Перспективные направления применения гидрогелей для внутрисуставного лечения остеоартрита

Введение. Остеоартрит (ОА) – это дегенеративное заболевание, которое приводит к постепенной потере хряща и образованию остеофитов, а соответственно – к нестабильности суставов, болям и ограниченной мобильности. Варианты лечения включают лекарственную терапию, физиотерапию, изменение образа жизни и операции по коррекции или замене суставов. Внутрисуставные методы лечения, такие как введение гидрогелей, модифицированных для конкретных клинических задач, становятся все более популярными благодаря своей способности обеспечивать целевое и эффективное облегчение с минимальными побочными эффектами.

Цель работы – оценка использования гидрогелей для внутрисуставного лечения остеоартрита на основании анализа научной литературы.

Материалы и методы. Литературные источники отобраны в базах данных PubMed, ScienceDirect и SciSpace с использованием тематических поисковых запросов: “hydrogel” AND “intra?articular” AND “osteoarthritis”. Период поиска был ограничен 2018–2023 гг. публикации. В результате первичного отбора статей по поисковым славам обнаружено 1 576 статей, после анализа и применения критериев исключения в обзор были включены 53 наиболее значимых источника.

Результаты. Определены два типа гидрогелей для внутрисуставного применения: инъекционные и имплантируемые. Инъекционные гидрогели применяют для замены синовиальной жидкости, доставки лекарственных средств или заполнения очаговых дефектов хряща. Имплантируемые гидрогели используют для замены или восстановления поврежденного хряща в суставах, пораженных ОА, что обеспечивает восстановление целостности их поверхности, редукцию болевого синдрома и улучшение функции.

Обсуждение. Гидрогели демонстрируют перспективность в качестве потенциального материала для лечения ОА, поскольку обладают рядом преимуществ, таких как биомимикрия, биосовместимость, малоинвазивность введения и способность доставлять терапевтические агенты непосредственно в пораженный сустав. Однако существует ряд ограничений: неконтролируемая деградация, небольшая долговечность, высокая вероятность негативных местных и системных иммунных реакций.

Заключение. Необходимы дальнейшие исследования для оптимизации конструкции и состава гидрогелей для клинического использования, включая разработку новых композиций с программируемыми свойствами, изучение долгосрочных эффектов и сравнение эффективности с другими методами лечения ОА. 

1. Georgiev T, Angelov AK. Modifiable risk factors in knee osteoarthritis: treatment implications. Rheumatol Int. 2019;39(7):1145–1157. https://doi.org/10.1007/S00296-019-04290-Z.

2. Harlaar J, Macri EM, Wesseling M. Osteoarthritis year in review 2021: mechanics. Osteoarthritis Cartilage. 2022;30(5):663–670. https://doi.org/10.1016/j.joca.2021.12.012.

3. Al-Khazraji BK, Appleton CT, Beier F et al. Osteoarthritis, cerebrovascular dysfunction and the common denominator of inflammation: a narrative review. Osteoarthritis Cartilage. 2018;26(4):462–470. https://doi.org/10.1016/J.JOCA.2018.01.011.

4. Sun ARJ, Udduttula A, Li J et al. Cartilage tissue engineering for obesity-induced osteoarthritis: Physiology, challenges, and future prospects. J Orthop Translat. 2020;26:3–15. https://doi.org/10.1016/J.JOT.2020.07.004.

5. Pak J, Lee JH, Pak N et al. Cartilage regeneration in humans with adipose tissue-derived stem cells and adipose stromal vascular fraction cells: updated status. Int J Mol Sci. 2018;19(7):2146. https://doi.org/10.3390/ijms19072146.

6. Armiento AR, Alini M, Stoddart MJ. Articular fibrocartilage – why does hyaline cartilage fail to repair? Adv Drug Deliv Rev. 2019;146:289–305. https://doi.org/10.1016/J.ADDR.2018.12.015.

7. Murata K, Kokubun T, Morishita Y et al. Controlling abnormal joint movement inhibits response of osteophyte formation. Cartilage. 2018;9(4):391–401. https://doi.org/10.1177/1947603517700955.

8. van der Kraan PM. The interaction between joint inflammation and cartilage repair. Tissue Eng Regen Med. 2019;16(4):327–334. https://doi.org/10.1007/S13770-019-00204-Z.

9. Rathbun AM, Schuler MS, Stuart EA et al. Depression subtypes in individuals with or at risk for symptomatic knee osteoarthritis. Arthritis Care Res (Hoboken). 2020;72(5):669–678. https://doi.org/10.1002/ACR.23898.

10. Gahunia HK, Pritzker KPH. Structure and function of articular cartilage. Articular Cartilage of the Knee: Health, Disease and Therapy. 2020. pp. 3–70. https://doi.org/10.1007/978-1-4939-7587-7_1.

