Conflicts of Interest:

The authors have no conflicts of interest to disclose.

Abstract

The treatment of anterior cruciate ligament (ACL) injury is a prominent and costly component within orthopaedics. Even with success of the current gold standard of treatment, surgical ACL replacement, there are risks of postoperative comorbidities such as osteoarthritis (OA). A promising methodology that has emerged from Dr. Martha Murray’s team at Boston Children’s Hospital is the bridge-enhanced ACL repair (BEAR) procedure. This technique uses tissue engineering to regenerate and “bridge” together the severed ends of the ACL rather than constructing a new ligament. The BEAR procedure has shown great promise in early clinical trials, but longitudinal follow-up is needed. The purpose of this study was to compile preclinical and clinical studies of the BEAR procedure to better understand its advances, limitations, and future directions; to our knowledge, this has not been done in the current literature.

Keywords

anterior cruciate ligament, bridge-enhanced ACL repair, osteoarthritis, graft, knee, sports medicine.

Abbreviations

ACL: anterior cruciate ligament

BEAR: bridge-enhanced ACL repair

OA: osteoarthritis

IKDC: International Knee Documentation Committee

Introduction

Injuries to the anterior cruciate ligament (ACL) are estimated to affect up to 400,000 individuals per year[1] and cost over $2 billion in healthcare-related expenses.[2] The ACL is 1 of 2 ligaments that make up the center of the knee joint and is responsible for preventing anterior translation of the tibia relative to the femur, more commonly referred to as hyperextension.[3] The ACL is essential for maintaining stability and proper knee biomechanics.[4] Although colloquially considered a sports injury, ACL tears and/or ruptures are becoming exceedingly more common among non-athletes.[5] The overall adjusted annual incidence of ACL tears was found to be 68.6 per 100,000 person-years with peak incidence in males 19–25 years of age and in females at 14–18 years of age.[6] Given the prevalence and debilitating nature of ACL injuries, continuously improving treatment approaches remains of the utmost interest within orthopaedics and medicine as a whole.

As with any injury in the body, ACL tears can present at different stages and gravities. If the tear is minor or the individual has low physical demands of the knee joint, physical therapy is often the treatment of choice. However, if the tear is severe causing knee buckling or an active lifestyle is desired, the current standard of care involves surgically removing the torn ACL and replacing it with a tendinous graft via holes drilled into both the femur and tibia as anchors. This graft can be obtained from a number of sources. Autografts can be harvested from the patient during the same operation (hamstring tendon, patellar tendon, or quadriceps tendon) or cadaveric allografts; although autografts are more commonly used, there lacks a clear consensus as to which is superior.[7][8][9][10][11]

ACL reconstructions are generally considered successful (75–97% patient satisfaction), necessary, and low-risk procedures.[12][13][14][15][16] However, adverse consequences of the procedure can manifest beyond an immediate “successful” reconstruction.[17][18][19][20] For example, 10–15% of ACL reconstruction surgeries require a secondary, revision surgery at some point.[15] Overall, patient satisfaction and stability are improved by revisions but are significantly lower than in successful primary procedures.[21] Although minimally invasive ACL reconstructions have been performed using arthroscopy, they pose a high incidence of complications compared to other orthopaedic arthroscopic procedures.[22] There is evidence to show that patients are also at an increased risk of injury just 2 years following a primary ACL reconstruction, especially young athletes.[23] Interestingly, this increased risk involves both the operated knee and the contralateral knee.[24] These mechanisms of susceptibility remain unclear.

