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  • Use of bone morphogenetic proteins in mesenchymal stem cell stimulation of cartilage and bone repair

    Abstract

    The extracellular matrix-associated bone morphogenetic proteins (BMPs) govern a plethora of biological processes. The BMPs are members of the transforming growth factor-β protein superfamily, and they actively participate to kidney development, digit and limb formation, angiogenesis, tissue fibrosis and tumor development. Since their discovery, they have attracted attention for their fascinating perspectives in the regenerative medicine and tissue engineering fields. BMPs have been employed in many preclinical and clinical studies exploring their chondrogenic or osteoinductive potential in several animal model defects and in human diseases. During years of research in particular two BMPs, BMP2 and BMP7 have gained the podium for their use in the treatment of various cartilage and bone defects. In particular they have been recently approved for employment in non-union fractures as adjunct therapies. On the other hand, thanks to their otentialities in biomedical applications, there is a growing interest in studying the biology of mesenchymal stem cell (MSC), the rules underneath their differentiation abilities, and to test their true abilities in tissue engineering. In fact, the specific differentiation of MSCs into targeted celltype lineages for transplantation is a primary goal of the regenerative medicine. This review provides an overview on the current knowledge of BMP roles and signaling in MSC biology and differentiation capacities. In particular the article focuses on the potential clinical use of BMPs and MSCs concomitantly, in cartilage and bone tissue repair.

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  • Current clinical evidence for the use of mesenchymal stem cells in articular cartilage repair

    Abstract

    Introduction: Articular cartilage is renowned for its poor intrinsic capacity for repair. Current treatments for osteoarthritis are limited in their ability to reliably restore the native articular cartilage structure and function. Mesenchymal stem cells (MSCs) present an attractive treatment option for articular cartilage repair, with a recent expansion of clinical trials investigating their use in patients.

    Areas covered: This paper provides a current overview of the clinical evidence on the use of MSCs in articular cartilage repair.

    Expert opinion: The article demonstrates robust clinical evidence that MSCs have significant potential for the regeneration of hyaline articular cartilage in patients. The majority of clinical trials to date have yielded significantly positive results with minimal adverse effects. However the clinical research is still in its infancy. The optimum MSC source, cell concentrations, implantation technique, scaffold, growth factors and rehabilitation protocol for clinical use are yet to be identified. A larger number of randomised control trials are required to objectively compare the clinical efficacy and long-term safety of the various techniques. As the clinical research continues to evolve and address these challenges, it is likely that MSCs may become integrated into routine clinical practice in the near future.

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  • Application of marrow mesenchymal stem cell-derived extracellular matrix in peripheral nerve tissue engineering

    Abstract

    To advance molecular and cellular therapy into the clinic for peripheral nerve injury, modification of neural scaffolds with the extracellular matrix (ECM) of peripheral nerves has been established as a promising alternative to direct inclusion of support cells and/or growth factors within a neural scaffold, while cell-derived ECM proves to be superior to tissue-derived ECM in the modification of neural scaffolds. Based on the fact that bone marrow mesenchymal stem cells (BMSCs), just like Schwann cells, are adopted as support cells within a neural scaffold, in this study we used BMSCs as parent cells to generate ECM for application in peripheral nerve tissue engineering. A chitosan nerve guidance conduit (NGC) and silk fibroin filamentous fillers were respectively prepared for co-culture with purified BMSCs, followed by decellularization to stimulate ECM deposition. The ECM-modified NGC and lumen fillers were then assembled into a chitosan-silk fibroin-based, BMSC-derived, ECM-modified neural scaffold, which was implanted into rats to bridge a 10 mm-long sciatic nerve gap. Histological and functional assessments after implantation showed that regenerative outcomes achieved by our engineered neural scaffold were better than those achieved by a plain chitosan-silk fibroin scaffold, and suggested the benefits of BMSC-derived ECM for peripheral nerve repair. Copyright

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  • The development of submucosal injection of platelet rich plasma for accelerating orthodontic tooth movement and preserving pressure side alve

