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Whittle SL, Johnston RV, McDonald S, Worthley D, Campbell TM, Cyril S, Bapna T, Zhang J, Buchbinder R. Stem cell injections for osteoarthritis of the knee. Cochrane Database Syst Rev 2025; 4:CD013342. [PMID: 40169165 PMCID: PMC11961299 DOI: 10.1002/14651858.cd013342.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/03/2025]
Abstract
BACKGROUND Stem cells are specialised precursor cells that can replace aged or damaged cells and thereby maintain healthy tissue function. Stem cell therapy is increasingly used as a treatment for knee osteoarthritis, despite the lack of clarity around the mechanism by which stem cell therapy may slow down disease progression in osteoarthritis, and uncertainty regarding its benefits and harms. OBJECTIVES To assess the benefits and harms of stem cell injections for people with osteoarthritis of the knee. A secondary objective is to maintain the currency of the evidence, using a living systematic review approach. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase on 15 September 2023, unrestricted by date or language of publication. We also searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) for relevant trial protocols and ongoing trials. SELECTION CRITERIA We included randomised controlled trials (RCTs), or trials using quasi-randomised methods of participant allocation, comparing stem cell injection with placebo injection, no treatment or usual care, glucocorticoid injection, other injections, exercise, drug therapy, surgical interventions, and supplements and complementary therapies in people with knee osteoarthritis. DATA COLLECTION AND ANALYSIS Two review authors selected studies for inclusion, extracted trial characteristics and outcome data, assessed risk of bias and assessed the certainty of evidence using the GRADE approach. The primary comparison was stem cell injection compared with placebo injection. The primary time point for pain, function and quality of life was three to six months, and the end of the trial period for participant-reported success, joint structure changes and adverse event outcomes. Major outcomes were pain, function, quality of life, global assessment of success, radiographic joint progression, withdrawals due to adverse events and serious adverse events. MAIN RESULTS We found 25 randomised trials (1341 participants) comparing stem cell injections with placebo injection (eight trials), no treatment or usual care (analgesia, weight loss and exercise) (two trials), glucocorticoid injection (one trial), hyaluronic acid injection (seven trials), platelet-rich plasma injections (two trials), oral acetaminophen (paracetamol) (one trial), non-steroidal anti-inflammatory drugs plus physical therapy plus hyaluronic acid injection (one trial) and stem cell injection plus intra-articular co-intervention versus co-intervention alone (three trials) in people with osteoarthritis of the knee. Trials were predominantly small, with sample sizes ranging from 6 to 252 participants, with only two trials having more than 100 participants. The average age of participants across trials ranged from 51 to 66 years, and symptom duration varied from one to 10 years. Placebo-controlled trials were largely free from bias, while most trials without a placebo control were susceptible to performance and detection biases. Here, we limit reporting to the main comparison, stem cell injection versus placebo injection. Compared with placebo injection, stem cell injection may slightly improve pain and function up to six months after treatment. Mean pain (0 to 10 scale, 0 no pain) was 4.5 out of 10 points with placebo injection and 1.2 points better (2.5 points better to 0 points better) with stem cell injection (I2 = 80%; 7 studies, 445 participants). Mean function (0 to 100 scale, 0 best function) was 46.3 points with placebo injection and 14.2 points better (25.3 points better to 3.1 points better) with stem cell injection (I2 = 82%; 7 studies, 432 participants). We are uncertain whether stem cell injections improve quality of life or increase the number of people who report treatment success compared to placebo injection, because the certainty of the evidence was very low. Mean quality of life was 45.3 points with placebo injection and 22.8 points better (18.0 points worse to 63.7 points better) with stem cell injection (I2 = 96%; 2 studies, 288 participants) at up to six months follow-up. At the end of follow-up, 89/168 participants (530 per 1000) in the placebo injection group reported treatment success compared with 126/180 participants (683 per 1000) in the stem cell injection group (risk ratio (RR) 1.29, 95% CI 1.10 to 1.53; I2 = 0%; 4 trials, 348 participants). We downgraded the evidence to low certainty for pain and function due to indirectness (as the source, method of preparation and dose of stem cells varied across studies), and suspected publication bias (up to three larger RCTs have been conducted but withdrawn prior to reporting of results). For quality of life and treatment success, we further downgraded the evidence to very low certainty due to imprecision in addition to indirectness and suspected publication bias. We are uncertain of the potential harms associated with stem cell injection, as there were very low event rates for serious adverse events. At the end of follow-up, 5/219 participants (23 per 1000) in the placebo injection group experienced serious adverse events compared with 4/242 participants (16 per 1000) in the stem cell injection group (RR 0.72, 95% CI 0.20 to 2.64; I2 = 0%; 7 trials, 461 participants) and there were no reported withdrawals due to adverse events. We downgraded the evidence to very low certainty due to indirectness, suspected publication bias and imprecision. Radiographic progression was not assessed in any of the included studies. AUTHORS' CONCLUSIONS Compared with placebo injections and based upon low-certainty evidence, stem cell injections for people with knee osteoarthritis may slightly improve pain and function. We are uncertain of the effects of stem cell injections on quality of life or the number who report treatment success. Although the putative benefits of stem cell therapies for osteoarthritis include potential regenerative effects on damaged tissues, particularly articular cartilage, we remain uncertain of the effect of stem cell injections on structural progression in the knee (measured by radiographic appearance). There is also uncertainty regarding the safety of stem cell injections. Serious adverse events were infrequently reported, although all invasive joint procedures (including injections) carry a small risk of septic arthritis. The risk of other important harms, including potential concerns related to the use of a therapy with the theoretical capacity to promote cell growth, or to the use of allogeneic cells, remains unknown.
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Affiliation(s)
- Samuel L Whittle
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
- Rheumatology Unit, Queen Elizabeth Hospital, Woodville South, Australia
| | - Renea V Johnston
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Steve McDonald
- Cochrane Australia, School of Public Health & Preventive Medicine, Monash University, Melbourne, Australia
| | - Daniel Worthley
- Gastrointestinal Cancer Biology Group, South Australian Health and Medical Research Institute, Adelaide, Australia
| | - T Mark Campbell
- Physical Medicine and Rehabilitation, Elisabeth Bruyère Hospital, Ottawa, Canada
| | - Sheila Cyril
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Tanay Bapna
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Jason Zhang
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Rachelle Buchbinder
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
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Kataria S, Inggas MAM, Patel U, Wijaya JH, Yabut K, Ayub MA, Maniyar P, Upadhyay N, Davitashvili B, Patel J, Shah S, Turjman T, Turjman H, Shekoohi S, Kaye AD. A Systematic Review and Meta-Analysis of Stem Cell Therapies for Pain in Diabetic Neuropathy, Osteoarthritis, and Spinal Cord Injuries. Curr Pain Headache Rep 2025; 29:29. [PMID: 39841308 DOI: 10.1007/s11916-024-01331-6] [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] [Accepted: 09/05/2024] [Indexed: 01/23/2025]
Abstract
PURPOSE OF REVIEW The use of stem cell therapy is a rapidly evolving and progressing frontier of science that has been used to treat illnesses such as malignancies, immunodeficiencies, and metabolic syndromes. This review aims to give an overview of the use of stem cell therapy in the treatment of pain caused by diabetic neuropathy, osteoarthritis, and other spinal cord pathologies. RECENT FINDINGS Pain is defined as a generalized or localized feeling of distress related to a physical or emotional stimulus and can be caused by a multitude of pathologies. The field of pain management has explored many strategies such as gene therapies, neuromodulation, platelet-rich plasma, and numerous pharmacotherapies. The approach to the delivery of these strategies has varied, with the method of stem cell therapy delivery being the focus of this present investigation. In addition, we combined several different studies to analyze the effects of stem cell therapies and improvement in pain scores quantified by the visual analog scale (VAS). The overall results showed a mean difference of -2.58, suggesting that the stem cell treatment group had a lower VAS score at 6 months compared to the control group. The use of different types of stem cells, such as pluripotent and mesenchymal stem cells, play a critical role in the care of cases suffering from pain. Effective delivery methods are evolving and can transform treatment options in the future, for which large cohort studies are warranted.
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Affiliation(s)
- Saurabh Kataria
- Department of Neurology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, 71103, USA
| | | | | | | | - Kevin Yabut
- Louisiana State University Health Science Center, School of Medicine, Shreveport, LA, 71103, USA
| | | | - Pankti Maniyar
- GMERS medical college , Gotri, Vadodara, Gujarat, 390021, India
| | - Nihar Upadhyay
- Department of Internal Medicine, GMERS medical college and Hospital, Gotri, Vadodara, India
| | | | - Jayshil Patel
- Benchmark Physical therapy, Upstream Rehabilitation, Knoxville, TN, 37920, USA
| | - Siddhi Shah
- R. N. Cooper Municipal General Hospital, Mumbai, India
| | - Tawfiq Turjman
- School of Medicine, Royal College of Surgeons in Ireland, Busaiteen, Bahrain
| | - Hisham Turjman
- School of Medicine, Royal College of Surgeons in Ireland, Busaiteen, Bahrain
| | - Sahar Shekoohi
- Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA, 71103, USA
| | - Alan D Kaye
- Departments of Anesthesiology and Pharmacology, Toxicology, and Neurosciences, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA, 71103, USA
- Louisiana Addiction Research Center, Shereveport, LA, 71103, USA
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Sadeghirad B, Rehman Y, Khosravirad A, Sofi-Mahmudi A, Zandieh S, Jomy J, Patel M, Couban RJ, Momenilandi F, Burnham R, Poolman RW, Busse JW. Mesenchymal stem cells for chronic knee pain secondary to osteoarthritis: A systematic review and meta-analysis of randomized trials. Osteoarthritis Cartilage 2024; 32:1207-1219. [PMID: 38777213 DOI: 10.1016/j.joca.2024.04.021] [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: 02/12/2024] [Revised: 04/07/2024] [Accepted: 04/22/2024] [Indexed: 05/25/2024]
Abstract
OBJECTIVE To assess the effectiveness of mesenchymal stem cells (MSCs) for chronic knee pain secondary to osteoarthritis (OA). METHODS We searched MEDLINE, EMBASE, CINAHL, and Cochrane Central to September 2023 for trials that (1) enrolled patients with chronic pain associated with knee OA, and (2) randomized them to MSC therapy vs. placebo or usual care. We performed random-effects meta-analysis and used Grading of Recommendations, Assessment, Development, and Evaluation to assess the certainty of evidence. RESULTS We included 16 trials (807 participants). At 3-6 months, MSC therapy probably results in little to no difference in pain relief (weighted mean difference [WMD] -0.74 cm on a 10 cm visual analog scale [VAS], 95% confidence interval [95%CI] -1.16 to -0.33; minimally important difference [MID] 1.5 cm) or physical functioning (WMD 2.23 points on 100-point 36-item Short Form Survey (SF-36) physical functioning subscale, 95%CI -0.97 to 5.43; MID 10-points; both moderate certainty). At 12 months, injection of MSCs probably results in little to no difference in pain (WMD -0.73 cm on a 10 cm VAS, 95%CI -1.69 to 0.24; moderate certainty) and may improve physical functioning (WMD 19.36 points on 100-point SF-36 PF subscale, 95%CI -0.19 to 38.9; low certainty). MSC therapy may increase risk of any adverse events (risk ratio [RR] 2.67, 95%CI 1.19 to 5.99; low certainty) and pain and swelling of the knee joint (RR 1.58, 95%CI 1.04 to 2.38; low certainty). CONCLUSIONS Intra-articular injection of MSCs for chronic knee pain associated with OA probably provides little to no improvement in pain or physical function.
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Affiliation(s)
- Behnam Sadeghirad
- Michael G. DeGroote National Pain Centre, McMaster University, Hamilton, Ontario, Canada; Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Yasir Rehman
- Michael G. DeGroote National Pain Centre, McMaster University, Hamilton, Ontario, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Azin Khosravirad
- Michael G. DeGroote National Pain Centre, McMaster University, Hamilton, Ontario, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Ahmad Sofi-Mahmudi
- Michael G. DeGroote National Pain Centre, McMaster University, Hamilton, Ontario, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Sara Zandieh
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Jane Jomy
- Michael G. DeGroote National Pain Centre, McMaster University, Hamilton, Ontario, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Mansi Patel
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Rachel J Couban
- Michael G. DeGroote National Pain Centre, McMaster University, Hamilton, Ontario, Canada; Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada
| | - Feryal Momenilandi
- Functional Neurosurgery Research Center, Shohada Tajrish Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Velenjak, Tehran, Iran
| | - Robert Burnham
- Division of Physical Medicine and Rehabilitation, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Rudolf W Poolman
- Department of Orthopedic Surgery, Onze Lieve Vrouwe Gasthuis, Amsterdam, North Holland, The Netherlands
| | - Jason W Busse
- Michael G. DeGroote National Pain Centre, McMaster University, Hamilton, Ontario, Canada; Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.
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Zhang X, Cui C, Lin F. Efficacy and safety of mesenchymal stem cell injections for knee osteoarthritis: A systematic review and meta-analysis. JOURNAL OF RESEARCH IN MEDICAL SCIENCES : THE OFFICIAL JOURNAL OF ISFAHAN UNIVERSITY OF MEDICAL SCIENCES 2024; 29:55. [PMID: 39629035 PMCID: PMC11613985 DOI: 10.4103/jrms.jrms_515_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 02/08/2024] [Accepted: 03/18/2024] [Indexed: 12/06/2024]
Abstract
Background There have not been any clear studies on the use of mesenchymal stem cells (MSCs) to treat osteoarthritis (OA) in the knee. Materials and Methods This study investigates the effects of different MSC dosages on pain alleviation in individuals with OA in the knee by conducting a meta-analysis of existing randomized controlled trials. Electronic resources such as Google Scholar, PubMed, Cochrane Library, and Web of Science were searched up until June 2023. Treatment effect sizes were computed using the knee osteoarthritis outcome score (KOOS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the Knee Society Score (KSS). Random or fixed effect models were applied to aggregate the data. We performed a subgroup analysis according to dosage level. The heterogeneity of the research was investigated using the Chi-square test and the I2 index. Results The meta-analysis included 26 studies with a total sample size of 739 patients. A significant reduction in pain was observed 1 year and 2 years following the injection of MSCs into the injured joint, as indicated by the Visual Analogue Scale, WOMAC, KOOS, and KSS indexes (P < 0.05). Patients on MSCs reported much reduced pain after 1 and 2 years compared to the control group (P < 0.05). Subgroup and meta-regression analyses revealed no statistically significant variations in the effectiveness of MSC dosage (P < 0.05). The studies did not report any adverse effects. Conclusion Different dosages of MSCs had the same pain-relieving effects on patients with OA in the knee. MSC injections were safe and beneficial in such cases.