Prior ACL injury and subsequent reconstruction lead to a greater likelihood of developing osteoarthritis (OA) and requiring a total knee arthroplasty (TKA), otherwise known as a knee replacement.[25][26][27][28][29][30][31][32][33][34] Commonly referred to as “wear and tear,” OA is a degenerative joint disease that can affect any joint, but symptoms are exacerbated when weight-bearing joints are involved. OA results in the destruction of the meniscus, the rubber-like fibrocartilage wedged within the knee joint that acts as a shock absorber between the tibia and femur.[35] OA is the most common joint disorder and among the costliest to manage. Other risk factors for OA include but certainly are not limited to socioeconomic status, obesity, age, and past physical activity.[36][37] Unfortunately, the meniscus is largely avascular, thus severely limiting repair following degeneration or tear; currently there is no curative treatment for OA besides a TKA.[37] The mechanism by which ACL repair contributes to the development of OA remains unknown, but substantial evidence supports an association38-45 with theories involving collateral damage during injury and abnormal distribution of forces following ACL injury and repair.[46][47] Notably, patients who have had ACL reconstruction have been largely found to be at higher risk for developing OA compared to those with healthy knees. However, OA rates improve when comparing patients treated with ACL reconstruction to patients with untreated ACL injuries.[48] Preoperative and postoperative rehabilitation is essential surrounding ACL surgery to ensure regaining of proper gait biomechanics and weight distribution.[49][50][51] Additionally, if a TKA is performed, a prior ACL reconstruction leads to a significant increase in TKA operative time.[25] Altogether, the conventional ACL reconstruction is a beneficial treatment, but there are substantial areas for perioperative improvement.

A promising avenue for improving treatment of ACL injuries is the bridge-enhanced ACL repair (BEAR) procedure. BEAR was developed by Dr. Martha Murray and her team at Boston Children’s Hospital with the goal of mending many of the long-term detriments of the current gold standard. The theory behind BEAR is grounded in the principle that repairing the native ACL is preferred to introducing a graft that requires bone tunneling, thus presenting an invaluable tool for such work.[52][53][54] Historically, bleeding occurs from the torn ACL, but fibrinolytic factors in the synovial (joint) fluid surrounding it inhibit clot formation as well as building of the proteinaceous scaffolding essential for healing.[54][55][56] This is in contrast to tears of the medial collateral ligament (MCL), which connects the femur and the tibia as well but does so along the inner portion of the thigh and therefore is not within the joint itself. MCL tears do lead to clot formation and therefore allow severed ends to reconnect and heal without surgical intervention.[57] The capacity for the BEAR procedure to “bridge” this gap between torn ends addresses this significant obstacle in ACL repair.

The BEAR procedure begins with placing sutures in the 2 torn ends of the ACL and inserting a proteinaceous sponge in between these ends. Once the sponge scaffold is in place, a blood draw is performed from the patient’s arm, and the blood is injected into the sponge to create an environment conducive to ligament healing. The sutures attached to the ends of the torn ACL are then pulled so that the ends of the torn ACL enter the sponge. Over the course of 8 to 12 weeks, the body naturally replaces the sponge and connects the ends of the torn ACL once again.[1][54][58][59][60] The BEAR procedure has potential to offer preservation of nerve fibers at the ligament insertion sites pivotal for knee proprioception and biomechanics, which is especially important given the skeletal immaturity of younger patients.[61]

The purpose of this study is to provide a current report of preclinical and clinical studies implementing the BEAR procedure with elucidation of advantages and disadvantages at each step. To our knowledge, no other studies have compiled both preclinical and clinical data; we aim to fill this gap and provide a concise report of in vivo evidence comparing the BEAR procedure with traditional ACL repair. Furthermore, we believe this work to be applicable to multiple areas of medicine outside of orthopaedics in that musculoskeletal injuries often present initially in the primary care setting where treatment and follow-up extend into fields such as radiology, physical therapy, pain management, physical medicine, and rehabilitation, as well as others.

Materials and Methods

Our approach consisted of qualitative review of the current PubMed literature on the bridge-enhanced ACL repair (BEAR) procedure. Being a new procedure, we aimed to compile the growing body of knowledge into a concise report detailing its efficacy and impact on the field of medicine. Dr. Martha Murray of Boston Children’s Hospital has pioneered the procedure, and research from her group was the linchpin of our review. Other searched keywords for our review include ACL repair, sports medicine, BEAR, biomechanical outcomes, knee surgery, osteoarthritis, bioactive scaffold, injury, and ligament reconstruction. Inclusion criteria were based on reliability and rigor of study design with an emphasis on outcomes-based approaches. We did not include statistical analyses in our review.

