Annotated Regenerative Medicine Peer-Reviewed Articles

Arthroscopic Partial Meniscectomy versus Sham Surgery for a Degenerative Meniscal Tear

  • Abstract

    BACKGROUND:

    Arthroscopic partial meniscectomy is one of the most common orthopedic procedures, yet rigorous evidence of its efficacy is lacking.

    METHODS:

    We conducted a multicenter, randomized, double-blind, sham-controlled trial in 146 patients 35 to 65 years of age who had knee symptoms consistent with a degenerative medial meniscus tear and no knee osteoarthritis. Patients were randomly assigned to arthroscopic partial meniscectomy or sham surgery. The primary outcomes were changes in the Lysholm and Western Ontario Meniscal Evaluation Tool (WOMET) scores (each ranging from 0 to 100, with lower scores indicating more severe symptoms) and in knee pain after exercise (rated on a scale from 0 to 10, with 0 denoting no pain) at 12 months after the procedure.

    RESULTS:

    In the intention-to-treat analysis, there were no significant between-group differences in the change from baseline to 12 months in any primary outcome. The mean changes (improvements) in the primary outcome measures were as follows: Lysholm score, 21.7 points in the partial-meniscectomy group as compared with 23.3 points in the sham-surgery group (between-group difference, −1.6 points; 95% confidence interval [CI], −7.2 to 4.0); WOMET score, 24.6 and 27.1 points, respectively (between-group difference, −2.5 points; 95% CI, −9.2 to 4.1); and score for knee pain after exercise, 3.1 and 3.3 points, respectively (between-group difference, −0.1; 95% CI, −0.9 to 0.7). There were no significant differences between groups in the number of patients who required subsequent knee surgery (two in the partial-meniscectomy group and five in the sham-surgery group) or serious adverse events (one and zero, respectively).

    CONCLUSION:

    In this trial involving patients without knee osteoarthritis but with symptoms of a degenerative medial meniscus tear, the outcomes after arthroscopic partial meniscectomy were no better than those after a sham surgical procedure. (Funded by the Sigrid Juselius Foundation and others; ClinicalTrials.gov number, NCT00549172.)

  • Raine Sihvonen, M.D., Mika Paavola, M.D., Ph.D., Antti Malmivaara, M.D., Ph.D., Ari Itälä, M.D., Ph.D., Antti Joukainen, M.D., Ph.D., Heikki Nurmi, M.D., Juha Kalske, M.D., and Teppo L.N. Järvinen, M.D., Ph.D. for the Finnish Degenerative Meniscal Lesion Study (FIDELITY) Group

Intra-discal injection of autologous, hypoxic cultured bone marrow-derived mesenchymal stem cells in five patients with chronic lower back pain: a long-term safety and feasibility study.

  • Abstract

    BACKGROUND:

    Chronic low back pain due to disc degeneration represents a major social and economic burden worldwide. The current standard of care is limited to symptomatic relief and no current approved therapy promotes disc regeneration. Bone marrow-derived mesenchymal stem cells (MSCs) are easily accessible and well characterized. These MSCs are multipotent and exhibit great tissue regenerative potential including bone, cartilage, and fibrous tissue regeneration. The use of this cell-based biologic for treating protruding disc herniation and/or intervertebral disc degeneration is a promising therapeutic strategy, due to their known regenerative, immuno-modulatory and anti-inflammatory properties.

    METHODS:

    Five patients diagnosed with degenerative disc disease received an intra-discal injection of autologous, hypoxic cultured, bone marrow-derived mesenchymal stem cells (15.1-51.6 million cells) as part of a previous study. These patients were re-consented to participate in this study in order to assess long-term safety and feasibility of intra-discal injection of autologous, hypoxic cultured, bone marrow-derived mesenchymal stem cells 4-6 years post mesenchymal stem cell infusion. The follow-up study consisted of a physical examination, a low back MRI, and a quality of life questionnaire.

