R.V. Plotnitsky1, N.I. Abdullina2, S.V. Piatnitskaia3, V.A. Markelov4, V.A. Solntsev5, K.V. Danilko6

1–6 Institute of Fundamental Medicine, Bashkir State Medical University (Ufa, Russia)

1 plot.roma@yandex.ru, 2 abdullinanuri@gmail.com, 3 svpyatnickaya@bashgmu.ru, 4 vadim.solncev@inbox.ru, 5 marckelow.vitalick2017@yandex.ru, 6 kse-danilko@yandex.ru

In Russia and in the world many people suffer from joint diseases. The existing ways of restoring the affected joints are not effective and safe enough. New approaches are needed to reduce traumatization and increase the number of fully recovered patients.

The aim is to review publications from the last 10 years with studies of materials used in the repair of articular cartilage injuries and to analyze the positive and negative aspects of the materials described.

Literature search in databases PubMed Google Scholar revealed 67 publications describing various materials used in the repair of articular cartilage injuries. All the materials are categorized according to the approach to their creation: cellular approach; approach using synthetic polymers; and approach using polymers of natural origin. Publications that investigate combinations of the materials found and discuss their properties are also identified.

One of the solutions in the therapy of partial cartilage damage is the use of autologous chondrocytes, but their application in the clinic is difficult due to the difficulty of their obtaining and culturing due to the loss of chondrogenic phenotype. The solution to this problem may be the use of mesenchymal stem cells. In addition to the cellular approach, the ideal material for cartilage regeneration is currently considered to be cell-free cartilage matrix, which has good biocompatibility and cartilage-specific microenvironment However, their obtaining in a significant volume is also difficult, and research is being conducted in the direction of using other natural polymers, for example, hyaluronic acid, collagen, chitosan, gelatin. In addition to biomaterials, various polymeric materials are also being actively researched.

In summary, articular cartilage repair is a dynamic, interdisciplinary field that is constantly evolving. In this review, we have considered various cellular technologies, natural and synthetic polymers, and their combinations for the repair of cartilage defects. To date, approaches to articular cartilage repair are constantly improving, but significant challenges remain, such as maintaining a stable chondrocyte phenotype, preventing scaffold and cell degradation, maintaining the strength of engineered constructs, and their immunogenicity. In the future, we should expect the solution of the above problems, introduction of complex methods of treatment with lower financial costs and shorter recovery period.

Plotnitsky R.V., Abdullina N.I., Piatnitskaia S.V., Markelov V.A., Solntsev V.A., Danilko K.V. Regenerative technologies for the therapy of cartilaginous joint injuries: review. Technologies of Living Systems. 2025. V. 22. № 3. Р. 74-85. DOI: https://doi.org/10.18127/ j20700997-202503-08 (In Russian).