Discussion

Biomechanical Advantages

There are numerous biomechanical advantages of the BEAR procedure to traditional ACL reconstructive surgery. From a structural and anatomical perspective, maintaining the inert ligamentous properties and alignment corresponds with minimized total cartilage lesion 1-year post-op. In both metrics, the BEAR procedure showed superior results as reported by Kiapour et al. They found that the BEAR was better able to maintain the natural properties and alignment of the native ACL, leading to a reduction in tibiofemoral cartilage damage.[62] The repaired grafts have also been shown to be comparable to reconstructed ones. In preclinical animal models, the strength of each type of graft was measured, and no statistical difference was found.[63][64] These data were taken further and applied to current clinical trials in which similar results were shown in humans.[59][60]

Additional data supporting the use of the BEAR procedure has recently emerged from clinical trials. These data include information on the postoperative comparisons between repaired and reconstructed groups as well as comparisons of strength, stability, and tissue integrity. As supported by Micheli et al, there were no statistical differences found when evaluating the 2 groups at 3 and 6 months post-op. In this same study, there were also no differences in International Knee Documentation Committee (IKDC) scores, effusion, range of motion, or AP laxity, all supporting the success and reliability of the BEAR procedure.[65] Lastly, all ten of the participants in the first in-human study showed tissue presence in the region of torn ACL at 3 and 6 months by MRI.[60] It should be acknowledged that analysis of long-term stability requires further study and patient follow-up.[59][65] Preclinical and clinical studies using the BEAR procedure are outlined in Table 1.

Quality of Life Benefits

Along with the outlined biomechanical advantages of the BEAR procedure, mounting evidence support its ability to improve patient quality of life. Following ACL reconstruction, patients are 3 times more likely to develop osteoarthritis (OA) in the reconstructed knee compared to their healthy contralateral knee.[39] The degenerative nature of OA causes debilitating pain and presents as a substantial comorbidity for ACL reconstruction patients.[66] Although preliminary, preclinical data provides significant evidence that the BEAR procedure can help minimize OA following ACL surgery.[60][67] In conjunction with OA pain, implementing the BEAR procedure eliminates the need for a tissue graft and, therefore, reduces comorbidities associated with additional surgical trauma and musculoskeletal compromise. As with any surgical intervention, the risk of infection is a concern following traditional ACL reconstruction and tissue grafting. In the case of the BEAR procedure, midterm data from the first in-human study shows no infection or severe adverse reactions following the BEAR procedure in patients.[65] These findings are extremely promising and warrant more longitudinal studies, especially given the already low risk of deep joint infection during ACL reconstruction in conjunction with the sample size of the study.

Limitations and Future Directions

Despite the significant promise and innovation aforementioned, limitations of the BEAR procedure exist. The most prominent issue is the procedure’s utility given current study inclusion criteria[68][69]; more specifically, current research has focused exclusively on mid-substance tears, which does not account for 70% of repairs.[70] Furthermore, the published work on ACL tears has not included patients with more than 50% of the ACL length lost. This is a major potential detriment that needs to be addressed with future research as it may eliminate many future candidates. Moreover, there has been a longstanding correlation between sex and ACL tears, in which females are at a higher risk than males.[71] Initial animal studies showed significantly lower biomechanical measurements of success in female pigs. These measurements include side-to-side comparisons and cartilage damage assessments, both of which favored males.[64] Interestingly, initial animal studies have also showed less favorable outcomes in female pigs who received dissolvable sutures during their BEAR procedure. However, the use of non-dissolvable sutures was shown to improve female outcomes to mirror those of males.[63] These data expose another potential loss of utility for the BEAR procedure that should be further researched in order to ensure equal efficacy across sexes. Finally, the long-term stability of the primary repair requires further follow-up as the BEAR procedure recipients have not experienced its effects sufficiently to acquire longitudinal data. Another limitation to the current review is that it does not heavily integrate the basic science literature, which emphasizes the tissue engineering and scaffold testing that has been done in the most primitive stages of the BEAR procedure’s development.