    Abstract

    Although the surgical-assisted accelerated orthodontic tooth movement has been proved to be the most effective one currently, its disadvantages are it is a bone surgery, and it causes loss of alveolar bone that undermines the periodontal support of the target teeth. The submucosal injection of platelet rich plasma (PRP) is a technique developed for accelerating orthodontic tooth movement by simulating the effects of bone insult without surgery and loss of alveolar bone. We have revealed clinically that submucosal injection of PRP accelerated the mandibular or maxillary alignment 1.7 folds faster in average, and the acceleration was dose-dependent when the PRP fold (platelet count in PRP/platelet count in blood) was <12.5. The optimal PRP fold for a more than 2-fold acceleration of orthodontic alignment ranged from 9.5 to 12.5 folds. On the other hand, the injection of PRP on the pressure side of en masse anterior retraction decreased 71-77% of alveolar bone loss, and this was dose-dependent. The pressure side of en masse anterior retraction had no alveolar bone loss when the PRP fold was higher than 11.0. In conclusion, the optimal PRP fold for the best performance in acceleration of orthodontic tooth movement and preservation of the pressure side alveolar bone is 11.0-12.5.

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  • Pharmacological priming of adipose-derived stem cells promotes myocardial repair

    Abstract

    Adipose-derived stem cells (ADSCs) have myocardial regeneration potential, and transplantation of these cells following myocardial infarction (MI) in animal models leads to modest improvements in cardiac function. We hypothesized that pharmacological priming of pre-transplanted ADSCs would further improve left ventricular functional recovery after MI. We previously identified a compound from a family of 3,5-disubstituted isoxazoles, ISX1, capable of activating an Nkx2-5-driven promoter construct. Here, using ADSCs, we found that ISX1 (20 mM, 4 days) triggered a robust, dose-dependent, fourfold increase in Nkx2-5 expression, an early marker of cardiac myocyte differentiation and increased ADSC viability in vitro. Co-culturing neonatal cardiomyocytes with ISX1-treated ADSCs increased early and late cardiac gene expression. Whereas ISX1 promoted ADSC differentiation toward a cardiogenic lineage, it did not elicit their complete differentiation or their differentiation into mature adipocytes, osteoblasts, or chondrocytes, suggesting that re-programming is cardiomyocyte specific. Cardiac transplantation of ADSCs improved left ventricular functional recovery following MI, a response which was significantly augmented by transplantation of ISX1- pretreated cells. Moreover, ISX1-treated and transplanted ADSCs engrafted and were detectable in the myocardium 3 weeks following MI, albeit at relatively small numbers. ISX1 treatment increased histone acetyltransferase (HAT) activity in ADSCs, which was associated with histone 3 and histone 4 acetylation. Finally, hearts transplanted with ISX1-treated ADSCs manifested significant increases in neovascularization, which may account for the improved cardiac function. These findings suggest that a strategy of drug-facilitated initiation of myocyte differentiation enhances exogenously transplanted ADSC persistence in vivo, and consequent tissue neovascularization, to improve cardiac function.

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  • Antimicrobial properties of platelet-rich preparations. A systematic review of the current pre-clinical evidence

    Abstract

    In recent years autologous platelet concentrates (APCs) have become popular in several medicine fields, representing a valuable adjunct to regenerative surgical procedures. Beneficial effects in the control of postsurgical discomfort and infection have also been frequently reported, suggesting that APC may possess anti-inflammatory and antimicrobial properties. The aim of the present review was to summarize the current evidence regarding the antimicrobial effects of platelet concentrates, investigated by in vitro and animal studies. This review was conducted following a systematic approach. An electronic search was performed on MEDLINE, EMBASE and Scopus databases using appropriate search terms, without language or time restrictions. Preclinical studies assessing the antimicrobial activity of APC were included and divided according to the experimental design. Twenty in vitro studies and four animal studies, investigating APC effects on a broad range of microorganisms, were included. In in vitro studies APC reduced the growth of microorganisms during the first hours of incubation, while they could not completely break down the microbial load. In fact, over time a recovery of bacterial growth was always observed, suggesting that APCs display a bacteriostatic rather than a microbicidal activity. All animal studies showed that APC administered by local injections were able to reduce the infection caused by different microorganisms, although to a lesser extent compared to antibiotics. In conclusion, although the exact action mechanisms of interaction with microbial pathogens need further investigation, platelet concentrates proved to have antimicrobial properties, and therefore could represent a useful natural substance for controlling postoperative infections at surgical sites.

