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1.
Cytotherapy ; 22(9): 486-493, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32565131

RESUMO

PURPOSE: The prevalence of connective tissue progenitor cells within a cell-based therapy is often quantified using the colony-forming unit fibroblast (CFU-F) assay. The present study investigates the feasibility of using cryopreserved bone marrow aspirate concentrate (BMAC) as an alternative cell source to fresh BMAC for CFU-F quantification. METHODS: Freshly prepared and corresponding cryopreserved BMAC samples from patients receiving autologous cell therapy (n = 98) were analyzed using the CFU-F assay for comparison. Cultures were established by directly plating BMAC at low cell densities and maintained for a 2-week growth period. Colonies were enumerated to determine CFU-F frequency, and a subset of cultures was imaged and analyzed to quantify colony area and density. RESULTS: A nonlinear relationship was observed between plating density and CFU-F frequency over a wide range in plating densities (~30-fold). Cryopreserved BMAC yielded recoverable (77 ± 23%) and viable (73 ± 9%) nucleated cells upon thawing. After cryopreservation, CFU-F frequencies were found to be significantly lower (56.6 ± 34.8 vs. 50.3 ± 31.7 colonies per million nucleated cells). Yet the number of CFU-F in fresh and cryopreserved BMAC were strongly correlated (r = 0.87) and had similar area and densities. Further, moderate correlations were observed between the number of CFU-F and nucleated cells, and both the mean colony area and density were negatively correlated with patient age. Notably, no relationship was found between CFU-F frequency and age, regardless of whether fresh or cryopreserved BMAC was used. CONCLUSIONS: Freshly prepared and cryopreserved BMAC yielded correlated results when analyzed using the CFU-F assay. Our findings support the cryogenic storage of patient BMAC samples for retrospective CFU-F analyses, offering a potential alternative for characterizing BMAC and furthering our understanding of progenitor cells in relation to clinical outcome.

2.
Int J Sports Phys Ther ; 15(2): 301-325, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32269863

RESUMO

Interventional orthobiologics is changing the landscape of orthopedic medicine. Various methods exist for treatment of many different musculoskeletal pathologies. Candidacy for such injections remains a debated topic, and current research is underway for stratifying the patients that would be most successful for certain techniques. Described in this commentary are the various methods of interventional orthobiologic techniques available such as: prolotherapy, platelet rich plasma (PRP), mesenchymal stromal cells (MSCs), culture-expanded MSCs and amniotic-based products. Here we review the healing cascade and how this relates to the application of the various injectates and rehabilitation protocols. In conclusion, there exists orthobiologic techniques for the healing of a multitude of musculoskeletal ailments, from ligamentous instabilities/tears, tendon derangements and osteoarthritis, however candidacy grades continue to be an area for discussion as to which type of treatment is the most beneficial, and which rehabilitation protocols are required. More randomized controlled trials and comparative analyses are needed for direct correlative conclusions for which interventional orthobiologic treatment and rehabilitation protocol is best after each respective treatment. Level of Evidence: 5.

