Ligament Biology and Healing¶
Overview¶
Ligament healing is a complex biological process where early controlled motion of stable or surgically stabilized joints improves scar behavior [1]. However, no treatment to date stimulates true ligament regeneration [1]. Early ligament function depends on the cellular population of the repair [2], while early graft function relies on maintaining organized collagen [2]. The anterior cruciate ligament (ACL) has limited healing capability due to a lack of localized hematoma and low reparative cell supply [4]. In contrast, extra-articular ligaments like the medial collateral ligament (MCL) heal spontaneously but with poor mechanical properties [4].
Anterolateral ligament (ALL) injuries also exhibit limited intrinsic healing potential, with only 30.3% healing by 12 months after ACL reconstruction [21]. Treatment of acute tears of the medial ligaments, with or without an associated tear of the anterior cruciate ligament, provides good long-term results and remains recommended [33]. There is a growing body of evidence supporting the use of platelet-rich plasma (PRP) in selected indications for knee disorders [20]. Further work is needed for primary ACL repair, which may prove to be the new frontier in ligament repair [7].
Regarding novel scaffolds, histological analysis shows that additional cell seeding did not enhance osteointegration of a silk fiber–based ACL scaffold [13]. A longer observation period is necessary to determine if a true ligament-bone enthesis will form with this scaffold [13]. In the broader literature, a variety of definitions of failure are used among studies regarding patients who underwent anterior cruciate ligament reconstruction [31].
How It Works¶
Healing Potential and Biological Constraints: No treatment identified to date stimulates true ligament regeneration [1]. The anterior cruciate ligament (ACL) has limited capability to heal due to a lack of localized hematoma and low reparative cell supply [4]. In contrast, extra-articular ligaments like the medial collateral ligament (MCL) heal spontaneously but with poor mechanical properties [4]. Injury leads to an antifibrotic, catabolic response in the rabbit anterior cruciate ligament [24]. This antifibrotic, catabolic response in the ACL may prevent fibrosis and diminish the risk for loss of joint motion [24].
Cellular and Hemorrhagic Factors: Early ligament function after repair is dependent on the cellular population of the repair [2]. Bleeding at the ligament injury site increases the healing response, evidenced by increased macrophage counts and collagen gene expression [6]. However, biomechanical testing did not demonstrate functional differences despite increased healing response markers associated with hemorrhage [6].
Biologic Augmentation Strategies: The application of a basic fibroblast growth factor (bFGF)-impregnated pellet enhances the healing potential of the partially lacerated ACL [10]. The addition of a collagen-platelet composite (CPC) to a suture repair enhances the structural properties of the ACL [17]. The improvement in ACL healing with a CPC is associated with increased cellularity within the healing ligament [17]. Histologically, additional cell seeding did not enhance osteointegration of a novel silk fiber-based ACL scaffold [13]. A longer observation period is necessary to determine if a true ligament-bone enthesis will be formed with silk fiber-based ACL scaffolds [13].
Clinical and Surgical Implications: Early controlled motion of stable or surgically stabilized joints appears to improve ligament scar behavior [1]. Early graft function after reconstruction is dependent on the maintenance of organized collagen [2]. New techniques utilizing growth factors, cell, and gene therapies may offer the potential to enhance the rate and quality of healing of ligaments of the knee [8]. Recent improvements in ACL reconstruction have focused on strategies to improve graft placements and methodologies to enhance graft healing [9]. New biologic engineering strategies are evolving for clinical application in ACL reconstruction [9]. Further work is needed for primary ACL repair, which may prove to be a new frontier in ligament repair [7]. Clinically applicable solutions to prevent adhesions in tendon healing remain elusive despite progress in understanding the mechanism of tendon healing and adhesions [25].