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  • Adipose-derived mesenchymal stem cells and platelet-rich plasma synergistically ameliorate the surgical-induced osteoarthritis in Beagle dogs

    Abstract

    Background The purpose of this study is to investigate the clinical effects of platelet-rich plasma (PRP) and adipose-derived mesenchymal stem cell (MSC) as the fundamental treatment of osteoarthritis (OA).

    Methods

    Twenty four Beagle dogs were used as cranial cruciate ligament transection models. The dogs were divided into four groups (n = 6) according to the intra-articular injection materials: the control group with phosphate-buffered saline (PBS), the PRP group with PRP, the MSC group with MSCs emerged in PBS, and the MSC and PRP co-treatment (MP) group with MSCs and PRP.

    Results

    Lameness score, focal compression strength, articular extracellular matrix (ECM) compositions, histopathology, and real-time PCR were used to evaluate the effects of PRP and MSCs on canine OA. In the order of MP, PRP, and MSC group, these all showed positive effects on the evaluated categories. The lameness scores were lower, and the focal compression strengths of the affected femoral articular surface cartilages were higher than those in the OA control group. Also, the inflammatory changes, when evaluated with Mankin scoring and histomorphologic examination, were significantly ameliorated with the treatment of PRP and/or MSCs. The glycosaminoglycan and collagen composition of extracellular matrix was more favorable in the test groups. The ECM-related genes significantly increased through the up-regulation, while the protein expressions of inflammatory cytokines were decreased through the inhibitory effects of PRP and MSCs on chondrocyte apoptosis and inflammatory cytokines.

    Conclusions

    Taken together, this study suggests that PRP and MSCs treatments have a beneficial effect on OA via the stimulation of ECM synthesis and chondrocyte proliferation and via the inhibition of inflammatory reaction.

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  • Improving Stem Cell Therapeutics with Mechanobiology

    Summary

    In recent years, it has become clear that mechanical cues play an integral role in maintaining stem cell functions. Here we discuss how integrating physical approaches and engineering principles in stem cell biology, including culture systems, preclinical models, and functional assessment, may improve clinical application in regenerative medicine.

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  • Use of PRP in Sports Medicine

    Introduction

    Musculoskeletal injuries are one of the most common cause of severe long-term pain and physical disability in sports medicine.Healing of these injuries is often too slow and sometimes incomplete, decreasing performance of athlete and long-standing pain and discomfort.The progressve understanding of mechanisms required for successful tissue repair has set the basis for the possibility of making injured tissues heal faster.

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  • Effectiveness of platelet-rich plasma in the treatment of moderate knee osteoarthritis: a randomized prospective study

    Abstract

    [Purpose] To assess the effects of different numbers of platelet-rich plasma (PRP) applications on pain and physical function in grade 3 knee osteoarthritis (OA). [Subjects and Methods] A total of 102 patients with grade 3 knee OA were randomly divided into three groups: Group 1 received a single injection of PRP, Group 2 received two injections of PRP two weeks apart, Group 3 received three injections of PRP at 2-weeks intervals. All patients were evaluated with a visual analog scale (VAS), the Western Ontario and McMaster Universities Arthritis Index (WOMAC), and the Timed-Up and Go test (TUG) before the treatment and at 1, 3 and 6 months after the treatment. [Results] Ninety-eight patients (15 males, 83 females) completed the study. The mean ages of the patients were 53.5 ±6.6, 54.9 ±5.3, and 55.1 ±5.6 €…years in Group 1, Group 2, and Group 3, respectively. Statistically significant improvements were noted in all of the evaluated measures in all of the groups. The mean differences of Group 1-Group 2 and Group 1-Group 3 WOMAC total, WOMAC pain, WOMAC stiffness, and WOMAC function scores were statistically significant. [Conclusion] PRP is an effective treatment for functional status and pain in moderate knee osteoarthritis and a minimum of two injections is appropriate.

