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Cartilage Biology and Repair

Overview

Success in cell-based orthopaedic treatment options for cartilage trauma and early osteoarthritic degeneration depends on strategies relying on known mechanisms of chondrocyte regulation [1]. Current clinical treatments for articular cartilage defects have limited ability to repair tissue and often result in mechanically inferior cartilage [6]. Emerging regenerative approaches and strategies are being discussed to address the limitations of current clinical treatments for articular cartilage defects [6]. No single technology fully meets the essential requirements for effective cartilage healing while remaining easily applicable during surgical procedures [7]. Various problems remain unresolved for successful repair associated with the formation of hyaline cartilage in vivo [9].

Optimal management of cartilage defects is controversial [4]. Autologous chondrocyte implantation, matrix-induced autologous chondrocyte implantation, osteochondral autograft transplantation, and osteochondral allograft improve knee function and pain [10]. When selecting a procedure for cartilage repair, patient and cartilage defect characteristics should be assessed to determine the best technique for each individual patient [10]. Some efficacy has been shown of mesenchymal stem cells (MSCs) for cartilage repair in osteoarthritis, but the evidence of efficacy on clinical outcomes and cartilage repair remains limited [3]. Despite promising results shown by cell therapies and platelet-rich plasma (PRP) for treating degenerative joint conditions, additional studies are needed to provide more definitive conclusions [42].

Future rigorous research methods could minimize common biases in cartilage defect management through strict study design, patient selection criteria, larger patient enrollment, more extended follow-up, and standardization of clinical treatment pathways [4]. A variety of definitions of failure are used to evaluate knee chondral restorative surgery outcomes in the orthopaedic literature [37]. Revision surgery is the most common definition of failure in studies evaluating knee cartilage restoration outcomes [37]. New advances in noninvasive detection of cartilage biochemistry provide insight into the ultrastructure of cartilage repair tissue [5]. Noninvasive detection of cartilage biochemistry may eventually obviate the need for surgical biopsy and provide an objective assessment of treatment outcome [5]. Magnetic resonance imaging has created an important role for reproducible, noninvasive, and objective evaluation and monitoring of cartilage in the setting of trauma, degenerative arthritides, and surgical treatment for cartilage injury [46].

How It Works

Understanding the basic science of cartilage and changes occurring in osteoarthritis is imperative to develop novel strategies to diagnose and treat this disorder [22]. A profound understanding of the basic anatomic aspects of subchondral bone and the pathophysiology of diseases affecting it is key to developing targeted and effective therapeutic strategies for osteochondral defects [21]. Future advances in osteoarthritis research require an ontogenetic framework that recognizes and interprets interactions of mechanics and biology on the organ, tissue, cell, and molecular level [23].

Extracellular matrix destruction in osteoarthritic articular cartilage resembles that in the hypertrophic zone of fetal growth plate during endochondral ossification [11]. Understanding mechanisms underlying developmental skeletogenesis facilitates the development of regenerative approaches by harnessing the inherent regenerative potential of skeletal tissues [18]. Understanding interactions between mechanics and biology is an important step toward developing tissue engineering approaches and therapeutic interventions for cartilage pathologies such as osteoarthritis [19].

Exosome-based therapeutic strategies against osteoarthritis are supported by findings that mesenchymal stem cell-derived miR-125b-1-3p-abundant exosomes alleviate osteoarthritis by modulating the KDM6B-H3K27me3-FOXM1 axis [20]. Improved understanding of biophysical and molecular pathways involved in chondrocyte mechanotransduction can provide insight into the development of novel therapeutic approaches for osteoarthritis [25].

Articular cartilage design involves cell-and-matrix composition and structure that make normal function possible, along with interactions between chondrocytes and their matrix necessary to maintain the tissue [26]. Mechanical degradation in cartilage may underlie the onset of microcracks, leading to physiological loading that the cartilage is unable to repair by its nature [27]. Apoptosis activation by the extrinsic pathway in osteoarthritic cartilage suggests that apoptosis-positive cells may act as a protection mechanism after sublethal injury to facilitate repair [24].

What the Evidence Shows

Current clinical treatments for articular cartilage defects have limited ability to repair tissue and often result in mechanically inferior cartilage [6]. No single technology fully meets the essential requirements for effective cartilage healing while remaining easily applicable during surgical procedures [7]. Various problems remain unresolved for a successful repair associated with the formation of hyaline cartilage in vivo [9]. Success in cell-based orthopaedic treatment for cartilage trauma and early osteoarthritic degeneration depends on strategies relying on known mechanisms of chondrocyte regulation [1].

Autologous Chondrocyte Implantation (ACI): Improves knee function and pain with considerations for patient and cartilage defect characteristics [10]. Matrix-Induced Autologous Chondrocyte Implantation (MACI): Improves knee function and pain with considerations for patient and cartilage defect characteristics [10]. Osteochondral Autograft Transplantation (OATS): Improves knee function and pain with considerations for patient and cartilage defect characteristics [10]. Osteochondral Allograft: Improves knee function and pain with considerations for patient and cartilage defect characteristics [10]. When selecting a procedure, patient and cartilage defect characteristics should be assessed to determine the best technique for each individual patient [10]. Basic science and clinical studies support the safety and efficacy of fresh osteochondral allograft transplantation for managing a wide spectrum of chondral and osteochondral knee disorders [16].