3.
Pain Physician ; 23(2): E85-E131, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32214287

RESUMO

BACKGROUND: The use of bone marrow concentrate (BMC) for treatment of musculoskeletal disorders has become increasingly popular over the last several years, as technology has improved along with the need for better solutions for these pathologies. The use of cellular tissue raises a number of issues regarding the US Food and Drug Administration's (FDA) regulation in classifying these treatments as a drug versus just autologous tissue transplantation. In the case of BMC in musculoskeletal and spine care, this determination will likely hinge on whether BMC is homologous to the musculoskeletal system and spine. OBJECTIVES: The aim of this review is to describe the current regulatory guidelines set in place by the FDA, specifically the terminology around "minimal manipulation" and "homologous use" within Regulation 21 CFR Part 1271, and specifically how this applies to the use of BMC in interventional musculoskeletal medicine. METHODS: The methodology utilized here is similar to the methodology utilized in preparation of multiple guidelines employing the experience of a panel of experts from various medical specialties and subspecialties from differing regions of the world. The collaborators who developed these position statements have submitted their appropriate disclosures of conflicts of interest. Trustworthy standards were employed in the creation of these position statements. The literature pertaining to BMC, its effectiveness, adverse consequences, FDA regulations, criteria for meeting the standards of minimal manipulation, and homologous use were comprehensively reviewed using a best evidence synthesis of the available and relevant literature. RESULTS/Summary of Evidence: In conjunction with evidence-based medicine principles, the following position statements were developed: Statement 1: Based on a review of the literature in discussing the preparation of BMC using accepted methodologies, there is strong evidence of minimal manipulation in its preparation, and moderate evidence for homologous utility for various musculoskeletal and spinal conditions qualifies for the same surgical exemption. Statement 2: Assessment of clinical effectiveness based on extensive literature shows emerging evidence for multiple musculoskeletal and spinal conditions. • The evidence is highest for knee osteoarthritis with level II evidence based on relevant systematic reviews, randomized controlled trials and nonrandomized studies. There is level III evidence for knee cartilage conditions. • Based on the relevant systematic reviews, randomized trials, and nonrandomized studies, the evidence for disc injections is level III. • Based on the available literature without appropriate systematic reviews or randomized controlled trials, the evidence for all other conditions is level IV or limited for BMC injections. Statement 3: Based on an extensive review of the literature, there is strong evidence for the safety of BMC when performed by trained physicians with the appropriate precautions under image guidance utilizing a sterile technique. Statement 4: Musculoskeletal disorders and spinal disorders with related disability for economic and human toll, despite advancements with a wide array of treatment modalities. Statement 5: The 21st Century Cures Act was enacted in December 2016 with provisions to accelerate the development and translation of promising new therapies into clinical evaluation and use. Statement 6: Development of cell-based therapies is rapidly proliferating in a number of disease areas, including musculoskeletal disorders and spine. With mixed results, these therapies are greatly outpacing the evidence. The reckless publicity with unsubstantiated claims of beneficial outcomes having putative potential, and has led the FDA Federal Trade Commission (FTC) to issue multiple warnings. Thus the US FDA is considering the appropriateness of using various therapies, including BMC, for homologous use. Statement 7: Since the 1980's and the description of mesenchymal stem cells by Caplan et al, (now called medicinal signaling cells), the use of BMC in musculoskeletal and spinal disorders has been increasing in the management of pain and promoting tissue healing. Statement 8: The Public Health Service Act (PHSA) of the FDA requires minimal manipulation under same surgical procedure exemption. Homologous use of BMC in musculoskeletal and spinal disorders is provided by preclinical and clinical evidence. Statement 9: If the FDA does not accept BMC as homologous, then it will require an Investigational New Drug (IND) classification with FDA (351) cellular drug approval for use. Statement 10: This literature review and these position statements establish compliance with the FDA's intent and corroborates its present description of BMC as homologous with same surgical exemption, and exempt from IND, for use of BMC for treatment of musculoskeletal tissues, such as cartilage, bones, ligaments, muscles, tendons, and spinal discs. CONCLUSIONS: Based on the review of all available and pertinent literature, multiple position statements have been developed showing that BMC in musculoskeletal disorders meets the criteria of minimal manipulation and homologous use. KEY WORDS: Cell-based therapies, bone marrow concentrate, mesenchymal stem cells, medicinal signaling cells, Food and Drug Administration, human cells, tissues, and cellular tissue-based products, Public Health Service Act (PHSA), minimal manipulation, homologous use, same surgical procedure exemption.


Assuntos
Transplante de Medula Óssea/normas , Medicina Baseada em Evidências/normas , Doenças Musculoesqueléticas/terapia , Manejo da Dor/normas , Médicos/normas , Sociedades Médicas/normas , Medula Óssea/fisiologia , Transplante de Medula Óssea/métodos , Medicina Baseada em Evidências/métodos , Humanos , Doenças Musculoesqueléticas/diagnóstico , Doenças Musculoesqueléticas/epidemiologia , Dor/diagnóstico , Dor/epidemiologia , Manejo da Dor/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration/normas
4.
J Transl Med ; 17(1): 115, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30961655