What the Evidence Shows¶
Healing Biology and Regeneration: The anterior cruciate ligament (ACL) has limited healing capability due to a lack of localized hematoma and low reparative cell supply [4]. Conversely, extra-articular ligaments such as the medial collateral ligament (MCL) heal spontaneously but with poor mechanical properties [4]. Bleeding at the injury site increases the healing response, evidenced by increased macrophage counts and collagen gene expression [6], though biomechanical testing did not demonstrate functional differences despite these markers [6]. Genetic alterations in key proteoglycans and glycoproteins affect structural development and repair, representing potential drug targets for pathological mechanisms [12].
Biologic Augmentation Strategies: New techniques utilizing growth factors, cell therapies, and gene therapies may enhance the rate and quality of ligament healing [8]. Application of a basic fibroblast growth factor (bFGF)-impregnated pellet enhances the healing potential of partially lacerated ACLs in canine models [10]. Addition of a collagen-platelet composite (CPC) to suture repair enhances structural properties in porcine models, associated with increased cellularity [17]. Evidence for platelet-rich plasma augmentation is scattered, requiring more standardization [18]. Preserving small amounts of muscle on tendon grafts is feasible for improving biological success in humans [19]. Recent efforts focus on optimizing the graft-bone interface to promote healing rate and strength [16].
Graft Behavior and Deficits: Early ligament function after repair depends on the cellular population of the repair [2]. Early graft function after reconstruction depends on the maintenance of organized collagen [2]. Despite remodeling, ACL grafts retain a deficit in tensile strength and stiffness compared to the original ligament [14]. This deficit may explain high failure rates in the first year after reconstruction [14]. Autografts and allografts demonstrate equivalent clinical results in posterior cruciate, collateral, and multi-ligament knee reconstruction [35].
Clinical Outcomes and Surgical Decision-Making: Early controlled motion of stable or surgically stabilized joints improves ligament scar behavior [1]. Nonoperative and operative treatments of MCL injuries lead to equally good results [28]. Better functional and clinical outcomes have been achieved with reconstruction rather than repair in multiligament-injured knees [26]. Lateral tenodesis appears to improve the restoration of laxity more effectively than augmented direct anatomical repair in chronic ankle instability [27]. Anterolateral ligament (ALL) injuries have limited intrinsic healing potential, with only 30.3% healing by 12 months after ACL reconstruction [21]. Patients with poor ligament quality have inferior clinical outcomes after arthroscopic all-inside anterior talofibular ligament repair [22]. Poor ligament quality is associated with lower scores and fewer patients exceeding the minimal clinically important difference threshold for sports-related activities [22]. Nonabsorbable suture augmentation protects ligaments from early failure but may negatively impact final strength and composition due to stress shielding [23].
Future Directions and Limitations: Recent improvements in ACL reconstruction focus on strategies to improve graft placement and methodologies to enhance healing [9]. New biologic engineering strategies are evolving for clinical application [9]. Ligament tissue biodegradable devices require dimensioning considerations for composite material solutions in rehabilitation [32]. Potential causes of failure after ACL reconstruction include graft failure, loss of motion, extensor mechanism dysfunction, osteoarthritis, and infection [34]. There is a deficiency in the literature regarding consistent, meaningful postoperative return to sport timelines following lateral ankle ligament repair [11]. More high-quality large randomized clinical trials with longer follow-up comparing ACL suture repair and reconstruction are needed [15].
Practical Considerations¶
The ACL has limited capability to heal due to a lack of localized hematoma and low reparative cell supply [4]. In contrast, extra-articular ligaments like the MCL heal spontaneously but with poor mechanical properties [4]. Bleeding at the ligament injury site increases the healing response, evidenced by increased macrophage counts and collagen gene expression [6]. However, biomechanical testing did not demonstrate functional differences despite these increased healing response markers associated with hemorrhage [6].
Early controlled motion of stable or surgically stabilized joints appears to improve ligament scar behavior [1]. Early ligament function after repair is dependent on the cellular population of the repair [2]. Early graft function after reconstruction is dependent on the maintenance of organized collagen [2]. Despite remodelling, the graft retains a deficit in tensile strength and stiffness compared to the original ligament [14]. This deficit in tensile strength and stiffness of the graft may explain high failure rates in the first year [14].