11. Lyndin M, Gluschenko N, Sikora V et al. Morphofunctional features of articular cartilage structure. Folia Med Cracov. 2019;59(3):81–93. https://doi.org/10.24425/FMC.2019.131138.

12. Chow YY, Chin KY. The Role of inflammation in the pathogenesis of osteoarthritis. Mediators Inflamm. 2020;2020:8293921. https://doi.org/10.1155/2020/8293921.

13. Øiestad BE, Juhl CB, Culvenor AG et al. Knee extensor muscle weakness is a risk factor for the development of knee osteoarthritis: an updated systematic review and meta-analysis including 46 819 men and women. Br J Sports Med. 2022;56(5):349–355. https://doi.org/10.1136/BJSPORTS-2021-104861.

14. Emami A, Namdari H, Parvizpour F, Arabpour Z. Challenges in osteoarthritis treatment. Tissue Cell. 2023;80. https://doi.org/10.1016/j.tice.2022.101992.

15. Richard MJ, Driban JB, McAlindon TE. Pharmaceutical treatment of osteoarthritis. Osteoarthritis Cartilage. 2022;31(4):458–466. https://doi.org/10.1016/j.joca.2022.11.005.

16. Mou D, Yu Q, Zhang J et al. Intra-articular injection of chitosan-based supramolecular hydrogel for osteoarthritis treatment. Tissue Eng Regen Med. 2021;18(1):113–125. https://doi.org/10.1007/s13770-020-00322-z.

17. Bierbrauer KL, Alasino RV, Barclay FE et al. Biocompatible hydrogel for intra-articular implantation comprising cationic and anionic polymers of natural origin: In vivo evaluation in a rabbit model. Polymers (Basel). 2021;13(24):4426. https://doi.org/10.3390/POLYM13244426.

18. Mellati A, Akhtari J. Injectable hydrogels: a review of injectability mechanisms and biomedical applications. Research in Molecular Medicine (RMM). 2019;6(4):1–14. https://doi.org/10.18502/RMM.V6I4.4799.

19. Rizzo F, Kehr NS. Recent advances in injectable hydrogels for controlled and local drug delivery. Adv Healthc Mater. 2021;10(1):e2001341. https://doi.org/10.1002/ADHM.202001341.

20. Wei W, Ma Y, Yao X et al. Advanced hydrogels for the repair of cartilage defects and regeneration. Bioact Mater. 2020;6(4):998–1011. https://doi.org/10.1016/j.bioactmat.2020.09.030.

21. Gonçalves C, Carvalho DN, Silva TH et al. Engineering of viscosupplement biomaterials for treatment of osteoarthritis: a comprehensive review. Adv Eng Mater. 2022;24:2101541. https://doi.org/10.1002/ADEM.202101541.

22. Cai Z, Zhang H, Wei Y et al. Shear-thinning hyaluronan-based fluid hydrogels to modulate viscoelastic properties of osteoarthritis synovial fluids. Biomater Sci. 2019;7(8):3143–3157. https://doi.org/10.1039/C9BM00298G.

23. Scognamiglio F, Travan A, Donati I et al. A hydrogel system based on a lactose-modified chitosan for viscosupplementation in osteoarthritis. Carbohydr Polym. 2020;248:116787. https://doi.org/10.1016/J.CARBPOL.2020.116787.

24. Toropitsyn E, Pravda M, Rebenda D et al. A composite device for viscosupplementation treatment resistant to degradation by reactive oxygen species and hyaluronidase. J Biomed Mater Res B Appl Biomater. 2022;110(12):2595–2611. https://doi.org/10.1002/JBM.B.35114.

25. Pontes-Quero GM, García-Fernández L, Aguilar MR et al. Active viscosupplements for osteoarthritis treatment. Semin Arthritis Rheum. 2019;49(2):171–183. https://doi.org/10.1016/J.SEMARTHRIT.2019.02.008.

26. Cao Y, Ma Y, Tao Y et al. Intra-articular drug delivery for osteoarthritis treatment. Pharmaceutics. 2021;13(12):2166. https://doi.org/10.3390/pharmaceutics13122166.

27. Gambaro FM, Ummarino A, Andón FT et al. Drug delivery systems for the treatment of knee osteoarthritis: A systematic review of in vivo studies. Int J Mol Sci. 2021;22(17):9137. https://doi.org/10.3390/IJMS22179137.

28. Makvandi P, Della Sala F, Di Gennaro M et al. A hyaluronic acid-based formulation with simultaneous local drug delivery and antioxidant ability for active viscosupplementation. ACS Omega. 2022;7(12):10039–10048. https://doi.org/10.1021/ACSOMEGA.1C05622.