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Affiliation(s)
- Xinguang Zhang
- Department of Joint Surgery, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Cunbao Cui
- Department of Joint Surgery, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Feng Lin
- Department of Joint Surgery, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
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Shah S, Ghosh D, Otsuka T, Laurencin CT. Classes of Stem Cells: From Biology to Engineering. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2024; 10:309-322. [PMID: 39387056 PMCID: PMC11463971 DOI: 10.1007/s40883-023-00317-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/30/2023] [Accepted: 08/16/2023] [Indexed: 10/12/2024]
Abstract
Purpose The majority of adult tissues are limited in self-repair and regeneration due to their poor intrinsic regenerative capacity. It is widely recognized that stem cells are present in almost all adult tissues, but the natural regeneration in adult mammals is not sufficient to recover function after injury or disease. Historically, 3 classes of stem cells have been defined: embryonic stem cells (ESCs), adult mesenchymal stem cells (MSCs), and induced pluripotent stem cells (iPSCs). Here, we have defined a fourth fully engineered class: the synthetic artificial stem cell (SASC). This review aims to discuss the applications of these stem cell classes in musculoskeletal regenerative engineering. Method We screened articles in PubMed and bibliographic search using a combination of keywords. Relevant and high-cited articles were chosen for inclusion in this narrative review. Results In this review, we discuss the different classes of stem cells that are biologically derived (ESCs and MSCs) or semi-engineered/engineered (iPSCs, SASC). We also discuss the applications of these stem cell classes in musculoskeletal regenerative engineering. We further summarize the advantages and disadvantages of using each of the classes and how they impact the clinical translation of these therapies. Conclusion Each class of stem cells has advantages and disadvantages in preclinical and clinical settings. We also propose the engineered SASC class as a potentially disease-modifying therapy that harnesses the paracrine action of biologically derived stem cells to mimic regenerative potential. Lay Summary The majority of adult tissues are limited in self-repair and regeneration, even though stem cells are present in almost all adult tissues. Historically, 3 classes of stem cells have been defined: embryonic stem cells (ESCs), adult mesenchymal stem cells (MSCs), and induced pluripotent stem cells (iPSCs). Here, we have defined a fourth, fully engineered class: the synthetic artificial stem cell (SASC). In this review, we discuss the applications of each of these stem cell classes in musculoskeletal regenerative engineering. We further summarize the advantages and disadvantages of using each of these classes and how they impact the clinical translation of these therapies.
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Affiliation(s)
- Shiv Shah
- The Cato T. Laurencin Institute for Regenerative Engineering, University of Connecticut, 263 Farmington Avenue, Farmington, CT 06030-3711, USA
- Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health, Farmington, CT, USA
- Department of Chemical and Biomolecular Engineering, University of Connecticut, Storrs, CT, USA
| | - Debolina Ghosh
- The Cato T. Laurencin Institute for Regenerative Engineering, University of Connecticut, 263 Farmington Avenue, Farmington, CT 06030-3711, USA
| | - Takayoshi Otsuka
- The Cato T. Laurencin Institute for Regenerative Engineering, University of Connecticut, 263 Farmington Avenue, Farmington, CT 06030-3711, USA
- Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health, Farmington, CT, USA
| | - Cato T. Laurencin
- The Cato T. Laurencin Institute for Regenerative Engineering, University of Connecticut, 263 Farmington Avenue, Farmington, CT 06030-3711, USA
- Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health, Farmington, CT, USA
- Department of Chemical and Biomolecular Engineering, University of Connecticut, Storrs, CT, USA
- Department of Orthopedic Surgery, University of Connecticut Health, Farmington, CT, USA
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT, USA
- Department of Materials Science and Engineering, University of Connecticut, Storrs, CT, USA
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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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Subramanyam K, Poornima S, Kumar S, Hasan Q. Short-Term Clinical Results of Single-Injection Autologous Bone Marrow Aspirate Concentrate (BMAC) as a Therapeutic Option/Tool in Knee Osteoarthritis. BIOLOGICS 2024; 4:218-231. [DOI: 10.3390/biologics4020015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Purpose: Knee osteoarthritis (KOA) is a very common cartilage disorder affecting millions of people globally and is characterized by pain, stiffness, swelling, loss of articular cartilage, and osteophyte formation, resulting in disability. The presently available treatments for KOA are palliative. Hence, there is a need to explore a non-surgical treatment portfolio. Bone marrow aspirate concentrate (BMAC) is one of the predominant attention-drawing managements/treatments for KOA in recent times due to its potential advantages of disease-modifying and regeneration capacities. Principle: This study aimed to evaluate the role of single-injection autologous BMAC as a therapeutic option in the treatment of KOA and evaluate the functional and clinical outcomes of KOA patients. In this study, 132 patients with KOA (Kellgren and Lawrence (KL) grade II and III) were included as per the inclusion criteria. Autologous bone marrow was aspirated and separated, and concentrated bone marrow aspirate was administered into the knee joint of the affected individual. Results: At the end of the 12th month (end of the follow-up period), 95% of patients showed complete pain relief and improvement in joint function, which shows that the results were promising and encouraging. Unpaired t-test results also indicated that the two-tailed p-value is less than 0.0001, and the difference is extremely statistically significant. No adverse effects were observed in the study patients. Conclusions: BMAC therapy has potential, with satisfactory, efficient, and durable results in KL grades II and III in KOA patients. This can be a safe alternative therapy in the treatment of KOA, especially in the early grades of OA. In summary, to the best of our knowledge, this is the first study from India that evaluated BMAC efficacy both subjectively and objectively in KOA (KL-II and KL-III) patients.
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Affiliation(s)
- Krishna Subramanyam
- Department of Orthopaedics, Kamineni Hospitals, LB Nagar, Hyderabad 500074, India
- Department of Orthopaedics, Yashoda Hospitals, Malakpet, Hyderabad 500036, India
| | - Subhadra Poornima
- Department of Genetics and Molecular Medicine, Kamineni Academy of Medical Sciences and Research Centre, LB. Nagar, Hyderabad 500074, India
- Department of Genetics and Molecular Medicine, Kamineni Life Sciences, Moula Ali, Hyderabad 500047, India
| | - Satish Kumar
- Department of Orthopaedics, Yashoda Hospitals, Malakpet, Hyderabad 500036, India
| | - Qurratulain Hasan
- Department of Genetics and Molecular Medicine, Kamineni Academy of Medical Sciences and Research Centre, LB. Nagar, Hyderabad 500074, India
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Park S, Park S, Jang JN, Choi YS, Kim DS, Sohn JE, Park JH. Radiofrequency ablation versus intra-articular mesenchymal stem cell injection for knee osteoarthritis: a systematic review and network meta-analysis. Reg Anesth Pain Med 2024:rapm-2024-105526. [PMID: 38876799 DOI: 10.1136/rapm-2024-105526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Accepted: 05/28/2024] [Indexed: 06/16/2024]
Abstract
BACKGROUND Knee osteoarthritis (OA) is a prevalent degenerative disease and causes disability, pain and imposes a substantial burden on patients. Conventional treatments for knee OA show limited effectiveness. Consequently, innovative treatments, such as radiofrequency ablation (RFA) and intra-articular mesenchymal stem cells (IA MSC), have gained attention for addressing these limitations. OBJECTIVE We compared the efficacy of RFA and IA MSC for knee OA through a network meta-analysis (NMA). EVIDENCE REVIEW A literature search was conducted using PubMed, MEDLINE, Embase, Cochrane Library, Web of Science and handsearching. Randomized controlled trials (RCTs) comparing RFA or IA MSC to conventional treatments for knee OA were included. The primary outcomes comprised the pain score and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). The clinical outcomes were compared using a frequentist approach, and the treatments were ranked using the surface under the cumulative ranking curve (SUCRA) values. FINDINGS We included 34 RCTs (n=2371). Our NMA revealed that RFA and IA MSC were significantly more effective than conventional treatments in managing pain at both 3 and 6 months with moderate certainty. Specifically, RFA demonstrated the highest SUCRA values, indicating its superior efficacy. For WOMAC scores, both RFA and MSC showed significant improvements at 3 months, with RFA maintaining its lead at 6 months, although MSC did not display significant superiority at this stage. CONCLUSIONS This analysis suggests that RFA and MSC are resilient treatment options in knee OA. Despite some study heterogeneity, these treatments consistently outperformed conventional treatments, particularly in the short to mid-term, although with varying levels of certainty in their efficacy. PROSPERO REGISTRATION NUMBER CRD42023492299.
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Affiliation(s)
- Sukhee Park
- Catholic Kwandong University College of Medicine, Gangneung, Republic of Korea
| | - Soyoon Park
- Catholic Kwandong University College of Medicine, Gangneung, Gangwon-do, Republic of Korea
| | - Jae Ni Jang
- Catholic Kwandong University College of Medicine, Gangneung, Gangwon-do, Republic of Korea
| | - Young-Soon Choi
- Catholic Kwandong University College of Medicine, Gangneung, Gangwon-do, Republic of Korea
| | | | | | - Ji-Hoon Park
- Department of Anesthesiology and Pain Medicine, Keimyung University College of Medicine, Daegu, Republic of Korea
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Ding QX, Wang X, Li TS, Li YF, Li WY, Gao JH, Liu YR, Zhuang W. Comparative Analysis of Short-Term and Long-Term Clinical Efficacy of Mesenchymal Stem Cells from Different Sources in Knee Osteoarthritis: A Network Meta-Analysis. Stem Cells Int 2024; 2024:2741681. [PMID: 38882598 PMCID: PMC11178400 DOI: 10.1155/2024/2741681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 04/28/2024] [Accepted: 05/13/2024] [Indexed: 06/18/2024] Open
Abstract
Background Joint articular injection of mesenchymal stem cells (MSCs) has emerged as a novel treatment approach for osteoarthritis (OA). However, the effectiveness of MSCs derived from different sources in treating OA patients remains unclear. Therefore, this study aimed to explore the differences between the effectiveness and safety of different sources of MSCs. Materials and Methods For inclusion consideration, we searched trial registries and published databases, including PubMed, Cochrane Library, Embase, and Web of Science databases. Revman (V5.3), STATA (V16.0), and R (V4.0) were utilized for conducting data analysis, while the Cochrane Risk of Bias Tool was employed for assessing the quality of the studies. We derived outcome measures at 6 and 12 months based on the duration of study follow-up, including visual analog scale (VAS) score, WOMAC score, WOMAC pain, WOMAC Functional Limitation, and WOMAC stiffness. The evaluation time for short-term effectiveness is set at 6 months, while 12 months is utilized as the longest follow-up time for most studies to assess long-term effectiveness. Results The evaluation of literature quality showed that the included studies had excellent methodological quality. A meta-analysis revealed that different sources of MSCs improved knee function and pain more effectively among patients suffering from knee OA (KOA) than controls. The results of the network meta-analysis showed the following: short-term functional improvement (the indexes were evaluated after 6 months of follow-up) (WOMAC total score: bone marrow-derived MSC (BMMSC) vs. adipose-derived MSC (ADMSC) (mean difference (MD) = -20.12, 95% confidence interval (CI) -125.24 to 42.88), umbilical cord-derived MSC (UCMSC) (MD = -7.81, 95% CI -158.13 to 74.99); WOMAC stiffness: BMMSC vs. ADMSC (MD = -0.51, 95% CI -7.27 to 4.29), UCMSC (MD = -0.75, 95% CI -9.74 to 6.63); WOMAC functional limitation: BMMSC vs. ADMSC (MD = -12.22, 95% CI -35.05 to 18.86), UCMSC (MD = -9.31, 95% CI -44.26 to 35.27)). Long-term functional improvement (the indexes were evaluated after 12 months of follow-up) (WOMAC total: BMMSC vs. ADMSC (MD = -176.77, 95% CI -757.1 to 378.25), UCMSC (MD = -181.55, 95% CI -937.83 to 541.13); WOMAC stiffness: BMMSC vs. ADMSC (MD = -0.5, 95% CI -26.05 to 18.61), UCMSC (MD = -1.03, 95% CI -30.44 to 21.69); WOMAC functional limitation: BMMSC vs. ADMSC (MD = -5.18, 95% CI -316.72 to 177.1), UCMSC (MD = -8.33, 95% CI -358.78 to 218.76)). Short-term pain relief (the indexes were evaluated after 6 months of follow-up) (VAS score: UCMSC vs. BMMSC (MD = -10.92, 95% CI -31.79 to 12.03), ADMSC (MD = -14.02, 95% CI -36.01 to 9.81), PLMSC (MD = -17.09, 95% CI -46.31 to 13.17); WOMAC pain relief: BMMSC vs. ADMSC (MD = -11.42, 95% CI -39.52 to 11.77), UCMSC (MD = -6.73, 95% CI -47.36 to 29.15)). Long-term pain relief (the indexes were evaluated after 12 months of follow-up) (VAS score: BMMSC vs. UCMSC (MD = -4.33, 95% CI -36.81 to 27.08), ADMSC (MD = -11.43, 95% CI -37.5 to 13.42); WOMAC pain relief: UCMSC vs. ADMSC (MD = 0.23, 95% CI -37.87 to 38.11), BMMSC (MD = 5.89, 95% CI -25.39 to 51.41)). According to the GRADE scoring system, WOMAC, VAS, and AE scores were of low quality. Conclusion Meta-analysis suggests MSCs can effectively treat KOA by improving pain and knee function compared to control groups. In terms of functional improvement in KOA patients, both short-term (6-month follow-up) and long-term (12-month follow-up) results indicated that while the differences between most treatments were not statistically significant, bone marrow-derived MSCs may have some advantages over other sources of MSCs. Additionally, BM-MSCs and UC-MSCs may offer certain benefits over ADMSCs in terms of pain relief for KOA patients, although the variances between most studies were not statistically significant. Therefore, this study suggests that BM-MSCs may present clinical advantages over other sources of MSCs.
