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Stemcell Research & Evidence - Orthopaedics

New Zealand Stem Cell Therapy Auckland & Christchurch

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New Zealand Stem Cell Clinic Auckland & Christchurch

Cell therapy for disc degeneration - potentials and pitfalls

Orthop Clin North Am. 2004 Jan;35(1):85-93.


Spine Service, Department of Orthopaedic Surgery, St. George Hospital Campus, University of New South Wales, Research and Education Centre, South Street, Kogarah, Sydney NSW 2217, Australia.


Disc degeneration is considered a major source of pain in patients with chronic low back pain. Novel strategies to cure or decrease the symptoms and increase the patient's quality of life and function are under development. Until recently conservative treatment and fusion surgery were the main therapeutic options. Disc prostheses are undergoing clinical evaluation. The potential for cell transplantation to the intervertebral disc with mature autologous disc cells, chondrocytes, or stem cells is in early stages of investigation. Cell transplantation potentially can increase proteoglycan production and induce disc regeneration or slow down the degeneration process. In animal models, transplantation of autologous disc cells and chondrocytes (derived from costal cartilage) has been demonstrated to be feasible and may slow disc degeneration.

New strategies for disc repair: novel preclinical trials

J Orthop Sci. 2005;10(1):112-8.


Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, Bohseidai, Isehara, 259-1193, Japan.


Degeneration of lumbar intervertebral discs is a major cause of low back complaints, an irreversible occurrence with no currently available treatment. Furthermore, various surgical procedures can accelerate disc degeneration. On the other hand, recent experimental studies on disc cells have demonstrated an important role for the nucleus pulposus in preserving overall disc structure. The author's group has already found that nucleus pulposus cells activated annulus fibrous cells, and reinsertion of nucleus pulposus cells slowed further disc degeneration. We have designed three subsequent studies that were designed to examine further possibilities for clinical transplantation: (1) activation of nucleus pulposus cells by mesenchymal stem cells; (2) focus on the multilineage differentiation potential of mesenchymal stem cells as an alternative cell source for cell transplantation therapy of disc degeneration; (3) the possibility of a human nucleus pulposus cell line as a cell source for cell transplantation therapy. Activation of nucleus pulposus could be achieved by co-culture with autogenous mesenchymal stem cells allowed to have direct cellular interaction. This would be a useful clinical cell source. Induction of nucleus pulposus cells by autogenous mesenchymal stem cells also would be an important subject for a clinical trial. Clinical application of the cells derived from a human nucleus pulposus cell line is an important project to be undertaken in the near future.

Regenerative effects of transplanting mesenchymal stem cells embedded in atelocollagen to the degenerated intervertebral disc

Biomaterials. 2006 Jan;27(3):335-45.


Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan.


Intervertebral disc (IVD) degeneration, a common cause of low back pain in humans, is a relentlessly progressive phenomenon with no currently available effective treatment. In an attempt to solve this dilemma, we transplanted autologous mesenchymal stem cells (MSCs) from bone marrow into a rabbit model of disc degeneration to determine if stem cells could repair degenerated IVDs. LacZ expressing MSCs were transplanted to rabbit L2-L3, L3-L4 and L4-L5 IVDs 2 weeks after induction of degeneration. Changes in disc height by plain radiograph, T2-weighted signal intensity in magnetic resonance imaging (MRI), histology, immunohistochemistry and matrix associated gene expressions were evaluated between normal controls (NC) without operations, sham operated with only disc degeneration being induced, and MSC-transplanted animals for a 24-week period. Results showed that after 24 weeks post-MSC transplantation, degenerated discs of MSC-transplanted group animals regained a disc height value of about 91%, MRI signal intensity of about 81%, compared to NC group discs. On the other hand, sham-operated group discs demonstrated the disc height value of about 67% and MRI signal intensity of about 60%. Macroscopic and histological evaluations confirmed relatively preserved nucleus with circular annulus structure in MSC-transplanted discs compared to indistinct structure seen in sham. Restoration of proteoglycan accumulation in MSC-transplanted discs was suggested from immunohistochemistry and gene expression analysis. These data indicate that transplantation of MSCs effectively led to regeneration of IVDs in a rabbit model of disc degeneration as suggested in our previous pilot study. MSCs may serve as a valuable resource in cell transplantation therapy for degenerative disc disease.

Stem cell regeneration of the nucleus pulposus

Spine J. 2004 Nov-Dec;4(6 Suppl):348S-353S.


Department of Orthopaedic Surgery, Thomas Jefferson University, 925 Chestnut Street, Philadelphia, PA 19107, USA.


Low back pain due to disc degeneration is one of the largest health problems faced in this nation when judged by lost work time and direct as well as indirect costs. Many experimental methods are being explored to treat or to reverse the effect of disc degeneration. This article reviews the strategy of a tissue engineering approach to disc regeneration. Mesenchymal stem cells (MSC) such as those obtained from marrow stroma when exposed to the appropriate microenvironment (hypoxia, growth factor, three dimensional culture) differentiate into nucleus pulposus-like cells. These then may be candidates for transplantation and nucleus repopulation. While the work is in its infancy, there is significant optimism that next steps will lead to organ culture models of disc degeneration and regeneration, and ultimately to in vivo rescue of degenerating discs with stem cell treatment.

Bone mesenchymal stem cells transplanted into rabbit intervertebral discs can increase proteoglycans

Clin Orthop Relat Res. 2005 Jan;(430):219-26.


Institute of Endemic Bone Diseases, Medical College of Xi'an Jiaotong University, Xi'an, P.R. of China.


