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Current Stem Cell Research & Therapy

Author(s): Wanyun Feng, Chaohua Zhu, Ruoxiang Miao, Danni Li, Xi Xiong, Ruyu Wang, Guobin Liu* and Jun Ma*

DOI: 10.2174/1574888X19666230914123443

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Comparative Efficacy of Endogenous Stem Cells Recruiting Hydrogels and Stem Cell-loaded Hydrogels in Knee Cartilage Regeneration: A Meta- analysis

Page: [993 - 1008] Pages: 16

  • * (Excluding Mailing and Handling)

Abstract

Background: Cartilage defects remain a challenge in diseases such as osteoarthritis (OA) and fractures. Scientists have explored the use of hydrogels in conjunction with stem cell technology as a tissue engineering method to treat cartilage defects in joints. In recent years, research into hydrogels containing stem cell technology for cartilage repair has mainly focused on two categories: stem cell-loaded hydrogels and endogenous stem cell recruiting hydrogels. The latter, utilizing cell-free products, represents a novel concept with several advantages, including easier dose standardization, wider sources, and simpler storage. This meta-analysis aims to assess and compare the therapeutic effects of endogenous stem cell recruiting hydrogels and stem cell-loaded hydrogels in promoting articular cartilage regeneration in animal models, with the goal of exploring endogenous stem cell recruiting hydrogels as a promising replacement therapy for knee cartilage regeneration in preclinical animal studies.

Methods: We systematically searched PubMed, Web of Science, Cochrane Library, and Embase until January 2023 using key words related to stem cells, cartilage regeneration and hydrogel. A random-effects meta-analysis was performed to evaluate the therapeutic effect on newborn cartilage formation. Stratified analyses were also carried out by independently classifying trials according to similar characteristics. The level of evidence was determined using the GRADE method.

Results: Twenty-eight studies satisfied the inclusion criteria. Comprehensive analyses revealed that the use of endogenous stem cell recruiting hydrogels significantly promoted the formation of new cartilage in the knee joint, as evidenced by the histological score (3.77, 95% CI 2.40, 5.15; p < 0.0001) and the International Cartilage Repair Society (ICRS) macroscopic score (3.00, 95% CI 1.83, 4.18; p = 0.04), compared with the control group. The stem cell-loaded hydrogels also increased cartilage regeneration in the knee with the histological score (3.13, 95% CI 2.22, 4.04; p = 0.02) and the ICRS macroscopic score (2.49, 95% CI 1.16, 3.82; p = 0.03) in comparison to the control. Significant heterogeneity between studies was observed, and further stratified and sensitivity analyses identified the transplant site and modelling method as the sources of heterogeneity.

Conclusion: The current study indicates that both endogenous stem cell recruiting hydrogels and stem cell loaded hydrogels can effectively promote knee joint cartilage regeneration in animal trials.