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Affiliation(s)
- Qi Xin Ding
- Henan University of Chinese Medicine, Zhengzhou, China
| | - Xu Wang
- Henan University of Chinese Medicine, Zhengzhou, China
| | | | | | - Wan Yue Li
- First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Jia Huan Gao
- Henan Provincial People's Hospital, Zhengzhou, China
| | - Yu Rong Liu
- Shandong First Medical University, Jinan, China
| | - WeiSheng Zhuang
- Henan Provincial People's Hospital, Zhengzhou, China
- Henan University of Chinese Medicine, Zhengzhou, China
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10
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Kyriakidis T, Pitsilos C, Iosifidou M, Tzaveas A, Gigis I, Ditsios K, Iosifidis M. Stem cells for the treatment of early to moderate osteoarthritis of the knee: a systematic review. J Exp Orthop 2023; 10:102. [PMID: 37804354 PMCID: PMC10560289 DOI: 10.1186/s40634-023-00665-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 09/27/2023] [Indexed: 10/09/2023] Open
Abstract
PURPOSE Mesenchymal stem cells (MSCs) present a valuable treatment option for knee osteoarthritis with promising results. The purpose of the present study was to systematically review the clinical and functional outcomes following mesenchymal stem cell application focusing on early to moderate knee osteoarthritis. METHODS A systematic search was done using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in Pubmed, Scopus, Web of Science, and Cochrane Library databases. All Studies published between 2017 and March 2023 on patients treated with single mesenchymal stem cell injection for Kellgren-Lawrence grade I-III knee osteoarthritis reported on clinical and functional outcomes were included. RESULTS Twelve articles comprising 539 patients and 576 knees treated with a single intraarticular injection of MSCs for knee osteoarthritis were included in the current systematic review. In eligible studies, the reported outcomes were improved concerning patient-reported outcomes measures, knee function, pain relief, and quality of patient's life. CONCLUSION Based on high-level evidence studies, single intraarticular injection of MSCs is a safe, reliable, and effective treatment option for Kellgren-Lawrence grade I-III knee osteoarthritis. However, the lack of homogeneity in the included studies and the variance in MSCs sources and preparations should be noted. LEVEL OF EVIDENCE III.
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Affiliation(s)
- Theofylaktos Kyriakidis
- Department of Orthopaedic Surgery and Traumatology, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium.
- 2nd Department of Orthopaedic Surgery and Traumatology, Aristotle University of Thessaloniki, "G. Gennimatas" General Hospital, Ethnikis Aminis 41, 54635, Thessaloniki, Hellas, Greece.
- 3rd Orthopaedic Department, Interbalkan Medical Center, Thessaloniki, Greece.
| | - Charalampos Pitsilos
- 2nd Department of Orthopaedic Surgery and Traumatology, Aristotle University of Thessaloniki, "G. Gennimatas" General Hospital, Ethnikis Aminis 41, 54635, Thessaloniki, Hellas, Greece
| | | | - Alexandros Tzaveas
- 3rd Orthopaedic Department, Interbalkan Medical Center, Thessaloniki, Greece
| | - Ioannis Gigis
- 2nd Department of Orthopaedic Surgery and Traumatology, Aristotle University of Thessaloniki, "G. Gennimatas" General Hospital, Ethnikis Aminis 41, 54635, Thessaloniki, Hellas, Greece
| | - Konstantinos Ditsios
- 2nd Department of Orthopaedic Surgery and Traumatology, Aristotle University of Thessaloniki, "G. Gennimatas" General Hospital, Ethnikis Aminis 41, 54635, Thessaloniki, Hellas, Greece
| | - Michael Iosifidis
- 3rd Orthopaedic Department, Interbalkan Medical Center, Thessaloniki, Greece
- Orthobiology Surgery Center, Thessaloniki, Greece
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11
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Gupta PK, Maheshwari S, Cherian JJ, Goni V, Sharma AK, Tripathy SK, Talari K, Pandey V, Sancheti PK, Singh S, Bandyopadhyay S, Shetty N, Kamath SU, Prahaldbhai PS, Abraham J, Kannan S, Bhat S, Parshuram S, Shahavi V, Sharma A, Verma NN, Kumar U. Efficacy and Safety of Stempeucel in Osteoarthritis of the Knee: A Phase 3 Randomized, Double-Blind, Multicenter, Placebo-Controlled Study. Am J Sports Med 2023; 51:2254-2266. [PMID: 37366164 DOI: 10.1177/03635465231180323] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/28/2023]
Abstract
BACKGROUND Osteoarthritis is a chronic, progressive, and degenerative condition with limited therapy options. Recently, biologic therapies have been an evolving option for the management of osteoarthritis. PURPOSE To assess whether allogenic mesenchymal stromal cells (MSCs) have the potential to improve functional parameters and induce cartilage regeneration in patients with osteoarthritis. STUDY DESIGN Randomized controlled trial; Level of evidence, 1. METHODS A total of 146 patients with grade 2 and 3 osteoarthritis were randomized to either an MSC group or placebo group with a ratio of 1:1. There were 73 patients per group who received either a single intra-articular injection of bone marrow-derived MSCs (BMMSCs; 25 million cells) or placebo, followed by 20 mg per 2 mL of hyaluronic acid under ultrasound guidance. The primary endpoint was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score. The secondary endpoints were WOMAC subscores for pain, stiffness, and physical function; the visual analog scale score for pain; and magnetic resonance imaging findings using T2 mapping and cartilage volume. RESULTS Overall, 65 patients from the BMMSC group and 68 patients from the placebo group completed 12-month follow-up. The BMMSC group showed significant improvements in the WOMAC total score compared with the placebo group at 6 and 12 months (percentage change: -23.64% [95% CI, -32.88 to -14.40] at 6 months and -45.60% [95% CI, -55.97 to -35.23] at 12 months P < .001; percentage change, -44.3%). BMMSCs significantly improved WOMAC pain, stiffness, and physical function subscores as well as visual analog scale scores at 6 and 12 months (P < .001). T2 mapping showed that there was no worsening of deep cartilage in the medial femorotibial compartment of the knee in the BMMSC group at 12-month follow-up, whereas in the placebo group, there was significant and gradual worsening of cartilage (P < .001). Cartilage volume did not change significantly in the BMMSC group. There were 5 adverse events that were possibly/probably related to the study drug and consisted of injection-site swelling and pain, which improved within a few days. CONCLUSION In this small randomized trial, BMMSCs proved to be safe and effective for the treatment of grade 2 and 3 osteoarthritis. The intervention was simple and easy to administer, provided sustained relief of pain and stiffness, improved physical function, and prevented worsening of cartilage quality for ≥12 months. REGISTRATION CTRI/2018/09/015785 (National Institutes of Health and Clinical Trials Registry-India).
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Affiliation(s)
- Pawan Kumar Gupta
- Stempeutics Research, Bangalore, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Sunil Maheshwari
- Medilink Hospital and Research Centre, Ahmedabad, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Joe Joseph Cherian
- St John's Medical College, Bangalore, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Vijay Goni
- Postgraduate Institute of Medical Education and Research, Chandigarh, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Arun Kumar Sharma
- Sawai Man Singh Hospital & Medical College, Jaipur, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Sujith Kumar Tripathy
- All India Institutes of Medical Sciences, Bhubaneswar, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Keerthi Talari
- Yashoda Hospital, Hyderabad, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Vivek Pandey
- Kasturba Medical College, Manipal, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Parag Kantilal Sancheti
- Sancheti Institute for Orthopaedics and Rehabilitation, Pune, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Saurabh Singh
- Banaras Hindu University, Varanasi, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Syamasis Bandyopadhyay
- Apollo Gleneagles Hospital, Kolkata, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Naresh Shetty
- Ramaiah Medical College, Bangalore, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Surendra Umesh Kamath
- Kasturba Medical College Hospital, Mangalore, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Purohit Sharad Prahaldbhai
- Sanjivani Super Specialty Hospital, Ahmedabad, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Jijy Abraham
- Stempeutics Research, Bangalore, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Suresh Kannan
- Stempeutics Research, Bangalore, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Samatha Bhat
- Stempeutics Research, Bangalore, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Shivashankar Parshuram
- Stempeutics Research, Bangalore, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Vinayaka Shahavi
- Alkem Laboratories, Mumbai, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Akhilesh Sharma
- Alkem Laboratories, Mumbai, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Nikhil N Verma
- Rush University Medical Center, Chicago, Illinois, USA
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Uday Kumar
- Stempeutics Research, Bangalore, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
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12
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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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13
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Almahasneh F, Abu-El-Rub E, Khasawneh RR. Mechanisms of analgesic effect of mesenchymal stem cells in osteoarthritis pain. World J Stem Cells 2023; 15:196-208. [PMID: 37181003 PMCID: PMC10173815 DOI: 10.4252/wjsc.v15.i4.196] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/25/2023] [Accepted: 03/27/2023] [Indexed: 04/26/2023] Open
Abstract
Osteoarthritis (OA) is the most common musculoskeletal disease, and it is a major cause of pain, disability and health burden. Pain is the most common and bothersome presentation of OA, but its treatment is still suboptimal, due to the short-term action of employed analgesics and their poor adverse effect profile. Due to their regenerative and anti-inflammatory properties, mesenchymal stem cells (MSCs) have been extensively investigated as a potential therapy for OA, and numerous preclinical and clinical studies found a significant improvement in joint pathology and function, pain scores and/or quality of life after administration of MSCs. Only a limited number of studies, however, addressed pain control as the primary end-point or investigated the potential mechanisms of analgesia induced by MSCs. In this paper, we review the evidence reported in literature that support the analgesic action of MSCs in OA, and we summarize the potential mechanisms of these antinociceptive effects.
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Affiliation(s)
- Fatimah Almahasneh
- Basic Medical Sciences, Faculty of Medicine -Yarmouk University, Irbid 21163, Jordan
| | - Ejlal Abu-El-Rub
- Basic Medical Sciences, Faculty of Medicine -Yarmouk University, Irbid 21163, Jordan.
| | - Ramada R Khasawneh
- Basic Medical Sciences, Faculty of Medicine -Yarmouk University, Irbid 21163, Jordan
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14
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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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15
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Householder NA, Raghuram A, Agyare K, Thipaphay S, Zumwalt M. A Review of Recent Innovations in Cartilage Regeneration Strategies for the Treatment of Primary Osteoarthritis of the Knee: Intra-articular Injections. Orthop J Sports Med 2023; 11:23259671231155950. [PMID: 37138944 PMCID: PMC10150434 DOI: 10.1177/23259671231155950] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 11/09/2022] [Indexed: 05/05/2023] Open
Abstract
Background The pathology of primary osteoarthritis (OA) begins with structural cartilage damage, which initiates a self-propagating inflammatory pathway that further exacerbates cartilage deterioration. Current standard of care for knee primary OA involves treating the inflammatory symptoms to manage pain, which includes intra-articular (IA) injections of cortisone, an anti-inflammatory steroid, followed by a series of joint-cushioning hyaluronic acid gel injections. However, these injections do not delay the progression of primary OA. More focus on the underlying cellular pathology of OA has prompted researchers to develop treatments targeting the biochemical mechanisms of cartilage degradation. Purpose Researchers have yet to develop a United States Food and Drug Administration (FDA)-approved injection that has been demonstrated to significantly regenerate damaged articular cartilage. This paper reviews the current research on experimental injections aimed at achieving cellular restoration of the hyaline cartilage tissue of the knee joint. Study Design Narrative review. Methods The authors conducted a narrative literature review examining studies on primary OA pathogenesis and a systematic review of non-FDA-approved IA injections for the treatment of primary OA of the knee, described as "disease-modifying osteoarthritis drugs" in phase 1, 2, and 3 clinical trials. Conclusion New treatment approaches for primary OA investigate the potential of genetic therapies to restore native cartilage. It is clear that the most promising IA injections that could improve treatment of primary OA are bioengineered advanced-delivery steroid-hydrogel preparations, ex vivo expanded allogeneic stem cell injections, genetically engineered chondrocyte injections, recombinant fibroblast growth factor therapy, injections of selective proteinase inhibitors, senolytic therapy via injections, injectable antioxidant therapies, injections of Wnt pathway inhibitors, injections of nuclear factor-kappa β inhibitors, injections of modified human angiopoietin-like-3, various potential viral vector-based genetic therapy approaches, and RNA genetic technology administered via injections.