We sought to determine whether transplanted allogeneic bone mesenchymal stem cells can survive and increase the amount of proteoglycans in intervertebral discs. We used the rabbit intervertebral disc as a model, creating three groups: an uninjected control group, a group injected with saline, and a group injected with 1 x 10(5) of bone mesenchymal stem cells containing trace marker gene LacZ from young rabbits. At 1, 3, and 6 months, X-gal staining and DNA-polymerase chain reaction of the neomycin-resistant gene were used to ascertain cell location. Reverse transcription-polymerase chain reaction and enzyme-linked immunosorbant assay analysis were done to evaluate the effect on the disc matrix. Transplanted mesenchymal stem cells were located and identified in the group injected with mesenchymal stem cells, whereas we detected none in the saline and control groups. The amount of mRNA and protein of proteoglycan and collagen Type II in the mesenchymal stem cells group was increased, whereas the amount of collagen Type I did not change. We found no changes in the saline group. Our data suggest transplanted allogenic bone mesenchymal stem cells can survive and increase proteoglycan amount, supporting its potential use as a treatment of intervertebral disc degeneration.

Light-activated gene transduction of recombinant adeno-associated virus in human mesenchymal stem cells

Gene Ther. 2004 Jan;11(1):34-41.


The Center for Musculoskeletal Research, University of Rochester, Rochester, NY 14642, USA.


Deficiencies in skeletal tissue repair and regeneration lead to conditions like osteoarthritis, osteoporosis and degenerative disc disease. While no cure for these conditions is available, the use of human bone marrow derived-mesenchymal stem cells (HuMSCs) has been shown to have potential for cell-based therapy. Furthermore, recombinant adeno-associated viruses (rAAV) could be used together with HuMSCs for in vivo or ex vivo gene therapy. Unfortunately, the poor transduction efficiency of these cells remains a significant obstacle. Here, we describe the properties of ultraviolet (UV) light-activated gene transduction (LAGT) with rAAV in HuMSCs, an advance toward overcoming this limitation. Using direct fluorescent image analysis and real-time quantitative PCR to evaluate enhanced green fluorescent protein (eGFP) gene expression, we found that the optimal effects of LAGT with limited cytotoxicity occurred at a UV dose of 200 J/m(2). Furthermore, this UV irradiation had no effect on either the chondrogenic or osteogenic potential of HuMSCs. Significant effects of LAGT in HuMSCs could be detected as early as 12 h after exposure and persisted over 21 days, in a time and energy-dependent manner. This LAGT effect was maintained for more than 8 h after irradiation and required only a 10-min exposure to rAAV after UV irradiation. Finally, we show that the production of secreted TGFbeta1 protein from rAAV-TGFbeta1-IRES-eGFP infected to HuMSCs is highly inducible by UV irradiation. These results demonstrate that LAGT combined with rAAV is a promising procedure to facilitate gene induction in HuMSCs for human gene therapy.

Biologic strategies for the therapy of intervertebral disc degeneration

Expert Opin Biol Ther. 2003 Dec;3(8):1209-14.


Department of Orthopaedic Surgery, Carolinas Medical Center, PO Box 32861, Charlotte, NC 28232, USA.


Recent advances in tissue engineering have led to promising new approaches for the biologic treatment of disc degeneration. At present, there is no effective therapy for disc degeneration, a condition which results in large healthcare and socio-economic costs. This article will examine the current approaches used in biologic therapies for disc degeneration, including cell-based tissue engineering, gene therapy and the application of mesenchymal stem cells, and discuss their therapeutic potential, as demonstrated in animal models and experimental studies to date.

Ossification of the posterior longitudinal ligament of the lumbar spine: a case series

Neurosurgery. 2010 Nov;67(5):1311-8; discussion 1318.


Department of Orthopaedic Surgery, Kyushu University Hospital, Fukuoka, Japan.


Background: Reports on ossification of the posterior longitudinal ligament (OPLL) of the lumbar spine have so far been limited.

Objective: To evaluate surgically documented cases of lumbar OPLL at our facility to clarify its characteristics and analyze clinical outcomes.

Methods: During the past 27 years, 6192 patients underwent operations for degenerative lumbar spine diseases. Of these, we selected surgically treated lumbar OPLL patients from our database to analyze the clinical and radiological disease characteristics. Surgical results were classified according to the Japanese Orthopaedic Association scale.

Results: Only 10 patients underwent surgery for lumbar OPLL: 6 men and 4 women (mean age 44.1 years). Among these, OPLL developed in 4 patients at multiple vertebral body levels and in 6 at a single level. Coexisting lumbar disc herniation was observed in 4 patients. Although the rate of maximum canal stenosis brought about by OPLL was relatively high (mean 45.1%), unilateral radicular symptoms were the most frequently observed, and only 2 patients exhibited typical lumbar claudication caused by the canal stenosis. Two patients underwent surgery via an anterior approach and 8 via a posterior approach. The mean preoperative Japanese Orthopaedic Association scale score was 7.9, which improved to 17.8 postoperatively. No neurological deterioration caused by surgery was observed in any case.

Conclusion: Although the frequency of lumbar OPLL requiring surgical treatment was remarkably low, its clinical condition varies greatly among patients depending on the localization and degree of ossification. To achieve a better surgical outcome, precise diagnosis with computed tomography and an appropriate surgical approach are important.

Recent advances in disc cell biology

Spine (Phila Pa 1976). 2003 Jan 15;28(2):186-93.


Department of Orthopaedic Surgery, Carolinas Medical Center, Charlotte, North Carolina 28232, USA.


Study design: There have been many advances over the past decade in understanding and experimentally modulating biologic aspects of intervertebral disc cell function. An overview of the current state of this biologic research is presented.

Objectives: To provide clinicians with a review of important recent advances in biologic studies of the disc and their implications for potential disc therapies.

Summary of background data: Historically, anatomic, biochemical, radiologic, and biomechanical studies of the intervertebral disc formed the foundation on which our understanding of disc function was built. Magnetic resonance imaging techniques that allowed viewing of soft tissue components of the disc further advanced imaging capabilities.

Methods: Recent publications are reviewed.

Results: Experimental approaches over the past decade have enabled researchers to look more critically at disc cell function. This is important because disc cell function produces the extracellular matrix components of the disc, which, in turn, shape the disc's subsequent physiologic and biomechanical functions. New approaches to the study of disc cell function, methods to manipulate disc cells, studies of intact discs and disc nutrition, vertebral endplate structure and function, tissue engineering, gene therapy, and the potential of stem cells in disc therapy are reviewed and discussed.

