete in his or her ability to continue with their chosen sport. 113 Repetitive overhead throwing imparts high valgus and extension loads to the athlete's shoulder and elbow, often leading to either acute or chronic injury or progressive structural change and long-term problems in the overhead athlete. 45

Schmitt et al . 102 examined 21 elite javelin throwing athletes at an average of 19 years after the end of their high-performance phase (mean age at follow-up was 50 years). Five athletes (24%) complained about transient shoulder pain and three (16%) about elbow pain in their throwing arm affecting activities of daily living. All dominant elbows had advanced degeneration (osteophytes).

Elbow intra-articular lesions are recognized as consequences of repetitive stress and overuse. Shanmugam and Maffulli 9 reported follow-up (mean 3.6 years) of lesions of the articular surface of the elbow joint in a group of 12 gymnasts (six females and six males). This group showed a high frequency of osteochondritic lesions, intra-articular loose bodies and precocious signs of joint ageing. Residual mild pain in the elbow at full extension occurring after activity was present in 10 patients and all patients showed marked loss of elbow extension compared with their first visit.

Glenoid labral tears require repair, and shoulder instability is currently approached operatively more often. A review article found that conservative management of traumatic shoulder dislocations in adolescents was associated with high rates of recurrent instability (up to 100%). Therefore, surgical shoulder stabilization is recommended. The outcomes of surgical management are presented in the next section.

A distinct clinical entity is the ‘little league shoulder’, which is characterized by progressive upper arm pain with throwing and is more commonly seen in male baseball pitchers between ages 11 and 14 years. It is thought to be Salter-Harris type I stress fracture. Activity modification, education to improve throwing mechanics and core muscle training are recommended. It is not known how this condition behaves in the long term, regarding structural damage and development of degenerative changes.

Overhead athletes are plagued by shoulder and elbow injuries or overuse syndromes that can affect their performance and cause degeneration and pain in the long term.

The association between knee OA and meniscectomy has been well documented. In former athletes 114 – 116 it is associated with OA (Table  3 ). Meniscectomy in children and adolescents 117 – 123 has been associated with unfavourable results and radiographic arthritic changes in the long term (Table  4 ). However, radiographic criteria were not always clearly defined. To assess the long-term outcomes of meniscectomy, we also evaluated studies with a minimum follow-up of 10 years in the adult general population 106 , 124 – 129 (Table  5 ). Many of the ‘older’ studies providing the long-term outcomes represent results of open total meniscectomies. The overall message is that radiographic degeneration is common in meniscectomized knees, and patients are at risk of developing OA. The condition of the articular cartilage is a prognostic factor. However, clinical and radiographic findings do not always correlate. Resection should be limited to the torn part of the meniscus.

Menicectomy and osteoarthritis in athletes.

Menicectomy in children and adolescents.

Meniscectomy in adults / general popaltion—long-term outcomes.

Given the long-term problems associated with meniscectomies, preservation of the substance of the meniscus after injury is currently advocated. Based on this concept, arthroscopic meniscal repair techniques have been developed. 125 In the general population, encouraging clinical results with failure rates of 27–30% at 6–7 years follow-up have been reported. 130–132 One study 133 evaluated 45 meniscal repairs in 42 elite athletes followed for an average of 8.5 years. In 83% of them an ACL reconstruction was performed as well. Return to their sport was possible in 81% at an average of 10 months after surgery. They identified 11 failures (24%), seven of which were associated with a new injury. The medial meniscus re-ruptured more frequently compared with the lateral (36.4 versus 5.6%, respectively).

Mintzer et al . 134 retrospectively reviewed the outcome of meniscal repair in 26 young athletes involved in several sports at an average follow-up of 5 years (range: 2–13.5). No failures were reported, with 85% of patients performing high level of sports activities.

In general, the results of meniscal repairs in the general population, as well as in athletes, are encouraging.

ACL reconstruction and OA

Knee injuries can result in ligament ruptures and/or meniscal tears and are recognized as a risk factor of OA. A systematic review on studies published until 2006 135 reported on the prognosis of conservatively managed ACL injuries showed that there was an average reduction of 21% at the level of activities (Tegner score evaluation). ACL reconstruction is therefore a procedure frequently performed in athletic individuals, as they desire to maintain a high level of activities. However, does ACL reconstruction affect the incidence of knee degeneration and symptoms in the long term? We identified three studies 108 , 109 , 136 comparing operative versus non-operative management of ACL ruptures specifically in athletes, in regard to OA.

Two studies from Sweden investigating the prevalence of OA after ACL rupture in male 108 and female 109 soccer players were discussed earlier. Both found no difference in the incidence of radiographic arthritis between surgically and conservatively treated players, more than 10 years after their injury.

A comparative study 136 on high-level athletes with ACL injury showed no statistical difference between the patients treated conservatively or operatively (patella tendon graft) with respect to OA or meniscal lesions of the knee, as well as activity level, objective and subjective functional outcome. The patients who were treated operatively had a significantly better stability of the knee at examination.

Several studies present outcomes of ACL injuries in the general population. A recent systematic review included 31 studies (seven were prospective) reporting radiographic outcomes regarding OA, with more than 10 years follow-up after ACL injury. 137 The prevalence of OA in the injured knee varied from 1 to 100%, whereas in the contralateral knee it was 0–38%. Isolated ACL tears were associated with low OA incidence between 0 and 13%, whereas in the presence of additional meniscal injury, it was 21–48%. Meniscal injury and meniscectomy were the most frequently reported risk factors for OA. The authors scored the quality of the studies and found that studies scoring high reported low incidence of OA. Data extraction indicated that ACL reconstruction as a single factor did not prevent the development of knee OA. 137

There is lack of evidence to support a protective role of reconstructive surgery of the ACL against OA, both in athletes as well as in the general population.

ACL reconstruction in skeletally immature patients is a relatively new trend. 138 The concern is intra-operative epiphysis damage and growth disturbance, a complication which has been avoided in several studies. 139–143

The earliest published study 144 compared non-operative versus operative management of ACL ruptures in 42 skeletally immature athletes (age range: 4–17 years) followed for a mean of 5.3 years. They used a composite knee score based on clinical examination and a patient questionnaire and found superior results in the operatively treated patients. Age and growth plate maturity did not influence results. They recommended ACL reconstruction for active athletic children.

One of the early reports showed that there were no growth disturbances at a mean of 3.3 years after surgery in 9 children, however, with two re-ruptures. Those children could not return to athletic activities. 139

In a series of 57 ACL reconstructions, 15 patients had reached completion of growth when examined at follow-up, none had signs of growth disturbance, whereas clinical scoring was good or excellent in all patients. 142

Another study compared the outcomes of two management strategies in 56 children with ACL ruptures, namely ligament reconstruction in the presence of open physis, or delayed reconstruction after skeletal maturity. The ‘early’ reconstruction group had evidence of less medial meniscal tears (16 versus 41%), and no evidence of growth disturbances, at 27 months mean follow-up. 140

After 1.5–7.5 years follow-up of 19 ACL reconstructions in 20 athletic teenagers (age range: 11.8–15.6 years), all but one had returned to sports, none had tibiofemoral malalignment or a leg-length discrepancy of more than 1 cm, and the modified Lysholm score was 93 out of 95. 143

Finally, 55 children (ages 8 to 16 years, mean 13 years) were followed for a mean of 3.2 years (range: 1–7.5 years) after ACL reconstruction, with no evidence of growth disturbances. Clinical scores showed normal or almost normal values (higher than 90 out of 100 possible points) and 88% of the patients went back to normal or almost normal sports according to the Tegner score. 141

Overall, the clinical results are encouraging and iatrogenic epiphysis damage does not seem to be a problem, possibly because physeal sparing procedures were used. The study designs, however, are inadequate to answer the question of whether early or delayed ACL reconstruction results in the best possible outcome in skeletally immature patients.

Anterior impingement syndrome is a generally accepted diagnosis for a condition characterized by anterior ankle pain with limited and painful dorsiflexion. The cause can be either soft tissue or bony obstruction. Arthroscopic debridement is currently considered a routine procedure, and chondral lesions are now more frequently identified as causes of ankle pain. Few reports specifically in athletes are available 145–149 (Table  6 ). Short-term outcomes only are available. It is not known whether arthritis is a long-term consequence.

Ankle arthroscopy in athletes.

Only recently has the hip received attention as a recognized site of sports injuries, possibly as a result of the evolution of hip arthroscopy which allowed recognition of intra-articular pathology. 150 Acetabular labrum and chondral lesions can be addressed arthroscopically, and patients' satisfaction rates up to 75% have been reported. 44 One study evaluated the outcome of hip arthroscopy in 15 athletes (mean age: 32 years, range: 14–70) followed for 10 years. Nine were recreational athletes, four high school and two intercollegiate athletes. Diagnoses included cartilage lesion (8), labral tear (7), arthritis (5), avascular necrosis (1), loose body (1) and synovitis (1). The median improvement in the modified Harris hip score was 45 points (from 51 preoperatively to 96, on the 100-point scale), with 13 patients (87%) returning to their sport. All five athletes with arthritis eventually underwent total hip arthroplasty at an average of 6 years. 43 Long-term outcomes regarding progression of joint degeneration after traumatic chondral or labral damage are not available.

Operative management of shoulder injuries in athletes

Labral tears require repair, whereas shoulder instability is currently approached operatively more often. Conservative management of traumatic shoulder dislocations in adolescents is associated with high rates of recurrent instability (up to 100%), whereas recurrent dislocations were reported in up to 12%, at an average of 3 years after arthroscopic stabilization. Shoulder dislocations are particularly common in rugby, the characteristic mechanism of injury being tackling, whereas labral tears are common in the ‘overhead’ athlete'. Published results in athletes 151 – 162 (Table  7 ) show that operative stabilization of the shoulder is initially successful, but instability and pain can recur in the long term. Results of arthroscopic techniques in the management of intra-articular pathologies are promising, but long-term outcomes are unknown (Table  7 ).

RCT, randomized controlled trial; VAS, visual analogue scale.

Operative management of elbow injuries in athletes

Elbow ulnar collateral ligament (UCL) insufficiency is one of the frequently recognized injuries in the overhead athlete, as a result of excessive valgus stress. It constitutes a potentially career threatening injury and requires surgical repair. 163 The use of a muscle-splitting approach, avoiding handling of the ulnar nerve, and the use of the docking technique for stabilization is recommended 164 , 165 (Table  8 ). Recent advantages in arthroscopic surgical techniques and ligament reconstruction in the elbow have improved the prognosis for return to competition for highly motivated athletes. The results of arthroscopic debridement 150 , 166 (Table  7 ) need to be evaluated in the long term.

Operative management of elbow injuries in athletes.

UCL, ulnar collateral ligament.

Operative management of wrist injuries in athletes

A review of the literature shows that 3–9% of all athletic injuries occur in the hand or wrist, and are more common in adolescent athletes than adults. 46 In this article, we focused on TFCC injuries and acute scaphoid fractures in athletes.

TFCC injuries are an increasingly recognized cause of ulnar-sided wrist pain, and can be particularly disabling in the competitive athlete. Advances in wrist arthroscopy made endoscopic debridement and repair of the TFCC possible. McAdams et al . 47 treated arthroscopically TFCC tears in 16 competitive athletes (mean age: 23.4 years). Repair of unstable tears was performed in 11 (69%) and debridement only in 5 (31%). Return to play averaged 3.3 months (range: 3–7 months). The mean duration of follow-up was 2.8 years (range: 2–4.2 years). Clinical scores (mini-DASH and mini-DASH sports module) improved significantly. No long-term outcomes are available.

Operative management of scaphoid fractures in athletes, even if undisplaced, is recommended if early return to sports is desired. One study followed 12 athletes treated operatively for a scaphoid fracture. They were able to return to sports at 6 weeks. At an average follow-up of 2.9 years, 9 of 12 athletes had range of motion equal to the uninjured side, and grip strength was equal to the unaffected side in 10 of 12 athletes. 49

Participation in sports offers potential benefits for individuals of all ages, such as combating obesity and enhancing cardiovascular fitness. 1 On the other hand, negative consequences of musculoskeletal injuries sustained during sports may compromise function in later life, limiting the ability to experience pain-free mobility and engage in fitness-enhancing activity. 167 Increasingly, successful management of sports-related injuries has allowed more athletes to return to participation. The knee is the joint most commonly associated with sports injuries, and therefore is most at risk of developing degenerative changes. It is not clear whether radiographic OA always correlates with symptoms and reduced quality of life. Furthermore, even effective management of meniscal or ACL injury does not reduce the risk of developing subsequent OA. 137 , 168 OA in an injured joint is caused by intra-articular pathogenic processes initiated at the time of injury, combined with long-term changes in dynamic joint loading. Variation in outcomes involves not only the exact type of injury (e.g. ACL rupture with or without meniscal damage), 137 but also additional variables associated with the individual such as age, sex, genetics, obesity, muscle strength, activity and reinjury. A better understanding of these variables may improve future prevention and treatment strategies. 169

In many of the long-term studies (the majority being retrospective case series), several methodological flaws have to be highlighted. A recent systematic review on OA after ACL injuries 137 suggested that some studies may overestimate the prevalence of long-term OA. The authors in several studies mention that a proportion of the index group of injured athletes were available for follow-up or consented for radiographic examination. One can argue that these patients were the ones with symptoms, therefore the prevalence of OA (after ACL rupture for example) may appear higher than it really is. Presentation of outcomes was not always based on robust criteria. Different clinical scores and radiographic classifications have been used, and therefore results between studies are not directly comparable. In the majority of the studies, it was not clarified whether radiographic appearance correlated with symptoms, and how important these were for the quality of life of the patients. Disabling arthritis requiring intervention may actually be delayed for more than 20–30 years. 107 , 112 Furthermore, long-term studies present outcomes of older techniques, not used any more in clinical practice (e.g. primary ACL repair or total meniscectomy). Evolution in surgical or rehabilitation techniques might have improved outcomes of certain injuries. Therefore, currently known ‘long-term outcomes’ may only reflect the results of techniques used in the past and not what we should expect in the future. Increasing awareness of athletes and trainers, new diagnostic and musculoskeletal imaging modalities, improved surgical and rehabilitation methods, but also analysis of injury patterns in different sports and development of injury prevention strategies might be beneficial to minimize the effects of sports injuries in the years to come.

What is the true incidence of arthritis in the long term? Will it be a disabling condition for the former athlete, in the coming decades? Currently, joint preserving procedures (e.g. microfractures, 145 mosaicplaty, 170 autologous chondrocyte implantation, 171 , 172 realignment osteotomies 173 and implant arthroplasties 174 ) have evolved and allow middle aged or older patients to live without pain and maintain an active life style. Meniscal transplantation shows encouraging results. 175 Should therefore an increased risk for developing musculoskeletal problems prevent children and adults from being active in sports? 176 Do the benefits of participating in sports outweigh the risks?

A survey in Sweden showed that 80% of former track and field athletes with an age range of 50–80 years felt they were in good health, compared with 61% of the referents, despite higher prevalence of hip arthritis in former athletes. Low back disorders were similar in the two groups, shoulder and neck problems were lower in former athletes, and knee arthritis was similar in the two groups. 177

No definite answer can be given to the previously addressed questions, based on available evidence. Future research should involve questionnaires assessing the HRQL in former athletes, to be compared with the general population. 27 , 178–181

Physical injury is an inherent risk in sports participation and, to a certain extent, must be considered an inevitable cost of athletic training and competition. Injury may lead to incomplete recovery and residual symptoms, drop out from sports, and can cause joint degeneration in the long term. Few well-conducted studies are available on the long-term follow-up of former athletes, and, in general, we lack studies reporting on the HRQL to be compared with the general population. Advances in arthroscopic techniques allow operative management of most intra-articular post-traumatic pathologies in the lower and upper limb joints, but long-term outcomes are not available yet. It is important to balance the negative effects of sports injuries with the many social, psychological and health benefits that a serious commitment to sport brings. 9

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Overuse injuries in sport: a comprehensive overview

• R. Aicale 1 ,
• D. Tarantino 1 &
• N. Maffulli 1 , 2  

Journal of Orthopaedic Surgery and Research volume  13 , Article number:  309 ( 2018 ) Cite this article

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The absence of a single, identifiable traumatic cause has been traditionally used as a definition for a causative factor of overuse injury. Excessive loading, insufficient recovery, and underpreparedness can increase injury risk by exposing athletes to relatively large changes in load. The musculoskeletal system, if subjected to excessive stress, can suffer from various types of overuse injuries which may affect the bone, muscles, tendons, and ligaments.

We performed a search (up to March 2018) in the PubMed and Scopus electronic databases to identify the available scientific articles about the pathophysiology and the incidence of overuse sport injuries. For the purposes of our review, we used several combinations of the following keywords: overuse, injury, tendon, tendinopathy, stress fracture, stress reaction, and juvenile osteochondritis dissecans.

Overuse tendinopathy induces in the tendon pain and swelling with associated decreased tolerance to exercise and various types of tendon degeneration. Poor training technique and a variety of risk factors may predispose athletes to stress reactions that may be interpreted as possible precursors of stress fractures. A frequent cause of pain in adolescents is juvenile osteochondritis dissecans (JOCD), which is characterized by delamination and localized necrosis of the subchondral bone, with or without the involvement of articular cartilage. The purpose of this compressive review is to give an overview of overuse injuries in sport by describing the theoretical foundations of these conditions that may predispose to the development of tendinopathy, stress fractures, stress reactions, and juvenile osteochondritis dissecans and the implication that these pathologies may have in their management.

Conclusions

Further research is required to improve our knowledge on tendon and bone healing, enabling specific treatment strategies to be developed for the management of overuse injuries.

The specific definition of overuse injury was most commonly based on the concept of an injury occurring in the absence of a single, identifiable traumatic cause [ 1 ]. Professional soccer players sustain on average 2.0 injuries per season, which cause them to miss 37 days in a 300-day season on average [ 2 ]. Following the updated injury etiology model, training and match load contribute, together with intrinsic and extrinsic risk factors, to the multifactorial and dynamic etiology of injury [ 3 ]. Not only excessive loading and insufficient recovery, but also underpreparedness may increase injury risk by exposing players to relatively large changes, or spikes, in load during periods with higher training and match loads [ 4 ].

The tendons transfer the force produced from muscular contraction to the bone. In most instances, sports-related tendinopathies present well-defined histopathological lesions, providing an explanation for the chronicity of symptoms which often occur in athletes with tendinopathies [ 5 , 6 , 7 , 8 ].

The aim of the present article is to investigate the physiopathology, clinical presentation, diagnostic tools, and management of the most common overuse sport injuries. In particular, we focus on tendinopathy, stress reaction, stress fracture, and juvenile osteochondritis dissecans, which are the most frequent lesion caused by overuse. Furthermore, in the first part of this study, to better understand the changes of the bone, muscle, and tendon structures, we mention different mechanisms present in an overuse situation.

Overuse tendinopathy induces in the affected tendon pain and swelling, and associated decreased load tolerance and function during exercise of the limb [ 9 , 10 ]. Various types of tendon degeneration have been described at electron microscopy, namely (a) hypoxic degeneration, (b) hyaline degeneration, (c) mucoid or myxoid degeneration, (d) fibrinoid degeneration, (e) lipoid degeneration, (f) calcification, and (g) fibrocartilaginous and bony metaplasia [ 11 ]. Healing of tendinopathic tendons relies on the intrinsic ability of tenocytes to respond to the stimulus induced by the injury to the surrounding tissue matrix [ 12 , 13 ] and consists of a cellular response including apoptosis (programmed cell death), chemotaxis, proliferation, and differentiation [ 14 ]. The mechanism underlying the precise sequence of these events, which balance the effectiveness of healing and any subsequent predisposition to repetitive damage, remains obscure.

The essence of tendinopathy is a “failed healing response.” This model suggests that, after an acute insult to the tendon, an early inflammatory response that would normally result in successful injury resolution veers toward an ineffective healing response [ 15 ], with degeneration and proliferation of tenocytes, disruption of collagen fibers, and subsequent increase in non-collagenous matrix [ 7 , 16 , 17 , 18 , 19 ] (Table  1 ).

Poor training technique and a variety of risk factors may predispose players to lower limb overuse injuries affecting the bone, including stress reactions to full-fledged stress fractures. The underlying principle of the bone response to stress is Wolff’s law, whereby changes in the stresses imposed on the bone lead to changes in its internal architecture [ 20 , 21 ]. Stress fractures, defined as microfractures of the cortical bone tissue, affect thousands of athletes per year [ 22 , 23 ]. Certain subpopulations, including runners, gymnasts, and female athletes, exhibit higher rates of stress fractures [ 24 , 25 ]. If left untreated, a stress fracture can progress to a complete fracture of a bone, which may require surgical fixation [ 26 ]. In addition, factors contributing to stress fractures increase the risk for osteoporosis, a substantial long-term health concern [ 27 ].

Stress reactions of the musculoskeletal system may be interpreted as possible precursors of stress fractures. Biological tissues, in contrast to artificial products, can react in numerous and complex ways. This can lead not only to a continual weakening of the tissue, but also to adaption phenomena in response to overuse. The causes of such stress reactions are still unclear.

Juvenile osteochondritis dissecans (JOCD) is a frequent cause of pain in adolescents, both athletes and non-athletes. JOCD is characterized by delamination and localized necrosis of the subchondral bone, with or without the involvement of the overlying articular cartilage [ 28 , 29 , 30 , 31 ]. The etiology remains unclear, but repetitive microtrauma, such as that typical of overuse injury, is considered the significant factor leading to JOCD [ 28 , 29 ].

The role of inflammation and molecular factors in overuse injuries

The effects of an altered inflammatory response.

In this model, the question arises as to why the healing response is successful in some individuals but fails in others. More importantly, can we identify factors which may increase the risk of this ineffective healing response? For example, the incidence of tendinopathy is increased in individuals with obesity and decreased insulin sensitivity, as seen in patients with type 1 and type 2 diabetes mellitus (T1/T2DM) [ 10 , 32 , 33 , 34 ]. Evidence for a chronic, low-grade inflammatory state in obesity is represented principally by marked increases in plasma levels of proinflammatory cytokines such as tumor necrosis factor (TNF)-a and interleukin (IL)-6, and proinflammatory chemokines such as monocyte chemoattractant protein (MCP)-1 [ 34 ].

Patients with type 1 and type 2 diabetes exhibit a less effective healing response [ 35 ]. Recently, it has been demonstrated the presence of an independent relationship between impaired insulin sensitivity and the development of chronic low-grade inflammation through a protein, the levels of which are normally physiologically inhibited by insulin, called FOXO1, a key upregulator of the proinflammatory cytokine IL-b [ 35 ].