1. Kloppenburg M., Berenbaum F. Osteoarthritis year in review 2019: epidemiology and therapy. Osteoarthritis and cartilage. 2020. V. 28(3). P. 242–248. DOI: 10.1016/J.JOCA.2020.01.002
2. Daley E.L.H., Kuttig J., Stegemann J.P. Development of Modular, Dual-Perfused Osteochondral Constructs for Cartilage Repair. Tissue engineering Part C, Methods. 2019. V. 25(3). P. 127–136. DOI. P. 10.1089/TEN.TEC.2018.0356
3. Novakov V.B., Novakova O.N., Sorokina I.N. i dr. Geneticheskie markery osteoartroza kolennogo sustava u zhenshchin Central'nogo CHernozem'ya Rossii. Nauchnye rezul'taty biomedicinskih issledovanij. 2023. T. 9(2). S. 191–205. DOI: 10.18413/2658-6533-2023-9-2-0-4 (in Russian).
4. Bianchi V.J., Lee A., Anderson J. et al. Redifferentiated Chondrocytes in Fibrin Gel for the Repair of Articular Cartilage Lesions. The American journal of sports medicine. 2019. V. 47(10). P. 2348–2359. DOI: 10.1177/0363546519857571
5. McGivern S., Boutouil H., Al-Kharusi G. et al. Translational Application of 3D Bioprinting for Cartilage Tissue Engineering. Bioengineering (Basel, Switzerland). 2021. V. 8(10). DOI: 10.3390/BIOENGINEERING8100144
6. Hunter D.J., Bierma-Zeinstra S. Osteoarthritis. Lancet (London, England). 2019. V. 393(10182). P. 1745–1759. DOI: 10.1016/S0140-6736(19)30417-9
7. Wei W., Ma Y., Yao X. et al. Advanced hydrogels for the repair of cartilage defects and regeneration. Bioactive materials. 2020. V. 6(4). P. 998–1011. DOI: 10.1016/J.BIOACTMAT.2020.09.030
8. Wu Y., Kennedy P., Bonazza N. et al. Three-Dimensional Bioprinting of Articular Cartilage: A Systematic Review. Cartilage. 2021. V. 12(1). P. 76–92. DOI: 10.1177/1947603518809410
9. Jacobi M., Villa V., Magnussen R.A., Neyret P. MACI – a new era? Sports medicine, arthroscopy, rehabilitation, therapy & technology : SMARTT. 2011. V. 3(1). DOI: 10.1186/1758-2555-3-10
10. Benthien J.P., Behrens P. Nanofractured autologous matrix induced chondrogenesis (NAMIC©) – Further development of collagen membrane aided chondrogenesis combined with subchondral needling: A technical note. Knee. 2015. V. 22(5). P. 411–415. DOI: 10.1016/j.knee.2015.06.010
11. Kwon H., Brown W.E., Lee C.A. et al. Surgical and tissue engineering strategies for articular cartilage and meniscus repair. Nature reviews Rheumatology. 2019. V. 15(9). P. 550–570. DOI: 10.1038/S41584-019-0255-1
12. Smith L., Jakubiec A., Biant L., Tawy G. The biomechanical and functional outcomes of autologous chondrocyte implantation for articular cartilage defects of the knee: A systematic review. The Knee. 2023. V. 44. P. 31–42. DOI: 10.1016/J.KNEE.2023.07.004
13. Carey J.L., Remmers A.E., Flanigan D.C. Use of MACI (Autologous Cultured Chondrocytes on Porcine Collagen Membrane) in the United States: Preliminary Experience. Orthopaedic journal of sports medicine. 2020. V. 8(8). DOI: 10.1177/2325967120941816
14. Migliorini F., Vaishya R., Bell A. et al. Fixation of the Membrane during Matrix-Induced Autologous Chondrocyte Implantation in the Knee: A Systematic Review. Life (Basel, Switzerland). 2022. V. 12(11). DOI: 10.3390/LIFE12111718
15. Lee Y.H.D., Suzer F., Thermann H. Autologous Matrix-Induced Chondrogenesis in the Knee: A Review. Cartilage. 2014. V. 5(3). P. 145–153. DOI: 10.1177/1947603514529445
16. Mithoefer K., Mcadams T., Williams R.J. et al. Clinical efficacy of the microfracture technique for articular cartilage repair in the knee: an evidence-based systematic analysis. The American journal of sports medicine. 2009. V. 37(10). P. 2053–2063. DOI: 10.1177/0363546508328414
17. Carluccio S., Martinelli D., Palamà M.E.F. et al. Progenitor Cells Activated by Platelet Lysate in Human Articular Cartilage as a Tool for Future Cartilage Engineering and Reparative Strategies. Cells. 2020. V. 9. P. 1052. DOI: 10.3390/CELLS9041052