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  • Human Cells, Tissues, and Cellular and Tissue-Based Products From Adipose Tissue: Regulatory Considerations; Draft Guidance for Industry; Availability

    Summary

    The Food and Drug Administration (FDA) is announcing the availability of a draft document entitled \"Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) from Adipose Tissue: Regulatory Considerations; Draft Guidance for Industry\" dated December 2014. The draft guidance document provides sponsors, clinicians, and other establishments that manufacture and use adipose tissue, with recommendations for complying with the regulatory framework for HCT/Ps. For purposes of applying the HCT/P regulatory framework, FDA considers connective tissue, including adipose tissue, to be a structural tissue. This draft guidance is not final nor is it in effect at this time.

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  • AUTOLOGOUS BONE MARROW DERIVED MESENCHYMAL STEM CELLS DOES HELP IN EARLY OSTEOARTHRITIS KNEE

    Abstract

    Introduction: There is no effective therapy available today that alters the pathobiologic course of osteoarthritis. Recent advances have shown Mesenchymal stem cells to be a potential disease modifying treatment. Considering the tissue differentiation property and vast paracrine effects of MSCs we proposed the present study to find out the safety and efficacy of Mesenchymal stem cells in osteoarthritis of knee joint.

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  • Multipotent Mesenchymal Stem Cell Treatment for Discogenic Low Back Pain and Disc Degeneration

    Abstract

    Low back pain with resultant loss of function, decreased productivity, and high economic costs is burdensome for both the individual and the society. Evidence suggests that intervertebral disc pathology is a major contributor to spine-related pain and degeneration. When commonly used conservative therapies fail, traditional percutaneous or surgical options may be beneficial for pain relief but are suboptimal because of their inability to alter disc microenvironment catabolism, restore disc tissue, and/or preserve native spine biomechanics. Percutaneously injected Multipotent Mesenchymal Stem Cell (MSC) therapy has recently gained clinical interest for its potential to revolutionarily treat disc-generated (discogenic) pain and associated disc degeneration. Unlike previous therapies to date, MSCs may uniquely offer the ability to improve discogenic pain and provide more sustained improvement by reducing disc microenvironment catabolism and regenerating disc tissue. Consistent treatment success has the potential to create a paradigm shift with regards to the treatment of discogenic pain and disc degeneration.

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  • Glenoid Labral Tear: follow up case series on ultrasound guided autologous platelet rich plasma in conjunction with a progressive rehabilitation program [version 1; referees: 1 approved, 1 approved with reservations, 1 not approved]

    Abstract

    Background: Labral tears commonly occur in both the general and sporting population, often leading to significant pain and dysfunction. Patients often engage in progressive rehabilitative programs, and surgical intervention may be required in severe cases. Autologous platelet rich plasma (PRP) injections have been growing in popularity in musculoskeletal medicine as an alternative to corticosteroid injections. This paper looks at the effectiveness of PRP injections in glenoid labral lesions.

    Methods: The clinical and radiological findings are presented for two patients who have been treated with autologous PRP into the glenohumeral joint adjacent to the labral tear, in conjunction with a progressive rehabilitative program. Follow up occurred at 18 months and 13 months, respectively.

    Results: Both subjects tolerated the PRP injection well with no adverse effects, and were compliant with their rehabilitative programs. On initial presentation, pain on the visual analogue scale (VAS) was 7/10 and 6/10 and at follow up it was reported as 0/10. Both subjects have now returned to normal sporting and work activities.