    RESULTS:

    Patients’ lower back MRI showed absence of neoplasms or abnormalities surrounding the treated region. Based on the physical examination and the quality of life questionnaire, no adverse events were reported due to the procedure or to the stem cell treatment 4-6 years post autologous, hypoxic cultured mesenchymal stem cell infusion. All patients self-reported overall improvement, as well as improvement in strength, post stem cell treatment, and four out of five patients reported improvement in mobility.

    CONCLUSION:

    This early human clinical data suggests the safety and feasibility of the clinical use of hypoxic cultured bone marrow-derived mesenchymal stem cells for the treatment of lower back pain due to degenerative disc disorders and support further studies utilizing hypoxic cultured bone marrow-derived stem cells. The overall improvements reported are encouraging, but a larger double-blind, controlled, randomized clinical study with significant number of patients and implementation of validated endpoint measurements are next steps in order to demonstrate efficacy of this cell-based biologic.

  • Elabd C, Centeno CJ, Schultz JR, Lutz G, Ichim T, Silva FJ

Treatment of discogenic back pain with autologous bone marrow concentrate injection with minimum two year follow-up.

  • Abstract

    PURPOSE:

    The purpose of this study is to assess safety and feasibility of intradiscal bone marrow concentrate (BMC) injections to treat discogenic pain as an alternative to surgery.

    METHODS:

    A total of 26 patients (11 male, 15 female, aged 18-61 years, 13 single level, 13 two level) that met inclusion criteria of chronic (> 6 months) discogenic low back pain, degenerative disc pathology assessed by magnetic resonance imaging (MRI) with modified Pfirrmann grade of IV-VII at one or two levels, candidate for surgical intervention (failed conservative treatment and radiologic findings) and a visual analogue scale (VAS) pain score of 40 mm or more at initial visit. Initial Oswestry Disability Index (ODI) and VAS pain score average was 56.5 % and 80.1 mm (0-100), respectively. Adverse event reporting, ODI score, VAS pain score, MRI radiographic changes, progression to surgery and cellular analysis of BMC were noted. Retrospective cell analysis by flow cytometry and colony forming unit-fibroblast (CFU-F) assays were performed to characterise each patient’s BMC and compare with clinical outcomes. The BMC was injected into the nucleus pulposus of the symptomatic disc(s) under fluoroscopic guidance. Patients were evaluated clinically prior to treatment and at three, six, 12 and 24 months and radiographically prior to treatment and at 12 months.

    RESULTS:

    There were no complications from the percutaneous bone marrow aspiration or disc injection. Of 26 patients, 24 (92 %) avoided surgery through 12 months, while 21 (81 %) avoided surgery through two years. Of the 21 surviving patients, the average ODI and VAS scores were reduced to 19.9 and 27.0 at three months and sustained to 18.3 and 22.9 at 24 months, respectively (p ≤ 0.001). Twenty patients had follow-up MRI at 12 months, of whom eight had improved by at least one Pfirrmann grade, while none of the discs worsened. Total and rate of pain reduction were linked to mesenchymal stem cell concentration through 12 months. Only five of the 26 patients elected to undergo surgical intervention (fusion or artificial disc replacement) by the two year milestone.

    CONCLUSIONS:

    This study provides evidence of safety and feasibility in the non-surgical treatment of discogenic pain with autologous BMC, with durable pain relief (71 % VAS reduction) and ODI improvements (> 64 %) through two years.

  • Pettine K, Suzuki R, Sand T, Murphy M

Reduced chondrogenic and adipogenic activity of mesenchymal stem cells from patients with advanced osteoarthritis.

  • Abstract

    OBJECTIVE:

    Mesenchymal stem cells (MSCs) are resident in the bone marrow throughout normal adult life and have the capacity to differentiate along a number of connective tissue pathways, among them bone, cartilage, and fat. To determine whether functionally normal MSC populations may be isolated from patients with advanced osteoarthritis (OA), we have compared cells from patients undergoing joint replacement with cells from normal donors. Cell populations were compared in terms of yield, proliferation, and capacity to differentiate.