Graphical Abstract

[1]
Park YB, Ha CW, Kim JA, Kim S, Park YG. Comparison of undifferentiated versus chondrogenic predifferentiated mesenchymal stem cells derived from human umbilical cord blood for cartilage repair in a rat model. Am J Sports Med 2019; 47(2): 451-61.
[http://dx.doi.org/10.1177/0363546518815151] [PMID: 30640523]
[2]
Wang X, Song X, Li T, et al. Aptamer-functionalized bioscaffold enhances cartilage repair by improving stem cell recruitment in osteochondral defects of rabbit knees. Am J Sports Med 2019; 47(10): 2316-26.
[http://dx.doi.org/10.1177/0363546519856355] [PMID: 31233332]
[3]
Zscharnack M, Hepp P, Richter R, et al. Repair of chronic osteochondral defects using predifferentiated mesenchymal stem cells in an ovine model. Am J Sports Med 2010; 38(9): 1857-69.
[http://dx.doi.org/10.1177/0363546510365296] [PMID: 20508078]
[4]
Uppuluri VNVA, Thukani SS, Bhimavarapu SK, Elumalai L. Polymeric hydrogel scaffolds: Skin tissue engineering and regeneration. Adv Pharm Bull 2022; 12(3): 437-48.
[http://dx.doi.org/10.34172/apb.2022.069] [PMID: 35935050]
[5]
Lei Y, Wang Y, Shen J, et al. Stem cell‐recruiting injectable microgels for repairing osteoarthritis. Adv Funct Mater 2021; 31(48): 2105084.
[http://dx.doi.org/10.1002/adfm.202105084]
[6]
Fan W, Yuan L, Li J, et al. Injectable double-crosslinked hydrogels with kartogenin-conjugated polyurethane nano-particles and transforming growth factor β3 for in-situ cartilage regeneration. Mater Sci Eng C 2020; 110: 110705.
[http://dx.doi.org/10.1016/j.msec.2020.110705] [PMID: 32204019]
[7]
Zhang Y, Liu M, Pei R. An in situ gelling BMSC-laden collagen/silk fibroin double network hydrogel for cartilage regeneration. Materials Advances 2021; 2(14): 4733-42.
[http://dx.doi.org/10.1039/D1MA00285F]
[8]
Zhou S, Bei Z, Wei J, et al. Mussel-inspired injectable chitosan hydrogel modified with catechol for cell adhesion and cartilage defect repair. J Mater Chem B Mater Biol Med 2022; 10(7): 1019-30.
[http://dx.doi.org/10.1039/D1TB02241E] [PMID: 34994756]
[9]
Zhu Y, Ye L, Cai X, Li Z, Fan Y, Yang F. Icariin-loaded hydrogel regulates bone marrow mesenchymal stem cell chondrogenic differentiation and promotes cartilage repair in osteoarthritis. Front Bioeng Biotechnol 2022; 10: 755260.
[http://dx.doi.org/10.3389/fbioe.2022.755260] [PMID: 35223781]
[10]
Zhang FX, Liu P, Ding W, et al. Injectable mussel‐inspired highly adhesive hydrogel with exosomes for endogenous cell recruitment and cartilage defect regeneration. Biomaterials 2021; 278: 121169.
[http://dx.doi.org/10.1016/j.biomaterials.2021.121169] [PMID: 34626937]
[11]
Muhammad SA, Nordin N, Mehat MZ, Fakurazi S. Comparative efficacy of stem cells and secretome in articular cartilage regeneration: a systematic review and meta-analysis. Cell Tissue Res 2019; 375(2): 329-44.
[http://dx.doi.org/10.1007/s00441-018-2884-0] [PMID: 30084022]
[12]
Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. PLoS Med 2021; 18(3): e1003583.
[http://dx.doi.org/10.1371/journal.pmed.1003583] [PMID: 33780438]
[13]
Chen C, Huang S, Chen Z, et al. Kartogenin (KGN)/synthetic melanin nanoparticles (SMNP) loaded theranostic hydrogel scaffold system for multiparametric magnetic resonance imaging guided cartilage regeneration. Bioeng Transl Med 2022; 8(1): e10364.
[PMID: 36684070]
[14]
Chen Y, Chen Y, Xiong X, et al. Hybridizing gellan/alginate and thixotropic magnesium phosphate-based hydrogel scaffolds for enhanced osteochondral repair. Mater Today Bio 2022; 14: 100261.
[http://dx.doi.org/10.1016/j.mtbio.2022.100261] [PMID: 35494405]
[15]
Dong Y, Liu Y, Chen Y, et al. Spatiotemporal regulation of endogenous MSCs using a functional injectable hydrogel system for cartilage regeneration. NPG Asia Mater 2021; 13(1): 71.
[http://dx.doi.org/10.1038/s41427-021-00339-3]
[16]
