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Dhillon J, Maguire JA, Kraeutler MJ. Stromal cell-based injection therapies for the treatment of knee osteoarthritis: A systematic review of level I randomized controlled trials. OSTEOARTHRITIS AND CARTILAGE OPEN 2025; 7:100608. [PMID: 40290651 PMCID: PMC12033899 DOI: 10.1016/j.ocarto.2025.100608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 03/27/2025] [Indexed: 04/30/2025] Open
Abstract
Objective To systematically review randomized controlled trials (RCTs) to compare clinical outcomes of stromal cell-based injection therapies versus other non-operative treatment modalities for the treatment of knee osteoarthritis (OA). Method A systematic review was performed by searching PubMed, Cochrane Library, and EMBASE to locate RCTs, published since 2019, comparing stromal cell-based injection therapies versus other non-operative modalities for the treatment of knee OA. The search terms used were: knee AND osteoarthritis AND injection AND randomized. Results Seventeen studies (all Level I evidence) were included in this review with 972 patients undergoing treatment with stromal cell-based therapy (Intervention Group) and 651 patients in the control group (Control Group). Among the 17 studies, 7 used autologous adipose-derived mesenchymal stromal cells (MSCs) (ADMSCs), 2 studies used allogeneic ADMSCs, 4 used autologous bone marrow-derived MSCs (BMMSCs), 1 used allogeneic BMMSCs, 1 used allogeneic placental MSCs, 1 used umbilical cord-derived MSCs (UCMSCs), and 1 study used autologous ADMSCs, BMMSCs, or allogeneic UCMSCs. All but 3 studies reported significantly better clinical or radiological outcomes in the Intervention Group at final follow-up. A total of 5 and 3 studies reported adverse events occurring in the Intervention and the Control groups, respectively, but they were all self-limiting. Conclusions Patients undergoing treatment of knee OA with MSCs might be expected to experience improvements in clinical and radiological outcomes in comparison to other non-operative modalities. Additional studies with mid-to long-term outcomes are needed to better determine the efficacy and safety of MSCs for the treatment of knee OA.
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Affiliation(s)
- Jaydeep Dhillon
- Samaritan Health Services, Department of Orthopedics, Corvallis, OR 97330, USA
| | - James A. Maguire
- St. Joseph's University Medical Center, Department of Orthopaedic Surgery, Paterson, NJ 07503, USA
| | - Matthew J. Kraeutler
- Texas Tech University Health Sciences Center, Department of Orthopaedic Surgery & Rehabilitation, Lubbock, TX 79430, USA
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Kim Y, Kim H, Yun SY, Lee BK. Primed IFN-γ-Umbilical Cord Stem Cells Ameliorate Temporomandibular Joint Osteoarthritis. Tissue Eng Part A 2025; 31:351-360. [PMID: 38787325 DOI: 10.1089/ten.tea.2023.0370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/25/2024] Open
Abstract
Temporomandibular joint osteoarthritis (TMJOA) is a degenerative disorder affecting the temporomandibular joint (TMJ), marked by persistent inflammation and structural damage to the joint. Only symptomatic treatment is available for managing TMJOA. Human umbilical cord mesenchymal stem cells (hUC-MSCs) show potential for treating TMJOA via their immune-modulating actions in the disease area. In addition, stimulation of inflammatory cytokines such as interferon-gamma in hUC-MSCs improves the therapeutic activity of naïve stem cells. Emerging evidence indicates that macrophages play significant roles in regulating joint inflammation through diverse secreted mediators in the pathogenesis of TMJOA. This study was conducted to evaluate the effects of inflammatory cytokine-stimulated hUC-MSCs in repairing TMJOA-induced cartilage lesions and the role of macrophages in the disease. Our in vitro data showed that stimulated hUC-MSCs induce M2 polarization of macrophages and enhance the expression of anti-inflammatory molecules. These effects were subsequently validated in vivo. In a rat model of TMJOA, stimulated hUC-MSCs ameliorated inflammation and increased M2 macrophages ratio. Our results indicate that hUC-MSCs stimulated by inflammatory cytokines modulate the activation of M2 macrophages, thereby shifting the local osteoarthritis microenvironment toward a prochondrogenic state and facilitating cartilage repair in inflammatory conditions. Stimulating hUC-MSCs with inflammatory cytokines could potentially offer an effective therapeutic approach for TMJOA, with macrophages playing a pivotal role in immune modulation.
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Affiliation(s)
- Yerin Kim
- AMIST, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
| | - Hyunjeong Kim
- Asan Institute for Life Science, Asan Medical Center, Asan Medical Institute of Convergence Science and Technology, Seoul, Korea
| | - So-Yeon Yun
- AMIST, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
| | - Bu-Kyu Lee
- AMIST, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
- Asan Institute for Life Science, Asan Medical Center, Asan Medical Institute of Convergence Science and Technology, Seoul, Korea
- Department of Oral and Maxillofacial Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
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Aabling RR, Rusan M, Møller AMJ, Munk-Pedersen N, Holm C, Elmengaard B, Pedersen M, Møller BK. A Narrative Review on Manufacturing Methods Employed in the Production of Mesenchymal Stromal Cells for Knee Osteoarthritis Therapy. Biomedicines 2025; 13:509. [PMID: 40002922 PMCID: PMC11853043 DOI: 10.3390/biomedicines13020509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 02/06/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Knee osteoarthritis (OA) is a chronic, progressive, inflammatory, and degenerative whole-joint disease. Early-stage OA treatments typically include physiotherapy, weight-loss, pain relief medications, and intra-articular knee injections, such as corticosteroids, hyaluronic acid, or platelet-rich plasma. These treatments primarily provide symptomatic relief rather than reversing or halting disease progression. Recently, mesenchymal stromal cell (MSC) injections have garnered attention due to their immunomodulatory and regenerative capacities. MSCs, which can be derived from sources such as bone marrow, umbilical cord, or adipose tissue, and can be allogeneic or autologous, have demonstrated promising results in both animal models and several human studies. However, different protocols have been employed, presenting challenges for comparing outcomes. In this review, we address these variable settings, evaluate current practices, and identify key factors critical in optimizing MSC-based therapies by critically reviewing clinical trials of ex vivo expanded MSC therapies for OA undertaken between 2008 and 2023. Specific attention was given to two key aspects: (1) the cell culture process employed in manufacturing of autologous or allogeneic MSC products, and (2) the post-culture methods employed in storage, reconstitution and administration of the MSCs. Our findings suggest that standardizing MSC production for clinical applications remains a significant challenge, primarily due to variations in tissue sources, harvesting techniques, and manufacturing protocols, and due to broad discrepancies in reporting. Thus, we propose a set of minimal reporting criteria to guide future clinical trials. A common reporting guideline is a critical step towards a more standardized MSC production across different laboratories and clinical settings, thereby enhancing reproducibility and advancing the field of regenerative medicine for knee OA, as well as other disease settings.
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Affiliation(s)
- Rasmus Roost Aabling
- Comparative Medicine Lab, SDCA-Steno Diabetes Center Aarhus, Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 99 and 11, DK-8200 Aarhus, Denmark
| | - Maria Rusan
- Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgårdsvej 21A, DK-8200 Aarhus, Denmark;
- Department of Clinical Pharmacology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark;
| | - Anaïs Marie Julie Møller
- Center for Gene and Cellular Therapy, Department of Clinical Immunology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark;
| | - Naija Munk-Pedersen
- Comparative Medicine Lab, Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark; (N.M.-P.); (M.P.)
| | - Carsten Holm
- Department of Orthopedic Surgery, Elective Surgery Centre, Silkeborg Regional Hospital, Falkevej 1G, DK-8600 Silkeborg, Denmark; (C.H.); (B.E.)
| | - Brian Elmengaard
- Department of Orthopedic Surgery, Elective Surgery Centre, Silkeborg Regional Hospital, Falkevej 1G, DK-8600 Silkeborg, Denmark; (C.H.); (B.E.)
| | - Michael Pedersen
- Comparative Medicine Lab, Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark; (N.M.-P.); (M.P.)
| | - Bjarne Kuno Møller
- Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark;
- Center for Gene and Cellular Therapy, Department of Clinical Immunology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark;
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Pakdaman Kolour SS, Nematollahi S, Dehbozorgi M, Fattahi F, Movahed F, Esfandiari N, Kahrizi MS, Ghavamikia N, Hajiagha BS. Extracecellulr vesicles (EVs) microRNAs (miRNAs) derived from mesenchymal stem cells (MSCs) in osteoarthritis (OA); detailed role in pathogenesis and possible therapeutics. Heliyon 2025; 11:e42258. [PMID: 40007782 PMCID: PMC11850152 DOI: 10.1016/j.heliyon.2025.e42258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 01/23/2025] [Accepted: 01/23/2025] [Indexed: 02/27/2025] Open
Abstract
The primary cause of pain and disability in the world is osteoarthritis (OA), a common joint disease characterized by the primary pathological alteration in articular cartilage deterioration. The general outcome of treatment is not acceptable despite current interventions. Therefore, joint replacement surgery is frequently needed by patients with severe OA. Mesenchymal stem cells (MSCs) have become a practical treatment choice for preclinical and clinical OA palliation in recent years, mainly due to their unique immunomodulatory attributes. Further, attractive candidates for cell-free therapy for OA are MSC-derived extracecellulr vesicles (EVs) that convey bioactive molecules of the original cells, such as microRNAs. These EVs have been shown to significantly influence the regulation of various physiological activities of cells in the joint cavity. Dysregulated miRNAs upregulate the synthesis of enzymes that degrade cartilage, downregulate the expression of components in the cartilage matrix, promote the production of proinflammatory cytokines, induce programmed cell death in chondrocytes, inhibit the process of autophagy in chondrocytes, and participate in pathways related to pain. MiRNAs are also found in extracellular membranous vesicles (EVs), such as exosomes, and play a role in intercellular communication in osteoarthritic joints. Thus, the biosynthesis, chemical makeup, and mechanism of action of miRNAs-enriched EVs in OA are all thoroughly covered in this review. We additionally discussed how miRNA-enriched MSC-EVs might be used therapeutically to change intercellular interaction in OA.
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Affiliation(s)
| | - Saeide Nematollahi
- Department of Radiology, Kerman University of Paramedical Sciences, Kerman, Iran
| | | | | | - Fatemeh Movahed
- Department of Gynecology, Tehran University of Medical Sciences, Tehran, Iran
| | | | | | - Nima Ghavamikia
- Cardiovascular Research Institute, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Bahareh Salmanian Hajiagha
- Department of Cellular and Molecular Biology, Faculty of Basic Science, East Tehran Branch, Islamic Azad University, Tehran, Iran
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Figueroa-Valdés AI, Luz-Crawford P, Herrera-Luna Y, Georges-Calderón N, García C, Tobar HE, Araya MJ, Matas J, Donoso-Meneses D, de la Fuente C, Cuenca J, Parra E, Lillo F, Varela C, Cádiz MI, Vernal R, Ortloff A, Nardocci G, Castañeda V, Adasme-Vidal C, Kunze-Küllmer M, Hidalgo Y, Espinoza F, Khoury M, Alcayaga-Miranda F. Clinical-grade extracellular vesicles derived from umbilical cord mesenchymal stromal cells: preclinical development and first-in-human intra-articular validation as therapeutics for knee osteoarthritis. J Nanobiotechnology 2025; 23:13. [PMID: 39806427 PMCID: PMC11730155 DOI: 10.1186/s12951-024-03088-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 12/30/2024] [Indexed: 01/16/2025] Open
Abstract
Osteoarthritis (OA) is a joint disease characterized by articular cartilage degradation. Persistent low-grade inflammation defines OA pathogenesis, with crucial involvement of pro-inflammatory M1-like macrophages. While mesenchymal stromal cells (MSC) and their small extracellular vesicles (sEV) hold promise for OA treatment, achieving consistent clinical-grade sEV products remains a significant challenge. This study aims to develop fully characterized, reproducible, clinical-grade batches of sEV derived from umbilical cord (UC)-MSC for the treatment of OA while assessing its efficacy and safety. Initially, a standardized, research-grade manufacturing protocol was established to ensure consistent sEV production. UC-MSC-sEV characterization under non-cGMP conditions showed consistent miRNA and protein profiles, suggesting their potential for standardized manufacturing. In vitro studies evaluated the efficacy, safety, and potency of sEV; animal studies confirmed their effectiveness and safety. In vitro, UC-MSC-sEV polarized macrophages to an anti-inflammatory M2b-like phenotype, through STAT1 modulation, indicating their potential to create an anti-inflammatory environment in the affected joints. In silico studies confirmed sEV's immunosuppressive signature through miRNA and proteome analysis. In an OA mouse model, sEV injected intra-articularly (IA) induced hyaline cartilage regeneration, validated by histological and μCT analyses. The unique detection of sEV signals within the knee joint over time highlights its safety profile by confirming the retention of sEV in the joint. The product development of UC-MSC-sEV involved refining, standardizing, and validating processes in compliance with GMP standards. The initial assessment of the safety of the clinical-grade product via IA administration in a first-in-human study showed no adverse effects after a 12 month follow-up period. These results support the progress of this sEV-based therapy in an early-phase clinical trial, the details of which are presented and discussed in this work. This study provides data on using UC-MSC-sEV as local therapy for OA, highlighting their regenerative and anti-inflammatory properties and safety in preclinical and a proof-of-principle clinical application.
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Affiliation(s)
- Aliosha I Figueroa-Valdés
- Laboratorio de Medicina Nano-Regenerativa, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los Andes, Santiago, Chile
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Patricia Luz-Crawford
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los Andes, Santiago, Chile
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Yeimi Herrera-Luna
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los Andes, Santiago, Chile
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Nicolás Georges-Calderón
- Laboratorio de Medicina Nano-Regenerativa, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los Andes, Santiago, Chile
- Programa de Doctorado en Biomedicina, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Cynthia García
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los Andes, Santiago, Chile
- Programa de Doctorado en Biomedicina, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Hugo E Tobar
- Laboratorio de Medicina Nano-Regenerativa, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los Andes, Santiago, Chile
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - María Jesús Araya
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los Andes, Santiago, Chile
- Programa de Doctorado en Biomedicina, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - José Matas
- Centro de Terapia Celular, Clínica Universidad de los Andes, Santiago, Chile
- Departmento de Cirugía Ortopédica, Clínica Universidad de los Andes, Santiago, Chile
| | - Darío Donoso-Meneses
- Laboratorio de Medicina Nano-Regenerativa, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los Andes, Santiago, Chile
- Programa de Doctorado en Biomedicina, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | | | - Jimena Cuenca
- Laboratorio de Medicina Nano-Regenerativa, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los Andes, Santiago, Chile
- Consorcio REGENERO, Chilean Consortium for Regenerative Medicine, Santiago, Chile
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
- Cells for Cells, Santiago, Chile
| | - Eliseo Parra
- Consorcio REGENERO, Chilean Consortium for Regenerative Medicine, Santiago, Chile
| | - Fernando Lillo
- Consorcio REGENERO, Chilean Consortium for Regenerative Medicine, Santiago, Chile
| | - Cristóbal Varela
- Departmento de Radiología, Clínica Universidad de los Andes, Santiago, Chile
| | - María Ignacia Cádiz
- Laboratorio de Medicina Nano-Regenerativa, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los Andes, Santiago, Chile
- Consorcio REGENERO, Chilean Consortium for Regenerative Medicine, Santiago, Chile
- Cells for Cells, Santiago, Chile
| | - Rolando Vernal
- Laboratorio de Biología Periodontal, Facultad de Odontología, Universidad de Chile, Santiago, Chile
| | - Alexander Ortloff
- Departamento de Ciencias Veterinarias y Salud Pública, Facultad de Recursos Naturales, Universidad Católica de Temuco, Temuco, Chile
| | - Gino Nardocci
- Laboratorio de Biología Molecular y Bioinformática, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los Andes, Santiago, Chile
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
- Escuela de Medicina, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Verónica Castañeda
- Laboratorio de Biología Molecular y Bioinformática, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los Andes, Santiago, Chile
- Programa de Doctorado en Biomedicina, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Catalina Adasme-Vidal
- Laboratorio de Medicina Nano-Regenerativa, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los Andes, Santiago, Chile
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Maximiliano Kunze-Küllmer
- Consorcio REGENERO, Chilean Consortium for Regenerative Medicine, Santiago, Chile
- Cells for Cells, Santiago, Chile
- EVast Bio, Miami, FL, USA
| | - Yessia Hidalgo
- Laboratorio de Medicina Nano-Regenerativa, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los Andes, Santiago, Chile
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Francisco Espinoza
- Consorcio REGENERO, Chilean Consortium for Regenerative Medicine, Santiago, Chile
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
- Centro de Terapia Celular, Clínica Universidad de los Andes, Santiago, Chile
- Departmento de Reumatología, Clínica Universidad de los Andes, Santiago, Chile
| | - Maroun Khoury
- Laboratorio de Medicina Nano-Regenerativa, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los Andes, Santiago, Chile.