Conclusions: Many believe that disc degeneration has a cellular basis. New research is helping us better understand healthy, aging, and degenerating discs. Modern methods to manipulate and modulate disc cell function open exciting and challenging new therapeutic possibilities for future biologic treatments of disc degeneration.

Transplantation of mesenchymal stem cells embedded in Atelocollagen gel to the intervertebral disc: a potential therapeutic model for disc degeneration

Biomaterials. 2003 Sep;24(20):3531-41.


Department of Orthopaedic Surgery, Functional Reconstruction, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan.


Intervertebral disc degeneration is considered to be one of the major causes of low back pain. Despite this irreversible phenomenon, attempts to decelerate disc degeneration using various techniques have been reported. However, to date there has been no proven technique effective for broad clinical application. Based on previous studies, we hypothesize that maintenance of proteoglycan content in the disc is achieved by avoiding the depletion of nucleus pulposus and preserving the structure of the annulus is a primary factor in decelerating disc degeneration. One novel approach to solve the dilemma of intervertebral disc degeneration is found at the stem cell level. Mesenchymal stem cells (MSCs) are known to possess the ability to differentiate into various kinds of cells from mesenchymal origin. Although the majority of cells that contribute to disc formation are known to obtain chondrocyte-like phenotypes, no reported study has emphasized the correlation with mesenchymal stem cells. To evaluate the possible potential of MSCs in disc cell research and treatment of degenerative disc disease, autologous MSCs embedded in Atelocollagen gel were transplanted into the discs of rabbits which had undergone a procedure proven to induce degeneration. The results suggest that MSC transplantation is effective in decelerating disc degeneration in experimental models and provided new hopes for treatment of degenerative disc disease in humans. Atelocollagen gel served as an important carrier of MSCs in transplantation, permitting proliferation, matrix synthesis and differentiation of MSCs. This study strengthens the viable efficacy of practical application of MSCs in treatment of intervertebral disc disease.

Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells

Pain Physician. 2008 May-Jun;11(3):343-53.


Regenerative Sciences Inc (RSI), Centeno-Schultz Clinic, Westminster, CO 80020, USA.


Background: The ability to repair tissue via percutaneous means may allow interventional pain physicians to manage a wide variety of diseases including peripheral joint injuries and osteoarthritis. This review will highlight the developments in cellular medicine that may soon permit interventional pain management physicians to treat a much wider variety of clinical conditions and highlight an interventional case study using these technologies

Objective: To determine if isolated and expanded human autologous mesenchymal stem cells could effectively regenerate cartilage and meniscal tissue when percutaneously injected into knees.

Design: Case Study

Setting: Private Interventional Pain Management practice.

Methods: An IRB approved study with a consenting volunteer in which mesenchymal stem cells were isolated and cultured ex-vivo from bone marrow aspiration of the iliac crest. The mesenchymal stem cells were then percutaneously injected into the subject's knee with MRI proven degenerative joint disease. Pre- and post-treatment subjective visual analog pain scores, physical therapy assessments, and MRIs measured clinical and radiographic changes.

Results: At 24 weeks post-injection, the patient had statistically significant cartilage and meniscus growth on MRI, as well as increased range of motion and decreased modified VAS pain scores.

Conclusion: The described process of autologous mesenchymal stem cell culture and percutaneous injection into a knee with symptomatic and radiographic degenerative joint disease resulted in significant cartilage growth, decreased pain and increased joint mobility in this patient. This has significant future implications for minimally invasive treatment of osteoarthritis and meniscal injury.

Repair of meniscal cartilage white zone tears using a stem cell/collagen-scaffold implant

Biomaterials. 2010 Mar;31(9):2583-91.


Department of Clinical Science at North Bristol, University of Bristol, UK.


Injuries to the avascular region of knee meniscal cartilage do not heal spontaneously. To address this problem we have developed a new stem cell/collagen-scaffold implant system in which human adult bone marrow mesenchymal stem cells are seeded onto a biodegradable scaffold that allows controlled delivery of actively dividing cells to the meniscus surface. Sandwich constructs of two white zone ovine meniscus discs with stem cell/collagen-scaffold implant in between were cultured in vitro for 40 days. Histomorphometric analysis revealed superior integration in the stem cell/collagen-scaffold groups compared to the cell-free collagen membrane or untreated controls. The addition of TGF-beta1 to differentiate stem cells to chondrocytes inhibited integration. Biomechanical testing demonstrated a significant 2-fold increase in tensile strength in all constructs using the stem cell/collagen-scaffold compared to control groups after 40 days in culture. Integration was significantly higher when collagen membranes were used that had a more open/spongy structure adjacent to both meniscal cartilage surfaces, whereas a collagen scaffold designed for osteoinduction failed to induce any integration of meniscus. In conclusion, the stem cell/collagen-scaffold implant is a potential therapeutic treatment for the repair of white zone meniscal cartilage tears.

Role of mesenchymal stem cells in tissue engineering of meniscus

J Biomed Mater Res A. 2010 Sep 15;94(4):1150-61.


Department of Trauma Surgery, University Hospital of Regensburg, Regensburg, Germany.