Biologic Augmentation: New techniques utilizing growth factors and cell and gene therapies may offer the potential to enhance the rate and quality of healing of ligaments of the knee [8]. The application of a bFGF-impregnated pellet enhances the healing potential of the partially lacerated ACL [10]. There is a growing body of evidence to support the use of PRP in selected indications for knee disorders [20]. Recent efforts at advancing the clinical success of ACL reconstruction have focused on strategies to enhance and optimize the biologic environment of the graft-bone interface [16]. Optimizing the biologic environment of the graft-bone interface aims to promote and potentially improve the healing rate and strength of the reconstruction [16]. Future studies should provide more standardization to investigate the benefits of biological augmentation in ACL surgery [18]. Preserving small amounts of muscle on tendon grafts is feasible for improving the biological success of ACL reconstruction in humans [19].
Surgical Technique and Outcomes: Recent improvements in ACL reconstruction have focused on strategies to improve graft placements and methodologies to enhance graft healing [9]. New biologic engineering strategies are evolving for clinical application in ACL reconstruction [9]. Further work is needed for primary ACL repair, though there is renewed interest and focus for this approach [7]. More high-quality large randomized clinical trials with longer follow-up comparing ACL suture repair and reconstruction are needed [15]. Nonabsorbable suture augmentation protects the ligament from early failure [23]. Stress shielding from nonabsorbable suture augmentation may negatively impact the final strength and composition of the reconstructed ligament [23].
Ankle and Spine Applications: There is a clear deficiency in the literature pertaining to consistent, meaningful postoperative return to sport timeline following lateral ankle ligament repair [11]. Patients with poor ligament quality have inferior clinical outcomes, particularly in terms of sports-related activities, after arthroscopic all-inside anterior talofibular ligament repair [22]. Patients with poor ligament quality have lower scores and fewer patients exceeding the minimal clinically important difference threshold [22]. Minimally invasive techniques and ligament-preserving decompression may help mitigate effects of iatrogenic alterations on adjacent segment degeneration after lumbar fusion surgery [29]. Further research is necessary to fully elucidate mechanisms regarding iatrogenic alterations on adjacent segment degeneration after lumbar fusion surgery [29].
General Health: Exercise is generally recommended for musculoskeletal health during pregnancy but requires counseling on contraindications and specific conditions [30].
Key Evidence¶
- [L5] Early controlled motion of stable or surgically stabilized joints appears to improve ligament scar behavior, but no treatment identified to date stimulates true ligament regeneration. (10.5435/00124635-199603000-00002)
- [L5] These findings suggest there may be key biological differences in development and maintenance of ACL tissue after repair or reconstruction, with early ligament function dependent on cellular population of the repair but early graft function dependent on the maintenance of organized collagen. (10.1177/2325967113512457)
- [L5] The paper outlines that the ACL has limited capability to heal due to a lack of localized hematoma and low reparative cell supply, whereas extra-articular ligaments like the MCL heal spontaneously but with poor mechanical properties. (10.1186/1758-2555-2-12)
- [L5] This study suggests there is an increased healing response with bleeding at the ligament injury site, evidenced by increased macrophage counts and collagen gene expression, though biomechanical testing did not demonstrate functional differences. (10.1177/03635465030310050501)