18. Jia L., Zhang P., Ci Z. et al. Acellular cartilage matrix biomimetic scaffold with immediate enrichment of autologous bone marrow mononuclear cells to repair articular cartilage defects. Materials today Bio. 2022. V. 15. DOI: 10.1016/J.MTBIO.2022.100310
19. Gupta P.K., Das A.K., Chullikana A., Majumdar A.S. Mesenchymal stem cells for cartilage repair in osteoarthritis. Stem cell research & therapy. 2012. V. 3(4). DOI: 10.1186/SCRT116
20. Wang M., Wu Y., Li G. et al. Articular cartilage repair biomaterials: strategies and applications. Materials today Bio. 2024. V. 24. DOI: 10.1016/J.MTBIO.2024.100948
21. Yang Y., Wu Y., Yang D. et al. Secretive derived from hypoxia preconditioned mesenchymal stem cells promote cartilage regeneration and mitigate joint inflammation via extracellular vesicles. Bioactive materials. 2023. V. 27. P. 98–112. DOI: 10.1016/J.BIOACTMAT.2023.03.017
22. Chen X., Li J., Wang E. et al. Dynamic compression combined with SOX-9 overexpression in rabbit adipose-derived mesenchymal stem cells cultured in a three-dimensional gradual porous PLGA composite scaffold upregulates HIF-1α expression. Journal of biomedical materials research Part A. 2015. V. 103(12). P. 3886–3895. DOI: 10.1002/JBM.A.35530
23. Fernández-Pernas P., Barrachina L., Marquina M. et al. Mesenchymal stromal cells for articular cartilage repair: preclinical studies. European cells & materials. 2020. V. 40. P. 88–114. DOI: 10.22203/ECM.V040A06
24. Yin H., Mao K., Huang Y. et al. Tendon stem/progenitor cells are promising reparative cell sources for multiple musculoskeletal injuries of concomitant articular cartilage lesions associated with ligament injuries. Journal of Orthopaedic Surgery and Research. 2023. V. 18(1). P. 1–10. DOI: 10.1186/S13018-023-04313-3/FIGURES/5
25. Zhang P., Chen J., Sun Y. et al. A 3D multifunctional bi-layer scaffold to regulate stem cell behaviors and promote osteochondral regeneration. Journal of materials chemistry B. 2023. V. 11(6). P. 1240–1261. DOI: 10.1039/D2TB02203F
26. Abatangelo G., Vindigni V., Avruscio G. et al. Hyaluronic Acid: Redefining Its Role. Cells. 2020. V. 9(7). P. 1–19. DOI: 10.3390/CELLS9071743
27. Lu D., Zeng Z., Geng Z. et al. Macroporous methacrylated hyaluronic acid hydrogel with different pore sizes for in vitro and in vivo evaluation of vascularization. Biomedical materials (Bristol, England). 2022. V. 17(2). DOI: 10.1088/1748-605X/AC494B
28. Wang M., Deng Z., Guo Y., Xu P. Designing functional hyaluronic acid-based hydrogels for cartilage tissue engineering. Materials today Bio. 2022. V. 17. DOI: 10.1016/J.MTBIO.2022.100495
29. Sun X., Song W., Teng L. et al. MiRNA 24-3p-rich exosomes functionalized DEGMA-modified hyaluronic acid hydrogels for corneal epithelial healing. Bioactive materials. 2022. V. 25. P. 640–656. DOI: 10.1016/J.BIOACTMAT.2022.07.011
30. Lazarini M., Bordeaux-Rego P., Giardini-Rosa R. et al. Natural Type II Collagen Hydrogel, Fibrin Sealant, and Adipose-Derived Stem Cells as a Promising Combination for Articular Cartilage Repair. Cartilage. 2017. V. 8(4). P. 439–443. DOI: 10.1177/1947603516675914
31. Parmar P.A., St-Pierre J.P., Chow L.W. et al. Enhanced articular cartilage by human mesenchymal stem cells in enzymatically mediated transiently RGDS-functionalized collagen-mimetic hydrogels. Acta biomaterialia. 2017. V. 51. P. 75–88. DOI: 10.1016/J.ACTBIO.2017.01.028
32. Wong C.C., Chen C.H., Chiu L.H. et al. Facilitating In Vivo Articular Cartilage Repair by Tissue-Engineered Cartilage Grafts Produced From Auricular Chondrocytes. The American journal of sports medicine. 2018. V. 46(3). P. 713–727. DOI: 10.1177/0363546517741306
33. Li H., Hu C., Yu H., Chen C. Chitosan composite scaffolds for articular cartilage defect repair: a review. RSC Advances. 2018. V. 8(7). P. 3736–3749. DOI: 10.1039/C7RA11593H
34. Aranaz I., Alcántara A.R., Civera M.C. et al. Chitosan: An Overview of Its Properties and Applications. Polymers. 2021. V. 13(19). DOI: 10.3390/POLYM13193256