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Affiliation(s)
| | - Akshay Raghuram
- School of Medicine, Texas Tech University
Health Sciences Center, Lubbock, Texas, USA
| | - Kofi Agyare
- School of Medicine, Texas Tech University
Health Sciences Center, Lubbock, Texas, USA
| | - Skyler Thipaphay
- School of Medicine, Texas Tech University
Health Sciences Center, Lubbock, Texas, USA
| | - Mimi Zumwalt
- School of Medicine, Texas Tech University
Health Sciences Center, Lubbock, Texas, USA
- Mimi Zumwalt, MD, Orthopaedics
Department, Texas Tech University Health Sciences Center, 3601 4th Street, Stop 9436,
Lubbock, TX 79430-9436, USA ()
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16
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He A, Liu Y, Sang S, Zhang R, Jiang Z, Mao Y, Liu W. Regulation of Chondrocyte Differentiation by miR-455-3p Secreted by Bone Marrow Stem Cells through Phosphatase and Tensin Homolog Deleted on Chromosome Ten/Phosphoinositide 3-Kinase-Protein Kinase B. Stem Cells Int 2023; 2023:6738768. [PMID: 36845968 PMCID: PMC9946738 DOI: 10.1155/2023/6738768] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/30/2022] [Accepted: 01/18/2023] [Indexed: 02/17/2023] Open
Abstract
The effects of the regulation of phosphatase and tensin homolog deleted on chromosome ten (PTEN) by microribonucleic acid- (miR-) 455-3p on bone marrow stem cells' (BMSCs') chondrogenic development were examined based on the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signal pathway. The alterations in miR-455-3p and PTEN were identified using osteoarthritis (OA) and healthy chondrocytes. Rats raised on the SD diet had their BMSCs isolated for chondrocyte-induced differentiation (blank group), transfected miR-455-3p mimic (mimic group), and inhibitor (inhibitor group). Besides, cell proliferation, alizarin red mineralization staining, and the activity of alkaline phosphatase (ALP) were detected. Real-time fluorescent quantitation polymerase chain reaction (PCR) and Western blot were utilized to detect Runx2, OPN, OSX, COL2A1 mRNA, and the difference between PI3K and AKT. Dual-luciferase reporter (DLR) genes were selected to analyze the target relationship of miR-455-3p to PTEN. It was demonstrated that miR-455-3p in OA was downregulated, while PTEN was upregulated (P < 0.05) in comparison to healthy chondrocytes (P < 0.05). Versus those in the blank group, alizarin red mineralization staining and the activity of ALP increased; RUNX, OPN, OSX, COL2A1 mRNA, p-PI3K, and p-AKT were elevated in the mimic group (P < 0.05). Versus those in the blank and mimic groups, alizarin red mineralization staining and the activity of ALP reduced; RUNX, OPN, OSX, COL2A1 mRNA, p-PI3K, and p-AKT were downregulated in the inhibitor group (P < 0.05). miR-455-3p could target PTEN to inhibit its expression, thus activating the PI3K/AKT signal pathway and promoting BMSCs chondrocyte-induced differentiation. The research results provided reference for the occurrence of OA and the study on therapeutic target.
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Affiliation(s)
- Axiang He
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 201306, China
| | - Yaru Liu
- Department of Food Science and Engineering, Shanghai Ocean University, Shanghai 201306, China
| | - Shang Sang
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 201306, China
| | - Renbo Zhang
- Department of Food Science and Engineering, Shanghai Ocean University, Shanghai 201306, China
| | - Zheng Jiang
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 201306, China
| | - Yanjie Mao
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 201306, China
| | - Wanjun Liu
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 201306, China
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Muthu S, Patil SC, Jeyaraman N, Jeyaraman M, Gangadaran P, Rajendran RL, Oh EJ, Khanna M, Chung HY, Ahn BC. Comparative effectiveness of adipose-derived mesenchymal stromal cells in the management of knee osteoarthritis: A meta-analysis. World J Orthop 2023; 14:23-41. [PMID: 36686284 PMCID: PMC9850793 DOI: 10.5312/wjo.v14.i1.23] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 10/20/2022] [Accepted: 12/13/2022] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Osteoarthritis (OA) is the most common joint disorder, is associated with an increasing socioeconomic impact owing to the ageing population. AIM To analyze and compare the efficacy and safety of bone-marrow-derived mesenchymal stromal cells (BM-MSCs) and adipose tissue-derived MSCs (AD-MSCs) in knee OA management from published randomized controlled trials (RCTs). METHODS Independent and duplicate electronic database searches were performed, including PubMed, EMBASE, Web of Science, and Cochrane Library, until August 2021 for RCTs that analyzed the efficacy and safety of AD-MSCs and BM-MSCs in the management of knee OA. The visual analog scale (VAS) score for pain, Western Ontario McMaster Universities Osteoarthritis Index (WOMAC), Lysholm score, Tegner score, magnetic resonance observation of cartilage repair tissue score, knee osteoarthritis outcome score (KOOS), and adverse events were analyzed. Analysis was performed on the R-platform using OpenMeta (Analyst) software. Twenty-one studies, involving 936 patients, were included. Only one study compared the two MSC sources without patient randomization; hence, the results of all included studies from both sources were pooled, and a comparative critical analysis was performed. RESULTS At six months, both AD-MSCs and BM-MSCs showed significant VAS improvement (P = 0.015, P = 0.012); this was inconsistent at 1 year for BM-MSCs (P < 0.001, P = 0.539), and AD-MSCs outperformed BM-MSCs compared to controls in measures such as WOMAC (P < 0.001, P = 0.541), Lysholm scores (P = 0.006; P = 0.933), and KOOS (P = 0.002; P = 0.012). BM-MSC-related procedures caused significant adverse events (P = 0.003) compared to AD-MSCs (P = 0.673). CONCLUSION Adipose tissue is superior to bone marrow because of its safety and consistent efficacy in improving pain and functional outcomes. Future trials are urgently warranted to validate our findings and reach a consensus on the ideal source of MSCs for managing knee OA.
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Affiliation(s)
- Sathish Muthu
- Department of Orthopaedics, Government Medical College and Hospital, Dindigul 624001, Tamil Nadu, India
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida 201310, Uttar Pradesh, India
- Research Associate, Orthopaedic Research Group, Coimbatore 641045, Tamil Nadu, India
- Indian Stem Cell Study Group Association, Lucknow 226001, Uttar Pradesh, India
| | - Sandesh C Patil
- Department of Orthopaedic Rheumatology, Dr. RML National Law University, Lucknow 226012, Uttar Pradesh, India
| | - Naveen Jeyaraman
- Indian Stem Cell Study Group Association, Lucknow 226001, Uttar Pradesh, India
- Department of Orthopaedic Rheumatology, Dr. RML National Law University, Lucknow 226012, Uttar Pradesh, India
| | - Madhan Jeyaraman
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida 201310, Uttar Pradesh, India
- Research Associate, Orthopaedic Research Group, Coimbatore 641045, Tamil Nadu, India
- Indian Stem Cell Study Group Association, Lucknow 226001, Uttar Pradesh, India
- Department of Orthopaedics, ACS Medical College & Hospital, Dr MGR Educational and Research Institute, Chennai 600056, Tamil Nadu, India
| | - Prakash Gangadaran
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu 41944, South Korea
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, South Korea
| | - Ramya Lakshmi Rajendran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, South Korea
| | - Eun Jung Oh
- Department of Plastic and Reconstructive Surgery, CMRI, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, South Korea
| | - Manish Khanna
- Indian Stem Cell Study Group Association, Lucknow 226001, Uttar Pradesh, India
| | - Ho Yun Chung
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu 41944, South Korea
- Department of Plastic and Reconstructive Surgery, CMRI, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, South Korea
- Department of Plastic and Reconstructive Surgery, School of Medicine, Kyungpook National University, Daegu 41944, South Korea
| | - Byeong-Cheol Ahn
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu 41944, South Korea
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, South Korea
- Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu 41944, South Korea
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Song X, Gu L, Yang Q, Wu J, Chen J, Tian X, Sun L, Chen L. Thermosensitive injectable hydrogel loaded with hypoxia-induced exosomes maintains chondrocyte phenotype through NDRG3-mediated hypoxic response. CHINESE CHEM LETT 2022. [DOI: 10.1016/j.cclet.2022.108079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Jeyaraman M, Muthu S, Nischith DS, Jeyaraman N, Nallakumarasamy A, Khanna M. PRISMA-Compliant Meta-Analysis of Randomized Controlled Trials on Osteoarthritis of Knee Managed with Allogeneic vs Autologous MSCs: Efficacy and Safety Analysis. Indian J Orthop 2022; 56:2042-2059. [PMID: 36507199 PMCID: PMC9705690 DOI: 10.1007/s43465-022-00751-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 09/06/2022] [Indexed: 02/08/2023]
Abstract
STUDY DESIGN Meta-analysis. OBJECTIVES Our objective is to review the randomized controlled trials (RCTs) that have been conducted previously on the topic of osteoarthritis of the knee to assess and compare the efficacy and safety of autologous and allogeneic sources of mesenchymal stromal cells (MSCs) in the treatment of osteoarthritis. MATERIALS AND METHODS We searched the electronic databases PubMed, Embase, Web of Science, and the Cochrane Library until August 2021 for randomised controlled trials (RCTs) analysing the efficacy and safety of autologous and allogeneic sources of MSCs in the management of knee osteoarthritis. These searches were conducted independently and in duplicate. The outcomes that were taken into consideration for analysis were the visual analogue score (VAS) for pain, the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC), the Lysholm score, and adverse events. The OpenMeta [Analyst] software was utilised to carry out the analysis in the R platform. RESULTS In total, 21 studies with a total of 936 patients were considered for this analysis. Because none of the studies made a direct comparison of the autologous and allogeneic sources of MSCs, we pooled the results of all of the included studies of both sources and made a comparative analysis of how the two types of MSCs fared in their respective applications. Although both allogeneic and autologous sources of MSCs demonstrated significantly better VAS improvement after 6 months (p = 0.006, p = 0.001), this trend was not maintained after 1 year for the allogeneic source (p = 0.171, p = 0.027). When compared to their respective controls based on WOMAC scores after 1 year, autologous sources (p = 0.016) of MSCs performed better than allogeneic sources (p = 0.186).A similar response was noted between the sources at 2 years in their Lysholm scores (p = 0.682, p = 0.017), respectively. Moreover, allogeneic sources (p = 0.039) of MSCs produced significant adverse events than autologous sources (p = 0.556) compared to their controls. CONCLUSION Our analysis of literature showed that autologous sources of MSCs stand superior to allogeneic sources of MSC with regard to their consistent efficacy for pain, functional outcomes, and safety. However, we strongly recommend that further studies be conducted that are of a high enough quality to validate our findings and reach a consensus on the best source of MSCs for use in cellular therapy treatments for knee osteoarthritis. SUPPLEMENTARY INFORMATION The online version contains supplementary material available at 10.1007/s43465-022-00751-z.
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Affiliation(s)
- Madhan Jeyaraman
- Department of Orthopaedics, Faculty of Medicine, Sri Lalithambigai Medical College and Hospital, Dr. MGR Educational and Research Institute, Chennai, Tamil Nadu India
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Uttar Pradesh, Greater Noida, India
- Indian Stem Cell Study Group (ISCSG) Association, Uttar Pradesh, Lucknow, India
| | - Sathish Muthu
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Uttar Pradesh, Greater Noida, India
- Indian Stem Cell Study Group (ISCSG) Association, Uttar Pradesh, Lucknow, India
- Department of Orthopaedics, Government Medical College and Hospital, Dindigul, Tamil Nadu India
| | - D. S. Nischith
- Indian Stem Cell Study Group (ISCSG) Association, Uttar Pradesh, Lucknow, India
- Fellow in Orthopaedic Rheumatology, Dr. RML National Law University, Uttar Pradesh, Lucknow, India
| | - Naveen Jeyaraman
- Indian Stem Cell Study Group (ISCSG) Association, Uttar Pradesh, Lucknow, India
- Fellow in Orthopaedic Rheumatology, Dr. RML National Law University, Uttar Pradesh, Lucknow, India
- Fellow in Joint Replacement, Atlas Hospitals, Tiruchirappalli, Tamil Nadu India
| | - Arulkumar Nallakumarasamy
- Indian Stem Cell Study Group (ISCSG) Association, Uttar Pradesh, Lucknow, India
- Fellow in Orthopaedic Rheumatology, Dr. RML National Law University, Uttar Pradesh, Lucknow, India
- Department of Orthopaedics, All India Institute of Medical Sciences, Bhubaneswar, Odisha India
| | - Manish Khanna
- Indian Stem Cell Study Group (ISCSG) Association, Uttar Pradesh, Lucknow, India
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Zhang Y, Yang H, He F, Zhu X. Intra-articular injection choice for osteoarthritis: making sense of cell source-an updated systematic review and dual network meta-analysis. Arthritis Res Ther 2022; 24:260. [PMID: 36443838 PMCID: PMC9703652 DOI: 10.1186/s13075-022-02953-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 11/10/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Intra-articular injection is indicated for mild or moderate osteoarthritis (OA). However, the superiority of cell-based injection and the role of diverse cell sources are still unclear. This study aimed to compare the therapeutic effect of intra-articular injection with mesenchymal stem cells (MSCs) and cell-free methods for OA treatment. METHODS A literature search of published scientific data was carried out from PubMed, MEDLINE, Embase, Cochrane Library, Web of Science, and China National Knowledge Internet (CNKI). Randomized controlled trials (RCTs) compared the efficacy and safety of MSC and cell-free intra-articular injection treatments for OA with at least 6-month follow-up. RESULTS Dual network meta-analysis validated the therapeutic advantages of MSC treatments (VAS, Bayesian: 90% versus 10% and SUCRA: 94.9% versus 5.1%; WOMAC total, Bayesian: 83% versus 17% and SUCRA: 90.1% versus 9.9%) but also suggested a potential negative safety induced by cell injection (adverse events, Bayesian: 100% versus 0% and SUCRA: 98.2% versus 1.8%). For the MSC source aspect, adipose mesenchymal stem cells (ADMSCs) and umbilical cord mesenchymal stem cells (UBMSCs) showed a better curative effect on pain relief and function improvement compared with bone marrow mesenchymal stem cells (BMMSCs). CONCLUSION Intra-articular injection of MSCs is associated with more effective pain alleviation and function improvement than cell-free OA treatment. However, the potential complications induced by MSCs should be emphasized. A comparative analysis of the MSC sources showed that ADMSCs and UBMSCs exerted a better anti-arthritic efficacy than BMMSCs. Schematic illustration of MSC-based intra-articular injection for treating OA. Three major MSCs (UBMSCs, ADMSCs, and BMMSCs) are extracted and expanded in vitro. Subsequently, the amplified MSCs are concentrated and injected into the knee joint to treat OA.
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Affiliation(s)
- Yijian Zhang
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Soochow University, No. 899 Pinghai Road, Suzhou, 215006, China
- Orthopaedic Institute, Medical College, Soochow University, No. 708 Renmin Road, Suzhou, 215007, China
| | - Huilin Yang
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Soochow University, No. 899 Pinghai Road, Suzhou, 215006, China.
- Orthopaedic Institute, Medical College, Soochow University, No. 708 Renmin Road, Suzhou, 215007, China.
| | - Fan He
- Orthopaedic Institute, Medical College, Soochow University, No. 708 Renmin Road, Suzhou, 215007, China.
| | - Xuesong Zhu
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Soochow University, No. 899 Pinghai Road, Suzhou, 215006, China.