- Consorcio REGENERO, Chilean Consortium for Regenerative Medicine, Santiago, Chile.
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile.
- Cells for Cells, Santiago, Chile.
- EVast Bio, Miami, FL, USA.
| | - Francisca Alcayaga-Miranda
- Laboratorio de Medicina Nano-Regenerativa, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los Andes, Santiago, Chile.
- Consorcio REGENERO, Chilean Consortium for Regenerative Medicine, Santiago, Chile.
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile.
- Cells for Cells, Santiago, Chile.
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Woolley K, Milan N, Master Z, Feeley BT. Evaluation of Spin in Clinical Trials of Mesenchymal Stromal Cells for the Treatment of Knee Osteoarthritis: A Systematic Review. Am J Sports Med 2025:3635465241274155. [PMID: 39772944 DOI: 10.1177/03635465241274155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
BACKGROUND The regenerative potential of mesenchymal stromal cells (MSCs) has sparked interest in their use for knee osteoarthritis. Concurrently, there have been investigations on how data in scientific journals are reported and how they may influence readers' interpretations, or "spin bias." These studies are at risk for bias, given the limited number of patients and inconsistent blinding or controls. The risk of spin bias also complicates the interpretation, as results may be presented in a way that favors a particular outcome. PURPOSE To quantify and characterize spin bias in clinical trials of MSCs for knee osteoarthritis. STUDY DESIGN Systematic review. METHODS PubMed and Embase searches were conducted using the terms "mesenchymal stem cells" or "MSCs" and "knee arthritis" or "osteoarthritis" and "therapy" or "treatment" or "regeneration." Overall, 2 independent reviewers classified spin as high, moderate, or low and as 1 of 3 types: (1) emphasizing statistically significant results, (2) interpreting nonsignificant results as treatment effectiveness, and (3) claiming treatment benefits despite nonsignificant results. Journals were categorized as orthopaedic or nonorthopaedic. Descriptive statistics, the chi-square test, and the Fisher exact test were used to analyze the data, with alpha set at P < .05. RESULTS Among the 54 studies, spin was found in 80.0% of articles, with 14.5% having high, 25.5% moderate, and 40.0% low levels of spin. Type 1 was found in 54.5% of articles, type 2 in 18.2%, and type 3 in 29.1%. Spin was less frequently observed in the Methods section of articles compared with the abstract (17.52; P = .003). Reports on adipose-derived MSCs were associated with a higher frequency and level of spin compared with reports on MSCs from other sources (18.92; P = .026). There was no difference in the frequency of spin between orthopaedic and nonorthopaedic journals (0.48; P = .49) and no association with the impact factor (5.34; P = .07). There was no association between spin and financial disclosures (0.02; P = .577). CONCLUSION Spin bias was present in most MSC-related trials for knee osteoarthritis, with a higher frequency among those that utilized adipose-derived MSCs. Understanding the prevalence and strategies of spin can mitigate any potential misinterpretations of study outcomes.
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Affiliation(s)
- Katherine Woolley
- Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Nesa Milan
- Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Zubin Master
- Department of Social Sciences and Health Policy, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
- Maya Angelou Center for Health Equity, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Brian T Feeley
- Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, California, USA
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Lin X, Zhang Y, Li J, Oliver BG, Wang B, Li H, Yong KT, Li JJ. Biomimetic multizonal scaffolds for the reconstruction of zonal articular cartilage in chondral and osteochondral defects. Bioact Mater 2025; 43:510-549. [PMID: 40115881 PMCID: PMC11923379 DOI: 10.1016/j.bioactmat.2024.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 09/02/2024] [Accepted: 10/01/2024] [Indexed: 03/23/2025] Open
Abstract
Chondral and osteochondral injuries are frequently encountered in clinical practice. However, articular cartilage has limited self-healing capacity due to its sophisticated zonal structure and avascular nature, introducing significant challenges to the restoration of chondral and osteochondral tissues after injury. Improperly repaired articular cartilage can lead to irreversible joint damage and increase the risk of osteoarthritis progression. Cartilage tissue engineering using stratified scaffolds with multizonal design to match the zonal structure of articular cartilage may help to meet the complex regeneration requirements of chondral and osteochondral tissues, and address the drawbacks experienced with single-phase scaffolds. Navigating the heterogeneity in matrix organisation and cellular composition across cartilage zones is a central consideration in multizonal scaffold design. With emphasis on recent advances in scaffold design and fabrication strategies, this review captures emerging approaches on biomimetic multizonal scaffolds for the reconstruction of zonal articular cartilage, including strategies on replicating native tissue structure through variations in fibre orientation, porous structure, and cell types. Exciting progress in this dynamic field has highlighted the tremendous potential of multizonal scaffolding strategies for regenerative medicine in the recreation of functional tissues.
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Affiliation(s)
- Xiaoqi Lin
- School of Biomedical Engineering, Faculty of Engineering and IT, University of Technology Sydney, NSW, 2007, Australia
| | - Ye Zhang
- School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW, 2007, Australia
| | - Jiarong Li
- School of Biomedical Engineering, Faculty of Engineering and IT, University of Technology Sydney, NSW, 2007, Australia
| | - Brian G Oliver
- School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW, 2007, Australia
- Woolcock Institute of Medical Research, Macquarie University, Macquarie Park, NSW, 2113, Australia
| | - Bin Wang
- Department of Orthopaedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Haiyan Li
- Chemical and Environmental Engineering Department, School of Engineering, STEM College, RMIT University, Melbourne, VIC, 3000, Australia
| | - Ken-Tye Yong
- School of Biomedical Engineering, Faculty of Engineering, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Jiao Jiao Li
- School of Biomedical Engineering, Faculty of Engineering and IT, University of Technology Sydney, NSW, 2007, Australia
- Woolcock Institute of Medical Research, Macquarie University, Macquarie Park, NSW, 2113, Australia
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Zampogna B, Parisi FR, Ferrini A, Zampoli A, Papalia GF, Shanmugasundaram S, Papalia R. Safety and efficacy of autologous adipose-derived stem cells for knee osteoarthritis in the elderly population: A systematic review. J Clin Orthop Trauma 2024; 59:102804. [PMID: 39628863 PMCID: PMC11609259 DOI: 10.1016/j.jcot.2024.102804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 07/17/2024] [Accepted: 11/06/2024] [Indexed: 12/06/2024] Open
Abstract
INTRODUCTION Osteoarthritis (OA) is a progressive joint disease, and over 240 million people suffer from symptomatic OA, primarily in the knee, and mainly affects the elderly population over 65. A combination of different risk factors leads to biological changes in the microenvironments of the joints, causing cartilage overload and chondrocyte aging. Adipose-derived MSCs (ADSCs) are demonstrated to improve joint environments with an effective therapy for Knee OA. This review focused on patients over 65 years old to evaluate the effectiveness of ADSC therapies in treating KOA in elderly patients and demonstrate that complications are not higher in this cohort of patients. MATERIALS AND METHODS We conducted a bibliography search through the PubMed, Scopus, and Cochrane databases for English-language and human clinical trials published until Feb 7, 2024. We extracted the following study characteristics: Authors, year of publication, type of study, number of patients, number of knees, sex, Kellgren-Lawrence classification, culture ADSC, Number of cells injected, mean follow-up, adverse events, significant complications, and clinical outcomes data were extracted recorded and analyzed. RESULTS According to inclusion criteria, seven clinical trials on autologous adipose-derived stem cells were considered. Four studies analyzed stem cells as a stromal vascular fraction (SVF), two as ADSC cultured, and 1 study investigated the MAT procedure. All studies reported improved clinical outcomes using autologous adipose-derived stem cells, on 339 knees. Post-treatment increased KOOS, WOMAC, IKS, VAS, and Lysholm knee scores were highlighted. All studies showed an improvement in all outcomes scores, and regarding complications, only 44 knees underwent adverse events, but no significant complications were found in all the studies reported. CONCLUSIONS The current systematic review demonstrated that using autologous adipose-derived stem cells improved clinical outcomes and is effective and safe in elderly patients. Additionally, this study will encourage orthopedic surgeons not to consider surgery as the only solution in elderly patients who are refractory to treatment and do not show end-stage knee osteoarthritis. LEVEL OF EVIDENCE Level IV, systematic review of level IV studies.
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Affiliation(s)
- Biagio Zampogna
- Department of Orthopaedic and Trauma Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128, Roma, Italy
- Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128, Roma, Italy
- BIOMORF Department, Biomedical, Dental and Morphological and Functional Images, University of Messina. A.O.U. Policlinico “G. Martino”, Messina, Italy
| | - Francesco Rosario Parisi
- Department of Orthopaedic and Trauma Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128, Roma, Italy
- Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128, Roma, Italy
| | - Augusto Ferrini
- Department of Orthopaedic and Trauma Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128, Roma, Italy
- Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128, Roma, Italy
| | - Andrea Zampoli
- Department of Orthopaedic and Trauma Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128, Roma, Italy
- Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128, Roma, Italy
| | - Giuseppe Francesco Papalia
- Department of Orthopaedic and Trauma Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128, Roma, Italy
- Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128, Roma, Italy
| | | | - Rocco Papalia
- Department of Orthopaedic and Trauma Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128, Roma, Italy
- Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128, Roma, Italy
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Riggle C, McLellan M, Bohlen H, Wang D. Complications of Stem Cell-Based Injections for Knee Osteoarthritis: A Systematic Review. HSS J 2024:15563316241271058. [PMID: 39564419 PMCID: PMC11572451 DOI: 10.1177/15563316241271058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 05/27/2024] [Indexed: 11/21/2024]
Abstract
Knee osteoarthritis (OA) remains a common cause of knee pain and dysfunction. Stem cell-based injections have been widely used for the treatment of knee OA, but the types and rates of post-injection complications are not well characterized. We sought to characterize the type and severity of adverse events and quantify the frequency of adverse events associated with stem cell injections used to treat knee OA. We conducted a systematic review that followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. We searched the PubMed and the Cochrane library databases for studies on adverse events and complications associated with stem cell-based therapies used to treat knee OA published from January 2000 through June 2021. Inclusion criteria were the use of intra-articular autologous bone marrow stem cells (BMSCs) or bone marrow aspirate concentrate (BMAC), autologous adipose-derived mesenchymal stem cells (ADMSCs) including microfragmented lipoaspirate, concentrated adipose tissue, cultured stem cells, autologous stromal vascular fraction (SVF), or umbilical or placental derived stem cells in human participants. Primary data extracted from included studies were patient demographics, methods of treatment, and reported character, duration, and severity of adverse events. A total of 427 studies were screened, and 48 studies were included, including randomized controlled trials, prospective studies, and retrospective studies. Among the 1924 patients in the analysis, there was an overall 12.3% rate of transient adverse events, the most frequent being swelling and pain at the injection site. Umbilical cord-derived (51.7%) and cultured ADMSC (29.5%) injections had a significantly higher occurrence of these adverse events than BMSC and SVF injections. No other adverse events, including infection, fat embolism, or medical complications, were reported. Despite significant heterogeneity of the included studies in terms of the protocol, formulation, timing, and location of injections, the findings of this systematic review suggest that, in the short term, treatment of knee OA with autologous mesenchymal stem cell injections poses no risk of major complications (infection, sepsis, neoplasm, embolism, or death) and poses moderate risk of swelling and pain at the injection site lasting less than 4 weeks. Further long-term studies are needed to conclusively determine the safety profile of these injections.
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Affiliation(s)
- Clara Riggle
- Department of Orthopaedic Surgery, University of California, Irvine, Orange, CA, USA
| | - Maddison McLellan
- Department of Orthopaedic Surgery, University of California, Irvine, Orange, CA, USA
| | - Hunter Bohlen
- Department of Orthopaedic Surgery, University of California, Irvine, Orange, CA, USA
| | - Dean Wang
- Department of Orthopaedic Surgery, University of California, Irvine, Orange, CA, USA
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Song K, Hu J, Yang M, Xia Y, He C, Yang Y, Zhu S. Pulsed electromagnetic fields potentiate bone marrow mesenchymal stem cell chondrogenesis by regulating the Wnt/β-catenin signaling pathway. J Transl Med 2024; 22:741. [PMID: 39107784 PMCID: PMC11301989 DOI: 10.1186/s12967-024-05470-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Accepted: 07/03/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND Pulsed electromagnetic fields (PEMFs) show promise as a treatment for knee osteoarthritis (KOA) by reducing inflammation and promoting chondrogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). PURPOSE To identify the efficacy window of PEMFs to induce BMSCs chondrogenic differentiation and explore the cellular mechanism under chondrogenesis of BMSCs in regular and inflammatory microenvironments. METHODS BMSCs were exposed to PEMFs (75 Hz, 1.6/2/3/3.8 mT) for 7 and 14 days. The histology, proliferation, migration and chondrogenesis of BMSCs were assessed to identify the optimal parameters. Using these optimal parameters, transcriptome analysis was performed to identify target genes and signaling pathways, validated through immunohistochemical assays, western blotting, and qRT-PCR, with or without the presence of IL-1β. The therapeutic effects of PEMFs and the effective cellular signaling pathways were evaluated in vivo. RESULTS BMSCs treated with 3 mT PEMFs showed the optimal chondrogenesis on day 7, indicated by increased expression of ACAN, COL2A, and SOX9, and decreased levels of MMP3 and MMP13 at both transcriptional and protein levels. The advantages of 3 mT PEMFs diminished in the 14-day culture groups. Transcriptome analysis identified sFRP3 as a key molecule targeted by PEMF treatment, which competitively inhibited Wnt/β-catenin signaling, regardless of IL-1β presence or duration of exposure. This inhibition of the Wnt/β-catenin pathway was also confirmed in a KOA mouse model following PEMF exposure. CONCLUSIONS PEMFs at 75 Hz and 3 mT are optimal in inducing early-stage chondrogenic differentiation of BMSCs. The induction and chondroprotective effects of PEMFs are mediated by sFRP3 and Wnt/β-catenin signaling, irrespective of inflammatory conditions.
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Affiliation(s)
- Kangping Song
- Rehabilitation Medicine Center, Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, #37 Guoxue Alley, Wuhou strict, Chengdu, Sichuan, 610041, PR China
- Key Laboratory of Rehabilitation Medicine in Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
- School of Rehabilitation Sciences, West China School of Medicine, Sichuan University, Chengdu, China
| | - Jing Hu
- Rehabilitation Medicine Center, Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, #37 Guoxue Alley, Wuhou strict, Chengdu, Sichuan, 610041, PR China
- Key Laboratory of Rehabilitation Medicine in Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
- School of Rehabilitation Sciences, West China School of Medicine, Sichuan University, Chengdu, China
| | - Ming Yang
- The Lab of Aging Research, State Key Laboratory of Biotherapy, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, Chengdu, China
| | - Yong Xia
- Rehabilitation Medicine Center, Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, #37 Guoxue Alley, Wuhou strict, Chengdu, Sichuan, 610041, PR China
- Key Laboratory of Rehabilitation Medicine in Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
- School of Rehabilitation Sciences, West China School of Medicine, Sichuan University, Chengdu, China
| | - Chengqi He
- Rehabilitation Medicine Center, Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, #37 Guoxue Alley, Wuhou strict, Chengdu, Sichuan, 610041, PR China
- Key Laboratory of Rehabilitation Medicine in Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
- School of Rehabilitation Sciences, West China School of Medicine, Sichuan University, Chengdu, China
| | - Yonghong Yang
- Rehabilitation Medicine Center, Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, #37 Guoxue Alley, Wuhou strict, Chengdu, Sichuan, 610041, PR China.
- Key Laboratory of Rehabilitation Medicine in Sichuan Province, West China Hospital, Sichuan University, Chengdu, China.
- School of Rehabilitation Sciences, West China School of Medicine, Sichuan University, Chengdu, China.
| | - Siyi Zhu
- Rehabilitation Medicine Center, Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, #37 Guoxue Alley, Wuhou strict, Chengdu, Sichuan, 610041, PR China.
- Key Laboratory of Rehabilitation Medicine in Sichuan Province, West China Hospital, Sichuan University, Chengdu, China.
- School of Rehabilitation Sciences, West China School of Medicine, Sichuan University, Chengdu, China.