    METHODS:

    MSCs were prepared from bone marrow aspirates obtained from the iliac crest or from the tibia/femur during joint surgery. In vitro chondrogenic activity was measured as glycosaminoglycan and type II collagen deposition in pellet cultures. Adipogenic activity was measured as the accumulation of Nile Red O-positive lipid vacuoles, and osteogenic activity was measured as calcium deposition and by von Kossa staining.

    RESULTS:

    Patient-derived MSCs formed colonies in primary culture that were characteristically spindle-shaped with normal morphology. The primary cell yield in 36 of 38 cell cultures from OA donors fell within the range found in cultures from normal donors. However, the proliferative capacity of patient-derived MSCs was significantly reduced. There was a significant reduction in in vitro chondrogenic and adipogenic activity in cultures of patient-derived cells compared with that in normal cultures. There was no significant difference in in vitro osteogenic activity. There was no decline in chondrogenic potential with age in cells obtained from individuals with no evidence of OA.

    CONCLUSION:

    These results raise the possibility that the increase in bone density and loss of cartilage that are characteristic of OA may result from changes in the differentiation profile of the progenitor cells that contribute to the homeostatic maintenance of these tissues.

  • Min KH, Byun JH, Heo CY, Kim EH, Choi HY, Pak CS.

Effect of Low-Level Laser Therapy on Human Adipose-Derived Stem Cells: In Vitro and In Vivo Studies.

  • Abstract

    Low-level laser irradiation stimulated the proliferation of mouse mesenchymal stem cells without causing nuclear alterations. The biostimulation of mesenchymal stem cells using laser therapy might be an important tool for regenerative therapy and tissue engineering.

  • Murphy JM, Dixon K, Beck S, Fabian D, Feldman A, Barry F.

Low-level laser irradiation induces in vitro proliferation of mesenchymal stem cells.

  • Abstract

    Low-level laser irradiation stimulated the proliferation of mouse mesenchymal stem cells without causing nuclear alterations. The biostimulation of mesenchymal stem cells using laser therapy might be an important tool for regenerative therapy and tissue engineering.

  • Barboza CA, Ginani F, Soares DM, Henriques AC, Freitas Rde A.

Low-Level Laser Effect on Proliferation, Migration, and Antiapoptosis of Mesenchymal Stem Cells

  • Abstract

    Mesenchymal stem cells (MSCs) have been proved to be an important element in cell-based therapy. Photobiomodulation used extremely low-level lasers (LLLs) to affect the behavior of cells. The effect mechanism of LLLs on MSCs from human remained to be discovered. In this study, cell viability was assessed using MTS assays and cell cycle was evaluated by fluorescence-activated cell sorting (FACS). The influence of LLLs on mitochondrial biogenesis (fission or fusion) and function (ATP, reactive oxygen species [ROS], nitric oxide [NO]) was evaluated by transmission electron microscope, FACS, quantitative real time polymerase chain reaction (q-PCR), and immunocytochemistry. Cell migration and cytoskeleton alteration (actin and tubulin) were evaluated using transwell assay, immunocytochemistry, enzyme-linked immunosorbent assay, and western blotting. Cell apoptosis was evaluated using FACS, immunocytochemistry, and western blotting. We investigated that certain influence of LLLs on MSCs in vitro 6 or 24 h after 1 h of LLL irradiation. The mechanism of the effects included proliferation rate increase mediated by increased S phase proportion; mitochondrial biogenesis and function alteration mediated by fusion (Mfn1, Mfn2, and Opa-1) and fission (Fis1, Drp-1, and MTP18)-related proteins, NRF1, TFAM, PGC-1a, and upregulated intracellular ROS and NO concentration; migration acceleration through the ERK1/2 and FAK pathway and upregulation of growth factors such as HGF and PDGF; and resistance to apoptosis with increased Bcl-2 and decreased Bax, or through tunneling nanotube formation between LLL-treated MSCs and 5-fluorouracil-induced apoptotic MSCs. These observations suggested that LLLs enhanced stem cell survival and therapeutic function, which could appear to be an innovative pretreatment in the application of MSCs.