Considering the influence that a prolonged state of low-grade systemic inflammation may have on the healing process after acute tendon injury, it must be appreciated that tendon healing is a delicate and prolonged process even under optimal physiological conditions [ 10 , 34 ]. Even minor disruptions to any of the noted healing stages could result in a much more prolonged and complicated resolution of injury. Similarly, if several minor disruptions to this process occur (in the form, for example, of microtraumas), complete healing and resolution of injury become progressively unlikely [ 10 ].

The acute inflammatory phase noted in the first few days after a tendon injury is marked by the migration of inflammatory cells such as macrophages and monocytes [ 36 ]. As the chronic inflammatory state in obesity is associated with a reduction in the numbers of circulating macrophages [ 33 ], such a decrease in the availability of circulating cells may result in the mounting of a less effective early healing response.

Such findings are consistent with a post-injury state of “failed healing,” in which evidence of matrix disorganization, increased amounts of extracellular ground substance, and a degree of separation between collagen fibers has been noted [ 37 , 38 ], with associated greater vulnerability to future mechanical strain [ 10 ].

This relationship may help to explain the influence that mechanical overuse plays in the development of tendinopathy. Examining the incidence of tendinopathy among patients with type 2 diabetes, unilateral or bilateral tendinopathy was found in 32% of the diabetic patients studied versus 10% of controls [ 39 ]. Also, when the incidence of unilateral tendinopathy among diabetic patients was examined more closely, 45% were found to occur in the right shoulder compared with just 27% in the left shoulder [ 33 ].

Molecular factors in overuse injury

A lack of exposure to adequate levels of physiological stress over a prolonged time period or “underloading” may paradoxically predispose to overload injury [ 34 ]. An underloaded tendon may become unable to cope with increased demands imposed on it. Thus, underuse of a tendon may result in an imbalance between matrix metalloproteinases and their inhibitors (tissue inhibitors of matrix metalloproteinases), with resultant tendon degradation [ 34 ].

Molecular agents may link the events of tendon degeneration and ineffective tendon healing with the production and persistence of reactive oxygen species within both the intra- and extra-cellular milieu of the tendon tissue [ 40 ]. The reactive oxygen production is strongly influenced by lifestyle factors, e.g., nutrition and the intensity and frequency of exercise.

The term reactive oxygen species (ROS) encompasses reactive species derived from oxygen. A free radical is any species capable of independent existence that contains one or more unpaired electrons [ 41 ]. Physiologically relevant ROS include the superoxide anion (O 2− ), hydrogen peroxide (H 2 O 2 ), hydroxyl radical (HO − ), singlet oxygen ( 1 O 2 ), and peroxyl radicals (RO 2− ). An inter-related group of radical and non-radical reactive species is the reactive nitrogen species (RNS) [ 42 , 43 , 44 ].

The principal site for ROS formation in non-stressed cells is the mitochondrial respiratory chain. This series of coupled redox reactions leads to the formation of ATP with molecular oxygen the ultimate electron acceptor and being reduced to water [ 45 , 46 ].

ROS may mediate processes of cell proliferation [ 47 ], differentiation [ 48 ], and adaptive responses [ 45 , 49 ]. At higher levels, ROS may initiate and/or execute the demise of the cell through programmed as well as necrotic cell death mechanisms [ 50 , 51 , 52 ].

Traditionally, ROS are viewed as imposing cellular and tissue damage via lipid peroxidation, DNA damage, and protein modification [ 45 , 53 ]. However, in themselves, O 2− and H 2 O 2 are not potent biological oxidizers [ 45 ], although certain proteins may be prone to direct modification by these species. ROS production is involved in various cancers (e.g., the lung, colon), coronary heart disease, autoimmune diseases, etc. [ 41 ]. Furthermore, ROS are implicated in overuse exercise-related damage in muscle [ 49 ] and may impair fracture healing in the bone [ 54 ].

Cells and tissues contain many antioxidant molecules, but many antioxidants are also capable of acting as pro-oxidants [ 55 ]. For example, ascorbic acid in the presence of iron/copper generates HO − , and with flavonoids may generate O 2− [ 55 ].

ROS may be involved in tendinopathies or other stress reactions: indeed, synthesis, structure, and integrity of connective tissues are influenced by them. Reactive species may be produced within the intra- and extra-tendinous environment. Evidence suggest that ROS constitute a stress factor during not-hard exercise [ 49 ]. Excessive exercise induces elevated ROS production, primarily from mitochondria [ 56 ]. Exercise also stimulates the immune response [ 56 , 57 , 58 ], with increased leucocyte numbers, in particular granulocytes. Exhaustive exercise in cross-country skiers produced neutrophil mobilization and increased ROS generation on subsequent stimulation. Enhanced phagocytic O 2− generation accurs approximately 24 h after exhaustive exercise [ 59 ].

Increased phagocyte activity probably does not contribute to elevated ROS production during short-term exercise, but may act as a secondary source of ROS during recovery from heavy exercise [ 59 ].

During cyclical tendon loading, the period of maximum tensile load is associated with ischemia, and relaxation with reperfusion. This restoration of normal tissue oxygenation may lead to enhanced ROS production [ 59 , 60 ]. There is potential for re-oxygenation resulting in a cycle of enhanced ROS production, most probably at sublethal levels within the non-degenerate tendon [ 40 ].

Hyperthermia is a feature of tendon use inducing ROS production. During exercise, the central core temperature of the muscles can exceed 47 °C [ 49 ], a temperature resulting in increased ROS production in mitochondria [ 49 ]. Similarly, in exercising the tendon, core temperatures may reach 45 °C, contributing to their damage [ 60 ].

During fibrogenesis, ROS, primarily derived from specialized phagocytes and products arising from lipid peroxidation, induce overexpression of fibrogenic cytokines and increase the synthesis of collagen [ 61 ]. Endogenous and exogenous ROS may also exert effects on tenocyte proliferation, development, and viability, with implications on both tendinopathy and post-rupture healing [ 62 ]. Tenocytes are motile and highly proliferative and rapidly increase in number following injury [ 62 ].

Tenocyte numbers are altered in degenerated tendons, and the selective deletion of tenocytes from damaged tendon may be a factor in degeneration, but also a prerequisite to healing. Heightened levels of ROS production may not only induce cell death, but also determine the mechanistic form of that death, in particular, the ratio of programed cell death (PCD): necrosis [ 51 ].

High concentrations of H 2 O 2 can prevent apoptosis. Conversely, “bursts” of ROS [ 51 , 63 ] and reductions in antioxidant enzyme activity [ 64 ] frequently accompany the induction of apoptosis, and oxidative stress is a common feature of the late phase of apoptosis [ 51 ]. For example, the pro-apoptotic transcription factor p53 demonstrates impaired DNA binding following exposure to ROS. However, it can induce apoptosis by induction of enhanced mitochondrial ROS generation [ 65 ].

Overuse sport injuries

Tendinopathy: consideration and management.

Tendinopathy has been hypothesized to result from inflammatory changes in the tendon, and secondary to its frequent or excessive use, assigning the label of “tendinitis” or “tendonitis” to such a presentation [ 9 , 10 , 66 ]. However, anti-inflammatory agents are largely unsuccessful in the treatment of the condition [ 15 , 66 ], and with the increase in histopathological data showing degenerative changes but little inflammation, the inflammatory hypothesis in overuse tendon injury became decreasingly popular [ 10 , 15 , 36 , 67 ]. The term “tendonitis” became increasingly replaced by “tendinosis” [ 36 ], but a definitive diagnosis of either should only be made following histopathological confirmation [ 15 , 36 , 67 ].

However, it became evident that tendon biopsies from operated patients were likely to represent the end stage of a pathological continuum [ 10 ], probably demonstrating a different histopathological picture to that which would be seen in the initial stages of injury [ 36 , 67 ]. This was supported by evidence from human and animal biopsies that showed that both peritendinitis and a failed healing response, wrongly labeled “tendinosis,” could be present concurrently [ 36 ].

In tendinopathic lesions, the parallel orientation of collagen fibers is lost, with a decrease in collagen fiber diameter and in the overall density of collagen. Collagen microtears may also occur and may be surrounded by erythrocytes, fibrin, and fibronectin deposits. Normally, collagen fibers in tendons are tightly bundled in a parallel fashion. In tendinopathic samples, there is unequal and irregular crimping, loosening, and increased waviness of collagen fibers, with an increase in type III (reparative) collagen [ 17 , 19 , 68 , 69 , 70 , 71 ]. Vascularity is typically increased, and blood vessels are randomly oriented, sometimes perpendicular to collagen fibers [ 72 , 73 ]. Inflammatory lesions [ 72 , 73 , 74 , 75 ] and granulation tissue [ 74 , 75 ] are infrequent and, when found, are associated with partial rupture: therefore, tenocytes are abnormally plentiful in some areas [ 76 , 77 ].

Tendinopathies are common in elite and recreational athletes and are traditionally considered overuse injuries, involving excessive tensile loading and subsequent breakdown of the loaded tendon [ 78 , 79 ]. Although acute traumatic conditions such as ligament and muscle tears receive much attention in the lay press, tendinopathies account for much of the lost time in practice and competition [ 80 , 81 ].

Biopsy studies have shown that classic inflammatory changes are not frequently seen in chronic tendon conditions and that histopathology features in tendinopathic tendons are clearly different from normal tendons [ 82 , 83 ].

All tendons can develop tendinopathy [ 5 , 84 ]. The supraspinatus, common wrist extensor, quadriceps, patellar, posterior tibialis, and Achilles tendons are probably the most commonly affected tendons. Insertional tendinopathy is one of the most common forms of tendinopathy, and, in particular, the supraspinatus, common wrist extensor, quadriceps, and patellar tendons are most affected by it [ 84 ]. The Achilles tendon, on the other hand, can present tendinopathy of the main body of the tendon, paratendinopathy and insertional tendinopathy, each with different clinical features and management implications [ 84 ].

Achilles tendinopathy (AT) is a common overuse injury among athletes, with an increasing incidence over the past 30 years [ 85 , 86 ]. AT is particularly prevalent in athletes whose sport involve running and jumping activities [ 87 , 88 ] and is thus common in sports such as soccer. In the four principal soccer leagues in England, there are an average of 3.5 Achilles tendon-related injuries per week in the preseason and an average of one injury per week in the competitive season [ 89 , 90 ].

Tendinopathies may result from excessive loading of the tendon and subsequent mechanical breakdown of the loaded tendon [ 91 ]. Theoretically, repeated microinjuries may occur, and the tendon may be able to heal a certain level of microinjury. However, as training and heavy loading of the tendon continues, this healing process may be overwhelmed, and a further injury ensues.

Other factors in addition to training errors may lead to increased loading of the tendon, such as poor technique [ 92 , 93 ] or inadequate athletic equipment [ 94 ]. Also, intrinsic factors, such as the status of the muscles, ligaments, and bones surrounding the tendon, may alter the level of the load on the tendon [ 19 ]. Recent biomechanical studies about failure modes of the muscle-tendon units have shown that failure occurs within the muscle near the muscle-tendon junction [ 95 , 96 ].

Relatively, little is known about the role of neuronal regulation in tendinopathy, and the source of pain has not been clarified yet [ 97 ]. The presence of pain in tendinopathy requires not only mechanical changes, but also alterations in the way the local cells and the peripheral nerves react to this change. A recent systematic review showed that the peripheral neuronal phenotype is altered in tendinopathy [ 97 ] and that the peripheral and central pain processing pathways are important factors in the pathogenesis of painful human tendinopathy. Changes in the peripheral neuronal phenotype may be the primary source of pain [ 97 ] .

Clinical history and examination are essential for diagnosis. Clinically, tendinopathy is characterized by pain, swelling (diffuse or localized), and impaired performance [ 6 ].

Pain is the cardinal symptom, and it occurs at the beginning and a short while after the end of a training session. As the pathological process progresses, pain may occur during the entire exercise session, and, in severe cases, it may interfere with the activities of daily living. Clinical examination is the best diagnostic tool. In tendinopathy of the main body of the Achilles tendon, the location of pain is 2–6 cm above the insertion into the calcaneum, and pain on palpation is a reliable and accurate test for diagnosis [ 98 ].

In addition to the swelling on the posteromedial aspect of the tendon and palpation pain, some clinical tests have been described for non-insertional AT diagnosis. They can be divided into palpation tests (tendon thickening, crepitus, pain on palpation, the Royal London Hospital (RLH) test, the painful arc sign) and tendon loading tests (pain on passive dorsiflexion, pain on single heel raise, and pain on hopping).

Plain radiography can be used to diagnose associated or incidental bony abnormalities [ 99 ].

Ultrasound is an effective imaging method since it correlates well with the histopathologic findings despite being an operator-dependent [ 100 ]. MRI studies should be performed only if the ultrasound scan remains unclear. The ultrasound (US) signs of hypoechoic areas, spindle-shaped thickening, neovascularization, and paratenon blurring [ 101 ] are associated with AT [ 102 ] and may be potential predictors of future tendinopathy [ 87 ] when present in asymptomatic individuals.

The first line of management for AT is conservative, and different treatments such as nonsteroidal anti-inflammatory drugs, physical therapy, taping, cryotherapy, shock wave therapy, hyperthermia, and various peritendinous injections have been used with varying success [ 103 ]. The management of AT lacks strong evidence-based support, because few treatment modalities have been investigated in randomized controlled trials [ 103 ], and approximately 25% of patients do not respond to conservative management [ 104 ]. Good results have been reported with eccentric exercises [ 105 , 106 ], but these alone may not work in all patients [ 107 ], and their mechanism of action is not completely understood [ 106 ]. These are the most effective conservative treatment for non-insertional AT. The most commonly used protocol is the Alfredson’s protocol: the exercises are performed in three sets of 15 repetitions, twice a day for 12 weeks [ 108 ].

ESWT, when compared with eccentric strengthening in a RCT, showed comparable outcomes, with 60% of the patients at least significantly improved in both of the treatment groups, and significantly better than those in the “wait and see” control group [ 109 ]. Where available, ESWT should probably be a second-line treatment.

Various injection therapies have been proposed [ 110 ]. In a recent systematic review [ 111 ], only ultrasound-guided sclerosing polidocanol injections seemed to yield promising results, but these results do not appear to have been duplicated outside Scandinavia [ 112 ]: indeed, Ebbesen et al. [ 113 ], in a RTC, concludes that polidocanol injections are a safe treatment, but in the mid-term, the effects are the same of a placebo treatment for chronic Achilles tendinopathy. The use of platelet-rich plasma (PRP) is growing exponentially, especially among sports medicine physicians, but the only well-designed RCT published on PRP in AT showed no significant difference in pain or activity level between PRP and saline injection at 6, 12, or 24 weeks when combined with an eccentric stretching program [ 114 ]. High-volume image-guided injections (HVIGI) significantly reduce pain and improve function in patients with resistant AT [ 115 ]. A recent study found relevant clinical results with the contemporaneous administration of platelet-rich plasma and high-volume image-guided injections of saline treatments, which influence tendon repair by different mechanisms and grants a greater improvement for patellar tendinopathy [ 116 ].

Conservative treatment fails in between one quarter and one third of patients, and surgical intervention is required [ 117 ]. Minimally invasive therapies which strip the paratenon from the tendon, either directly [ 118 ] or indirectly with high-volume fluid injection [ 115 ], have shown good initial results in relieving the symptoms of non-insertional AT [ 103 , 119 ].

Another technique consists in multiple percutaneous longitudinal tenotomies, which can be performed under ultrasound guidance [ 120 , 121 ]. Minimally invasive surgical treatment would appear to be a useful intermediate step between failed conservative treatment and formal open surgery [ 103 ].

The high recurrence rate (27%) for AT when managed conservatively reflects the chronic and recurrent character of this condition. The frequent relapse of symptoms when players return to football after a short rehabilitation period could be explained if the pain is only the tip of the iceberg. Therefore, it could be suggested that a longer rehabilitation period at the first signs of AT could be beneficial to avoid recurrences [ 122 ].

Stress reaction and stress fracture

Stress reactions may be interpreted as precursors of stress fractures [ 123 ]. The causes of such stress are still unclear. For example, it is unknown to what extent a predisposition to these stress symptoms by mechanical stress alone or whether other factors such as physical condition, nutrition, or even hormone balance come in to play. Early diagnosis considerably reduces the impairment of the healing process. The treatment of a stress reaction should be the same as for a diagnosed stress fracture [ 123 ]. Much of our epidemiological knowledge about stress fractures originates from research on military recruits [ 124 ] and high school athletes [ 25 ].

The response of the bone to repetitive stress is increased osteoclastic activity over osteoblastic new bone formation, which results in temporary weakening of the bone [ 125 ]. The eventual adaptive response is periosteal new bone formation to provide reinforcement [ 126 ]. However, if physical stress continues, an osteoclastic activity may predominate, resulting initially in microfractures (commonly seen as bone marrow edema on MRI, consistent with a stress reaction), and eventually, a true cortical break (stress fracture) may result [ 1 ]. If strain becomes excessive or adequate rest is not implemented, stress reaction and eventually a stress fracture can results [ 126 , 127 ].

There is a difference between stress fractures from fatigue and insufficiency type. Fatigue fractures are the typical overuse stress fractures observed in athletes and military recruits with normal bone density. They result from an imbalance in the ability of the bone to keep up with skeletal repair from an excessive bone strain with progressive accumulation of microdamage [ 126 ]. An insufficiency fracture is seen in those with low bone mineral density (BMD), such as runners with the female athlete triad; metabolic bone disease; or osteoporosis. Insufficiency fractures result from poor bone remodeling (increased resorption and depressed formation) in response to normal strain [ 126 ].

Rizzone et al. [ 128 ] investigated the epidemiology of stress fractures in 671 collegiate student-athletes for the academic years 2004–2005 through 2013–2014. The rate of stress fracture was highest among endurance athletes and higher in women than in men. Higher rates among female athletes were found not only in cross-country athletes, indoor track, and outdoor track athletes, but also in basketball and soccer athletes. Twenty-two percent of stress fractures were recurrent, and 20% resulted in season-ending injuries [ 128 ].

The number of reports in the literature of lower extremity stress fractures in female soccer athletes is small [ 129 ]. Of the 18 million Americans who play soccer, 78% are younger than 18 years and more than 40% are female [ 130 ]. Women collegiate soccer increased from 1855 athletes on 80 teams during the 1981–1982 seasons to 22,682 athletes on 956 teams during the 2007–2008 seasons, making women’s soccer the NCAA sport with the greatest number of athletes [ 131 ]. A study of 2016 [ 132 ] showed that elite female soccer athletes are susceptible to stress fractures and menstrual dysfunction and experience delayed onset of menarche despite normal BMI and appropriate body perception and attitudes toward eating. Education about the detrimental effects of menstrual dysfunction and the importance of adequate energy balance and nutritional requirements should be encouraged to minimize the risk for poor bone health, manifesting as a stress fracture in the short term and osteoporosis over the long term in these athletes [ 132 , 133 ].

The typical history of a stress fracture is localized pain of insidious onset which is initially not present at the start but occurs toward the end of a run. A sign of a more advanced fracture is pain progressing to occur during non-running-related activities, affecting day-to-day walking [ 126 ].

Defining the causative risk factors for stress fractures is difficult because there are many interrelated variables which make risk assessment problematic to study independently. Extrinsic and intrinsic factors may lead to stress fractures [ 126 , 133 , 134 ]. An increase in frequency, duration, or intensity of training load is often cited as a primary risk factor [ 135 ]. Hard training surfaces are also factors associated with lower-limb overuse injuries [ 135 ]. Training in shoes older than 6 months is a risk factor for stress fractures, likely related to the decrement in shock absorption as shoes age [ 135 ].

Regarding the intrinsic factors, Bennell et al. [ 22 ] demonstrated that smaller calf girth and less muscle mass in the lower limb of female runners was associated with a higher incidence of stress fractures. Kinematic and kinetic biomechanical variables have also been recently studied as potential risk factors for stress fractures; for example, in runners, an excessive hip adduction and rear-foot eversion are predictors of tibial stress fractures [ 136 ].

The hallmark physical examination finding is focal bony tenderness. Overlying swelling, erythema, or warmth are other potential examination findings. Less sensitive tests for fractures of long bones include the fulcrum test and hop test [ 137 ]. A functional kinetic chain assessment is useful to elucidate biomechanical factors that may predispose the runner to injury. Evaluating muscle imbalances, leg-length discrepancies, foot mechanics, genu varum, and femoral anteversion is appropriate because all have been associated with stress fractures [ 137 ].

Radiographic imaging should be used to supplement the clinical history and physical examination if uncertainty persists. Imaging can also be used to grade the severity of an injury and can thus be helpful in guiding treatment. CT is best used to differentiate lesions seen on a bone scan that may mimic stress fracture, including osteoid osteoma, osteomyelitis, and malignancy [ 138 ]. MRI is becoming the imaging study of choice, with many considering MRI the gold standard for the evaluation of bony stress injuries [ 139 ].

It is not only important to understand the significance of protection and rest, but also to understand the predisposing factors to the injury. Treatment is the time to explore and treat the contributing risk factors. For example, if low bone density is found, appropriate treatment is mandatory; if biomechanical issues are identified, and inappropriate shoes and training are determined, and specific rehabilitation is required [ 126 ].

Therapeutic ultrasound and electrical stimulation are purported modalities for enhancing the healing rate of fractures. Therapeutic ultrasound has been demonstrated to decrease healing time in acute tibial shaft, in distal radius fractures, and in navicular stress injuries [ 140 , 141 ]. Electrical stimulation for bone growth has some support in delayed unions and non-unions, but only in uncontrolled trials for stress fractures [ 142 ].

Juvenile osteochondritis dissecans (JOCD)

JOCD is a frequent cause of knee pain in adolescent athletes and non-athletes, with an incidence higher in boys than in girls [ 143 , 144 ] and with delamination and localized necrosis of the subchondral bone. The etiology remains unclear [ 28 , 29 , 31 ]. Repetitive microtrauma, such as that of overuse injury, is considered the significant factor leading to JOCD [ 28 , 29 , 145 ].

The most common site of JOCD is the medial femoral condyle, accounting for 85% of the cases [ 28 ]. The term “osteochondritis” suggests an inflammatory etiology: however, histology shows damage of the bone and cartilage with no inflammation [ 146 ]. Local bone vascular insufficiency is also postulated to contribute to JOCD [ 29 ].

Highly active athletes present with a history of aching and gradual onset of knee pain of several days to weeks duration, typically located over the anterior portion of the knee, worse during activity. There may be a history of intermittent knee effusion following a practice or game session [ 29 ].

The examination may reveal mild effusion or limitation of motion of the knee. Findings may also vary depending on the stage of the disease [ 147 ]. In the early stages, with the articular cartilage over the femoral condyle still intact, the signs are non-specific. In the later stages, when the articular cartilage is eroded, the fragment may separate and become an intra-articular loose body. This can cause pain, effusion, and locking. Typically, in lesions, the medial femoral condyle when the athlete flexes and internally rotates the leg, from full extension to about 30°, pain is elicited and is relieved upon external rotation [ 28 , 29 ].