- [L5] Further work is clearly needed but there is renewed interest and focus for primary ACL repair that may yet prove the new frontier in ligament repair. (10.1186/s40634-018-0136-6)
- [L5] New techniques utilizing growth factors and cell and gene therapies may offer the potential to enhance the rate and quality of healing of ligaments of the knee. (10.5435/00124635-200011000-00004)
- [L5] Recent improvements in anterior cruciate ligament reconstruction have focused on strategies to improve graft placements and methodologies to enhance graft healing, with new biologic engineering strategies evolving for clinical application. (10.1177/0363546507311690)
- [L5] The application of a bFGF-impregnated pellet seems to enhance the healing potential of the partially lacerated ACL. (10.1007/s001670050049)
- [L4] The review identifies a clear deficiency in the literature pertaining to consistent, meaningful postoperative return to sport timeline following lateral ankle ligament repair. (10.1136/jisakos-2016-000064)
- [L4] This review summarizes genetic alterations and knockdown approaches to assess the role of key proteoglycans and glycoproteins in the structural development, function, and repair of tendon, ligament, and enthesis, identifying these genes as potential drug targets for disrupting pathological mechanisms leading to tendinopathy, ligamentopathy, and enthesopathy. (10.1155/2013/154812)
- [L5] Histologically, additional cell seeding did not enhance osteointegration, and a longer observation period is necessary to see if a true ligament-bone enthesis will be formed. (10.1177/0363546518818792)
- [L5] It notes that despite remodelling, the graft retains a deficit in tensile strength and stiffness compared to the original ligament, which may explain high failure rates in the first year. (10.1136/jisakos-2015-000041)
- [L1] More high-quality large randomized clinical trials with longer follow-up comparing ACL suture repair and reconstruction are needed. (10.1177/0363546520904690)
- [L5] Recent efforts at advancing the clinical success of ACL reconstruction have focused on strategies to enhance and optimize the biologic environment of the graft-bone interface to promote and potentially improve the healing rate and strength of the reconstruction. (10.1016/j.csm.2012.08.010)
- [L5] The addition of a CPC to a suture repair enhanced the structural properties of the ACL, and the improvement was associated with increased cellularity within the healing ligament. (10.1177/0363546509339915)
- [L1] Future studies should provide more standardisation to investigate the benefits of biological augmentation in ACL surgery. (10.1002/ksa.12127)
- [L5] Preserving small amounts of muscle on tendon grafts is feasible for improving the biological success of ACL reconstruction in humans. (10.1007/s00167-012-2181-5)
- [L5] There is a growing body of evidence to support the use of PRP in selected indications for knee disorders. (10.1302/2058-5241.2.160004)
- [L4] ALL injuries occurred in the majority of ACL-injured knees and had limited intrinsic healing potential, with only 30.3% healing by 12 months after ACLR. (10.1177/03635465211013015)
- [L3] However, patients with poor ligament quality have inferior clinical outcomes, particularly in terms of sports-related activities, as reflected by both lower scores and fewer patients exceeding the minimal clinically important difference threshold. (10.1016/j.arthro.2025.04.032)
- [L5] Although nonabsorbable suture augmentation protects the ligament from early failure, stress shielding may negatively impact the final strength and composition of the reconstructed ligament. (10.1016/j.jhsa.2021.09.014)
- [L5] The results suggest that injury leads to an antifibrotic, catabolic response in the rabbit anterior cruciate ligament, possibly to prevent fibrosis and diminish the risk for loss of joint motion. (10.1177/0363546508316283)
- [L5] Clinically applicable solutions to prevent adhesions remain elusive despite progress in understanding the mechanism of tendon healing and adhesions. (10.1016/j.jhsa.2017.06.013)
