Current Situation of Adipose-Derived Stem Cells Treatments for Knee Ostheoarthritis and Hypothesis for a New Protocol Based on Cryoconservation and Multiple Injections of Mechanically Fragmented Adipose Tissue Extracts
Main Article Content
Abstract
Osteoarthritis (OA) is a widespread degenerative joint disease. The knee arthroplasty has represented for about 40 years the main treatment option, when pain and functional decrease became unbearable for the patient. The knee arthroplasty represents a challenging surgical operation, in which, based on current data available, about 20% of the patients are left totally or partially unsatisfied with the clinical result.
A recent therapeutic alternative for mild-to-moderate grade OA (Kellgren-Lawrence grade II to III) in order to delay (or ultimately avoid) the need for prosthetic surgery, is a treatment with Adipose-Derived Stem Cells (or ADSCs). The safety and efficacy in terms of functional improvement, cartilage repair and inflammation reduction were already reported for OA treatment through a single intra-articular injection of Micro-Fragmented Autologous Fat Tissue (M-FAT), which is known to be rich in ADSCs. This efficacy period appears to be ranging from several months to a few years.
Research has shown that the effect of single-dose M-FAT treatment, despite being evident in most cases, is not statistically uniform among the studies now available. This is also due to different treatment protocols, that leave to every research group the ultimate choice of preparation methods, rules and exclusion criteria.
It is possible, because of this, to hypothesize a new kind of treatment protocol based on a single surgical harvesting operation. The extract would then need to be cryopreserved and administered multiple times over a several-years period. We hope, thanks to the subsequent injections of purified extract, to prolong and boost the effect of the treatment.
We tried to elaborate, based on our experience in the field, a new protocol for this multi-injection treatment. This protocol is going to be applied to a small number of patients and evaluated over time, to elaborate the actual benefit from a treatment like this.
Article Details
How to Cite
RUCCI, M. et al.
Current Situation of Adipose-Derived Stem Cells Treatments for Knee Ostheoarthritis and Hypothesis for a New Protocol Based on Cryoconservation and Multiple Injections of Mechanically Fragmented Adipose Tissue Extracts.
Medical Research Archives, [S.l.], v. 11, n. 6, june 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3747>. Date accessed: 15 may 2024.
doi: https://doi.org/10.18103/mra.v11i6.3747.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Peat G, Thomas MJ. Osteoarthritis year in review 2020: epidemiology & therapy. Osteoarthritis Cartilage. 2021;29(2):180-189. doi:10.1016/J.JOCA.2020.10.007
2. Bistolfi A, Massazza G, Lee GC, Deledda D, Berchialla P, Crova M. Comparison of fixed and mobile-bearing total knee arthroplasty at a mean follow-up of 116 months. J Bone Joint Surg Am. 2013;95(12). doi:10.2106/JBJS.L.00327
3. Kurtz SM, Ong KL, Lau E, Bozic KJ. Impact of the economic downturn on total joint replacement demand in the United States: updated projections to 2021. J Bone Joint Surg Am. 2014;96(8):624-630. doi:10.2106/JBJS.M.00285
4. Alessio-Mazzola M, Clemente A, Russo A, et al. Clinical radiographic outcomes and survivorship of medial pivot design total knee arthroplasty: a systematic review of the literature. Arch Orthop Trauma Surg. 2022;142(11):3437-3448. doi:10.1007/S00402-021-04210-6