Radiographic examination, with comparison with the other knee, is indicated when JOCD is suspected. In addition to the anteroposterior (AP) and lateral views, a tunnel view is useful to better identify the lesion, which appears as a well-demarcated radiolucent area [ 29 , 31 ]. In those who demonstrate significant edema, a hemarthrosis or discomfort, and inability to bear weight without pain, an MRI is often obtained. An MRI can be helpful in identifying unstable lesions [ 31 ].

Suzue et al. [ 148 ] investigated the prevalence of JOCD in children and adolescent soccer players using a questionnaire, distributed to 1162 players. Of these, 547 patients experienced pain in the legs or lumbar spine. Radiographic or ultrasonographic examination was performed in 106 players, and 80 (75.5%) were diagnosed JOCD. In conclusion, the majority of players who had experienced pain and were found to have osteochondritis had severe injuries such as JOCD or lumbar spondylolysis [ 148 ].

Early diagnosis followed by restriction of activities and symptomatic treatment of pain generally allows for healing of lesions over a period of 8–12 weeks [ 30 , 31 , 149 ]. Spontaneous healing of the lesion is the usual outcome in children and adolescents with open distal femoral physis. Prognosis is excellent in younger patients [ 149 ].

Treatment is based on the stability of the lesion and the status of the overlying cartilage. The lesion may be unstable or loose, and these cases as well as in those athletes with large effusions or with marked symptoms which do not improve with conservative care may go to surgery for drilling, reattachment, or excision of the osteochondral lesion [ 31 ].

Overuse injuries can affect the muscle, tendon, and bone. Tendon injuries give rise to substantial morbidity, and current understanding of the mechanisms involved in tendon injury and repair is limited. Tendon physiology and structure may include ROS involvement in various aspects of the predisposition to and participation in the degenerative process and subsequent response to injury. Bone can be damaged by repeated microtrauma and overuse. Stress reaction and stress fractures are very common in athletes, and the treatment consists in the treatment of the risk factors. Further research is required to improve our knowledge of tendon and bone healing. This will enable specific treatment strategies to be developed.

Abbreviations

Anteroposterior

Achilles tendinopathy

Bone mineral density

Food and Drug Administration

High-volume image-guided injections

Interleukin

Juvenile osteochondritis dissecans

Low-intensity pulsed ultrasound

Monocyte chemoattractant protein

Programed cell death

Pulsed electromagnetic fields

Platelet-rich plasma

Royal London Hospital

Reactive nitrogen species

Reactive oxygen species

Tumor necrosis factor

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Aicale, R., Tarantino, D. & Maffulli, N. Overuse injuries in sport: a comprehensive overview. J Orthop Surg Res 13 , 309 (2018). https://doi.org/10.1186/s13018-018-1017-5

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Research Article

Patients’ experiences and wellbeing after injury: A focus group study

Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Validation, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliation Trauma TopCare, ETZ Hospital (Elisabeth-TweeSteden Ziekenhuis), Tilburg, The Netherlands

Roles Formal analysis, Supervision, Writing – review & editing

Affiliation Center of Research on Psychological and Somatic Disorders, Department of Medical and Clinical Psychology, Tilburg University, Tilburg, The Netherlands

Roles Data curation, Writing – review & editing

Affiliation Department of Medical Psychology; ETZ Hospital (Elisabeth-TweeSteden Ziekenhuis), Tilburg, The Netherlands

Roles Conceptualization, Supervision, Writing – review & editing

Affiliation Department of Orthopaedics, ETZ Hospital (Elisabeth-TweeSteden Ziekenhuis), Tilburg, The Netherlands

Roles Conceptualization, Funding acquisition, Supervision, Writing – review & editing

• Eva Visser, 
• Brenda Leontine Den Oudsten, 
• Marjan Johanna Traa, 
• Taco Gosens, 
• Jolanda De Vries

• Published: January 7, 2021
• https://doi.org/10.1371/journal.pone.0245198
• Reader Comments

Injury can have physical, psychological and social consequences. It is unclear which factors have an impact on patients’ wellbeing after injury. This study aimed to explore, using focus groups, patients’ experiences and wellbeing after injury and which factors, impede or facilitate patients’ wellbeing.

Trauma patients, treated in the shock room of the Elisabeth-TweeSteden Hospital, the Netherlands, participated in focus groups. Purposive sampling was used. Exclusion criteria were younger than 18 years old, severe traumatic brain injury, dementia, and insufficient knowledge of the Dutch language. The interviews were recorded, transcribed verbatim, and analyzed using coding technique open, axial, and selective coding, based on phenomenological approach.

Six focus groups (3 to 7 participants) were held before data saturation was reached. In total, 134 patients were invited, 28 (21%) agreed to participate (Median age: 59.5; min. 18 –max. 84). Main reasons to decline were fear that the discussion would be too confronting or patients experienced no problems regarding the trauma or treatment. Participants experienced difficulties on physical (no recovery to pre-trauma level), psychological (fear of dying or for permanent limitations, symptoms of posttraumatic stress disorder, cognitive dysfunction), social (impact on relatives and social support) wellbeing. These are impeding factors for recovery. However, good communication, especially clarity about the injury and expectations concerning recovery and future perspectives could help patients in surrendering to care. Patients felt less helpless when they knew what to expect.

Conclusions

This is the first study that explored patients’ experiences and wellbeing after injury. Patients reported that their injury had an impact on their physical, psychological, and social wellbeing up to 12 months after injury. Professionals with the knowledge of consequences after injury could improve their anticipation on patients’ need.

Citation: Visser E, Den Oudsten BL, Traa MJ, Gosens T, De Vries J (2021) Patients’ experiences and wellbeing after injury: A focus group study. PLoS ONE 16(1): e0245198. https://doi.org/10.1371/journal.pone.0245198

Editor: Andrew Soundy, University of Birmingham, UNITED KINGDOM

Received: May 2, 2020; Accepted: December 27, 2020; Published: January 7, 2021

Copyright: © 2021 Visser et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: Data cannot be shared publicly, because data from this study may contain potentially or sensitive patient information. Data are anonymized, however nevertheless, due to relatively few severe cases, patients could be identified (Medical Ethics Committee Brabant). Therefore, data from this study will be made available for researchers who meet criteria for access to confidential data. Requests may be sent to: [email protected] .

Funding: This study was supported by a grant (80-84200-98-15213) of the Dutch organization for health research and care innovation (ZonMW) section TopCare projects.

Competing interests: The authors have declared that no competing interests exist.

Introduction

In 2017, mortality rates from injury were the highest in Dutch persons younger than 35 years of age compared to other ages [ 1 ]. Due to trauma registration and implementation of specialized trauma care, the quality of trauma care improved and survivorship increased [ 1 – 6 ]. Nevertheless, patients who were less satisfied with general health and recovery after injury needed more medical care, they had a longer hospital stay, and they visited the hospital more often [ 7 ]. This resulted in an increase in costs of care. In the Netherlands, the total costs of injuries were €3.5 billion annually [ 6 , 8 ].

After experiencing a single traumatic event (e.g., fall or car accident), survivors will go through a process of medical treatment and rehabilitation: from the ambulance or trauma helicopter to the shock room, possible hospital stay, and finally rehabilitation [ 9 ]. The shock room is situated at the emergency department and, for severely injured patients, it is the interface between prehospital management and inpatient care [ 10 ]. Adverse physical (e.g., problems on wound repair and pain) [ 11 – 13 ], psychological [ 14 , 15 ], and social (e.g., broken marriages and difficulties in resumption to work) [ 16 , 17 ] outcomes may occur after injury. Patients can experience anxiety [ 18 ], depressive symptoms [ 18 , 19 ], acute stress disorder (ASD) [ 20 ], and posttraumatic stress disorder (PTSD) [ 14 , 18 , 21 , 22 ] after injury. These consequences can arise almost directly after injury or months or years later [ 23 – 25 ]. Even though they are often not recognized, they can have an impact on patients’ wellbeing. Yet, it is unclear which factors have an impact on patients’ experiences and wellbeing after injury, treatment and recovery. For that reason, qualitative research is needed to evaluate patients’ experiences after injury and which factors impede or facilitate patients’ wellbeing.

Although patients’ perspectives after injury have previously been explored, they evaluated one type of injury (e.g., traumatic brain injury (TBI) or burn injuries) [ 26 , 27 ] or one type of trauma mechanism (e.g., motor vehicle accident) [ 28 , 29 ]. Therefore, results cannot be generalized to the entire trauma population. Research is focused on recovery from different types of injury (e.g., multi trauma, spinal cord injury, and TBI) [ 29 ] will provide a broader overview than currently available.

To our knowledge, no focus group study was previously conducted that focused on a process of trauma care (i.e., treatment short after injury, in the shock room and hospital, and rehabilitation) and patients’ wellbeing [ 30 , 31 ]. Therefore, this study aimed to explore patients’ experiences and wellbeing after injury, treatment, and rehabilitation. Moreover, factors that impede or facilitate patients’ wellbeing were evaluated.

Material and methods

Study design.

A focus group study design was used to evaluate the aims of this study. Focus groups, a commonly used method of qualitative research [ 32 , 33 ], were held, because they facilitate an in-depth exploration of a person’s perspective through group interaction. Moreover, memories could be triggered by a comment from another participant [ 32 , 33 ]. Otherwise, they can also be triggered by sharing and comparing participants’ own experiences [ 34 ].

This study is part of a mixed-method study. The protocol of this mixed-method has been published elsewhere [ 35 ]. The medical ethical committee Brabant (METC Brabant) approved the study (project number NL55386.028.15). This study is also registered in the Netherlands Trail Register (number NTR6258). All participants gave written informed consent. Participation was voluntarily and, except for an exit ticket for the parking lot, no financial reward was given.

Participants and procedure

Eligible patients who experienced an injury, were treated in the shock room of the ETZ Hospital (Elisabeth-TweeSteden Hospital), Tilburg, the Netherlands. These patients were registered in the Brabant trauma registry and a researcher (EV) received a database from this registry. In addition to being treated in the shock room, another inclusion criterion was being aged 18 years or older. Persons were excluded if they had severe TBI (i.e., Glasgow Coma Score ≤ 8), dementia, or insufficient knowledge of the Dutch language (verbal and in writing). Patients’ medical records were reviewed on eligibility. Eligible patients received an information letter and were invited to participate in the study. Then, EV contacted the patients, by telephone, to explain the purpose of the study and to ask for their participation. Patients who were willing to participate in a focus group discussion received additional information about the date, time, and location.

To attain a variety of experiences and a representative sample of the heterogeneous trauma population, patients were divided into three groups: (i) Injury Severity Score (ISS) < 16 (one single injury or mild/moderate injurie(s)), (ii) ISS ≥ 16 (i.e., severe multiple injuries), and (iii) mild or moderate TBI (i.e., Glasgow Coma Score ≥ 9). Six to ten patients were invited to participate in each group. In addition, patients were selected based on sex and age. The researcher (EV) invited equal numbers of male and female patients and a variety of ages for each group in order to attain a variety of experiences and a representative sample of the trauma population. In this way, the presence of maximum variability within the primary data could be warranted, the maximum variation sampling could be clearly set out, and trauma patients with all kind of trauma mechanism and injuries could be included. The purposive sampling method was used [ 32 , 33 ].

In order to obtain reliability and validity [ 36 , 37 ], a manual was developed. The purpose of the focus groups, diversity of study population, and the procedure of the focus groups itself (e.g., introduction by the moderator, questions for participants (e.g., data collection), and finishing the discussion) were set out in this manual. Clear research questions were needed to obtain relevant answers (i.e., validity) and to ensure that the study is replicable (i.e., reliability) [ 37 ]. All focus groups had the same structure and were audio-recorded. Two reviewers (EV and BDO) independently reviewed the transcripts to ensure that data saturation (i.e., no new information was found during discussions) was reached. Moreover, to strengthen validity and comprehensiveness, this study was conducted and reported according to the consolidated criteria for reporting qualitative research (COREQ) checklist for qualitative research [ 36 ].

Data collection

The focus group meetings took place in a conference room at the hospital. The focus groups were led by a moderator (EV) and an assistant (MT). The moderator started the focus group by giving an introduction of the moderators and the purpose of the focus group meeting. Then, the patients were asked to share their experiences, by answering the main questions “Which experiences after injury impressed you the most?” and “Can you describe the consequences of injury on your life?””. Then, follow-up questions were asked by the moderator to obtain how these experiences impede or facilitate patients’ wellbeing, for example; “Could you describe your feelings after injury, hospitalization, and rehabilitation?”. In addition, in order to stimulate conversation flow and involve other participants in the discussions, follow-up questions were asked, for instance, “Does someone (i.e. another participant) recognize these experiences, consequences, or feelings?” and “In what way do you experience changes in wellbeing?”. Using this method, the moderator made sure that every participant had the opportunity to interact in the discussion and that participants were motivated to talk with each other [ 32 , 36 ]. Participants’ experiences were clustered on a flipchart on the basis of the trauma procedure; (i) moment of injury, (ii) treatment from medical staff from the ambulance or the trauma helicopter, (iii) treatment in the shock room, (iv) hospital stay, (v) moment of discharge, and (vi) period after discharge and/or rehabilitation. Also, the assistant moderator took field notes, handled logistics, and monitored the audio recording equipment [ 32 ].

At the end of each focus group, participants provided information on sociodemographics (i.e., age, sex, marital status, and education level). In addition, they completed the self-report questionnaires; Impact of Event Scale revised (IES-R) for measuring PTSD and the Hospital Anxiety and Depression Scale (HADS) for measuring anxiety and depressive symptoms.

The 22 items IES-R measures symptoms severity of intrusion, avoidance, and hyperarousal. It uses a 5-point Likert scale ranging from 0 ( not at all ) to 4 ( extremely ) [ 38 ]. The cut-off score for a probable diagnosis of PTSD is ≥ 33. The IES-R, as well as the Dutch version, has good psychometric properties [ 38 , 39 ].

The HADS assess anxiety (7 items) depressive symptoms (7 items) and uses a 4-point rating scale ranging from 0 ( not at all ) to 3 ( very much )). Cut-off scores of ≥11 for one of the subscale were regarded as a psychological complaint. The questionnaire is shown to be reliable and valid [ 40 ] and has good psychometric properties [ 41 ].

Data analysis

The focus group meetings were analyzed using a phenomenological approach [ 42 ]. The recorded focus groups were transcribed verbatim. Then, data analysis proceeded stepwise using the open, axial, and selective coding technique [ 32 , 33 ]. First, open coding was used to identify experiences and consequences of injury on patients’ wellbeing: physical, psychological, and social wellbeing. In addition, moments in time of trauma treatment or recovery, which were related to patients’ experiences were explored. Then, axial and selective coding was used to interpret and explain patients’ experiences by determining different themes and subthemes (level 1 and level 2) based on physical, psychological, and social wellbeing. These codes consisted of short sentences or single words, for example, ‘ASD symptom’ (i.e., theme (level 1) in psychological wellbeing) and ‘nightmares’ (i.e., subtheme (level 2) of ASD in psychological wellbeing), or ‘dependent of care’ (i.e., theme in social wellbeing), ‘loss of control’ (i.e., subtheme level 1 in social wellbeing) and ‘reassurance to hear voice of relative’ (i.e., subtheme level 2 in social wellbeing).

Two researchers (EV and BDO) independently coded and analyzed each of the transcripts Using the computer program Atlas.ti was. Demographics and responses on the questionnaires were analyzed chi-square tests and independent t-tests using SPSS version 24.

After six focus groups data saturation was reached. The duration of the meetings varied between 60 to 90 minutes. In total, 135 patients were invited of which 28 (21%) agreed to participate ( Fig 1 ).

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https://doi.org/10.1371/journal.pone.0245198.g001

The main reasons for declining participation were that patients indicated that they did not have enough time to participate (22%) or they did not experience any problems after injury (9%). In contrast, a subgroup declined, because participation was too confronting for them (19%). They were afraid that sharing experiences with others could be a trigger for re-experiencing their trauma. The six groups consisted of three up to seven participants ( Table 1 ). The median age was 59.5 (min. 18 –max. 84) and the mean ISS was 11.8 (SD = 9.9).

https://doi.org/10.1371/journal.pone.0245198.t001

Based on the IES-R, six (27%) focus group patients had a possible diagnosis of PTSD 12 months after injury. Patients with a possible diagnosis scored different on the subscales. For example, one patient scored moderately (score: 2) on avoidance and extremely (score: 4) on intrusion and hyper arousal, whereas two other patients scored quite a bit (score 3) on all subscales. With regard to the HADS [ 40 ], five (22%) patients were anxious and four (17%) had depressive symptoms 12 months after injury. Four patients (17%) showed symptoms of PTSD, anxiety and depression.

During the focus group discussions, seven patients described symptoms of PTSD during rehabilitation, such as having (severe) sleeping problems or nightmares, or re-experiencing trauma. Two of these patients were diagnosed with PTSD by a registered health psychologist, of which one patient (veteran) was diagnosed with PTSD before injury. The other patient developed PTSD as a result of her trauma. This patient also had limited physical (e.g., pain) and psychological functioning (e.g., concentration problems) in such a way that she lost her job and needed to stop her education.

Physical wellbeing

Table 2 shows the major themes and subthemes of physical wellbeing after injury.

https://doi.org/10.1371/journal.pone.0245198.t002

Patients reported not being recovered to the pre-trauma functional level, because physical limitations were still present after 12 months.

“ The physician said that my complaints would diminish over time . However , I still cannot walk well and I am in pain every day . I lost my job and I had to quit my education . Most difficult is that I am only 18 years old and I have lost everything (Female , ISS < 16) ”.

Patients experienced that the time they needed to recover from activities was much longer than they expected to be. They had to take small steps during rehabilitation, because they experienced physical limitations (e.g., pain or fatigue). Especially severely injured patients (ISS ≥ 16) stated that they ignored physical limitations, because they were motivated to work hard and fully recover as soon as possible.

“ I wanted to recover as quickly as possible , but I was hampered by others (rehabilitation specialist or psychotherapists) . It was very difficult to cope with that , because I wanted to make progress instead of doing nothing (Male , ISS < 16) ”.

However, the rehabilitation specialist or physiotherapist often instructed them to slow down in order to respect their physical boundaries. Patients stated that rehabilitation, in this phase, could be frustrating.

“ I had to adapt all the time during rehabilitation , because I was not physically capable to rehabilitate the way I hoped and thought I could (Male , ISS < 16) ”.

Yet, looking back on this rehabilitation phase, patients acknowledged that the rehabilitation specialist, physiotherapist, and nurses played an important role by guiding the patients how they could recognize, adapt, and cope with their physical boundaries. Moreover, health care professionals (HCPs) educated patients how to balance activities and rest, because activities takes a lot of energy. In this way, patients were able to keep their limitations in mind so they did not cross their boundaries.

“ It takes a lot of effort to do the things I like to do (Female , ISS < 16) ”.

Psychological wellbeing

Table 3 shows the major themes and subthemes related to psychological wellbeing after injury.

https://doi.org/10.1371/journal.pone.0245198.t003

Severely injured patients experienced a fear of dying short after injury, during treatment in the ambulance, and in the shock room.

“ Then just after injury , I saw blood spouting from my leg . I thought that I had an arterial bleeding and was convinced that I would die within a few minutes (Female , ISS ≥ 16) ”.

During hospitalization and recovery, patients realized that they survived the injury. The previously experiences fears, like fear of dying, were followed by a fear for permanent physical limitation.

“ The perspective of ending up in a wheelchair was difficult , because I am a fanatic sportsman (Male , ISS ≥ 16) ”.

The fear for permanent physical limitations caused uncertainty about the future. Patients did not know what to expect. In addition, patients who were sedated, were unconscious, or had posttraumatic amnesia during treatment in the ambulance and shock room, described that they were confused and anxious about what had actually happened.

“ My anxiety emerged during treatment in the shock room . I mainly had questions about the cause of my injury , for instance : ‘What did I experienced ? ’ and ‘What has happened to me’ ? (Male , ISS ≥ 16) ”. “ The most impressive memory was when I woke up on the ICU after three days of being unconscious . I thought I had a nightmare , but my nightmare was in fact reality (Male , ISS ≥ 16) ”.

Then, during hospital stay and after being discharged, patients described symptoms of ASD during hospitalization and/or PTSD during rehabilitation.

“ During the first weeks after injury , I had a lot of nightmares about my leg amputation (Female , ISS ≥ 16) ”. “ When I am sad , I see the white car approaching me and I re-experience the injury again (Female , ISS ≥ 16) ”.

In contrast, patients stated that feelings of helplessness and being dependent of others were difficult experiences to cope with. Especially severely injured patients (ISS ≥ 16) discussed that they were motivation to recover, because they wanted to be autonomous instead of feeling helpless.

“ I did not want to feel helpless . Therefore , I was very motivated to recover (Male , ISS ≥ 16) ”.

In addition to patients’ frustrations, angriness, and other negative feelings, they also stated that they experienced adverse and favorable outcomes concerning their (subjective) personality, emotions, and behavior. Changes in (subjective) personality are describe by the participant selves and not determined by a questionnaire. Patients felt satisfied with these changes.

“ The trauma changed me . Before my injury , I was quite a reserved person , but now I am more open and kind (Male , ISS ≥ 16) ”. “ My emotions became more intense . For example , when I am happy , I am happier than I used to be (Male , ISS ≥ 16) ”. “ Due to trauma , I became easier satisfied instead of being a perfectionist (Female , ISS < 16) ”.

Patients often had no memories about their injury and treatment in the ambulance. The first memories emerged during treatment in the shock room or during hospitalization. Patients reported mental fatigue during rehabilitation. Moreover, they experienced (in some cases) permanent cognitive problems with recognition of persons, concentration (e.g., reading), reduction in information processing speed, and being forgetful. They also experienced mental fatigue.

“ It just feels like I am ten years older . My mental speed is reduced . I am not the person who I used be (Male , ISS ≥ 16) ”.

Cognitive dysfunction resulted in problems with resumption of work.

“ I would like to have a job , however , I have to accept that I am not able to work anymore , because I am not able to concentrate and cannot even read a book (Male , ISS < 16) ”.

To deal with psychological consequences (e.g., anxiety, changes in subjective personality, and cognitive dysfunction, Table 3 ), some patients described to use an avoidance coping strategy during hospitalization and/or rehabilitation. As they avoided trauma-related physical activities. They had a fear of falling.

“ My bike is still there but I do not look at it anymore (Male , ISS < 16) ”.