  • Kan Yin, Rongjia Zhu, Shihua Wang, Robert Chunhua Zhao

Low level laser (LLL) attenuate LPS-induced inflammatory responses in mesenchymal stem cells via the suppression of NF-κB signaling pathway in vitro

  • Abstract

    Considering promising results in animal models and patients, therapeutic use of MSCs for immune disease is likely to undergo continued evaluation. Low-lever laser (LLL) has been widely applied to retard the inflammatory reaction. LLL treatment can potentially be applied in anti-inflammatory therapy followed by regenerative medicine therapy.

  • Kan Yin, Rongjia Zhu, Shihua Wang, Robert Chunhua Zhao

Prolotherapy and Low Level Laser Therapy: A Synergistic Approach to Pain Management in Chronic Osteoarthritis.

  • Abstract

    Regenerative injection therapy and low level laser therapy are alternative remedies known for their success in the treatment and symptomatic management of chronic musculoskeletal conditions. In response to the growing demand for alternative therapies in the face of the opioid epidemic, the authors conduct a literature review to investigate the potential for prolotherapy and LLLT to be used adjunctively to manage chronic osteoarthritis (OA). OA is a degenerative chronic musculoskeletal condition on the rise in North America, and is frequently treated with opioid medications. The regenerative action of prolotherapy and pain-modulating effects of LLLT may make these two therapies well-suited to synergistically provide improved outcomes for osteoarthritis patients without the side effects associated with opioid use. A narrative descriptive review through multiple medical databases (Google Scholar, PubMed, and MedLine) is conducted, restricted by the use of medical subject headings. 71 articles were selected for reading in full, and 40 articles were selected for use in the study after reading in full. A review of the literature revealed good clinical results in the use of prolotherapy and LLLT separately to manage chronic musculoskeletal pain due to osteoarthritis and other chronic conditions. It is also recognized in the literature that prolotherapy works most effectively when used adjunctively with other treatments. Downsides to the use of prolotherapy include mild side effects of pain, stiffness and bruising and potential adverse events as a result of injection. This study is limited by the lack of clinical trials available involving both LLLT and prolotherapy injections used adjunctively, and by the low number of high impact literature concerning the treatment of (specifically) osteoarthritis by alternative methods. The authors suggest that practicing health care providers consider utilizing LLLT and prolotherapy together as a supplementary method in the management of chronic pain due to osteoarthritis, to minimize the long-term prescription of opioids and emphasize a less invasive treatment for this debilitating condition.

  • Tieppo Francio V, Dima RS, Towery C, Davani S

Mesenchymal stem cells for cartilage repair in osteoarthritis

  • Abstract

    Osteoarthritis (OA) is a degenerative disease of the connective tissue and progresses with age in the older population or develops in young athletes following sports-related injury. The articular cartilage is especially vulnerable to damage and has poor potential for regeneration because of the absence of vasculature within the tissue. Normal load-bearing capacity and biomechanical properties of thinning cartilage are severely compromised during the course of disease progression. Although surgical and pharmaceutical interventions are currently available for treating OA, restoration of normal cartilage function has been difficult to achieve. Since the tissue is composed primarily of chondrocytes distributed in a specialized extracellular matrix bed, bone marrow stromal cells (BMSCs), also known as bone marrow-derived ‘mesenchymal stem cells’ or ‘mesenchymal stromal cells’, with inherent chondrogenic differentiation potential appear to be ideally suited for therapeutic use in cartilage regeneration. BMSCs can be easily isolated and massively expanded in culture in an undifferentiated state for therapeutic use. Owing to their potential to modulate local microenvironment via anti-inflammatory and immunosuppressive functions, BMSCs have an additional advantage for allogeneic application. Moreover, by secreting various bioactive soluble factors, BMSCs can protect the cartilage from further tissue destruction and facilitate regeneration of the remaining progenitor cells in situ. This review broadly describes the advances made during the last several years in BMSCs and their therapeutic potential for repairing cartilage damage in OA.