- Orthopaedic Institute, Medical College, Soochow University, No. 708 Renmin Road, Suzhou, 215007, China.
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Liu A, Yu W, Chen J, Guo T, Niu P, Feng H, Jia Y. Methodological Quality and Risk of Bias of Systematic Reviews and Meta-Analyses on Stem Cells for Knee Osteoarthritis: A Cross-Sectional Survey. Stem Cells Dev 2022; 31:431-444. [PMID: 35316077 DOI: 10.1089/scd.2022.0060] [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: 11/12/2022] Open
Abstract
Clinical guidelines need high-quality studies to support clinical decision making, in which the evidence often was collected from systematic reviews (SRs) and/or meta-analyses (MAs). At present, the methodological quality and risk of bias (RoB) of SRs/MAs on stem cell therapy for the treatment of knee osteoarthritis (KOA) has been poorly investigated. This study aims to strictly evaluate the methodological quality and RoB in SRs/MAs of stem cell therapy for KOA. Four electronic databases (PubMed, Embase, Cochrane Library, and Web of Science databases) were searched, from inception to October 5, 2021. SRs/MAs involving randomized control trials or cohort studies on stem cell therapy for the treatment of KOA were included. The methodological quality and RoB were assessed using AMSTAR 2 and ROBIS tool, respectively. In total, 22 SRs/MAs were included. According to the results obtained by AMSTAR 2 tool, all SRs/MAs were rated as "Critically low." Main methodological weaknesses were as follows: up to 81.82% did not meet protocol registration requirements, only 13.64% provided a list of excluded studies and justification, and 13.64% investigated and discussed the publication bias. ROBIS-based RoB assessment showed that all the SRs/MAs were rated as "High." Besides, the lack of following the implementation of the PRISMA reporting guideline seems to reduce the methodological quality of the studies. The overall methodological quality of the SRs/MAs concerning the application of stem cell therapy in treating KOA is "Critically low," while the RoB is high. It is difficult to provide effective evidence for the formulation of guidelines for KOA treatment. We suggest that the relevant methodological quality assessment should be carried out in the future before the SRs/MAs are used as clinical evidence. In addition, it may be necessary for many journals to include the checklist with a submitted article. PROSPERO registration number: CRD42021246924.
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Affiliation(s)
- Aifeng Liu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Weijie Yu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Jixin Chen
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Tianci Guo
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Puyu Niu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Huichuan Feng
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yizhen Jia
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
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One of the Primary Functions of Tissue-Resident Pluripotent Pericytes Cells May Be to Regulate Normal Organ Growth and Maturation: Implications for Attempts to Repair Tissues Later in Life. Int J Mol Sci 2022; 23:ijms23105496. [PMID: 35628309 PMCID: PMC9146368 DOI: 10.3390/ijms23105496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/10/2022] [Accepted: 05/12/2022] [Indexed: 12/04/2022] Open
Abstract
Adult mesenchymal stem cells were reported more than 30 years ago. Since then, their potential to repair and regenerate damaged or diseased tissues has been studied intensively in both preclinical models and human trials. Most of the need for such tissue repair/regeneration is in older populations, so much of the effort has been performed with autologous cells in older patients. However, success has been difficult to achieve. In the literature, it has been noted that such progenitor cells from younger individuals often behave with more vigorous activity and are functionally enhanced compared to those from older individuals or animals. In addition, cells with the characteristics of mesenchymal stem cells or pluripotent mesenchymal regulatory cells exist in nearly all tissues and organs as pericytes since fetal life. Such evidence raises the possibility that one of the primary roles of these organ-specific cells is to regulate organ growth and maturation, and then subsequently play a role in the maintenance of organ integrity. This review will discuss the evidence to support this concept and the implications of such a concept regarding the use of these progenitor cells for the repair and regeneration of tissues damaged by injury or disease later in life. For the latter, it may be necessary to return the organ-specific progenitor cells to the functional state that contributed to their effectiveness during growth and maturation rather than attempting to use them after alterations imposed during the aging process have been established and their function compromised.
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Bolia IK, Bougioukli S, Hill WJ, Trasolini NA, Petrigliano FA, Lieberman JR, Weber AE. Clinical Efficacy of Bone Marrow Aspirate Concentrate Versus Stromal Vascular Fraction Injection in Patients With Knee Osteoarthritis: A Systematic Review and Meta-analysis. Am J Sports Med 2022; 50:1451-1461. [PMID: 34102078 DOI: 10.1177/03635465211014500] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Knee injection using either bone marrow aspirate concentrate (BMAC) or stromal vascular fraction (SVF) from adipose tissue has been shown to result in symptomatic improvement in patients with knee osteoarthritis (OA). It is still unclear whether one of these therapies is superior over the other. PURPOSE To systematically report the clinical studies evaluating BMAC and SVF in the treatment of knee OA and to compare the clinical efficacy of these 2 injection therapies. STUDY DESIGN Meta-analysis; Level of evidence, 4. METHODS This meta-analysis was performed per the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines. Studies were included if they reported the clinical outcomes after a single BMAC or SVF injection in the knee joint of patients with OA. Studies evaluating preparations of culture-expanded stem cells were excluded. A random effects model was used; the clinical efficacy of BMAC or SVF injection was assessed using the standardized mean difference (SMD) and compared. Visual analog scale (VAS) scores for pain and Western Ontario and McMaster Universities Osteoarthritis (WOMAC) knee index were the primary outcomes. The level of statistical significance was set at P < .05. RESULTS Ten studies and 472 patients with knee OA who received either BMAC (233 patients) or SVF (239 patients) were included. Patients who received an injection had improved VAS outcomes (mean ± SD): from 5.8 ± 1.3 to 2.6 ± 17 for BMAC and from 6.4 ± 1.4 to 3.4 ± 0.5 for SVF. They also experienced significantly reduced pain (SMD [VAS], 2.6 for BMAC and 3.4 for SVF) and improved function (SMD [WOMAC], 1.4 for BMAC and 1.2 for SVF). However, the SVF injection had a significantly greater effect on pain reduction than did the BMAC injection (P < .0001). Based on WOMAC, the clinical effect of BMAC versus SVF knee injection in patients with knee OA was equivalent (P = .626). Results were limited by the presence of publication bias as well as variability in the preparation methods utilized in the BMAC and SVF injection protocols. Complications were reported in 50% of the BMAC studies (knee stiffness, persistent knee swelling) and 67% of the SVF studies (knee swelling, knee pain, positive SVF cultures without symptoms of infection, and bleeding at the abdominal harvest site). CONCLUSION A single BMAC or SVF injection into the knee joint of patients with OA resulted in symptomatic improvement at short-term follow-up. However, SVF seemed to be more effective than did BMAC in the reduction of knee pain. There was significant variation in the BMAC and SVF injection preparation techniques used across the studies and a lack of stratification of outcomes based on the radiologic classification of OA. Therefore, these results should be taken with caution.
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Affiliation(s)
- Ioanna K Bolia
- USC Epstein Family Center for Sports Medicine at Keck Medicine of USC, Los Angeles, California, USA
| | - Sofia Bougioukli
- USC Epstein Family Center for Sports Medicine at Keck Medicine of USC, Los Angeles, California, USA
| | - William J Hill
- USC Epstein Family Center for Sports Medicine at Keck Medicine of USC, Los Angeles, California, USA
| | - Nicholas A Trasolini
- USC Epstein Family Center for Sports Medicine at Keck Medicine of USC, Los Angeles, California, USA
| | - Frank A Petrigliano
- USC Epstein Family Center for Sports Medicine at Keck Medicine of USC, Los Angeles, California, USA
| | - Jay R Lieberman
- USC Epstein Family Center for Sports Medicine at Keck Medicine of USC, Los Angeles, California, USA
| | - Alexander E Weber
- USC Epstein Family Center for Sports Medicine at Keck Medicine of USC, Los Angeles, California, USA
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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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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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Muthu S, Mir AA, Kumar R, Yadav V, Jeyaraman M, Khanna M. What is the clinically significant ideal mesenchymal stromal cell count in the management of osteoarthritis of the knee? - Meta-analysis of randomized controlled trials. J Clin Orthop Trauma 2022; 25:101744. [PMID: 35004170 PMCID: PMC8719017 DOI: 10.1016/j.jcot.2021.101744] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 12/17/2021] [Indexed: 02/08/2023] Open
Abstract
STUDY DESIGN Meta-analysis. OBJECTIVES We aim to identify the clinically significant ideal Mesenchymal Stem Cell (MSC) count in the management of osteoarthritis of knee from Randomized Controlled Trials (RCTs) available in the literature. MATERIALS AND METHODS We conducted independent and duplicate electronic database searches including PubMed, Embase, Web of Science, and Cochrane Library till August 2021 for RCTs conducted in the management of knee osteoarthritis using MSC therapy specifying the quantity of MSCs delivered. We categorized the studies based on the MSC count utilized in them into four groups namely <1 × 107 MSCs (Group I), 1-5x107 MSCs (Group II), 5-10 × 107 MSCs (Group III), and >10 × 107 MSCs (Group IV). Visual Analog Score (VAS) for Pain, Western Ontario McMaster Universities Osteoarthritis Index (WOMAC), Lysholm score, Knee Osteoarthritis Outcome Score (KOOS), and adverse events were the outcomes analyzed. Analysis was performed in R-platform using OpenMeta [Analyst] software. RESULTS 14 studies involving 564 patients were included for analysis. We noted incremental decrease in the VAS with increasing dosage of MSCs at 12 months [Group I,WMD = 2.641(p = 0.854); Group II, WMD = -4.853(p = 0.379); Group III, WMD = -12.154 (p = 0.316); Group IV, WMD = -15.935(p = 0.116)], and 24 months [Group I,WMD = -6(p = 0.001); Group II, WMD = -15(p = 0.001); Group IV, WMD = -20(p = 0.001)]. We also noted incremental improvement in the WOMAC, KOOS with increasing dosage of MSCs at 12 months [Group I, WMD = 7(p = 0.001); Group II, WMD = 28(p = 0.001); Group IV, WMD = 30(p = 0.001)] and [Group II, WMD = -2.562(p = 0.676); Group III, WMD = 7.670(p = 0.099); Group IV, WMD = 13.475(p = 0.261)] respectively. However, we noted significant reduction in the Lysholm score in Group IV, compared to the others at 12 months (WMD = -12.5, 95%CI[-25.883,0.883]) and 24 months (WMD = -6.6, 95%CI[-23.596,10.396]). We did not find any significant increase in the adverse events with incremental dosage of MSCs in any of the groups compared. CONCLUSION Compared to the four dosage groups of MSCs analyzed, Group III showed consistent significant improvement in pain and functional outcomes analyzed compared to the other groups. Hence, we recommend a cell volume of 5-10 × 107 cells to be delivered to the target site to obtain superior benefits out of the procedure. However, we urge future trials of sufficient quality to validate our findings to arrive at a consensus on the ideal count of MSCs to be delivered in the cellular therapy for knee osteoarthritis.
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Affiliation(s)
- Sathish Muthu
- Department of Orthopaedics, Government Medical College and Hospital, Dindigul, Tamil Nadu, India
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, India
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, India
| | - Ayaz Ali Mir
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, India
- Fellow in Orthopaedic Rheumatology, Dr. RML National Law University, Lucknow, Uttar Pradesh, India
| | - Rakesh Kumar
- Department of Orthopaedics, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Vijendra Yadav
- Department of Orthopaedics, Sanjay Gandhi Institute of Trauma & Orthopaedics, Bengaluru, Karnataka, India
| | - Madhan Jeyaraman
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, India
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, India
- Department of Orthopaedics, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Manish Khanna
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, India
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Jeyaraman M, Shivaraj B, Bingi SK, Ranjan R, Muthu S, Khanna M. Does vehicle-based delivery of mesenchymal stromal cells give superior results in knee osteoarthritis? Meta-analysis of randomized controlled trials. J Clin Orthop Trauma 2022; 25:101772. [PMID: 35127439 PMCID: PMC8803619 DOI: 10.1016/j.jcot.2022.101772] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 01/06/2022] [Accepted: 01/13/2022] [Indexed: 02/08/2023] Open
Abstract
STUDY DESIGN Meta-analysis. OBJECTIVES We aim to analyze and compare the efficacy and safety of vehicle-based delivery of Mesenchymal Stromal Cells (MSCs) in the management of osteoarthritis of the knee from Randomized Controlled Trials (RCTs) available in the literature. MATERIALS AND METHODS We conducted independent and duplicate electronic database searches including PubMed, Embase, Web of Science, and Cochrane Library till August 2021 for RCTs analyzing the efficacy and safety of vehicle-based delivery of MSCs in the management of knee osteoarthritis. Visual Analog Score (VAS) for Pain, Western Ontario McMaster Universities Osteoarthritis Index (WOMAC), Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score, and adverse events were the outcomes analyzed. Analysis was performed in R-platform using OpenMeta [Analyst] software. RESULTS 21 studies involving 936 patients were included for analysis. None of the studies made a direct comparison of the direct and vehicle-based delivery of MSCs, hence we pooled the results of all the included studies of both groups and made a comparative analysis of their outcomes. Although at 6 months, both direct and vehicle-based delivery of MSCs showed significantly better VAS improvement (p = 0.002, p = 0.010), it was not consistent at 1 year for the vehicle delivery (p = 0.973). During 6 months and 12 months, direct delivery of MSCs (p < 0.001, p < 0.001) outperformed vehicle delivery (p = 0.969, p = 0.922) compared to their control based on WOMAC scores respectively. Both direct (p = 0.713) and vehicle-based delivery (p = 0.123) of MSCs did not produce significant adverse events compared to their controls. CONCLUSION Our analysis of literature showed that current clinically employed methods of vehicle-based delivery of MSCs such as platelet-rich plasma, hyaluronic acid did not demonstrate superior results compared to direct delivery, concerning the efficacy of treatment measured by improvement in pain, functional outcomes, and safety. Hence, we urge future clinical trials to be conducted to validate the effectiveness of advanced delivery vehicles such as composite bioscaffolds to establish their practical utility in cartilage regeneration with respect to its encouraging in-vitro evidence.