Patients tended to tone down the impact of their trauma by thinking: ‘It is just an injury’. However, looking back on the trauma procedure, they acknowledged that they should not underestimate the impact of their trauma.

Social wellbeing

Table 4 shows the major themes and subthemes of social wellbeing after injury, including experiences that are related to the environment.

https://doi.org/10.1371/journal.pone.0245198.t004

Patients’ injury had an impact on their family, because their family feared that the patient would not survive the physical trauma.

“ The impact of my trauma is bigger for my family than for myself (Male , ISS ≥ 16) ”.

This fear often resulted in partners who became overanxious during rehabilitation.

“ My wife pleases me not to go on the bike by saying : “Go find another hobby” (Male , ISS < 16) ”.

In addition, a patient acknowledged that his injury, the fact that he became dependent of others had negatively influenced his marriage.

“ I was angry all the time because of physical limitations I became dependent of others . It was difficult for my wife to cope with my angriness . Due to my rehabilitation , I felt a little bit better , because limitations decreased (Male , ISS < 16) ”.

Patients experienced a loss of control when they had difficulties with being dependent of care from family and health care providers.

“ It was frustrating to be dependent of care (e . g ., need help by taking a bath) , because I found it difficult to be naked , but I had no choice (Female , ISS < 16) ”.

Although being dependent of others can be difficult, patients were grateful with the help they received from others. Moreover, patients thought that support of relatives and friends could help them to recover.

“ When I got out of bed I was not able to walk . In a period of time , I have learned to walk again step by step with the support of others . In the future , I will ride my bike again (Male , ISS < 16) ”.

Moreover, patients felt reassured when they heard voices of relatives shortly after injury. Especially elderly patients (i.e., > 70 years old), who were dependent of relatives’ care before injury, reported that the need for the right social support is crucial. These patients experienced more difficulties with social support, because they had a limited social network and in some cases (almost) no one to fall back on compared with younger participants.

“ I am all alone after losing my wife a few years ago (Male , ISS ≥ 16) ”. “ I need a lot of help from my neighbors , because my children live far away ”.

Almost every participant thought that communication could be improved between medical staff in hospital, general practitioners, authorities, and patients. Since almost every patient provided an example of not being well or incorrectly informed by a HCP. For instance, during hospitalization, patients needed more information about their treatment or prognosis of recovery.

“ If they (physicians) explained the consequences of my brain injury more clearly , then I would be more able to cope with the consequences (♂ , ISS≥16) ”.

Patients illustrated that medical staff could reassure them during treatment. In addition, they could also clarify patients’ injury severity and inform them about their treatment, prognosis, and future outcomes. However, during hospital stay, patients felt that there was limited time for information transfer. Furthermore, they had to take on one’s own initiative for receiving care. Patients thought that good communication could facilitate recovery during hospital stay and recovery.

“ I had to ask everything , including my medication , because I did not receive the care I needed (Male , ISS < 16) ”. “ I had to wait a while to be referred for rehabilitation . So , I was the one who arranged physiotherapy during that period , because I wanted to recover (Male , ISS ≥ 16) ”.

Patients described that lack of clarity about their injury severity and trauma treatment emerged during treatment in the shock room.

“ It (shock room) was very hectic , because different physicians were present . Also , I went back and forth to several rooms for different examinations . I had no idea what happened during treatment (Male , ISS ≥ 16) ”.

At that moment, patients experienced a lack of communication between themselves and HCPs since there was no time to communicate.

“ One of the medical staff asked me : “Can we cut your clothes ? ” But before I could answer , I lay in my naked butt (Male , ISS < 16) ”.

Patients felt that they were not being taken seriously due to a lack of communication. If information was provided, some patients did not completely understand it. Medical jargon was often used. In addition, multiple physicians were involved in patients’ treatment, but they did not introduce themselves or explained what they were doing. Patients felt a loss of control in this overwhelming situation. Therefore, due to a lack of information transfers, patients reported that being well reassured short after injury and during treatment in the shock room could help them to surrender to medical care.

“ The nurse was very kind to me . She told me : “It is going to be ok and we will take good care of you . ” (Female , ISS < 16) ”.

Moreover, patients reported miscommunication between authorities (e.g., hospital and general practitioners or hospital and rehabilitation specialists).

“ I assumed that my GP was informed by the hospital about my injury . Unfortunately , he did not receive any information (Male , ISS < 16) ”.

Patients described that the media attention negatively affected patients’ social interactions after injury, because the media provided false information.

“ Within half an hour there was some story on the news about two seriously injured people , but that was incorrect . This news caused a lot of gossip in town (Male , ISS < 16) ”.

After being discharged and during rehabilitation, patients reported having problems with practical issues, such as problems with finance, health insurance, or difficulties with the re-examination for their driver’s license. Although patients were dependent on authorities, they needed to take own initiative to solve these problems.

“ I am frustrated because the claim for damages has been rejected (Male , ISS ≥ 16) ”.

This study aimed to explore and describe patients’ experiences and wellbeing after injury, treatment, and rehabilitation. Moreover, factors that impede or facilitate patients’ wellbeing were examined. Patients explained that they did not recovered to their pre-injury functional level up to12 months after injury. One of the reasons could be the presence of PTSD, anxiety, and depressive symptoms 12 months after injury, which is in line with previous studies [ 28 , 43 ]. Moreover, patients experienced feelings of helplessness, a fear of dying, and/or a fear for a worse outcome short after injury and during treatment in the shock room. They illustrated that feelings of loss of control occurred, because treatment in the shock room was explained as overwhelming and patients needed to surrender to care. Also, patients stated that they needed more information about the injury and treatment when they were in the ambulance and shock room, especially when they did not remember their injury. In some cases, it can be difficult to inform the patient when rapid screening and treatment in the shock room is crucial for survival. In this life-threatening phase, the main goal is fast recognition and prompt treatment of severe injuries [ 10 ] by ‘treat first what kills first’ (i.e., ABCDE-method in trauma treatment) [ 44 ]. This has shown to be essential for long-term outcomes [ 10 ]. Nevertheless, patients illustrated that reassurance by a physician or nurse could help them to surrender to medical care. Moreover, in line with other studies, nurses could help them to cope with feelings of insecurity [ 30 , 45 ].

Furthermore, this study showed that patients had to deal with adverse changes in physical (i.e., pain, stiffness), emotional, cognitive functioning [ 46 ], and (subjective) personality [ 47 , 48 ]. For instance, memory impairment, loss of autonomy, and problems in work, marriage and income, could play an important role as obstructive indicators for these changes [ 46 ]. In line with the literature, changes in personality could be related to TBI [ 48 – 50 ], while patients’ perception on positive changes in (subjective) personality or emotions might be a result from a change in internal standards or values, i.e., response shift [ 47 ]. Furthermore, satisfaction with care improved if a health care provider was interested and involved in patients’ care and recovery [ 28 , 51 ]. Especially during rehabilitation, when patients struggled with resumption to work and financial stress, the need for positive support from their employer or authorities was high [ 26 , 29 , 52 ].

In addition, patients stated that good communication regarding treatment and rehabilitation is imperative and it needs further improvement [ 28 ]. Lack of clarity about patients’ treatment or prognosis, emerged when patients were not well, insufficient, or incorrectly informed by the doctor about expectations and consequences of injury on their wellbeing (i.e., physical, psychological, and social). Moreover, patients felt that they were not being heard by HCP. There is a need for further explanation about the outcome of recovery on all domains. One of the reasons for lack of clarity or insufficient information transfer was that patients could not remember the provided information as a result of cognitive deficits from injury. Another reason could be found in limited time to contact between patients and HCPs, which can be a result of high workload and time pressure [ 53 ]. Furthermore, patients had to take self-initiative for receiving care (e.g. asking about their own medication), which could be frustrating when they were dependent of others. Miscommunication could be due to a lack of connection or expectations in communication [ 51 ]. For example, the content of communication from a trauma surgeon could be oriented on medical or physical outcomes whereas patients’ content was focused on personal (i.e., emotional of psychological) needs [ 51 ]. Another reason for the presence of miscommunication could explained by the concept of testimonial injustice (i.e., gaining knowledge by being told by others) [ 54 ], which is part of epistemic injustice [ 55 ].

To our knowledge, this is the first study that explored patients’ perspectives on injury, treatment in the shock room and hospital, and rehabilitation using a focus group design. This provided knowledge insight which experiences were present on a specific moment after injury. For instance, after being treated in the shock room, a fear of dying during treatment in the shock room could change in anxiety for permanent physical limitations during hospitalization of rehabilitation. Moreover, the focus has been on psychological consequences and functioning. These topics were under evaluated in the field of trauma research. Moreover, trauma patients with different types of injuries (e.g., fractures, upper and/or lower extremity injuries, traumatic amputation, and TBI) and trauma mechanism (motor vehicle accident, fall, and collision) were included. The qualitative design of this study facilitated an in-depth exploration about patients’ experiences. In-depth discussions were stimulated, because participants shared their perspectives. Finally, the focus groups were led by the same moderator and conducted in the same standardized manner. The focus groups were conducted using a reliable and valid methodology which resulted in robust data with group data saturation [ 32 , 33 , 42 ]. To facilitate validity, all participants were capable to answer the research questions. They also provided a whole range of responses to the research questions to attain reliability.

Nevertheless, some limitations must be taken into account. First, the low response rate (21%) probably implied response bias [ 56 ]. In line with the literature [ 56 , 57 ], patients who declined participation were not interested, because they did not have any physical or psychological problems after trauma. Other patients explained that participation was too difficult, because they could be faced with their psychological problems (e.g., re-experiencing the trauma) when they were triggered by the group discussion. They did not want that. Another limitation was that one of the six focus group consisted of only three participants, because two other patients did not show up. Although this small number could influence the quality of the group dynamic [ 58 ], all three participants participated in the discussions in a way that group interaction occurred. This is in line with the literature, which illustrate that smaller focus groups could allow participants to open up about their experiences instead of larger groups [ 59 ]. Nevertheless, larger groups can facilitate more in-depth exploration of a persons’ perspectives and ideas. Third, selection bias could have occurred, because participants needed to be capable provide informed consent form. Otherwise, without consent, persons could not participate in this study. Our study population consisted of mainly Caucasian participants since sufficient knowledge of the Dutch language was an inclusion criterion.

Results from this qualitative study obtained several implications for future research and clinical practice. Since only patients participated in this study, future research could focus on how trauma care and patients’ recovery can further be improved by studying HCPs’ (e.g., trauma surgeon, emergency doctor, rehabilitation specialist, etc.) perspectives, their expectations and their role in providing health care. In addition, health care providers must be aware that, in addition to medical traumas, patients can suffer from psychological traumas (e.g., ASD and PTSD) and impaired wellbeing directly or months after injury. Nevertheless, HCPs’ contribution in care might affect patients’ recovery, because satisfaction with care could facilitate recovery. In order to predict who is at risk for psychological problems and disorders, patients can be screened almost directly after injury using the Injured Trauma and Survival Screen (ITSS) [ 60 ] or the Psychosocial Screening Instrument for physical Trauma patients (PSIT) [ 61 ]. Then, patients can be prevented from physical, psychological, and social consequences by providing early psychological treatment during hospitalization to improve patients’ wellbeing [ 62 ].

Patients reported that their injury had an impact on their physical, psychological, and social wellbeing after injury. These consequences were present up to 12 months after injury. HCPs with the knowledge on physical, psychological, and social consequences could, according to patients, improve anticipation on patients’ needs. This might contribute to patients’ satisfaction with health care.

Acknowledgments

We thank all patients for their participation. Also, we gratefully acknowledge Sophie Heesters for her help in transcribing the focus groups verbatim.

• 1. Centraal Bureau voor de Statistiek. Overledenen; ongevallen, inwoners van Nederland. 2016.
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• 34. Barbour RS, Morgan DL. A New Era in Focus Group Research: Challenges, Innovation and Practice. 1st ed: Palgrave Macmillan; 2017.
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An analysis of the effectiveness of rehabilitation protocols for patients with spinal cord injury: A systematic review

• Review Article
• Open access
• Published: 24 October 2023

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• Kyung Eun Lee 1 &
• Bogja Jeoung   ORCID: orcid.org/0000-0002-7144-6179 2  

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SCI may cause loss of sensory function, paralysis, and limited functional mobility. The specificity of SCI has expanded the scope of medical trials and given rise to therapeutic options that incorporate new technologies with robotics and electronic devices. We aimed to identify various therapeutic options and develop effective treatment regimens.

We conducted the systematic review using the following digital databases: MEDLINE/PubMed and Google Scholar. We focused on publications published between 2012 and 2023 and The following primary terms were searched: “Spinal cord injury rehabilitation,” “Spinal cord injury exercise,” and “Spinal cord injury therapy,” with the Boolean operator “AND/OR” used for additional searches. A total of 110 relevant articles were identified during the selection process. After screening and assessing eligibility, the final 17 studies were included in this systematic review

Results & conclusion

The current paper gave a taxonomy of electrical instrumentation and traditional rehabilitation technologies. We also discovered that FES is used as a comprehensive regimen that involves both the upper and lower extremities, and that locomotor training using robots is beneficial in improving walking ability. We discovered that diversified training programs using conventional methods concentrated on the physical independence of patients with chronic SCI.

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Introduction

Spinal cord injury (SCI) is a catastrophic disease that causes decreased aerobic capacity, glucose intolerance, and insulin resistance due to autonomic dysfunction, physical inactivity, and significant deconditioning (Gorgey et al. 2014 ). In addition, several individuals with SCI are significantly less active due to wheelchair dependency, and these metabolic changes tend to lead to cardiovascular diseases (Warburton et al. 2007 ). The negative effects experienced by patients with SCI have led researchers to study the need for physical rehabilitation in these patients. Therefore, substantial progress has been made in SCI treatment (Eng et al. 2007 ). Therapies for SCI, such as drug, radiotherapy, diet, and rehabilitation therapies, can be approached in various ways. Proper rehabilitation based on injury severity plays an important role in building joints and preventing muscle strength loss. From a metabolic perspective, treatment is also thought to be important for maintaining smooth functioning of the respiratory and digestive systems (Nas et al. 2015 ). Over the past few decades, several studies have shown that clinical intervention and rehabilitation have a positive effect on physical and functional recovery in patients with SCI. However, significant progress on SCI treatment should be made considering that there are no practical and conclusive alternative treatments to SCI. A previous study has adopted various approaches; however, this sporadic accumulation is not a practical measure. Little empirical data support the efficacy of the multiple specialized therapies offered in SCI (Whiteneck et al. 2009 ). In addition, rehabilitation comes in several shapes and forms, and there are different approaches depending on the patient’s condition, such as paralysis (e.g., tetraplegia, paraplegia). The specificity of SCI has expanded the scope of medical trials and given rise to therapeutic options that incorporate new technologies with robotics and electronic devices. Although these attempts have been positive catalysts for addressing the chronic problems of SCI, specific protocols and their outcomes are not well documented. As a result, we attempted to systematically analyze the protocols and effects of rehabilitation to provide knowledge on which methods work efficiently in practice. This study aimed to comprehensively evaluate the equipment and methods used for SCI rehabilitation. Through a systematic review, the current paper presents comprehensive data on interventions provided by all therapy professionals and adds to the result-driven criteria for medical decision-making by organizing research designs (i.e., purpose, participant and exercise descriptions, and results).

Search strategy and data resource

This systematic review implemented the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. From April 2023 to May 2023, a systematic search of relevant papers was conducted using the following digital databases: MEDLINE/PubMed and Google Scholar. We focused on publications published between 2012 and 2023 and included only articles on humans written in English. The search was narrowed to include only full-text clinical trial articles. The following primary terms were searched: “Spinal cord injury rehabilitation,” “Spinal cord injury exercise,” and “Spinal cord injury therapy,” with the Boolean operator “AND/OR” used for additional searches.

Selection criteria

The following criteria for eligibility were created in accordance with the Population, Intervention, Comparison, Outcomes, and Study strategy: (1) Population (P): Individuals with an SCI (except where an individual without disabilities acts as an individual with disabilities); (2) Intervention (I): Rehabilitation, exercise, and/or physical treatment for SCI; (3) Comparison (C): No rehabilitation or other interventions; (4) Outcomes (O): Results of intervention in terms of functional improvement and treatment effectiveness (e.g., pain reduction, gait performance, body composition, and treatment effectiveness); and (5) Study (S): Controlled medical trials and protocols. In addition, the studies included randomized clinical trials, controlled clinical trials, observational studies, and case studies. Meta-analyses, reviews, letters, and proceedings were excluded.

Data synthesis and extraction process

This systematic review collected papers in accordance with the PRISMA 2020 guidelines, and three independent examiners were engaged in the study selection and extraction procedure. Subsequently, two authors inspected and evaluated the results. Finally, the researchers and reviewers reached a consensus on the selection and extraction process. In the identification process, a search engine in a scientific database was used to identify papers by combining keywords. Duplicated and irrelevant papers were excluded from the collected papers after searching. In the screening step, articles that did not meet the criteria were eliminated from the analysis list by screening titles and abstracts. Studies that did not include individuals with SCI were also excluded. Next, to verify the eligibility of the selected articles, each researcher reviewed the entire article and excluded articles. Studies with ambiguity were selected or excluded through discussions between the researchers and evaluators.

Assessment of quality of studies

The Physiotherapy Evidence Database (PEDro) was used to verify the quality of the collected articles. The PEDro scale is used to grade the methodology-related “quality” of each medical trial in the PEDro database. The PEDro scale is intended to assist users of the PEDro database in quickly determining which randomized clinical trials are likely to be valid internally and may have adequate statistical data to make the findings comprehensible (Sherrington et al. 2000 ). It consists of the following 11 items: eligibility standard, random and concealed allocation, group similarity at baseline, blinding, < 15% dropout, intention-to-treat analysis, between-group statistical comparisons, and variability. Each item contributes 1 point to the total PEDro score, except for the first item (Maher et al. 2003 ). The PEDro scores of the current study are provided in Appendix 1 .

Identification of studies

A total of 110 relevant articles were identified during the selection process. Fifteen duplicated records and 17 irrelevant topics were removed. After screening and assessing eligibility, the final 17 studies were included in this systematic review. A flow diagram of the selection process is shown in Fig. 1 .

Flow diagram of the study selection

General overview

Articles related to the rehabilitation of patients with SCI were collected according to the criteria mentioned above, and 17 papers were derived. To precisely analyze exercise protocols, 12 electronic- and robot-based papers and 5 conventional types of rehabilitation articles were classified. This was examined by dividing the number of study participants by average age, duration of injury (years), level of injury (C1–T12), exercise design, research purpose, assessment, and results. The table of research results is presented in Table 1 .

• Robotic- and electronic-based rehabilitation

Twelve publications discussed electronic and robotic therapies for the survivors of SCI. For the systematic analysis, rehabilitation devices and methods were classified into functional electronic stimulation (FES) and robotic and locomotor training (LT).

Functional electrical stimulation rehabilitation

Six articles [1, 2, 3, 4, 5, 6] employed FES rehabilitation using rowing, cycling, and ergometers. FES rowing training (FESRT) was covered in four studies [1, 2, 3, 5]. Afshari et al. ( 2022 ) [1] assessed the effects of FESRT on the body composition profiles in the subacute phase of SCI. This clinical trial involved a hybrid exercise involving the upper and lower limbs, which required more muscular activity. Following a substantial increase in total and leg lean mass (p < 0.05), FESRT contributed to a greater exercise ability and a propensity for reduced body fat accumulation. Vivodtzev et al. ( 2020 ) [2] instructed patients with high-level SCI (T3–C4) to undergo a whole-body FES rowing protocol with noninvasive ventilation. After 3 months of training, the participants showed an improvement in their capacity to take up oxygen for certain ventilations. Chou et al. ( 2020 ) [3] and Kim et al. ( 2014 ) [5] employed rowing exercise interventions in the survivors of SCI. This protocol led to improvements in the patients’ motor function and body composition. Gorgey et al. ( 2019 ) [4] and Thrasher et al. ( 2013 ) [6] focused on the lower extremities using FES cycling and ergometry. Gorgey et al. ( 2019 ) [4] confirmed that FES lower limb cycling had positive effects on cardiometabolic results and aerobic fitness. Similarly, Thrasher et al. ( 2013 ) [6] designed FES leg cycle ergometry training to compare patients with incomplete and complete SCI. Following 40 exercise sessions, the researchers noted improvements in the power output of the lower extremities and fatigue test.

Robotic and locomotor training

Of the selected articles, six studies [7, 8, 9, 10, 11, 12] used LT as a rehabilitation program for patients with SCI. Onushko et al. ( 2019 ) [7] attempted to determine how sympathetic–somatomotor (SS) coupling in individuals with incomplete SCI (iSCI) can be affected by high- and low-intensity LT. In their study, the participants performed stepping tasks during 20 sessions for 4–6 weeks. The researchers discovered that high-intensity training might outperform low-intensity training, indicating that SS coordination in individuals with iSCI may change depending on the intensity of the intervention. Similarly, Leech et al. ( 2016 ) [8] evaluated the effects of exercise intensity on walking function and quality. They also found that high-intensity LT resulted in more favorable outcomes in terms of gait speed and muscle activity than low-intensity LT. Leech and George ( 2017 ) [9] employed a high-intensity LT program in patients with iSCI and noted that physical indicators (e.g., serum brain-derived neurotrophic factor, insulin-like growth factor-1) were enhanced following the intervention. Consequently, both studies reported that higher LT intensities were associated with greater improvements in patients with iSCI. Martinez et al. ( 2018 ) [10] also revealed that a body weight-supported treadmill using Lokomat ® (Hocoma) improved locomotor function, including the motor score of the lower limb and balance. Gorman et al. ( 2019 ) [11] also used Lokomat ® to assess and compare cardiorespiratory effects. The initial robotic session lasted 20 min and was subsequently extended in 5-min increments in future sessions until the exercise lasted 45 min. Each session began with a 5-min warm-up, followed by personalized, trained gait exercises, and finished with a 5-min cool-down. Peak VO 2 level measured using robotic treadmill ergometry statistically improved (14.7%, p = 0.03) during the period of the robotic intervention. In a study by Francisco et al. ( 2017 ) [12], 10 individuals with chronic cervical SCI underwent robot-assisted arm training. They performed single-degree-of-freedom upper limb exercises to demonstrate the feasibility, tolerance, and efficacy of MAHI Exo-II for cervical SCI. This device is an electronically operated upper extremity haptic exoskeleton appliance developed for rehabilitation. The treatments were modified based on the movement ability of each joint. After robotic intervention, arm and hand functions (Jebsen-Taylor Hand Function Test, Action Research Arm Test) were improved. In addition, it was found that both trainings using robots improved the targeted physical function.

Conventional rehabilitation

Based on the abovementioned criteria, traditional rehabilitation methods for patients with SCI are categorized into resistance training, balance task, aerobic exercise, and mixed training. Five articles [13, 14, 15, 16, 17] were used for the systematic analysis. The table of research results is presented in Table 2 .