  • Pawan K Gupta, Anjan K Das, Anoop Chullikana and Anish S Majumdar

Mesenchymal stem cells for cartilage repair

  • Abstract

    It has been discovered that mesenchymal stem cells (MSCs) in a polymeric carrier implanted into a cartilage and/or bone defect will differentiate to form cartilage and/or bone, as appropriate. Suitable polymeric carriers include porous meshes or sponges formed of synthetic or natural polymers, as well as polymer solutions. A presently preferred material is a polyglycolic acid mesh.

  • Daniel A. Grande, Paul A. Lucas

Inhibition of TAK1 and/or JAK Can Rescue Impaired Chondrogenic Differentiation of Human Mesenchymal Stem Cells in Osteoarthritis-Like Conditions

  • Abstract

    Objective: To rescue chondrogenic differentiation of human mesenchymal stem cells (hMSCs) in osteoarthritic conditions by inhibition of protein kinases.

    Methods: hMSCs were cultured in pellets. During early chondrogenic differentiation, these were exposed to osteoarthritic synovium-conditioned medium (OAS-CM), combined with the Janus kinase (JAK)-inhibitor tofacitinib and/or the transforming growth factor β-activated kinase 1 (TAK1)-inhibitor oxozeaenol. To evaluate effects on chondrogenesis, the glycosaminoglycan (GAG) content of the pellets was measured at the time that chondrogenesis was manifest in control cultures. Moreover, mRNA levels of matrix molecules and enzymes were measured during this process, using real-time polymerase chain reaction (RT-PCR). Initial experiments were performed with hMSCs from a fetal donor, and results of these studies were confirmed with hMSCs from adult donors.

  • Henk M. van Beuningen, PhD, Marloes L. de Vries-van Melle, MSc, Elly L. Vitters, MSc, Wim Schreurs, MD, PhD, Wim B. van den Berg, PhD, Gerjo J.V.M. van Osch, PhD, and Peter M. van der Kraan, PhD

Stem Cells for the Treatment of Knee Osteoarthritis: A Comprehensive Review

  • Abstract

    Knee osteoarthritis (KOA) is a very challenging condition to treat and can be resistant to medications, procedures, and even surgery. Surgery may not be an option for some patients due to obesity or comorbidities. Regenerative medicine utilizing stem cells, platelet rich plasma (PRP), cord tissue (Worton’s Jelly), and cytokine modulation is very promising in the treatment of KOA.

  • Zhao L, Kaye AD, Abd-Elsayed A

Mesenchymal stem cells in osteoarthritis

  • Abstract

    Accumulating evidence indicates that every tissue contains stem cells. Our understanding of the biology of stem cells reveals that these cell populations have a critical role in the homeostasis and repair of tissues. Besides the local stem cell niches, additional compartments in the body such as the bone marrow may serve as reservoirs for stem cell populations. On more extensive tissue damage, and guided by local repair responses, “reparative” cell populations are mobilized from more distant stem cell reservoirs and migrate to the site of injury, thereby contributing in many aspects of local tissue repair.