RESUMO

BACKGROUND: The number of Mesenchymal Stem/Stromal Cells (MSCs) in the human bone marrow (BM) is small compared to other cell types. BM aspirate concentration (BMAC) may be used to increase numbers of MSCs, but the composition of MSC subpopulations and growth factors after processing are unknown. The purpose of this study was to assess the enrichment of stem/progenitor cells and growth factors in BM aspirate by two different commercial concentration devices versus standard BM aspiration. METHODS: 120 mL of BM was aspirated from the iliac crest of 10 male donors. Each sample was processed simultaneously by either Emcyte GenesisCS® (Emcyte) or Harvest SmartPReP2 BMAC (Harvest) devices and compared to untreated BM aspirate. Samples were analyzed with multicolor flow cytometry for cellular viability and expression of stem/progenitor cells markers. Stem/progenitor cell content was verified by quantification of colony forming unit-fibroblasts (CFU-F). Platelet, red blood cell and total nucleated cell (TNC) content were determined using an automated hematology analyzer. Growth factors contents were analyzed with protein quantification assays. Statistical analyses were performed by ANOVA analysis of variance followed by Tukey's multiple comparison test or Wilcoxon matched-pairs signed rank test with p < 0.05 for significance. RESULTS: Cell viability after processing was approximately 90% in all groups. Compared to control, both devices significantly enriched TNCs and platelets, as well as the CD45-CD73+ and CD45-CD73+CD90+ cell populations. Further, Harvest significantly concentrated CD45-CD10+, CD45-CD29+, CD45-CD90+, CD45-CD105+, CD45-CD119+ cells, and CD45dimCD90+CD271+ MSCs, whereas Emcyte significantly enriched CD45dimCD44+CD271+ MSCs. BM concentration also increased the numbers of CFU-F, platelet-derived growth factor, vascular endothelial growth factor, macrophage colony-stimulating factor, interleukin-1b, VCAM-1 and total protein. Neither system concentrated red blood cells, hematopoietic stem cells or bone morphogenetic proteins. CONCLUSION: This data could contribute to the development of BMAC quality control assays as both BMAC systems concentrated platelets, growth factors and non-hematopoietic stem cell subpopulations with distinct phenotypes without loss of cell viability when compared to unprocessed BM.


Assuntos
Medula Óssea/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Células-Tronco/citologia , Adulto , Contagem de Células , Sobrevivência Celular , Ensaio de Unidades Formadoras de Colônias , Humanos , Células-Tronco/metabolismo , Sucção
5.
Int Orthop ; 42(1): 223, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29110069

RESUMO

The published online version contains mistake in Acknowledgment Section. The author name "Steve Gorin, M.D." should have been "Steven Gorin, D.O, M.S.Ed.".

6.
Phys Med Rehabil Clin N Am ; 27(4): 919-939, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27788908

RESUMO

Bone marrow aspiration (BMA) is increasingly being used to harvest stem cells for use in regenerative medicine. The focus of BMA in interventional orthopedics is to maximize the yield of mesenchymal stem cells. The authors present an improved method for BMA that involves fluoroscope or ultrasound guidance combined with anesthesia; in the authors' experience, it produces the highest possible stem cell yield and is well tolerated by patients. The authors provide a step-by-step guide to the process, along with a discussion of technical and other considerations and quick reference guides for ultrasound- and fluoroscope-guided BMA.


Assuntos
Células da Medula Óssea/citologia , Transplante de Medula Óssea/métodos , Medula Óssea , Humanos , Células-Tronco Multipotentes/citologia , Sucção
7.
J Transl Med ; 14: 253, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27585696

RESUMO

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.


Assuntos
Dor Crônica/terapia , Disco Intervertebral/patologia , Dor Lombar/terapia , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Células-Tronco Mesenquimais/citologia , Adulto , Hipóxia Celular , Células Cultivadas , Vias de Administração de Medicamentos , Estudos de Viabilidade , Feminino , Humanos , Injeções , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Transplante Autólogo , Adulto Jovem
8.
Int Orthop ; 40(8): 1755-1765, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27026621

RESUMO

INTRODUCTION: The purpose of the present investigation is to report on detailed complications among a much larger group of 2372 orthopaedic patients treated with stem cell injections who were followed in a treatment registry for up to nine years. METHODS: All patients underwent an MSC-based, percutaneous injection treatment of an orthopaedic condition between December 2005 and September 2014 at one of 18 clinical facilities. Treated areas of the body included the knee, hip, ankle/foot, hand/wrist, elbow, shoulder, and spine. The patients were followed prospectively via enrollment in a treatment registry. Patients were followed prospectively at one, three, six and 12 months, and annually thereafter, using an electronic system, ClinCapture software. RESULTS: A total of 3012 procedures were performed on 2372 patients with follow-up period of 2.2 years. A total of 325 adverse events were reported. The majority were pain post-procedure (n = 93, 3.9 % of the study population) and pain due to progressive degenerative joint disease (n = 90, 3.8 % of the study population). Seven cases reported neoplasms, a lower rate than in the general population. The lowest rate of adverse events was observed among patients injected with BMC alone. CONCLUSION: Lowest rate of adverse events was among those patients receiving BMC injections alone, but the higher rate of AEs for BMC plus adipose and cultured cells was readily explained by the nature of the therapy or the longer follow-up. There was no clinical evidence to suggest that treatment with MSCs of any type in this study increased the risk of neoplasm.