Table 1. Summary of current studies available on the BEAR procedure

Study

Model Organism

Study Type

Objective

Outcome

Adverse Events

Kiapour et al 2017

Mini pigs

Controlled laboratory study

Unilateral ACL reconstruction vs unilateral BEAR: analysis of cartilage damage at 1-year post-op

Less damage in bridge-enhanced repair compared to traditional reconstruction

Altered joint motion in ACL reconstruction group – joint damage

Vavken et al 2012

Skeletally immature pigs

Controlled laboratory study

Compare biomechanical outcomes in BEAR vs. ACL reconstruction at 15 weeks post-op

No measures of biomechanical differences were found to be statistically different between the 2 procedures

None

Murray et al 2016

Human

Non-randomized cohort study

Comparison of postoperative factors following BEAR vs. ACL reconstruction

No statistical difference

None

Micheli et al 2017

Human

Non-randomized cohort study

Determine if BEAR would be safe in humans and compare the early outcomes of this technique with ACL reconstruction

IKDC scores, effusion, AP laxity, and range of motion recovery all found to be similar between bridge-enhanced ACL repair and ACL reconstruction groups

None

Murray and Fleming 2013

Yucatan mini pigs

Controlled laboratory study

Compare the tensile properties of the repair grafts as well as the level of cartilaginous damage at 6 and 12 months post-op; BEAR vs conventional ACL reconstruction

Graft integrity after BEAR was not significantly different from conventional ACL reconstruction; less cartilage damage after BEAR

None

We have included all, to our knowledge, preclinical and clinical BEAR studies in the current literature. This includes respective study parameters and outcomes. The purpose of this table is to concisely summarize current data, and no statistical analyses were performed.

Conclusion

Current methods of ACL reconstruction have offered patients sound therapeutic options and have led to restored knee stability and functionality. These traditional methods encounter significant drawbacks as patients are left more vulnerable to developing OA and subsequent surgical intervention. We have compounded preclinical and preliminary human trial data on the recently developed BEAR procedure. To date, the BEAR procedure continues to demonstrate great promise as a viable treatment for ACL tears. However, as aforementioned, it must continue to produce outcomes that rival the current gold standard and ameliorate its current limitations.

Acknowledgments

We would like to acknowledge and thank Clifford Craig, MD, Bruce Miller, MD, and the department of orthopaedic surgery at the University of Michigan, Ann Arbor, MI, for their developmental support on this review.

References

    1. Boston Children’s Hospital, Anterior Cruciate Ligament Program. Bridge-Enhanced® ACL Repair Clinical Trial. www.childrenshospital.org/centers-and-services/anterior-cruciate-ligament-program/research-and-innovation/bridge-enhanced-acl-repair-trial.return to textreturn to text

    2. Centers for Disease Control and Prevention (CDC). Funded Injury Control Research Centers (ICRCs). 2010. https://www.cdc.gov/injury/erpo/icrc/2009/1-r49-ce001495-01.html. Reviewed July 13, 2010.return to text

    3. Butler DL, Noyes FR, Grood ES. Ligamentous restraints to anterior-posterior drawer in the human knee. A biomechanical study. J Bone Joint Surg Am. 1980;62(2):259–270. return to text

    4. Kraeutler MJ, Wolsky RM, Vidal AF, Bravman JT. Anatomy and biomechanics of the native and reconstructed anterior cruciate ligament: surgical implications. J Bone Joint Surg Am. 2017;99(5):438–445. doi:10.2106/JBJS.16.00754return to text

    5. Yucens M, Aydemir AN. Trends in anterior cruciate ligament reconstruction in the last decade: a web-based analysis. J Knee Surg. 2018. doi:10.1055/s-0038-1655764return to text

    6. Sanders TL, Maradit Kremers H, Bryan AJ, et al. Incidence of anterior cruciate ligament tears and reconstruction: a 21-year population-based study. Am J Sports Med. 2016;44(6):1502–1507. doi:10.1177/0363546516629944return to text

    7. Macaulay AA, Perfetti DC, Levine WN. Anterior cruciate ligament graft choices. Sports Health. 2012;4(1):63–68. doi:10.1177/1941738111409890return to text

    8. Dheerendra SK, Khan WS, Singhal R, Shivarathre DG, Pydisetty R, Johnstone D. Anterior cruciate ligament graft choices: a review of current concepts. Open Orthop J. 2012;6:281–286. doi:10.2174/1874325001206010281return to text