Tissue engineering is a promising approach for the treatment of tissue defects. Mesenchymal stem cells are of potential use as a source of repair cells or of important growth factors for tissue engineering. The purpose of this study was to examine the role of mesenchymal stem cells in meniscal tissue repair. This was tested using several cell and biomaterial-based treatment options for repair of defects in the avascular zone of rabbit menisci. Circular meniscal punch defects (2 mm) were created in the avascular zone of rabbit menisci and left empty or filled with hyaluronan-collagen composite matrices without cells, loaded with platelet-rich plasma, autologous bone marrow, or autologous mesenchymal stem cells. In some experiments, matrices with stem cells were precultured in chondrogenic medium for 14 days before implantation. Rabbits were then allowed free cage movement after surgery for up to 12 weeks. Untreated defects and defects treated with cell-free implants had muted fibrous healing responses. Neither bone marrow nor platelet-rich plasma loaded in matrices produced improvement in healing compared with cell-free implants. The implantation of 14 days precultured chondrogenic stem cell-matrix constructs resulted in fibrocartilage-like repair tissue, which was only partially integrated with the native meniscus. Non-precultured mesenchymal stem cells in hyaluronan-collagen composite matrices stimulated the development of completely integrated meniscus-like repair tissue. The study shows the necessity of mesenchymal stem cells for the repair of meniscal defects in the avascular zone. Mesenchymal stem cells seem to fulfill additional repair qualities besides the delivery of growth factors.

Mesenchymal stem cell-based therapy for cartilage repair: a review

Knee Surg Sports Traumatol Arthrosc. 2009 Nov;17(11):1289-97.


Oslo Sports Trauma Research Center, Norwegian School of Sports Sciences, PO Box 4014, Ullevaal Stadion, 0806 Oslo, Norway.


Articular cartilage injury remains one of the major concerns in orthopaedic surgery. Mesenchymal stem cell (MSC) transplantation has been introduced to avoid some of the side effects and complications of current techniques. The purpose of this paper is to review the literature on MSC-based cell therapy for articular cartilage repair to determine if it can be an alternative treatment for cartilage injury. MSCs retain both high proliferative potential and multipotentiality, including chondrogenic differentiation potential, and a number of successful results in transplantation of MSCs into cartilage defects have been reported in animal studies. However, the use of MSCs for cartilage repair is still at the stage of preclinical and phase I studies, and no comparative clinical studies have been reported. Therefore, it is difficult to make conclusions in human studies. This requires randomized clinical trials to evaluate the effectiveness of MSC-based cell therapy for cartilage repair.

Transplantation of meniscus regenerated by tissue engineering with a scaffold derived from a rat meniscus and mesenchymal stromal cells derived from rat bone marrow

Artif Organs. 2008 Jul;32(7):519-24.


Department of Orthopaedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.


The purpose of this study was to assess transplantation of regenerated menisci using scaffolds from normal allogeneic menisci and bone-marrow-derived mesenchymal stromal cells (BM-MSCs) of rats. We reported that scaffolds derived from normal menisci seeded with BM-MSCs in vitro could form meniscal tissues within 4 weeks. Then, we hypothesized that our tissues could be more beneficial than allogeneic menisci regarding early maturation and chondroprotective effect. Bone marrow was aspirated from enhanced green fluorescent protein transgenic rats. BM-MSCs were isolated and seeded onto scaffolds which were prepared from Sprague-Dawley rat menisci. After 4 weeks in coculture, the tissues were transplanted to the defect of menisci. Repopulation of BM-MSCs and expression of extracellular matrices were observed in the transplanted tissues at 4 weeks after surgery. At 8 weeks, articular cartilage in the cell-free group was more damaged compared to that in the cell-seeded group or the meniscectomy group.

Regeneration of meniscus cartilage in a knee treated with percutaneously implanted autologous mesenchymal stem cells

Med Hypotheses. 2008 Dec;71(6):900-8.


Regenerative Sciences Inc, Centeno-Schultz Clinic, Westminster, CO 80020, USA.


Mesenchymal stem cells are pluripotent cells found in multiple human tissues including bone marrow, synovial tissues, and adipose tissues. They have been shown to differentiate into bone, cartilage, muscle, and adipose tissue and represent a possible promising new therapy in regenerative medicine. Because of their multi-potent capabilities, mesenchymal stem cell (MSC) lineages have been used successfully in animal models to regenerate articular cartilage and in human models to regenerate bone. The regeneration of articular cartilage via percutaneous introduction of mesenchymal stem cells (MSC's) is a topic of significant scientific and therapeutic interest. Current treatment for cartilage damage in osteoarthritis focuses on surgical interventions such as arthroscopic debridement, microfracture, and cartilage grafting/transplant. These procedures have proven to be less effective than hoped, are invasive, and often entail a prolonged recovery time. We hypothesize that autologous mesenchymal stem cells can be harvested from the iliac crest, expanded using the patient's own growth factors from platelet lysate, then successfully implanted to increase cartilage volume in an adult human knee. We present a review highlighting the developments in cellular and regenerative medicine in the arena mesenchymal stem cell therapy, as well as a case of successful harvest, expansion, and transplant of autologous mesenchymal stem cells into an adult human knee that resulted in an increase in meniscal cartilage volume.

Intra-articular Injected synovial stem cells differentiate into meniscal cells directly and promote meniscal regeneration without mobilization to distant organs in rat massive meniscal defect

Stem Cells. 2009 Apr;27(4):878-87.


Section of Orthopedic Surgery, Tokyo Medical and Dental University, Tokyo, Japan.


Osteoarthritis in the knees, which can be caused by meniscal defect, constitutes an increasingly common medical problem. Repair for massive meniscal defect remains a challenge owing to a lack of cell kinetics for the menisci precursors in knee joint. The synovium plays pivotal roles during the natural course of meniscal healing and contains mesenchymal stem cells (MSCs) with high chondrogenic potential. Here, we investigated whether intra-articular injected synovium-MSCs enhanced meniscal regeneration in rat massive meniscal defect. To track the injected cells, we developed transgenic rats expressing dual luciferase (Luc) and LacZ. The cells derived from synovium of the rats demonstrated colony-forming ability and multipotentiality, both characteristics of MSCs. Hierarchical clustering analysis revealed that gene expression of meniscal cells was closer to that of synovium-MSCs than to that of bone marrow-MSCs. Two to 8 weeks after five million Luc/LacZ+ synovium-MSCs were injected into massive meniscectomized knee of wild-type rat, macroscopically, the menisci regenerated much better than it did in the control group. After 12 weeks, the regenerated menisci were LacZ positive, produced type 2 collagen, and showed meniscal features by transmission electron microscopy. In in-vivo luminescence analysis, photons increased in the meniscus-resected knee over a 3-day period, then decreased without detection in all other organs. LacZ gene derived from MSCs could not be detected in other organs except in synovium by real-time PCR. Synovium-MSCs injected into the massive meniscectomized knee adhered to the lesion, differentiated into meniscal cells directly, and promoted meniscal regeneration without mobilization to distant organs.