Ji X, Lei Z, Yuan M, et al. Cartilage repair mediated by thermosensitive photocrosslinkable TGFβ1-loaded GM-HPCH via immunomodulating macrophages, recruiting MSCs and promoting chondrogenesis. Theranostics 2020; 10(6): 2872-87.
[http://dx.doi.org/10.7150/thno.41622] [PMID: 32194841]
[17]
Kim SJ, Kim JE, Kim SH, et al. Therapeutic effects of neuropeptide substance P coupled with self-assembled peptide nanofibers on the progression of osteoarthritis in a rat model. Biomaterials 2016; 74: 119-30.
[http://dx.doi.org/10.1016/j.biomaterials.2015.09.040] [PMID: 26454050]
[18]
Ma Z, Song W, He D, Zhang X, He Y, Li H. Smart µ‐fiber hydrogels with macro‐porous structure for sequentially promoting multiple phases of articular cartilage regeneration. Adv Funct Mater 2022; 32(22): 2113380.
[http://dx.doi.org/10.1002/adfm.202113380]
[19]
Mimura T, Imai S, Okumura N, et al. Spatiotemporal control of proliferation and differentiation of bone marrow-derived mesenchymal stem cells recruited using collagen hydrogel for repair of articular cartilage defects. J Biomed Mater Res B Appl Biomater 2011; 98B(2): 360-8.
[http://dx.doi.org/10.1002/jbm.b.31859] [PMID: 21648062]
[20]
Yan W, Xu X, Xu Q, et al. An injectable hydrogel scaffold with kartogenin-encapsulated nanoparticles for porcine cartilage regeneration: A 12-month follow-up study. Am J Sports Med 2020; 48(13): 3233-44.
[http://dx.doi.org/10.1177/0363546520957346] [PMID: 33026830]
[21]
Wang Y, Ling C, Chen J, et al. 3D-printed composite scaffold with gradient structure and programmed biomolecule delivery to guide stem cell behavior for osteochondral regeneration. Biomater Adv 2022; 140: 213067.
[22]
Yu X, Lin F, Li P, et al. Porous scaffolds with enzyme-responsive Kartogenin release for recruiting stem cells and promoting cartilage regeneration. Chem Eng J 2022; 447.
[23]
Yu H, Feng M, Mao G, et al. Implementation of photosensitive, injectable, interpenetrating, and kartogenin-modified GELMA/PEDGA biomimetic scaffolds to restore cartilage integrity in a full-thickness osteochondral defect model. ACS Biomater Sci Eng 2022; 8(10): 4474-85.
[http://dx.doi.org/10.1021/acsbiomaterials.2c00445] [PMID: 36074133]
[24]
Chen C, Song J, Qiu J, Zhao J. Repair of a meniscal defect in a rabbit model through use of a thermosensitive, injectable, in situ crosslinked hydrogel with encapsulated bone mesenchymal stromal cells and transforming growth factor β1. Am J Sports Med 2020; 48(4): 884-94.
[http://dx.doi.org/10.1177/0363546519898519] [PMID: 31967854]
[25]
Park YB, Ha CW, Kim JA, et al. Effect of transplanting various concentrations of a composite of human umbilical cord blood-derived mesenchymal stem cells and hyaluronic acid hydrogel on articular cartilage repair in a rabbit model. PLoS One 2016; 11(11): e0165446.
[http://dx.doi.org/10.1371/journal.pone.0165446] [PMID: 27824874]
[26]
Peng L, Zhou Y, Lu W, et al. Characterization of a novel polyvinyl alcohol/chitosan porous hydrogel combined with bone marrow mesenchymal stem cells and its application in articular cartilage repair. BMC Musculoskelet Disord 2019; 20(1): 257.
[http://dx.doi.org/10.1186/s12891-019-2644-7] [PMID: 31138200]
[27]
Qi BW, Yu AX, Zhu SB, Zhou M, Wu G. Chitosan/poly(vinyl alcohol) hydrogel combined with Ad-hTGF-β1 transfected mesenchymal stem cells to repair rabbit articular cartilage defects. Exp Biol Med 2013; 238(1): 23-30.
[http://dx.doi.org/10.1258/ebm.2012.012223] [PMID: 23479760]
[28]
Zhu Y, Kong L, Farhadi F, et al. An injectable continuous stratified structurally and functionally biomimetic construct for enhancing osteochondral regeneration. Biomaterials 2019; 192: 149-58.
[http://dx.doi.org/10.1016/j.biomaterials.2018.11.017] [PMID: 30448699]
[29]