Microfracture (MF): Provides effective short-term functional improvement of knee function but insufficient data are available on its long-term results [12]. The meta-analysis shows no significant difference between microfracture (MF) and MF with scaffold in treating knee cartilage defects, though some long-term RCTs demonstrate statistically significant differences [41]. Cartilage repair surgery prevents progression of knee degeneration over 6 years compared to non-operated control subjects with initially identical defects [28].

Mesenchymal Stem Cells (MSCs): Some efficacy has been shown of mesenchymal stem cells (MSCs) for cartilage repair in osteoarthritis; however, the evidence of efficacy of intra-articular MSCs on both clinical outcomes and cartilage repair remains limited [3]. Most studies reported successful cartilage repair with synovium-derived MSC (sMSC) transplantation despite variability in animals, cell harvesting techniques, methods of delivery, and outcome measures [29]. sMSC transplantation holds promise as a treatment option for focal cartilage defects [29]. There is insufficient evidence from the studies included in the review to say whether cell-based therapy is superior to other treatment strategies in articular cartilage lesions of the knee [43]. This systematic review underlined the difficulties in understanding the real need for cells to increase the scaffold-based cartilage healing potential because of the heterogeneity of products used as well as the design of the published studies [8].

Growth Factors: The application of growth factors in the treatment of local cartilage defects as well as osteoarthritis appears promising; however, further research is needed at both the basic science and clinical levels before routine application [31]. Vitamin D: The role of vitamin D supplementation in the treatment or prevention of osteoarthritis remains uncertain [34].

Scaffolds: This review evaluates bi-phasic and multi-phasic scaffold-based approaches for osteochondral tissue regeneration, highlighting the importance of an interface layer between bone and cartilage [47]. This aragonite-based scaffold was safe and effective in the treatment of chondral and osteochondral lesions in the knee, including patients with mild to moderate osteoarthritis, and provided superior outcomes as compared with the control group [35].

Combined Procedures: Clinical outcomes after combined meniscal allograft transplantation (MAT) and cartilage repair/restoration are similar to those after either procedure in isolation [15]. Focal Metallic Implants (FMI): In clinical practice, a thorough analysis of pre-existing defects on the opposing cartilage is recommended when focal metallic implants (FMI) are considered [17].

Patellar Lesions: In this systematic review with meta-analysis, overall good to excellent outcomes were observed for all identified treatments for isolated patellar cartilage lesions, with mean estimated failure rates less than 10% and PROMs ranging from 70% to 85% of the maximum score [44]. Pediatric Population: Articular cartilage repair techniques appear to be safe in children and adolescents, with no differences in complication rates reported when compared with adult patients [14]. Hip Cartilage: Nonoperative treatment remains the mainstay of management for patients with articular cartilage injury of the hip, and there is a heterogeneity of support in the scientific literature regarding the efficacy of biologic injections for cartilage disease of the hip [39].

The literature on existing cartilage treatment options is limited by heterogeneity in surgical procedures and reporting of non-standardised outcome measures [32]. Optimal management of cartilage defects is controversial, and future rigorous research methods could minimize common biases through strict study design, patient selection criteria, larger patient enrollment, more extended follow-up, and standardization of clinical treatment pathways [4]. The vast majority of cartilage repair procedures were applied in degenerative, non-traumatic cartilage defects [13].

New advances in noninvasive detection of cartilage biochemistry provide insight into the ultrastructure of cartilage repair tissue, eventually obviating the need for surgical biopsy and providing an objective assessment of treatment outcome [5]. This review describes subchondral bone cysts in the context of articular cartilage repair to improve investigations of these pathological changes [45]. By blocking TGF-β1 with losartan, the repair cartilage tissue after marrow stimulation (BMS) was superior to the other groups and consisted primarily of hyaline cartilage in a rabbit osteochondral defect model [40].

Practical Considerations

Current clinical treatments for articular cartilage defects have limited ability to repair tissue and often result in mechanically inferior cartilage [6]. No single technology fully meets the essential requirements for effective cartilage healing while remaining easily applicable during surgical procedures [7]. Success in cell-based orthopaedic treatment options for cartilage trauma and early osteoarthritic degeneration depends on strategies relying on known mechanisms of chondrocyte regulation [1]. Regenerating cartilage through cell culture remains challenging with respect to sourcing cells, their availability, chondrogenic capabilities, and the lasting viability of the graft [36]. Various problems remain unresolved for a successful repair associated with the formation of hyaline cartilage in vivo [9].

Optimal management of cartilage defects is controversial [4]. Future rigorous research methods could minimize common biases through strict study design, patient selection criteria, larger patient enrollment, more extended follow-up, and standardization of clinical treatment pathways [4]. Difficulties exist in understanding the real need for cells to increase scaffold-based cartilage healing potential due to the heterogeneity of products and study designs [8]. Some efficacy has been shown of mesenchymal stem cells (MSCs) for cartilage repair in osteoarthritis, but the evidence of efficacy on both clinical outcomes and cartilage repair remains limited [3].

Microfracture: Provides effective short-term functional improvement of knee function, but insufficient data are available on its long-term results [12].