Partial regeneration of the human hip via autologous bone marrow nucleated cell transfer

Pain Physician. 2006 Jul;9(3):253-6.


The Centeno-Schultz Clinic, 11080 Circle Point Road, Building 2, Suite 140, Westminster, CO 80020, USA.


History: This is a case report of a 64-year-old white male with a 20 year history of unilateral hip pain that had become debilitating over the last several years. On intake, Harris hip score was rated as: Pain subscale = 10, Function subscale = 32, Deformity subscale = 4, Motions subscale = 4.775 with a total score of 50.8 out of 100. MRI of the affected hip showed severe degeneration with spurring, decrease in joint space, and several large subchondral cysts. The patient had been evaluated by an orthopedic surgeon and told he was a candidate for bipolar hip replacement.

Method: Two autologous nucleated cell collections were performed from bone marrow with subsequent isolation and transfers into the intra-articular hip using a hyaluronic acid and thrombin activated platelet rich plasma scaffold. Marrow samples were processed by centrifugation and lysis techniques to isolate nucleated cells.

Conclusion: This report describes partial by articular surface regeneration 8 weeks after intraarticular bone marrow transfer. Post-op 3.0T FGRE MRI showed neocortex formation when compared to immediate pre-op MRI and objective improvements were noted that coincided with subjective reports of improvement.

Stem cell therapy for osteonecrosis of the femoral head

Expert Opin Biol Ther. 2005 Apr;5(4):437-42.


Department of Rheumatology and Physical Medicine, Erasme University Hospital, Université Libre de Bruxelles, 808 route de Lennik, 1070 Bruxelles, Belgium.


Aseptic non-traumatic osteonecrosis of the femoral head is a painful disorder of the hip that can lead to femoral head collapse and the need for total hip replacement. As osteonecrosis may be a disease of mesenchymal cells or bone cells, the possibility has been raised that bone marrow containing osteogenic precursors implanted into the necrotic lesion could be of benefit in this condition. Indeed, bone marrow contains adult stem cells, such as haematopoietic stem cells, mesenchymal stem cells and multipotent stem cells, that might have osteogenic properties. The efficacy of bone marrow implantation into the osteonecrotic zone was studied in two prospective trials. This treatment avoided the progression of the disease to the stage of the subchondral fracture (stage III) and reduced the need for total hip replacement. The mechanisms involved might include improved osteogenesis and angiogenesis. This new therapeutic approach should modify the treatment of early-stage osteonecrosis of the femoral head.

Treatment of early avascular necrosis of femoral head by core decompression combined with autologous bone marrow mesenchymal stem cells transplantation


Department of Orthopedics, the Orthopedic Surgery Center of Chinese PLA, Southwest Hospital, Third Military Medical University, Chongqing, 400038, P.R. China.


Objective: To compare the clinical outcomes of the core decompression combined with autologous bone marrow mesenchymal stem cells (BMSCs) transplantation with the isolated core decompression for the treatment of early avascular necrosis of the femoral head (ANFH).

Methods: From May 2006 to October 2008, 8 patients (16 hips) with early ANFH were treated. There were 7 males and 1 female with an average age of 35.7 years (range, 19-43 years). According to the system of the Association Research Circulation Osseous (ARCO): 4 hips were classified as stage II a, 2 as stage II b, 1 as stage II c, and 1 as stage III a in group A; 2 hips were classified as stage II a, 2 as stage II b, 3 as stage II c, and 1 as stage III a in group B. The average disease course was 1.1 years (range, 4 months to 2 years). The patients were randomly divided into 2 groups according to left or right side: group A, only the core decompression was used; group B, both the core decompression and autologous BMSCs transplantation were used. The Harris score and visual analogue scale (VAS) score were determined, imaging evaluation was carried out by X-rays and MRI pre- and post-operatively. The erythrocyte sedimentation rate, C-reactive protein, liver function, renal function, and immunoglobulin were detected for safety evaluation.

Results: All incisions healed by first intention. Eight patients were followed up 12-42 months (23.5 months on average). The clinical symptoms of pain and claudication were gradually improved. The Harris scores and VAS scores of all patients were increased significantly at 3, 6, and 12 months after operation (P < 0.05). There was no significant difference between groups A and B 3 and 6 months after operation (P > 0.05), but there was significant difference between groups A and B 12 months after operation (P < 0.05). The necrosis area of femoral head in groups A and B were 18.13% +/- 2.59% and 13.25% +/- 2.12%, respectively, showing significant difference (P < 0.05). In group A, femoral head collapsed 12 months after operation in 1 case of stage III. No complication of fever, local infection

Conclusion: The core decompression and the core decompression combined with BMSCs transplantation are both occurred. effective for the treatment of early ANFH. The core decompression combined with BMSCs transplantation is better than core decompression in the relief of pain and postponing head collapse.

Evaluation of Intravenously Delivered Allogeneic Mesenchymal Stem Cells for Treatment of Elbow Osteoarthritis in Dogs

Vet Comp Orthop Traumatol. 2019 May;32(3):173-181.


Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States.


Objectives: The aim of this study was to evaluate the safety and collect pilot data measuring clinical effects of intravenously administered, adipose-derived, culture-expanded, allogeneic mesenchymal stem cells in dogs with elbow osteoarthritis.

Materials and methods: Dogs (n = 13) with naturally occurring elbow osteoarthritis received three intravenous doses of allogeneic canine mesenchymal stem cells via an open-label clinical trial. Primary outcome measures collected over a 6-month study period included objective gait analysis, accelerometry, owner questionnaires and joint fluid analysis.