  • Frank P. Luyten

Intra‐Articular Injection of Mesenchymal Stem Cells for the Treatment of Osteoarthritis of the Knee: A Proof‐of‐Concept Clinical Trial

  • Abstract

    Mesenchymal stem cells (MSCs) are known to have a potential for articular cartilage regeneration. However, most studies focused on focal cartilage defect through surgical implantation. For the treatment of generalized cartilage loss in osteoarthritis, an alternative delivery strategy would be more appropriate. The purpose of this study was to assess the safety and efficacy of intra‐articular injection of autologous adipose tissue derived MSCs (AD‐MSCs) for knee osteoarthritis. We enrolled 18 patients with osteoarthritis of the knee and injected AD MSCs into the knee. The phase I study consists of three dose‐escalation cohorts; the low‐dose (1.0 × 107 cells), mid‐dose (5.0 × 107), and high‐dose (1.0 × 108) group with three patients each. The phase II included nine patients receiving the high‐dose. The primary outcomes were the safety and the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) at 6 months. Secondary outcomes included clinical, radiological, arthroscopic, and histological evaluations. There was no treatment‐related adverse event. The WOMAC score improved at 6 months after injection in the high‐dose group. The size of cartilage defect decreased while the volume of cartilage increased in the medial femoral and tibial condyles of the high‐dose group. Arthroscopy showed that the size of cartilage defect decreased in the medial femoral and medial tibial condyles of the high‐dose group. Histology demonstrated thick, hyaline‐like cartilage regeneration. These results showed that intra‐articular injection of 1.0 × 108 AD MSCs into the osteoarthritic knee improved function and pain of the knee joint without causing adverse events, and reduced cartilage defects by regeneration of hyaline‐like articular cartilage. Stem Cells 2014;32:1254–1266

  • Chris Hyunchul Jo, Young Gil Lee, Won Hyoung Shin, Hyang Kim, Jee Won Chai, Eui Cheol Jeong, Ji Eun Kim, Hackjoon Shim, Ji Sun Shin, Il Seob Shin, Jeong Chan Ra, Sohee Oh, and Kang Sup Yoon

Mesenchymal Stem Cells in Tissue Repair

  • Abstract

    The advent of mesenchymal stem cell (MSC)-based therapies for clinical therapeutics has been an exciting and new innovation for the treatment of a variety of diseases associated with inflammation, tissue damage, and subsequent regeneration and repair. Application-based ability to measure MSC potency and fate of the cells post-MSC therapy are the variables that confound the use of MSCs therapeutics in human diseases. An evaluation of MSC function and applications with attention to detail in the preparation as well as quality control and quality assurance are only as good as the assays that are developed. In vivo measures of efficacy and potency require an appreciation of the overall pathophysiology of the model and standardization of outcome measures. The new concepts of how MSC’s participate in the tissue regeneration and wound repair process and further, how this is impacted by estimates of efficacy and potency are important new topics. In this regard, this chapter will review some of the in vitro and in vivo assays for MSC function and activity and their application to the clinical arena.

  • Amy M. DiMarino, Arnold I. Caplan, and Tracey L. Bonfield

The Holy Grail of Orthopedic Surgery: Mesenchymal Stem Cells—Their Current Uses and Potential Applications

  • Abstract

    Only select tissues and organs are able to spontaneously regenerate after disease or trauma, and this regenerative capacity diminishes over time. Human stem cell research explores therapeutic regenerative approaches to treat various conditions. Mesenchymal stem cells (MSCs) are derived from adult stem cells; they are multipotent and exert anti-inflammatory and immunomodulatory effects. They can differentiate into multiple cell types of the mesenchyme, for example, endothelial cells, osteoblasts, chondrocytes, fibroblasts, tenocytes, vascular smooth muscle cells, and sarcomere muscular cells. MSCs are easily obtained and can be cultivated and expanded in vitro; thus, they represent a promising and encouraging treatment approach in orthopedic surgery. Here, we review the application of MSCs to various orthopedic conditions, namely, orthopedic trauma; muscle injury; articular cartilage defects and osteoarthritis; meniscal injuries; bone disease; nerve, tendon, and ligament injuries; spinal cord injuries; intervertebral disc problems; pediatrics; and rotator cuff repair. The use of MSCs in orthopedics may transition the practice in the field from predominately surgical replacement and reconstruction to bioregeneration and prevention. However, additional research is necessary to explore the safety and effectiveness of MSC treatment in orthopedics, as well as applications in other medical specialties.