Autologous chondrocyte implantation, matrix-induced autologous chondrocyte implantation, osteochondral autograft transplantation, and osteochondral allograft: Improve knee function and pain with considerations for patient and cartilage defect characteristics [10]. When selecting a procedure, patient and cartilage defect characteristics should be assessed to determine the best technique for each individual patient [10]. Basic science and clinical studies support the safety and efficacy of fresh osteochondral allograft transplantation for managing a wide spectrum of chondral and osteochondral knee disorders [16].

Articular cartilage repair techniques appear to be safe in children and adolescents, with no differences in complication rates reported when compared with adult patients [14]. Clinical outcomes after combined meniscal allograft transplantation (MAT) and cartilage repair/restoration are similar to those after either procedure in isolation [15]. In clinical practice, a thorough analysis of pre-existing defects on the opposing cartilage is recommended when focal metallic implants (FMI) are considered [17]. Currently employed treatments for knee cartilage defects in the United States are cost-effective in most clinically acceptable applications [30].

New advances in noninvasive detection of cartilage biochemistry provide insight into the ultrastructure of cartilage repair tissue, eventually obviating the need for surgical biopsy and providing an objective assessment of treatment outcome [5]. The recent literature contains some limited evidence on the efficacy, potential toxicity, and long-term safety of glucosamine and chondroitin sulfate for the treatment of patients with osteoarthritis [38].