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Fares MY, Shehade TH, Daher M, Boufadel P, Koa J, Abboud JA. Mesenchymal Stem Cell Injections for the Treatment of Osteoarthritis: A Systematic Review of Clinical Trials. Acta Orthop Belg 2024; 90:319-333. [PMID: 39440509 DOI: 10.52628/90.2.12364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
Objectives Osteoarthritis is a prevalent degenerative disease that affects many people worldwide. The use of mesenchymal stem cells (MSCs) in the setting of osteoarthritis has been explored by many clinical trials in the literature. Exploring these clinical trials is important for assessing the benefit of this modality in the setting of osteoarthritis. Methods On November 9, 2022, a search was conducted on PubMed/MEDLINE databases to explore clinical trials involving MSC injections for osteoarthritis. Only articles that were clinical trials, explored the use of MSC injections in osteoarthritis, involved human subjects, and written in English language, were included. Relevant data was extracted from the included trials. Results A total of 43 trials were included (N=43). The knee was most the commonly explored joint (95.4%), and adipose tissue was the most commonly utilized MSC source (49%). All but one trial (97.7%) reported clinical improvement in the MSC group on follow up, and 33 trials (76.7%) reported better clinical outcomes in the MSC groups when compared to control groups. Twenty-three trials (53.5%) used imaging to evaluate outcomes following MSC injections, out of which twenty (46.5%) reported improvements in the affected joint. Similarly, four trials (9.3%) used second look arthroscopy, out of which three (7%) reported better outcomes on follow up. Conclusion While published trials show good therapeutic potential for MSC injections in the setting of osteoarthritis, several discrepancies render the efficiency and reliability of this modality equivocal. The adoption of standardized protocols, employment of comprehensive evaluation tools, and reporting negative results is essential in order to appropriately assess the utility of MSC injections for the treatment of osteoarthritis.
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Chen B, Sun Y, Xu G, Jiang J, Zhang W, Wu C, Xue P, Cui Z. Role of crosstalk between synovial cells and chondrocytes in osteoarthritis (Review). Exp Ther Med 2024; 27:201. [PMID: 38590580 PMCID: PMC11000048 DOI: 10.3892/etm.2024.12490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 02/07/2024] [Indexed: 04/10/2024] Open
Abstract
Osteoarthritis (OA) is a low-grade, nonspecific inflammatory disease that affects the entire joint. This condition is characterized by synovitis, cartilage erosion, subchondral bone defects, and subpatellar fat pad damage. There is mounting evidence demonstrating the significance of crosstalk between synovitis and cartilage destruction in the development of OA. To comprehensively explore the phenotypic alterations of synovitis and cartilage destruction, it is important to elucidate the crosstalk mechanisms between chondrocytes and synovial cells. Furthermore, the updated iteration of single-cell sequencing technology reveals the interaction between chondrocyte and synovial cells. In the present review, the histological and pathological alterations between cartilage and synovium during OA progression are described, and the mode of interaction and molecular mechanisms between synovial cells and chondrocytes in OA, both of which affect the OA process mainly by altering the inflammatory environment and cellular state, are elucidated. Finally, the current OA therapeutic approaches are summarized and emerging therapeutic targets are reviewed in an attempt to provide potential insights into OA treatment.
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Affiliation(s)
- Baisen Chen
- Department of Orthopedics, Nantong City No. 1 People's Hospital and Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Yuyu Sun
- Department of Orthopedics, Nantong Third People's Hospital, Nantong, Jiangsu 226003, P.R. China
| | - Guanhua Xu
- Department of Orthopedics, Nantong City No. 1 People's Hospital and Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Jiawei Jiang
- Department of Orthopedics, Nantong City No. 1 People's Hospital and Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Wenhao Zhang
- Medical School of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Chunshuai Wu
- Department of Orthopedics, Nantong City No. 1 People's Hospital and Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Pengfei Xue
- Department of Orthopedics, Nantong City No. 1 People's Hospital and Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Zhiming Cui
- Department of Orthopedics, Nantong City No. 1 People's Hospital and Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
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Rashidi N, Slater A, Peregrino G, Santin M. A novel, microfluidic high-throughput single-cell encapsulation of human bone marrow mesenchymal stromal cells. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2024; 35:19. [PMID: 38526655 PMCID: PMC10963554 DOI: 10.1007/s10856-024-06785-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Accepted: 02/17/2024] [Indexed: 03/27/2024]
Abstract
The efficacy of stem-cell therapy depends on the ability of the transplanted cells to escape early immunological reactions and to be retained at the site of transplantation. The use of tissue engineering scaffolds or injectable biomaterials as carriers has been proposed, but they still present limitations linked to a reliable manufacturing process, surgical practice and clinical outcomes. Alginate microbeads are potential candidates for the encapsulation of mesenchymal stromal cells with the aim of providing a delivery carrier suitable for minimally-invasive and scaffold-free transplantation, tissue-adhesive properties and protection from the immune response. However, the formation of stable microbeads relies on the cross-linking of alginate with divalent calcium ions at concentrations that are toxic for the cells, making control over the beads' size and a single-cell encapsulation unreliable. The present work demonstrates the efficiency of an innovative, high throughput, and reproducible microfluidic system to produce single-cell, calcium-free alginate coatings of human mesenchymal stromal cells. Among the various conditions tested, visible light and confocal microscopy following staining of the cell nuclei by DAPI showed that the microfluidic system yielded an optimal single-cell encapsulation of 2000 cells/min in 2% w/v alginate microcapsules of reproducible morphology and an average size of 28.2 ± 3.7 µm. The adhesive properties of the alginate microcapsules, the viability of the encapsulated cells and their ability to escape the alginate microcapsule were demonstrated by the relatively rapid adherence of the beads onto tissue culture plastic and the cells' ability to gradually disrupt the microcapsule shell after 24 h and proliferate. To mimic the early inflammatory response upon transplantation, the encapsulated cells were exposed to proliferating macrophages at different cell seeding densities for up to 2 days and the protection effect of the microcapsule on the cells assessed by time-lapse microscopy showing a shielding effect for up to 48 h. This work underscores the potential of microfluidic systems to precisely encapsulate cells by good manufacturing practice standards while favouring cell retention on substrates, viability and proliferation upon transplantation.
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Affiliation(s)
- Narjes Rashidi
- Centre for Regenerative Medicine and Devices, University of Brighton, Huxley Building Lewes Road, Brighton, BN2 4GJ, UK
- School of Applied Sciences, University of Brighton, Huxley Building Lewes Road, Brighton, BN2 4GJ, UK
| | - Alex Slater
- Centre for Regenerative Medicine and Devices, University of Brighton, Huxley Building Lewes Road, Brighton, BN2 4GJ, UK
- School of Applied Sciences, University of Brighton, Huxley Building Lewes Road, Brighton, BN2 4GJ, UK
| | - Giordana Peregrino
- Centre for Regenerative Medicine and Devices, University of Brighton, Huxley Building Lewes Road, Brighton, BN2 4GJ, UK
- School of Applied Sciences, University of Brighton, Huxley Building Lewes Road, Brighton, BN2 4GJ, UK
| | - Matteo Santin
- Centre for Regenerative Medicine and Devices, University of Brighton, Huxley Building Lewes Road, Brighton, BN2 4GJ, UK.
- School of Applied Sciences, University of Brighton, Huxley Building Lewes Road, Brighton, BN2 4GJ, UK.
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Khoury MA, Chamari K, Tabben M, Alkhelaifi K, Papacostas E, Marín Fermín T, Laupheimer M, D′Hooghe P. Knee Osteoarthritis: Clinical and MRI Outcomes After Multiple Intra-Articular Injections With Expanded Autologous Adipose-Derived Stromal Cells or Platelet-Rich Plasma. Cartilage 2023; 14:433-444. [PMID: 37350015 PMCID: PMC10807730 DOI: 10.1177/19476035231166127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 03/09/2023] [Accepted: 03/12/2023] [Indexed: 06/24/2023] Open
Abstract
OBJECTIVE To directly compare clinical and MRI outcomes of multiple intra-articular injections of adipose-derived stromal cells (ASCs) or platelet-rich plasma (PRP) in patients with knee osteoarthritis (OA). DESIGN We retrospectively compared 24-month outcomes in (1) 27 patients receiving 3-monthly intra-articular injections with a total of 43.8 million ASCs and (2) 23 patients receiving 3-monthly injections of 3-ml preparation of PRP. All patients had Kellgren-Lawrence grade 1, 2, or 3 knee OA with failed conservative medical therapy. The Numeric Pain Rating Scale (NPRS) scores; Knee injury and Osteoarthritis Outcome Score (KOOS) at baseline, 6, 12, and 24 months after the first injection; and the MRI Osteoarthritis Knee Score (MOAKS) at 12 and 24 months were considered as outcomes. RESULTS No major complications occurred in any patient. Both groups significantly improved in pain NPRS score and KOOS at 6 months. At 12- and 24-month evaluations, the ASC group significantly decreased scores to a greater degree (P < 0.001) than the PRP group. MOAKS scores indicated a decrease in disease progression in the ASC group. CONCLUSION Both ASCs and PRP were safe and resulted in clinical improvement in patients with knee OA at 6 months; however, at 12 and 24 months, ASCs outperformed leukocyte-poor PRP in clinical and radiological outcomes.
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Affiliation(s)
| | - Karim Chamari
- Aspetar Orthopaedic and Sports Medicine Hospital, Doha, Qatar
| | | | | | | | | | | | - Pieter D′Hooghe
- Aspetar Orthopaedic and Sports Medicine Hospital, Doha, Qatar
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Zhang A, Wong JKU, Redzikultsava K, Baldry M, Alavi SK, Wang Z, van Koten E, Weiss A, Bilek M, Yeo GC, Akhavan B. A cost-effective and enhanced mesenchymal stem cell expansion platform with internal plasma-activated biofunctional interfaces. Mater Today Bio 2023; 22:100727. [PMID: 37529421 PMCID: PMC10388840 DOI: 10.1016/j.mtbio.2023.100727] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 06/30/2023] [Accepted: 07/07/2023] [Indexed: 08/03/2023] Open
Abstract
Mesenchymal stem cells (MSCs) used for clinical applications require in vitro expansion to achieve therapeutically relevant numbers. However, conventional planar cell expansion approaches using tissue culture vessels are inefficient, costly, and can trigger MSC phenotypic and functional decline. Here we present a one-step dry plasma process to modify the internal surfaces of three-dimensional (3D) printed, high surface area to volume ratio (high-SA:V) porous scaffolds as platforms for stem cell expansion. To address the long-lasting challenge of uniform plasma treatment within the micrometre-sized pores of scaffolds, we developed a packed bed plasma immersion ion implantation (PBPI3) technology by which plasma is ignited inside porous materials for homogeneous surface activation. COMSOL Multiphysics simulations support our experimental data and provide insights into the role of electrical field and pressure distribution in plasma ignition. Spatial surface characterisation inside scaffolds demonstrates the homogeneity of PBPI3 activation. The PBPI3 treatment induces radical-containing chemical structures that enable the covalent attachment of biomolecules via a simple, non-toxic, single-step incubation process. We showed that PBPI3-treated scaffolds biofunctionalised with fibroblast growth factor 2 (FGF2) significantly promoted the expansion of MSCs, preserved cell phenotypic expression, and multipotency, while reducing the usage of costly growth factor supplements. This breakthrough PBPI3 technology can be applied to a wide range of 3D polymeric porous scaffolds, paving the way towards developing new biomimetic interfaces for tissue engineering and regenerative medicine.
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Affiliation(s)
- Anyu Zhang
- School of Biomedical Engineering, University of Sydney, NSW 2006, Australia
- School of Physics, University of Sydney, NSW 2006, Australia
- Sydney Nano Institute, University of Sydney, NSW 2006, Australia
| | - Johnny Kuan Un Wong
- Charles Perkins Centre, University of Sydney, NSW 2006, Australia
- School of Life and Environmental Sciences, University of Sydney, NSW 2006, Australia
- Sydney Nano Institute, University of Sydney, NSW 2006, Australia
| | - Katazhyna Redzikultsava
- School of Biomedical Engineering, University of Sydney, NSW 2006, Australia
- School of Physics, University of Sydney, NSW 2006, Australia
| | - Mark Baldry
- School of Biomedical Engineering, University of Sydney, NSW 2006, Australia
- School of Physics, University of Sydney, NSW 2006, Australia
- Sydney Nano Institute, University of Sydney, NSW 2006, Australia
| | - Seyedeh Kh Alavi
- School of Biomedical Engineering, University of Sydney, NSW 2006, Australia
- School of Physics, University of Sydney, NSW 2006, Australia
| | - Ziyu Wang
- Charles Perkins Centre, University of Sydney, NSW 2006, Australia
- School of Life and Environmental Sciences, University of Sydney, NSW 2006, Australia
| | | | - Anthony Weiss
- Charles Perkins Centre, University of Sydney, NSW 2006, Australia
- School of Life and Environmental Sciences, University of Sydney, NSW 2006, Australia
| | - Marcela Bilek
- School of Biomedical Engineering, University of Sydney, NSW 2006, Australia
- School of Physics, University of Sydney, NSW 2006, Australia
- Charles Perkins Centre, University of Sydney, NSW 2006, Australia
- Sydney Nano Institute, University of Sydney, NSW 2006, Australia
| | - Giselle C Yeo
- Charles Perkins Centre, University of Sydney, NSW 2006, Australia
- School of Life and Environmental Sciences, University of Sydney, NSW 2006, Australia
| | - Behnam Akhavan
- School of Biomedical Engineering, University of Sydney, NSW 2006, Australia
- School of Physics, University of Sydney, NSW 2006, Australia
- Sydney Nano Institute, University of Sydney, NSW 2006, Australia
- School of Engineering, University of Newcastle, Callaghan, NSW 2308, Australia
- Hunter Medical Research Institute (HMRI), Precision Medicine Program, New Lambton Heights, NSW, 2305, Australia
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Zhang Z, Zhao S, Sun Z, Zhai C, Xia J, Wen C, Zhang Y, Zhang Y. Enhancement of the therapeutic efficacy of mesenchymal stem cell-derived exosomes in osteoarthritis. Cell Mol Biol Lett 2023; 28:75. [PMID: 37770821 PMCID: PMC10540339 DOI: 10.1186/s11658-023-00485-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 08/29/2023] [Indexed: 09/30/2023] Open
Abstract
Osteoarthritis (OA), a common joint disorder with articular cartilage degradation as the main pathological change, is the major source of pain and disability worldwide. Despite current treatments, the overall treatment outcome is unsatisfactory. Thus, patients with severe OA often require joint replacement surgery. In recent years, mesenchymal stem cells (MSCs) have emerged as a promising therapeutic option for preclinical and clinical palliation of OA. MSC-derived exosomes (MSC-Exos) carrying bioactive molecules of the parental cells, including non-coding RNAs (ncRNAs) and proteins, have demonstrated a significant impact on the modulation of various physiological behaviors of cells in the joint cavity, making them promising candidates for cell-free therapy for OA. This review provides a comprehensive overview of the biosynthesis and composition of MSC-Exos and their mechanisms of action in OA. We also discussed the potential of MSC-Exos as a therapeutic tool for modulating intercellular communication in OA. Additionally, we explored bioengineering approaches to enhance MSC-Exos' therapeutic potential, which may help to overcome challenges and achieve clinically meaningful OA therapies.
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Affiliation(s)
- Zehao Zhang
- School of Clinical Medicine, Jining Medical University, Jining, 272067, Shandong, China
| | - Sheng Zhao
- School of Clinical Medicine, Jining Medical University, Jining, 272067, Shandong, China
| | - Zhaofeng Sun
- School of Clinical Medicine, Jining Medical University, Jining, 272067, Shandong, China
| | - Chuanxing Zhai
- School of Clinical Medicine, Jining Medical University, Jining, 272067, Shandong, China
| | - Jiang Xia
- Department of Chemistry, The Chinese University of Hong Kong, Shatin, Hong Kong, SAR, China
| | - Caining Wen
- Department of Joint Surgery and Sports Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272029, Shandong, China.
| | - Yuge Zhang
- Department of Joint Surgery and Sports Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272029, Shandong, China.
| | - Yuanmin Zhang
- Department of Joint Surgery and Sports Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272029, Shandong, China.
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Gherghel R, Macovei LA, Burlui MA, Cardoneanu A, Rezus II, Mihai IR, Rezus E. Osteoarthritis—The Role of Mesenchymal Stem Cells in Cartilage Regeneration. APPLIED SCIENCES 2023; 13:10617. [DOI: 10.3390/app131910617] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Osteoarthritis (OA) is a condition that can cause substantial pain, loss of joint function, and a decline in quality of life in patients. Numerous risk factors, including aging, genetics, and injury, have a role in the onset of OA, characterized by structural changes within the joints. Most therapeutic approaches focus on the symptoms and try to change or improve the structure of the joint tissues. Even so, no treatments have been able to stop or slow the progression of OA or give effective and long-lasting relief of symptoms. In the absence of disease-modifying drugs, regenerative medicine is being investigated as a possible treatment that can change the course of OA by changing the structure of damaged articular cartilage. In regenerative therapy for OA, mesenchymal stem cells (MSCs) have been the mainstay of translational investigations and clinical applications. In recent years, MSCs have been discovered to be an appropriate cell source for treating OA due to their ability to expand rapidly in culture, their nontumorigenic nature, and their ease of collection. MSCs’ anti-inflammatory and immunomodulatory capabilities may provide a more favorable local environment for the regeneration of injured articular cartilage, which was thought to be one of the reasons why they were seen as more suited for OA. In addition to bone marrow, MSCs have also been isolated from adipose tissue, synovium, umbilical cord, cord blood, dental pulp, placenta, periosteum, and skeletal muscle. Adipose tissue and bone marrow are two of the most essential tissues for therapeutic MSCs. Positive preclinical and clinical trial results have shown that, despite current limitations and risks, MSC-based therapy is becoming a promising approach to regenerative medicine in treating OA.