Resistance training

Silva et al. ( 2020 ) [13] studied the effects of circuit resistance training (CRT) in individuals with SCI. The participants consisted of patients with chronic SCI, primarily those with injury levels from T4 to T11. CRT protocols involved physical and motor abilities (e.g., frontal lift, agility station, biceps curl). The interventions consisted of activities that were easy for patients to follow in their daily routine and could be performed directly in a wheelchair. After 12 weeks of exercise, although there were no differences in bone-related indicators, the patients’ muscle strength (p = 0.028) and agility (p = 0.028) improved.

Balance training

Sadeghi et al. ( 2018 ) [14] used rebound therapy for spinal cord rehabilitation. This intervention involves exercising on a trampoline to improve static stability. The participants performed core stability training and upper extremity exercises on a trampoline and several basic exercises using instruments, such as balls and balloons. After the participants practiced the exercises thrice a week, rebound therapy was found to have a positive effect on several standing stability parameters (p < .01).

Aerobic training

Aerobic training for patients with SCI has been addressed in studies by Wouda et al. ( 2016 ) [15] and DiPiro et al. ( 2016 ) [16]. Wouda et al. ( 2016 ) [15] aimed to determine whether high-intensity interval training (HIIT) increases physical capacity and fitness levels more than moderate-intensity training (MIT) and standard care. The two experimental groups were trained for 12 weeks at intensities of 70% (MIT) and 85–95% (HIIT) of HRmax. The intervention program consisted of jogging or running according to the patient’s fitness level and physical condition. The results showed no differences in effectiveness among the three groups (i.e., HITT, MIT, and standard care). DiPiro et al. ( 2016 ) [16] also used an aerobic exercise training (AET) program for iSCI. Ten patients were instructed to perform a non-task-specific, voluntary, progressive AET protocol. The researchers discovered significant improvements in aerobic and locomotor capacities.

Mixed training

Lotter et al. ( 2020 ) [17] identified the effects of task-specific therapies compared with impairment-based therapies on gait performance. Impairment-based training includes non-walking training, whereas the task-specific method involves training involving rehabilitation approaches (e.g., strengthening, balance, and aerobic exercise). Weight machines were used for the strengthening activities. During balance training, patients performed standing or sitting activities on unbalanced surfaces (e.g., foam, trampoline) or dual upper limb balance tasks. Aerobic exercise involved cycling or stepping (e.g., NuStep LLC). The protocol consisted of 20 sessions over 6 weeks, with the intensity set at 70–80% HRmax. The researchers found that task-specific training had a positive effect on the determinants of mobility capacity.

This systematic review included 17 articles that examined the effects of various physical rehabilitation protocols on SCI. Six FES papers, six articles related to robotic training and LT, and five publications on traditional treatment modalities were analyzed and categorized. Based on our analysis of the technology and protocols of rehabilitation, we described how previous studies have applied physical rehabilitation for SCI and their rehabilitative features and results. Several researchers have adopted and developed electromechanical technologies for clinical trials. Among these methods, FES, which utilizes short electrical impulses to produce movements in the paralyzed muscle, is the most frequently employed approach for increasing motor skills in patients (Lynch and Popovic 2008 ). These treatments use the undamaged neuromuscular system to provide various therapeutic exercise alternatives, facilitate functional rehabilitation, and manage or prevent complications (Ho et al. 2014 ). Increasing the level of physical activity is crucial for individuals with SCI, whose physical activity has been significantly reduced, and electrical stimulation can maximize this. FES is applied in various ways, including rowing, cycling, and ergometry (Gorgey et al. 2019 ). The studies analyzed in this review also employed FES rowing [1, 2, 3, 5] and FES cycling [4, 6]. In terms of rehabilitation protocols, the duration of the exercises ranged from 30 min to 3 h, and the duration ranged from 3 months to 6 months. This was mainly conducted with the observation and assistance of therapists, and the intensity was set after monitoring the subjects’ exercise levels through a test. In addition, four studies [1, 2, 4, 6] included acclimation sessions to electrical stimulation before the full intervention. This adaptation process appears to be a necessary step in the rehabilitation of FES in patients with SCI. External factors, such as unfamiliarity with the intervention and nervousness, may have a negative effect on an individual’s initial performance on a specific measure (Awad et al. 2013 ). Various tests and acclimation training make it easier for participants to adapt to new stimuli and increase the reliability of the results. The FES publications that we analyzed primarily investigated biological responses after FES rehabilitation and showed improvements in metabolic factors. Body composition [1, 4, 5], cardiorespiratory function [1, 2, 4, 6], and neural factors [3] showed positive outcomes. FES rehabilitation tended to emphasize the movements and effects of the entire body rather than focusing on a single extremity [1, 2, 3]. Davis et al. ( 2008 ) and Duffell et al. ( 2010 ) also suggested that although the initial goal of FES was to reinstate the lower extremity, FES-evoked exercise enhanced whole-body metabolism in subjects with SCI. Thus, hybrid FES allows patients to perform voluntary upper extremity and FES-assisted lower body exercises simultaneously, reducing disabling limitations and focusing on their treatment (Andrews et al. 2017 ). Therefore, FES is expected to provide conative exercises with multiple effects.

Another group of this analysis, robotic training and LT, is devoted to the rehabilitative properties and effectiveness of electromechanical robots as assistive devices for patients with SCI and physical activity limitations. This clinical practice allows individuals to practice gait motions more independently of assistance, probably with their body weight supported and with robotic motion of the lower limbs (Laursen et al. 2016 ). After an injury, patients experience a decrease in gait speed, limited functional mobility, and an increased risk of falls (Louie et al. 2015 ). Ultimately, enhancing mobility and activity is important for individuals with SCI. In this context, studies on LT have focused on the effects of ambulation and improvements in lower extremity function. In this review, five [7, 8, 9, 10, 11] publications reported positive changes in walking ability, lower limb kinematic data, and motor scores with locomotor and robotic training. Several studies related to robotic training and LT have examined the function (e.g., speed) and quality (e.g., kinematics) of locomotion. In the training paradigm, the intervention time ranged from 30 min to 3 hours and the duration ranged from 4 weeks to 3 months. Compared with FES, this intervention was slightly shorter in duration. They employed Lokomat® robotic treadmill training device (Hocoma, Inc.) [10, 11] and MAHI Exo-II robotic device [12]. Several studies have focused on individuals with iSCI. Morawietz and Moffat ( 2013 ) attributed this inclination to the growing number of individuals with iSCI who have great possibilities for improvement. In cases of incomplete injury, it is critical to enhance physical activity and to return to regular activities; hence, gait training is deemed critical. Patients with iSCI should concentrate on the physical problems such as reducing activities and limiting participation (Carpenter et al. 2007 ). These findings confirm that rehabilitation should be tailored to the patient’s condition and that ambulation training is an important rehabilitation strategy for patients with iSCI. Furthermore, several publications [7, 8, 9] have focused on exercise intensity. They compared the effects of low- and high-intensity exercise to verify which exercise was effective for individuals with SCI. In summary, these studies showed that higher intensities were more beneficial for the cardiometabolic aspects.

Although the abovementioned clinical practices are relatively new approaches that use new technologies, some studies have employed conventional rehabilitation for SCI. The analyzed papers dealt with resistance, aerobics, balance, and mixed methods. The participants performed functional exercises that encompassed physical and motor skills. Researchers using traditional methods have designed their own exercise programs or followed guidelines, such as the American College of Sports Medicine guidelines and the 2008 Physical Activity Guidelines for Americans [16]. Regarding the exercise protocol, the intervention time ranged from 20 to 40 min, and the duration ranged from 6 to 12 weeks. Unlike other methods in the study, participants in the traditional regimens had a long duration of injury (i.e., time since injury). This treatment is expected to be used in chronic patients who require active movements rather than assistive devices. Importantly, these studies emphasized patient independence during intervention [13, 14]. These programs were designed to be performed and reproduced on their own and were implemented in the wheelchair itself.

In conclusion, this systematic analysis confirmed that FES might target the whole-body exercise effect and that robotic training was effective in improving walking ability. These devices play supportive roles and exert various metabolic effects. In addition, traditional methods are expected to work well in patients with chronic SCI who need to enhance their physical independence. We found that appropriate rehabilitation is required depending on the patient’s injury and paralysis level and that protocols, such as exercise intensity and duration, should be different. The combination of SCI and technology is constantly evolving, with several different studies reported annually. For this quantitative flood, it is important to provide a precise direction regarding which treatments are effective, at what stage, and for which patients. Therefore, by simultaneously reviewing and analyzing both technological and conventional rehabilitation, this study presents a holistic view of effective intervention protocols and results. This limitation suggests that the systematic review could include studies with low quality and small effect, which can potentially bias the outcomes. In addition, Spanish and German papers were excluded from the analysis.

SCI may cause loss of sensory function, paralysis, and limited functional mobility. Researchers have adopted several rehabilitation approaches to reduce these negative effects in patients with SCI. We aimed to identify various therapeutic options and develop effective treatment regimens. First, it examined research involving technologies that utilize electrical instruments and conventional rehabilitation. We also found that FES is utilized as a comprehensive rehabilitation program, including the upper and lower limbs, and that LT with robots is effective in enhancing walking ability. Using traditional methods, we discovered that various training programs emphasize the physical independence of patients with chronic SCI. This systematic review presents specific findings that hold the potential to provide practical rehabilitation options for patients with SCI.

Data availability

Not applicable.

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Acknowledgments

This study was supported by the Translational R&D Program on Smart Rehabilitation Exercises (NCR-TRSRE-Eq01A), National Rehabilitation Center, Ministry of Health and Welfare, Korea.

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Lee, K.E., Jeoung, B. An analysis of the effectiveness of rehabilitation protocols for patients with spinal cord injury: A systematic review. J Public Health (Berl.) (2023). https://doi.org/10.1007/s10389-023-02115-9

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Moral Injury: An Integrative Review

Affiliations.

• 1 Mental Health Service, San Francisco Veterans Affairs Healthcare System, San Francisco, CA, USA.
• 2 Department of Psychiatry, University of California-San Francisco, San Francisco, CA, USA.
• 3 Department of Social and Behavioral Sciences, University of California-San Francisco, San Francisco, CA, USA.
• 4 Massachusetts Veterans Epidemiological Research and Information Center, VA Boston Healthcare System, Boston, MA, USA.
• 5 Departments of Psychiatry and Psychology, Boston University, Boston, MA, USA.
• 6 National Center for Veterans Studies, The University of Utah, Salt Lake City, UT, USA.
• 7 Department of Psychology, The University of Utah, Salt Lake City, UT, USA.
• 8 Department of Psychology, Palo Alto University, Palo Alto, CA, USA.
• PMID: 30688367
• DOI: 10.1002/jts.22362

Abstract in English, Spanish, Chinese

Individuals who are exposed to traumatic events that violate their moral values may experience severe distress and functional impairments known as "moral injuries." Over the last decade, moral injury has captured the attention of mental health care providers, spiritual and faith communities, media outlets, and the general public. Research about moral injury, especially among military personnel and veterans, has also proliferated. For this article, we reviewed scientific research about moral injury. We identified 116 relevant epidemiological and clinical studies. Epidemiological studies described a wide range of biological, psychological/behavioral, social, and religious/spiritual sequelae associated with exposure to potentially morally injurious events. Although a dearth of empirical clinical literature exists, some authors debated how moral injury might and might not respond to evidence-based treatments for posttraumatic stress disorder (PTSD) whereas others identified new treatment models to directly address moral repair. Limitations of the literature included variable definitions of potentially morally injurious events, the absence of a consensus definition and gold-standard measure of moral injury as an outcome, scant study of moral injury outside of military-related contexts, and clinical investigations limited by small sample sizes and unclear mechanisms of therapeutic effect. We conclude our review by summarizing lessons from the literature and offering recommendations for future research.

Spanish Abstracts by Asociación Chilena de Estrés Traumático (ACET) Daño Moral: Una revisión integrativa REVISION INTEGRATIVA DE LA INVESTIGACION EN DAÑO MORAL Las personas que están expuestas a eventos traumáticos que violan sus valores morales pueden experimentar una angustia grave y discapacidades funcionales conocidas como “daño moral”. En la última década, el daño moral ha captado la atención de proveedores de servicios de salud mental, comunidades espirituales y religiosas, medios de comunicación y el público en general. La investigación sobre daño moral, especialmente entre el personal militar y los veteranos, también ha proliferado. Para este artículo, revisamos la investigación científica sobre el daño moral. Se identificaron 116 estudios epidemiológicos y clínicos relevantes. Los estudios epidemiológicos describieron una amplia gama de secuelas biológicas, psicológicas / conductuales, sociales y religiosas / espirituales asociadas con la exposición a eventos potencialmente dañinos moralmente. Aunque existe una escasez de literatura clínica empírica, algunos autores debatieron cómo el daño moral podría y no podría responder a los tratamientos basados ​​en la evidencia para el trastorno de estrés postraumático (TEPT), mientras que otros identificaron nuevos modelos de tratamiento para abordar directamente la reparación moral. Las limitaciones de la literatura incluyeron definiciones de variables de eventos potencialmente perjudiciales desde el punto de vista moral, la ausencia de una definición consensuada y una medida de gold-estándar de daño moral y sus consecuencias, escaso estudio de daño moral fuera de contextos relacionados con el ejército e investigaciones clínicas limitadas por muestra de tamaño pequeños y mecanismos poco claros del efecto terapéutico. Concluimos nuestra revisión resumiendo las lecciones de la literatura y ofreciendo recomendaciones para futuras investigaciones.

Traditional and Simplified Chinese Abstracts by the Asian Society for Traumatic Stress Studies (AsianSTSS) 簡體及繁體中文撮要由亞洲創傷心理研究學會翻譯 Moral Injury: An Integrative Review Traditional Chinese 標題: 道德創傷:一項綜合評估 撮要: 經歷與自己的道德價值相違的創傷事件, 可導致嚴重悲痛和功能損傷, 此為「道德創傷」。過去十年來, 心理治療人士、信仰團體、媒體和普羅大眾開始關注道德創傷, 而針對道德創傷的研究, 特別是專門檢視現役和退役軍人的研究, 亦大大提升。本文將審視有關道德創傷的科學研究, 找出116份相關的流行病學及臨床研究。流行病學研究描述跟經歷潛在會導致道德創傷的事件相關的生物學、心理/行為、社會、信仰/精神層面廣泛的後遺症。雖然目前只有少量具臨床實證的文獻, 但當中有些探討針對創傷後壓力症(PTSD)的實證為本治療是否能治理道德創傷, 有些則找出新的治療模型以直接治理道德創傷。這些文獻的限制, 包括對潛在會導致道德創傷的事件有不同定義、缺乏對定義的共識、未能得出測量道德創傷的黃金標準、缺乏軍事相關環境以外的道德創傷研究, 而臨床研究的樣本數量小而且療效的機制模糊。最後, 我們總結文獻帶來的貢獻, 並為未來研究提供建議。 Simplified Chinese 标题: 道德创伤:一项综合评估 撮要: 经历与自己的道德价值相违的创伤事件, 可导致严重悲痛和功能损伤, 此为「道德创伤」。过去十年来, 心理治疗人士、信仰团体、媒体和普罗大众开始关注道德创伤, 而针对道德创伤的研究, 特别是专门检视现役和退役军人的研究, 亦大大提升。本文将审视有关道德创伤的科学研究, 找出116份相关的流行病学及临床研究。流行病学研究描述跟经历潜在会导致道德创伤的事件相关的生物学、心理/行为、社会、信仰/精神层面广泛的后遗症。虽然目前只有少量具临床实证的文献, 但当中有些探讨针对创伤后压力症(PTSD)的实证为本治疗是否能治理道德创伤, 有些则找出新的治疗模型以直接治理道德创伤。这些文献的限制, 包括对潜在会导致道德创伤的事件有不同定义、缺乏对定义的共识、未能得出测量道德创伤的黄金标准、缺乏军事相关环境以外的道德创伤研究, 而临床研究的样本数量小而且疗效的机制模糊。最后, 我们总结文献带来的贡献, 并为未来研究提供建议。.

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Traumatic Spinal Cord Injury: An Overview of Pathophysiology, Models and Acute Injury Mechanisms

Traumatic spinal cord injury (SCI) is a life changing neurological condition with substantial socioeconomic implications for patients and their care-givers. Recent advances in medical management of SCI has significantly improved diagnosis, stabilization, survival rate and well-being of SCI patients. However, there has been small progress on treatment options for improving the neurological outcomes of SCI patients. This incremental success mainly reflects the complexity of SCI pathophysiology and the diverse biochemical and physiological changes that occur in the injured spinal cord. Therefore, in the past few decades, considerable efforts have been made by SCI researchers to elucidate the pathophysiology of SCI and unravel the underlying cellular and molecular mechanisms of tissue degeneration and repair in the injured spinal cord. To this end, a number of preclinical animal and injury models have been developed to more closely recapitulate the primary and secondary injury processes of SCI. In this review, we will provide a comprehensive overview of the recent advances in our understanding of the pathophysiology of SCI. We will also discuss the neurological outcomes of human SCI and the available experimental model systems that have been employed to identify SCI mechanisms and develop therapeutic strategies for this condition.

Introduction

Spinal cord injury (SCI) is a debilitating neurological condition with tremendous socioeconomic impact on affected individuals and the health care system. According to the National Spinal Cord Injury Statistical Center, there are 12,500 new cases of SCI each year in North America ( 1 ). Etiologically, more than 90% of SCI cases are traumatic and caused by incidences such as traffic accidents, violence, sports or falls ( 2 ). There is a reported male-to-female ratio of 2:1 for SCI, which happens more frequently in adults compared to children ( 2 ). Demographically, men are mostly affected during their early and late adulthood (3rd and 8th decades of life) ( 2 ), while women are at higher risk during their adolescence (15–19 years) and 7th decade of their lives ( 2 ). The age distribution is bimodal, with a first peak involving young adults and a second peak involving adults over the age of 60 ( 3 ). Adults older than 60 years of age whom suffer SCI have considerably worse outcomes than younger patients, and their injuries usually result from falls and age-related bony changes ( 1 ).

The clinical outcomes of SCI depend on the severity and location of the lesion and may include partial or complete loss of sensory and/or motor function below the level of injury. Lower thoracic lesions can cause paraplegia while lesions at cervical level are associated with quadriplegia ( 4 ). SCI typically affects the cervical level of the spinal cord (50%) with the single most common level affected being C5 ( 1 ). Other injuries include the thoracic level (35%) and lumbar region (11%). With recent advancements in medical procedures and patient care, SCI patients often survive these traumatic injuries and live for decades after the initial injury ( 5 ). Reports on the clinical outcomes of patients who suffered SCI between 1955 and 2006 in Australia demonstrated that survival rates for those suffering from tetraplegia and paraplegia is 91.2 and 95.9%, respectively ( 5 ). The 40-year survival rate of these individuals was 47 and 62% for persons with tetraplegia and paraplegia, respectively ( 5 ). The life expectancy of SCI patients highly depends on the level of injury and preserved functions. For instance, patients with ASIA Impairment Scale (AIS) grade D who require a wheelchair for daily activities have an estimated 75% of a normal life expectancy, while patients who do not require wheelchair and catheterization can have a higher life expectancy up to 90% of a normal individual ( 6 ). Today, the estimated life-time cost of a SCI patient is $2.35 million per patient ( 1 ). Therefore, it is critical to unravel the cellular and molecular mechanisms of SCI and develop new effective treatments for this devastating condition. Over the past decades, a wealth of research has been conducted in preclinical and clinical SCI with the hope to find new therapeutic targets for traumatic SCI.

An Overview of Primary Injury

SCI commonly results from a sudden, traumatic impact on the spine that fractures or dislocates vertebrae. The initial mechanical forces delivered to the spinal cord at the time of injury is known as primary injury where “displaced bone fragments, disc materials, and/or ligaments bruise or tear into the spinal cord tissue” ( 7 – 9 ). Notably, most injuries do not completely sever the spinal cord ( 10 ). Four main characteristic mechanisms of primary injury have been identified that include: (1) Impact plus persistent compression; (2) Impact alone with transient compression; (3) Distraction; (4) Laceration/transection ( 8 , 11 ). The most common form of primary injury is impact plus persistent compression, which typically occurs through burst fractures with bone fragments compressing the spinal cord or through fracture-dislocation injuries ( 8 , 12 , 13 ). Impact alone with transient compression is observed less frequently but most commonly in hyperextension injuries ( 8 ). Distraction injuries occur when two adjacent vertebrae are pulled apart causing the spinal column to stretch and tear in the axial plane ( 8 , 12 ). Lastly, laceration and transection injuries can occur through missile injuries, severe dislocations, or sharp bone fragment dislocations and can vary greatly from minor injuries to complete transection ( 8 ). There are also distinct differences between the outcomes of SCI in military and civilian cases. Compared to civilian SCI, blast injury is the common cause of SCI in battlefield that usually involves multiple segments of the spinal cord ( 14 ). Blast SCI also results in higher severity scores and is associated with longer hospital stays ( 15 ). A study on American military personnel, who sustained SCI in a combat zone from 2001 to 2009, showed increased severity and poorer neurological recovery compared to civilian SCI ( 15 ). Moreover, lower lumbar burst fractures and lumbosacral dissociation happen more frequently in combat injuries ( 1 ). Regardless of the form of primary injury, these forces directly damage ascending and descending pathways in the spinal cord and disrupt blood vessels and cell membranes ( 11 , 16 ) causing spinal shock, systemic hypotension, vasospasm, ischemia, ionic imbalance, and neurotransmitter accumulation ( 17 ). To date, the most effective clinical treatment to limit tissue damage following primary injury is the early surgical decompression (< 24 h post-injury) of the injured spinal cord ( 18 , 19 ). Overall, the extent of the primary injury determines the severity and outcome of SCI ( 20 , 21 ).

An Overview on Clinical Classification Systems for Spinal Cord Injury

Functional classification of SCI has been developed to establish reproducible scoring systems by which the severity of SCI could be measured, compared, and correlated with the clinical outcomes ( 20 ). Generally, SCI can be classified as either complete or incomplete. In complete SCI, neurological assessments show no spared motor or sensory function below the level of injury ( 4 ). In the past decades, several scoring systems have been employed for clinical classification of neurological deficits following SCI. The first classification system, “Frankel Grade,” was developed by Frankel and colleagues in 1969 ( 22 ). They assessed the severity and prognosis of SCI using numerical sensory and motor scales ( 22 ). This was a 5-grade system in which Grade A was the most severe SCI with complete loss of sensory and motor function below the level of injury. Grade B represented complete motor loss with preserved sensory function and sacral sparing. Patients in Grade C and D had different degrees of motor function preservation and Grade E represented normal sensory and motor function. The “Frankel Grade” was widely utilized after its publication due to its ease of use. However, lack of clear distinction between Grades C and D and inaccurate categorization of motor improvements in patients over time, led to its replacement by other scoring systems ( 20 ).