5. Hofmann S, Seitlinger G, Djahani O, Pietsch M. The painful knee after TKA: a diagnostic algorithm for failure analysis. Knee Surg Sports Traumatol Arthrosc. 2011;19(9):1442-1452. doi:10.1007/S00167-011-1634-6
6. Kurtz SM, Lau E, Watson H, Schmier JK, Parvizi J. Economic burden of periprosthetic joint infection in the United States. J Arthroplasty. 2012;27(8 Suppl). doi:10.1016/J.ARTH.2012.02.022
7. White RH, Romano PS, Zhou H, Rodrigo J, Bargar W. Incidence and time course of thromboembolic outcomes following total hip or knee arthroplasty. Arch Intern Med. 1998;158(14):1525-1531. doi:10.1001/ARCHINTE.158.14.1525
8. Palazzo C, Nguyen C, Lefevre-Colau MM, Rannou F, Poiraudeau S. Risk factors and burden of osteoarthritis. Ann Phys Rehabil Med. 2016;59(3):134-138. doi:10.1016/J.REHAB.2016.01.006
9. Goldring MB, Goldring SR. Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis. Ann N Y Acad Sci. 2010;1192:230-237. doi:10.1111/J.1749-6632.2009.05240.X
10. Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum. 2012;64(6):1697-1707. doi:10.1002/ART.34453
11. Epanomeritakis IE, Lee E, Lu V, Khan W. The Use of Autologous Chondrocyte and Mesenchymal Stem Cell Implants for the Treatment of Focal Chondral Defects in Human Knee Joints-A Systematic Review and Meta-Analysis. Int J Mol Sci. 2022;23(7). doi:10.3390/IJMS23074065
12. Lee JJ, Lee SJ, Lee TJ, Yoon TH, Choi CH. Results of microfracture in the osteoarthritic knee with focal full-thickness articular cartilage defects and concomitant medial meniscal tears. Knee Surg Relat Res. 2013;25(2):71-76. doi:10.5792/KSRR.2013.25.2.71
13. Mella C, Nuñez A, Villalón I. Treatment of acetabular chondral lesions with microfracture technique. SICOT J. 2017;3. doi:10.1051/SICOTJ/2017027
14. Rönn K, Reischl N, Gautier E, Jacobi M. Current surgical treatment of knee osteoarthritis. Arthritis. 2011;2011:1-9. doi:10.1155/2011/454873
15. Kwon DG, Kim MK, Jeon YS, Nam YC, Park JS, Ryu DJ. State of the Art: The Immunomodulatory Role of MSCs for Osteoarthritis. Int J Mol Sci. 2022;23(3). doi:10.3390/IJMS23031618
16. Murphy JM, Dixon K, Beck S, Fabian D, Feldman A, Barry F. Reduced chondrogenic and adipogenic activity of mesenchymal stem cells from patients with advanced osteoarthritis. Arthritis Rheum. 2002;46(3):704-713. doi:10.1002/ART.10118
17. Ravalli S, Szychlinska MA, Lauretta G, di Rosa M, Musumeci G. Investigating lubricin and known cartilage-based biomarkers of osteoarthritis. Expert Rev Mol Diagn. 2020;20(4):443-452. doi:10.1080/14737159.2020.1733978
18. Koenig KM, Ong KL, Lau EC, et al. The Use of Hyaluronic Acid and Corticosteroid Injections Among Medicare Patients With Knee Osteoarthritis. J Arthroplasty. 2016;31(2):351-355. doi:10.1016/J.ARTH.2015.08.024
19. Han SB, Seo IW, Shin YS. Intra-Articular Injections of Hyaluronic Acid or Steroids Associated With Better Outcomes Than Platelet-Rich Plasma, Adipose Mesenchymal Stromal Cells, or Placebo in Knee Osteoarthritis: A Network Meta-analysis. Arthroscopy. 2021;37(1):292-306. doi:10.1016/J.ARTHRO.2020.03.041
20. A M, S A. Intra-articular therapy in hip osteoarthritis. Clin Cases Miner Bone Metab. 2017;14(2):179. doi:10.11138/CCMBM/2017.14.1.179
21. Ma X long, Kuang M jie, Zhao J, et al. Efficacy and safety of intraarticular hyaluronic acid and corticosteroid for knee osteoarthritis: A meta-analysis. Int J Surg. 2017;39:95-103. doi:10.1016/J.IJSU.2017.01.087
22. Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage. 2019;27(11):1578-1589. doi:10.1016/J.JOCA.2019.06.011
23. Kon E, Filardo G, Drobnic M, et al. Non-surgical management of early knee osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2012;20(3):436-449. doi:10.1007/S00167-011-1713-8