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Affiliation(s)
- Madhan Jeyaraman
- Department of Orthopaedics, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, India
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, India
| | - B. Shivaraj
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, India
- Dr. RML National Law University, Lucknow, Uttar Pradesh, India
| | - Shiva Kumar Bingi
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, India
- Dr. RML National Law University, Lucknow, Uttar Pradesh, India
| | - Rajni Ranjan
- Department of Orthopaedics, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Sathish Muthu
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, India
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, India
- Department of Orthopaedics, Government Medical College and Hospital, Dindigul, Tamil Nadu, India
| | - Manish Khanna
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, India
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Jeyaraman M, Bingi SK, Muthu S, Jeyaraman N, Packkyarathinam RP, Ranjan R, Sharma S, Jha SK, Khanna M, Rajendran SNS, Rajendran RL, Gangadaran P. Impact of the Process Variables on the Yield of Mesenchymal Stromal Cells from Bone Marrow Aspirate Concentrate. Bioengineering (Basel) 2022; 9:57. [PMID: 35200410 PMCID: PMC8869489 DOI: 10.3390/bioengineering9020057] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/18/2022] [Accepted: 01/20/2022] [Indexed: 02/07/2023] Open
Abstract
Human bone marrow (BM) has been highlighted as a promising source of mesenchymal stromal cells (MSCs) containing various growth factors and cytokines that can be potentially utilized in regenerative procedures involving cartilage and bone. However, the proportion of MSCs in the nucleated cell population of BM is only around 0.001% to 0.01% thereby making the harvesting and processing technique crucial for obtaining optimal results upon its use in various regenerative processes. Although several studies in the literature have given encouraging results on the utility of BM aspiration concentrate (BMAC) in various regenerative procedures, there is a lack of consensus concerning the harvesting variables such as choice of anesthetic agent to be used, site of harvest, size of the syringe to be used, anticoagulant of choice, and processing variables such as centrifugation time, and speed. In this review article, we aim to discuss the variables in the harvesting and processing technique of BMAC and their impact on the yield of MSCs in the final concentrate obtained from them.
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Affiliation(s)
- Madhan Jeyaraman
- Department of Orthopaedics, Faculty of Medicine, Sri Lalithambigai Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai 600095, India;
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida 201310, India;
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, India; (S.K.B.); (M.K.)
| | - Shiva Kumar Bingi
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, India; (S.K.B.); (M.K.)
- Fellow in Orthopaedic Rheumatology, Dr. RML National Law University, Lucknow 226010, India
| | - Sathish Muthu
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida 201310, India;
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, India; (S.K.B.); (M.K.)
- Department of Orthopaedics, Government Medical College and Hospital, Dindigul 624304, India
| | - Naveen Jeyaraman
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, India; (S.K.B.); (M.K.)
- Fellow in Orthopaedic Rheumatology, Dr. RML National Law University, Lucknow 226010, India
- Fellow in Joint Replacement, Department of Orthopaedics, Atlas Hospitals, Tiruchirappalli 620002, India
| | | | - Rajni Ranjan
- Department of Orthopaedics, School of Medical Sciences and Research, Sharda University, Greater Noida 201310, India;
| | - Shilpa Sharma
- Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi 110029, India;
| | - Saurabh Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida 201310, India;
| | - Manish Khanna
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, India; (S.K.B.); (M.K.)
- Department of Orthopaedics, Prasad Institute of Medical Sciences, Lucknow 226401, India
| | - Sree Naga Sowndary Rajendran
- Department of Medicine, Sri Venkateshwaraa Medical College Hospital and Research Centre, Puducherry 605102, India;
| | - Ramya Lakshmi Rajendran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Korea;
| | - Prakash Gangadaran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Korea;
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu 41944, Korea
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Wu H, Peng Z, Xu Y, Sheng Z, Liu Y, Liao Y, Wang Y, Wen Y, Yi J, Xie C, Chen X, Hu J, Yan B, Wang H, Yao X, Fu W, Ouyang H. Engineered adipose-derived stem cells with IGF-1-modified mRNA ameliorates osteoarthritis development. Stem Cell Res Ther 2022; 13:19. [PMID: 35033199 PMCID: PMC8760691 DOI: 10.1186/s13287-021-02695-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 09/20/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Osteoarthritis (OA), a prevalent degenerative disease characterized by degradation of extracellular matrix (ECM), still lacks effective disease-modifying therapy. Mesenchymal stem cells (MSCs) transplantation has been regarded as the most promising approach for OA treatment while engrafting cells alone might not be adequate for effective regeneration. Genetic modification has been used to optimize MSC-based therapy; however, there are still significant limitations that prevent the clinical translation of this therapy including low efficacy and safety concerns. Recently, chemically modified mRNA (modRNA) represents a promising alternative for the gene-enhanced MSC therapy. In this regard, we hypothesized that adipose derived stem cells (ADSCs) engineered with modRNA encoding insulin-like growth factor 1 (IGF-1) were superior to native ADSCs on ameliorating OA development. METHODS Mouse ADSCs were acquired from adipose tissue and transfected with modRNAs. First, the kinetics and efficacy of modRNA-mediated gene transfer in mouse ADSCs were analyzed in vitro. Next, we applied an indirect co-culture system to analyze the pro-anabolic potential of IGF-1 modRNA engineered ADSCs (named as IGF-1-ADSCs) on chondrocytes. Finally, we evaluated the cell retention and chondroprotective effect of IGF-1-ADSCs in vivo using fluorescent labeling, histology and immunohistochemistry. RESULTS modRNA transfected mouse ADSCs with high efficiency (85 ± 5%) and the IGF-1 modRNA-transfected ADSCs facilitated burst-like production of bio-functional IGF-1 protein. In vitro, IGF-1-ADSCs induced increased anabolic markers expression of chondrocytes in inflammation environment compared to untreated ADSCs. In a murine OA model, histological and immunohistochemical analysis of knee joints harvested at 4 weeks and 8 weeks after OA induction suggested IGF-1-ADSCs had superior therapeutic effect over native ADSCs demonstrated by lower histological OARSI score and decreased loss of cartilage ECM. CONCLUSIONS These findings collectively supported the therapeutic potential of IGF-1-ADSCs for clinical OA management and cartilage repair.
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Affiliation(s)
- Haoyu Wu
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.,Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhi Peng
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.,Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Ying Xu
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.,Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Zixuan Sheng
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.,Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Yanshan Liu
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.,Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Youguo Liao
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.,Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Yin Wang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.,Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Ya Wen
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.,Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Junzhi Yi
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.,Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Chang Xie
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.,Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Xuri Chen
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.,Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiajie Hu
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.,Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Bingqian Yan
- Institute of Pediatric Translational Medicine, Department of Pediatric Cardiothoracic Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 310003, China
| | - Huijing Wang
- Institute of Pediatric Translational Medicine, Department of Pediatric Cardiothoracic Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 310003, China
| | - Xudong Yao
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.,Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Wei Fu
- Institute of Pediatric Translational Medicine, Department of Pediatric Cardiothoracic Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 310003, China.
| | - Hongwei Ouyang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China. .,Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, China. .,Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China. .,China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, 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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Muthu S, Kartheek RR, Jeyaraman N, Rajendran RL, Khanna M, Jeyaraman M, Packkyarathinam RP, Gangadaran P, Ahn BC. Is Culture Expansion Necessary in Autologous Mesenchymal Stromal Cell Therapy to Obtain Superior Results in the Management of Knee Osteoarthritis?-Meta-Analysis of Randomized Controlled Trials. Bioengineering (Basel) 2021; 8:220. [PMID: 34940373 PMCID: PMC8698637 DOI: 10.3390/bioengineering8120220] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/10/2021] [Accepted: 12/15/2021] [Indexed: 02/05/2023] Open
Abstract
Study Design: Meta-analysis. Objectives: We aimed to analyze the impact of cultured expansion of autologous mesenchymal stromal cells (MSCs) in the management of osteoarthritis of the knee from randomized controlled trials (RCTs) available in the literature. Materials and Methods: We conducted independent and duplicate electronic database searches including PubMed, Embase, Web of Science, and Cochrane Library until August 2021 for RCTs analyzing the efficacy and safety of culture-expanded compared to non-cultured autologous MSCs in the management of knee osteoarthritis. The Visual Analog Score (VAS) for pain, Western Ontario McMaster University's Osteoarthritis Index (WOMAC), Lysholm score, Knee Osteoarthritis Outcome Score (KOOS), and adverse events were the analyzed outcomes. Analysis was performed in R-platform using OpenMeta [Analyst] software. Results: Overall, 17 studies involving 767 patients were included for analysis. None of the studies made a direct comparison of the culture expanded and non-cultured MSCs, hence we pooled the results of all the included studies of non-cultured and cultured types of MSC sources and made a comparative analysis of the outcomes. At six months, culture expanded MSCs showed significantly better improvement (p < 0.001) in VAS outcome. Uncultured MSCs, on the other hand, demonstrated significant VAS improvement in the long term (12 months) in VAS (p < 0.001), WOMAC (p = 0.025), KOOS score (p = 0.016) where cultured-expanded MSCs failed to demonstrate a significant change. Culturing of MSCs did not significantly increase the complications noted (p = 0.485). On sub-group analysis, adipose-derived uncultured MSCs outperformed culture-expanded MSCs at both short term (six months) and long term (12 months) in functional outcome parameters such as WOMAC (p < 0.001, p = 0.025), Lysholm (p < 0.006), and KOOS (p < 0.003) scores, respectively, compared to their controls. Conclusions: We identified a void in literature evaluating the impact of culture expansion of MSCs for use in knee osteoarthritis. Our indirect analysis of literature showed that culture expansion of autologous MSCs is not a necessary factor to obtain superior results in the management of knee osteoarthritis. Moreover, while using uncultured autologous MSCs, we recommend MSCs of adipose origin to obtain superior functional outcomes. However, we urge future trials of sufficient quality to validate our findings to arrive at a consensus on the need for culture expansion of MSCs for use in cellular therapy of knee osteoarthritis.
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Affiliation(s)
- Sathish Muthu
- Department of Orthopaedics, Government Medical College and Hospital, Dindigul 624001, Tamil Nadu, India;
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida 201310, Uttar Pradesh, India
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India; (R.R.K.); (N.J.); (M.K.)
| | - Randhi Rama Kartheek
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India; (R.R.K.); (N.J.); (M.K.)
- Fellow in Orthopaedic Rheumatology, Dr. RML National Law University, Lucknow 226010, Uttar Pradesh, India
| | - Naveen Jeyaraman
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India; (R.R.K.); (N.J.); (M.K.)
- Fellow in Orthopaedic Rheumatology, Dr. RML National Law University, Lucknow 226010, Uttar Pradesh, India
- Department of Orthopaedics, Atlas Hospitals, Tiruchirappalli 620002, Tamil Nadu, India
| | - Ramya Lakshmi Rajendran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea;
| | - Manish Khanna
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India; (R.R.K.); (N.J.); (M.K.)
- Department of Orthopaedics, Prasad Institute of Medical Sciences, Lucknow 226401, Uttar Pradesh, India
| | - Madhan Jeyaraman
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida 201310, Uttar Pradesh, India
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India; (R.R.K.); (N.J.); (M.K.)
- Department of Orthopaedics, Faculty of Medicine—Sri Lalithambigai Medical College and Hospital, Dr. MGR Educational and Research Institute, Chennai 600095, Tamil Nadu, India
| | - Rathinavelpandian Perunchezhian Packkyarathinam
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India; (R.R.K.); (N.J.); (M.K.)
- Department of Orthopaedics, Government Medical College, Omandurar Government Estate, Chennai 600002, Tamil Nadu, India
| | - Prakash Gangadaran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea;
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Byeong-Cheol Ahn
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea;
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu 41944, Korea
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Jeyaraman M, Muthu S, Ganie PA. Does the Source of Mesenchymal Stem Cell Have an Effect in the Management of Osteoarthritis of the Knee? Meta-Analysis of Randomized Controlled Trials. Cartilage 2021; 13:1532S-1547S. [PMID: 32840122 PMCID: PMC8808923 DOI: 10.1177/1947603520951623] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
STUDY DESIGN Meta-analysis. OBJECTIVES To compare the efficacy and safety of bone marrow(BM)-derived mesenchymal stem cell(MSCs) and adipose-derived(AD) MSCs in the management of osteoarthritis of knee from randomized controlled trials(RCTs) available in the literature. MATERIALS AND METHODS We conducted electronic database searche from PubMed, Embase, and Cochrane Library till May 2020 for RCTs analyzing the efficacy and safety of MSCs in management of osteoarthritis of knee. Visual Analog Score(VAS) for Pain, Western Ontario McMaster Universities Osteoarthritis Index(WOMAC), Lysholm Knee Scale(Lysholm), Whole-Organ Magnetic Resonance Imaging Score(WORMS), Knee Osteoarthritis Outcome Score(KOOS), and adverse events were the outcomes analyzed. Analysis was performed in R platform using OpenMeta[Analyst] software. RESULTS Nineteen studies involving 811 patients were included for analysis. None of the studies compared the source of MSCs for osteoarthritis of knee and results were obtained by pooled data analysis of both sources. At 6 months, AD-MSCs showed significantly better VAS(P<0.001,P=0.069) and WOMAC(P=0.134,P=0.441) improvement than BM-MSCs, respectively, compared to controls. At 1 year, AD-MSCs outperformed BM-MSCs compared to their control in measures like WOMAC(P=0.007,P=0.150), KOOS(P<0.001;P=0.658), and WORMS(P<0.001,P=0.041), respectively. Similarly at 24 months, AD-MSCs showed significantly better Lysholm score(P=0.037) than BM-MSCs(P=0.807) although VAS improvement was better with BM-MSCs at 24 months(P<0.001). There were no significant adverse events with either of the MSCs compared to their controls. CONCLUSION Our analysis establishes the efficacy, safety, and superiority of AD-MSC transplantation, compared to BM-MSC, in the management of osteoarthritis of knee from available literature. Further RCTs are needed to evaluate them together with standardized doses.