Other classification methods followed Frankel's system. In 1987, Bracken et al. at Yale University School of Medicine classified motor and sensory functions separately in a 5 and 7-scale systems, respectively ( 23 ). However, this scoring system failed to account for sacral function ( 20 ). Moreover, integration of motor and sensory classifications was impossible in this system and it was abandoned due to complexity and impracticality in clinical settings ( 20 ). Several other scoring systems were developed in 1970' and 1980's by different groups such as Lucas and Ducker at the Maryland Institute for Emergency Medical Services in late 1970's ( 24 ), Klose and colleagues at the University of Miami Neuro-spinal Index (UMNI) in early 1980s ( 25 ) and Chehrazi and colleagues (Yale Scale) in 1981 ( 26 ). These scoring systems also became obsolete due to their disadvantage in evaluation of sacral functions, difficulty of use or discrepancies between their motor and sensory scoring sub-systems ( 20 ).

American Spinal Injury Association (ASIA) Scoring System

The ASIA scoring system is currently the most widely accepted and employed clinical scoring system for SCI. ASIA was developed in 1984 by the American Spinal Cord Injury Association and has been updated over time to improve its reliability ( Figure 1 ). In this system, sensory function is scored from 0–2 and motor function from 0 to 5 ( 20 ). The ASIA impairment score (AIS) ranges from complete loss of sensation and movement (AIS = A) to normal neurological function (AIS = E). The first step in ASIA system is to identify the neurological level of injury (NLI). In this assessment, except upper cervical vertebrae that closely overlay the underlying spinal cord segments, the anatomical relationship between the spinal cord segments and their corresponding vertebra is not reciprocally aligned along the adult spinal cord ( 20 ). At thoracic and lumbar levels, each vertebra overlays a spinal cord segment one or two levels below and as the result, a T11 vertebral burst fracture results in neurological deficit at and below L1 spinal cord segment. Hence, the neurological level of injury (NLI) is defined as “the most caudal neurological level at which all sensory and motor functions are normal” ( 20 ). Upon identifying the NLI, if the injury is complete (AIS = A), “zone of partial preservation” (ZPP) is determined ( 20 ). ZPP is defined as all the segments below the NLI that have some preserved sensory or motor function. A precise record of ZPP enables the examiners to distinguish spontaneous from treatment-induced functional recovery, thus, essential for evaluating the therapeutic efficacy of treatments ( 20 ). Complete loss of motor and preservation of some sensory functions below the neurological level of the injury is categorized as AIS B ( 20 ). If motor function is also partially spared below the level of the injury, AIS score can be C or D ( 20 ). The AIS is scored D when the majority of the muscle groups below the level of the injury exhibit strength level of 3 or higher (for more details see Figure 1 ). ASIA classification combines the assessments of motor, sensory and sacral functions, thus addressing the shortcomings of previous scoring systems ( 20 ). The validity and reproducibility of ASIA system combined with its accuracy in prediction of patients' outcome have made it the most accepted and reliable clinical scoring system utilized for neurological classification of SCI ( 20 ).

ASIA scoring for the neurological classification of the SCI. A sample scoring sheet used for ASIA scoring in clinical setting is provided (adopted from: http://asia-spinalinjury.org ).

Neurological Outcomes of Spinal Cord Injury

In clinical management of SCI, neurological outcomes are generally determined at 72 h after injury using ASIA scoring system ( 20 , 27 ). This time-point has shown to provide a more precise assessment of neurological impairments after SCI ( 28 ). One important predictor of functional recovery is to determine whether the injury was incomplete or complete. As time passes, SCI patients experience some spontaneous recovery of motor and sensory functions. Most of the functional recovery occurs during the first 3 months and in most cases reaches a plateau by 9 months after injury ( 20 ). However, additional recovery may occur up to 12–18 months post-injury ( 20 ). Long term outcomes of SCI are closely related to the level of the injury, the severity of the primary injury and progression of secondary injury, which will be discussed in this review.

Depending on the level of SCI, patients experience paraplegia or tetraplegia. Paraplegia is defined as the impairment of sensory or motor function in lower extremities ( 27 , 28 ). Patients with incomplete paraplegia generally have a good prognosis in regaining locomotor ability (~76% of patients) within a year ( 27 ). Complete paraplegic patients, however, experience limited recovery of lower limb function if their NLI is above T9 ( 29 ). An NLI below T9 is associated with 38% chance of regaining some lower extremity function ( 29 ). In patients with complete paraplegia, the chance of recovery to an incomplete status is only 4% with only half of these patients regaining bladder and bowel control ( 29 ). Tetraplegia is defined as partial or total loss of sensory or motor function in all four limbs. Patients with incomplete tetraplegia will gain better recovery than complete tetra- and paraplegia ( 30 ). Unlike complete SCI, recovery from incomplete tetraplegia usually happens at multiple levels below the NLI ( 20 ). Patients generally reach a plateau of recovery within 9–12 months after injury ( 20 ). Regaining some motor function within the first month after the injury is associated with a better neurological outcome ( 20 ). Moreover, appearance of muscle flicker (a series of local involuntary muscle contractions) in the lower extremities is highly associated with recovery of function ( 31 ). Patients with complete tetraplegia, often (66–90%) regain function at one level below the injury ( 28 , 30 ). Importantly, initial muscle strength is an important predictor of functional recovery in these patients ( 20 ). Complete tetraplegic patients with cervical SCI can regain antigravity muscle function in 27% of the cases when their initial muscle strength is 0 on a 5-point scale ( 32 ). However, the rate of regaining antigravity muscle strength at one caudal level below the injury increases to 97% when the patients have initial muscle strength of 1–2 on a 5-point scale ( 33 ).

An association between sensory and motor recovery has been demonstrated in SCI where spontaneous sensory recovery usually follows the pattern of motor recovery ( 20 , 34 ). Maintenance of pinprick sensation at the zone of partial preservation or in sacral segments has been shown as a reliable predictor of motor recovery ( 35 ). One proposed reason for this association is that pinprick fibers in lateral spinothalamic tract travel in proximity of motor fibers in the lateral corticospinal tract, and thus, preservation of sensory fibers can be an indicator of the integrity of motor fiber ( 20 ). Diagnosis of an incomplete injury is of great importance and failure to detect sensory preservation at sacral segments results in an inaccurate assessment of prognosis ( 20 ).

Experimental Models of Spinal Cord Injury

An overview of available animal models.

In the past few decades, various animal models have been developed to allow understanding the complex biomedical mechanisms of SCI and to develop therapeutic strategies for this condition. An ideal animal model should have several characteristics including its relevance to the pathophysiology of human SCI, reproducibility, availability, and its potential to generate various severities of injury ( 36 ).

Small rodents are the most frequently employed animals in SCI studies due to their availability, ease of use and cost-effectiveness compared to primates and larger non-primate models of SCI ( 36 , 37 ). Among rodents, rats more closely mimic pathophysiological, electrophysiological, functional, and morphological features of non-primate and human SCI ( 38 ). In rat ( 39 ), cat ( 40 ), monkey ( 41 ), and human SCI ( 17 ), a cystic cavity forms in the center of the spinal cord, which is a surrounded by a rim of anatomically preserved white matter. A study by Metz and colleagues compared the functional and anatomical outcomes of rat contusive injuries and human chronic SCI ( 42 ). High resolution MRI assessments identified that SCI-induced neuroanatomical changes such as spinal cord atrophy and size of the lesion were significantly correlated with the electrophysiological and functional outcomes in both rat and human contusive injuries ( 42 ). Histological assessments in rats also showed a close correlation between the spared white matter and functional preservation following injury ( 42 ). These studies provide evidence that rat models of contusive SCI could serve as an adequate model to develop and evaluate the structural and functional benefits of therapeutic strategies for SCI ( 42 ).

Mice show different histopathology than human SCI in which the lesion site is filled with dense fibrous connective-like tissue ( 43 – 46 ). Mouse SCI studies show the presence of fibroblast-like cells expressing fibronectin, collagen, CD11b, CD34, CD13, and CD45 within the lesion core of chronic SCI, while it is absent in the injured spinal cord of rats ( 47 ). Another key difference between rat and mice SCI is the time-point of inflammatory cell infiltration. While microglia/macrophage infiltration is relatively consistent between rat and mouse models of SCI ( 47 ), there is a temporal difference in infiltration of neutrophils and T cells between the two species ( 47 , 48 ). In SCI rats, infiltration of neutrophils, the first responders, peaks at 6 h post injury, followed by a significant decline at 24–48 h after SCI ( 48 ). Similarly, in mouse SCI, neutrophil infiltration occurs within 6 h following injury; however, their numbers continue to rise and do not peak until 3–14 days post injury ( 49 ). T cell infiltration also varies between rat and mouse SCI models ( 50 ). In rats, T cell infiltration occurs between 3 and 7 days post injury and declines by 50% in the following 2 weeks ( 47 ), whereas in mice, T cell infiltration is not detected until 14 days post injury and their number doubles between 2 and 6 weeks post injury ( 47 ). Regardless of their pathophysiological relevance, mice have been used extensively in SCI studies primarily due to the availability of transgenic and mutant mouse models that have allowed uncovering molecular and cellular mechanisms of SCI ( 38 ).

In recent years, there has been emerging interest in employment of non-human primates and other larger animals such as pig, dog and cat as intermediate pre-clinical models ( 51 – 53 ) to allow more effective translation of promising treatments from rodent models to human clinical trials ( 50 ). Although rodents have served as invaluable models for studying SCI mechanisms and therapeutic development, larger mammals, in particular non-human primates, share a closer size, neuroanatomy, and physiology to humans. Importantly, their larger size provides a more relevant platform for drug development, bioengineering inventions, and electrophysiological and rehabilitation studies. Nonetheless, both small and large animal models of SCI have limitations in their ability to predict the outcome in human SCI. One important factor is high degree of variability in the nature of SCI incidence, severity and location of the injury in human SCI, while in laboratory animal models, these variabilities are less ( 36 ). Values acquired by clinical scoring systems such as ASIA or Frankel scoring systems lack the consistency of the data acquired from laboratory settings, which makes the translation of therapeutic interventions from experimental to clinical settings challenging ( 36 ). A significant effect from an experimental treatment in consistent laboratory settings may not be reproducible in clinical settings due to high variability and heterogeneity in human populations and their injuries ( 36 ). To date, several pharmacological and cellular preclinical discoveries have led to human clinical trials based on their efficacy in improving the outcomes of SCI in small animal models. However, the majority of these trials failed to reproduce the same efficacy in human SCI. Thus, in pre-clinical studies, animal models, and study designs should be carefully chosen to reflect the reality of clinical setting as closely as possible ( 36 ). Larger animals provide the opportunity to refine promising therapeutic strategies prior to testing in human SCI; however, their higher cost, need for specialized facilities and small subject (sample) size have limited their use in SCI research ( 50 ). Thus, rodents are currently the most commonly employed models for preclinical discoveries and therapeutic development, while the use of larger animals is normally pursued for late stage therapies that have shown efficacy and promise in small animal models. Table 1 provides a summary of available SCI models.

Summary of SCI models.

An Overview of Experimental Models of Spinal Cord Injury

Animal models are also classified based on the type of SCI. The following sections will provide an overview on the available SCI models that are developed based on injury mechanisms, their specifications and relevance to human SCI ( Table 1 ).

Transection Models

A complete transection model of SCI is relatively easy to reproduce ( 51 ). However, this model is less relevant to human SCI as a complete transection of the spinal cord rarely happens ( 51 ). While they do not represent clinical reality of SCI, transection models are specifically suitable for studying axonal regeneration or developing biomaterial scaffolds to bridge the gap between proximal and distal stamps of the severed spinal cord ( 51 ). Due to complete disconnection from higher motor centers, this model is also suitable for studying the role of propriospinal motor and sensory circuits in recovery of locomotion following SCI ( 51 , 80 ). Partial transection models including hemi-section, unilateral transection and dorsal column lesions are other variants of transection models ( 51 ). Partial transection models are valuable for investigation of nerve grafting, plasticity and where a comparison between injured and non-injured pathways is needed in the same animal ( 51 ). However, these models lead to a less severe injury and higher magnitude of spontaneous recovery rendering them less suitable for development and evaluation of new therapies ( 51 ).

Contusive Models

Contusion is caused by a transient physical impact to the spinal cord and is clinically-relevant. There are currently three types of devices that can produce contusion injury in animal models: weight-drop apparatus, electromagnetic impactor, and a recently introduced air gun device ( 51 ). The impactor model was first introduced by Gruner at New York University (NYU) in 1992 ( 81 ). The original NYU impactor included a metal rod of specific weight (10 g) that could be dropped on the exposed spinal cord from a specific height to induce SCI ( 51 ). This model allowed induction of a defined severity of SCI by adjusting the height, which the rod fell on the spinal cord ( 81 ). Parameters such as time, velocity at impact and biomechanical response of the tissue can be recorded for analysis and verification ( 51 ). The NYU impactor was later renamed to Multicenter Animal Spinal Cord Injury Study (MASCIS) impactor, and conditions surrounding the study and use of the MASCIS impactor were standardized ( 51 ). Since its introduction, the MASCIS impactor has been updated twice. The most recent version, MACIS III, was introduced in 2012 and included both electromagnetic control and digital recording of the impact parameters ( 51 ). However, inability to control duration of impact and “weight bounce,” that could cause multiple impacts, have been known limitations of MASCIS impactors ( 51 ).

The Infinite Horizon (IH) impactor is another type of impactor that utilizes a stepping motor to generate force-controlled impact in contrast to free fall in the MASICS impactor ( 51 ). This feature allows for better control over the force of impact and prevents “weight bounce” as the computer-controlled metal impounder can be immediately retracted upon transmitting a desired force to the spinal cord ( 51 ). IH impactor can be set to different force levels to provide mild, moderate and severe SCI in rats (ex. 100, 150, and 200 kdyn) ( 51 ). A limitation with IH impactors is unreliability of their clamps in holding the spinal column firmly during the impact that can cause inconsistent parenchymal injury and neurological deficits ( 51 ).

Ohio State University (OSU) impactor is a computer controlled electromagnetic impactor that was originally invented in 1987 and refined in 1992 to improve reliability ( 58 ). As the OSU impactor is electromagnetically controlled, multiple strikes are avoided ( 51 ). Subsequently, a modified version of the OSU impactor was developed in 2000 for use in mice ( 43 ). However, the OSU impactor is limited by its inability to determine the precise initial contact point with the spinal cord due to displacement of CSF upon loading the device ( 51 ). To date, MASCIS, IH and OSU impactor devices have been employed extensively and successfully to induce SCI. These impactor devices are available for small and large animals such as mice, rats, marmosets, cats, and pigs ( 51 , 82 ).

Compressive Models

Compressive models of SCI have been also employed for several decades ( 61 ). While contusion injury is achieved by applying a force for a very brief period (milliseconds), the compression injury consists of an initial contusion for milliseconds followed by a prolonged compression through force application for a longer duration (seconds to minutes) ( 51 ). Thus, compression injury can be categorized as contusive-compressive models ( 51 ). Various models of compressive SCI are available.

Clip compression is the most commonly used compression model of SCI in rat and mice ( 51 , 61 , 62 , 83 ). It was first introduced by Rivlin and Tator in 1978 ( 61 ). In this model, following laminectomy, a modified aneurism clip with a calibrated closing force is applied to the spinal cord for a specific duration of time (usually 1 min) to induce a contusive-compressive injury ( 51 ). The severity of injury can be calibrated and modified by adjusting the force of the clip and the duration of compression ( 51 ). For example, applying a 50 g clip for 1 min typically produces a severe SCI, while a 35 g clip creates a moderate to severe injury with the same duration ( 83 ). Aneurysm clips were originally designed for use in rat SCI, however, in recent years smaller and larger clips have been developed to accommodate its use in mice ( 62 ) and pig models ( 52 ). The clip compression model has several advantages compared to contusion models. This method is less expensive and easier to perform ( 51 ). Importantly, in contrast to the impactor injury that contusion is only applied dorsally to the spinal cord, the clip compression model provides contusion and compression simultaneously both dorsally and ventrally. Hence, clip compression model more closely mimics the most common form of human SCI, which is primarily caused by dislocation and burst compression fractures ( 83 ). Despite its advantages, clip compression model can create variabilities such as the velocity of closing and actual delivered force that cannot be measured precisely at the time of application ( 51 ).

Calibrated forceps compression has been also employed to induce SCI in rodents. This simple and inexpensive compressive model was first utilized in 1991 for induction of SCI in guinea pigs ( 64 ). In this method, a calibrated forceps with a spacer is used to compress the spinal cord bilaterally ( 51 ). This model lacks the initial impact and contusive injury, which is associated with most cases of human traumatic SCI. Accordingly, this model is not a clinically relevant model for reproducing human SCI pathology and therapeutic development ( 51 ).

Balloon Compression model has been also utilized extensively in primates and larger animals such as dogs and cats ( 84 – 86 ). In this model, a catheter with an inflatable balloon is inserted in the epidural or subdural space. The inflation of the balloon with air or saline for a specific duration of time provides the force for induction of SCI ( 51 ). Generally, all compression models (clip, forceps, and balloon) have the same limitation as the velocity and amount of force are unmeasurable ( 51 ).

In conclusion, while existing animal models do not recapitulate all clinical aspects of human SCI, the compression and contusion models are considered to be the most relevant and commonly employed methods for understanding the secondary injury mechanisms and therapeutic development for SCI.

Overview of Secondary Mechanisms of Spinal Cord Injury

Secondary injury begins within minutes following the initial primary injury and continues for weeks or months causing progressive damage of spinal cord tissue surrounding the lesion site ( 7 ). The concept of secondary SCI was first introduced by Allen in 1911 ( 87 ). While studying SCI in dogs, he observed that removal of the post traumatic hematomyelia improved neurological outcome. He hypothesized that presence of some “biochemical factors” in the necrotic hemorrhagic lesion causes further damage to the spinal cord ( 87 ). The term of secondary injury is still being used in the field and is referred to a series of cellular, molecular and biochemical phenomena that continue to self-destruct spinal cord tissue and impede neurological recovery following SCI ( Figure 2 ) ( 20 ).

Summary of secondary injury processes following traumatic spinal cord injury. Diagram shows the key pathophysiological events that occur after primary injury and lead to progressive tissue degeneration. Vascular disruption and ischemia occur immediately after primary injury that initiate glial activation, neuroinflammation, and oxidative stress. These acute changes results in cell death, axonal injury, matrix remodeling, and formation of a glial scar.

Secondary injury can be temporally divided into acute, sub-acute, and chronic phases. The acute phase begins immediately following SCI and includes vascular damage, ionic imbalance, neurotransmitter accumulation (excitotoxicity), free radical formation, calcium influx, lipid peroxidation, inflammation, edema, and necrotic cell death ( 7 , 20 , 88 ). As the injury progresses, the sub-acute phase of injury begins which involves apoptosis, demyelination of surviving axons, Wallerian degeneration, axonal dieback, matrix remodeling, and evolution of a glial scar around the injury site ( Figure 3 ). Further changes occur in the chronic phase of injury including the formation of a cystic cavity, progressive axonal die-back, and maturation of the glial scar ( 7 , 89 – 92 ). Here, we will review the key components of acute secondary injury that contribute to the pathophysiology of SCI ( Figures 2 , ​ ,3 3 ).

Pathophysiology of traumatic spinal cord injury. This schematic diagram illustrates the composition of normal and injured spinal cord. Of note, while these events are shown in one figure, some of the pathophysiological events may not temporally overlap and can occur at various phases of SCI, which are described here. Immediately after primary injury, activation of resident astrocytes and microglia and subsequent infiltration of blood-borne immune cells results in a robust neuroinflammatory response. This acute neuroinflammatory response plays a key role in orchestrating the secondary injury mechanisms in the sub-acute and chronic phases that lead to cell death and tissue degeneration, as well as formation of the glial scar, axonal degeneration and demyelination. During the acute phase, monocyte-derived macrophages occupy the epicenter of the injury to scavenge tissue debris. T and B lymphocytes also infiltrate the spinal cord during sub-acute phase and produce pro-inflammatory cytokines, chemokines, autoantibodies reactive oxygen and nitrogen species that contribute to tissue degeneration. On the other hand, M2-like macrophages and regulatory T and B cells produce growth factors and pro-regenerative cytokines such as IL-10 that foster tissue repair and wound healing. Loss of oligodendrocytes in acute and sub-acute stages of SCI leads to axonal demyelination followed by spontaneous remyelination in sub-acute and chronic phases. During the acute and sub-acute phases of SCI; astrocytes, OPCs and pericytes, which normally reside in the spinal cord parenchyma, proliferate and migrate to the site of injury and contribute to the formation of the glial scar. The glial scar and its associated matrix surround the injury epicenter and create a cellular and biochemical zone with both beneficial and detrimental roles in the repair process. Acutely, the astrocytic glial scar limits the spread of neuroinflammation from the lesion site to the healthy tissue. However, establishment of a mature longstanding glial scar and upregulation of matrix chondroitin sulfate proteoglycans (CSPGs) are shown to inhibit axonal regeneration/sprouting and cell differentiation in subacute and chronic phases.

Vascular Injury, Ischemia and Hypoxia

Disruption of spinal cord vascular supply and hypo-perfusion is one of the early consequences of primary injury ( 93 ). Hypovolemia and hemodynamic shock in SCI patients due to excessive bleeding and neurogenic shock result in compromised spinal cord perfusion and ischemia ( 93 ). Larger vessels such as anterior spinal artery usually remain intact ( 94 , 95 ), while rupture of smaller intramedullary vessels and capillaries that are susceptible to traumatic damage leads to extravasation of leukocytes and red blood cells ( 93 ). Increased tissue pressure in edematous injured spinal cord and hemorrhage-induced vasospasm in intact vessels further disrupts blood flow to the spinal cord ( 93 , 95 ). In rat and monkey models of SCI, there is a progressive reduction in blood flow at the lesion epicenter within the first few hours after injury which remains low for up to 24 h ( 96 ). The gray matter is more prone to ischemic damage compared to the white matter as it has a 5-fold higher density of capillary beds and contains neurons with high metabolic demand ( 95 , 97 , 98 ). After injury, white matter blood flow typically returns to normal levels within 15 min post injury, whereas there are multiple hemorrhages in the gray matter and as a result, re-perfusion usually does not occur for the first 24 h ( 9 , 99 , 100 ). Vascular insult, hemorrhage and ischemia ultimately lead to cell death and tissue destruction through multiple mechanisms, including oxygen deprivation, loss of adenosine triphosphate (ATP), excitotoxicity, ionic imbalance, free radical formation, and necrotic cell death. Cellular necrosis and release of cytoplasmic content increase the extracellular level of glutamate causing glutamate excitotoxicity ( 93 , 101 ). Moreover, re-establishment of blood flow in ischemic tissue leads to further damage through generating free radicals and eliciting an inflammatory response ( 93 , 102 ) that will be discussed in this review.