24. Alessio-Mazzola M, Lovisolo S, Sonzogni B, et al. Clinical outcome and risk factor predictive for failure of autologous PRP injections for low-to-moderate knee osteoarthritis. J Orthop Surg (Hong Kong). 2021;29(2). doi:10.1177/23094990211021922
25. Laver L, Marom N, Dnyanesh L, Mei-Dan O, Espregueira-Mendes J, Gobbi A. PRP for Degenerative Cartilage Disease: A Systematic Review of Clinical Studies. Cartilage. 2017;8(4):341-364. doi:10.1177/1947603516670709
26. Dai WL, Zhou AG, Zhang H, Zhang J. Efficacy of Platelet-Rich Plasma in the Treatment of Knee Osteoarthritis: A Meta-analysis of Randomized Controlled Trials. Arthroscopy. 2017;33(3):659-670.e1. doi:10.1016/J.ARTHRO.2016.09.024
27. Andia I, Maffulli N. A contemporary view of platelet-rich plasma therapies: moving toward refined clinical protocols and precise indications. Regenerative Med. 2018;13(6). doi:10.2217/RME-2018-0042
28. Chahla J, Cinque ME, Piuzzi NS, et al. A Call for Standardization in Platelet-Rich Plasma Preparation Protocols and Composition Reporting: A Systematic Review of the Clinical Orthopaedic Literature. J Bone Joint Surg Am. 2017;99(20):1769-1779. doi:10.2106/JBJS.16.01374
29. Zhao J, Huang H, Liang G, Zeng LF, Yang W, Liu J. Effects and safety of the combination of platelet-rich plasma (PRP) and hyaluronic acid (HA) in the treatment of knee osteoarthritis: a systematic review and meta-analysis. BMC Musculoskelet Disord. 2020;21(1). doi:10.1186/S12891-020-03262-W
30. Di Matteo B, Polignano A, Onorato F, et al. Knee Intraosseous Injections: A Systematic Review of Clinical Evidence of Different Treatment Alternatives. Cartilage. 2021;13(1_suppl):1165S-1177S. doi:10.1177/1947603520959403
31. Tanamas SK, Wluka AE, Pelletier JP, et al. Bone marrow lesions in people with knee osteoarthritis predict progression of disease and joint replacement: a longitudinal study. Rheumatology (Oxford). 2010;49(12):2413-2419. doi:10.1093/RHEUMATOLOGY/KEQ286
32. Betzler BK, Chee YYJ, Bin Abd Razak HR. Intraosseous Injections Are Safe And Effective in Knee Osteoarthritis: A Systematic Review. Arthrosc Sports Med Rehabil. 2021;3(5):e1557-e1567. doi:10.1016/j.asmr.2021.06.006
33. Filardo G, Madry H, Jelic M, Roffi A, Cucchiarini M, Kon E. Mesenchymal stem cells for the treatment of cartilage lesions: From preclinical findings to clinical application in orthopaedics. Knee Surgery, Sports Traumatology, Arthroscopy. 2013;21(8):1717-1729. doi:10.1007/s00167-012-2329-3
34. Trivisonno A, Alexander RW, Baldari S, et al. Intraoperative Strategies for Minimal Manipulation of Autologous Adipose Tissue for Cell- and Tissue-Based Therapies: Concise Review. Stem Cells Transl Med. 2019;8(12):1265-1271. doi:10.1002/SCTM.19-0166
35. Strioga M, Viswanathan S, Darinskas A, Slaby O, Michalek J. Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev. 2012;21(14):2724-2752. doi:10.1089/SCD.2011.0722
36. Melief SM, Zwaginga JJ, Fibbe WE, Roelofs H. Adipose tissue-derived multipotent stromal cells have a higher immunomodulatory capacity than their bone marrow-derived counterparts. Stem Cells Transl Med. 2013;2(6):455-463. doi:10.5966/sctm.2012-0184
37. De Francesco F, Gravina P, Busato A, et al. Stem Cells in Autologous Microfragmented Adipose Tissue: Current Perspectives in Osteoarthritis Disease. Int J Mol Sci. 2021;22(19). doi:10.3390/IJMS221910197
38. Kokai LE, Marra K, Rubin JP. Adipose stem cells: biology and clinical applications for tissue repair and regeneration. Transl Res. 2014;163(4):399-408. doi:10.1016/J.TRSL.2013.11.009