Assuntos
Células Cultivadas/citologia , Articulação do Joelho/cirurgia , Doenças Musculoesqueléticas/fisiopatologia , Ortopedia , Dor/etiologia , Células Cultivadas/química , Células Cultivadas/metabolismo , Humanos , Injeções Intra-Articulares
9.
BMC Musculoskelet Disord ; 16: 258, 2015 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-26385099

RESUMO

BACKGROUND: Prior studies describing the treatment of symptomatic knee osteoarthritis with injections of bone marrow concentrate have provided encouraging results. The relationship between the cellular dose contained within the bone marrow concentrate and efficacy of the treatment, however, is unclear. In the present study we describe clinical outcomes for symptomatic knee osteoarthritis in relation to higher and lower cell concentrations contained within a bone marrow concentrate treatment protocol. METHODS: Data from an ongoing patient registry was culled to identify 373 patients that received bone marrow concentrate injections for the treatment of 424 osteoarthritic knee joints. The clinical scales for these patients were assessed at baseline and then tracked post-procedure at 1, 3, 6 and 12 months, and annually thereafter. Tracked outcomes included the numeric pain scale; a lower extremity functional questionnaire; an International Knee Documentation Committee scale; and a subjective improvement rating scale. Using pain and functional outcome measures, a receiver operating characteristic analysis was used to define an optimal clinical outcome threshold at which bone marrow nucleated cell count could be divided into either a lower or higher cell count group within a treatment protocol. RESULTS: The lower and higher cell count groups were defined using a threshold of 4 × 10(8) cells. There were 224 and 185 knee joints treated in the lower (≤4 × 10(8)) and higher (>4 × 10(8)) cell count groups respectively. Most joints were diagnosed with early stage knee osteoarthritis. Both the lower and higher cell count groups demonstrated significant positive results with the treatment for all of the pain and functional metrics. The higher cell count group reported lower post treatment numeric pain scale values, in comparison with the lower cell count group (1.6 vs. 3.2; P < 0.001). No significant differences were detected for the other metrics, however. CONCLUSIONS: Improved function and reduced pain was observed in patients treated with a bone marrow concentrate protocol regardless of cellular dose; however, patients receiving a higher concentration of cells reported a better pain outcome in comparison with the lower dose group. These preliminary findings suggest that cell dose may be an important factor governing clinical outcomes in autologous bone marrow concentrate treatment of knee osteoarthritis. Further studies using a larger patient population may help elucidate these findings.


Assuntos
Transplante de Medula Óssea/métodos , Articulação do Joelho/cirurgia , Osteoartrite do Joelho/cirurgia , Adulto , Idoso , Área Sob a Curva , Artralgia/diagnóstico , Artralgia/fisiopatologia , Artralgia/prevenção & controle , Fenômenos Biomecânicos , Exame de Medula Óssea , Contagem de Células , Avaliação da Deficiência , Feminino , Humanos , Injeções Intra-Articulares , Articulação do Joelho/fisiopatologia , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico , Osteoartrite do Joelho/fisiopatologia , Medição da Dor , Dor Pós-Operatória/fisiopatologia , Dor Pós-Operatória/prevenção & controle , Valor Preditivo dos Testes , Curva ROC , Recuperação de Função Fisiológica , Sistema de Registros , Índice de Gravidade de Doença , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento
10.
J Pain Res ; 8: 437-47, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26261424