    9. Dhammi IK, Rehan-Ul-Haq, Kumar S. Graft choices for anterior cruciate ligament reconstruction. Indian J Orthop. 2015;49(2):127–128. doi:10.4103/0019-5413.152393return to text

    10. Clark JC, Rueff DE, Indelicato PA, Moser M. Primary ACL reconstruction using allograft tissue. Clin Sports Med. 2009;28(2):223–244, viii. doi:10.1016/j.csm.2008.10.005return to text

    11. Kumar N, Bastrom TP, Dennis MM, Pennock AT, Edmonds EW. Adolescent medial patellofemoral ligament reconstruction: a comparison of the use of autograft versus allograft hamstring. Orthop J Sports Med. 2018;6(5). doi:10.1177/2325967118774272return to text

    12. Bach BR Jr. Revision anterior cruciate ligament surgery. Arthroscopy. 2003;19(10 Suppl 1):14–29. doi:10.1016/j.arthro.2003.09.044return to text

    13. Baer GS, Harner CD. Clinical outcomes of allograft versus autograft in anterior cruciate ligament reconstruction. Clin Sports Med. 2007;26(4):661–681. doi:10.1016/j.csm.2007.06.010return to text

    14. Noyes FR, Barber-Westin SD. Revision anterior cruciate surgery with use of bone-patellar tendon-bone autogenous grafts. J Bone Joint Surg Am. 2001;83-A(8):1131–1143. doi: 10.2106/00004623-200108000-00001 return to text

    15. Samitier G, Marcano AI, Alentorn-Geli E, Cugat R, Farmer KW, Moser MW. Failure of anterior cruciate ligament reconstruction. Arch Bone Jt Surg. 2015;3(4):220–240. return to textreturn to text

    16. Tibor LM, Long JL, Schilling PL, Lilly RJ, Carpenter JE, Miller BS. Clinical outcomes after anterior cruciate ligament reconstruction: a meta-analysis of autograft versus allograft tissue. Sports Health. 2010;2(1):56–72. doi:10.1177/1941738109347984return to text

    17. Christensen JE, Miller MD. Knee anterior cruciate ligament injuries: common problems and solutions. Clin Sports Med. 2018;37(2):265–280. doi:10.1016/j.csm.2017.12.006return to text

    18. Swiontkowski M. Systemic complications of ACL reconstruction. JBJS Case Connect. 2013;3(3 Suppl 5):e82. doi:10.2106/JBJS.CC.M.10002return to text

    19. Swiontkowski M. Technical complications of ACL reconstruction. JBJS Case Connect. 2013;3(3 Suppl 2):e71–e72. doi:10.2106/JBJS.CC.M.10001return to text

    20. Waterman BR, Arroyo W, Cotter EJ, Zacchilli MA, Garcia EJ, Owens BD. Septic arthritis after anterior cruciate ligament reconstruction: clinical and functional outcomes based on graft retention or removal. Orthop J Sports Med. 2018;6(3). doi:10.1177/2325967118758626return to text

    21. Carson EW, Anisko EM, Restrepo C, Panariello RA, O’Brien SJ, Warren RF. Revision anterior cruciate ligament reconstruction: etiology of failures and clinical results. J Knee Surg. 2004;17(3):127–132. return to text

    22. Hagino T, Ochiai S, Watanabe Y, et al. Complications after arthroscopic knee surgery. Arch Orthop Trauma Surg. 2014;134(11):1561–1564. doi:10.1007/s00402-014-2054-0return to text

    23. Paterno MV, Rauh MJ, Schmitt LC, Ford KR, Hewett TE. Incidence of second ACL injuries 2 years after primary ACL reconstruction and return to sport. Am J Sports Med. 2014;42(7):1567–1573. doi:10.1177/0363546514530088return to text

    24. Paterno MV, Rauh MJ, Schmitt LC, Ford KR, Hewett TE. Incidence of contralateral and ipsilateral anterior cruciate ligament (ACL) injury after primary ACL reconstruction and return to sport. Clin J Sport Med. 2012;22(2):116–121. doi:10.1097/JSM.0b013e318246ef9ereturn to text