39. Pagani S, Veronesi F, Giavaresi G, et al. Autologous Protein Solution Effect on Chondrogenic Differentiation of Mesenchymal Stem Cells from Adipose Tissue and Bone Marrow in an Osteoarthritic Environment. Cartilage. 2021;13(2_suppl):225S-237S. doi:10.1177/1947603521993217
40. Im G il, Kim TK. Regenerative Therapy for Osteoarthritis: A Perspective. Int J Stem Cells. 2020;13(2):177-181. doi:10.15283/IJSC20069
41. Ni Z, Zhou S, Li S, et al. Exosomes: roles and therapeutic potential in osteoarthritis. Bone Res. 2020;8(1). doi:10.1038/S41413-020-0100-9
42. Meng HYH, Lu V, Khan W. Adipose Tissue-Derived Mesenchymal Stem Cells as a Potential Restorative Treatment for Cartilage Defects: A PRISMA Review and Meta-Analysis. Pharmaceuticals (Basel). 2021;14(12). doi:10.3390/PH14121280
43. Hong Z, Chen J, Zhang S, et al. Intra-articular injection of autologous adipose-derived stromal vascular fractions for knee osteoarthritis: a double-blind randomized self-controlled trial. Int Orthop. 2019;43(5):1123-1134. doi:10.1007/S00264-018-4099-0
44. Lee WS, Kim HJ, Kim K il, Kim GB, Jin W. Intra-Articular Injection of Autologous Adipose Tissue-Derived Mesenchymal Stem Cells for the Treatment of Knee Osteoarthritis: A Phase IIb, Randomized, Placebo-Controlled Clinical Trial. Stem Cells Transl Med. 2019;8(6):504-511. doi:10.1002/SCTM.18-0122
45. Lu L, Dai C, Zhang Z, et al. Treatment of knee osteoarthritis with intra-articular injection of autologous adipose-derived mesenchymal progenitor cells: a prospective, randomized, double-blind, active-controlled, phase IIb clinical trial. Stem Cell Res Ther. 2019;10(1). doi:10.1186/S13287-019-1248-3
46. di Matteo B, Vandenbulcke F, Vitale ND, et al. Minimally Manipulated Mesenchymal Stem Cells for the Treatment of Knee Osteoarthritis: A Systematic Review of Clinical Evidence. Stem Cells Int. 2019;2019. doi:10.1155/2019/1735242
47. Michalek J, Moster R, Lukac L, et al. Autologous adipose tissue-derived stromal vascular fraction cells application in patients with osteoarthritis. Cell Transplant. Published online February 5, 2015. doi:10.3727/096368915X686760
48. Michalek J, Vrablikova A, Darinskas A, et al. Stromal vascular fraction cell therapy for osteoarthritis in elderly: Multicenter case-control study. J Clin Orthop Trauma. 2019;10(1):76-80. doi:10.1016/J.JCOT.2018.11.010
49. Bąkowski P, Kaszyński J, Baka C, et al. Patients with stage II of the knee osteoarthritis most likely benefit from the intra-articular injections of autologous adipose tissue-from 2 years of follow-up studies. Arch Orthop Trauma Surg. 2023;143(1). doi:10.1007/S00402-021-03979-W
50. Kim K il, Lee WS, Kim JH, Bae JK, Jin W. Safety and Efficacy of the Intra-articular Injection of Mesenchymal Stem Cells for the Treatment of Osteoarthritic Knee: A 5-Year Follow-up Study. Stem Cells Transl Med. 2022;11(6):586-596. doi:10.1093/STCLTM/SZAC024
51. Roato I, Belisario DC, Compagno M, et al. Concentrated adipose tissue infusion for the treatment of knee osteoarthritis: clinical and histological observations. Int Orthop. 2019;43(1):15-23. doi:10.1007/S00264-018-4192-4
52. Roato I, Alotto D, Belisario DC, et al. Adipose Derived-Mesenchymal Stem Cells Viability and Differentiating Features for Orthopaedic Reparative Applications: Banking of Adipose Tissue. Stem Cells Int. 2016;2016. doi:10.1155/2016/4968724
2. Bistolfi A, Massazza G, Lee GC, Deledda D, Berchialla P, Crova M. Comparison of fixed and mobile-bearing total knee arthroplasty at a mean follow-up of 116 months. J Bone Joint Surg Am. 2013;95(12). doi:10.2106/JBJS.L.00327
3. Kurtz SM, Ong KL, Lau E, Bozic KJ. Impact of the economic downturn on total joint replacement demand in the United States: updated projections to 2021. J Bone Joint Surg Am. 2014;96(8):624-630. doi:10.2106/JBJS.M.00285