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Affiliation(s)
- Madhan Jeyaraman
- Department of Orthopaedics, School of
Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh,
India
| | - Sathish Muthu
- Government Hospital, Velayuthampalayam,
Karur, Tamil Nadu, India
| | - Parvez Ahmad Ganie
- Department of Orthopaedics, School of
Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh,
India
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Wei X, Riehl JT. Platelet-Rich Plasma and Stem Cell Injections in the Treatment of Arthritis of the Knee. Orthopedics 2021; 44:376-383. [PMID: 34618635 DOI: 10.3928/01477447-20211001-07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Platelet-rich plasma (PRP) and stem cell (SC) injections have become increasingly common in the treatment of knee arthritis. This systematic review was performed to answer the following questions: (1) What effects does intraarticular PRP injection have in the setting of knee arthritis? (2) What effects does intra-articular SC injection have in the setting of knee arthritis? (3) What adverse events have been reported in the literature from PRP injections for knee arthritis? (4) What adverse events have been reported in the literature from SC injections for knee arthritis? [Orthopedics. 2021;44(6):376-383.].
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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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Loo SJQ, Wong NK. Advantages and challenges of stem cell therapy for osteoarthritis (Review). Biomed Rep 2021; 15:67. [PMID: 34155451 PMCID: PMC8212446 DOI: 10.3892/br.2021.1443] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 04/12/2021] [Indexed: 12/21/2022] Open
Abstract
Osteoarthritis (OA) is a degenerative disorder of the cartilage and is one of the leading causes of disability, particularly amongst the elderly, wherein patients with advanced-stage OA experience chronic pain and functional impairment of the limbs, thus resulting in a significantly reduced quality of life. The currently available treatments primarily revolve around symptom management, and is thus palliative rather than curative. The aim of the present review is to briefly discuss the limitations of some of the currently available treatments for patients with OA, and highlight the value of the potential use of stem cells in cellular therapy, which is widely regarded as the breakthrough that can address the present unmet medical needs for treatment of degenerative diseases, such as OA. The advantages of stem cell therapy, particularly mesenchymal stem cells, and the challenges involved are also discussed in this review.
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Affiliation(s)
- Stephanie Jyet Quan Loo
- Division of Applied Biomedical Sciences and Biotechnology, School of Health Sciences, International Medical University, Kuala Lumpur 57000, Malaysia
| | - Nyet Kui Wong
- Division of Applied Biomedical Sciences and Biotechnology, School of Health Sciences, International Medical University, Kuala Lumpur 57000, Malaysia
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Bryk M, Karnas E, Mlost J, Zuba-Surma E, Starowicz K. Mesenchymal stem cells and extracellular vesicles for the treatment of pain: Current status and perspectives. Br J Pharmacol 2021; 179:4281-4299. [PMID: 34028798 DOI: 10.1111/bph.15569] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 03/26/2021] [Accepted: 05/05/2021] [Indexed: 12/20/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are multipotent progenitor cells of mesodermal origin. Due to their capacity for self-renewal and differentiation into several cell types, MSCs have been extensively studied in experimental biology and regenerative medicine in recent years. Moreover, MSCs release extracellular vesicles (EVs), which might be partly responsible for their regenerative properties. MSCs regulate several processes in target cells via paracrine signalling, such as immunomodulation, anti-apoptotic signalling, tissue remodelling, angiogenesis and anti-fibrotic signalling. The aim of this review is to provide a detailed description of the functional properties of MSCs and EVs and their potential clinical applications, with a special focus on pain treatment. The analgesic, anti-inflammatory and regenerative properties of MSCs and EVs will be discussed for several diseases, such as neuropathic pain, osteoarthritis and spinal cord injury.
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Affiliation(s)
- Marta Bryk
- Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
| | - Elżbieta Karnas
- Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Jakub Mlost
- Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
| | - Ewa Zuba-Surma
- Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
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Extracellular Vesicles from Mesenchymal Stem Cells as Potential Treatments for Osteoarthritis. Cells 2021; 10:cells10061287. [PMID: 34067325 PMCID: PMC8224601 DOI: 10.3390/cells10061287] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/12/2021] [Accepted: 05/20/2021] [Indexed: 02/07/2023] Open
Abstract
Osteoarthritis (OA) is a chronic degenerative disorder of the joint and its prevalence and severity is increasing owing to ageing of the population. Osteoarthritis is characterized by the degradation of articular cartilage and remodeling of the underlying bone. There is little understanding of the cellular and molecular processes involved in pathophysiology of OA. Currently the treatment for OA is limited to painkillers and anti-inflammatory drugs, which only treat the symptoms. Some patients may also undergo surgical procedures to replace the damaged joints. Extracellular vesicles (EV) play an important role in intercellular communications and their concentration is elevated in the joints of OA patients, although their mechanism is unclear. Extracellular vesicles are naturally released by cells and they carry their origin cell information to be delivered to target cells. On the other hand, mesenchymal stem cells (MSCs) are highly proliferative and have a great potential in cartilage regeneration. In this review, we provide an overview of the current OA treatments and their limitations. We also discuss the role of EV in OA pathophysiology. Finally, we highlight the therapeutic potential of MSC-derived EV in OA and their challenges.
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Andia I, Maffulli N. Mesenchymal stromal cell products for intra-articular knee injections for conservative management of osteoarthritis. Ther Adv Musculoskelet Dis 2021; 13:1759720X21996953. [PMID: 33680097 PMCID: PMC7897835 DOI: 10.1177/1759720x21996953] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 02/01/2021] [Indexed: 02/06/2023] Open
Abstract
Sports injuries and secondary joint problems, mainly of the knee, are common, especially in sports associated with high impact activities and/or torsional loading. The consequences can be career ending in elite athletes and reduce exercise activities in recreational people. Various cell products can be injected intra-articularly. First, fresh cellular mixtures can be prepared and injected in the same day, such as stromal vascular fraction of adipose tissue (SVF) and bone marrow concentrates (BMCs). Second, autologous mesenchymal stromal cells (MSCs) can be isolated from BMCs or SVF and, after several weeks of laboratory expansion, several millions of MSCs can be obtained for intra-articular injection. Finally, allogeneic MSCs from the bone marrow, adipose tissue or perinatal tissues of selected donors constitute an ‘off-the-shelf’ experimental treatment for injection delivery in patients with osteoarthritis of the knee. The perceived efficacy of all these products is based on the hypothesis of a paracrine mechanism of action: when living cells are delivered within the joint, they establish a molecular cross-talk with immune cells and local cell phenotypes, thereby modulating inflammation with subsequent modifications in the catabolic/degenerative milieu. Current clinical research examines whether injection delivery of MSCs translates into actual clinical benefits. Overall, clinical studies lack the quality needed to answer major research questions, including clinical and structural efficacy, optimal cell dose, and number of injections and specific protocol for cell delivery. Poor experimental designs are exacerbated by the diversity of patient phenotypes that hinder comparisons between treatments. Further understanding of disease pathology is paramount to develop potent function assays and understand whether the host tissue, the cell product or both should be primed before MSCs are injected intra-articularly.
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Affiliation(s)
- Isabel Andia
- Queen Mary University of London, Barts and the London School of Medicine and Dentistry, London E1 4DG, UK
| | - Nicola Maffulli
- Regenerative Therapies, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo, Bizkaia, Spain
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Stem cell transplantation for the treatment of osteochondral defects of the knee: Operative technique for a single-stage transplantation procedure using bone marrow-derived mesenchymal stem cells. Knee 2021; 28:400-409. [PMID: 32680778 DOI: 10.1016/j.knee.2020.05.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 04/25/2020] [Accepted: 05/13/2020] [Indexed: 02/02/2023]
Abstract
BACKGROUND Autologous chondrocyte implantation (ACI) is a NICE-approved technique to regenerate hyaline cartilage in chondral and osteochondral defects (OCDs). The drawbacks of ACI include that it requires a two-stage approach, involves a lengthy rehabilitation process and is expensive. Bone marrow harvest with mesenchymal stem cell transplantation using a single-stage procedure and an accelerated rehabilitation programme has been developed to overcome this. The aim of this paper is to describe the surgical technique for stem cell transplantation of the knee for OCDs with reference to case examples. METHODS The surgical technique for stem cell transplantation of the knee for OCDs is described, with reference to three cases. Magnetic resonance imaging was performed at six months postoperatively. RESULTS The surgical technique is described in this paper. The three patient cases described all improved clinically with reduced pain and improved function at a minimum of six months follow-up. CONCLUSIONS Stem cell transplantation has the potential to produce favourable outcomes for patients with osteochondral defects of the knee. This single-stage approach and accelerated rehabilitation is associated with reduced financial costs. A long-term prospective study of this technique is currently underway at our institution and randomised controlled trials are planned to demonstrate the effectiveness over other techniques.
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Mesenchymal Stem Cell Therapy for Osteoarthritis: Practice and Possible Promises. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1387:107-125. [DOI: 10.1007/5584_2021_695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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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 2020; 18:S1699-258X(20)30244-8. [PMID: 33309229 DOI: 10.1016/j.reuma.2020.10.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 09/22/2020] [Accepted: 10/15/2020] [Indexed: 10/22/2022]
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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Shah S, Otsuka T, Bhattacharjee M, Laurencin CT. Minimally Invasive Cellular Therapies for Osteoarthritis Treatment. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2020. [DOI: 10.1007/s40883-020-00184-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Kim SH, Djaja YP, Park YB, Park JG, Ko YB, Ha CW. Intra-articular Injection of Culture-Expanded Mesenchymal Stem Cells Without Adjuvant Surgery in Knee Osteoarthritis: A Systematic Review and Meta-analysis. Am J Sports Med 2020; 48:2839-2849. [PMID: 31874044 DOI: 10.1177/0363546519892278] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Although many clinical studies have assessed the efficacy of mesenchymal stem cells (MSCs) in knee osteoarthritis, evidence on their efficacy remains unclear owing to heterogeneity of cell entity and concomitant procedures. PURPOSE To determine the efficacy of culture-expanded MSCs in knee osteoarthritis in terms of clinical outcome and cartilage repair via meta-analysis of randomized controlled trials (RCTs) without adjuvant surgery. STUDY DESIGN Meta-analysis. METHODS PubMed, Embase, the Cochrane Library, CINAHL, and Scopus were searched from inception to December 31, 2018. RCTs with culture-expanded MSCs for treating knee osteoarthritis were included. Studies with adjuvant surgery or cell concentrate were excluded. Quality was assessed by the Cochrane Collaboration risk-of-bias tool. For meta-analysis, data on clinical outcomes were measured using a visual analog scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and data on cartilage repair were measured using the Whole-Organ Magnetic Resonance Imaging Score (WORMS); categorization related to improvement was extracted. RESULTS Six RCTs (203 patients) were included. Two studies were deemed to have a low risk of bias. In pooled analysis, the only significant difference was in the VAS score (mean difference, -13.55; 95% CI, -22.19 to -4.9). In cumulative pain analysis with VAS and WOMAC pain scores, there was significant improvement after treatment (standardized mean difference, -0.54; 95% CI, -0.85 to -0.23). There was no significant difference in cartilage repair assessed by magnetic resonance imaging (standardized mean difference, 0.11; 95% CI, -0.51 to 0.73), WORMS (standardized mean difference, 1.68; 95% CI -14.84 to 18.21), or categorical results (odds ratio, 1.56; 95% CI, 0.32-7.59). CONCLUSION Intra-articular injection of culture-expanded MSCs without adjuvant surgery can improve pain for patients experiencing knee osteoarthritis at short-term follow-up (6-12 months). However, evidence regarding function and cartilage repair remains limited.
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Affiliation(s)
- Seong Hwan Kim
- Department of Orthopedic Surgery, Hyundae General Hospital, Chung-Ang University, Namyangju-Si, Kyunggi-Do, Republic of Korea
| | - Yoshi Pratama Djaja
- Department of Orthopedic and Traumatology, Fatmawati General Hospital, South Jakarta, Indonesia
| | - Yong-Beom Park
- Department of Orthopedic Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - Jung-Gwan Park
- Department of Orthopedic Surgery, Madisesang Hospital, Seoul, Republic of Korea
| | - Young-Bong Ko
- Department of Orthopedic Surgery, Jounachim Hospital, Gyeonggi-do, Republic of Korea
| | - Chul-Won Ha
- Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Saltzman BM, Frank RM, Davey A, Cotter EJ, Redondo ML, Naveen N, Wang KC, Cole BJ. Lack of standardization among clinical trials of injection therapies for knee osteoarthritis: a systematic review. PHYSICIAN SPORTSMED 2020; 48:266-289. [PMID: 32027200 DOI: 10.1080/00913847.2020.1726716] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Purpose: Osteoarthritis (OA) of the knee is a debilitating, expensive, and prevalent disease, and interest in the non-surgical management of knee OA has grown recently. Our objective was to systematically assess the level of heterogeneity among all clinical trials and published studies regarding injections for knee osteoarthritis, in terms of treatment of interest, outcomes evaluated, and time points of outcome assessment. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were utilized to review all published studies and publically available clinical trials from 1 January 2013 to 3 May 2019evaluating intra-articular injections to treat knee OA. Their treatment group and specifics of methodology were scrutinized and compared. Results: 84 published studies and 114 clinical trials were included. Within the 84 published studies, the most common injection treatment studied was hyaluronic acid [N = 22; 26.2%]. In total, 29 different injection treatment groups were utilized. The most common time point for patient evaluation post-injection was 6 months (N = 33 studies; 50.0%), and ranged from 1 week (N = 9 studies; 13.6%) to 7 years (N = 1 study; 1.5%). The most common patient-reported outcome (PRO) measure assessed in the included studies was Western Ontario and McMaster's University Osteoarthritis Index (WOMAC) [N = 44 studies; 66.7%]. For the 114 clinical trials identified, the most common injection treatment studied is platelet-rich plasma in isolation (N = 19; 16.7%). Forty-two different injection treatment types/groups are utilized. The most common PRO measure assessed was WOMAC (N = 77 trials; 67.5%). Overall there were 34 different patient-reported outcome measures used. Conclusions: Research efforts to find the most effective injection therapy for knee OA continue with a tremendous number of injection therapies still being evaluated. Substantial heterogeneity exists in these completed and ongoing trials in terms of patient demographics, OA grades, outcome scores and relatively short-term timing of assessments, with no clear standardization of testing protocol despite proposing to answer the same clinical question. We recommend that studies of this genre going forward be standardized in terms of outcome measures and longer-term follow-up time points, and should incorporate functional assessment evaluations and imaging studies.