Results: No acute adverse events were observed following repeated intravenous treatment with allogeneic mesenchymal stem cells. A significant improvement in mean client-specific outcome measure (CSOM) activity score and CSOM behaviour score was observed when pre-treatment values were compared with post-treatment values (day >28). In contrast, mean peak vertical force significantly decreased from baseline to post-treatment (>day 28). Weekly activity counts did not show a significant difference between baseline to post-treatment time points. Synovial fluid biomarkers did not change during treatment, and labelled mesenchymal stem cells were rarely detected in synovial fluid samples collected after mesenchymal stem cell administration.

Clinical significance: For dogs with naturally occurring elbow osteoarthritis, intravenous administration of mesenchymal stem cells was clinically well tolerated. While some subjective outcome measures showed significant improvements, objective outcome measures did not confirm similar changes. Further research is needed before intravenous mesenchymal stem cells can be recommended as a treatment for elbow osteoarthritis in dogs.

Recent Developments in Clinical Applications of Mesenchymal Stem Cells in the Treatment of Rheumatoid Arthritis and Osteoarthritis

Front Immunol. 2021 Mar 8;12:631291.


Catholic Induced Pluripotent Stem Cell Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea.


Mesenchymal stem cell (MSC) therapies have been used as cell-based treatments for decades, owing to their anti-inflammatory, immunomodulatory, and regenerative properties. With high expectations, many ongoing clinical trials are investigating the safety and efficacy of MSC therapies to treat arthritic diseases. Studies on osteoarthritis (OA) have shown positive clinical outcomes, with improved joint function, pain level, and quality of life. In addition, few clinical MSC trials conducted on rheumatoid arthritis (RA) patients have also displayed some optimistic outlook. The largely positive outcomes in clinical trials without severe side effects establish MSCs as promising tools for arthritis treatment. However, further research is required to investigate its applicability in clinical settings. This review discusses the most recent advances in clinical studies on MSC therapies for OA and RA.

Human adipose-derived mesenchymal stem cells for osteoarthritis

Regen Med. 2018 Apr;13(3):295-307.


Department of Rheumatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.


Aim: This study aimed to evaluate the safety and therapeutic potential of autologous human adipose-derived mesenchymal stem cells (haMSCs) in patients with osteoarthritis.

Materials & methods: Safety and efficacy of haMSCs were preclinically assessed in vitro and in BALB/c-nu nude mice. 18 patients were enrolled and divided into three dose groups: the low-dose, mid-dose and high-dose group (1 × 107, 2 × 107 and 5 × 107 cells, respectively), provided three injections and followed up for 96 weeks.

Results & conclusion: The preclinical study established the safety and efficacy of haMSCs. Intra-articular injections of haMSCs were safe and improved pain, function and cartilage volume of the knee joint, rendering them a promising novel treatment for knee osteoarthritis. The dosage of 5 × 107 haMSCs exhibited the highest improvement ( Identifier: NCT01809769).

Microscopic histopathology of chronic refractory lateral epicondylitis

Am J Sports Med. 1992 Nov-Dec;20(6):746-9.


Division of Pathology, Mayo Clinic, Rochester, Minnesota 55905.


The histopathologic features from 11 patients who were treated surgically for lateral epicondylitis were graded and compared to similar tissue from 12 cadaveric specimens. All studies were done by a single pathologist who had no knowledge of the origin of the specimen. The surgical specimens were interpreted as abnormal in all 11 specimens, and all 12 of the control specimens were reported as being without histologic abnormality. Vascular proliferation was present in 10 of 11 and focal hyaline degeneration was recorded in all 11 of the surgical specimens. Neither feature was present in any of the control material (P < 0.001). These data suggest that chronic refractory lateral epicondylitis requiring surgery is a degenerative rather than inflammatory process. This may account for the lack of response to rest and antiinflammatory medication.

Research progress in the use of mesenchymal stem cells and their derived exosomes in the treatment of osteoarthritis

Ageing Res Rev. 2022 Sep;80:101684.


Departments of Geriatrics, First Affiliated Hospital of China Medical University, Shenyang, China. Electronic address:


Osteoarthritis (OA), as a common orthopedic disease with cartilage injury as its main pathological feature, has a complex pathogenesis and existing medical technology remains unable to reverse the progress of cartilage degeneration caused thereby. In recent years, mesenchymal stem cells (MSCs) and their secreted exosomes have become a focus of research into cartilage regeneration. MSCs have the potential to differentiate into a variety of cells. Under specific conditions, they can be promoted to differentiate into chondrocytes and maintain the function and stability of chondrocytes. Exosomes secreted by MSCs, as an intercellular messenger, can treat OA in a variety of ways through bioactive factors carried therewith, such as protein, lipid, mRNA, and miRNA. This study reviewed the application of MSCs and their exosomes from different sources in the prevention of OA, which provides a new idea for the treatment of OA.

Therapeutic effects of bone marrow mesenchymal stem cells-derived exosomes on osteoarthritis

J Cell Mol Med. 2021 Oct;25(19):9281-9294.


Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, China.


Mesenchymal stem cells (MSCs) have shown chondroprotective effects in clinical models of osteoarthritis (OA). However, effects of MSC-derived exosomes on OA remain unclear. The study aimed to investigate the therapeutic potential of exosomes from human bone marrow MSCs (BM-MSCs) in alleviating OA. The anterior cruciate ligament transection (ACLT) and destabilization of the medial meniscus (DMM) surgery were performed on the knee joints of a rat OA model, followed by intra-articular injection of BM-MSCs or their exosomes. In addition, BM-MSC-derived exosomes were administrated to primary human chondrocytes to observe the functional and molecular alterations. Both of BM-MSCs and BM-MSC-derived exosomes alleviated cartilage destruction and subchondral bone remodelling in OA rat model. Administration of BM-MSCs and exosomes could reduce joint damage and restore the trabecular bone volume fraction, trabecular number and connectivity density of OA rats. In addition, in vitro assays showed that BM-MSCs-exosomes could maintain the chondrocyte phenotype by increasing collagen type II synthesis and inhibiting IL-1β-induced senescence and apoptosis. Furthermore, exosomal lncRNA MEG-3 also reduced the senescence and apoptosis of chondrocytes induced by IL-1β, indicating that lncRNA MEG-3 might partially account the anti-OA effects of BM-MSC exosomes. The exosomes from BM-MSCs exerted beneficial therapeutic effects on OA by reducing the senescence and apoptosis of chondrocytes, suggesting that MSC-derived exosomes might provide a candidate therapy for OA treatment.