4. Alessio-Mazzola M, Clemente A, Russo A, et al. Clinical radiographic outcomes and survivorship of medial pivot design total knee arthroplasty: a systematic review of the literature. Arch Orthop Trauma Surg. 2022;142(11):3437-3448. doi:10.1007/S00402-021-04210-6
5. Hofmann S, Seitlinger G, Djahani O, Pietsch M. The painful knee after TKA: a diagnostic algorithm for failure analysis. Knee Surg Sports Traumatol Arthrosc. 2011;19(9):1442-1452. doi:10.1007/S00167-011-1634-6
6. Kurtz SM, Lau E, Watson H, Schmier JK, Parvizi J. Economic burden of periprosthetic joint infection in the United States. J Arthroplasty. 2012;27(8 Suppl). doi:10.1016/J.ARTH.2012.02.022
7. White RH, Romano PS, Zhou H, Rodrigo J, Bargar W. Incidence and time course of thromboembolic outcomes following total hip or knee arthroplasty. Arch Intern Med. 1998;158(14):1525-1531. doi:10.1001/ARCHINTE.158.14.1525
8. Palazzo C, Nguyen C, Lefevre-Colau MM, Rannou F, Poiraudeau S. Risk factors and burden of osteoarthritis. Ann Phys Rehabil Med. 2016;59(3):134-138. doi:10.1016/J.REHAB.2016.01.006
9. Goldring MB, Goldring SR. Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis. Ann N Y Acad Sci. 2010;1192:230-237. doi:10.1111/J.1749-6632.2009.05240.X
10. Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum. 2012;64(6):1697-1707. doi:10.1002/ART.34453
11. Epanomeritakis IE, Lee E, Lu V, Khan W. The Use of Autologous Chondrocyte and Mesenchymal Stem Cell Implants for the Treatment of Focal Chondral Defects in Human Knee Joints-A Systematic Review and Meta-Analysis. Int J Mol Sci. 2022;23(7). doi:10.3390/IJMS23074065
12. Lee JJ, Lee SJ, Lee TJ, Yoon TH, Choi CH. Results of microfracture in the osteoarthritic knee with focal full-thickness articular cartilage defects and concomitant medial meniscal tears. Knee Surg Relat Res. 2013;25(2):71-76. doi:10.5792/KSRR.2013.25.2.71
13. Mella C, Nuñez A, Villalón I. Treatment of acetabular chondral lesions with microfracture technique. SICOT J. 2017;3. doi:10.1051/SICOTJ/2017027
14. Rönn K, Reischl N, Gautier E, Jacobi M. Current surgical treatment of knee osteoarthritis. Arthritis. 2011;2011:1-9. doi:10.1155/2011/454873
15. Kwon DG, Kim MK, Jeon YS, Nam YC, Park JS, Ryu DJ. State of the Art: The Immunomodulatory Role of MSCs for Osteoarthritis. Int J Mol Sci. 2022;23(3). doi:10.3390/IJMS23031618
16. Murphy JM, Dixon K, Beck S, Fabian D, Feldman A, Barry F. Reduced chondrogenic and adipogenic activity of mesenchymal stem cells from patients with advanced osteoarthritis. Arthritis Rheum. 2002;46(3):704-713. doi:10.1002/ART.10118
17. Ravalli S, Szychlinska MA, Lauretta G, di Rosa M, Musumeci G. Investigating lubricin and known cartilage-based biomarkers of osteoarthritis. Expert Rev Mol Diagn. 2020;20(4):443-452. doi:10.1080/14737159.2020.1733978
18. Koenig KM, Ong KL, Lau EC, et al. The Use of Hyaluronic Acid and Corticosteroid Injections Among Medicare Patients With Knee Osteoarthritis. J Arthroplasty. 2016;31(2):351-355. doi:10.1016/J.ARTH.2015.08.024
19. Han SB, Seo IW, Shin YS. Intra-Articular Injections of Hyaluronic Acid or Steroids Associated With Better Outcomes Than Platelet-Rich Plasma, Adipose Mesenchymal Stromal Cells, or Placebo in Knee Osteoarthritis: A Network Meta-analysis. Arthroscopy. 2021;37(1):292-306. doi:10.1016/J.ARTHRO.2020.03.041
20. A M, S A. Intra-articular therapy in hip osteoarthritis. Clin Cases Miner Bone Metab. 2017;14(2):179. doi:10.11138/CCMBM/2017.14.1.179
21. Ma X long, Kuang M jie, Zhao J, et al. Efficacy and safety of intraarticular hyaluronic acid and corticosteroid for knee osteoarthritis: A meta-analysis. Int J Surg. 2017;39:95-103. doi:10.1016/J.IJSU.2017.01.087
22. Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage. 2019;27(11):1578-1589. doi:10.1016/J.JOCA.2019.06.011
23. Kon E, Filardo G, Drobnic M, et al. Non-surgical management of early knee osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2012;20(3):436-449. doi:10.1007/S00167-011-1713-8
24. Alessio-Mazzola M, Lovisolo S, Sonzogni B, et al. Clinical outcome and risk factor predictive for failure of autologous PRP injections for low-to-moderate knee osteoarthritis. J Orthop Surg (Hong Kong). 2021;29(2). doi:10.1177/23094990211021922
25. Laver L, Marom N, Dnyanesh L, Mei-Dan O, Espregueira-Mendes J, Gobbi A. PRP for Degenerative Cartilage Disease: A Systematic Review of Clinical Studies. Cartilage. 2017;8(4):341-364. doi:10.1177/1947603516670709
26. Dai WL, Zhou AG, Zhang H, Zhang J. Efficacy of Platelet-Rich Plasma in the Treatment of Knee Osteoarthritis: A Meta-analysis of Randomized Controlled Trials. Arthroscopy. 2017;33(3):659-670.e1. doi:10.1016/J.ARTHRO.2016.09.024
27. Andia I, Maffulli N. A contemporary view of platelet-rich plasma therapies: moving toward refined clinical protocols and precise indications. Regenerative Med. 2018;13(6). doi:10.2217/RME-2018-0042
28. Chahla J, Cinque ME, Piuzzi NS, et al. A Call for Standardization in Platelet-Rich Plasma Preparation Protocols and Composition Reporting: A Systematic Review of the Clinical Orthopaedic Literature. J Bone Joint Surg Am. 2017;99(20):1769-1779. doi:10.2106/JBJS.16.01374
29. Zhao J, Huang H, Liang G, Zeng LF, Yang W, Liu J. Effects and safety of the combination of platelet-rich plasma (PRP) and hyaluronic acid (HA) in the treatment of knee osteoarthritis: a systematic review and meta-analysis. BMC Musculoskelet Disord. 2020;21(1). doi:10.1186/S12891-020-03262-W
30. Di Matteo B, Polignano A, Onorato F, et al. Knee Intraosseous Injections: A Systematic Review of Clinical Evidence of Different Treatment Alternatives. Cartilage. 2021;13(1_suppl):1165S-1177S. doi:10.1177/1947603520959403
31. Tanamas SK, Wluka AE, Pelletier JP, et al. Bone marrow lesions in people with knee osteoarthritis predict progression of disease and joint replacement: a longitudinal study. Rheumatology (Oxford). 2010;49(12):2413-2419. doi:10.1093/RHEUMATOLOGY/KEQ286
32. Betzler BK, Chee YYJ, Bin Abd Razak HR. Intraosseous Injections Are Safe And Effective in Knee Osteoarthritis: A Systematic Review. Arthrosc Sports Med Rehabil. 2021;3(5):e1557-e1567. doi:10.1016/j.asmr.2021.06.006
33. Filardo G, Madry H, Jelic M, Roffi A, Cucchiarini M, Kon E. Mesenchymal stem cells for the treatment of cartilage lesions: From preclinical findings to clinical application in orthopaedics. Knee Surgery, Sports Traumatology, Arthroscopy. 2013;21(8):1717-1729. doi:10.1007/s00167-012-2329-3
34. Trivisonno A, Alexander RW, Baldari S, et al. Intraoperative Strategies for Minimal Manipulation of Autologous Adipose Tissue for Cell- and Tissue-Based Therapies: Concise Review. Stem Cells Transl Med. 2019;8(12):1265-1271. doi:10.1002/SCTM.19-0166
35. Strioga M, Viswanathan S, Darinskas A, Slaby O, Michalek J. Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev. 2012;21(14):2724-2752. doi:10.1089/SCD.2011.0722
36. Melief SM, Zwaginga JJ, Fibbe WE, Roelofs H. Adipose tissue-derived multipotent stromal cells have a higher immunomodulatory capacity than their bone marrow-derived counterparts. Stem Cells Transl Med. 2013;2(6):455-463. doi:10.5966/sctm.2012-0184
37. De Francesco F, Gravina P, Busato A, et al. Stem Cells in Autologous Microfragmented Adipose Tissue: Current Perspectives in Osteoarthritis Disease. Int J Mol Sci. 2021;22(19). doi:10.3390/IJMS221910197