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Affiliation(s)
- Robert Gherghel
- Department of Orthopedics and Trauma Surgery, Piatra Neamt Emergency Hospital, 700115 Piatra Neamt, Romania
| | - Luana Andreea Macovei
- Department of Rheumatology and Rehabilitation, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania
| | - Maria-Alexandra Burlui
- Department of Rheumatology and Rehabilitation, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania
| | - Anca Cardoneanu
- Department of Rheumatology and Rehabilitation, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania
| | - Ioana-Irina Rezus
- Department of Dermatology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania
| | - Ioana Ruxandra Mihai
- Department of Rheumatology and Rehabilitation, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania
| | - Elena Rezus
- Department of Rheumatology and Rehabilitation, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania
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Jakl V, Popp T, Haupt J, Port M, Roesler R, Wiese S, Friemert B, Rojewski MT, Schrezenmeier H. Effect of Expansion Media on Functional Characteristics of Bone Marrow-Derived Mesenchymal Stromal Cells. Cells 2023; 12:2105. [PMID: 37626914 PMCID: PMC10453497 DOI: 10.3390/cells12162105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 08/07/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
The therapeutic efficacy of mesenchymal stromal cells (MSCs) has been shown to rely on their immunomodulatory and regenerative properties. In order to obtain sufficient numbers of cells for clinical applications, MSCs have to be expanded ex vivo. Expansion media with xenogeneic-free (XF) growth-promoting supplements like human platelet lysate (PL) or serum- and xenogeneic-free (SF/XF) formulations have been established as safe and efficient, and both groups provide different beneficial qualities. In this study, MSCs were expanded in XF or SF/XF media as well as in mixtures thereof. MSCs cultured in these media were analyzed for phenotypic and functional properties. MSC expansion was optimal with SF/XF conditions when PL was present. Metabolic patterns, consumption of growth factors, and secretome of MSCs differed depending on the type and concentration of supplement. The lactate per glucose yield increased along with a higher proportion of PL. Many factors in the supernatant of cultured MSCs showed distinct patterns depending on the supplement (e.g., FGF-2, TGFβ, and insulin only in PL-expanded MSC, and leptin, sCD40L PDGF-AA only in SF/XF-expanded MSC). This also resulted in changes in cell characteristics like migratory potential. These findings support current approaches where growth media may be utilized for priming MSCs for specific therapeutic applications.
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Affiliation(s)
- Viktoria Jakl
- Institute for Transfusion Medicine, University Hospital Ulm, 89081 Ulm, Germany; (V.J.)
| | - Tanja Popp
- Bundeswehr Institute of Radiobiology, 80937 Munich, Germany (J.H.); (M.P.)
| | - Julian Haupt
- Bundeswehr Institute of Radiobiology, 80937 Munich, Germany (J.H.); (M.P.)
- Clinic for Trauma Surgery and Orthopedics, Army Hospital Ulm, 89081 Ulm, Germany
| | - Matthias Port
- Bundeswehr Institute of Radiobiology, 80937 Munich, Germany (J.H.); (M.P.)
| | - Reinhild Roesler
- Core Unit of Mass Spectrometry and Proteomics, Ulm University Medical Center, 89081 Ulm, Germany; (R.R.); (S.W.)
| | - Sebastian Wiese
- Core Unit of Mass Spectrometry and Proteomics, Ulm University Medical Center, 89081 Ulm, Germany; (R.R.); (S.W.)
| | - Benedikt Friemert
- Clinic for Trauma Surgery and Orthopedics, Army Hospital Ulm, 89081 Ulm, Germany
| | - Markus T. Rojewski
- Institute for Transfusion Medicine, University Hospital Ulm, 89081 Ulm, Germany; (V.J.)
- Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service Baden-Württemberg—Hessia and University Hospital Ulm, 89081 Ulm, Germany
| | - Hubert Schrezenmeier
- Institute for Transfusion Medicine, University Hospital Ulm, 89081 Ulm, Germany; (V.J.)
- Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service Baden-Württemberg—Hessia and University Hospital Ulm, 89081 Ulm, Germany
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Ouzin M, Kogler G. Mesenchymal Stromal Cells: Heterogeneity and Therapeutical Applications. Cells 2023; 12:2039. [PMID: 37626848 PMCID: PMC10453316 DOI: 10.3390/cells12162039] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/06/2023] [Accepted: 08/08/2023] [Indexed: 08/27/2023] Open
Abstract
Mesenchymal stromal cells nowadays emerge as a major player in the field of regenerative medicine and translational research. They constitute, with their derived products, the most frequently used cell type in different therapies. However, their heterogeneity, including different subpopulations, the anatomic source of isolation, and high donor-to-donor variability, constitutes a major controversial issue that affects their use in clinical applications. Furthermore, the intrinsic and extrinsic molecular mechanisms underlying their self-renewal and fate specification are still not completely elucidated. This review dissects the different heterogeneity aspects of the tissue source associated with a distinct developmental origin that need to be considered when generating homogenous products before their usage for clinical applications.
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Affiliation(s)
- Meryem Ouzin
- Institute for Transplantation Diagnostics and Cell Therapeutics, University Hospital Düsseldorf, 40225 Düsseldorf, Germany;
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20
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Obrecht M, Zurbruegg S, Accart N, Lambert C, Doelemeyer A, Ledermann B, Beckmann N. Magnetic resonance imaging and ultrasound elastography in the context of preclinical pharmacological research: significance for the 3R principles. Front Pharmacol 2023; 14:1177421. [PMID: 37448960 PMCID: PMC10337591 DOI: 10.3389/fphar.2023.1177421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 06/16/2023] [Indexed: 07/18/2023] Open
Abstract
The 3Rs principles-reduction, refinement, replacement-are at the core of preclinical research within drug discovery, which still relies to a great extent on the availability of models of disease in animals. Minimizing their distress, reducing their number as well as searching for means to replace them in experimental studies are constant objectives in this area. Due to its non-invasive character in vivo imaging supports these efforts by enabling repeated longitudinal assessments in each animal which serves as its own control, thereby enabling to reduce considerably the animal utilization in the experiments. The repetitive monitoring of pathology progression and the effects of therapy becomes feasible by assessment of quantitative biomarkers. Moreover, imaging has translational prospects by facilitating the comparison of studies performed in small rodents and humans. Also, learnings from the clinic may be potentially back-translated to preclinical settings and therefore contribute to refining animal investigations. By concentrating on activities around the application of magnetic resonance imaging (MRI) and ultrasound elastography to small rodent models of disease, we aim to illustrate how in vivo imaging contributes primarily to reduction and refinement in the context of pharmacological research.
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Affiliation(s)
- Michael Obrecht
- Diseases of Aging and Regenerative Medicines, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Stefan Zurbruegg
- Neurosciences Department, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Nathalie Accart
- Diseases of Aging and Regenerative Medicines, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Christian Lambert
- Diseases of Aging and Regenerative Medicines, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Arno Doelemeyer
- Diseases of Aging and Regenerative Medicines, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Birgit Ledermann
- 3Rs Leader, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Nicolau Beckmann
- Diseases of Aging and Regenerative Medicines, Novartis Institutes for BioMedical Research, Basel, Switzerland
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Carneiro DDC, Araújo LTD, Santos GC, Damasceno PKF, Vieira JL, Santos RRD, Barbosa JDV, Soares MBP. Clinical Trials with Mesenchymal Stem Cell Therapies for Osteoarthritis: Challenges in the Regeneration of Articular Cartilage. Int J Mol Sci 2023; 24:9939. [PMID: 37373096 DOI: 10.3390/ijms24129939] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/13/2023] [Accepted: 04/18/2023] [Indexed: 06/29/2023] Open
Abstract
Osteoarthritis (OA) is a whole-joint disease primarily characterized by the deterioration of hyaline cartilage. Current treatments include microfracture and chondrocyte implantation as early surgical strategies that can be combined with scaffolds to repair osteochondral lesions; however, intra-articular (IA) injections or implantations of mesenchymal stem cells (MSCs) are new approaches that have presented encouraging therapeutic results in animal models and humans. We critically reviewed clinical trials with MSC therapies for OA, focusing on their effectiveness, quality, and outcomes in the regeneration of articular cartilage. Several sources of autologous or allogeneic MSCs were used in the clinical trials. Minor adverse events were generally reported, indicating that IA applications of MSCs are potentially safe. The evaluation of articular cartilage regeneration in human clinical trials is challenging, particularly in the inflammatory environment of osteoarthritic joints. Our findings indicate that IA injections of MSCs are efficacious in the treatment of OA and the regeneration of cartilage, but that they may be insufficient for the full repair of articular cartilage defects. The possible interference of clinical and quality variables in the outcomes suggests that robust clinical trials are still necessary for generating reliable evidence with which to support these treatments. We suggest that the administration of just-sufficient doses of viable cells in appropriate regimens is critical to achieve effective and durable effects. In terms of future perspectives, genetic modification, complex products with extracellular vesicles derived from MSCs, cell encapsulation in hydrogels, and 3D bioprinted tissue engineering are promising approaches with which to improve MSC therapies for OA.
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Affiliation(s)
| | - Lila Teixeira de Araújo
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador 40296-710, Bahia, Brazil
- SENAI Institute of Advanced Health Systems, University Center SENAI CIMATEC, Salvador 41650-010, Bahia, Brazil
| | - Girlaine Café Santos
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador 40296-710, Bahia, Brazil
| | | | | | - Ricardo Ribeiro Dos Santos
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador 40296-710, Bahia, Brazil
- SENAI Institute of Advanced Health Systems, University Center SENAI CIMATEC, Salvador 41650-010, Bahia, Brazil
| | | | - Milena Botelho Pereira Soares
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador 40296-710, Bahia, Brazil
- SENAI Institute of Advanced Health Systems, University Center SENAI CIMATEC, Salvador 41650-010, Bahia, Brazil
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Copp G, Robb KP, Viswanathan S. Culture-expanded mesenchymal stromal cell therapy: does it work in knee osteoarthritis? A pathway to clinical success. Cell Mol Immunol 2023; 20:626-650. [PMID: 37095295 PMCID: PMC10229578 DOI: 10.1038/s41423-023-01020-1] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 03/29/2023] [Indexed: 04/26/2023] Open
Abstract
Osteoarthritis (OA) is a degenerative multifactorial disease with concomitant structural, inflammatory, and metabolic changes that fluctuate in a temporal and patient-specific manner. This complexity has contributed to refractory responses to various treatments. MSCs have shown promise as multimodal therapeutics in mitigating OA symptoms and disease progression. Here, we evaluated 15 randomized controlled clinical trials (RCTs) and 11 nonrandomized RCTs using culture-expanded MSCs in the treatment of knee OA, and we found net positive effects of MSCs on mitigating pain and symptoms (improving function in 12/15 RCTs relative to baseline and in 11/15 RCTs relative to control groups at study endpoints) and on cartilage protection and/or repair (18/21 clinical studies). We examined MSC dose, tissue of origin, and autologous vs. allogeneic origins as well as patient clinical phenotype, endotype, age, sex and level of OA severity as key parameters in parsing MSC clinical effectiveness. The relatively small sample size of 610 patients limited the drawing of definitive conclusions. Nonetheless, we noted trends toward moderate to higher doses of MSCs in select OA patient clinical phenotypes mitigating pain and leading to structural improvements or cartilage preservation. Evidence from preclinical studies is supportive of MSC anti-inflammatory and immunomodulatory effects, but additional investigations on immunomodulatory, chondroprotective and other clinical mechanisms of action are needed. We hypothesize that MSC basal immunomodulatory "fitness" correlates with OA treatment efficacy, but this hypothesis needs to be validated in future studies. We conclude with a roadmap articulating the need to match an OA patient subset defined by molecular endotype and clinical phenotype with basally immunomodulatory "fit" or engineered-to-be-fit-for-OA MSCs in well-designed, data-intensive clinical trials to advance the field.
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Affiliation(s)
- Griffin Copp
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada
- Krembil Research Institute, University Health Network, Toronto, ON, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
| | - Kevin P Robb
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada
- Krembil Research Institute, University Health Network, Toronto, ON, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
| | - Sowmya Viswanathan
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada.
- Krembil Research Institute, University Health Network, Toronto, ON, Canada.
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada.
- Department of Medicine, Division of Hematology, University of Toronto, Toronto, ON, Canada.
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23
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Shang Z, Wanyan P, Zhang B, Wang M, Wang X. A systematic review, umbrella review, and quality assessment on clinical translation of stem cell therapy for knee osteoarthritis: Are we there yet? Stem Cell Res Ther 2023; 14:91. [PMID: 37061744 PMCID: PMC10105961 DOI: 10.1186/s13287-023-03332-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 04/06/2023] [Indexed: 04/17/2023] Open
Abstract
BACKGROUND The success of stem cell therapy for knee osteoarthritis (KOA) in preclinical animal models has accelerated the pace of clinical translation. However, it remains uncertain whether the current scientific evidence supports the clinical application of stem cells in treating KOA. A comprehensive evaluation of the safety and efficacy of stem cell therapies and scientific evidence quality is necessary. METHODS Using "stem cells" and "knee osteoarthritis" as the search terms, several databases, including PubMed, Web of Science, Cochrane, Embase, and Clinicaltrials.gov, were searched on August 25, 2022, and updated on February 27, 2023. Clinical studies that reported adverse reactions (ARs) of stem cell therapy in KOA patients were included without limiting the type of studies. Quantitative systematic reviews of stem cell therapy for KOA that conducted meta-analysis were included. Two researchers conducted literature screening and data extraction independently, and the evidence quality was evaluated according to the Institute of Health Economics and AMSTAR 2 criteria. RESULTS Fifty clinical studies and 13 systematic reviews/meta-analyses (SRs/MAs) were included. Nineteen ARs were reported in 50 studies, including five knee-related ARs, seven common ARs, and seven other ARs. Some studies reported over 10% prevalence of knee pain (24.5%; 95% CI [14.7%, 35.7%]), knee effusion (12.5%; 95% CI [4.8%, 22.5%]), and knee swelling (11.9%; 95% CI [3.5%, 23.5%]). Additionally, two studies have reported cases of prostate cancer and breast tumors, respectively. However, these two studies suggest that stem cell therapy does not bring significant ARs to patients. SRs/MAs results revealed that stem cell therapy relieved pain in patients over time but did not improve knee function. However, current clinical studies have limited evidence regarding study objectives, test designs, and patient populations. Similarly, SRs/MAs have inadequate evidence regarding study design, risk of bias assessment, outcome description, comprehensive discussion, and potential conflicts of interest. CONCLUSIONS The inefficacy of stem cells, the risk of potential complications, and the limited quality of evidence from current studies precluded any recommendation for using stem cell products in patients with KOA. Clinical translation of stem cell therapies remains baseless and should be cautiously approached until more robust evidence is available. PROSPERO registration number: CRD42022355875.
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Affiliation(s)
- Zhizhong Shang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, China
| | - Pingping Wanyan
- Gansu University of Chinese Medicine, Lanzhou, 730000, China
- The Second Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Baolin Zhang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, China
| | - Mingchuan Wang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, China
| | - Xin Wang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, China.
- Chengren Institute of Traditional Chinese Medicine, Lanzhou, 730000, Gansu Province, China.
- Department of Spine, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China.