RESUMO

INTRODUCTION: This was a prospective case series designed to investigate treatment for anterior cruciate ligament (ACL) tears using an injection of autologous bone marrow concentrate. METHODS: Consecutive adult patients presenting to a private outpatient interventional musculoskeletal and pain practice with knee pain, ACL laxity on exam, and magnetic resonance imaging (MRI) evidence of a grade 1, 2, or 3 ACL tears with less than 1 cm retraction were eligible for this study. Eligible patients were treated with an intraligamentous injection of autologous bone marrow concentrate, using fluoroscopic guidance. Pre- and postprocedural sagittal MRI images of the ACLs were analyzed using ImageJ software to objectively quantify changes between pre- and posttreatment scans. Five different types of measurement of ACL pixel intensity were examined as a proxy for ligament integrity. In addition pain visual analog scale (VAS) and Lower Extremity Functional Scale (LEFS) values were recorded at baseline and at 1 month, 3 months, 6 months, and annually postinjection. Objective outcomes measured were pre- to post-MRI measurement changes, as analyzed by the ImageJ software. Subjective outcomes measured were changes in the VAS and LEFS, and a self-rated percentage improvement. RESULTS: Seven of ten patients showed improvement in at least four of five objective measures of ACL integrity in their postprocedure MRIs. In the entire study group, the mean gray value, median, raw integrated density, and modal gray value all decreased toward low-signal ACLs (P=0.01, P=0.02, P=0.002, and P=0.08), indications of improved ligament integrity. Seven of ten patients responded to the self-rated metrics follow up. The mean VAS change was a decrease of 1.7 (P=0.25), the mean LEFS change was an increase of 23.3 (P=0.03), and mean reported improvement was 86.7%. CONCLUSION: Based on this small case series, autologous bone marrow concentrate shows promise in the treatment of grade 1, 2, and possibly grade 3 ACL tears without retraction. Further investigation using a controlled study design is warranted.

11.
J Pain Res ; 8: 269-76, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26089699

RESUMO

INTRODUCTION: Shoulder pain is a common musculoskeletal complaint in the general population. Bone marrow concentrate (BMC) injections offer promising potential as a minimally invasive approach for treatment of shoulder pain in degenerative disease. In this study, we investigated the clinical outcomes of the BMC injections for treatment of shoulder pain and disability due to osteoarthritis (OA) and rotator cuff tears in a treatment registry population. METHODS: A total of 115 shoulders in 102 patients were treated with autologous BMC injections for symptomatic OA at the glenohumeral joint and/or rotator cuff tears. Data were collected for factors potentially influencing outcome, including age, sex, body mass index, and the type of condition treated (ie, OA or rotator cuff tear). Clinical outcomes were assessed serially over time using the disabilities of the arm, shoulder and hand score (DASH), the numeric pain scale (NPS), and a subjective improvement rating scale. Baseline scores were compared to the most recent outcome scores at the time of the analysis and adjusted for demographic differences. We reported comparisons of pre- and post-treatment scores, the differences between osteoarthritis and rotator cuff groups, and the predictive effects on the clinical outcomes. RESULTS: At the most current follow-up assessment after treatment, the average DASH score decreased (improved) from 36.1 to 17.1 (P<0.001) and the average numeric pain scale value decreased (improved) from 4.3 to 2.4 (P<0.001). These changes were associated with an average subjective improvement of 48.8%. No differences were observed between outcomes among the shoulders treated for OA versus rotator cuff tears, nor did age, sex, or body mass index influence pain or functional outcomes. There were no significant treatment-related adverse events reported. DISCUSSION: We observed preliminarily encouraging results following BMC injections for shoulder OA and rotator cuff tears. These results serve as basis for the design of an adequately powered randomized controlled trial.

12.
PM R ; 7(4 Suppl): S4-S7, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25864659

RESUMO

Stem cells therapies have been in preclinical development for the past 2 decades. A rapidly evolving regulatory landscape has restrained many of these technologies from advancing from the bench to the bedside. Although the large-scale clinical safety of stem cell therapies remains to be fully tested, the total number of patients who have safely received these therapies is large and growing. Prima facie evidence would dictate that certain types of cell therapy are likely safer than others. Understanding the current regulation regarding stem cells involves a discussion of their safety profile, as the 2 issues are closely intertwined.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/tendências , Transplante de Células-Tronco/tendências , Terapia Genética/métodos , Terapia Genética/tendências , Humanos
13.
PM R ; 6(1): 70-7, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24439149

RESUMO

The use of stem cells in orthopedics has been researched for many years, with robust animal data that show efficacy in cartilage healing, tendon repair, and intervertebral disk treatment. Early clinical data are also just starting to be published, and these results are encouraging. Safety data in large case series, some that lasted for many years, have also been published. The field of tissue engineering with stem cells in musculoskeletal impairments has the potential to reduce morbidity and improve clinical outcomes. The regulatory environment for this area of medicine is still developing.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/fisiologia , Osteoartrite/terapia , Tecido Adiposo/citologia , Animais , Terapia Biológica/tendências , Células da Medula Óssea , Diferenciação Celular , Células Cultivadas , Regulamentação Governamental , Humanos , Degeneração do Disco Intervertebral/terapia , Coleta de Tecidos e Órgãos , Pesquisa Médica Translacional , Transplante Autólogo , Transplante Homólogo , Estados Unidos , United States Food and Drug Administration
14.
Stem Cells Transl Med ; 3(3): 365-74, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24436443