Key Evidence

  • [L5] Success in current efforts towards cell-based orthopaedic treatment options in cases of cartilage trauma and early stages of osteoarthritic degeneration will strictly depend on strategies that rely on known mechanisms of a chondrocyte's regulation. (10.1016/j.injury.2008.01.044)
  • [L2] Some efficacy has been shown of MSCs for cartilage repair in osteoarthritis; however, the evidence of efficacy of intra-articular MSCs on both clinical outcomes and cartilage repair remains limited. (10.1016/j.arthro.2018.07.028)
  • [L1] Optimal management of cartilage defects is controversial, and future rigorous research methods could minimize common biases through strict study design and patient selection criteria, larger patient enrollment, more extended follow-up, and standardization of clinical treatment pathways. (10.1016/j.arthro.2012.02.022)
  • [L5] New advances in noninvasive detection of cartilage biochemistry provide insight into the ultrastructure of cartilage repair tissue, eventually obviating the need for surgical biopsy and providing an objective assessment of treatment outcome. (10.1016/j.csm.2008.08.004)
  • [L4] Current clinical treatments for articular cartilage defects have limited ability to repair tissue and often result in mechanically inferior cartilage; emerging regenerative approaches and strategies informing future treatment options are discussed to address these limitations. (10.3389/fbioe.2021.770655)
  • [L4] Currently, no single technology fully meets the essential requirements for effective cartilage healing while remaining easily applicable during surgical procedures. (10.3390/jcm12206434)
  • [L4] This systematic review underlined the difficulties in understanding the real need for cells to increase the scaffold-based cartilage healing potential because of the heterogeneity of products used as well as the design of the published studies. (10.1016/j.arthro.2014.11.017)
  • [L4] Various problems remain unresolved for a successful repair associated with the formation of hyaline cartilage in vivo. (10.1155/2012/168385)
  • [L1] When selecting a procedure, patient and cartilage defect characteristics should be assessed to determine the best technique for each individual patient. (10.1002/ksa.12525)
  • [L5] The paper concludes that extracellular matrix destruction in osteoarthritic articular cartilage resembles that in the hypertrophic zone of fetal growth plate during endochondral ossification, suggesting common regulatory mechanisms that could provide new approaches for treatment by targeting chondrocyte phenotype reparation. (10.1155/2011/683970)
  • [L1] This systematic analysis shows that microfracture provides effective short-term functional improvement of knee function but insufficient data are available on its long-term results. (10.1177/0363546508328414)
  • [L4] The vast majority of cartilage repair procedures were applied in degenerative, non-traumatic cartilage defects. (10.1007/s00402-016-2453-5)
  • [L5] Articular cartilage repair techniques appear to be safe in children and adolescents, with no differences in complication rates reported when compared with adult patients. (10.1177/2325967118760190)
  • [L4] Clinical outcomes after combined MAT and cartilage repair/restoration are similar to those after either procedure in isolation. (10.1016/j.arthro.2010.08.007)
  • [L5] Basic science and clinical studies support the safety and efficacy of fresh osteochondral allograft transplantation for managing a wide spectrum of chondral and osteochondral knee disorders. (10.5435/jaaos-22-03-199)
  • [L5] In clinical practice, a thorough analysis of pre-existing defects on the opposing cartilage is recommended when FMI is considered. (10.1186/s12891-020-03292-4)
  • [Paper] Understanding the mechanisms underlying developmental skeletogenesis should greatly facilitate the development of regenerative approaches to cartilage repair by harnessing the inherent regenerative potential of skeletal tissues. (10.1097/01.blo.0000143560.41767.ee)
  • [L5] Understanding these interactions is an important step toward developing tissue engineering approaches and therapeutic interventions for cartilage pathologies, such as osteoarthritis. (10.1007/s11926-014-0451-6)
  • [L5] These findings provide a theoretical rationale and identify promising therapeutic targets for the development of exosome-based therapeutic strategies against OA. (10.1186/s13018-026-06765-9)
  • [L5] A profound understanding of the basic anatomic aspects of the subchondral bone, together with the pathophysiology of diseases affecting it, is the key to develop targeted and effective therapeutic strategies to treat osteochondral defects. (10.1007/s00167-010-1054-z)
  • [L5] Understanding the basic science of cartilage and the changes that occur in osteoarthritis is imperative to develop novel strategies to diagnose and treat this disorder. (10.1016/j.csm.2004.08.007)
  • [L5] Future advances in osteoarthritis research will be possible if research is conducted within an ontogenetic framework that recognizes and interprets the interactions of mechanics and biology on the organ, tissue, cell, and molecular level. (10.1097/01.blo.0000144970.05107.7e)
  • [L4] The study demonstrated apoptosis activation by the extrinsic pathway in OA cartilage, suggesting that apoptosis-positive cells may act as a protection mechanism after sublethal injury to facilitate repair. (10.1007/s00167-010-1215-0)
  • [Paper] An improved understanding of the biophysical and molecular pathways involved in chondrocyte mechanotransduction can provide insight into the development of novel therapeutic approaches for osteoarthritis. (10.1016/j.berh.2011.11.013)
  • [L5] This review covers the current understanding of the design of articular cartilage (the cell-and-matrix composition and the structure that make normal function of the cartilage possible) as well as the interactions between chondrocytes and their matrix that are necessary to maintain the tissue. (10.2106/00004623-199704000-00021)
  • [L5] This mechanical degradation may underlie onset of microcracks within the cartilage, leading to physiological loading that the cartilage by its nature is unable to repair. (10.1016/j.otsr.2021.103116)
  • [L3] Cartilage repair surgery prevents progression of knee degeneration over 6 years compared to non-operated control subjects with initially identical defects. (10.1007/s00167-018-5321-8)
  • [L2] Most studies reported successful cartilage repair with sMSC transplantation despite the variability of animals, cell harvesting techniques, methods of delivery, and outcome measures. sMSC transplantation holds promise as a treatment option for focal cartilage defects. (10.3389/fbioe.2019.00314)
  • [L2] Currently employed treatments for knee cartilage defects in the United States are cost-effective in most clinically acceptable applications. (10.1177/0363546519834557)
  • [L4] The application of growth factors in the treatment of local cartilage defects as well as osteoarthritis appears promising; however, further research is needed at both the basic science and clinical levels before routine application. (10.1007/s11999-011-1857-3)
  • [L5] Existing cartilage treatment options include marrow stimulation, osteochondral tissue transfer or transplantation, cell-free synthetic scaffolds and cell-based repair strategies, but the literature is limited by heterogeneity in surgical procedures and reporting of non-standardised outcome measures. (10.1136/jisakos-2015-000037)
  • [L4] The role of vitamin D supplementation in the treatment or prevention of OA remains uncertain. (10.1177/2325967117711376)
  • [L1] This aragonite-based scaffold was safe and effective in the treatment of chondral and osteochondral lesions in the knee, including patients with mild to moderate osteoarthritis, and provided superior outcomes as compared with the control group. (10.1177/03635465231151252)
  • [L4] Regenerating cartilage through cell culture remains challenging, particularly with respect to sourcing cells, their availability, chondrogenic capabilities and the lasting viability of the graft. (10.1530/eor-2024-0083)
  • [L1] A variety of definitions of failure are used to evaluate knee chondral restorative surgery outcomes in the orthopaedic literature. (10.1016/j.asmr.2024.101044)
  • [L5] The recent literature contains some limited evidence on the efficacy, potential toxicity, and long-term safety of glucosamine and chondroitin sulfate for the treatment of patients with osteoarthritis. (10.5435/00124635-200103000-00001)
  • [Paper] Nonoperative treatment remains the mainstay of management for patients with articular cartilage injury of the hip, and there is a heterogeneity of support in the scientific literature regarding the efficacy of biologic injections for cartilage disease of the hip. (10.1016/j.csm.2017.02.010)
  • [L5] By blocking TGF-b1 with losartan, the repair cartilage tissue after BMS was superior to the other groups and consisted primarily of hyaline cartilage. (10.1177/0363546519898681)
  • [L1] The meta-analysis shows no significant difference between MF and MF with scaffold in treating knee cartilage defects, though some long-term RCTs demonstrate statistically significant differences. (10.1002/ksa.12495)
  • [L4] Despite promising results shown by cell therapies and PRP for treating degenerative joint conditions, additional studies are needed to provide more definitive conclusions. (10.2106/jbjs.rvw.19.00075)
  • [L1] There is insufficient evidence from the studies included in this review to say whether cell-based therapy is superior to other treatment strategies in articular cartilage lesions of the knee. (10.1016/j.arthro.2009.02.007)
  • [Paper] In this systematic review with meta-analysis, overall good to excellent outcomes were observed for all identified treatments, with mean estimated failure rates less than 10% and PROMs ranging from 70% to 85% of the maximum score. (10.1177/23259671261443877)
  • [L4] This review describes subchondral bone cysts in the context of articular cartilage repair to improve investigations of these pathological changes. (10.1002/ctm2.248)
  • [L5] Magnetic resonance imaging has created an undeniably important role for reproducible, noninvasive, and objective evaluation and monitoring of cartilage in the setting of trauma, degenerative arthritides, and surgical treatment for cartilage injury. (10.1177/0363546505281938)
  • [L4] This review evaluates bi-phasic and multi-phasic scaffold-based approaches for osteochondral tissue regeneration, highlighting the importance of an interface layer between bone and cartilage. (10.3390/ijms19061755)