29. Toropitsyn E, Ščigalková I, Pravda M, Velebný V. Injectable Hyaluronicacid hydrogel containing platelet derivatives for synovial fluid viscosupplementation and growth factors delivery. Macromol Biosci. 2023;23(4):e2200516. https://doi.org/10.1002/MABI.202200516.

30. Xu J, Feng Q, Lin S et al. Injectable stem cell-laden supramolecular hydrogels enhance in situ osteochondral regeneration via the sustained co-delivery of hydrophilic and hydrophobic chondrogenic molecules. Biomaterials. 2019;210:51–61. https://doi.org/10.1016/J.BIOMATERIALS.2019.04.031.

31. Prince DA, Villamagna IJ, Borecki A et al. Thermoresponsive and covalently cross-linkable hydrogels for intraarticular drug delivery. ACS Appl Bio Mater. 2019;2(8):3498–3507. https://doi.org/10.1021/acsabm.9b00410.

32. Li J, Weber E, Guth-Gundel S et al. Tough composite hydrogels with high loading and local release of biological drugs. Adv Healthc Mater. 2018;7(9):e1701393. https://doi.org/10.1002/ADHM.201701393.

33. Liu L, Xiang Y, Wang Z et al. Adhesive liposomes loaded onto an injectable, self-healing and antibacterial hydrogel for promoting bone reconstruction. NPG Asia Mater. 2019;11:81. https://doi.org/10.1038/S41427-019-0185-Z.

34. Ishikawa S, Yoshikawa Y, Kamata H et al. Injectable hydrogels with phase-separated structures that can encapsulate live cells. BioRxiv. 2022. https://doi.org/10.1101/2022.01.31.478579.

35. Moeinzadeh S, Park Y, Lin S, Yang YP. In-situ stable injectable collagen-based hydrogels for cell and growth factor delivery. Materialia (Oxf). 2021;15:100954. https://doi.org/10.1016/J.MTLA.2020.100954.

36. Young SA, Riahinezhad H, Amsden BG. In situ -forming, mechanically resilient hydrogels for cell delivery. J Mater Chem B. 2019;7(38):5742–5761. https://doi.org/10.1039/C9TB01398A.

37. Zhu S, Li Y, He Z et al. Advanced injectable hydrogels for cartilage tissue engineering. Front Bioeng Biotechnol. 2022;10:954501. https://doi.org/10.3389/fbioe.2022.954501.

38. Yu W, Hu B, Boakye-Yiadom KO et al. Injectable hydrogel mediated delivery of gene-engineered adiposederived stem cells for enhanced osteoarthritis treatment. Biomater Sci. 2021;9(22):7603–7616. https://doi.org/10.1039/D1BM01122G.

39. Wang S, Qiu Y, Qu L et al. Hydrogels for treatment of different degrees of osteoarthritis. Front Bioeng Biotechnol. 2022;10:858656. https://doi.org/10.3389/fbioe.2022.858656.

40. Gaetano G, Giuseppe P, Salvatore PF et al. Hyaluronic-based antibacterial hydrogel coating for implantable biomaterials in orthopedics and trauma: from basic research to clinical applications. Chapter Hydrogels. 2018. https://doi.org/10.5772/INTECHOPEN.73203.

41. Garg D, Matai I, Sachdev A. Toward designing of anti-infective hydrogels for orthopedic implants: from lab to clinic. ACS Biomater Sci Eng. 2021;7(6):1933–1961. https://doi.org/10.1021/ACSBIOMATERIALS.0C01408.

42. Takemura S, Minoda Y, Sugama R et al. Comparison of a Vitamin E-infused highly crosslinked polyethylene insert and a conventional polyethylene insert for primary total knee arthroplasty at two years postoperatively. Bone Joint J. 2019;101–B(5):559–564. https://doi.org/10.1302/0301-620X.101B5.BJJ-2018-1355.R1.

43. De Meo D, Ceccarelli G, Iaiani G et al. Clinical application of antibacterial hydrogel and coating in orthopaedic and traumatology surgery. Gels. 2021;7(3):126. https://doi.org/10.3390/GELS7030126.

44. Zhang Y, Liu X, Zeng L et al. Polymer fiber scaffolds for bone and cartilage tissue engineering. Adv Funct Mater. 2019;29:1903279. https://doi.org/10.1002/ADFM.201903279.

45. Niu X, Li N, Du Z, Li X. Integrated gradient tissue-engineered osteochondral scaffolds: Challenges, current efforts and future perspectives. Bioact Mater. 2022;20:574–597. https://doi.org/10.1016/J.BIOACTMAT.2022.06.011.