RESUMO

In the realm of regenerative medicine, human mesenchymal stem cells (hMSCs) are gaining attention as a cell source for the repair and regeneration of tissues spanning an array of medical disciplines. In orthopedics, hMSCs are often delivered in a site-specific manner at the area of interest and may require the concurrent application of local anesthetics (LAs). To address the implications of using hMSCs in combination with anesthetics for intra-articular applications, we investigated the effect that clinically relevant doses of amide-type LAs have on the viability of bone marrow-derived hMSCs and began to characterize the mechanism of LA-induced hMSC death. In our study, culture-expanded hMSCs from three donors were exposed to the amide-type LAs ropivacaine, lidocaine, bupivacaine, and mepivacaine. To replicate the physiological dilution of LAs once injected into the synovial capsule, each anesthetic was reduced to 12.5%, 25%, and 50% of the stock solution and incubated with each hMSC line for 40 minutes, 120 minutes, 360 minutes, and 24 hours. At each time point, cell viability assays were performed. We found that extended treatment with LAs for 24 hours had a significant impact on both hMSC viability and adhesion. In addition, hMSC treatment with three of the four anesthetics resulted in cell death via apoptosis following brief exposures. Ultimately, we concluded that amide-type LAs induce hMSC apoptosis in a time- and dose-dependent manner that may threaten clinical outcomes, following a similar trend that has been established between these particular anesthetics and articular chondrocytes both in vitro and in vivo.


Assuntos
Amidas/farmacologia , Anestésicos Locais/farmacologia , Bupivacaína/farmacologia , Lidocaína/farmacologia , Mepivacaína/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Adulto , Apoptose/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Terapia Baseada em Transplante de Células e Tecidos , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Pessoa de Meia-Idade , Ropivacaina , Fatores de Tempo
15.
Wien Med Wochenschr ; 164(5-6): 83-7, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23949564

RESUMO

In the present study, we describe six patients who received autologous mesenchymal stem cell (MSC) therapy for symptomatic carpometacarpal (CMC) joint and hand osteoarthritis (OA). Six patients who received injections of adult autologous culture expanded MSCs in their thumb CMC joints were followed for 1 year posttreatment, and matched with four procedure candidates who remained untreated. We observed positive outcomes in the treatment group for both symptoms and function related to the OA, compared with a reported worsening among the untreated controls. While these results should be interpreted with caution because of the small number of treated subjects and lack of placebo control and randomization, we find sufficient evidence for further investigation of MSC therapy as an alternative to more invasive surgery in patients with OA of the hand.


Assuntos
Articulações Carpometacarpais/fisiologia , Transplante de Células-Tronco Mesenquimais/métodos , Osteoartrite/terapia , Estudos Controlados Antes e Depois , Humanos , Injeções Intra-Articulares , Osteoartrite/fisiopatologia
16.
Curr Stem Cell Res Ther ; 6(4): 368-78, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22023622