Sarsenova M, Raimagambetov Y, Issabekova A, et al. Regeneration of osteochondral defects by combined delivery of synovium-derived mesenchymal stem cells, TGF-β1 and BMP-4 in heparin-conjugated fibrin hydrogel. Polymers 2022; 14(24): 5343.
[http://dx.doi.org/10.3390/polym14245343] [PMID: 36559710]
[30]
Cui P, Pan P, Qin L, et al. Nanoengineered hydrogels as 3D biomimetic extracellular matrix with injectable and sustained delivery capability for cartilage regeneration. Bioact Mater 2023; 19: 487-98.
[http://dx.doi.org/10.1016/j.bioactmat.2022.03.032] [PMID: 35600973]
[31]
Hooijmans CR, Rovers MM, de Vries RBM, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol 2014; 14(1): 43.
[http://dx.doi.org/10.1186/1471-2288-14-43] [PMID: 24667063]
[32]
Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50(4): 1088-101.
[http://dx.doi.org/10.2307/2533446] [PMID: 7786990]
[33]
Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315(7109): 629-34.
[http://dx.doi.org/10.1136/bmj.315.7109.629] [PMID: 9310563]
[34]
Santesso N, Glenton C, Dahm P, et al. GRADE guidelines 26: Informative statements to communicate the findings of systematic reviews of interventions. J Clin Epidemiol 2020; 119: 126-35.
[http://dx.doi.org/10.1016/j.jclinepi.2019.10.014] [PMID: 31711912]
[35]
Santesso N, Carrasco-Labra A, Langendam M, et al. Improving GRADE evidence tables part 3: detailed guidance for explanatory footnotes supports creating and understanding GRADE certainty in the evidence judgments. J Clin Epidemiol 2016; 74: 28-39.
[http://dx.doi.org/10.1016/j.jclinepi.2015.12.006] [PMID: 26796947]
[36]
Guyatt GH, Thorlund K, Oxman AD, et al. GRADE guidelines: 13. Preparing Summary of Findings tables and evidence profiles—continuous outcomes. J Clin Epidemiol 2013; 66(2): 173-83.
[http://dx.doi.org/10.1016/j.jclinepi.2012.08.001] [PMID: 23116689]
[37]
Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction—GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 2011; 64(4): 383-94.
[http://dx.doi.org/10.1016/j.jclinepi.2010.04.026] [PMID: 21195583]
[38]
Sterne JAC, Sutton AJ, Ioannidis JPA, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 2011; 343(jul22 1): d4002.
[http://dx.doi.org/10.1136/bmj.d4002] [PMID: 21784880]
[39]
Li H, Hu C, Yu H, Chen C. Chitosan composite scaffolds for articular cartilage defect repair: A review. RSC Advances 2018; 8(7): 3736-49.
[http://dx.doi.org/10.1039/C7RA11593H] [PMID: 35542907]
[40]
Rimmer S. Biomedical hydrogels: biochemistry, manufacture and medical applications. Elsevier 2011.
[http://dx.doi.org/10.1533/9780857091383]
[41]
Choi B, Kim S, Lin B, Wu BM, Lee M. Cartilaginous extracellular matrix-modified chitosan hydrogels for cartilage tissue engineering. ACS Appl Mater Interfaces 2014; 6(22): 20110-21.
[http://dx.doi.org/10.1021/am505723k] [PMID: 25361212]
[42]
Awasthi S, Gaur JK, Pandey SK, Bobji MS, Srivastava C. High-strength, strongly bonded nanocomposite hydrogels for cartilage repair. ACS Appl Mater Interfaces 2021; 13(21): 24505-23.
[http://dx.doi.org/10.1021/acsami.1c05394] [PMID: 34027653]
[43]
Zhang W, Ouyang H, Dass CR, Xu J. Current research on pharmacologic and regenerative therapies for osteoarthritis. Bone Res 2016; 4(1): 15040.
[http://dx.doi.org/10.1038/boneres.2015.40] [PMID: 26962464]
[44]
Deng Z, Jin J, Wang S, et al. Narrative review of the choices of stem cell sources and hydrogels for cartilage tissue engineering. Ann Transl Med 2020; 8(23): 1598.
[http://dx.doi.org/10.21037/atm-20-2342] [PMID: 33437797]
[45]
Lu J, Shen X, Sun X, et al. Increased recruitment of endogenous stem cells and chondrogenic differentiation by a composite scaffold containing bone marrow homing peptide for cartilage regeneration. Theranostics 2018; 8(18): 5039-58.
[http://dx.doi.org/10.7150/thno.26981] [PMID: 30429885]
[46]
Qi X, Guo X, Su C. Clinical outcomes of the transplantation of stem cells from various human tissue sources in the management of liver cirrhosis: A systematic review and meta-analysis. Curr Stem Cell Res Ther 2015; 10(2): 166-80.