The future role of mesenchymal stem cells in the management of shoulder disorders

Arthroscopy. 2013 Oct;29(10):1702-11.


Department of Trauma and Orthopedic Surgery, Trauma Center Murnau, Murnau, Germany.


Purpose: Biologics may help to optimize the healing environment after rotator cuff repair. Mesenchymal stem cells (MSCs) may have the potential to regenerate a physiological enthesis, thereby improving healing at the repair site after rotator cuff repair.

Methods: The PubMed database was searched in May 2013. Only in vivo and in vitro studies reporting on stem cell use in the rotator cuff of humans or animals were included. Exclusion criteria consisted of the following: Level V evidence, systematic reviews, and studies reporting preliminary results.

Results: This query resulted in 141 citations. Of these, 90 were excluded based on the title of the study. A final group of 17 studies was included in this review (9 in vivo animal studies, 5 in vitro human studies, 1 in vitro animal study, 1 study reporting in vitro human and in vivo animal results, and 1 study reporting on clinical outcomes of human patients).

Conclusions: The current literature regarding therapeutic use of MSCs in shoulder surgery is limited. Although in vivo animal studies have shown some promising approaches to enhance tendon-to-bone healing, the use of MSCs for shoulder surgery should still be regarded as an experimental technique. Further basic and clinical research is needed until a procedure can be defined for the routine use of these cells in shoulder surgery.

Use of stem cells and growth factors in rotator cuff tendon repair

Curr Stem Cell Res Ther. 2015;10(1):5-10.


University College London Medical School, Gower Street, London WC1E 6BT, United Kingdom.


In this review, we analysed the role of stem cell and growth factor therapy on rotator cuff tendon repair. The injury to the rotator cuff tendons can be sustained in numerous ways and generally causes significant pain and disability to the affected individual. Following surgical repair of ruptured rotator cuff tendons re-rupture rates can be as high as 20-60%. In order to augment this repair process and to decrease the re-rupture rates tissue engineering methods can be used. These include the use of stem cells and growth factors. Mesenchymal stem cells are stem cells which can differentiate into a variety of connective tissue cell types and can therefore be utilised in repairing tendons. So far there has only been one human study using stem cells in rotator cuff tendon repair. This study has produced a positive result but consisted of only 14 patients and lacks a control group for comparison. Similar work has also been done using growth factors. Both individual and combination growth factor therapy have been used to improve rotator cuff tendon repair. However, the results so far have been disappointing with growth factors. For the purpose of future studies better techniques should be explored with regards to the delivery of stem cells and growth factors as well as the possibility of combining growth factor and stem cell therapy to improve repair rates.

Conditioned medium of human bone marrow-derived stem cells promotes tendon-bone healing of the rotator cuff in a rat model

Biomaterials. 2021 Apr;271:120714.


Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China.


Rotator cuff repair is a common surgery in sports medicine. During the surgery, torn tendon was re-fixed onto the bony surface. The majority of patients gain good results. However, re-tear occurs in some patients. The reason under this phenomenon is that the normal tendon-bone enthesis cannot be reconstructed. In order to strengthen the tendon-bone healing and promote enthesis regeneration, numerous manners are tested, among which stem cell related therapies are preferred. Stem cells, due to the ability of multi-lineage differentiation, are widely used in regenerative medicine. However, safety and ethics concerns limit its clinical use. Recent studies found that it is the secretome of stem cells that is biologically effective. On ground of this, we, in the current study, collected the conditioned medium of human bone marrow-derived stem cells (hBMSC-CM) and tested whether this acellular method could promote tendon-bone healing in a rat model of rotator cuff repair. By using histological, radiological, and biomechanical methods, we found that hBMSC-CM promoted tendon-bone healing of the rat rotator cuff. Then, we noticed that hBMSC-CM exerted an impact on macrophage polarization both in vivo and in vitro by inhibiting M1 phenotype and promoting M2 phenotype. Further, we proved that the benefit of hBMSC-CM on tendon-bone healing was related to its regulation on macrophage. Finally, we proved that, hBMSC-CM influenced macrophage polarization, which was, at least partially, related to Smad2/3 signaling pathway. Based on the experiments above, we confirmed the benefit of hBMSC-CM on tendon-bone healing, which relied on its immune-regulative property. Considering the accessibility and safety of acellular hBMSC-CM, we believe it is a promising candidate clinically for tendon-bone healing.

Injection of adipose stem cells in the treatment of rotator cuff disease - a narrative review of current evidence

Regen Med. 2022 Jul;17(7):477-489.


Department of Orthopedic Surgery, Henry Ford Hospital, Detroit, MI 48202, USA.


The purpose of this study is to summarize evidence for the use of adipose stem cell (ASC) injections in the treatment of rotator cuff tears (RCT) and identify future areas of study. A thorough literature search was performed to identify studies investigating the use of ASC injections in the treatment of RCTs. Among animal trials, it is unclear whether ASCs are of benefit for rotator cuff repair. In clinical trials, ASC injection may reduce retear rate with otherwise equivocal clinical outcomes. Although ASC injection may be safe, the literature does not provide a clear consensus as to the efficacy of ASC injections, nor does it delineate which patients would benefit most from this treatment.

Bone marrow mesenchymal stem cell-derived exosomes promote rotator cuff tendon-bone healing by promoting angiogenesis and regulating M1 macrophages in rats

Stem Cell Res Ther. 2020 Nov 25;11(1):496.