35. Kim D.Y., Park H., Kim S.W. et al. Injectable hydrogels prepared from partially oxidized hyaluronate and glycol chitosan for chondrocyte encapsulation. Carbohydrate polymers. 2017. V. 157. P. 1281–1287. DOI: 10.1016/J.CARBPOL.2016.11.002
36. Yang Y., Wang X., Yang F. et al. A Universal Soaking Strategy to Convert Composite Hydrogels into Extremely Tough and Rapidly Recoverable Double-Network Hydrogels. Advanced Materials. 2016. V. 28(33). P. 7178–7184. DOI: 10.1002/ADMA.201601742
37. Nazir F., Ashraf I., Iqbal M. et al. 6-deoxy-aminocellulose derivatives embedded soft gelatin methacryloyl (GelMA) hydrogels for improved wound healing applications: In vitro and in vivo studies. International Journal of Biological Macromolecules. 2021. V. 185.
    P. 419–433. DOI: 10.1016/J.IJBIOMAC.2021.06.112
38. Guo A., Zhang S., Yang R., Sui C. Enhancing the mechanical strength of 3D printed GelMA for soft tissue engineering applications. Materials today Bio. 2023. V. 24. DOI: 10.1016/J.MTBIO.2023.100939
39. Mikhailov O.V. Gelatin as It Is: History and Modernity. International journal of molecular sciences. 2023. V. 24(4). DOI: 10.3390/IJMS24043583
40. Santoro M., Tatara A.M., Mikos A.G. Gelatin carriers for drug and cell delivery in tissue engineering. Journal of Controlled Release. 2014. V. 190. P. 210–218. DOI: 10.1016/J.JCONREL.2014.04.014
41. Cong B., Sun T., Zhao Y., Chen M. Current and Novel Therapeutics for Articular Cartilage Repair and Regeneration. Therapeutics and clinical risk management. 2023. V. 19. P. 485–502. DOI: 10.2147/TCRM.S410277
42. Makarova E.B., Korch M.A., Fadeev F.A. i dr. Testirovanie gidrogelya p-HEMA v kachestve implantacionnogo materiala dlya zameshcheniya kostno-hryashchevyh defektov u zhivotnyh. Vestnik transplantologii i iskusstvennyh organov. 2022. T. 24(2). S. 71–82. DOI: 10.15825/1995-1191-2022-2-71-82 (in Russian).
43. Zare M., Bigham A., Zare M. et al. pHEMA: An Overview for Biomedical Applications. International journal of molecular sciences. 2021. V. 22(12). DOI: 10.3390/IJMS22126376
44. Shahrousvand M., Ghollasi M., Zarchi A.A.K., Salimi A. Osteogenic differentiation of hMSCs on semi-interpenetrating polymer networks of polyurethane/poly(2‑hydroxyethyl methacrylate)/cellulose nanowhisker scaffolds. International journal of biological macromolecules. 2019. V. 138. P. 262–271. DOI: 10.1016/J.IJBIOMAC.2019.07.080
45. Mehrali M., Thakur A., Pennisi C.P. et al. Nanoreinforced Hydrogels for Tissue Engineering: Biomaterials that are Compatible with Load-Bearing and Electroactive Tissues. Advanced materials (Deerfield Beach, Fla). 2017. V. 29(8). DOI: 10.1002/ADMA.201603612
46. Milner P.E., Parkes M., Puetzer J.L. et al. A low friction, biphasic and boundary lubricating hydrogel for cartilage replacement. Acta biomaterialia. 2018. V. 65. P. 102–111. DOI: 10.1016/J.ACTBIO.2017.11.002
47. Cooper B.G., Stewart R.C., Burstein D. et al. A Tissue-Penetrating Double Network Restores the Mechanical Properties of Degenerated Articular Cartilage. Angewandte Chemie (International ed in English). 2016. V. 55(13). P. 4226–4230. DOI: 10.1002/ANIE.201511767
48. Baker M.I., Walsh S.P., Schwartz Z., Boyan B.D. A review of polyvinyl alcohol and its uses in cartilage and orthopedic applications. Journal of biomedical materials research Part B, Applied biomaterials. 2012. V. 100(5). P. 1451–1457. DOI: 10.1002/JBM.B.32694
49. Oliveira A.S., Seidi O., Ribeiro N. et al. Tribomechanical Comparison between PVA Hydrogels Obtained Using Different Processing Conditions and Human Cartilage. Materials (Basel, Switzerland). 2019. V. 12(20). DOI: 10.3390/MA12203413
50. Sala R.L., Kwon M.Y., Kim M. et al. Thermosensitive Poly(N-vinylcaprolactam) Injectable Hydrogels for Cartilage Tissue Engineering. Tissue engineering Part A. 2017. V. 23(17-18). P. 935–945. DOI: 10.1089/TEN.TEA.2016.0464