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Jakl V, Ehmele M, Winkelmann M, Ehrenberg S, Eiseler T, Friemert B, Rojewski MT, Schrezenmeier H. A novel approach for large-scale manufacturing of small extracellular vesicles from bone marrow-derived mesenchymal stromal cells using a hollow fiber bioreactor. Front Bioeng Biotechnol 2023; 11:1107055. [PMID: 36761296 PMCID: PMC9904364 DOI: 10.3389/fbioe.2023.1107055] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 01/09/2023] [Indexed: 01/25/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are promising therapeutic candidates in a variety of diseases due to having immunomodulatory and pro-regenerative properties. In recent years, MSC-derived small extracellular vesicles (sEVs) have attracted increasing interest as a possible alternative to conventional cell therapy. However, translational processes of sEVs for clinical applications are still impeded by inconsistencies regarding isolation procedures and culture conditions. We systematically compared different methods for sEV isolation from conditioned media of ex vivo expanded bone marrow-derived MSCs and demonstrated considerable variability of quantity, purity, and characteristics of sEV preparations obtained by these methods. The combination of cross flow filtration with ultracentrifugation for sEV isolation resulted in sEVs with similar properties as compared to isolation by differential centrifugation combined with ultracentrifugation, the latter is still considered as gold standard for sEV isolation. In contrast, sEV isolation by a combination of precipitation with polyethylene glycol and ultracentrifugation as well as cross flow filtration and size exclusion chromatography resulted in sEVs with different characteristics, as shown by surface antigen expression patterns. The MSC culture requires a growth-promoting supplement, such as platelet lysate, which contains sEVs itself. We demonstrated that MSC culture with EV-depleted platelet lysate does not alter MSC characteristics, and conditioned media of such MSC cultures provide sEV preparations enriched for MSC-derived sEVs. The results from the systematic stepwise evaluation of various aspects were combined with culture of MSCs in a hollow fiber bioreactor. This resulted in a strategy using cross flow filtration with subsequent ultracentrifugation for sEV isolation. In conclusion, this workflow provides a semi-automated, efficient, large-scale-applicable, and good manufacturing practice (GMP)-grade approach for the generation of sEVs for clinical use. The use of EV-depleted platelet lysate is an option to further increase the purity of MSC-derived sEVs.
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Affiliation(s)
- Viktoria Jakl
- Institute for Transfusion Medicine, University Hospital Ulm, Ulm, Germany
| | - Melanie Ehmele
- Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service Baden-Württemberg—Hessia and University Hospital Ulm, Ulm, Germany
| | - Martina Winkelmann
- Institute for Transfusion Medicine, University Hospital Ulm, Ulm, Germany
| | - Simon Ehrenberg
- Institute for Transfusion Medicine, University Hospital Ulm, Ulm, Germany
| | - Tim Eiseler
- Clinic of Internal Medicine I, University Hospital Ulm, Ulm, Germany
| | - Benedikt Friemert
- Clinic for Trauma Surgery and Orthopedics, Army Hospital Ulm, Ulm, Germany
| | - Markus Thomas Rojewski
- Institute for Transfusion Medicine, University Hospital Ulm, Ulm, Germany
- Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service Baden-Württemberg—Hessia and University Hospital Ulm, Ulm, Germany
| | - Hubert Schrezenmeier
- Institute for Transfusion Medicine, University Hospital Ulm, Ulm, Germany
- Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service Baden-Württemberg—Hessia and University Hospital Ulm, Ulm, Germany
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Vonk LA. Potency Assay Considerations for Cartilage Repair, Osteoarthritis and Use of Extracellular Vesicles. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1420:59-80. [PMID: 37258784 DOI: 10.1007/978-3-031-30040-0_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Articular cartilage covers the ends of bones in synovial joints acting as a shock absorber that helps movement of bones. Damage of the articular cartilage needs treatment as it does not repair itself and the damage can progress to osteoarthritis. In osteoarthritis all the joint tissues are involved with characteristic progressive cartilage degradation and inflammation. Autologous chondrocyte implantation is a well-proven cell-based treatment for cartilage defects, but a main downside it that it requires two surgeries. Multipotent, aka mesenchymal stromal cell (MSC)-based cartilage repair has gained attention as it can be used as a one-step treatment. It is proposed that a combination of immunomodulatory and regenerative capacities make MSC attractive for the treatment of osteoarthritis. Furthermore, since part of the paracrine effects of MSCs are attributed to extracellular vesicles (EVs), small membrane enclosed particles secreted by cells, EVs are currently being widely investigated for their potential therapeutic effects. Although MSCs have entered clinical cartilage treatments and EVs are used in in vivo efficacy studies, not much attention has been given to determine their potency and to the development of potency assays. This chapter provides considerations and suggestions for the development of potency assays for the use of MSCs and MSC-EVs for the treatment of cartilage defects and osteoarthritis.
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Affiliation(s)
- Lucienne A Vonk
- Department of Orthopaedics, University Medical Center Utrecht, Utrecht, The Netherlands.
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26
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Issa MR, Naja AS, Bouji NZ, Sagherian BH. The role of adipose-derived mesenchymal stem cells in knee osteoarthritis: a meta-analysis of randomized controlled trials. Ther Adv Musculoskelet Dis 2022; 14:1759720X221146005. [PMID: 36601089 PMCID: PMC9806366 DOI: 10.1177/1759720x221146005] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 11/28/2022] [Indexed: 12/29/2022] Open
Abstract
Background Adipose-derived mesenchymal stem cells (ADMSCs) have recently been studied for the treatment of knee osteoarthritis. The goal is pain reduction and improvement of joint function leading to superior health-related quality of life. Objectives The aim of this study was to provide a comprehensive meta-analysis assessing the evidence on the use of ADMSCs in knee osteoarthritis. Design This is a Meta-analysis of randomised controlled trials. Data Sources and Methods PubMed/MEDLINE, Embase, and Cochrane Databases were searched for randomized controlled trials using ADMSCs to treat patients with knee osteoarthritis. Only trials comparing ADMSCs to placebo or conservative treatment were included. The outcomes studied were improvement in functional, pain, and quality of life scores along with radiographic findings. Results A total of four trials were included, representing 138 patients with knee osteoarthritis. WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) scores favored ADMSCs with a statistically and clinically significant difference over controls at 6- and 12-month follow-ups (p value < 0.0001). Pain, functional, and quality of life scores also favored ADMSCs at 12-month follow-up (p value < 0.0001). Conclusion ADMSCs are effective in treating knee osteoarthritis symptoms as observed by functional and pain improvements. Furthermore, ADMSCs injection showed improvement of cartilage integrity, which indicates the potential for regenerating the knee cartilage. Future trials with larger number of patients and longer follow-up periods would help to elaborate further the therapeutic potential of ADMSCs. Plain Language Summary Adipose-derived mesenchymal stem cells use in knee osteoarthritis Knee osteoarthritis is an extremely common disease that causes damage of the lining of the knee joint.This will lead to pain and limited range of motion of the knee hence limited functionality.Multiple treatments are used currently for knee osteoarthritis which all aim at slowing down the progression and limiting the need for knee replacement surgery.Adipose-derived mesenchymal stem cells (ADMSCs) are stem cells harvested from the fat around the belly. These stem cells have the potential to be converted into cells of a certain origin (cartilage, muscle, fat).Many studies are being performed to see whether these cells can transform to cartilage and repair the damaged knee joint.In this study, we tried to find how the results of different studies comparing the usual treatments for knee osteoarthritis with that of ADMSCs compared.We were mostly interested in the pain, functional, stiffness, and quality of life scores.We also reviewed the MRI findings to find out whether the lining of the knee joint improved.Four studies were included with 138 patients having knee osteoarthritis.WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) score which is a self-administered questionnaire evaluating hip and knee osteoarthritis, showed better results in patients receiving ADMSC injections compared with other usual treatments at 12-month follow-up.Pain, functional, stiffness, and quality of life scores also showed better results in ADMSCs at 12-month follow-up.MRI images also showed better cartilage lining in the patients treated with ADMSCs.We concluded that ADMSCs are both effective and safe to be used in treating knee osteoarthritis symptoms. However, studies with longer follow-up periods are needed to better assess the regenerative potential of ADMSCs.
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Affiliation(s)
- Mohamad R. Issa
- Division of Orthopaedic Surgery, Department of Surgery, Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Ahmad S. Naja
- Division of Orthopaedic Surgery, Department of Surgery, Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Nour Z. Bouji
- Clinical and Translational Science, School of Medicine, West Virginia University, Morgantown, WV, USA
| | - Bernard H. Sagherian
- Division of Orthopaedic Surgery, Department of Surgery, Faculty of Medicine, American University of Beirut Medical Center, P.O. Box 11-0236, Riad El-Solh, 1107 2020 Beirut, Lebanon
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Kwapisz A, Bowman M, Walters J, Cosh H, Burnikel B, Tokish J, Ye T, Mercuri J. Human Adipose- and Amnion-Derived Mesenchymal Stromal Cells Similarly Mitigate Osteoarthritis Progression in the Dunkin Hartley Guinea Pig. Am J Sports Med 2022; 50:3963-3973. [PMID: 36300544 DOI: 10.1177/03635465221126683] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Clinical trials are currently underway to investigate the efficacy of intra-articular administration of mesenchymal stromal cells (MSCs) to mitigate osteoarthritis (OA) progression in the knee. Although multiple MSC sources exist, studies have yet to determine whether differences in therapeutic efficacy exist between them. PURPOSE To compare the ability of intra-articularly injected adipose-derived MSCs (AD-MSCs) and amnion-derived MSCs (AM-MSCs) to mitigate the progression of knee OA in a small animal model of spontaneous OA, as well as to compare the therapeutic potential of MSCs in hyaluronic acid (HA) and in HA only with saline (OA) controls. STUDY DESIGN Controlled laboratory study. METHODS Injections of AD-MSCs or AM-MSCs suspended in HA or HA only were performed in the rear stifle joints of 3-month-old Dunkin Hartley guinea pigs (DHGPs). Repeat injections occurred at 2 and 4 months after the initial injection in each animal. Contralateral limbs received saline injections and served as untreated controls. Subsequently, joints were analyzed for osteoarthritic changes of the cartilage and subchondral bone via histologic and biochemical analyses. To evaluate MSC retention time in the joint space, DHGPs received a single intra-articular injection of fluorescently labeled AD-MSCs or AM-MSCs, and the fluorescence intensity was longitudinally tracked via an in vivo imaging system. RESULTS No statistically significant differences in outcomes were found when comparing the ability of AD-MSCs and AM-MSCs to mitigate OA. However, the injection of AD-MSCs, AM-MSCs, and HA-only treatments more effectively mitigated cartilage damage compared with that of saline controls by demonstrating higher amounts of cartilage glycosaminoglycan content and improved histological proteoglycan scoring while reducing the percentage of osteophytes present. CONCLUSION Intra-articular injection of AD-MSCs, AM-MSCs, or HA only was able to similarly mitigate the progression of cartilage damage and reduce the percentage of osteophytes compared with that of saline controls in the DHGP. However, this study was unable to establish the superiority of AD-MSCs versus AM-MSCs as a treatment to mitigate spontaneous OA. CLINICAL RELEVANCE MSCs demonstrate the ability to mitigate the progression of knee OA and thus may be used in a prophylactic approach to delay the need for end-stage treatment strategies.
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Affiliation(s)
- Adam Kwapisz
- Clinic of Orthopedics and Pediatric Orthopedics, Medical University of Lodz, Lodz, Poland
- Steadman Hawkins Clinic of the Carolinas, Department of Orthopaedic Surgery, Prisma Health, Greenville, South Carolina, USA
| | - Mackenzie Bowman
- Laboratory of Orthopaedic Tissue Regeneration & Orthobiologics, Department of Bioengineering, Clemson University, Clemson, South Carolina, USA
| | - Joshua Walters
- Laboratory of Orthopaedic Tissue Regeneration & Orthobiologics, Department of Bioengineering, Clemson University, Clemson, South Carolina, USA
| | - Heather Cosh
- Laboratory of Orthopaedic Tissue Regeneration & Orthobiologics, Department of Bioengineering, Clemson University, Clemson, South Carolina, USA
| | - Brian Burnikel
- Steadman Hawkins Clinic of the Carolinas, Department of Orthopaedic Surgery, Prisma Health, Greenville, South Carolina, USA
| | - John Tokish
- Mayo Clinic, Department of Orthopedic Surgery, Phoenix, Arizona, USA
| | - Tong Ye
- Nano and Functional Imaging Lab, Department of Bioengineering, Clemson University, Charleston, South Carolina, USA
| | - Jeremy Mercuri
- Laboratory of Orthopaedic Tissue Regeneration & Orthobiologics, Department of Bioengineering, Clemson University, Clemson, South Carolina, USA
- Frank H. Stelling and C. Dayton Riddle Orthopaedic Education and Research Laboratory, Clemson University Biomedical Engineering Innovation Campus, Greenville, South Carolina, USA
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Zhao J, Liang G, Han Y, Yang W, Xu N, Luo M, Pan J, Liu J, Zeng LF. Combination of mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP) in the treatment of knee osteoarthritis: a meta-analysis of randomised controlled trials. BMJ Open 2022; 12:e061008. [PMID: 36385022 PMCID: PMC9670925 DOI: 10.1136/bmjopen-2022-061008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 10/22/2022] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVES The purpose of this meta-analysis was to investigate the efficacy and safety of mesenchymal stem cells (MSCs) combined with platelet-rich plasma (PRP) in the treatment of knee osteoarthritis (KOA). DESIGN Systematic review and meta-analysis. PARTICIPANTS Patients with KOA. INTERVENTIONS Use of MSCs+PRP. PRIMARY AND SECONDARY OUTCOMES Visual Analogue Scale (VAS) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, Knee Injury and Osteoarthritis Outcome Score (KOOS) and adverse reactions. DATA SOURCES PubMed, Cochrane Library, Embase and China National Knowledge Infrastructure were searched from inception to 15 July 2021. MEASURES The OR or weighted mean difference (WMD) of relevant outcome indicators was calculated. Study quality was evaluated using the risk-of-bias assessment tool version 2.0. Heterogeneity among studies was evaluated by calculating I2. If I2＜50%, a fixed-effect model was applied; conversely, if I2 ≥50%, a random-effect model was applied. RESULTS Six controlled clinical trials with 493 cases were included. The meta-analysis results showed that in terms of the VAS score 3 months after treatment, MSCs+PRP had no significant effect on the reduction of the VAS score in patients with KOA compared with the control (p=0.09), hyaluronic acid (HA) (p=0.15) or PRP alone (p=0.07). MSCs+PRP was more effective in reducing the VAS score at 6 and 12 months after treatment than the control (WMD=-0.55, 95% CI -0.87 to -0.22, p<0.001), HA (WMD=-1.20, 95% CI -2.28 to -0.13, p=0.03) or PRP alone (WMD=-0.54, 95% CI -0.89 to -0.18, p=0.003). Regarding the decrease in the total WOMAC score at 3 and 6 months after treatment, MSCs+PRP showed better clinical efficacy than the control or HA alone (p<0.01). Compared with the control, MSCs+PRP exhibited no significant difference in reducing the total WOMAC score 12 months after treatment (p=0.39). There was no significant difference between MSCs+PRP and the control in terms of improvement of the KOOS 12 months after treatment (p=0.16). Compared with MSCs alone, MSCs+PRP exhibited no significant difference in the incidence of adverse reactions (p=0.22) 12 months after treatment. CONCLUSIONS Treatment with MSCs+PRP showed good clinical efficacy in improving pain and joint function in patients with KOA. Compared with MSCs alone, there was no significant difference in the incidence of adverse reactions with MSCs+PRP. PROSPERO REGISTRATION NUMBER CRD 42021275830.
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Affiliation(s)
- Jinlong Zhao
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China
- The Department of Sports Medicine of the Second Affiliated Hospital, Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, People's Republic of China
- The Research Team on Bone and Joint Degeneration and Injury, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, People's Republic of China
| | - Guihong Liang
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China
- The Department of Sports Medicine of the Second Affiliated Hospital, Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, People's Republic of China
- The Research Team on Bone and Joint Degeneration and Injury, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, People's Republic of China
| | - Yanhong Han
- The Department of Sports Medicine of the Second Affiliated Hospital, Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, People's Republic of China
| | - Weiyi Yang
- The Department of Sports Medicine of the Second Affiliated Hospital, Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, People's Republic of China
| | - Nanjun Xu
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China
| | - Minghui Luo
- The Department of Sports Medicine of the Second Affiliated Hospital, Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, People's Republic of China
| | - Jianke Pan
- The Department of Sports Medicine of the Second Affiliated Hospital, Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, People's Republic of China
| | - Jun Liu
- The Research Team on Bone and Joint Degeneration and Injury, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, People's Republic of China
- Guangdong Second Traditional Chinese Medicine Hospital (Guangdong Province Enginering Technology Research Institute of Traditional Chinese Medicine), Guangzhou, Guangdong, China
- The Fifth School of Clinical Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Ling-Feng Zeng
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China
- The Department of Sports Medicine of the Second Affiliated Hospital, Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, People's Republic of China
- The Research Team on Bone and Joint Degeneration and Injury, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, People's Republic of China
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Ragni E, Perucca Orfei C, Valli F, Zagra L, de Girolamo L. Molecular Characterization of Secreted Factors and Extracellular Vesicles-Embedded miRNAs from Bone Marrow-Derived Mesenchymal Stromal Cells in Presence of Synovial Fluid from Osteoarthritis Patients. BIOLOGY 2022; 11:1632. [PMID: 36358333 PMCID: PMC9687557 DOI: 10.3390/biology11111632] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/02/2022] [Accepted: 11/04/2022] [Indexed: 02/07/2024]
Abstract
Bone marrow-derived mesenchymal stromal cells (BMSCs)-based therapies show a great potential to manage inflammation and tissue degeneration in osteoarthritis (OA) patients. Clinical trials showed the ability to manage pain and activation of immune cells and allowed restoration of damaged cartilage. To date, a molecular fingerprint of BMSC-secreted molecules in OA joint conditions able to support clinical outcomes is missing; the lack of that molecular bridge between BMSC activity and clinical results hampers clinical awareness and translation into practice. In this study, BMSCs were cultured in synovial fluid (SF) obtained from OA patients and, for the first time, a thorough characterization of soluble factors and extracellular vesicles (EVs)-embedded miRNAs was performed in this condition. Molecular data were sifted through the sieve of molecules and pathways characterizing the OA phenotype in immune cells and joint tissues. One-hundred and twenty-five secreted factors and one-hundred and ninety-two miRNAs were identified. The combined action of both types of molecules was shown to, first, foster BMSCs interaction with the most important OA immune cells, such as macrophages and T cells, driving their switch towards an anti-inflammatory phenotype and, second, promote cartilage homeostasis assisting chondrocyte proliferation and attenuating the imbalance between destructive and protective extracellular matrix-related players. Overall, molecular data give an understanding of the clinical results observed in OA patients and can enable a faster translation of BMSC-based products into everyday clinical practice.