See Also

  • Osteoarthritis

References

[1] Perspectives on articular cartilage biology and osteoarthritis. Injury. 2008. DOI: 10.1016/j.injury.2008.01.044

[3] Intra-articular Mesenchymal Stem Cells in Osteoarthritis of the Knee: A Systematic Review of Clinical Outcomes and Evidence of Cartilage Repair. Arthroscopy: The Journal of Arthroscopic & Related Surgery. 2019. DOI: 10.1016/j.arthro.2018.07.028

[4] Limitations and Sources of Bias in Clinical Knee Cartilage Research. Arthroscopy. 2012. DOI: 10.1016/j.arthro.2012.02.022

[5] New Techniques in Articular Cartilage Imaging. Clinics in Sports Medicine. 2009. DOI: 10.1016/j.csm.2008.08.004

[6] Strategies for Articular Cartilage Repair and Regeneration. Frontiers in Bioengineering and Biotechnology. 2021. DOI: 10.3389/fbioe.2021.770655

[7] Knee Cartilage Lesion Management—Current Trends in Clinical Practice. Journal of Clinical Medicine. 2023. DOI: 10.3390/jcm12206434

[8] Scaffold‐Based Cartilage Treatments: With or Without Cells? A Systematic Review of Preclinical and Clinical Evidence. Arthroscopy. 2015. DOI: 10.1016/j.arthro.2014.11.017

[9] Stem Cells and Gene Therapy for Cartilage Repair. Stem Cells International. 2012. DOI: 10.1155/2012/168385

[10] Autologous chondrocyte implantation, matrix‐induced autologous chondrocyte implantation, osteochondral autograft transplantation and osteochondral allograft improve knee function and pain with considerations for patient and cartilage defects characteristics: A systematic review and meta‐analysis. Knee Surgery, Sports Traumatology, Arthroscopy. 2024. DOI: 10.1002/ksa.12525

[11] Developmental Mechanisms in Articular Cartilage Degradation in Osteoarthritis. Arthritis. 2011. DOI: 10.1155/2011/683970

[12] Clinical Efficacy of the Microfracture Technique for Articular Cartilage Repair in the Knee. The American Journal of Sports Medicine. 2009. DOI: 10.1177/0363546508328414

[13] Cartilage repair surgery for full-thickness defects of the knee in Germany: indications and epidemiological data from the German Cartilage Registry (KnorpelRegister DGOU). Archives of Orthopaedic and Trauma Surgery. 2016. DOI: 10.1007/s00402-016-2453-5

[14] Articular Cartilage Repair of the Knee in Children and Adolescents. Orthopaedic Journal of Sports Medicine. 2018. DOI: 10.1177/2325967118760190

[15] Biological Knee Reconstruction: A Systematic Review of Combined Meniscal Allograft Transplantation and Cartilage Repair or Restoration. Arthroscopy. 2010. DOI: 10.1016/j.arthro.2010.08.007

[16] Fresh Osteochondral Allograft Transplantation for the Knee. Journal of the American Academy of Orthopaedic Surgeons. 2014. DOI: 10.5435/jaaos-22-03-199

[17] Effects of focal metallic implants on opposing cartilage – an in-vitro study with an abrasion test machine. BMC Musculoskeletal Disorders. 2020. DOI: 10.1186/s12891-020-03292-4

[18] Biology of Developmental and Regenerative Skeletogenesis. Clinical Orthopaedics & Related Research. 2004. DOI: 10.1097/01.blo.0000143560.41767.ee

[19] The Mechanobiology of Articular Cartilage: Bearing the Burden of Osteoarthritis. Current Rheumatology Reports. 2014. DOI: 10.1007/s11926-014-0451-6

[20] Mesenchymal stem cell-derived miR-125b-1-3p-abundant exosomes alleviate osteoarthritis by modulating the KDM6B-H3K27me3-FOXM1 axis. Journal of Orthopaedic Surgery and Research. 2026. DOI: 10.1186/s13018-026-06765-9

[21] The basic science of the subchondral bone. Knee Surgery, Sports Traumatology, Arthroscopy. 2010. DOI: 10.1007/s00167-010-1054-z

[22] Basic Science of Articular Cartilage and Osteoarthritis. Clinics in Sports Medicine. 2005. DOI: 10.1016/j.csm.2004.08.007

[23] The Mechanobiology of Articular Cartilage Development and Degeneration. Clinical Orthopaedics & Related Research. 2004. DOI: 10.1097/01.blo.0000144970.05107.7e

[24] Characterization of apoptosis in articular cartilage derived from the knee joints of patients with osteoarthritis. Knee Surgery, Sports Traumatology, Arthroscopy. 2010. DOI: 10.1007/s00167-010-1215-0

[25] Biomechanical factors in osteoarthritis. Best Practice & Research Clinical Rheumatology. 2011. DOI: 10.1016/j.berh.2011.11.013

[26] Instructional Course Lectures, The American Academy of Orthopaedic Surgeons - Articular Cartilage. Part I. The Journal of Bone & Joint Surgery. 1997. DOI: 10.2106/00004623-199704000-00021

[27] Early impairment of cartilage poroelastic properties in an animal model of ACL tear. Orthopaedics & Traumatology: Surgery & Research. 2022. DOI: 10.1016/j.otsr.2021.103116