Ionic Imbalance, Excitotoxicity and Oxidative Damage

Within few minutes after primary SCI, the combination of direct cellular damage and ischemia/hypoxia triggers a significant rise of extracellular glutamate, the main excitatory neurotransmitter in the CNS ( 7 ). Glutamate binds to ionotropic (NMDA, AMPA, and Kainate receptors) as well as metabotropic receptors resulting in calcium influx inside the cells ( 103 – 105 ) ( 93 ). The effect of glutamate is not restricted to neurons as its receptors are vastly expressed on the surface of all glia and endothelial cells ( 103 – 106 ). Astrocytes can also release excess glutamate extracellularly upon elevation of their intracellular Ca 2+ levels. Reduced ability of activated astrocytes for glutamate re-uptake from the interstitial space due to lipid peroxidation results in further accumulation of glutamate in the SCI milieu ( 93 ). Using microdialysis, elevated levels of glutamate have been detected in the white matter in the acute stage of injury ( 107 ). Based on a study by Panter and colleagues, glutamate increase is detected during the first 20–30 min post SCI and returns to the basal levels after 60 min ( 108 ).

Under normal condition, concentration of free Ca 2+ can considerably vary in different parts of the cell ( 109 ). In the cytosol, Ca 2+ ranges from 50–100 nM while it approaches 0.5–1.0 mM in the lumen of endoplasmic reticulum ( 110 – 112 ). A long-lasting abnormal increase in Ca 2+ concentration in cytosol, mitochondria or endoplasmic reticulum has detrimental consequences for the cell ( 109 – 113 ). Mitochondria play a central role in calcium dependent neuronal death ( 113 ). In neurons, during glutamate induced excitotoxicity, NMDA receptor over-activity leads to mitochondrial calcium overload, which can cause apoptotic or necrotic cell death ( 113 ). Shortly after SCI, Ca 2+ enters mitochondria through the mitochondrial calcium uniporter (MCU) ( 114 ). While the amount of mitochondrial calcium is limited during the resting state of a neuron, they can store a high amount of Ca 2+ following stimulation ( 113 ). Calcium overload also activates a host of protein kinases and phospholipases that results in calpain mediated protein degradation and oxidative damage due to mitochondrial failure ( 93 ). In the injured white matter, astrocytes, oligodendrocytes and myelin are also damaged by the increased release of glutamate and Ca 2+ -dependent excitotoxicity ( 115 ). Within the first few hours after injury, oligodendrocytes show signs of caspase-3 activation and other apoptotic features, and their density declines ( 116 ). Interestingly, while glutamate excitotoxicity is triggered by ionic imbalance in the white matter, in the gray matter, it is largely associated with the activity of neuronal NMDA receptors ( 117 , 118 ). Altogether, activation of NMDA receptors and consequent Ca 2+ overload appears to induce intrinsic apoptotic pathways in neurons and oligodendrocytes and causes cell death in the first week of SCI in the rat ( 119 , 120 ). Administration of NMDA receptor antagonist (MK-801) shortly following SCI has been associated with improved functional recovery and reduced edema ( 121 ).

Mitochondrial calcium overload also impedes mitochondrial respiration and results in ATP depletion disabling Na + /K + ATPase and increasing intracellular Na + ( 119 , 122 – 124 ). This reverses the function of the Na + dependent glutamate transporter that normally utilizes Na + gradient to transfer glutamate into the cells ( 119 , 125 , 126 ). Moreover, the excess intracellular Na + reverses the activity of Na + /Ca 2+ exchanger allowing more Ca + influx ( 127 ). Cellular depolarization activates voltage gated Na + channels that results in entry of Cl − and water into the cells along with Na + causing swelling and edema ( 128 ). Increased Na + concentration over-activates Na + /H + exchanger causing a rise in intracellular H + ( 101 , 129 ). Resultant intracellular acidosis increases membrane permeability to Ca 2+ that exacerbates the injury-induced ionic imbalance ( 101 , 129 ). Axons are more susceptible to the damage caused by ionic imbalance due to their high concentration of voltage gated Na + channels in the nodes of Ranvier ( 7 ). Accumulating evidence shows that administration of Na + channel blockers such as Riluzole attenuates tissue damage and improves functional recovery in SCI underlining sodium as a key player in secondary injury mechanisms ( 130 – 133 ).

SCI results in production of free radicals and nitric oxide (NO) ( 114 ). Mitochondrial Ca 2+ overload activates NADPH oxidase (NOX) and induces generation of superoxide by electron transport chain (ETC) ( 114 ). Reactive oxygen and nitrogen species (ROS and RNS) produced by the activity of NOX and ETC activates cytosolic poly (ADP ribose) polymerase (PARP). PARP consumes and depletes NAD + causing failure of glycolysis, ATP depletion and cell death ( 114 ). Moreover, PAR polymers produced by PARP activity, induce the release of apoptosis inducing factor (AIF) from mitochondria and induce cell death ( 114 ). On the other hand, acidosis caused by SCI results in the release of intracellular iron from ferritin and transferrin ( 93 ). Spontaneous oxidation of Fe 2+ to Fe 3+ gives rise to more superoxide radicals ( 93 ). Subsequently, the Fenton reaction between Fe 3+ and hydrogen peroxide produces highly reactive hydroxyl radicals ( 134 ). The resultant ROS and RNS react with numerous targets including lipids in the cell membrane with the most deleterious effects ( 93 , 135 ). Because free radicals are short-lived and difficult to assess, measurements of their activity and final products, such as Malondialdehyde (MDA), are more reliable following SCI. Current evidence indicates that MDA levels are elevated as early as 1 h and up to 1 week after SCI ( 136 , 137 ).

Oxidation of lipids and proteins is one of the key mechanisms of secondary injury following SCI ( 93 ). Lipid peroxidation starts when ROSs interact with polyunsaturated fatty acids in the cell membrane and generate reactive lipids that will then form lipid peroxyl radicals upon interacting with free superoxide radicals ( 138 , 139 ). Each lipid peroxyl radical can react with a neighboring fatty acid, turn it into an active lipid and start a chain reaction that continues until no more unsaturated lipids are available or terminates when the reactive lipid quenches with another radical ( 93 ). The final products of this “termination” step of the lipid peroxidation is 4-hydroxynonenal (HNE) and 2-propenal, which are highly toxic to the cells ( 138 – 140 ). Lipid peroxidation is also an underlying cause of ionic imbalance through destabilizing cellular membranes such as cytoplasmic membrane and endoplasmic reticulum ( 93 ). Moreover, lipid peroxidation leads to Na + /K + ATPase dysfunction that exacerbates the intracellular Na + overload ( 141 ). In addition to ROS associated lipid peroxidation, amino acids are subject to significant RNS associated oxidative damage following SCI ( 93 ). RNSs (containing ONOO − ) can nitrate the tyrosine residues of amino acids to form 3-nitrotyrosine (3-NT), a marker for peroxynitrite (ONOO − ) mediated protein damage ( 139 ). Lipid and protein oxidation following SCI has a number of detrimental consequences at cellular level including mitochondrial respiratory and metabolic failure as well as DNA alteration that ultimately lead to cell death ( 141 ).

Cell Death in Spinal Cord Injury

Cell death is a major event in the secondary injury mechanisms that affects neurons and glia after SCI ( 142 – 145 ). Cell death can happen through various mechanisms in response to various injury-induced mediators. Necrosis and apoptosis were originally identified as two major cell death mechanisms following SCI ( 146 – 148 ). However, recent research has uncovered additional forms of cell death. In 2012, the “Nomenclature Committee on Cell Death” (NCCD) NCCD defined 12 different forms of cell death such as necroptosis, pyroptosis, and netosis ( 149 ). Among the identified modes of cell death, to date, necrosis, necroptosis, apoptosis, and autophagy have been studied more extensively in the context of SCI and will be discussed in this review.

Following SCI, neurons and glial cells die through necrosis as the result of mechanical damage at the time of primary injury that also continues to the acute and subacute stages of injury ( 7 , 150 ). Necrosis occurs due to a multitude of factors including accumulation of toxic blood components ( 151 ), glutamate excitotoxicity and ionic imbalance ( 152 ), ATP depletion ( 153 ), pro-inflammatory cytokine release by neutrophils and lymphocytes ( 154 , 155 ), and free radical formation ( 142 , 156 – 158 ). It was originally thought that necrosis is caused by a severe impact on a cell that results in rapid cell swelling and lysis. However, follow up evidence showed that in the case of seizure, ischemia and hypoglycemia, necrotic neurons show signs of shrunken, pyknotic, and condensed nuclei, with swollen, irreversibly damaged mitochondria and plasma membrane that are surrounded by astrocytic processes ( 159 ). Moreover, necrosis was conventionally viewed as instantaneous energy-independent non-programmed cell death ( 142 , 156 ). However, recent research has identified another form of necrosis, termed as necroptosis, that is executed by regulated mechanisms.

Programmed necrosis or “necroptosis” has been described more recently as a highly regulated, caspase-independent cell death with similar morphological characteristics as necrosis ( 160 ). Necroptosis is a receptor-mediated process. It is induced downstream of the TNF receptor 1 (TNFR1) and is dependent on the activity of the receptor interacting protein kinase 1 (RIPK1) and RIPK3. Recent studies has uncovered a key role for RIPK1 as the mediator of necroptosis and a regulator of the innate immune response involved in both inflammation and cell death ( 161 ). Evidence from SCI studies show that lysosomal damage can potentiate necroptosis by promoting RIPK1 and RIPK3 accumulation ( 161 ). Interestingly, inhibition of necroptosis by necrostatin-1, a RIPK1 inhibitor, improves functional outcomes after SCI ( 150 ). These initial findings suggest that modulation of necroptosis pathways seems to be a promising target for neuroprotective strategies after SCI.

Apoptosis is the most studied mechanism of cell death after SCI. Apoptosis represents a programmed, energy dependent mode of cell death that begins within hours of primary injury ( 7 ). This process takes place in cells that survive the primary injury but endure enough insult to activate their apoptotic pathways ( 142 ). In apoptosis, the cell shrinks and is eventually phagocytosed without induction of an inflammatory response ( 156 ). Apoptosis typically occurs in a delayed manner in areas more distant to the injury site and most abundantly affects oligodendrocytes. In rat SCI, apoptosis happens as early as 4 h after the injury and reaches a peak at 7 day ( 156 ). At the site of injury majority of oligodendrocytes are lost within 7 days after SCI ( 162 ). However, apoptosis can be observed at a diminished rate for weeks after SCI ( 162 , 163 ). Microglia and astrocytes also undergo apoptosis ( 156 , 164 ). Interestingly, apoptotic cell death occurs in the chronically injured spinal cord in rat, monkey and human models of SCI, which is thought to be due to loss of trophic support from degenerating axons ( 146 , 165 ).

Apoptosis is induced through extrinsic and intrinsic pathways based on the triggering mechanism ( 166 ). The extrinsic pathway is triggered by activation of death receptors such as FAS and TNFR1, which eventually activates caspase 8 ( 167 ). The intrinsic pathway, however, is regulated through a balance between intracellular pro- and anti-apoptotic proteins and is triggered by the release of cytochrome C from mitochondria and activating caspase 9 ( 167 ). In SCI lesion, apoptosis primarily happens due to injury induced Ca 2+ influx, which activates caspases and calpain; enzymes involved in breakdown of cellular proteins ( 7 ). Moreover, it is believed that the death of neurons and oligodendrocytes in remote areas from the lesion epicenter can be mediated through cytokines such as TNF-α, free radical damage and excitotoxicity since calcium from damaged cells within the lesion barely reaches these remote areas ( 8 , 168 ). Fas mediated cell death has been suggested as a key mechanism of apoptosis following SCI ( 144 , 169 – 172 ). Post-mortem studies on acute and chronic human SCI and animal models revealed that Fas mediated apoptosis plays a role in oligodendrocyte apoptosis and inflammatory response at acute and subacute stages of SCI ( 173 ). Fas deficient mice exhibit a significant reduction in apoptosis and inflammatory response evidenced by reduced macrophage infiltration and inflammatory cytokine expression following SCI ( 173 ). Interestingly, Fas deficient mice show a significantly improved functional recovery after SCI ( 173 ) suggesting the promise of anti-apoptotic strategies for SCI.

SCI also results in a dysregulated autophagy ( 174 ). Normally, autophagy plays an important role in maintaining the homeostasis of cells by aiding in the turnover of proteins and organelles. In autophagy, cells degrade harmful, defective or unnecessary cytoplasmic proteins and organelles through a lysosomal dependent mechanism ( 175 , 176 ). The process of autophagy starts with the formation of an autophagosome around the proteins and organelles that are tagged for autophagy ( 176 ). Next, fusion of the phagosome with a lysosome form an autolysosome that begins a recycling process ( 176 ). In response to cell injury and endoplasmic reticulum (ER) stress, autophagy is activated and limits cellular loss ( 177 , 178 ). Current evidence suggests a neuroprotective role for autophagy after SCI ( 175 , 179 ). Dysregulation of autophagy contributes to neuronal loss ( 174 , 180 ). Accumulation of autophagosomes in ventral horn motor neurons have been detected acutely following SCI ( 181 ). Neurons with dysregulated autophagy exhibit higher expression of caspase 12 and become more prone to apoptosis ( 174 ). Moreover, blocking autophagy has been associated with neurodegenerative diseases such as Parkinson's and Alzheimer's disease ( 182 – 184 ). Autophagy promotes cell survival through elimination of toxic proteins and damaged mitochondria ( 185 , 186 ). Interestingly, autophagy is crucial in cytoskeletal remodeling and stabilizes neuronal microtubules by degrading SCG10, a protein involved in microtubule disassembly ( 179 ). Pharmacological induction of autophagy in a hemi-section model of SCI in mice has been associated with improved neurite outgrowth and axon regeneration, following SCI ( 179 ). Altogether, although further studies are needed, autophagy is currently viewed as a beneficial mechanism in SCI.

Adaptive and Innate Immune Response in Spinal Cord Injury

Neuroinflammation is a key component of the secondary injury mechanisms with local and systemic consequences. Inflammation was originally thought to be detrimental for the outcome of SCI ( 187 ). However, now it is well-recognized that inflammation can be both beneficial and detrimental following SCI, depending on the time point and activation state of immune cells ( 188 ). There are multiple cell types involved in the inflammatory response following injury including neutrophils, resident microglia, and astrocytes, dendritic cells (DCs), blood-born macrophages, B- and T-lymphocytes ( 189 ) ( Figure 4 ). The first phase of inflammation (0–2 days post injury) involves the recruitment of resident microglia and astrocytes and blood-born neutrophils to the injury site ( 190 ). The second phase of inflammation begins approximately 3 days post injury and involves the recruitment of blood-born macrophages, B- and T-lymphocytes to the injury site ( 189 , 191 – 193 ). T lymphocytes become activated in response to antigen presentation by macrophages, microglia and other antigen presenting cells (APCs) ( 194 ). CD4 + helper T cells produce cytokines that stimulate B cell antibody production and activate phagocytes ( 195 ) ( Figure 4 ). In SCI, B cells produce autoantibodies against injured spinal cord tissue, which exacerbate neuroinflammation and cause tissue destruction ( 196 ). While inflammation is more pronounced in the acute phase of injury, it continues in subacute and chronic phase and may persist for the remainder of a patients' life ( 193 ). Interestingly, composition and phenotype of inflammatory cells change based on the injury phase and the signals present in the injury microenvironment. It is established that microglia/macrophages, T cells, B cells are capable of adopting a pro-inflammatory or an anti-inflammatory pro-regenerative phenotype in the injured spinal cord ( 191 , 197 – 199 ). The role of each immune cell population in the pathophysiology of SCI will be discussed in detail in upcoming sections.

Immune response in spinal cord injury. Under normal circumstances, there is a balance between pro-inflammatory effects of CD4 + effector T cells (T eff ) and anti-inflammatory effects of regulatory T and B cells (T reg and B reg ). T reg and B reg suppress the activation of antigen specific CD4 + T eff cells through production of IL-10 and TGF-β. Injury disrupts this balance and promote a pro-inflammatory environment. Activated microglia/macrophages release pro-inflammatory cytokines and chemokines and present antigens to CD4 + T cells causing activation of antigen specific effector T cells. T eff cells stimulate antigen specific B cells to undergo clonal expansion and produce autoantibodies against spinal cord tissue antigens. These autoantibodies cause neurodegeneration through FcR mediated phagocytosis or complement mediated cytotoxicity. M1 macrophages/microglia release pro-inflammatory cytokines and reactive oxygen species (ROS) that are detrimental to neurons and oligodendrocytes. B reg cells possess the ability to promote T reg development and restrict T eff cell differentiation. B reg cells could also induce apoptosis in T eff cells through Fas mediate mechanisms.

Astrocytes are not considered an immune cell per se ; however, they play pivotal roles in the neuroinflammatory processes in CNS injury and disease. Their histo-anatomical localization in the CNS has placed them in a strategic position for participating in physiological and pathophysiological processes in the CNS ( 200 ). In normal CNS, astrocytes play major roles in maintaining CNS homeostasis. They contribute to the structure and function of blood-brain-barrier (BBB), provide nutrients and growth factors to neurons ( 200 ), and remove excess fluid, ions, and neurotransmitters such as glutamate from synaptic spaces and extracellular microenvironment ( 200 ). Astrocytes also play key roles in the pathologic CNS by regulating BBB permeability and reconstruction as well as immune cell activity and trafficking ( 201 ). Astrocytes contribute to both innate and adaptive immune responses following SCI by differential activation of their intracellular signaling pathways in response to environmental signals ( 201 ).

Astrocytes react acutely to CNS injury by increasing cytokine and chemokine production ( 202 ). They mediate chemokine production and recruitment of neutrophils through an IL-1R1-Myd88 pathway ( 202 ). Activation of the nuclear factor kappa b (NF-κB) pathway, one of the key downstream targets of interleukin (IL)1R-Myd88 axis, increases expression of intracellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM), which are necessary for adhesion and extravasation of leukocytes in inflammatory conditions such as SCI ( 201 , 202 ). Within minutes of injury, production of IL-1β is significantly elevated in astrocytes and microglia ( 203 ). Moreover, chemokines such as monocyte chemoattractant protein (MCP)-1, chemokine C-C motif ligand 2 (CCL2), C-X-C motif ligand 1 (CXCL1), and CXCL2 are produced by astrocytes, and enhance the recruitment of neutrophils and pro-inflammatory macrophages following injury ( 201 , 202 ). Astrocytes also promote pro-inflammatory M1-like phenotype in microglia/macrophages in the injured spinal cord through their production of TNF-α, IL-12, and IFN-γ ( 204 – 206 ). Interestingly, astrocytes also produce anti-inflammatory cytokines, such as TGF-β and IL-10, which can promote a pro-regenerative M2-like phenotype in microglia/macrophages ( 201 , 207 , 208 ).

Immunomodulatory role of astrocytes is defined by activity of various signaling pathways through a wide variety of surface receptors ( 200 ). For example, gp130, a member of IL-6 cytokine family, activates SHP2/Ras/Erk signaling cascade in astrocytes and limits neuroinflammation in autoimmune rodent models ( 209 ). TGF-β signaling in astrocytes has been implicated in modulation of neuroinflammation through inhibition of NF-κB activity and nuclear translocation ( 201 , 210 ). STAT3 is another key signaling pathway in astrocytes with beneficial properties in neuroinflammation. Increase in STAT3 phosphorylation enhances astrocytic scar formation and restricts the expansion of inflammatory cells in mouse SCI, which is associated with improved functional recovery ( 211 ). Detrimental signaling pathways in astrocytes are known to be activated by cytokines, sphingolipids and neurotrophins ( 200 ). As an example, IL-17 is a key pro-inflammatory cytokine produced by effector T cells that can bind to IL-17R on the astrocyte surface ( 200 ). Activation of IL-17R results in the activation of NF-κB, which enhances expression of pro-inflammatory mediators, activation of oxidative pathways and exacerbation of neuroinflammation ( 200 , 212 ). This evidence shows the significance of astrocytes in the inflammatory processes following SCI and other neuroinflammatory diseases of the CNS.

Neutrophils

Neutrophils infiltrate the spinal cord from the bloodstream within the first few hours after injury ( 213 ). Their population increases acutely in the injured spinal cord tissue and reaches a peak within 24 h post-injury ( 214 ). The presence of neutrophils is mostly limited to the acute phase of SCI as they are rarely found sub-acutely in the injured spinal cord ( 214 ). The role of neutrophils in SCI pathophysiology is controversial. Evidence shows that neutrophils contribute to phagocytosis and clearance of tissue debris ( 48 ). They release inflammatory cytokines, proteases and free radicals that degrade ECM, activate astrocytes and microglia and initiate neuroinflammation ( 48 ). Although neutrophils have been conventionally associated with tissue damage ( 48 , 215 ), their elimination compromises the healing process and impedes functional recovery ( 216 ).

To elucidate the role of neutrophils in SCI, Stirling and colleagues used a specific antibody to reduce circulating LyG6/Gr1 + neutrophils in a mouse model of thoracic contusive SCI ( 216 ). This approach significantly reduced neutrophil infiltration in the injured spinal cord by 90% at 24 and 48 h after SCI ( 216 ). Surprisingly, neutrophil depletion aggravated the neurological and structural outcomes in the injured animals suggesting a beneficial role for neutrophils in the acute phase of injury ( 216 ). It is shown that simulated neutrophils release IL-1 receptor antagonist that can exert neuroprotective effects following SCI ( 217 ). Moreover, ablation of neutrophils results in altered expression of cytokines and chemokines and downregulation of growth factors such as fibroblast growth factors (FGFs), vascular endothelial growth factors (VEGFs) and bone morphogenetic proteins (BMPs) in the injured spinal cord that seemingly disrupt the normal healing process ( 216 ). Altogether, neutrophils play important roles in regulating neuroinflammation at the early stage of SCI that shapes the immune response and repair processes at later stages. While neutrophils were originally viewed as being detrimental in SCI, emerging evidence shows their critical role in the repair process. Further investigations are required to elucidate the role of neutrophils in SCI pathophysiology.