    25. Chong ACM, Fisher BT, MacFadden LN, Piatt BE. Prior anterior cruciate ligament reconstruction effects on future total knee arthroplasty. J Arthroplasty. 2018;33(9):2821–2826. doi:10.1016/j.arth.2018.04.014return to textreturn to text

    26. Brophy RH, Gray BL, Nunley RM, Barrack RL, Clohisy JC. Total knee arthroplasty after previous knee surgery: expected interval and the effect on patient age. J Bone Joint Surg Am. 2014;96(10):801–805. doi:10.2106/JBJS.M.00105return to text

    27. Leroux T, Ogilvie-Harris D, Dwyer T, et al. The risk of knee arthroplasty following cruciate ligament reconstruction: a population-based matched cohort study. J Bone Joint Surg Am. 2014;96(1):2–10. doi:10.2106/JBJS.M.00393return to text

    28. Lizaur-Utrilla A, Martinez-Mendez D, Gonzalez-Parreno S, Marco-Gomez L, Miralles Munoz FA, Lopez-Prats FA. Total knee arthroplasty in patients with prior anterior cruciate ligament reconstruction. J Arthroplasty. 2018;33(7):2141–2145. doi:10.1016/j.arth.2018.02.054return to text

    29. Oiestad BE, Engebretsen L, Storheim K, Risberg MA. Knee osteoarthritis after anterior cruciate ligament injury: a systematic review. Am J Sports Med. 2009;37(7):1434–1443. doi:10.1177/0363546509338827return to text

    30. Pernin J, Verdonk P, Si Selmi TA, Massin P, Neyret P. Long-term follow-up of 24.5 years after intra-articular anterior cruciate ligament reconstruction with lateral extra-articular augmentation. Am J Sports Med. 2010;38(6):1094–1102. doi:10.1177/0363546509361018return to text

    31. Shelbourne KD, Benner RW, Gray T. Results of anterior cruciate ligament reconstruction with patellar tendon autografts: objective factors associated with the development of osteoarthritis at 20 to 33 years after surgery. Am J Sports Med. 2017;45(12):2730–2738. doi:10.1177/0363546517718827return to text

    32. Shelbourne KD, Gray T. Results of anterior cruciate ligament reconstruction based on meniscus and articular cartilage status at the time of surgery: five- to fifteen-year evaluations. Am J Sports Med. 2000;28(4):446–452. doi:10.1177/03635465000280040201return to text

    33. . Shelbourne KD, Gray T. Minimum 10-year results after anterior cruciate ligament reconstruction: how the loss of normal knee motion compounds other factors related to the development of osteoarthritis after surgery. Am J Sports Med. 2009;37(3):471-480. doi:10.1177/0363546508326709return to text

    34. Magnussen RA, Demey G, Lustig S, Servien E, Neyret P. Total knee arthroplasty for secondary osteoarthritis following ACL reconstruction: a matched-pair comparative study of intra-operative and early post-operative complications. Knee. 2012;19(4):275–278. doi:10.1016/j.knee.2011.05.001return to text

    35. Krishnan Y, Grodzinsky AJ. Cartilage diseases. Matrix Biol. 2018;71–72:51–69. doi:10.1016/j.matbio.2018.05.005return to text

    36. . Martel-Pelletier J, Barr AJ, Cicuttini FM, et al. Osteoarthritis. Nat Rev Dis Primers. 2016;2:16072. doi:10.1038/nrdp.2016.72return to text

    37. Nelson AE. Osteoarthritis year in review 2017: clinical. Osteoarthr Cartilage. 2018;26(3):319–325. doi:10.1016/j.joca.2017.11.014return to textreturn to text

    38. Nakamae A, Adachi N, Deie M, et al. Risk factors for progression of articular cartilage damage after anatomical anterior cruciate ligament reconstruction. Bone Joint J. 2018;100-B(3):285–293. doi:10.1302/0301-620X.100B3.BJJ-2017-0837.R1

    39. Barenius B, Ponzer S, Shalabi A, Bujak R, Norlen L, Eriksson K. Increased risk of osteoarthritis after anterior cruciate ligament reconstruction: a 14-year follow-up study of a randomized controlled trial. Am J Sports Med. 2014;42(5):1049–1057. doi:10.1177/0363546514526139return to text