[28] Cartilage repair surgery prevents progression of knee degeneration. Knee Surgery, Sports Traumatology, Arthroscopy. 2018. DOI: 10.1007/s00167-018-5321-8

[29] Synovium-Derived Mesenchymal Stem Cell Transplantation in Cartilage Regeneration: A PRISMA Review of in vivo Studies. Frontiers in Bioengineering and Biotechnology. 2019. DOI: 10.3389/fbioe.2019.00314

[30] Cost-efficacy of Knee Cartilage Defect Treatments in the United States. The American Journal of Sports Medicine. 2019. DOI: 10.1177/0363546519834557

[31] The Role of Growth Factors in Cartilage Repair. Clinical Orthopaedics & Related Research. 2011. DOI: 10.1007/s11999-011-1857-3

[32] Articular cartilage solutions for the knee: present challenges and future direction. Journal of ISAKOS. 2016. DOI: 10.1136/jisakos-2015-000037

[34] Vitamin D and Its Effects on Articular Cartilage and Osteoarthritis. Orthopaedic Journal of Sports Medicine. 2017. DOI: 10.1177/2325967117711376

[35] Aragonite-Based Scaffold Versus Microfracture and Debridement for the Treatment of Knee Chondral and Osteochondral Lesions: Results of a Multicenter Randomized Controlled Trial. The American Journal of Sports Medicine. 2023. DOI: 10.1177/03635465231151252

[36] Current trends in the treatment of focal cartilage lesions: a comprehensive review. EFORT Open Reviews. 2025. DOI: 10.1530/eor-2024-0083

[37] Revision Surgery Is the Most Common Definition of Failure in Studies Evaluating Knee Cartilage Restoration Outcomes: A Systematic Review. Arthroscopy, Sports Medicine, and Rehabilitation. 2024. DOI: 10.1016/j.asmr.2024.101044

[38] Use of Glucosamine and Chondroitin Sulfatein the Management of Osteoarthritis. Journal of the American Academy of Orthopaedic Surgeons. 2001. DOI: 10.5435/00124635-200103000-00001

[39] A Critical Review. Clinics in Sports Medicine. 2017. DOI: 10.1016/j.csm.2017.02.010

[40] Biologically Regulated Marrow Stimulation by Blocking TGF-β1 With Losartan Oral Administration Results in Hyaline-like Cartilage Repair: A Rabbit Osteochondral Defect Model. The American Journal of Sports Medicine. 2020. DOI: 10.1177/0363546519898681

[41] Does scaffold enhancement show significant superiority over microfracture alone for treating knee chondral defects? A systematic review and meta‐analysis of randomised clinical trials. Knee Surgery, Sports Traumatology, Arthroscopy. 2024. DOI: 10.1002/ksa.12495

[42] Glenohumeral Osteoarthritis: The Role for Orthobiologic Therapies. JBJS Reviews. 2020. DOI: 10.2106/jbjs.rvw.19.00075

[43] Cell‐Based Therapy in Articular Cartilage Lesions of the Knee. Arthroscopy. 2009. DOI: 10.1016/j.arthro.2009.02.007

[44] Outcomes of Restorative Treatment for Isolated Patellar Cartilage Lesions: A Systematic Review and Meta-analysis. Orthopaedic Journal of Sports Medicine. 2026. DOI: 10.1177/23259671261443877

[45] Cyst formation in the subchondral bone following cartilage repair. Clinical and Translational Medicine. 2020. DOI: 10.1002/ctm2.248

[46] Magnetic Resonance Imaging of Articular Cartilage. The American Journal of Sports Medicine. 2006. DOI: 10.1177/0363546505281938

[47] Recent Approaches to the Manufacturing of Biomimetic Multi-Phasic Scaffolds for Osteochondral Regeneration. International Journal of Molecular Sciences. 2018. DOI: 10.3390/ijms19061755

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Section 1 -- Definitions.

a. Adapted Material means material subject to Copyright and Similar Rights that is derived from or based upon the Licensed Material and in which the Licensed Material is translated, altered, arranged, transformed, or otherwise modified in a manner requiring permission under the Copyright and Similar Rights held by the Licensor. For purposes of this Public License, where the Licensed Material is a musical work, performance, or sound recording, Adapted Material is always produced where the Licensed Material is synched in timed relation with a moving image.

b. Adapter's License means the license You apply to Your Copyright and Similar Rights in Your contributions to Adapted Material in accordance with the terms and conditions of this Public License.

c. Copyright and Similar Rights means copyright and/or similar rights closely related to copyright including, without limitation, performance, broadcast, sound recording, and Sui Generis Database Rights, without regard to how the rights are labeled or categorized. For purposes of this Public License, the rights specified in Section 2(b)(1)-(2) are not Copyright and Similar Rights.

d. Effective Technological Measures means those measures that, in the absence of proper authority, may not be circumvented under laws fulfilling obligations under Article 11 of the WIPO Copyright Treaty adopted on December 20, 1996, and/or similar international agreements.

e. Exceptions and Limitations means fair use, fair dealing, and/or any other exception or limitation to Copyright and Similar Rights that applies to Your use of the Licensed Material.

f. Licensed Material means the artistic or literary work, database, or other material to which the Licensor applied this Public License.