- [L2] The review suggests that the best treatment does not exist, but better functional and clinical outcomes have been achieved with reconstruction rather than repair. (10.1016/j.injury.2019.01.052)
- [L3] Objectively, lateral tenodesis appears to improve more effectively restoration of laxity. (10.1007/s00167-018-5244-4)
- [L1] Nonoperative and operative treatments of medial collateral ligament injuries lead to equally good results. (10.1177/0363546505284889)
- [L1] Minimally invasive techniques and ligament-preserving decompression may help mitigate these effects, though further research is necessary to fully elucidate these mechanisms. (10.1186/s13018-025-05561-1)
- [L5] This article reviews existing literature on musculoskeletal health considerations before, during, and after pregnancy to provide practical information to orthopaedic surgeons treating women of all ages and athletic abilities, highlighting that exercise is generally recommended but requires counseling on contraindications and specific conditions. (10.5435/jaaos-d-21-00044)
- [L4] In this study, we found that a variety of definitions of failure are used among studies published in the orthopaedic literature. (10.1016/j.asmr.2023.100801)
- [L5] This bibliographic review focuses on ligament tissue rehabilitation and the dimensioning considerations of composite material solutions. (10.1016/j.jbiomech.2009.07.019)
- [L4] This previously described treatment of acute tears of the medial ligaments, with or without an associated tear of the anterior cruciate ligament, provides good long-term results and is still recommended. (10.2106/00004623-199506000-00018)
- [L4] This review article provides a comprehensive analysis of the potential causes of failure after anterior cruciate ligament reconstruction, including graft failure, loss of motion, extensor mechanism dysfunction, osteoarthritis, and infection. (10.1016/j.csm.2012.08.015)
- [L4] The review demonstrates equivalent clinical results with the use of autografts or allografts. (10.1007/s00167-019-05426-1)
See Also¶
- Osteoarthritis
References¶
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[2] Histological Predictors of Maximum Failure Loads Differ Between the Healing ACL and ACL Grafts After 6 and 12 Months In Vivo. Orthopaedic Journal of Sports Medicine. 2013. DOI: 10.1177/2325967113512457
[4] Functional tissue engineering of ligament healing. BMC Sports Science, Medicine and Rehabilitation. 2010. DOI: 10.1186/1758-2555-2-12
[6] Effect of Hemorrhage on Medial Collateral Ligament Healing in a Mouse Model. The American Journal of Sports Medicine. 2003. DOI: 10.1177/03635465030310050501
[7] Anterior cruciate ligament repair – past, present and future. Journal of Experimental Orthopaedics. 2018. DOI: 10.1186/s40634-018-0136-6
[8] Healing and Repair of Ligament Injuries in the Knee. Journal of the American Academy of Orthopaedic Surgeons. 2000. DOI: 10.5435/00124635-200011000-00004
[9] Strategies to Improve Anterior Cruciate Ligament Healing and Graft Placement. The American Journal of Sports Medicine. 2008. DOI: 10.1177/0363546507311690
[10] Effect of basic fibroblast growth factor on the healing of defects in the canine anterior cruciate ligament. Knee Surgery, Sports Traumatology, Arthroscopy. 1997. DOI: 10.1007/s001670050049
[11] Return to sport following lateral ankle ligament repair is under-reported: a systematic review. Journal of ISAKOS. 2017. DOI: 10.1136/jisakos-2016-000064
[12] Defects in Tendon, Ligament, and Enthesis in Response to Genetic Alterations in Key Proteoglycans and Glycoproteins: A Review. Arthritis. 2013. DOI: 10.1155/2013/154812
[13] Osteointegration of a Novel Silk Fiber–Based ACL Scaffold by Formation of a Ligament-Bone Interface. The American Journal of Sports Medicine. 2019. DOI: 10.1177/0363546518818792
[14] Review of Clancy's article on anterior and posterior cruciate ligament reconstruction in rhesus monkeys. Journal of ISAKOS. 2016. DOI: 10.1136/jisakos-2015-000041