Sports Medicine Center, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.


Background: Rotator cuff tears (RCTs) often require reconstructive surgery. Tendon-bone healing is critical for the outcome of rotator cuff reconstruction, but the process of tendon-bone healing is complex and difficult. Mesenchymal stem cells (MSCs) are considered to be an effective method to promote tendon-bone healing. MSCs have strong paracrine, anti-inflammatory, immunoregulatory, and angiogenic potential. Recent studies have shown that MSCs achieve many regulatory functions through exosomes. The purpose of this study was to explore the role of bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) in tendon-bone healing.

Methods: Our study found that BMSC-Exos promote the proliferation, migration, and angiogenic tube formation of human umbilical vein endothelial cells (HUVECs). The mechanism by which BMSC-Exos achieve this may be through the regulation of the angiogenic signaling pathway. In addition, BMSC-Exos can inhibit the polarization of M1 macrophages and inhibit the secretion of proinflammatory factors by M1 macrophages. After rotator cuff reconstruction in rats, BMSC-Exos were injected into the tail vein to analyze their effect on the rotator cuff tendon-bone interface healing.

Results: It was confirmed that BMSC-Exos increased the breaking load and stiffness of the rotator cuff after reconstruction in rats, induced angiogenesis around the rotator cuff endpoint, and promoted growth of the tendon-bone interface.

Conclusion: BMSC-Exos promote tendon-bone healing after rotator cuff reconstruction in rats by promoting angiogenesis and inhibiting inflammation.

Effect of autologous adipose-derived mesenchymal stem cell therapy in the treatment of an osteochondral lesion of the ankle

BMJ Case Rep. 2020 Jul 8;13(7):e234595.


Melbourne Stem Cell Centre, Box Hill North, Victoria, Australia


Osteochondral lesions (OCLs) of the talus are rare but can be associated with significant morbidity and may lead to the development of osteoarthritis. An improved understanding of the action of mesenchymal stem cells (MSCs) has seen renewed interest in their role in cartilage repair, with early preclinical and clinical research showing benefits in symptomatic and structural improvement. A 42-year-old man presented with an unstable OCL of the talus and onset of early osteoarthritis with a history of multiple previous ankle arthroscopies for ankle impingement. The patient underwent arthroscopic removal of the OCL in combination with adipose-derived MSC therapy. The patient reported progressive improvement as measured by the validated Foot and Ankle Disability Index. Repeat MRI with additional T2 mapping techniques showed successful regeneration of hyaline-like cartilage. This case is the first to show the successful use of MSC therapy in the management of an ankle OCL. Trial registration: Australian New Zealand Clinical Trials Registry - ACTRN12617000638336.

Mesenchymal Stem Cell Applications for Joints in the Foot and Ankle

Clin Podiatr Med Surg. 2018 Jul;35(3):323-330.


Cambridge Health Alliance, 1493 Cambridge Street, Cambridge, MA 02139, USA.


The use of mesenchymal stem cell injections is a new approach to the treatment of painful joints, particularly in the foot and ankle. Previous studies performed in the knee have considered allogeneic and xenogeneic injections, and autologous cells expanded in culture. This article considers these applications and considers the possibility of performing these types of injections in the foot and ankle joints.

Mesenchymal Stem Cell-Bearing Sutures for Tendon Repair and Healing in the Foot and Ankle

Foot Ankle Clin. 2016 Dec;21(4):885-890.


Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, 1520 San Pablo Street, Suite 2000, Los Angeles, CA 90033, USA.


MImproving the quality and strength of soft tissue repairs remains an important area of orthopedic research and innovation. The need for immobilization and early motion is an important balance essential for the successful treatment of tendon repair and reconstruction. Mesenchymal stem cell (MSC)-bearing sutures represent an emerging biological augmentation to traditional suture repair. Two previous large studies using stem cell sutures in rat Achilles tendon models have demonstrated early increased biomechanical strength and significantly increased ultimate failure strength. The MSCs seem to remain locally at the repair site and enhance the histologic repair quality of the tendon collagen.

Matrix-associated stem cell transplantation (MAST) in chondral lesions at the ankle

Foot Ankle Surg. 2019 Jun;25(3):264-271.


Department for Foot and Ankle Surgery Rummelsberg and Nuremberg, Germany. Electronic address:


Background: The aim of the study was to assess the 5-year-follow-up after matrix-associated stem cell transplantation (MAST) in chondral lesions at the ankle as part of a complex surgical approach.

Methods: In a prospective consecutive non-controlled clinical follow-up study, all patients with chondral lesion at the ankle that were treated with MAST from April 1, 2009 to May 31, 2012 were included. Size and location of the chondral lesions, method-associated problems and the Visual-Analogue-Scale Foot and Ankle (VAS FA) before treatment and at follow-up were analysed. Stem cell-rich blood was harvested from the ipsilateral pelvic bone marrow and centrifuged (10min, 1500RPM). The supernatant was used to impregnate a collagen I/III matrix (Chondro-Gide) that was fixed into the chondral lesion with fibrin glue.

Results: One hundred and twenty patients with 124 chondral lesions were included in the study. Age at the time of surgery was 35 years on average (range, 12-65 years), 74 (62%) were male. VAS FA before surgery was 45.2 on average (range, 16.4-73.5). Lesions were located at medial talar shoulder, n=55; lateral talar shoulder, n=58 (medial and lateral, n=4); tibia, n=11. Lesion size was 1.7cm2 on average (range, .8-6cm2). One hundred patients (83%) completed 5-year-follow-up after. VAS FA improved to 84.4 (range, 54.1-100; t-test, p<0.01).

Conclusions: MAST as part of a complex surgical approach led to improved and high validated outcome scores in the mid-term-follow-up. No method related complications were registered. Even though a control group is missing, we conclude that MAST as part of a complex surgical approach is an effective method for the treatment of chondral lesions of the ankle for at least five years.

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