    40. Crawford DC, Hallvik SE, Petering RC, et al. Post-operative complications following primary ACL reconstruction using allogenic and autogenic soft tissue grafts: increased relative morbidity risk is associated with increased graft diameter. Knee. 2013;20(6):520–525. doi:10.1016/j.knee.2013.04.013

    41. Lohmander LS, Ostenberg A, Englund M, Roos H. High prevalence of knee osteoarthritis, pain, and functional limitations in female soccer players twelve years after anterior cruciate ligament injury. Arthritis Rheum. 2004;50(10):3145–3152. doi:10.1002/art.20589

    42. Oiestad BE, Holm I, Aune AK, et al. Knee function and prevalence of knee osteoarthritis after anterior cruciate ligament reconstruction: a prospective study with 10 to 15 years of follow-up. Am J Sports Med. 2010;38(11):2201–2210. doi:10.1177/0363546510373876

    43. Struewer J, Frangen TM, Ishaque B, et al. Knee function and prevalence of osteoarthritis after isolated anterior cruciate ligament reconstruction using bone-patellar tendon-bone graft: long-term follow-up. Int Orthop. 2012;36(1):171–177. doi:10.1007/s00264-011-1345-0

    44. Wong SE, Feeley BT, Pandya NK. Complications after pediatric ACL reconstruction: a meta-analysis. J Pediatr Orthop. 2017. doi:10.1097/BPO.0000000000001075

    45. Cohen M, Amaro JT, Ejnisman B, et al. Anterior cruciate ligament reconstruction after 10 to 15 years: association between meniscectomy and osteoarthrosis. Arthroscopy. 2007;23(6):629–634. doi:10.1016/j.arthro.2007.03.094

    46. Di Stasi S, Hartigan EH, Snyder-Mackler L. Sex-specific gait adaptations prior to and up to 6 months after anterior cruciate ligament reconstruction. J Orthop Sports Phys Ther. 2015;45(3):207–214. doi:10.2519/jospt.2015.5062return to text

    47. Pietrosimone B, Blackburn JT, Padua DA, et al. Walking gait asymmetries six months following anterior cruciate ligament reconstruction predict twelve-month patient-reported outcomes. J Orthop Res. 2018;36(11):2932–2940. doi:10.1002/jor.24056return to text

    48. Paschos NK. Anterior cruciate ligament reconstruction and knee osteoarthritis. World J Orthop. 2017;8(3):212–217. doi:10.5312/wjo.v8.i3.212return to text

    49. Eckenrode BJ, Carey JL, Sennett BJ, Zgonis MH. Prevention and management of post-operative complications following ACL reconstruction. Curr Rev Musculoskelet Med. 2017;10(3):315–21 doi: 10.1007/s12178-017-9427-2return to text

    50. Treacy SH, Barron OA, Brunet ME, Barrack RL. Assessing the need for extensive supervised rehabilitation following arthroscopic ACL reconstruction. Am J Orthop (Belle Mead NJ). 1997;26(1):25–29. return to text

    51. Heard WM, Chahal J, Bach BR Jr. Recognizing and managing complications in ACL reconstruction. Sports Med Arthrosc Rev. 2013;21(2):106–112. doi:10.1097/JSA.0b013e318290070creturn to text

    52. Vavken P, Murray MM. Translational studies in anterior cruciate ligament repair. Tissue Eng Part B Rev. 2010;16(1):5–11. doi:10.1089/ten.teb.2009.0147return to text

    53. Murray MM. Current status and potential of primary ACL repair. Clin Sports Med. 2009;28(1):51–61. doi:10.1016/j.csm.2008.08.005return to text

    54. Perrone GS, Proffen BL, Kiapour AM, Sieker JT, Fleming BC, Murray MM. Bench-to-bedside: Bridge-enhanced anterior cruciate ligament repair. J Orthop Res. 2017;35(12):2606–2612. doi:10.1002/jor.23632return to textreturn to textreturn to text

    55. Harrold AJ. The defect of blood coagulation in joints. J Clin Pathol. 1961;14(3):305–308. return to text

    56. Murray MM, Martin SD, Martin TL, Spector M. Histological changes in the human anterior cruciate ligament after rupture. J Bone Joint Surg Am. 2000;82-A(10):1387–1397. doi:10.2106/00004623-200010000-00004 return to text