RESUMO

UNLABELLED: Mesenchymal stem cells (MSCs) hold great promise as therapeutic agents in regenerative medicine. Numerous animal studies have documented the multipotency of MSCs, showing their capabilities for differentiating into orthopedic tissues such as muscle, bone, cartilage, and tendon. However, the safety of culture expanded MSC's for human use has only just begun to be reported. METHODS: Between 2006 and 2010, two groups of patients were treated for various orthopedic conditions with culture-expanded, autologous, bone marrow-derived MSCs (group 1: n=50; group 2: n=290-one patient in both groups). Cells were cultured in monolayer culture flasks using an autologous platelet lysate technique and re-injected into peripheral joints or into intervertebral discs with use of c-arm fluoroscopy. While both groups had prospective surveillance for complications, Group 1 additionally underwent 3.0T MRI tracking of the re-implant sites. RESULTS: The mean age of patients treated was 53 +/- 13.85 years; 214 were males and 125 females with mean follow-up time from any procedure being 435 days +/- 261 days. Number of contacts initiated based on time from first procedure was 482 at 3 months, 433 at 6 months, 316 contacts at 12 months, 110 contacts at 24 months, and 22 contacts at 36 months. For Group 1, 50 patients underwent 210 MRI surveillance procedures at 3 months, 6 months, 1, 2, and 3 years which failed to demonstrate any tumor formation at the re-implant sites. Formal disease surveillance for adverse events based on HHS criteria documented significantly less morbidity than is commonly reported for more invasive surgical procedures, all of which were either self-limited or were remedied with therapeutic measures. Two patients were diagnosed with cancer out of 339 patients treated since study inception; however, this was almost certainly unrelated to the MSC therapy and the neoplasm rate in similar to that seen in the U.S. Caucasian population. Knee outcome data was collected on a subset of patients. Here, > 75% improvement was reported in 41.4% while decreasing the improvement threshold to > 50% improvement, 63.2% reported an improvement. At an average reporting time of 11.3 months from first procedure average reported relief in the knee sample equaled 53.1% (n=133 reporting). CONCLUSIONS: Using both intensive high field MRI tracking and complications surveillance in 339 patients, no neoplastic complications were detected at any stem cell re-implantation site. These findings are consistent with our prior publication and other published reports that also show no evidence of malignant transformation in vivo, following implantation of MSCs for orthopedic use.


Assuntos
Plaquetas/metabolismo , Articulação do Joelho/metabolismo , Células-Tronco Mesenquimais/citologia , Reimplante/métodos , Transplante Autólogo/métodos , Adulto , Idoso , Células da Medula Óssea/citologia , Técnicas de Cultura de Células , Avaliação de Medicamentos , Feminino , Fluoroscopia/métodos , Seguimentos , Humanos , Articulação do Joelho/cirurgia , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Procedimentos Ortopédicos , Estudos Prospectivos , Medicina Regenerativa , Reimplante/efeitos adversos , Inquéritos e Questionários , Resultado do Tratamento
17.
J Cosmet Dermatol ; 10(3): 171-3, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21896126

RESUMO

In the area of cosmetic dermatology, some physicians have been injecting activated platelet-rich plasma into the face to promote cosmesis or using it to enhance fat grafts. However, subtle changes to the federal drug code (21 CFR 1271.1) made in 2004, when applied to activated PRP, purport to make this autologous substance a federally regulated drug requiring an extensive and costly Biologics License Application. Are autologous cells drugs? Many physicians believe there are significant problems with this regulatory paradigm.


Assuntos
Controle de Medicamentos e Entorpecentes/legislação & jurisprudência , Plasma Rico em Plaquetas , United States Food and Drug Administration/legislação & jurisprudência , Humanos , Transplante Autólogo/legislação & jurisprudência , Estados Unidos
18.
Brain Inj ; 24(7-8): 988-94, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20545453

RESUMO

PRIMARY OBJECTIVE: Chiari malformation is defined as herniation of the cerebellar tonsils through the foramen magnum, also known as cerebellar tonsillar ectopia (CTE). CTE may become symptomatic following whiplash trauma. The purpose of the present study was to assess the frequency of CTE in traumatic vs non-traumatic populations. STUDY DESIGN: Case-control. METHODS AND PROCEDURES: Cervical MRI scans for 1200 neck pain patients were reviewed; 600 trauma (cases) and 600 non-trauma (controls). Half of the groups were scanned in a recumbent position and half were scanned in an upright position. Two radiologists interpreted the scans for the level of the cerebellar tonsils. MAIN OUTCOMES AND RESULTS: A total of 1195 of 1200 scans were read. CTE was found in 5.7% and 5.3% in the recumbent and upright non-trauma groups vs 9.8% and 23.3% in the recumbent and upright trauma groups (p = 0.0001). CONCLUSIONS: The results described in the present investigation are first to demonstrate a neuroradiographic difference between neck pain patients with and without a recent history of whiplash trauma. The results of prior research on psychosocial causes of chronic pain following whiplash are likely confounded because of a failure to account for a possible neuropathologic basis for the symptoms.