g. Licensed Rights means the rights granted to You subject to the terms and conditions of this Public License, which are limited to all Copyright and Similar Rights that apply to Your use of the Licensed Material and that the Licensor has authority to license.

h. Licensor means the individual(s) or entity(ies) granting rights under this Public License.

i. NonCommercial means not primarily intended for or directed towards commercial advantage or monetary compensation. For purposes of this Public License, the exchange of the Licensed Material for other material subject to Copyright and Similar Rights by digital file-sharing or similar means is NonCommercial provided there is no payment of monetary compensation in connection with the exchange.

j. Share means to provide material to the public by any means or process that requires permission under the Licensed Rights, such as reproduction, public display, public performance, distribution, dissemination, communication, or importation, and to make material available to the public including in ways that members of the public may access the material from a place and at a time individually chosen by them.

k. Sui Generis Database Rights means rights other than copyright resulting from Directive 96/9/EC of the European Parliament and of the Council of 11 March 1996 on the legal protection of databases, as amended and/or succeeded, as well as other essentially equivalent rights anywhere in the world.

l. You means the individual or entity exercising the Licensed Rights under this Public License. Your has a corresponding meaning.

Section 2 -- Scope.

a. License grant.

1. Subject to the terms and conditions of this Public License, the Licensor hereby grants You a worldwide, royalty-free, non-sublicensable, non-exclusive, irrevocable license to exercise the Licensed Rights in the Licensed Material to:

a. reproduce and Share the Licensed Material, in whole or in part, for NonCommercial purposes only; and

b. produce, reproduce, and Share Adapted Material for NonCommercial purposes only.

2. Exceptions and Limitations. For the avoidance of doubt, where Exceptions and Limitations apply to Your use, this Public License does not apply, and You do not need to comply with its terms and conditions.

3. Term. The term of this Public License is specified in Section 6(a).

4. Media and formats; technical modifications allowed. The Licensor authorizes You to exercise the Licensed Rights in all media and formats whether now known or hereafter created, and to make technical modifications necessary to do so. The Licensor waives and/or agrees not to assert any right or authority to forbid You from making technical modifications necessary to exercise the Licensed Rights, including technical modifications necessary to circumvent Effective Technological Measures. For purposes of this Public License, simply making modifications authorized by this Section 2(a) (4) never produces Adapted Material.

5. Downstream recipients.

a. Offer from the Licensor -- Licensed Material. Every recipient of the Licensed Material automatically receives an offer from the Licensor to exercise the Licensed Rights under the terms and conditions of this Public License.

b. No downstream restrictions. You may not offer or impose any additional or different terms or conditions on, or apply any Effective Technological Measures to, the Licensed Material if doing so restricts exercise of the Licensed Rights by any recipient of the Licensed Material.

6. No endorsement. Nothing in this Public License constitutes or may be construed as permission to assert or imply that You are, or that Your use of the Licensed Material is, connected with, or sponsored, endorsed, or granted official status by, the Licensor or others designated to receive attribution as provided in Section 3(a)(1)(A)(i).

b. Other rights.

1. Moral rights, such as the right of integrity, are not licensed under this Public License, nor are publicity, privacy, and/or other similar personality rights; however, to the extent possible, the Licensor waives and/or agrees not to assert any such rights held by the Licensor to the limited extent necessary to allow You to exercise the Licensed Rights, but not otherwise.

2. Patent and trademark rights are not licensed under this Public License.

3. To the extent possible, the Licensor waives any right to collect royalties from You for the exercise of the Licensed Rights, whether directly or through a collecting society under any voluntary or waivable statutory or compulsory licensing scheme. In all other cases the Licensor expressly reserves any right to collect such royalties, including when the Licensed Material is used other than for NonCommercial purposes.

Section 3 -- License Conditions.

Your exercise of the Licensed Rights is expressly made subject to the following conditions.

a. Attribution.

1. If You Share the Licensed Material (including in modified form), You must:

a. retain the following if it is supplied by the Licensor with the Licensed Material:

i. identification of the creator(s) of the Licensed Material and any others designated to receive attribution, in any reasonable manner requested by the Licensor (including by pseudonym if designated);

ii. a copyright notice;

iii. a notice that refers to this Public License;

iv. a notice that refers to the disclaimer of warranties;

v. a URI or hyperlink to the Licensed Material to the extent reasonably practicable;

b. indicate if You modified the Licensed Material and retain an indication of any previous modifications; and

c. indicate the Licensed Material is licensed under this Public License, and include the text of, or the URI or hyperlink to, this Public License.

2. You may satisfy the conditions in Section 3(a)(1) in any reasonable manner based on the medium, means, and context in which You Share the Licensed Material. For example, it may be reasonable to satisfy the conditions by providing a URI or hyperlink to a resource that includes the required information.

3. If requested by the Licensor, You must remove any of the information required by Section 3(a)(1)(A) to the extent reasonably practicable.

4. If You Share Adapted Material You produce, the Adapter's License You apply must not prevent recipients of the Adapted Material from complying with this Public License.

Section 4 -- Sui Generis Database Rights.

