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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).


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.


PubMed | Andrews Institute for Orthopaedics & Sports Medicine and Celling Biosciences
Type: | Journal: Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association | Year: 2017

To examine the number of viable stem cells contained in the postinjury effusion fluid and the waste byproducts of arthroscopic cruciate ligament surgery.This study included patients older than 18years of age with acute (<5weeks old) cruciate ligament injuries requiring arthroscopic surgery. The postinjury effusion fluid (effusion fluid), fat pad and cruciate ligament stump debridement tissue (byproduct tissue), and arthroscopic fluid collected during fat pad and/or stump debridement (byproduct fluid) were collected at the time of surgery from 30 individuals. Specimens were analyzed, investigating cell viability, nucleated cell counts, cell concentrations, colony-forming unit assays, and flow cytometry. Samples from the first 20 individuals were collected in small specimen containers, and samples from the last 10 individuals were collected in larger specimen containers.Cells of the injury effusion exhibited the greatest viability (86.4 1.31%) when compared with the small volume harvest byproduct tissue (50.2 2.5%, P= .0001), smallvolume harvest byproduct fluid (48.8 1.88%, P= .0001), large volume harvest byproduct tissue (70.1 5.6%, P= .0001), and large volume harvest byproduct fluid (60.3 3.41%, P= .0001). The culture analysis of fibroblast colony-forming units found on average 1916 281 progenitor cells in the effusion fluid, 2488 778 progenitor cells inthebyproduct tissue, and 2357 339 progenitor cells in the byproduct fluid. Flow cytometry confirmed the presenceofimmature cells and the presence of cells with markers typically expressed by known stem cell populations.Viable stem cells are mobilized to the postinjury effusion at the time of cruciate ligament injury and can be found in the byproduct waste of cruciate ligament surgery.The methodology around effusion fluid and byproduct tissue capture during cruciate ligament surgery should be investigated further. Cell amounts available from these tissues with current technologies are not sufficient for immediate evidence-based clinical application.


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.


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.


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.


Pettine K.,Premier Stem Cell Institute | Suzuki R.,Celling Biosciences | Sand T.,Celling Biosciences | Murphy M.,Celling Biosciences | Murphy M.,University of Texas at Austin
International Orthopaedics | Year: 2016

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. © 2015, SICOT aisbl.


PubMed | Celling Biosciences
Type: | Journal: Experimental & 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.


PubMed | Celling Biosciences, The Texas Institute and Scott and White Hospital
Type: Journal Article | Journal: Journal of clinical medicine | Year: 2015

For spinal fusions and the treatment of non-union fractures, biological substrates, scaffolds, or carriers often are applied as a graft to support regeneration of bone. The selection of an appropriate material critically influences cellular function and, ultimately, patient outcomes. Human bone marrow mesenchymal stem cells (BMSCs) are regarded as a critical component of bone healing. However, the interactions of BMSCs and commercial bone matrices are poorly reported. BMSCs were cultured with several commercially available bone substrates (allograft, demineralized bone matrix (DBM), collagen, and various forms of calcium phosphates) for 48 h to understand their response to graft materials during surgical preparation and the first days following implantation (cell retention, gene expression, pH). At 30 and 60 min, bone chips and inorganic substrates supported significantly more cell retention than other materials, while collagen-containing materials became soluble and lost their structure. At 48 h, cells bound to -tricalcium phosphate-hydroxyapatite (TCP-HA) and porous hydroxyapatite (HA) granules exhibited osteogenic gene expression statistically similar to bone chips. Through 24 h, the DBM strip and TCP-collagen became mildly acidic (pH 7.1-7.3), while the DBM poloxamer-putties demonstrated acidity (pH < 5) and the bioglass-containing carrier became basic (pH > 10). The dissolution of DBM and collagen led to a loss of cells, while excessive pH changes potentially diminish cell viability and metabolism. Extracts from DBM-poloxamers induced osteogenic gene expression at 48 h. This study highlights the role that biochemical and structural properties of biomaterials play in cellular function, potentially enhancing or diminishing the efficacy of the overall therapy.

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