Assuntos
Malformação de Arnold-Chiari/diagnóstico , Cervicalgia/diagnóstico , Traumatismos em Chicotada/diagnóstico , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Cervicalgia/etiologia , Posicionamento do Paciente , Traumatismos em Chicotada/complicações
19.
J Orthop Res ; 28(10): 1330-7, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20309952

RESUMO

Bone marrow-derived mesenchymal stem cells (BMDMSCs) have been targeted for use in enhancement of bone healing; and their osteogenic potential may be further augmented by genes encoding bone morphogenetic proteins (BMP's). The purpose of this study was to compare the effect of genetic modification of human and equine BMDMSCs with BMP-2 or -7 or BMP-2 and -7 on their osteoblastogenic differentiation in the presence or absence of dexamethasone. The BMDMSCs were harvested from the iliac crest of three human donors and tuber coxae of three equine donors. Monolayer cells were genetically modified using adenovirus vectors encoding BMP-2, -7 or both and cultured in the presence or absence of dexamethasone. Expression of BMPs was confirmed by enzyme linked immunosorbent assay (ELISA). To evaluate osteoblastic differentiation, cellular morphology was assessed every other day and expression and secretion of alkaline phosphatase (ALP), as well as expression levels of osteonectin (OSTN), osteocalcin (OCN), and runt-related transcription factor-2 (Runx2) were measured for up to 14 days. Human and equine BMDMSCs showed a capacity for osteogenic differentiation regardless of genetic modification or dexamethasone supplementation. Dexamethasone supplementation was more important for osteoblastogenic differentiation of equine BMDMSCs than human BMDMSCs. Genetic modification of BMDMSCs increased ALP secretion with AdBMP-2 homodimer having the greatest effect in both human and equine cells compared to AdBMP 7 or AdBMP 2/7. BMP protein elution rates reached their maximal concentration between day 4 and 8 and remained relatively stable thereafter, suggesting that genetically modified BMDMSCs could be useful for cell-based delivery of BMPs to a site of bone formation.


Assuntos
Células da Medula Óssea/citologia , Proteína Morfogenética Óssea 2/metabolismo , Proteína Morfogenética Óssea 7/metabolismo , Diferenciação Celular/efeitos dos fármacos , Dexametasona/farmacologia , Células-Tronco Mesenquimais/citologia , Osteoblastos/citologia , Adulto , Fosfatase Alcalina/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 7/genética , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Feminino , Cavalos , Humanos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Modelos Animais , Osteoblastos/metabolismo , Osteocalcina/metabolismo , Osteonectina/metabolismo , Transdução Genética
20.
Curr Stem Cell Res Ther ; 5(1): 81-93, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19951252

RESUMO

UNLABELLED: ABSTRUCT: Mesenchymal stem cells (MSCs) hold great promise as therapeutic agents in regenerative medicine. Numerous animal studies have documented the multipotency of MSCs, showing their capabilities for differentiating into orthopedic tissues such as muscle, bone, cartilage, and tendon. However, the complication rate for autologous MSC therapy is only now beginning to be reported. METHODS: Between 2005 and 2009, two groups of patients were treated for various orthopedic conditions with culture-expanded, autologous, bone marrow-derived MSCs (group 1: n=45; group 2: n=182). Cells were cultured in monolayer culture flasks using an autologous platelet lysate technique and re-injected into peripheral joints (n=213) or into intervertebral discs (n=13) with use of c-arm fluoroscopy. While both groups had prospective surveillance for complications, Group 1 additionally underwent 3.0T MRI tracking of the re-implant sites. RESULTS: Mean follow-up from the time of the re-implant procedure was 10.6 +/- 7.3 months. Serial MRI's at 3 months, 6 months, 1 year and 2 years failed to demonstrate any tumor formation at the re-implant sites. Formal disease surveillance for adverse events based on HHS criteria documented 7 cases of probable procedure-related complications (thought to be associated with the re-implant procedure itself) and three cases of possible stem cell complications, all of which were either self-limited or were remedied with simple therapeutic measures. One patient was diagnosed with cancer; however, this was almost certainly unrelated to the MSC therapy. CONCLUSIONS: Using both high field MRI tracking and general surveillance in 227 patients, no neoplastic complications were detected at any stem cell re-implantation site. These findings are consistent with other reports that also show no evidence of malignant transformation in vivo, following implantation of MSCs that were expanded in vitro for limited periods.


Assuntos
Técnicas de Cultura de Células , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Células-Tronco Mesenquimais/patologia , Procedimentos Ortopédicos/efeitos adversos , Complicações Pós-Operatórias , Adulto , Idoso , Plaquetas/patologia , Extratos Celulares , Proliferação de Células , Células Cultivadas , Feminino , Fluoroscopia , Seguimentos , Humanos , Imagem por Ressonância Magnética , Masculino , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Medicina Regenerativa , Transplante Autólogo
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