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Affiliation(s)
- Enrico Ragni
- Laboratorio di Biotecnologie applicate all’Ortopedia, IRCCS Istituto Ortopedico Galeazzi, Via R. Galeazzi 4, I-20161 Milan, Italy
| | - Carlotta Perucca Orfei
- Laboratorio di Biotecnologie applicate all’Ortopedia, IRCCS Istituto Ortopedico Galeazzi, Via R. Galeazzi 4, I-20161 Milan, Italy
| | - Federico Valli
- Chirurgia Articolare Sostitutiva e Chirurgia Ortopedica (CASCO), IRCCS Istituto Ortopedico Galeazzi, Via R. Galeazzi 4, I-20161 Milan, Italy
| | - Luigi Zagra
- Hip Department, IRCCS Istituto Ortopedico Galeazzi, Via R. Galeazzi 4, I-20161 Milan, Italy
| | - Laura de Girolamo
- Laboratorio di Biotecnologie applicate all’Ortopedia, IRCCS Istituto Ortopedico Galeazzi, Via R. Galeazzi 4, I-20161 Milan, Italy
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30
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Schmitz C. Intra-articular Injections of Mesenchymal Stem Cells Without Adjuvant Therapies for Knee Osteoarthritis: A Systematic Review and Meta-analysis: Letter to the Editor. Am J Sports Med 2022; 50:NP48-NP49. [PMID: 36177754 DOI: 10.1177/03635465221112083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
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Dabbadie A, Salerno A, Perriman A, Lian LY, Hollander AP. Development of chimeric forms of the matrix metalloproteinase 2 collagen binding domain as artificial membrane binding proteins for targeting stem cells to cartilage lesions in osteoarthritic joints. Biomaterials 2022; 285:121547. [PMID: 35533445 DOI: 10.1016/j.biomaterials.2022.121547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 08/06/2021] [Accepted: 04/23/2022] [Indexed: 11/16/2022]
Abstract
Targeting stem cells to cartilage lesions has the potential to enhance engraftment and chondrogenesis. Denatured type II collagen fibrils (gelatin) are exposed in lesions at the surface of osteoarthritic articular cartilage and are therefore ideal target sites. We have designed and investigated chimeric mutants of the three modules of the MMP-2 collagen binding domain (CBD) as potential ligands for stem cell targeting. We expressed full-length CBD for the first time and used it to identify the most important amino acid residues for binding to gelatin. Module 2 of CBD had the highest affinity binding to both Type I and Type II gelatin, whereas module 1 showed specificity for type II gelatin and module 3 for type I gelatin. We went on to generate chimeric forms of CBD consisting of three repeats of module 1 (111), module 2 (222) or module 3 (333). 111 lacked solubility and could not be further characterised. However 222 was found to bind to type II gelatin 14 times better than CBD, suggesting it would be optimal for attachment to cartilage lesions, whilst 333 was found to bind to type I gelatin 12 times better than CBD, suggesting it would be optimal for attachment to lesions in type I collagen-rich tissues. We coated 222 onto the external membrane of Mesenchymal Stem Cells and demonstrated higher attachment of the coated cells to type II gelatin than uncoated cells. We conclude that the three modules of CBD each have specific biological properties that can be exploited for targeting stem cells to cartilage lesions and other pathological sites.
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Affiliation(s)
- Anais Dabbadie
- Institute of Lifecourse and Medical Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool, L7 8TX, UK; Institute of Systems, Molecular and Integrative Biology, University of Liverpool, School of Biosciences, Crown Street, Liverpool, L69 7ZB, UK
| | - Anna Salerno
- Institute of Lifecourse and Medical Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool, L7 8TX, UK
| | - Adam Perriman
- School of Cellular and Molecular Medicine, University of Bristol, Medical Sciences Building, University Walk, Bristol, BS8 1TD, UK
| | - Lu-Yun Lian
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, School of Biosciences, Crown Street, Liverpool, L69 7ZB, UK
| | - Anthony P Hollander
- Institute of Lifecourse and Medical Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool, L7 8TX, UK.
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32
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Campbell TM, Dilworth FJ, Allan DS, Trudel G. The Hunt Is On! In Pursuit of the Ideal Stem Cell Population for Cartilage Regeneration. Front Bioeng Biotechnol 2022; 10:866148. [PMID: 35711627 PMCID: PMC9196866 DOI: 10.3389/fbioe.2022.866148] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 04/27/2022] [Indexed: 01/15/2023] Open
Abstract
Cartilage injury and degeneration are hallmarks of osteoarthritis (OA), the most common joint disease. OA is a major contributor to pain, loss of function, and reduced quality of life. Over the last decade, considerable research efforts have focused on cell-based therapies, including several stem cell-derived approaches to reverse the cartilage alterations associated with OA. Although several tissue sources for deriving cell-based therapies have been identified, none of the resident stem cell populations have adequately fulfilled the promise of curing OA. Indeed, many cell products do not contain true stem cells. As well, issues with aggressive marketing efforts, combined with a lack of evidence regarding efficacy, lead the several national regulatory bodies to discontinue the use of stem cell therapy for OA until more robust evidence becomes available. A review of the evidence is timely to address the status of cell-based cartilage regeneration. The promise of stem cell therapy is not new and has been used successfully to treat non-arthritic diseases, such as hematopoietic and muscle disorders. These fields of regenerative therapy have the advantage of a considerable foundation of knowledge in the area of stem cell repair mechanisms, the role of the stem cell niche, and niche-supporting cells. This foundation is lacking in the field of cartilage repair. So, where should we look for the ideal stem cell to regenerate cartilage? It has recently been discovered that cartilage itself may contain a population of SC-like progenitors. Other potential tissues include stem cell-rich dental pulp and the adolescent growth plate, the latter of which contains chondrocyte progenitors essential for producing the cartilage scaffold needed for bone growth. In this article, we review the progress on stem cell therapies for arthritic disorders, focusing on the various stem cell populations previously used for cartilage regeneration, successful cases of stem cell therapies in muscle and hemopoietic disorders, some of the reasons why these other fields have been successful (i.e., "lessons learned" to be applied to OA stem cell therapy), and finally, novel potential sources of stem cells for regenerating damaged cartilage in vivo.
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Affiliation(s)
- T Mark Campbell
- Elisabeth Bruyère Hospital, Ottawa, ON, Canada
- Bone and Joint Research Laboratory, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - F Jeffrey Dilworth
- Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - David S Allan
- Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada
| | - Guy Trudel
- Bone and Joint Research Laboratory, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada
- Department of Biochemistry, Immunology and Microbiology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
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33
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Samara O, Jafar H, Hamdan M, Al-Ta'mari A, Rahmeh R, Hourani B, Mandalawi N, Awidi A. Ultrasound-guided intra-articular injection of expanded umbilical cord mesenchymal stem cells in knee osteoarthritis: a safety/efficacy study with MRI data. Regen Med 2022; 17:299-312. [PMID: 35546314 DOI: 10.2217/rme-2021-0121] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: This study has the primary objective of studying the effect of Wharton jelly mesenchymal stem cells (WJMSCs) in the treatment of knee osteoarthritis. As a secondary end point, we report on the efficacy of such therapy. Patients and methods: 16 patients with advanced Kellgren stage were treated using two doses of expanded WJMSCs given 1 month apart. Patients were followed for 48 months using the Knee Injury and Osteoarthritis Outcome Score (KOOS) and 12 months using magnetic resonance imaging (MRI). Results: Treatment was well tolerated. One patient developed moderate effusion and one superficial phlebitis. We observed functional and pain improvement at 12 and 48 months (p < 0.0001), with statistically significant improvement on MRI scans at 12 months in cartilage loss, osteophytes, bone marrow lesions, effusion and synovitis (p < 0.01), and highly significant improvement in subchondral sclerosis (p < 0.0001). Conclusion: WJMSCs are safe and potentially effective in producing significant improvement in KOOS and MRI scores when administered intra-articularly in knee osteoarthritis cases under ultrasound guidance.
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Affiliation(s)
- Osama Samara
- Department of Radiology & Nuclear Medicine, School of Medicine, University of Jordan, Amman, Jordan.,Department of Radiology, Jordan University Hospital, Amman, Jordan
| | - Hanan Jafar
- Cell Therapy Center, University of Jordan, Amman, Jordan.,Department of Anatomy & Histology, School of Medicine, University of Jordan, Amman Jordan
| | - Mohammad Hamdan
- Department of Special Surgery, School of Medicine, University of Jordan, Amman, Jordan.,Department of Orthopedic Surgery, Jordan University Hospital, Amman, Jordan
| | - Ahmad Al-Ta'mari
- Cell Therapy Center, University of Jordan, Amman, Jordan.,Department of Internal Medicine, East Tennessee State University, TN, USA
| | - Reem Rahmeh
- Cell Therapy Center, University of Jordan, Amman, Jordan
| | - Bayan Hourani
- Cell Therapy Center, University of Jordan, Amman, Jordan
| | - Noor Mandalawi
- Department of Radiology, Jordan University Hospital, Amman, Jordan
| | - Abdalla Awidi
- Cell Therapy Center, University of Jordan, Amman, Jordan.,Department of Internal Medicine, Hematology-Oncology School of Medicine, University of Jordan, Amman, Jordan.,Department of Hematology-Oncology, Jordan University Hospital, Amman, Jordan
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Methodological Flaws in Meta-Analyses of Clinical Studies on the Management of Knee Osteoarthritis with Stem Cells: A Systematic Review. Cells 2022; 11:cells11060965. [PMID: 35326416 PMCID: PMC8946093 DOI: 10.3390/cells11060965] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 12/13/2022] Open
Abstract
(1) Background: Conclusions of meta-analyses of clinical studies may substantially influence opinions of prospective patients and stakeholders in healthcare. Nineteen meta-analyses of clinical studies on the management of primary knee osteoarthritis (pkOA) with stem cells, published between January 2020 and July 2021, came to inconsistent conclusions regarding the efficacy of this treatment modality. It is possible that a separate meta-analysis based on an independent, systematic assessment of clinical studies on the management of pkOA with stem cells may reach a different conclusion. (2) Methods: PubMed, Web of Science, and the Cochrane Library were systematically searched for clinical studies and meta-analyses of clinical studies on the management of pkOA with stem cells. All clinical studies and meta-analyses identified were evaluated in detail, as were all sub-analyses included in the meta-analyses. (3) Results: The inconsistent conclusions regarding the efficacy of treating pkOA with stem cells in the 19 assessed meta-analyses were most probably based on substantial differences in literature search strategies among different authors, misconceptions about meta-analyses themselves, and misconceptions about the comparability of different types of stem cells with regard to their safety and regenerative potential. An independent, systematic review of the literature yielded a total of 183 studies, of which 33 were randomized clinical trials, including a total of 6860 patients with pkOA. However, it was not possible to perform a scientifically sound meta-analysis. (4) Conclusions: Clinicians should interpret the results of the 19 assessed meta-analyses of clinical studies on the management of pkOA with stem cells with caution and should be cautious of the conclusions drawn therein. Clinicians and researchers should strive to participate in FDA and/or EMA reviewed and approved clinical trials to provide clinically and statistically valid efficacy.
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35
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Wang G, Xing D, Liu W, Zhu Y, Liu H, Yan L, Fan K, Liu P, Yu B, Li JJ, Wang B. Preclinical studies and clinical trials on mesenchymal stem cell therapy for knee osteoarthritis: A systematic review on models and cell doses. Int J Rheum Dis 2022; 25:532-562. [PMID: 35244339 DOI: 10.1111/1756-185x.14306] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 01/30/2022] [Accepted: 02/07/2022] [Indexed: 12/15/2022]
Abstract
AIM To provide a systematic analysis of the study design in knee osteoarthritis (OA) preclinical studies, focusing on the characteristics of animal models and cell doses, and to compare these to the characteristics of clinical trials using mesenchymal stem cells (MSCs) for the treatment of knee OA. METHOD A systematic and comprehensive search was conducted using the PubMed, Web of Science, Ovid, and Embase electronic databases for research papers published in 2009-2020 on testing MSC treatment in OA animal models. The PubMed database and ClinicalTrials.gov website were used to search for published studies reporting clinical trials of MSC therapy for knee OA. RESULTS In total, 9234 articles and two additional records were retrieved, of which 120 studies comprising preclinical and clinical studies were included for analysis. Among the preclinical studies, rats were the most commonly used species for modeling knee OA, and anterior cruciate ligament transection was the most commonly used method for inducing OA. There was a correlation between the cell dose and body weight of the animal. In clinical trials, there was large variation in the dose of MSCs used to treat knee OA, ranging from 1 × 106 to 200 × 106 cells with an average of 37.91 × 106 cells. CONCLUSION Mesenchymal stem cells have shown great potential in improving pain relief and tissue protection in both preclinical and clinical studies of knee OA. Further high-quality preclinical and clinical studies are needed to explore the dose effectiveness relationship of MSC therapy and to translate the findings from preclinical studies to humans.
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Affiliation(s)
- Guishan Wang
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, China.,Department of Orthopedic Surgery, Shanxi Medical University Second Affiliated Hospital, Taiyuan, China
| | - Dan Xing
- Arthritis Clinic & Research Center, Peking University People's Hospital, Beijing, China
| | - Wei Liu
- Beijing CytoNiche Biotechnology Co. Ltd, Beijing, China
| | - Yuanyuan Zhu
- Department of Pharmacy, Shanxi Medical University Second Affiliated Hospital, Taiyuan, China
| | - Haifeng Liu
- Department of Orthopedic Surgery, Shanxi Medical University Second Affiliated Hospital, Taiyuan, China
| | - Lei Yan
- Department of Orthopedic Surgery, Shanxi Medical University Second Affiliated Hospital, Taiyuan, China
| | - Kenan Fan
- Department of Health Statistics, School of Public Health, Shanxi Medical University, Taiyuan, China
| | - Peidong Liu
- Department of Orthopedic Surgery, Shanxi Medical University Second Affiliated Hospital, Taiyuan, China
| | - Baofeng Yu
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, China
| | - Jiao Jiao Li
- Faculty of Engineering and IT, School of Biomedical Engineering, University of Technology Sydney, Ultimo, New South Wales, Australia
| | - Bin Wang
- Department of Orthopedic Surgery, Shanxi Medical University Second Affiliated Hospital, Taiyuan, China.,Department of Orthopedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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36
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Comparison of the Effect of MFAT and MFAT + PRP on Treatment of Hip Osteoarthritis: An Observational, Intention-to-Treat Study at One Year. J Clin Med 2022; 11:jcm11041056. [PMID: 35207329 PMCID: PMC8880065 DOI: 10.3390/jcm11041056] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 02/14/2022] [Accepted: 02/16/2022] [Indexed: 01/27/2023] Open
Abstract
Hip osteoarthritis (OA) is a major contributor to reduced quality of life and concomitant disability associated with lost working life months. Intra-articular injection of various biological materials has shown promise in alleviating symptoms and potentially slowing down the degenerative process. Here, we compared the effects of treatment of a cohort of 147 patients suffering from grade 1–4 hip OA; with either micro-fragmented adipose tissue (MFAT), or a combination of MFAT with platelet-rich plasma (PRP). We found significant improvements in both the visual analogue score for pain (VAS) and Oxford hip score (OHS) that were similar for both treatments with over 60% having an improvement in the VAS score of 20 points or more. These results suggest a positive role for intra-articular injection of MFAT + PRP as a treatment for hip osteoarthritis which may be important particularly in low body mass index (BMI) patients where the difficulty in obtaining sufficient MFAT for treatment could be offset by using this combination of biologicals.