51. Lü J.M., Wang X., Marin-Muller C. et al. Current advances in research and clinical applications of PLGA-based nanotechnology. Expert review of molecular diagnostics. 2009. V. 9(4). P. 325–341. DOI: 10.1586/ERM.09.15
52. Mozaffari A., Mirzapour S.M., Rad M.S., Ranjbaran M. Cytotoxicity of PLGA-zinc oxide nanocomposite on human gingival fibroblasts. Journal of advanced periodontology & implant dentistry. 2023. V. 15(1). P. 28–34. DOI: 10.34172/JAPID.2023.010
53. Dong Z., Yuan Q., Huang K. et al. Gelatin methacryloyl (GelMA)-based biomaterials for bone regeneration. RSC advances. 2019. V. 9(31). P. 17737–17744. DOI: 10.1039/C9RA02695A
54. Yue K., Trujillo-de Santiago G., Alvarez M.M. et al. Synthesis, properties, and biomedical applications of gelatin methacryloyl (GelMA) hydrogels. Biomaterials. 2015. V. 73. P. 254–271. DOI: 10.1016/J.BIOMATERIALS.2015.08.045
55. Wang Y., Koole L.H., Gao C. et al. The potential utility of hybrid photo-crosslinked hydrogels with non-immunogenic component for cartilage repair. NPJ Regenerative medicine. 2021. V. 6(1). DOI: 10.1038/S41536-021-00166-8
56. Mouser V.H.M., Abbadessa A., Levato R. et al. Development of a thermosensitive HAMA-containing bio-ink for the fabrication of composite cartilage repair constructs. Biofabrication. 2017. V. 9(1). DOI: 10.1088/1758-5090/AA6265
57. Feng Q., Lin S., Zhang K. et al. Sulfated hyaluronic acid hydrogels with retarded degradation and enhanced growth factor retention promote hMSC chondrogenesis and articular cartilage integrity with reduced hypertrophy. Acta biomaterialia. 2017. V. 53. P. 329–342. DOI: 10.1016/J.ACTBIO.2017.02.015
58. Martyniak K., Lokshina A., Cruz M.A. et al. Biomaterial composition and stiffness as decisive properties of 3D bioprinted constructs for type II collagen stimulation. Acta biomaterialia. 2022. V. 152. P. 221–234. DOI: 10.1016/J.ACTBIO.2022.08.058
59. Wang G., An Y., Zhang X. et al. Chondrocyte Spheroids Laden in GelMA/HAMA Hybrid Hydrogel for Tissue-Engineered Cartilage with Enhanced Proliferation, Better Phenotype Maintenance, and Natural Morphological Structure. Gels (Basel, Switzerland). 2021. V. 7(4). DOI: 10.3390/GELS7040247
60. Zhao Y., Zhao X., Zhang R. et al. Cartilage Extracellular Matrix Scaffold With Kartogenin-Encapsulated PLGA Microspheres for Cartilage Regeneration. Frontiers in bioengineering and biotechnology. 2020. V. 8. DOI:10.3389/FBIOE.2020.600103
61. Park H., Choi B., Hu J., Lee M. Injectable chitosan hyaluronic acid hydrogels for cartilage tissue engineering. Acta biomaterialia. 2013. V. 9(1). P. 4779–4786. DOI: 10.1016/J.ACTBIO.2012.08.033
62. Farsi M., Asefnejad A., Baharifar H. A hyaluronic acid/PVA electrospun coating on 3D printed PLA scaffold for orthopedic application. Progress in biomaterials. 2022. V. 11(1). P. 67–77. DOI: 10.1007/S40204-022-00180-Z
63. Stockinger B., Shah K., Wincent E. AHR in the intestinal microenvironment: safeguarding barrier function. Nature reviews Gastroenterology & hepatology. 2021. V. 18(8). P. 559–570. DOI: 10.1038/S41575-021-00430-8
64. Kim H.S., Mandakhbayar N., Kim H.W. et al. Protein-reactive nanofibrils decorated with cartilage-derived decellularized extracellular matrix for osteochondral defects. Biomaterials. 2021. V. 269. DOI: 10.1016/J.BIOMATERIALS.2020.120214
65. Hsieh C.F., Chen C.H., Kao H.H. et al. PLGA/Gelatin/Hyaluronic Acid Fibrous Membrane Scaffold for Therapeutic Delivery of Adipose-Derived Stem Cells to Promote Wound Healing. Biomedicines. 2022. V. 10(11). DOI: 10.3390/BIOMEDICINES 10112902
66. Wasyłeczko M., Sikorska W., Chwojnowski A. Review of Synthetic and Hybrid Scaffolds in Cartilage Tissue Engineering. Membranes. 2020. V. 10(11). P. 1–28. DOI: 10.3390/MEMBRANES10110348
67. Liu F., Li W., Liu H. et al. Preparation of 3D Printed Chitosan/Polyvinyl Alcohol Double Network Hydrogel Scaffolds. Macromolecular bioscience. 2021. V. 21(4). DOI: 10.1002/MABI.202000398