[15] Efficacy of Nonaugmented, Static Augmented, and Dynamic Augmented Suture Repair of the Ruptured Anterior Cruciate Ligament: A Systematic Review of the Literature. The American Journal of Sports Medicine. 2020. DOI: 10.1177/0363546520904690
[16] ACL Graft Healing and Biologics. Clinics in Sports Medicine. 2013. DOI: 10.1016/j.csm.2012.08.010
[17] Collagen-Platelet Composite Enhances Biomechanical and Histologic Healing of the Porcine Anterior Cruciate Ligament. The American Journal of Sports Medicine. 2009. DOI: 10.1177/0363546509339915
[18] Platelet‐rich plasma augmentation in anterior cruciate ligament reconstruction: Evidence is still too scattered. A scoping review of randomised controlled trials. Knee Surgery, Sports Traumatology, Arthroscopy. 2024. DOI: 10.1002/ksa.12127
[19] Effect of muscle preserved on tendon graft on intra‐articular healing in anterior cruciate ligament reconstruction. Knee Surgery, Sports Traumatology, Arthroscopy. 2012. DOI: 10.1007/s00167-012-2181-5
[20] Platelet-rich plasma (PRP) for knee disorders. EFORT Open Reviews. 2017. DOI: 10.1302/2058-5241.2.160004
[21] The Anterolateral Ligament Has Limited Intrinsic Healing Potential: A Serial, 3-Dimensional–Magnetic Resonance Imaging Study of Anterior Cruciate Ligament–Injured Knees From the SANTI Study Group. The American Journal of Sports Medicine. 2021. DOI: 10.1177/03635465211013015
[22] Ligament Quality Predicts Recurrence and Functional Outcomes After Arthroscopic All‐Inside Anterior Talofibular Ligament Repair. Arthroscopy. 2025. DOI: 10.1016/j.arthro.2025.04.032
[23] Stress Shielding of Ligaments Using Nonabsorbable Suture Augmentation May Influence the Biology of Ligament Healing. The Journal of Hand Surgery. 2022. DOI: 10.1016/j.jhsa.2021.09.014
[24] Injury-Induced Changes in mRNA Levels Differ Widely between Anterior Cruciate Ligament and Medial Collateral Ligament. The American Journal of Sports Medicine. 2008. DOI: 10.1177/0363546508316283
[25] Molecular Biology of Flexor Tendon Healing in Relation to Reduction of Tendon Adhesions. The Journal of Hand Surgery. 2017. DOI: 10.1016/j.jhsa.2017.06.013
[26] Major concern in the multiligament-injured knee treatment: A systematic review. Injury. 2019. DOI: 10.1016/j.injury.2019.01.052
[27] Lateral ligament reconstruction and augmented direct anatomical repair restore ligament laxity in patients suffering from chronic ankle instability up to 15 years from surgery. Knee Surgery, Sports Traumatology, Arthroscopy. 2018. DOI: 10.1007/s00167-018-5244-4
[28] Operative and Nonoperative Treatments of Medial Collateral Ligament Rupture with Early Anterior Cruciate Ligament Reconstruction. The American Journal of Sports Medicine. 2006. DOI: 10.1177/0363546505284889
[29] Impact of iatrogenic alterations on adjacent segment degeneration after lumbar fusion surgery: a systematic review. Journal of Orthopaedic Surgery and Research. 2025. DOI: 10.1186/s13018-025-05561-1
[30] Musculoskeletal Considerations for Exercise and Sport: Before, During, and After Pregnancy. Journal of the American Academy of Orthopaedic Surgeons. 2021. DOI: 10.5435/jaaos-d-21-00044
[31] Various Definitions of Failure Are Used in Studies of Patients Who Underwent Anterior Cruciate Ligament Reconstruction. Arthroscopy, Sports Medicine, and Rehabilitation. 2023. DOI: 10.1016/j.asmr.2023.100801
[32] Development of ligament tissue biodegradable devices: A review. Journal of Biomechanics. 2009. DOI: 10.1016/j.jbiomech.2009.07.019
[33] The importance of the posterior oblique ligament in repairs of acute tears of the medial ligaments in knees with and without an associated rupture of the anterior cruciate ligament. Results of long-term follow-up.. The Journal of Bone & Joint Surgery. 1995. DOI: 10.2106/00004623-199506000-00018
[34] Failure of Anterior Cruciate Ligament Reconstruction. Clinics in Sports Medicine. 2013. DOI: 10.1016/j.csm.2012.08.015
[35] The use of allograft tissue in posterior cruciate, collateral and multi-ligament knee reconstruction. Knee Surgery, Sports Traumatology, Arthroscopy. 2019. DOI: 10.1007/s00167-019-05426-1