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Affiliation(s)
- Bryan M Saltzman
- Orthopaedic Surgery, Rush University Medical Center , Chicago, IL, USA
| | - Rachel M Frank
- Orthopaedic Surgery, Rush University Medical Center , Chicago, IL, USA
| | - Annabelle Davey
- Orthopaedic Surgery, Rush University Medical Center , Chicago, IL, USA
| | - Eric J Cotter
- Orthopaedic Surgery, Rush University Medical Center , Chicago, IL, USA
| | - Michael L Redondo
- Orthopaedic Surgery, Rush University Medical Center , Chicago, IL, USA
| | - Neal Naveen
- Orthopaedic Surgery, Rush University Medical Center , Chicago, IL, USA
| | - Kevin C Wang
- Orthopaedic Surgery, Rush University Medical Center , Chicago, IL, USA
| | - Brian J Cole
- Orthopaedic Surgery, Rush University Medical Center , Chicago, IL, USA
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Prodromos C, Finkle S, Rumschlag T, Lotus J. Autologous Mesenchymal Stem Cell Treatment is Consistently Effective for the Treatment of Knee Osteoarthritis: The Results of a Systematic Review of Treatment and Comparison to a Placebo Group. MEDICINES 2020; 7:medicines7080042. [PMID: 32722216 PMCID: PMC7459966 DOI: 10.3390/medicines7080042] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 07/14/2020] [Accepted: 07/23/2020] [Indexed: 12/13/2022]
Abstract
Background: Numerous studies have used autologous mesenchymal stem cell injections (AMSCI) to treat osteoarthritis. We hypothesized that AMSCI is an effective osteoarthritis treatment with increasing efficacy at higher doses. Methods: We conducted a PubMed search for human clinical studies using AMSCI for the treatment of osteoarthritis (OA) and a second search for placebo arms of injectate OA treatment. Inclusion criteria included treatment outcomes ratings both pre-treatment and at least 6 months post-treatment. Results: 45 AMSCI cohorts from 34 studies met criteria. All AMSCI cohorts showed improvement at mean 15.3 months post-treatment. Mean WOMAC and VAS scores improved at 6-months and at final follow-up (p < 0.0001 for all). Scores > 2 years were also significant (WOMAC p = 0.001/VAS p = 0.004). Results greatly exceeded the minimal clinically important difference (MCID) at each time point. AMSCI improvement also substantially exceeded previously published 6-month placebo-treatment improvement. No dose-response relationship was seen. AMSCI cohorts showed continuing improvement ≥ 6 months, and continued upward at one year. Placebo scores were already trending downward by 6 months. Conclusions: AMSCI is a consistently significantly effective treatment for osteoarthritis. It should no longer be stated that data is insufficient to establish AMSCI efficacy for OA. Given its excellent safety profile, AMSCI should be widely used for the treatment of osteoarthritis.
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Improved outcomes after mesenchymal stem cells injections for knee osteoarthritis: results at 12-months follow-up: a systematic review of the literature. Arch Orthop Trauma Surg 2020; 140:853-868. [PMID: 31456015 DOI: 10.1007/s00402-019-03267-8] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Indexed: 12/26/2022]
Abstract
PURPOSE According to the World Health organization (WHO), more than 10% in people older than 60 years suffer from osteoarthritis (OA). Over the last years, there has been an increased interest around regenerative medicine, especially regarding stem cell treatments and related applications. We hypothesize that stem cell therapies can represent a feasible option for idiopathic knee OA, delaying or even avoiding the joint replacement. To emphasize the potential of percutaneous injections of mesenchymal stem cells for knee OA, a comprehensive systematic review of the literature was conducted. MATERIAL AND METHODS Two independent authors (FM, GC) performed the literature search. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA). The main databases were accessed: Pubmed, Embase, Google Scholar, Cochrane Systematic Reviews, Scopus, AMED. For this systematic review, all articles treating percutaneous injections of mesenchymal stem cells for knee OA were considered. Because of the rapid advancements promoted by the scientific progress on stem cell expansion and processing, only articles published within the last five years were included. Solely articles reporting the outcomes of interest across 6- and 12-month follow-up were recruited for eligibility. We included only studies reporting quantitative data under the outcomes of interest. We referred for the quality assessment to the Coleman Methodology Score (CMS). The statistical analysis was performed with Review Manager Software 5.3 (The Nordic Cochrane Centre, Copenhagen). RESULTS A total of 18 studies were enrolled in the present study, comprising 1069 treated knees. The mean age of the samples was 57.39 ± 7.37 years. 72% of the included studies harvested the stem cells from the iliac crest (bone marrow-derived MSCs), the remaining 28% from the adipose tissue (adipose-derived MSCs). The mean visual analogic scale improved from 18.37 to 30.98 and 36.91 at 6- and 12-month follow-up, respectively. The mean WOMAC score improved from 25.66 to 25.23 and 15.60 at 6- and 12-month follow-up, respectively. The mean walking distance improved from 71.90 to 152.22 and 316.72 at 6- and 12-month follow-up, respectively. The mean Lequesne scale improved from 33.76 to 12.90 at 12-month follow-up. The KOOS score improved from 41.07 to 8.47% and 18.94 at 6- and 12-month follow-up. All the KOOS subscales improved significantly from the baseline. A total of 136 (12.7%) local complications were detected. CONCLUSION According to the current evidences and the main findings of this systematic review, we reported that MSC infiltrations for knee OA can represent a feasible option, leading to an overall remarkable improvement of all clinical and functional considered outcomes, regardless of the cell source. Patients treated at earlier-degeneration stages reported statistically significant greater outcomes. The pain and function scores were improved considerably, thus, leading to a significant improvement of patient participation in recreational activities and quality of life.
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Prodromos C, Finkle S. Autologous Biologic Treatment with Fat, Bone Marrow Aspirate and Platelet Rich Plasma Is an Effective Alternative to Total Knee Arthroplasty for Patients with Moderate Knee Arthrosis. MEDICINES (BASEL, SWITZERLAND) 2020; 7:E37. [PMID: 32630375 PMCID: PMC7344479 DOI: 10.3390/medicines7060037] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/12/2020] [Accepted: 06/18/2020] [Indexed: 12/15/2022]
Abstract
Background: Osteoarthrosis (OA) of the knee afflicts millions worldwide. Total Knee Arthroplasty (TKA) is common, but associated with substantial cost and morbidity. Prior studies of intra-articular injection of fat, bone marrow aspirate (BMA), and platelet rich plasma (PRP) have shown clinical benefit. We hypothesized that injection of autologous adipose tissue, BMA, and PRP would provide significant benefit for patients with moderate knee OA resulting in avoidance of total knee arthroplasty (TKA) in most, with discontinuance of NSAIDs and other drugs. Methods: 42 TKA candidate patients (47 knees) with moderate (Kellgren-Lawrence 2 and 3) knee OA who had failed conservative treatment had autologous adipose tissue, BMA, and PRP injection as an alternative to TKA in office using only local anesthetic. Patients had discontinuance of all nonsteroidal anti-inflammatory medicines (NSAIDs) and other analgesics, except acetaminophen, prior to treatment. Patients were evaluated with Knee injury and Osteoarthritis Outcome Score Physical Shortform (KOOS-PS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Single Assessment Numeric Evaluation (SANE) prior to treatment, and at 6 months, 1, and 2 years after treatment. Results: Follow up exceeded 80% at all time points. There were no significant adverse events. TKA was avoided in 97% at one and 86% at two years after treatment. Mean SANE, KOOS-PS, and WOMAC scores significantly improved at 6 months, 1, and 2 years post-treatment. WOMAC and SANE scores were higher at two versus one year post-treatment. Conclusions: Combined fat, BMA, and PRP injection is a safe and effective treatment for moderate knee OA, with reliable avoidance of TKA and possible continued improvement at two year follow-up.
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Affiliation(s)
- Chadwick Prodromos
- Illinois Sportsmedicine and Orthopaedic Centers, Glenview, IL 60025, USA;
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Ni Z, Zhou S, Li S, Kuang L, Chen H, Luo X, Ouyang J, He M, Du X, Chen L. Exosomes: roles and therapeutic potential in osteoarthritis. Bone Res 2020; 8:25. [PMID: 32596023 PMCID: PMC7305215 DOI: 10.1038/s41413-020-0100-9] [Citation(s) in RCA: 176] [Impact Index Per Article: 35.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 04/30/2020] [Accepted: 05/09/2020] [Indexed: 12/19/2022] Open
Abstract
Exosomes participate in many physiological and pathological processes by regulating cell-cell communication, which are involved in numerous diseases, including osteoarthritis (OA). Exosomes are detectable in the human articular cavity and were observed to change with OA progression. Several joint cells, including chondrocytes, synovial fibroblasts, osteoblasts, and tenocytes, can produce and secrete exosomes that influence the biological effects of targeted cells. In addition, exosomes from stem cells can protect the OA joint from damage by promoting cartilage repair, inhibiting synovitis, and mediating subchondral bone remodeling. This review summarizes the roles and therapeutic potential of exosomes in OA and discusses the perspectives and challenges related to exosome-based treatment for OA patients in the future.
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Affiliation(s)
- Zhenhong Ni
- Department of Wound Repair and Rehabilitation Medicine, Center of Bone Metabolism and Repair, Laboratory for Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Siru Zhou
- State Key Laboratory of Trauma, Burns and Combined Injury; Medical Cformation of H-type vessel in subchondral enter of Trauma and War Injury; Daping Hospital, Army Medical University of PLA, Chongqing, China
| | - Song Li
- Department of Wound Repair and Rehabilitation Medicine, Center of Bone Metabolism and Repair, Laboratory for Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
- Eleven Squadron Three Brigade, School of Basic Medical Science, Army Medical University, Chongqing, China
| | - Liang Kuang
- Department of Wound Repair and Rehabilitation Medicine, Center of Bone Metabolism and Repair, Laboratory for Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Hangang Chen
- Department of Wound Repair and Rehabilitation Medicine, Center of Bone Metabolism and Repair, Laboratory for Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Xiaoqing Luo
- Department of Wound Repair and Rehabilitation Medicine, Center of Bone Metabolism and Repair, Laboratory for Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Junjie Ouyang
- Department of Wound Repair and Rehabilitation Medicine, Center of Bone Metabolism and Repair, Laboratory for Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Mei He
- Department of Wound Repair and Rehabilitation Medicine, Center of Bone Metabolism and Repair, Laboratory for Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Xiaolan Du
- Department of Wound Repair and Rehabilitation Medicine, Center of Bone Metabolism and Repair, Laboratory for Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Lin Chen
- Department of Wound Repair and Rehabilitation Medicine, Center of Bone Metabolism and Repair, Laboratory for Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
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Bąkowski P, Kaszyński J, Wałecka J, Ciemniewska-Gorzela K, Bąkowska-Żywicka K, Piontek T. Autologous adipose tissue injection versus platelet-rich plasma (PRP) injection in the treatment of knee osteoarthritis: a randomized, controlled study - study protocol. BMC Musculoskelet Disord 2020; 21:314. [PMID: 32434498 PMCID: PMC7240999 DOI: 10.1186/s12891-020-03345-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 05/12/2020] [Indexed: 01/12/2023] Open
Abstract
Background Knee osteoarthritis (OA) is a common, chronic, progressive and degenerative disease which affects patients’ quality of life and may cause disability and social isolation. OA is a huge economic burden for the patient and a large strain for the whole healthcare system. Articular cartilage has a small potential to repair, with progressively more clinicians emphasizing cellular therapy. Subcutaneous fat tissue in human body is a large reservoir of mesenchymal stem cells (MSCs) and is been harvested in minimally invasive, simple procedure. Up to date there is no prospective randomized controlled studies demonstrating effectiveness and role of adipose tissue injections in OA treatment. The purpose of this study is to assess functional and clinical changes among patients with symptomatic knee OA treated with intra-articular injections of autologous adipose tissue or platelet rich plasma (PRP) and to compare efficacy of both therapeutic methods. Methods This is a prospective, randomized, controlled study. Patients who meet inclusion criteria will be allocated to Fat Tissue group or PRP group randomly. Subjects will receive an intra articular injection with autologous adipose tissue and PRP respectively. Patients will be assessed five times: before treatment and 1, 3, 6 and 12 months after the treatment. The assessment consists of patient reported outcome measures (The Knee injury and Osteoarthritis Outcome Score, International Knee Documentation Committee 2000, the Western Ontario and McMaster Universities Osteoarthritis Index, the Health Questionnaire EQ- 5D- 5 L), three functional tests (The Timed Up and Go Test, The 5 Times Sit to Stand Test, The 10 m Walk Test) and Maximal Isometric Voluntary Contraction. Discussion This study protocol has several strengths and weaknesses. One of strongest point of this study is the wide, multidimensional functional assessment which will give a large amount of objective data. On the other hand, lack of blinding has to be considered as a risk of both subject and investigator bias. Trial registration name of registry: ClinicalTrials.gov, trial registration number: NCT04321629, retrospectively registered on date of registration.
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Affiliation(s)
- Paweł Bąkowski
- Department of Orthopedic Surgery, Rehasport Clinic, Poznan, Poland.
| | - Jakub Kaszyński
- Department of Orthopedic Surgery, Rehasport Clinic, Poznan, Poland
| | - Joanna Wałecka
- Department of Orthopedic Surgery, Rehasport Clinic, Poznan, Poland
| | | | | | - Tomasz Piontek
- Department of Orthopedic Surgery, Rehasport Clinic, Poznan, Poland.,Department of Spine Disorders and Pediatric Orthopedics, University of Medical Sciences Poznan, Poznan, Poland
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Biologische Therapie der Gelenkarthrose. ARTHROSKOPIE 2020. [DOI: 10.1007/s00142-020-00363-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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