  • Roberto Berebichez-Fridman, Ricardo Gómez-García, Julio Granados-Montiel, Enrique Berebichez-Fastlicht, Anell Olivos-Meza, Julio Granados, Cristina Velasquillo, and Clemente Ibarra

Mesenchymal stem cells for cartilage regeneration in osteoarthritis

  • Abstract

    Osteoarthritis (OA) is a slowly progressive disease where cartilage of the synovial joint degenerates. It is most common in the elderly where patients experience pain and reduce physical activity. In combination with lack of conventional treatment, patients are often left with no other choices than arthroplasty. Over the last years, multipotent stromal cells have been used in efforts to treat OA. Mesenchymal stem/progenitor cells (MSCs) are stromal cells that can differentiate into bone, fat, and cartilage cells. They reside within bone marrow and fat. MSCs can also be found in synovial joints where they affect the progression of OA. They can be isolated and proliferated in an incubator before being applied in clinical trials. When it comes to treatment, emphasis has hitherto been on autologous MSCs, but allogenic cells from healthy donors are emerging as another source of the cells. The first adaptations of MSCs revolved in the use of cell-rich matrix, delivered as invasive surgical procedure, which resulted in production of hyaline cartilage and fibrocartilage. However, the demand for less invasive delivery of cells has prompted the use of direct intra-articular injections, wherein a large amount of suspended cells are implanted in the cartilage defect.

  • Baldur Kristjánsson and Sittisak Honsawek

Cartilage Regeneration in Osteoarthritic Patients by a Composite of Allogeneic Umbilical Cord Blood‐Derived Mesenchymal Stem Cells and Hyaluronate Hydrogel: Results from a Clinical Trial for Safety and Proof‐of‐Concept with 7 Years of Extended Follow‐Up

  • Abstract

    Few methods are available to regenerate articular cartilage defects in patients with osteoarthritis. We aimed to assess the safety and efficacy of articular cartilage regeneration by a novel medicinal product composed of allogeneic human umbilical cord blood‐derived mesenchymal stem cells (hUCB‐MSCs). Patients with Kellgren‐Lawrence grade 3 osteoarthritis and International Cartilage Repair Society (ICRS) grade 4 cartilage defects were enrolled in this clinical trial. The stem cell‐based medicinal product (a composite of culture‐expanded allogeneic hUCB‐MSCs and hyaluronic acid hydrogel [Cartistem]) was applied to the lesion site. Safety was assessed by the World Health Organization common toxicity criteria. The primary efficacy outcome was ICRS cartilage repair assessed by arthroscopy at 12 weeks. The secondary efficacy outcome was visual analog scale (VAS) score for pain on walking. During a 7‐year extended follow‐up, we evaluated safety, VAS score, International Knee Documentation Committee (IKDC) subjective score, magnetic resonance imaging (MRI) findings, and histological evaluations. Seven participants were enrolled. Maturing repair tissue was observed at the 12‐week arthroscopic evaluation. The VAS and IKDC scores were improved at 24 weeks. The improved clinical outcomes were stable over 7 years of follow‐up. The histological findings at 1 year showed hyaline‐like cartilage. MRI at 3 years showed persistence of the regenerated cartilage. Only five mild to moderate treatment‐emergent adverse events were observed. There were no cases of osteogenesis or tumorigenesis over 7 years. The application of this novel stem cell‐based medicinal product appears to be safe and effective for the regeneration of durable articular cartilage in osteoarthritic knees. Stem Cells Translational Medicine 2017;6:613–621