[http://dx.doi.org/10.2174/1574888X09666141112114011] [PMID: 25391380]
[47]
Mainil-Varlet P, Aigner T, Brittberg M, et al. Histological assessment of cartilage repair: A report by the Histology Endpoint Committee of the International Cartilage Repair Society (ICRS). J Bone Joint Surg Am 2003; 85(S2): 45-57.
[http://dx.doi.org/10.2106/00004623-200300002-00007] [PMID: 12721345]
[48]
Moon SJ, Woo YJ, Jeong JH, et al. Rebamipide attenuates pain severity and cartilage degeneration in a rat model of osteoarthritis by downregulating oxidative damage and catabolic activity in chondrocytes. Osteoarthr Cartil 2012; 20(11): 1426-38.
[http://dx.doi.org/10.1016/j.joca.2012.08.002] [PMID: 22890185]
[49]
O’Driscoll SW, Marx RG, Beaton DE, Miura Y, Gallay SH, Fitzsimmons JS. Validation of a simple histological-histochemical cartilage scoring system. Tissue Eng 2001; 7(3): 313-20.
[http://dx.doi.org/10.1089/10763270152044170] [PMID: 11429151]
[50]
Orth P, Madry H. Complex and elementary histological scoring systems for articular cartilage repair. Histol Histopathol 2015; 30(8): 911-9.
[PMID: 25876650]
[51]
Smith GD, Taylor J, Almqvist KF, et al. Arthroscopic assessment of cartilage repair: A validation study of 2 scoring systems. Arthroscopy 2005; 21(12): 1462-7.
[http://dx.doi.org/10.1016/j.arthro.2005.09.007] [PMID: 16376236]
[52]
van den Borne MPJ, Raijmakers NJH, Vanlauwe J, et al. International Cartilage Repair Society (ICRS) and Oswestry macroscopic cartilage evaluation scores validated for use in Autologous Chondrocyte Implantation (ACI) and microfracture. Osteoarthritis Cartilage 2007; 15(12): 1397-402.
[http://dx.doi.org/10.1016/j.joca.2007.05.005] [PMID: 17604187]
[53]
von Lewinski G, Pressel T, Hurschler C, Witte F. The influence of intraoperative pretensioning on the chondroprotective effect of meniscal transplants. Am J Sports Med 2006; 34(3): 397-406.
[http://dx.doi.org/10.1177/0363546505281801] [PMID: 16365376]
[54]
Wayne JS, McDowell CL, Shields KJ, Tuan RS. In vivo response of polylactic acid-alginate scaffolds and bone marrow-derived cells for cartilage tissue engineering. Tissue Eng 2005; 11(5-6): 953-63.
[http://dx.doi.org/10.1089/ten.2005.11.953] [PMID: 15998234]
[55]
Poorolajal J, Moradi L, Mohammadi Y, Cheraghi Z, Gohari-Ensaf F. Risk factors for stomach cancer: A systematic review and meta-analysis. Epidemiol Health 2020; 42: e2020004.
[http://dx.doi.org/10.4178/epih.e2020004] [PMID: 32023777]
[56]
Dini C, Nagay BE, Magno MB, Maia LC, Barão VAR. Photofunctionalization as a suitable approach to improve the osseointegration of implants in animal models—A systematic review and meta‐analysis. Clin Oral Implants Res 2020; 31(9): 785-802.
[http://dx.doi.org/10.1111/clr.13627] [PMID: 32564392]
[57]
Zein AFMZ, Sulistiyana CS, Raffaelo WM, Pranata R. Ivermectin and mortality in patients with COVID-19: A systematic review, meta-analysis, and meta-regression of randomized controlled trials. Diabetes Metab Syndr 2021; 15(4): 102186.
[http://dx.doi.org/10.1016/j.dsx.2021.102186] [PMID: 34237554]
[58]
Ferrer-Peña R, Cuenca-Martínez F, Romero-Palau M, et al. Effects of motor imagery on strength, range of motion, physical function, and pain intensity in patients with total knee arthroplasty: A systematic review and meta-analysis. Braz J Phys Ther 2021; 25(6): 698-708.
[http://dx.doi.org/10.1016/j.bjpt.2021.11.001] [PMID: 34872869]
[59]
Jimenez-Fonseca P, Salazar R, Valenti V, Msaouel P, Carmona-Bayonas A. Is short-course radiotherapy and total neoadjuvant therapy the new standard of care in locally advanced rectal cancer? A sensitivity analysis of the RAPIDO clinical trial. Ann Oncol 2022; 33(8): 786-93.
[http://dx.doi.org/10.1016/j.annonc.2022.04.010] [PMID: 35462008]