Where the Licensed Rights include Sui Generis Database Rights that apply to Your use of the Licensed Material:

a. for the avoidance of doubt, Section 2(a)(1) grants You the right to extract, reuse, reproduce, and Share all or a substantial portion of the contents of the database for NonCommercial purposes only;

b. if You include all or a substantial portion of the database contents in a database in which You have Sui Generis Database Rights, then the database in which You have Sui Generis Database Rights (but not its individual contents) is Adapted Material; and

c. You must comply with the conditions in Section 3(a) if You Share all or a substantial portion of the contents of the database.

For the avoidance of doubt, this Section 4 supplements and does not replace Your obligations under this Public License where the Licensed Rights include other Copyright and Similar Rights.

Section 5 -- Disclaimer of Warranties and Limitation of Liability.

a. UNLESS OTHERWISE SEPARATELY UNDERTAKEN BY THE LICENSOR, TO THE EXTENT POSSIBLE, THE LICENSOR OFFERS THE LICENSED MATERIAL AS-IS AND AS-AVAILABLE, AND MAKES NO REPRESENTATIONS OR WARRANTIES OF ANY KIND CONCERNING THE LICENSED MATERIAL, WHETHER EXPRESS, IMPLIED, STATUTORY, OR OTHER. THIS INCLUDES, WITHOUT LIMITATION, WARRANTIES OF TITLE, MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, NON-INFRINGEMENT, ABSENCE OF LATENT OR OTHER DEFECTS, ACCURACY, OR THE PRESENCE OR ABSENCE OF ERRORS, WHETHER OR NOT KNOWN OR DISCOVERABLE. WHERE DISCLAIMERS OF WARRANTIES ARE NOT ALLOWED IN FULL OR IN PART, THIS DISCLAIMER MAY NOT APPLY TO YOU.

b. TO THE EXTENT POSSIBLE, IN NO EVENT WILL THE LICENSOR BE LIABLE TO YOU ON ANY LEGAL THEORY (INCLUDING, WITHOUT LIMITATION, NEGLIGENCE) OR OTHERWISE FOR ANY DIRECT, SPECIAL, INDIRECT, INCIDENTAL, CONSEQUENTIAL, PUNITIVE, EXEMPLARY, OR OTHER LOSSES, COSTS, EXPENSES, OR DAMAGES ARISING OUT OF THIS PUBLIC LICENSE OR USE OF THE LICENSED MATERIAL, EVEN IF THE LICENSOR HAS BEEN ADVISED OF THE POSSIBILITY OF SUCH LOSSES, COSTS, EXPENSES, OR DAMAGES. WHERE A LIMITATION OF LIABILITY IS NOT ALLOWED IN FULL OR IN PART, THIS LIMITATION MAY NOT APPLY TO YOU.

c. The disclaimer of warranties and limitation of liability provided above shall be interpreted in a manner that, to the extent possible, most closely approximates an absolute disclaimer and waiver of all liability.

Section 6 -- Term and Termination.

a. This Public License applies for the term of the Copyright and Similar Rights licensed here. However, if You fail to comply with this Public License, then Your rights under this Public License terminate automatically.

b. Where Your right to use the Licensed Material has terminated under Section 6(a), it reinstates:

1. automatically as of the date the violation is cured, provided it is cured within 30 days of Your discovery of the violation; or

2. upon express reinstatement by the Licensor.

For the avoidance of doubt, this Section 6(b) does not affect any right the Licensor may have to seek remedies for Your violations of this Public License.

c. For the avoidance of doubt, the Licensor may also offer the Licensed Material under separate terms or conditions or stop distributing the Licensed Material at any time; however, doing so will not terminate this Public License.

d. Sections 1, 5, 6, 7, and 8 survive termination of this Public License.

Section 7 -- Other Terms and Conditions.

a. The Licensor shall not be bound by any additional or different terms or conditions communicated by You unless expressly agreed.

b. Any arrangements, understandings, or agreements regarding the Licensed Material not stated herein are separate from and independent of the terms and conditions of this Public License.

Section 8 -- Interpretation.

a. For the avoidance of doubt, this Public License does not, and shall not be interpreted to, reduce, limit, restrict, or impose conditions on any use of the Licensed Material that could lawfully be made without permission under this Public License.

b. To the extent possible, if any provision of this Public License is deemed unenforceable, it shall be automatically reformed to the minimum extent necessary to make it enforceable. If the provision cannot be reformed, it shall be severed from this Public License without affecting the enforceability of the remaining terms and conditions.

c. No term or condition of this Public License will be waived and no failure to comply consented to unless expressly agreed to by the Licensor.

d. Nothing in this Public License constitutes or may be interpreted as a limitation upon, or waiver of, any privileges and immunities that apply to the Licensor or You, including from the legal processes of any jurisdiction or authority.

Creative Commons is not a party to its public licenses. Notwithstanding, Creative Commons may elect to apply one of its public licenses to material it publishes and in those instances will be considered the “Licensor.” The text of the Creative Commons public licenses is dedicated to the public domain under the CC0 Public Domain Dedication. Except for the limited purpose of indicating that material is shared under a Creative Commons public license or as otherwise permitted by the Creative Commons policies published at creativecommons.org/policies, Creative Commons does not authorize the use of the trademark "Creative Commons" or any other trademark or logo of Creative Commons without its prior written consent including, without limitation, in connection with any unauthorized modifications to any of its public licenses or any other arrangements, understandings, or agreements concerning use of licensed material. For the avoidance of doubt, this paragraph does not form part of the public licenses.

Creative Commons may be contacted at creativecommons.org.