    57. Frank C, Woo SL, Amiel D, Harwood F, Gomez M, Akeson W. Medial collateral ligament healing. A multidisciplinary assessment in rabbits. Am J Sports Med. 1983;11(6):379–389. doi:10.1177/036354658301100602return to text

    58. Murray MM, Magarian E, Zurakowski D, Fleming BC. Bone-to-bone fixation enhances functional healing of the porcine anterior cruciate ligament using a collagen-platelet composite. Arthroscopy. 2010;26(9 Suppl):S49–57. doi:10.1016/j.arthro.2009.12.017return to text

    59. Murray MM, Flutie BM, Kalish LA, et al. The bridge-enhanced anterior cruciate ligament repair (BEAR) procedure: an early feasibility cohort study. Orthop J Sports Med. 2016;4(11). doi: 10.1177/2325967116672176return to textreturn to textreturn to text

    60. Proffen BL, Perrone GS, Roberts G, Murray MM. Bridge-enhanced ACL repair: a review of the science and the pathway through FDA investigational device approval. Ann Biomed Eng. 2015;43(3):805–818. doi:10.1007/s10439-015-1257-zreturn to textreturn to textreturn to textreturn to text

    61. Vavken P, Murray MM. The potential for primary repair of the ACL. Sports Med Arthrosc. 2011;19(1):44–49. doi:10.1097/JSA.0b013e3182095e5dreturn to text

    62. Kiapour AM, Fleming BC, Murray MM. Structural and anatomic restoration of the anterior cruciate ligament is associated with less cartilage damage 1 year After surgery: healing ligament properties affect cartilage damage. Orthop J Sports Med. 2017;5(8). doi:10.1177/2325967117723886return to text

    63. Kiapour AM, Fleming BC, Murray MM. Biomechanical outcomes of bridge-enhanced anterior cruciate ligament repair are influenced by sex in a preclinical model. Clin Orthop Relat Res. 2015;473(8):2599–2608. doi:10.1007/s11999-015-4226-9return to textreturn to text

    64. Vavken P, Fleming BC, Mastrangelo AN, Machan JT, Murray MM. Biomechanical outcomes after bioenhanced anterior cruciate ligament repair and anterior cruciate ligament reconstruction are equal in a porcine model. Arthroscopy. 2012;28(5):672–680. doi:10.1016/j.arthro.2011.10.008return to textreturn to text

    65. Micheli LJ, Flutie B, Fleming BC, Murray MM. Bridge-enhanced ACL repair: mid-term Results of the first-in-human study. Orthop J Sports Med. 2017;5(7). doi:10.1177/2325967117S00305return to textreturn to textreturn to text

    66. von Porat A, Roos EM, Roos H. High prevalence of osteoarthritis 14 years after an anterior cruciate ligament tear in male soccer players: a study of radiographic and patient relevant outcomes. Ann Rheum Dis. 2004;63(3):269–273. doi:10.1136/ard.2003.008136return to text

    67. Murray MM, Fleming BC. Use of a bioactive scaffold to stimulate anterior cruciate ligament healing also minimizes posttraumatic osteoarthritis after surgery. Am J Sports Med. 2013;41(8):1762–1770. doi:10.1177/0363546513483446return to text

    68. Nau T, Teuschl A. Regeneration of the anterior cruciate ligament: Current strategies in tissue engineering. World J Orthop. 2015;6(1):127–136. doi:10.5312/wjo.v6.i1.127return to text

    69. Proffen BL, Sieker JT, Murray MM. Bio-enhanced repair of the anterior cruciate ligament. Arthroscopy. 2015;31(5):990–997. doi:10.1016/j.arthro.2014.11.016return to text

    70. Goradia VK. PRESERVE ACL Repair Surgery. https://www.g2orthopedics.com/preserve-acl-repair-surgery/. return to text

    71. Voskanian N. ACL injury prevention in female athletes: review of the literature and practical considerations in implementing an ACL prevention program. Curr Rev Musculoskelet Med. 2013;6(2):158–163. doi:10.1007/s12178-013-9158-yreturn to text