46. Jiang W, Xiang X, Song M et al. An all-silk-derived bilayer hydrogel for osteochondral tissue engineering. Mater Today Bio. 2022;17:100485. https://doi.org/10.1016/J.MTBIO.2022.100485.

47. Zhao T, Wei Z, Zhu W, Weng X. Recent developments and current applications of hydrogels in osteoarthritis. Bioengineering (Basel). 2022;9(4):132. https://doi.org/10.3390/BIOENGINEERING9040132.

48. Radhakrishnan J, Manigandan A, Chinnaswamy P et al. Gradient nano-engineered in situ forming composite hydrogel for osteochondral regeneration. Biomaterials. 2018;162:82–98. https://doi.org/10.1016/J.BIOMATERIALS.2018.01.056.

49. Luo Y, Cao X, Chen J et al. Platelet-derived growth factor-functionalized scaffolds for the recruitment of synovial mesenchymal stem cells for osteochondral repair. Stem Cells Int. 2022;2022:2190447. https://doi.org/10.1155/2022/2190447.

50. Asensio G, Benito-Garzón L, Ramírez-Jiménez RA et al. Biomimetic gradient scaffolds containing hyaluronic acid and SR/ZN folates for osteochondral tissue engineering. Polymers (Basel). 2022;14(1):12. https://doi.org/10.3390/polym14010012.

51. Chuang EY, Chiang CW, Wong PC, Chen CH. Hydrogels for the application of articular cartilage tissue engineering: a review of hydrogels. Adv Mater Sci Eng. 2018;2018:4368910. https://doi.org/10.1155/2018/4368910.

52. Lim D, Renteria ES, Sime DS et al. Bioreactor design and validation for manufacturing strategies in tissue engineering. Biodes Manuf. 2022;5(1):43–63. https://doi.org/10.1007/S42242-021-00154-3.

53. Gamez C, Schneider-Wald B, Schuette A et al. Bioreactor for mobilization of mesenchymal stem/stromal cells into scaffolds under mechanical stimulation: Preliminary results. PLoS ONE. 2020;15(1):e0227553. https://doi.org/10.1371/journal.pone.0227553.

54. Daly AC, Sathy BN, Kelly DJ. Engineering large cartilage tissues using dynamic bioreactor culture at defined oxygen conditions. J Tissue Eng. 2018;9: 2041731417753718. https://doi.org/10.1177/2041731417753718.

55. Oprita EI, Iosageanu A, Craciunescu O. Progress in composite hydrogels and scaffolds enriched with icariin for osteochondral defect healing. Gels. 2022;8(10):648. https://doi.org/10.3390/gels8100648.

56. Kim YS, Guilak F. Engineering hyaluronic acid for the development of new treatment strategies for osteoarthritis. Int J Mol Sci. 2022;23(15):8662. https://doi.org/10.3390/ijms23158662.

57. Xu B, Ye J, Yuan FZ et al. Advances of stem cell-laden hydrogels with biomimetic microenvironment for osteochondral repair. Front Bioeng Biotechnol. 2020;8:247. https://doi.org/10.3389/FBIOE.2020.00247.

58. Mohammadinejad R, Kumar A, Ranjbar-Mohammadi M et al. Recent advances in natural gum-based biomaterials for tissue engineering and regenerative medicine: a review. Polymers (Basel). 2020;12(1):176. https://doi.org/10.3390/polym12010176.

59. Spitters TWGM, Stamatialis D, Petit A et al. In vitro evaluation of small molecule delivery into articular cartilage: effect of synovial clearance and compressive load. Assay Drug Dev Technol. 2019;17(4):191–200. https://doi.org/10.1089/ADT.2018.907.

60. Aisenbrey EA, Tomaschke A, Kleinjan E et al. A stereolithography-based 3D printed hybrid scaffold for in situ cartilage defect repair. Macromol Biosci. 2018;18(2): mabi.201700267. https://doi.org/10.1002/mabi.201700267.

61. Lam T, Dehne T, Krüger JP et al. Photopolymerizable gelatin and hyaluronic acid for stereolithographic 3D bioprinting of tissue-engineered cartilage. J Biomed Mater Res B Appl Biomater. 2019;107(8):2649–2657. https://doi.org/10.1002/JBM.B.34354.

62. Li W, Wu D, Hu D et al. Stress-relaxing double-network hydrogel for chondrogenic differentiation of stem cells. Mater Sci Eng C Mater Biol Appl. 2020;107:110333. https://doi.org/10.1016/J.MSEC.2019.110333.

63. Li H, Qi Z, Zheng S et al. The application of hyaluronic acid-based hydrogels in bone and cartilage tissue engineering. Adv Mater Sci Eng. 2019;2019: 3027303. https://doi.org/10.1155/2019/3027303.