Microglia and Macrophages

Following neutrophil invasion, microglia/macrophages populate the injured spinal cord within 2–3 days post-SCI. Macrophage population is derived from invading blood-borne monocytes or originate from the CNS resident macrophages that reside in the perivascular regions within meninges and subarachnoid space ( 218 , 219 ). The population of microglia/macrophages reaches its peak at 7–10 days post-injury in mouse SCI, followed by a decline in the subacute and chronic phases ( 20 , 220 ). While macrophages and microglia share many functions and immunological markers, they have different origins. Microglia are resident immune cells of the CNS that originate from yolk sac during the embryonic period ( 221 ). Macrophages are derived from blood monocytes, which originate from myeloid progeny in the bone marrow ( 222 , 223 ). Upon injury, acute disruption of brain-spinal cord barrier (BSB) enables monocytes, to infiltrate the spinal cord tissue and transform into macrophages ( 222 ). Macrophages populate the injury epicenter, while resident microglia are mainly located in the perilesional area ( 222 ). Once activated, macrophages, and microglia are morphologically and immunohistologically indistinguishable ( 224 ). Macrophages and microglia play a beneficial role in CNS regeneration. They promote the repair process by expression of growth promoting factors such as nerve growth factor (NGF), neurotrophin-3 (NT-3) and thrombospondin ( 225 , 226 ). Macrophages and microglia are important for wound healing process following SCI due to their ability for phagocytosis and scavenging damaged cells and myelin debris following SCI ( 222 , 227 ).

Based on microenvironmental signals, macrophages/microglia can be polarized to either pro-inflammatory (M1-like) or anti-inflammatory pro-regenerative (M2-like) phenotype, and accordingly contribute to injury or repair processes following SCI ( 191 , 224 , 228 – 230 ). Whether both microglia and macrophages possess the ability to polarize or it is mainly the property of monocyte derived macrophages is still a matter of debate and needs further elucidation ( 231 – 233 ). Some evidence show that Proinflammatory M1-like microglia/macrophages can be induced by exposure to T h 1 specific cytokine, interferon (IFN)-γ ( 224 , 230 ). Moreover, the SCI microenvironment appears to drive M1 polarization of activated macrophages ( 231 ). SCI studies have revealed that increased level of the proinflammatory cytokine, TNF-α, and intracellular accumulation of iron drives an M1-like proinflammatory phenotype in macrophages after injury ( 231 ). Importantly, following SCI, activated M1-like microglia/macrophages highly express MHCII and present antigens to T cells and contribute to the activation and regulation of innate and adaptive immune response ( Figure 4 ) ( 224 , 228 ). Studies on acute and subacute SCI and experimental autoimmune encephalomyelitis (EAE) models have shown that M1-like macrophages are associated with higher expression of chondroitin sulfate proteoglycans (CSPGs) and increased EAE severity and tissue damage ( 234 – 237 ). In vitro , addition of activated M1-like macrophages to dorsal root ganglion (DRG) neuron cultures leads to axonal retraction and failure of regeneration as the expression of CSPGs is much higher in M1-like compared to M2-like macrophages ( 237 , 238 ). M1-like macrophages also produce other repulsive factors such as repulsive guidance molecule A (RGMA) that is shown to induce axonal retraction following SCI ( 239 , 240 ). Interestingly, recent evidence shows that IFN-γ and TNFα polarized M1 microglia show reduced capacity for phagocytosis ( 241 ), a process that is critical for tissue repair after SCI.

Pro-regenerative M2-like microglia/macrophages, are polarized by T h 2 cytokines, IL-4 and IL-13 and exhibit a high level of IL-10, TGF-β, and arginase-1 with reduced NF-κB pathway activity ( 224 ). IL-10 is a potent immunoregulatory cytokine with positive roles in repair and regeneration following CNS injury ( 242 – 244 ). IL-10 knock-out mice show higher production of pro-inflammatory and oxidative stress mediators after SCI ( 245 ). Lack of IL-10 is also correlated with upregulated levels of pro-apoptotic factors such as Bax and reduced expression of anti-apoptotic factors such as Bcl-2 ( 245 ). SCI mice that lacked IL-10 exhibited poorer recovery of function compared to wild-type mice ( 245 ). Our recent studies show that IL-10 polarized M2 microglia show enhanced capacity for phagocytosis ( 241 ). We have also found that M2 polarized microglia enhance the ability of neural precursor cells for oligodendrocyte differentiation through IL-10 mediated mechanisms ( 241 ). In addition to immune modulation, M2-like microglia/macrophages promote axonal regeneration ( 224 ). However, similar to the detrimental effects of prolonged M1 macrophage response, excessive M2-like activity promotes fibrotic scar formation through the release of factors such as TGF-β, PDGF, VEGF, IGF-1, and Galectin-3 ( 224 , 246 – 248 ). Hence, a balance between proinflammatory M1 and pro-regenerative M2 macrophage/microglia response is beneficial for the repair of SCI ( 249 ).

T and B Lymphocytes

T and B lymphocytes play pivotal role in the adaptive immune response after SCI ( 194 ). Lymphocytes infiltrate the injured spinal cord acutely during the first week of injury and remain chronically in mouse and rat SCI ( 47 , 193 , 194 , 196 ). In contrast to the innate immune response that can be activated directly by foreign antigens, the adaptive immune response requires a complex signaling process in T cells elicited by antigen presenting cells ( 250 ). Similar to other immune cells, T and B lymphocytes adopt different phenotypes and contribute to both injury and repair processes in response to microenvironmental signals ( 194 , 251 ). SCI elicits a CNS-specific autoimmune response in T and B cells, which remains active chronically ( 196 ). Autoreactive T cells can exert direct toxic effects on neurons and glial cells ( 194 , 252 ). Moreover, T cells can indirectly affect neural cell function and survival through pro-inflammatory cytokine and chemokine production (e.g. IL-1β, TNF-α, IL-12, CCL2, CCL5, and CXCL10) ( 194 , 252 ). Genetic elimination of T cells (in athymic nude rats) or pharmacological inhibition of T cells (using cyclosporine A and tacrolimus) leads to improved tissue preservation and functional recovery after SCI ( 194 , 253 ) signifying the impact of T cells in SCI pathophysiology and repair.

Under normal circumstances, systemic autoreactive effector CD4 + helper T cells (T eff ) are suppressed by CD4 + FoxP3 + regulatory T cells (T reg ) ( Figure 4 ) ( 194 , 254 ). This inhibition is regulated through various mechanisms such as release of anti-inflammatory cytokines IL-10 and TGF-β by the T reg cells ( Figure 4 ) ( 194 ). Moreover, it is known that T reg mediated inhibition of antigen presentation by dendritic cells (DCs) prevent T eff cell activation ( 194 ). Following SCI, this T reg -T eff regulation is disrupted. Increased activity of autoreactive T eff cells contributes to tissue damage through production of pro-inflammatory cytokines and chemokines, promoting M1-like macrophage phenotype and induction of Fas mediated neuronal and oligodendroglial apoptosis ( Figure 4 ) ( 173 ). Moreover, autoreactive T eff cells promote activation and differentiation of antigen specific B cells to autoantibody producing plasma cells that contribute to tissue damage after SCI ( 255 ). In SCI and MS patients, myelin specific proteins such as myelin basic protein (MBP) significantly increase the population of circulating T cells ( 256 , 257 ). Moreover, serological assessment of SCI patients has shown high levels of CNS reactive IgM and IgG isotypes confirming SCI-induced autoimmune activity of T and B cells ( Figure 4 ) ( 196 , 258 , 259 ). In animal models of SCI, serum IgM level increases acutely followed by an elevation in the levels of IgG1 and IgG2a at later time-points ( 196 ). In addition to autoantibody production, autoreactive B cells contribute to CNS injury through pro-inflammatory cytokines that stimulate and maintain the activation states of T eff cells ( 194 , 260 ). B cell knockout mice (BCKO) that have no mature B cell but with normal T cells, show a reduction in lesion volume, lower antibody levels in the cerebrospinal fluid and improved recovery of function following SCI compared to wild-type counterparts ( 255 ). Of note, antibody mediated injury is regulated through complement activation as well as macrophages/microglia that express immunoglobulin receptors ( 193 , 255 ).

The effect of SCI on systemic B cell response is controversial. Evidence shows that SCI can suppress B cell activation and antibody production ( 261 ). Studies in murine SCI have shown that B cell function seems to be influenced by the level of injury ( 262 ). While injury to upper thoracic spinal cord (T3) suppresses the antibody production, a mid-thoracic (T9) injury has no effect on B cell antibody production ( 262 ). An increase in the level of corticosterone in serum together with elevation of splenic norepinephrine found to be responsible for the suppression of B cell function acutely following SCI ( 261 ). Elevated corticosterone and norepinephrine leads to upregulation of lymphocyte beta-2 adrenergic receptors eliciting lymphocyte apoptosis ( 194 ). This suggests a critical role for sympathetic innervation of peripheral lymphoid tissues in regulating B cell response following CNS injury ( 261 ). Despite their negative roles, B cells also contribute to spinal cord repair following injury through their immunomodulatory B reg phenotype ( Figure 4 ) ( 263 ). B reg cells control antigen-specific T cell autoimmune response through IL-10 production ( 264 ).

Detrimental effects of SCI-induced autoimmunity are not limited to the spinal cord. Autoreactive immune cells contribute to the exacerbation of post-SCI sequelae such as cardiovascular, renal and reproductive dysfunctions ( 194 ). For example, presence of an autoantibody against platelet prostacyclin receptor has been associated with a higher incidence of coronary artery disease in SCI patients ( 265 ). Collectively, evidence shows the critical role of adaptive immune system in SCI pathophysiology and repair. Thus, treatments that harness the pro-regenerative properties of the adaptive immune system can be utilized to reduce immune mediated tissue damage, improve neural tissue preservation and facilitate repair following SCI.

Glial Scar and Extracellular Matrix

Traumatic SCI triggers the formation of a glial scar tissue around the injury epicenter ( 266 , 267 ). The glial scar is a multifactorial phenomenon that is contributed f several populations in the injured spinal cord including activated astrocytes, NG2 + oligodendrocyte precursor cells (OPCs), microglia, fibroblasts, and pericytes ( 268 – 271 ). The heterogeneous scar forming cells and associated ECM provides a cellular and biochemical zone within and around the lesion ( Figure 3 ) ( 272 ). Resident and infiltrating inflammatory cells contribute to the process of glial activation and scar formation by producing cytokines (e.g., IL-1β and IL-6) chemokines and enzymes that activate glial cells or disrupt BSB ( 267 ). Activated microglia/macrophages produce proteolytic enzymes such as matrix metalloproteinases (MMPs) that increase vascular permeability and further disruption of the BSB ( 273 ). Inhibition of MMPs improves neural preservation and functional recovery in animal models of SCI ( 273 – 275 ). In addition to glial and immune cells, fibroblasts, pericytes and ependymal cells also contribute to the structure of the glial scar ( 267 ). In penetrating injuries where meninges are compromised, meningeal fibroblasts infiltrate the lesion epicenter ( 276 ). Fibroblasts contribute to the production of fibronectin, collagen, and laminin in the ECM of the inured spinal cord ( 267 ) and are a source of axon-repulsing molecules such as semaphorins that influence axonal regeneration following SCI ( 277 ). Fibroblasts have also been found in contusive injuries where meninges are intact ( 268 , 270 ). Studies using genetic fate mapping in these injuries have unraveled that perivascular pericytes and fibroblasts migrate to the injury site and form a fibrotic core in the scar which matures within 2 weeks post-injury ( 268 , 270 ). SCI also triggers proliferation and migration of the stem/progenitor cell pool of the spinal cord parenchyma and ependyma. These cells can give rise to new scar forming astrocytes and OPCs ( 278 – 280 ). In a mature glial scar, activated microglia/macrophages occupy the innermost portion closer to the injury epicenter surrounded by NG2 + OPCs ( Figure 3 ) ( 267 ), while reactive astrocytes reside in the injury penumbra and form a cellular barrier ( 267 ). Of note, in human SCI, the glial scar begins to form within the first hours after the SCI and remains chronically in the spinal cord tissue ( 281 ). The glial scar has been found within the injured human spinal cord up to 42 years after the injury ( 267 ).

Activated astrocytes play a leading role in the formation of the glial scar ( 267 ). Following injury, astrocytes increase their expression of intermediate filaments, GFAP, nestin and vimentin, and become hypertrophied ( 282 , 283 ). Reactive astrocytes proliferate and mobilize to the site of injury and form a mesh like structure of intermingled filamentous processes around the injury epicenter ( 284 , 285 ). The astrocytic glial scar has been shown to serve as a protective barrier that prevents the spread of infiltrating immune cells into the adjacent segments ( 267 , 284 , 286 ). Attenuating astrocyte reactivity and scar formation by blockade of STAT3 activation results in poorer outcomes in SCI ( 211 , 286 ). Reactive astrogliosis is also essential for reconstruction of the BBB, and blocking this process leads to exacerbated leukocyte infiltration, cell death, myelin damage, and reduced functional recovery ( 211 , 285 , 286 ). Despite the protective role of the astrocytic glial scar in acute SCI, its evolution and persistence in the sub-acute and chronic stages of injury has been considered as a potent inhibitor for spinal cord repair and regeneration ( 267 , 287 ). A number of inhibitory molecules have been associated with activated astrocytes and their secreted products such as proteoglycans and Tenascin-C ( 288 ). Thus, manipulation of the astrocytic scar has been pursued as a promising treatment strategy for SCI ( 267 , 289 ).

Chondroitin sulfate proteoglycans (CSPGs) are well-known for their contribution to the inhibitory role of the glial scar in axonal regeneration ( 290 – 295 ), sprouting ( 296 – 299 ), conduction ( 300 – 302 ), and remyelination ( 241 , 303 – 307 ). In normal condition, basal levels of CSPGs are expressed in the CNS that play critical roles in neuronal guidance and synapse stabilization ( 90 , 308 ). Following injury, CSPGs (neurocan, versican, brevican, and phosphacan) are robustly upregulated and reach their peak of expression at 2 weeks post-SCI and remain upregulated chronically ( 309 , 310 ). Mechanistically, disruption of BSB and hemorrhage following traumatic SCI triggers upregulation of CSPGs in the glial scar by exposing the scar forming cells to factors in plasma such as fibrinogen ( 311 ). Studies in cortical injury have shown that fibrinogen induces CSPG expression in astrocytes through TGFβ/Smad2 signaling pathway ( 311 ). The authors show that intracellular Smad2 translocation is essential for Smad2 signal transduction process and its inhibition reduces scar formation ( 312 ). In contrast, another study has identified that TGFβ induces CSPGs production in astrocytes through a SMAD independent pathway ( 313 ). This study showed a significant upregulation of CSPGs in SMAD2 and SMAD4 knockdown astrocytes. Interestingly, CSPG upregulation was found to be mediated by the activation of the phosphoinositide 3-kinase (PI3K)/Akt and mTOR axis ( 313 ). Further studies are required to confirm these findings.

Extensive research in the past few decades has demonstrated the inhibitory effect of CSPGs on axon regeneration ( 314 , 315 ). The first successful attempt on improving axon outgrowth and/or sprouting by enzymatic degradation of CSPGs using chondroitinase ABC (ChABC) in a rat SCI model was published in 2002 by Bradbury and colleagues ( 291 ). This study showed significant improvement in recovery of locomotor and proprioceptive functions following intrathecal delivery of ChABC in a rat model of dorsal column injury ( 291 ). This observation was followed by several other studies demonstrating the promise of CSPGs degradation in improvement of axon regeneration and sprouting of the serotonergic ( 295 , 297 , 299 , 303 ), sensory ( 293 , 298 , 316 ), corticospinal ( 291 , 297 , 303 , 317 ), and rubrospinal fibers ( 318 ) in animal models of CNS injury. Additionally, ChABC treatment is shown to be neuroprotective by preventing CSPG induced axonal dieback and degeneration ( 303 , 319 , 320 ). Studies by our group also showed that degradation of CSPGs using ChABC attenuates axonal dieback in corticospinal fibers in chronic SCI model in the rat ( 303 ). ChABC also blocks macrophage-mediated axonal degeneration in neural cultures and after SCI ( 238 ).

The inhibitory effects of astrocytic glial scar on axonal regeneration has been recently challenged after SCI ( 321 ). Using various transgenic mouse models, a study by Sofroniew's and colleagues has shown that spontaneous axon regrowth failed to happen following the ablation or prevention of astrocytic scar in acute and chronic SCI. They demonstrated that when the intrinsic ability of dorsal root ganglion (DRG) neurons for growth was enhanced by pre-conditioning injury as well as local delivery of a combination of axon growth promoting factors into the SCI lesion, the axons grew to the wall of the glial scar and CSPGs within the lesion. However, when astrocyte scarring was attenuated, the pre-conditioned/growth factor stimulated DRG neurons showed a reduced ability for axon growth ( 321 ). From these observations, the authors suggested a positive role for the astrocytic scar in axonal regeneration following SCI ( 321 ). Overall, this study points to the importance of reactive and scar forming astrocytes and their pivotal role in the repair process following SCI ( 322 ). This is indeed in agreement with previous studies by the same group that showed a beneficial role for activated astrocytes in functional recovery after SCI by limiting the speared of infiltrated inflammatory cells and tissue damage in SCI ( 285 ). It is also noteworthy that the glial scar is contributed by various cell populations and not exclusively by astrocytes ( 269 , 271 ). Therefore, the outcomes of this study need to be interpreted in the context of astrocytes and astrocytic scar. Moreover, the reduced capacity of the injured spinal cord for regeneration is not solely driven by the glial scar as other factors including inflammation and damaged myelin play important inhibitory role in axon regeneration ( 323 , 324 ). Taken together, further investigation is needed to delineate the mechanisms of the glial scar including the contribution of astrocyte-derived factors on axon regeneration in SCI.

Role of CSPGs on Endogenous Cell Response and Neuroinflammation

While CSPGs were originally identified as an inhibitor of axon growth and plasticity within the glial scar, emerging evidence has also identified them as an important regulator of endogenous cell response. Emerging evidence has identified CSPGs as an inhibitor of oligodendrocytes ( 241 , 272 , 306 ). Replacement of oligodendrocytes is an important repair process in SCI and other demyelinating conditions such as MS ( 90 ). SCI and MS triggers activation of endogenous OPCs and their mobilization to the site of injury ( 143 , 162 , 306 , 325 ). In vitro and in vivo evidence shows that CSPGs limit the recruitment of NPCs and OPCs to the lesion and inhibit oligodendrocyte survival, differentiation and maturation ( 145 , 272 , 305 , 306 , 326 ). Our group and others have shown that targeting CSPGs by ChABC administration or xyloside, or through inhibition of their signaling receptors enhances the capacity of NPCs and OPCs for proliferation, oligodendrocyte differentiation and remyelination following SCI and MS-like lesions ( 145 , 303 , 304 , 306 ).

Mechanistically, the inhibitory effects of CSPGs on axon growth and endogenous cell differentiation is mainly governed by signaling through receptor protein tyrosine phosphatase sigma (RPTPσ) and leukocyte common antigen-related phosphatase receptor (LAR) ( 327 ). RPTPσ is the main receptor mediating the inhibition of axon growth by CSPGs ( 327 , 328 ). Improved neuronal regeneration has been demonstrated in RPTPσ–/– mice model of SCI and peripheral nerve injury ( 328 , 329 ). Blockade of RPTPσ and LAR by intracellular sigma peptide (ISP) and intracellular LAR peptide (ILP), facilitates axon regeneration following SCI ( 327 , 330 ). Inhibition of RPTPσ results in significant improvement in locomotion and bladder function associated with serotonergic re-innervation below the level of injury in rat SCI ( 327 ). Our group has also shown that CSPGs induce caspase-3 mediated apoptosis in NPCs and OPCs in vitro and in oligodendrocytes in the injured spinal cord that is mediated by both RPTPσ and LAR ( 241 ). Inhibition of LAR and RPTPσ sufficiently attenuates CSPG-mediated inhibition of oligodendrocyte maturation and myelination in vitro and attenuated oligodendrocyte cell death after SCI ( 241 ).

CSPGs have been implicated in regulating immune response in CNS injury and disease. Interestingly, our recent studies indicated that CSPGs signaling appears to restrict endogenous repair by promoting a pro-inflammatory immune response in SCI ( 241 , 331 ). Inhibition of LAR and RPTPσ enhanced an anti-inflammatory environment after SCI by promoting the populations of pro-regenerative M2-like microglia/macrophages and regulatory T cells ( 241 ) that are known to promote repair process ( 224 ). These findings are also in agreement with recent studies in animal models of MS that unraveled a pro-inflammatory role for CSPGs in autoimmune demyelinating conditions ( 332 ). In MS and EAE, studies by Stephenson and colleagues have shown that CSPGs are abundant within “the leucocyte-containing perivascular cuff,” the entry point of inflammatory cells to the CNS tissue ( 332 ). Presence of CSPGs in these perivascular cuffs promotes “trafficking” of immune cells to induce a pro-inflammatory response in MS condition. In contrast to these new findings, early studies in SCI described that preventing CSPG formation with xyloside treatment at the time of injury results in poor functional outcome, while manipulation of CSPGs at 2 days after SCI was beneficial for functional recovery ( 333 ). These differential outcomes were associated with the modulatory role of CSPGs in regulating the response of macrophages/microglia. Disruption in CSPG formation immediately after injury promoted an M1 pro-inflammatory phenotype in macrophages/microglia, whereas delayed manipulation of CSPGs resulted in a pro-regenerative M2 phenotype ( 333 ). In EAE, by products of CSPG degradation also improve the outcomes by attenuating T cell infiltration and their expression of pro-inflammatory cytokines IFN-γ and TNFα ( 334 ).

These emerging findings suggest an important immunomodulatory role for CSPGs in CNS injury and disease; further investigations are needed to elucidate CSPG mechanisms in regulating neuroinflammation. Altogether, current evidence has identified a multifaceted inhibitory role for CSPGs in regulating endogenous repair mechanisms after SCI, suggesting that targeting CSPGs may present a promising treatment strategy for SCI.

Concluding Remarks

Traumatic SCI represents a heterogeneous and complex pathophysiology. While pre-clinical research on SCI has been an ongoing endeavor for over a century, our understanding of SCI mechanisms has been increased remarkably over the past few decades. This is mainly due to the development of new transgenic and preclinical animal models that has facilitated rapid discoveries in SCI mechanisms. Although SCI research has made an impressive advancement, much work is still needed to translate the gained knowledge from animal studies to clinical applications in humans.

Author Contributions

AA, SD, and SK-A have all contributed to literature review and writing this manuscript. AA and SK-A contributed to the production of figures. All authors have approved the final version of the manuscript.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

This work was supported by grants from the Canadian Institute of Health Research to SK-A. AA and SD were supported by studentships from Research Manitoba, the Children's Hospital Research Institute of Manitoba, the University of Manitoba GETS program, and the Manitoba Paraplegic Foundation.