  • Yong‐Beom Park, Chul‐Won Ha, Choong‐Hee Lee, Young Cheol Yoon, and Yong‐Geun Park

Mesenchymal regenerative medicine therapy in the treatment of osteoarthritis: reparative pathways, safety and efficacy – a review

  • Abstract

    Osteoarthritis is a leading cause of pain and disability across the world. With an aging population its prevalence is likely to further increase. Current accepted medical treatment strategies are aimed at symptom control rather than disease modification. Surgical options including joint replacement are not without possible significant complications. A growing interest in the area of regenerative medicine, led by an improved understanding of the role of mesenchymal stem cells in tissue homeostasis and repair, has seen recent focused efforts to explore the potential of stem cell therapies in the active management of symptomatic osteoarthritis. Encouragingly, results of pre-clinical and clinical trials have provided initial evidence of efficacy and indicated safety in the therapeutic use of mesenchymal stem cell therapies for the treatment of knee osteoarthritis. This paper explores the pathogenesis of osteoarthritis and how mesenchymal stem cells may play a role in future management strategies of this disabling condition.

  • Julien Freitag, Dan BatesRichard BoydKiran ShahAdele BarnardLeesa Huguenin and Abi Tenen

Stem Cell Application for Osteoarthritis in the Knee Joint:
A Mini Review

  • The aim of this review is to outline the latest advances in regenerative medicine therapy for knee osteoarthritis as well as highlight some of the advantages of regenerative medicine therapy over traditional approaches aimed at restoration of cartilage function in the knee.
  • Kristin Uth and Dimitar Trifonov

Current Perspectives in Stem Cell Research for Knee Cartilage Repair

  • This review draws attention to the different perspectives on regenerative medicine therapy for repairing damaged cartilage in the knees. It also provides adequate research about the issue with cartilage repair and the role of regenerative medicine therapy during recovery.
  • Patrick Orth, Ana Rey-Rico, Jagadeesh K Venkatesan, Henning Madry, and Magali Cucchiarini

Clinical Efficacy and Safety of Mesenchymal Stem Cell Transplantation for Osteoarthritis Treatment: A Meta-analysis

  • Abstract

    In this study, the researchers examine the therapeutic efficacy and safety of mesenchymal stem cells (MSCs) for knee osteoarthritis (OA) therapy. It provides significant information about the effectiveness of regenerative medicine therapy for knee osteoarthritis.

  • Ma Yubo, Li Yanyan, Li Li, Sun Tao, Lin Bo, and Chen Lin

Advances and Prospects in Stem Cells for Cartilage Regeneration

  • This review examines emerging trends on using stem cells in cartilage tissue repair and regenerative medicine. It focuses on the characterization of cartilage stem cells, the chondrogenic differentiation of stem cells, and the various strategies, approaches, and clinical studies.
  • Mingjie Wang, Zhiguo Yuan, Ning Ma, Chunxiang Hao, Weimin Guo, Gengyi Zou, Yu Zhang, Mingxue Chen, Shuang Gao, Jiang Peng, Aiyuan Wang, Yu Wang, Xiang Sui, Wenjing Xu, Shibi Lu, Shuyun Liu, and Quanyi Guo

Cartilage Repair by Mesenchymal Stem Cells: Clinical Trial Update and Perspectives

  • This review summarizes recently reported MSC-based clinical trials and discusses new research directions with particular focus on the potential application of MSC-derived extracellular vehicles, miRNAs and advanced gene editing techniques.
  • Wayne Yuk-wai Lee and Bin Wang

Mesenchymal Regenerative Medicine Therapy in the Treatment of Hip Osteoarthritis

  • This study was performed to investigate the safety and efficacy of the intra-articular infusion of ex vivo expanded autologous bone marrow-derived mesenchymal stem cells (BM-MSC) to a cohort of patients with articular cartilage defects in the hip.
  • Rodrigo Mardones, Claudio M. Jofré, L. Tobar, José J. Minguell

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