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Liu H.,Zimmer Orthobiologics Inc. | Zhao Z.,Novavax | Clarke R.B.,Zimmer Orthobiologics Inc. | Gao J.,Celling Biosciences | And 2 more authors.
American Journal of Sports Medicine | Year: 2013

Background: Articular cartilage undergoes substantial age-related changes in molecular composition, matrix structure, and mechanical properties. These age-related differences between juvenile and adult cartilage manifest themselves as markedly distinct potentials for tissue repair and regeneration. Purpose: To compare the biological properties and tissue regeneration capabilities of juvenile and adult bovine articular cartilage. Study Design: Controlled laboratory study. Methods: Articular cartilage harvested from juvenile (age, 4 months) and adult (age, 6-8 years) bovine femoral condyles was cultured for 4 weeks to monitor chondrocyte migration, glycosaminoglycan content conservation, and new tissue formation. The cartilage cell density and proliferative activity were also compared. Additionally, the effects of age-related changes on cartilage gene expression were analyzed using the Affymetrix GeneChip array. Results: Compared with adult cartilage, juvenile bovine cartilage demonstrated a significantly greater cell density, higher cell proliferation rate, increased cell outgrowth, elevated glycosaminoglycan content, and enhanced matrix metallopeptidase 2 activity. During 4 weeks in culture, only juvenile cartilage was able to generate new cartilaginous tissues, which exhibited pronounced labeling for proteoglycan and type II collagen but not type I collagen. With over 19,000 genes analyzed, distinctive gene expression profiles were identified. The genes mostly involved in cartilage growth and expansion, such as COL2A1, COL9A1, MMP2, MMP14, and TGFB3, were upregulated in juvenile cartilage, whereas the genes primarily responsible for structural integrity, such as COMP, FN1, TIMP2, TIMP3, and BMP2, were upregulated in adult cartilage. Conclusion: As the first comprehensive comparison between juvenile and adult bovine articular cartilage at the tissue, cellular, and molecular levels, the results strongly suggest that juvenile cartilage possesses superior chondrogenic activity and enhanced regenerative potential over its adult counterpart. Additionally, the differential gene expression profiles of juvenile and adult cartilage suggest possible mechanisms underlying cartilage age-related changes in their regeneration capabilities, structural components, and biological properties. Clinical Relevance: The results of this comparative study between juvenile and adult bovine articular cartilage suggest an enhanced regenerative potential of juvenile cartilage tissue in the restoration of damaged articular cartilage. © 2013 The Author(s). Source


Homma Y.,University of Tokyo | Homma Y.,University Paris Est Creteil | Sand T.,Celling Biosciences | Hernigou P.,University Paris Est Creteil
Current Orthopaedic Practice | Year: 2014

Hip osteonecrosis is a pathological condition resulting from cellular impairment from reductions in osteoblast activity and the local mesenchymal stem cell population. Cell-based therapies could correct such deficiencies by providing stem and other progenitor cells potentially to improve the local cellular environment in the affected hip. A rationale for the use of cytotherapy as well as a description of the technique of autologous bone marrow concentrate implantation are provided in the context of treating hip osteonecrosis. Current problems and future challenges with cytotherapy and associated techniques are discussed. © 2014 Wolters Kluwer Health. Source


Buchanan R.M.,University of Texas at Austin | Blashki D.,University of Melbourne | Murphy M.B.,Celling Biosciences
Chemical Engineering Progress | Year: 2014

The article discusses the state of various stem cell technologies, including the regulations that govern them and their translation to human clinical therapy. Autologous stem cells have been used successfully in the treatment of third-degree and radiation burns, spinal fusion, spinal cord injuries, cardiac repair after heart attack, MS, and Parkinson's disease beyond orthopedic applications. Stem cell therapies will be an integral part of regenerative medicine, and will play a major role in future clinical therapy. Some autologous stem-cell products available to physicians and patients today have demonstrated promising efficacy, with no evidence of safety risks. Source


Murphy M.B.,Celling Biosciences | Moncivais K.,Celling Biosciences | Caplan A.I.,Case Western Reserve University
Experimental and Molecular Medicine | Year: 2013

Mesenchymal stem cells (MSCs) are partially defined by their ability to differentiate into tissues including bone, cartilage and adipose in vitro, but it is their trophic, paracrine and immunomodulatory functions that may have the greatest therapeutic impact in vivo. Unlike pharmaceutical treatments that deliver a single agent at a specific dose, MSCs are site regulated and secrete bioactive factors and signals at variable concentrations in response to local microenvironmental cues. Significant progress has been made in understanding the biochemical and metabolic mechanisms and feedback associated with MSC response. The anti-inflammatory and immunomodulatory capacity of MSC may be paramount in the restoration of localized or systemic conditions for normal healing and tissue regeneration. Allogeneic MSC treatments, categorized as a drug by regulatory agencies, have been widely pursued, but new studies demonstrate the efficacy of autologous MSC therapies, even for individuals affected by a disease state. Safety and regulatory concerns surrounding allogeneic cell preparations make autologous and minimally manipulated cell therapies an attractive option for many regenerative, anti-inflammatory and autoimmune applications. © 2013 KSBMB. All rights reserved. Source


Pettine K.A.,Orthopedic Stem Cell Institute | Murphy M.B.,University of Texas at Austin | Suzuki R.K.,Celling Biosciences | Sand T.T.,Celling Biosciences
Stem Cells | Year: 2015

Degenerative disc disease (DDD) induces chronic back pain with limited nonsurgical options. In this open label pilot study, 26 patients (median age 40 years; range 18-61) received autologous bone marrow concentrate (BMC) disc injections (13 one level, 13 two levels). Pretreatment Oswestry disability index (ODI) and visual analog scale (VAS) were performed to establish baseline pain scores (average 56.5 and 79.3, respectively), while magnetic resonance imaging was independently scored according to the modified Pfirrmann scale. Approximately 1 ml of BMC was analyzed for total nucleated cell (TNC) content, colony-forming unit-fibroblast (CFU-F) frequency, differentiation potential, and phenotype characterization. The average ODI and VAS scores were reduced to 22.8 and 29.2 at 3 months, 24.4 and 26.3 at 6 months, and 25.0 and 33.2 at 12 months, respectively (p ≤ .0001). Eight of twenty patients improved by one modified Pfirrmann grade at 1 year. The average BMC contained 121 × 106 TNC/ml with 2,713 CFU-F/ml (synonymous with mesenchymal stem cells). Although all subjects presented a substantial reduction in pain, patients receiving greater than 2,000 CFU-F/ml experienced a significantly faster and greater reduction in ODI and VAS. Subjects older than 40 years who received fewer than 2,000 CFU-F/ml experienced an average pain reduction of 33.7% (ODI) and 29.1% (VAS) at 12 months, while all other patients' average reduction was 69.5% (ODI, p = .03) and 70.6% (VAS, p = .01). This study provides evidence of safety and feasibility in the nonsurgical treatment of DDD with autologous BMC and indicates an effect of mesenchymal cell concentration on discogenic pain reduction. Stem Cells 2015;33:146-156 © 2014 AlphaMed Press. Source

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