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Pandey V, Madi S, Gupta P. The promising role of autologous and allogeneic mesenchymal stromal cells in managing knee osteoarthritis. What is beyond Mesenchymal stromal cells? J Clin Orthop Trauma 2022; 26:101804. [PMID: 35242531 PMCID: PMC8857498 DOI: 10.1016/j.jcot.2022.101804] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/25/2022] [Accepted: 02/05/2022] [Indexed: 12/20/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) express a wide range of properties anticipated to be beneficial for treating genetic, mechanical, and age-related degeneration in diseases such as osteoarthritis (OA). Although contemporary conservative management of OA is successful in many patients with mild-moderate OA, it often fails to improve symptoms in many patients who are not a candidate for any surgical management. Further, existing conservative treatment strategies do not prevent the progression of the disease and therefore fail to provide a long-term pain-free life. On the other hand, tremendous progress has been taking place in the exciting field of regenerative medicine involving MSCs (autologous and allogeneic), with promising translation taking place from basic science to the bedside. In this review, we comprehensively discuss the potential role of MSCs in treating OA, both autologous and off-the-shelf, allogeneic stem cells. Further, newer therapies are in the offing to treat OA, such as exosomes and growth factors.
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Affiliation(s)
- Vivek Pandey
- Sports Injury and Arthroscopy Division, Orthopaedics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India,Corresponding author. Sports injury and arthroscopy division, Orthopaedics, Kasturba medical college, Manipal. Manipal academy of Higher education, Manipal, 576104, India.
| | - Sandesh Madi
- Sports Injury and Arthroscopy Division, Orthopaedics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Pawan Gupta
- Stempeutics Research Pvt. Ltd, Manipal Hospital, Whitefield, Banaglore, 560048, India
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Vicinanza C, Lombardi E, Da Ros F, Marangon M, Durante C, Mazzucato M, Agostini F. Modified mesenchymal stem cells in cancer therapy: A smart weapon requiring upgrades for wider clinical applications. World J Stem Cells 2022; 14:54-75. [PMID: 35126828 PMCID: PMC8788179 DOI: 10.4252/wjsc.v14.i1.54] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 08/06/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem stromal cells (MSC) are characterized by the intriguing capacity to home toward cancer cells after systemic administration. Thus, MSC can be harnessed as targeted delivery vehicles of cytotoxic agents against tumors. In cancer patients, MSC based advanced cellular therapies were shown to be safe but their clinical efficacy was limited. Indeed, the amount of systemically infused MSC actually homing to human cancer masses is insufficient to reduce tumor growth. Moreover, induction of an unequivocal anticancer cytotoxic phenotype in expanded MSC is necessary to achieve significant therapeutic efficacy. Ex vivo cell modifications are, thus, required to improve anti-cancer properties of MSC. MSC based cellular therapy products must be handled in compliance with good manufacturing practice (GMP) guidelines. In the present review we include MSC-improving manipulation approaches that, even though actually tested at preclinical level, could be compatible with GMP guidelines. In particular, we describe possible approaches to improve MSC homing on cancer, including genetic engineering, membrane modification and cytokine priming. Similarly, we discuss appropriate modalities aimed at inducing a marked cytotoxic phenotype in expanded MSC by direct chemotherapeutic drug loading or by genetic methods. In conclusion, we suggest that, to configure MSC as a powerful weapon against cancer, combinations of clinical grade compatible modification protocols that are currently selected, should be introduced in the final product. Highly standardized cancer clinical trials are required to test the efficacy of ameliorated MSC based cell therapies.
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Affiliation(s)
- Carla Vicinanza
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Elisabetta Lombardi
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Francesco Da Ros
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Miriam Marangon
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Cristina Durante
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Mario Mazzucato
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Francesco Agostini
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
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Xiang XN, Zhu SY, He HC, Yu X, Xu Y, He CQ. Mesenchymal stromal cell-based therapy for cartilage regeneration in knee osteoarthritis. Stem Cell Res Ther 2022; 13:14. [PMID: 35012666 PMCID: PMC8751117 DOI: 10.1186/s13287-021-02689-9] [Citation(s) in RCA: 79] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 12/07/2021] [Indexed: 02/08/2023] Open
Abstract
Osteoarthritis, as a degenerative disease, is a common problem and results in high socioeconomic costs and rates of disability. The most commonly affected joint is the knee and characterized by progressive destruction of articular cartilage, loss of extracellular matrix, and progressive inflammation. Mesenchymal stromal cell (MSC)-based therapy has been explored as a new regenerative treatment for knee osteoarthritis in recent years. However, the detailed functions of MSC-based therapy and related mechanism, especially of cartilage regeneration, have not been explained. Hence, this review summarized how to choose, authenticate, and culture different origins of MSCs and derived exosomes. Moreover, clinical application and the latest mechanistical findings of MSC-based therapy in cartilage regeneration were also demonstrated.
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Affiliation(s)
- Xiao-Na Xiang
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.,School of Rehabilitation Sciences, West China School of Medicine, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.,Key Laboratory of Rehabilitation Medicine in Sichuan Province, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China
| | - Si-Yi Zhu
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.,School of Rehabilitation Sciences, West China School of Medicine, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.,Key Laboratory of Rehabilitation Medicine in Sichuan Province, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China
| | - Hong-Chen He
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.,School of Rehabilitation Sciences, West China School of Medicine, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.,Key Laboratory of Rehabilitation Medicine in Sichuan Province, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China
| | - Xi Yu
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.,School of Rehabilitation Sciences, West China School of Medicine, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.,Key Laboratory of Rehabilitation Medicine in Sichuan Province, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China
| | - Yang Xu
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.,School of Rehabilitation Sciences, West China School of Medicine, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.,Key Laboratory of Rehabilitation Medicine in Sichuan Province, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China
| | - Cheng-Qi He
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China. .,School of Rehabilitation Sciences, West China School of Medicine, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China. .,Key Laboratory of Rehabilitation Medicine in Sichuan Province, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China. .,Rehabilitation Medicine Centre, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
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Álvarez Hernández P, de la Mata Llord J. Expanded Mesenchymal Stromal Cells in knee osteoarthritis: A systematic literature review. REUMATOLOGIA CLINICA 2022; 18:49-55. [PMID: 35090612 DOI: 10.1016/j.reumae.2020.10.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 10/15/2020] [Indexed: 06/14/2023]
Abstract
OBJECTIVE To analyse the efficacy and safety of intra-articular injection of expanded Mesenchymal Stromal Cells (MSCs) in knee osteoarthritis. METHODS Systematic Literature Review. A pre-defined search strategy was run in Medline, Embase and Cochrane Library until February 2018. INCLUSION CRITERIA knee osteoarthritis (grades II-IV Kellgren-Lawrence); intra-articular injection of MSCs (without surgical co-treatments); Randomized Controlled Trials (RCTs) or Quasi-experimental Clinical Trials (QCTs) N ≥ 10 and ≥6 months of follow-up were included. Evidence was assigned according to the Scottish Intercollegiate Guidelines Network (SIGN). RESULTS The search identified 252 articles. Nine proof-of-concept trials (3 RCTs, 6 QCTs) were included (N = 169). Evidence showed clinical improvement in 60% of patients. Structural benefit was reported in half of patients. Clinical benefit was observed from the 3rd month and structural improvement from the 6th. All studies reported maximum clinical and structural benefit a year following the implant. This benefit was sustained for up to 24 months. Studies with doses ≥40 × 106 showed more consistent clinical and structural benefits than those with lower doses. No systemic adverse reactions were reported. The most common adverse effect was pain and/or inflammation in the puncture area (13-53%). The use of donor cells was as safe as autologous implants. CONCLUSIONS Intra-articular implants of MSCs seem to be safe with no serious adverse effects. Low-quality evidence precludes conclusions regarding efficacy in this review. However, the clinical and structural benefits observed provide a rationale for using expanded MSCs implants in osteoarthritis patients. High-quality evidence trials are needed to further determine best protocols to maximize clinical and structural improvement.
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Kim KI, Lee WS, Kim JH, Bae JK, Jin W. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:586-596. [PMID: 35567774 PMCID: PMC9216498 DOI: 10.1093/stcltm/szac024] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 03/20/2022] [Indexed: 11/15/2022] Open
Abstract
Although successful short-term results of the intra-articular injection of mesenchymal stem cells (MSCs) for the conservative treatment of knee osteoarthritis (OA) have been reported, the mid-term results of the injection of adipose-derived (AD) MSCs remains unknown. We assessed the mid-term safety and efficacy of the intra-articular injection of ADMSCs in patients with knee OA. Eleven patients with knee OA were prospectively enrolled and underwent serial evaluations during a 5-year follow-up of a single intra-articular injection of autologous high-dose (1.0 × 108) ADMSCs. The safety profiles were assessed using the World Health Organization Common Toxicity Criteria. The clinical evaluations included visual analog scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores for pain and function, respectively. The radiologic evaluations included chondral defect area and whole-organ magnetic resonance imaging scores (WORMS) by serial magnetic resonance imaging (MRI). Hip-knee-ankle axis (HKAA) and Kellgren-Lawrence (K-L) grades were assessed on simple radiographs. No treatment-related adverse events occurred during the 5-year follow-up. Both VAS and total WOMAC scores improved significantly at 6 months after the injection and until the latest follow-up. Total WORMS was significantly improved until 3 years after the injection. However, the chondral defect size on MRI or other radiologic evaluations did not change significantly. A single intra-articular injection of autologous, high-dose ADMSCs provided safe and clinical improvement without radiologic aggravation for 5 years. Furthermore, structural changes in the osteoarthritic knee showed significant improvement up to 3 years, suggesting a possible option for disease-modifying outpatient treatment for patients with knee OA.
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Affiliation(s)
- Kang-Il Kim
- Department of Orthopaedic Surgery, Center for Joint Diseases, Kyung Hee University Hospital at Gangdong, Seoul, South Korea
- Department of Orthopaedic Surgery, School of Medicine, Kyung Hee University, Seoul, South Korea
| | - Woo-Suk Lee
- Department of Orthopaedic Surgery, College of Medicine, Gangnam Severance Hospital, Yonsei University, Seoul, South Korea
| | - Jun-Ho Kim
- Corresponding author: Jun-Ho Kim, Department of Orthopaedic Surgery, Center for Joint Diseases, Kyung Hee University Hospital at Gangdong, Seoul, South Korea. Tel: +82-10-7170-0409;
| | - Jung-Kwon Bae
- Department of Orthopaedic Surgery, Center for Joint Diseases, Kyung Hee University Hospital at Gangdong, Seoul, South Korea
| | - Wook Jin
- Department of Radiology, Kyung Hee University Hospital at Gandong, Seoul, South Korea
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Autologous Bone Marrow-Derived Chondrocytes for Patients with Knee Osteoarthritis: A Randomized Controlled Trial. Adv Orthop 2021; 2021:2146722. [PMID: 34845428 PMCID: PMC8627347 DOI: 10.1155/2021/2146722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 10/23/2021] [Accepted: 11/01/2021] [Indexed: 11/18/2022] Open
Abstract
Results There were a total of 60 patients who were followed up. Three patients in Group II were removed from the analysis as they underwent total knee arthroplasty (TKA). A notably significant improvement was noticed in the ABMDC group on all scores of VAS and MKSSSF with P < 0.0001. The control group continued to be dissatisfied with the treatment they were taking. Conclusions This study reveals that a single injection of 5 million of ABMDC was efficient in reducing the symptoms, improving the functional score and betterment of QOL.
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Peláez P, Damiá E, Torres-Torrillas M, Chicharro D, Cuervo B, Miguel L, del Romero A, Carrillo JM, Sopena JJ, Rubio M. Cell and Cell Free Therapies in Osteoarthritis. Biomedicines 2021; 9:1726. [PMID: 34829953 PMCID: PMC8615373 DOI: 10.3390/biomedicines9111726] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/12/2021] [Accepted: 11/16/2021] [Indexed: 12/18/2022] Open
Abstract
Osteoarthritis (OA) is the most common articular disease in adults and has a current prevalence of 12% in the population over 65 years old. This chronic disease causes damage to articular cartilage and synovial joints, causing pain and leading to a negative impact on patients' function, decreasing quality of life. There are many limitations regarding OA conventional therapies-pharmacological therapy can cause gastrointestinal, renal, and cardiac adverse effects, and some of them could even be a threat to life. On the other hand, surgical options, such as microfracture, have been used for the last 20 years, but hyaline cartilage has a limited regeneration capacity. In recent years, the interest in new therapies, such as cell-based and cell-free therapies, has been considerably increasing. The purpose of this review is to describe and compare bioregenerative therapies' efficacy for OA, with particular emphasis on the use of mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP). In OA, these therapies might be an alternative and less invasive treatment than surgery, and a more effective option than conventional therapies.
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Affiliation(s)
- Pau Peláez
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain; (P.P.); (M.T.-T.); (D.C.); (B.C.); (L.M.); (A.d.R.); (J.M.C.); (J.J.S.); (M.R.)
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Elena Damiá
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain; (P.P.); (M.T.-T.); (D.C.); (B.C.); (L.M.); (A.d.R.); (J.M.C.); (J.J.S.); (M.R.)
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Marta Torres-Torrillas
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain; (P.P.); (M.T.-T.); (D.C.); (B.C.); (L.M.); (A.d.R.); (J.M.C.); (J.J.S.); (M.R.)
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Deborah Chicharro
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain; (P.P.); (M.T.-T.); (D.C.); (B.C.); (L.M.); (A.d.R.); (J.M.C.); (J.J.S.); (M.R.)
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Belén Cuervo
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain; (P.P.); (M.T.-T.); (D.C.); (B.C.); (L.M.); (A.d.R.); (J.M.C.); (J.J.S.); (M.R.)
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Laura Miguel
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain; (P.P.); (M.T.-T.); (D.C.); (B.C.); (L.M.); (A.d.R.); (J.M.C.); (J.J.S.); (M.R.)
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Ayla del Romero
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain; (P.P.); (M.T.-T.); (D.C.); (B.C.); (L.M.); (A.d.R.); (J.M.C.); (J.J.S.); (M.R.)
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Jose Maria Carrillo
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain; (P.P.); (M.T.-T.); (D.C.); (B.C.); (L.M.); (A.d.R.); (J.M.C.); (J.J.S.); (M.R.)
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Joaquín J. Sopena
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain; (P.P.); (M.T.-T.); (D.C.); (B.C.); (L.M.); (A.d.R.); (J.M.C.); (J.J.S.); (M.R.)
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Mónica Rubio
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain; (P.P.); (M.T.-T.); (D.C.); (B.C.); (L.M.); (A.d.R.); (J.M.C.); (J.J.S.); (M.R.)
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
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Single-Cell RNA-Sequencing Identifies Infrapatellar Fat Pad Macrophage Polarization in Acute Synovitis/Fat Pad Fibrosis and Cell Therapy. Bioengineering (Basel) 2021; 8:bioengineering8110166. [PMID: 34821732 PMCID: PMC8615266 DOI: 10.3390/bioengineering8110166] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/22/2021] [Accepted: 10/26/2021] [Indexed: 12/13/2022] Open
Abstract
The pathogenesis and progression of knee inflammatory pathologies is modulated partly by residing macrophages in the infrapatellar fat pad (IFP), thus, macrophage polarization towards pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes is important in joint disease pathologies. Alteration of M1/M2 balance contributes to the initiation and progression of joint inflammation and can be potentially altered with mesenchymal stem cell (MSC) therapy. In an acute synovial/IFP inflammation rat model a single intra-articular injection of IFP-MSC was performed, having as controls (1) diseased rats not receiving IFP-MSC and (2) non-diseased rats. After 4 days, cell specific transcriptional profiling via single-cell RNA-sequencing was performed on isolated IFP tissue from each group. Eight transcriptomically distinct cell populations were identified within the IFP across all three treatment groups with a noted difference in the proportion of myeloid cells across the groups. Largely myeloid cells consisted of macrophages (>90%); one M1 sub-cluster highly expressing pro-inflammatory markers and two M2 sub-clusters with one of them expressing higher levels of canonical M2 markers. Notably, the diseased samples (11.9%) had the lowest proportion of cells expressing M2 markers relative to healthy (14.8%) and MSC treated (19.4%) samples. These results suggest a phenotypic polarization of IFP macrophages towards the pro-inflammatory M1 phenotype in an acute model of inflammation, which are alleviated by IFP-MSC therapy inducing a switch towards an alternate M2 status. Understanding the IFP cellular heterogeneity and associated transcriptional programs may offer insights into novel therapeutic strategies for disabling joint disease pathologies.