38. Kokai LE, Marra K, Rubin JP. Adipose stem cells: biology and clinical applications for tissue repair and regeneration. Transl Res. 2014;163(4):399-408. doi:10.1016/J.TRSL.2013.11.009
39. Pagani S, Veronesi F, Giavaresi G, et al. Autologous Protein Solution Effect on Chondrogenic Differentiation of Mesenchymal Stem Cells from Adipose Tissue and Bone Marrow in an Osteoarthritic Environment. Cartilage. 2021;13(2_suppl):225S-237S. doi:10.1177/1947603521993217
40. Im G il, Kim TK. Regenerative Therapy for Osteoarthritis: A Perspective. Int J Stem Cells. 2020;13(2):177-181. doi:10.15283/IJSC20069
41. Ni Z, Zhou S, Li S, et al. Exosomes: roles and therapeutic potential in osteoarthritis. Bone Res. 2020;8(1). doi:10.1038/S41413-020-0100-9
42. Meng HYH, Lu V, Khan W. Adipose Tissue-Derived Mesenchymal Stem Cells as a Potential Restorative Treatment for Cartilage Defects: A PRISMA Review and Meta-Analysis. Pharmaceuticals (Basel). 2021;14(12). doi:10.3390/PH14121280
43. Hong Z, Chen J, Zhang S, et al. Intra-articular injection of autologous adipose-derived stromal vascular fractions for knee osteoarthritis: a double-blind randomized self-controlled trial. Int Orthop. 2019;43(5):1123-1134. doi:10.1007/S00264-018-4099-0
44. Lee WS, Kim HJ, Kim K il, Kim GB, Jin W. Intra-Articular Injection of Autologous Adipose Tissue-Derived Mesenchymal Stem Cells for the Treatment of Knee Osteoarthritis: A Phase IIb, Randomized, Placebo-Controlled Clinical Trial. Stem Cells Transl Med. 2019;8(6):504-511. doi:10.1002/SCTM.18-0122
45. Lu L, Dai C, Zhang Z, et al. Treatment of knee osteoarthritis with intra-articular injection of autologous adipose-derived mesenchymal progenitor cells: a prospective, randomized, double-blind, active-controlled, phase IIb clinical trial. Stem Cell Res Ther. 2019;10(1). doi:10.1186/S13287-019-1248-3
46. di Matteo B, Vandenbulcke F, Vitale ND, et al. Minimally Manipulated Mesenchymal Stem Cells for the Treatment of Knee Osteoarthritis: A Systematic Review of Clinical Evidence. Stem Cells Int. 2019;2019. doi:10.1155/2019/1735242
47. Michalek J, Moster R, Lukac L, et al. Autologous adipose tissue-derived stromal vascular fraction cells application in patients with osteoarthritis. Cell Transplant. Published online February 5, 2015. doi:10.3727/096368915X686760
48. Michalek J, Vrablikova A, Darinskas A, et al. Stromal vascular fraction cell therapy for osteoarthritis in elderly: Multicenter case-control study. J Clin Orthop Trauma. 2019;10(1):76-80. doi:10.1016/J.JCOT.2018.11.010
49. Bąkowski P, Kaszyński J, Baka C, et al. Patients with stage II of the knee osteoarthritis most likely benefit from the intra-articular injections of autologous adipose tissue-from 2 years of follow-up studies. Arch Orthop Trauma Surg. 2023;143(1). doi:10.1007/S00402-021-03979-W
50. Kim K il, Lee WS, Kim JH, Bae JK, Jin W. Safety and Efficacy of the Intra-articular Injection of Mesenchymal Stem Cells for the Treatment of Osteoarthritic Knee: A 5-Year Follow-up Study. Stem Cells Transl Med. 2022;11(6):586-596. doi:10.1093/STCLTM/SZAC024
51. Roato I, Belisario DC, Compagno M, et al. Concentrated adipose tissue infusion for the treatment of knee osteoarthritis: clinical and histological observations. Int Orthop. 2019;43(1):15-23. doi:10.1007/S00264-018-4192-4
52. Roato I, Alotto D, Belisario DC, et al. Adipose Derived-Mesenchymal Stem Cells Viability and Differentiating Features for Orthopaedic Reparative Applications: Banking of Adipose Tissue. Stem Cells Int. 2016;2016. doi:10.1155/2016/4968724