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Solanki K, Shanmugasundaram S, Shetty N, Kim SJ. Articular cartilage repair & joint preservation: A review of the current status of biological approach. J Clin Orthop Trauma 2021; 22:101602. [PMID: 34631411 PMCID: PMC8488240 DOI: 10.1016/j.jcot.2021.101602] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/12/2021] [Accepted: 09/12/2021] [Indexed: 01/03/2023] Open
Abstract
The articular cartilage of the joint is the thin viscoelastic layer of the connective tissue. It has a unique anatomy and physiology, which makes the repair of the articular cartilage damage more difficult and challenging due to its limited healing capacity. Increasing knowledge regarding the importance of articular cartilage for joint preservation has led to increased attention on early identification of cartilage damage as well as degeneration in order to delay osteoarthritis. There are various treatment modalities ranging from preventive management, physical therapy, pharmacological, non-pharmacological and surgical treatments exist in current literature. However most of the studies have limited long term follow up and mainly consists of small case series and case reports. This is an up to date concise review discussing the available management options for articular cartilage damage starting to lifestyle modification to pharmacotherapy, physiotherapy, and osteobiologics till various joint preservation techniques that have been in use currently.
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Affiliation(s)
- Ketansinh Solanki
- Department of Arthroscopy and Trauma, Soundarapandian Bone and Joint Hospital, Chennai, India
| | - Saseendar Shanmugasundaram
- Department of Arthroscopy and Cartilage Reconstruction, Apollo Hospital, Muscat, Oman
- Corresponding author.
| | - Neha Shetty
- Kent Knee Unit, Spire Alexandra Hospital, Chatham, Kent, ME5 9PG, UK
| | - Seok-Jung Kim
- Department of Orthopaedic Surgery, College of Medicine, The Catholic University of Korea, Seoul, South Korea
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Tan SHS, Kwan YT, Neo WJ, Chong JY, Kuek TYJ, See JZF, Wong KL, Toh WS, Hui JHP. Intra-articular Injections of Mesenchymal Stem Cells Without Adjuvant Therapies for Knee Osteoarthritis: A Systematic Review and Meta-analysis. Am J Sports Med 2021; 49:3113-3124. [PMID: 33471552 DOI: 10.1177/0363546520981704] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND While many reviews have been performed to attempt to provide conclusive evidence regarding the outcomes of mesenchymal stem cells (MSCs) in osteoarthritis treatment, the evidence for MSC treatment in osteoarthritis remains contentious, as these reviews have been limited by the heterogeneous evidence available. PURPOSE To pool the results of treatment using intra-articular injections of MSCs without any adjuvant therapies for osteoarthritis. STUDY DESIGN Systematic review and meta-analysis. METHODS The review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. All clinical trials of level 1 or 2 evidence that reported clinical outcomes of patients with osteoarthritis of the knees treated using intra-articular injections of MSCs without any adjuvant therapies were included. RESULTS A total of 19 studies with 440 knees were included. All studies reported an improvement in the outcomes after intervention. The standardized mean differences (SMDs) for the visual analog scale (VAS) for pain at rest and upon exertion were -1.48 (95% CI, -1.85 to -1.11) and -2.25 (95% CI, -2.64 to -1.85), respectively. The SMDs for the total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and total Knee injury and Osteoarthritis Outcome Score were -1.19 (95% CI, -1.53 to -0.84) and 0.88 (95% CI, 0.66-1.10), respectively. Only the source of MSCs and whether the MSCs were cultured or uncultured were clinically important and statistically significant moderators of the treatment outcome. The use of bone marrow MSCs reduced the VAS for pain by 1.50 (95% CI, 0.04-2.96; P = .04) and reduced the total WOMAC by 23.2 (95% CI, 10.0-36.4; P < .01) as compared with adipose MSCs. The use of cultured MSCs reduced the VAS for pain by 2.19 (95% CI, 0.57-3.81; P < .01) and reduced the total WOMAC by 14.4 (95% CI, 1.21-27.5; P = .03) as compared with uncultured MSCs. CONCLUSION Intra-articular injections of MSCs without any adjuvant therapies improves pain and function for osteoarthritis. Significantly better outcomes were obtained with the use of bone marrow MSCs as compared with adipose MSCs and with the use of cultured MSCs as opposed to uncultured MSCs.
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Affiliation(s)
- Si Heng Sharon Tan
- Department of Orthopaedic Surgery, National University Health System, Singapore
| | - Yiu Tsun Kwan
- Department of Orthopaedic Surgery, National University Health System, Singapore
| | - Wei Jian Neo
- Department of Orthopaedic Surgery, National University Health System, Singapore
| | - Jia Yan Chong
- Department of Orthopaedic Surgery, National University Health System, Singapore
| | - Tze Yin Joshua Kuek
- Department of Orthopaedic Surgery, National University Health System, Singapore
| | - Jun Ze Fabian See
- Department of Orthopaedic Surgery, National University Health System, Singapore
| | - Keng Lin Wong
- Department of Orthopaedic Surgery, National University Health System, Singapore.,Department of Orthopaedic Surgery, Sengkang General Hospital, Singapore
| | - Wei Seong Toh
- Tissue Engineering Program, Life Sciences Institute, National University of Singapore, Singapore.,Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore
| | - James Hoi Po Hui
- Department of Orthopaedic Surgery, National University Health System, Singapore.,Tissue Engineering Program, Life Sciences Institute, National University of Singapore, Singapore
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Chung MJ, Son JY, Park S, Park SS, Hur K, Lee SH, Lee EJ, Park JK, Hong IH, Kim TH, Jeong KS. Mesenchymal Stem Cell and MicroRNA Therapy of Musculoskeletal Diseases. Int J Stem Cells 2021; 14:150-167. [PMID: 33377459 PMCID: PMC8138662 DOI: 10.15283/ijsc20167] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/24/2020] [Accepted: 11/30/2020] [Indexed: 02/06/2023] Open
Abstract
The therapeutic effects of mesenchymal stem cells (MSCs) in musculoskeletal diseases (MSDs) have been verified in many human and animal studies. Although some tissues contain MSCs, the number of cells harvested from those tissues and rate of proliferation in vitro are not enough for continuous transplantation. In order to produce and maintain stable MSCs, many attempts are made to induce differentiation from pluripotent stem cells (iPSCs) into MSCs. In particular, it is also known that the paracrine action of stem cell-secreted factors could promote the regeneration and differentiation of target cells in damaged tissue. MicroRNAs (miRNAs), one of the secreted factors, are small non-coding RNAs that regulate the translation of a gene. It is known that miRNAs help communication between stem cells and their surrounding niches through exosomes to regulate the proliferation and differentiation of stem cells. While studies have so far been underway targeting therapeutic miRNAs of MSDs, studies on specific miRNAs secreted from MSCs are still minimal. Hence, our ultimate goal is to obtain sufficient amounts of exosomes from iPSC-MSCs and develop them into therapeutic agents, furthermore to select specific miRNAs and provide safe cell-free clinical setting as a cell-free status with purpose of delivering them to target cells. This review article focuses on stem cell therapy on MSDs, specific microRNAs regulating MSDs and updates on novel approaches.
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Affiliation(s)
- Myung-Jin Chung
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea
| | - Ji-Yoon Son
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea
| | - SunYoung Park
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea.,Stem Cell Therapeutic Research Institute, Kyungpook National University, Daegu, Korea
| | - Soon-Seok Park
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea
| | - Keun Hur
- School of Medicine, Kyungpook National University, Daegu, Korea
| | - Sang-Han Lee
- Department of Food Science & Biotechnology, Kyungpook National University, Daegu, Korea
| | - Eun-Joo Lee
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea
| | - Jin-Kyu Park
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea.,Stem Cell Therapeutic Research Institute, Kyungpook National University, Daegu, Korea
| | - Il-Hwa Hong
- Department of Veterinary Pathology, College of Veterinary Medicine, Gyeongsang National University, Jinju, Korea
| | - Tae-Hwan Kim
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea
| | - Kyu-Shik Jeong
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea.,Stem Cell Therapeutic Research Institute, Kyungpook National University, Daegu, Korea
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García-Muñoz E, Vives J. Towards the standardization of methods of tissue processing for the isolation of mesenchymal stromal cells for clinical use. Cytotechnology 2021; 73:513-522. [PMID: 33994662 PMCID: PMC8109215 DOI: 10.1007/s10616-021-00474-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 05/04/2021] [Indexed: 12/11/2022] Open
Abstract
Multipotent mesenchymal stromal cells (MSCs) are currently the most extensively studied type of adult stem cells in advanced stages of development in the field of regenerative medicine. The biological properties of MSCs have generated great hope for their therapeutic use in degenerative and autoimmune conditions that, at present, lack effective treatment options. Over the last decades, MSCs have been typically obtained from adult bone marrow, but the extraction process is highly invasive and the quality and numbers of isolated cells is drastically influenced by patient age, medication and associated comorbidities. Therefore, there is currently an open discussion on the convenience of allogeneic over autologous treatments, despite potential disadvantages such as rejection by the host. This shift to the allogeneic setting entails the need for high production of MSCs to ensure availability of sufficient cell numbers for transplantation, and therefore making the search for alternative tissue sources of highly proliferative MSC cultures with low levels of senescence occurrence, which is one of the greatest current challenges in the scale up of therapeutic cell bioprocessing. Herein we (i) present the main isolation protocols of MSCs from bone marrow, adipose tissue and Wharton’s jelly of the umbilical cord; and (ii) compare their qualities from a bioprocess standpoint, addressing both quality and regulatory aspects, in view of their anticipated clinical use.
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Affiliation(s)
- Elisabeth García-Muñoz
- Banc de Sang iTeixits, Edifici Dr. Frederic Duran i Jordà, Passeig Taulat, 116, 08005 Barcelona, Spain
| | - Joaquim Vives
- Banc de Sang iTeixits, Edifici Dr. Frederic Duran i Jordà, Passeig Taulat, 116, 08005 Barcelona, Spain.,Musculoskeletal Tissue Engineering Group, Vall D'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Passeig de la Vall d'Hebron 129-139, 08035 Barcelona, Spain.,Departament de Medicina, Universitat Autònoma de Barcelona, Passeig de la Vall d'Hebron 129-139, 08035 Barcelona, Spain
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49
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Rodas G, Soler-Rich R, Rius-Tarruella J, Alomar X, Balius R, Orozco L, Masci L, Maffulli N. Effect of Autologous Expanded Bone Marrow Mesenchymal Stem Cells or Leukocyte-Poor Platelet-Rich Plasma in Chronic Patellar Tendinopathy (With Gap >3 mm): Preliminary Outcomes After 6 Months of a Double-Blind, Randomized, Prospective Study. Am J Sports Med 2021; 49:1492-1504. [PMID: 33783227 DOI: 10.1177/0363546521998725] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Patellar tendinopathy is common. The success of traditional management, including isometric or eccentric exercises combined with shockwave therapy and even surgery, is limited. Therefore, it is important to determine whether biological treatments such as ultrasound-guided intratendinous and peritendinous injections of autologous expanded bone marrow mesenchymal stem cells (BM-MSCs) or leukocyte-poor platelet-rich plasma (Lp-PRP) improve clinical outcomes in athletic patients with patellar tendinopathy. STUDY DESIGN Randomized controlled trial; Level of evidence, 2. METHODS A prospective, double-blinded, randomized, 2-arm parallel group, active controlled, phase 1/2 single-center clinical study was performed in patients who had proximal patellar tendinopathy with a lesion >3 mm. A total of 20 participants (age 18-48 years) with pain for >4 months (mean, 23.6 months) and unresponsive to nonoperative treatments were randomized into 2 groups. Of these, 10 participants were treated with BM-MSC (20 × 106 cells) and 10 with Lp-PRP. Both groups performed the same postintervention rehabilitation protocol. Outcomes included the Victorian Institute of Sport Assessment for pain (VISA-P), self-reported tendon pain during activity (visual analog scale [VAS]), muscle function by dynamometry, tendon thickness and intratendinous vascularity by ultrasonographic imaging and Doppler signal, ultrasound tissue characterization (UTC) echo type changes, and magnetic resonance imaging (MRI) T2-weighted mapping changes. Participants were followed longitudinally for 6 months. RESULTS The average VAS scores improved in both groups at all time points, and there was a significant reduction in pain during sporting activities (P < .05). In both groups, the average mean VISA-P scores at 6 months were significantly increased compared with baseline (66 BM-MSC group and 72.90 Lp-PRP group), with no significant differences in VAS or VISA-P scores between the groups. There were statistically significant greater improvements in tendon structure on 2-dimensional ultrasound and UTC in the BM-MSC group compared with the Lp-PRP group at 6 months. Similarly, the BM-MSC group demonstrated significant evidence of restoration of tendon structure on MRI compared with the Lp-PRP group at 6 months. Only the participants in the BM-MSC group showed evidence of normalization of tendon structure, with statistically significant differences between the groups on T2-weighted, fat-saturated sagittal and coronal scans and hypersignal in T2-weighted on spin-echo T2-weighted coronal MRI scan. Both treatments were safe, and no significant adverse events were reported in either group. CONCLUSION Treatment with BM-MSC or Lp-PRP in combination with rehabilitation in chronic patellar tendinopathy is effective in reducing pain and improving activity levels in active participants. Participants who received BM-MSC treatment demonstrated greater improvement in tendon structure compared with those who received Lp-PRP. REGISTRATION 2016-001262-28 (EudraCT identifier); NCT03454737 (ClinicalTrials.gov identifier).
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Affiliation(s)
- Gil Rodas
- Medical Department FC Barcelona, Barcelona, Spain.,Sports Medicine Unit, Clínic Hospital and Sant Joan de Déu Hospital, Barcelona, Spain
| | - Robert Soler-Rich
- Institut de Teràpia Regenerativa Tissular, Centro Médico Teknon, Barcelona, Spain
| | - Joan Rius-Tarruella
- Institut de Teràpia Regenerativa Tissular, Centro Médico Teknon, Barcelona, Spain
| | - Xavier Alomar
- Diagnóstico por la Imagen, Clínica Creu Blanca, Barcelona, Spain
| | - Ramon Balius
- Consell Català de l'Esport, Generalitat de Catalunya, Barcelona, Spain
| | - Lluís Orozco
- Institut de Teràpia Regenerativa Tissular, Centro Médico Teknon, Barcelona, Spain
| | - Lorenzo Masci
- Institute of Sports Exercise and Health (ISEH), London, UK
| | - Nicola Maffulli
- Department of Musculoskeletal Disorders, University of Salerno School of Medicine, Surgery and Dentistry, Salerno, Italy.,Centre for Sports and Exercise Medicine, Queen Mary University of London, London, UK.,School of Pharmacy and Bioengineering, Keele University School of Medicine, Staffordshire, UK
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50
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Zha K, Li X, Yang Z, Tian G, Sun Z, Sui X, Dai Y, Liu S, Guo Q. Heterogeneity of mesenchymal stem cells in cartilage regeneration: from characterization to application. NPJ Regen Med 2021; 6:14. [PMID: 33741999 PMCID: PMC7979687 DOI: 10.1038/s41536-021-00122-6] [Citation(s) in RCA: 107] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 02/01/2021] [Indexed: 01/31/2023] Open
Abstract
Articular cartilage is susceptible to damage but hard to self-repair due to its avascular nature. Traditional treatment methods are not able to produce satisfactory effects. Mesenchymal stem cells (MSCs) have shown great promise in cartilage repair. However, the therapeutic effect of MSCs is often unstable partly due to their heterogeneity. Understanding the heterogeneity of MSCs and the potential of different types of MSCs for cartilage regeneration will facilitate the selection of superior MSCs for treating cartilage damage. This review provides an overview of the heterogeneity of MSCs at the donor, tissue source and cell immunophenotype levels, including their cytological properties, such as their ability for proliferation, chondrogenic differentiation and immunoregulation, as well as their current applications in cartilage regeneration. This information will improve the precision of MSC-based therapeutic strategies, thus maximizing the efficiency of articular cartilage repair.
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Affiliation(s)
- Kangkang Zha
- Medical School of Chinese PLA, Beijing, China
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China
- School of Medicine, Nankai University, Tianjin, China
| | - Xu Li
- Musculoskeletal Research Laboratory, Department of Orthopedics and Traumatology, Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Zhen Yang
- Medical School of Chinese PLA, Beijing, China
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China
- School of Medicine, Nankai University, Tianjin, China
| | - Guangzhao Tian
- Medical School of Chinese PLA, Beijing, China
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China
- School of Medicine, Nankai University, Tianjin, China
| | - Zhiqiang Sun
- Medical School of Chinese PLA, Beijing, China
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China
- School of Medicine, Nankai University, Tianjin, China
| | - Xiang Sui
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China
| | - Yongjing Dai
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China
| | - Shuyun Liu
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China.
| | - Quanyi Guo
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China.
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