    Conclusions: The findings from this case series suggest that PRP in conjunction with appropriate rehabilitation can assist in the clinical recovery of glenoid labral tears. Further research is required with greater sample numbers and improved methodological parameters.

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  • Platelet-Rich Plasma for Frozen Shoulder: A Case Report

    Abstract

    Frozen shoulder is a glenohumeral joint disorder that perturbs movement because of adhesion and the existence of fibrosis in the shoulder capsule. Platelet-rich plasma can produce collagen and growth factors, which increases stem cells and consequently enhances the healing. To date, there is no evidence regarding the effectiveness of platelet-rich plasma in frozen shoulder. A 45-year-old man with shoulder adhesive capsulitis volunteered for this treatment. He underwent two consecutive platelet-rich plasma injections at the seventh and eighth month after initiation of symptoms. We measured pain, function, and ROM by the visual analogue scale (VAS), and scores from the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire and goniometer; respectively. After the first injection, the patient reported 60% improvement regarding diurnal shoulder pain, and no night pains. Also, two-fold improvement for ROM and more than 70% improvement for function were reported. This study suggests the use of platelet-rich plasma in frozen shoulder to be tested in randomized trials.

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  • Translation of cell therapy into clinical practice: validation of an application procedure for bone marrow progenitor cells and platelet rich plasma.

    Abstract

    Tissue regeneration can be improved by local application of autologous bone marrow derived progenitor cells (BMSC) and platelet rich plasma (PRP). However, there is a lack of standardized application procedures for clinical use. Therefore, a technique in accordance with the guidelines for advanced therapies medical products of the European Medicine Agency was developed and established.In detail, a process for the isolation and formulation of autologous bone marrow cells (BMC) and PRP in a clinical setting was validated. To investigate the influence of storage time and temperature on gel formation and gel stability, different concentrations of BMC were stored with and without additional platelets, thrombin and fibrinogen and analyzed over a period of 28 days. In addition, cell vitality using a live-dead staining and migration ability of human mesenchymal stem cells (hMSC) in the gel clot was investigated.For an optimized stable gel clot, human BMC and PRP should be combined with 10% to 20% fibrinogen (9 mg/mL to 18 mg/mL) and 5% to 20% thrombin (25 I.E. to 100 I.E.). Both freshly prepared and stored cells for 1 to 7 days had a stable consistence over 28 days at 37

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  • Effect of bone marrow-derived stem cells on chondrocytes from patients with osteoarthritis

    Abstract

    Increasing numbers of individuals are suffering from osteoarthritis every year, and the directed intra-articular injection of bone marrow stem cells has provided a promising treatment strategy for osteoarthritis. Although a number of studies have demonstrated that intra-articular injection of bone marrow stem cells produced desirable results, the mechanism underlying this effect has not been elucidated. In the current study, the effect of bone marrow stem cells on chondrocytes from patients with osteoarthritis was observed in a co-culture system. Human chondrocytes were obtained from patients with osteoarthritis who underwent surgical procedures and bone marrow stem cells were obtained from bone marrow aspirates, and then the chondrocytes were then cultured alone or cocultured with bone marrow stem cells in 0.4-

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  • Real-time-guided bone regeneration around standardized critical size calvarial defects using bone marrow-derived mesenchymal stem cells and collagen membrane with and without using tricalcium phosphate: an in vivo micro-computed tomographic and histologic

    Abstract

    The aim of the present real time in vivo micro-computed tomography (µCT) and histologic experiment was to assess the efficacy of guided bone regeneration (GBR) around standardized calvarial critical size defects (CSD) using bone marrow-derived mesenchymal stem cells (BMSCs), and collagen membrane (CM) with and without tricalcium phosphate (TCP) graft material. In the calvaria of nine female Sprague-Dawley rats, full-thickness CSD (diameter 4.6 mm) were created under general anesthesia. Treatment-wise, rats were divided into three groups. In group 1, CSD was covered with a resorbable CM; in group 2, BMSCs were filled in CSD and covered with CM; and in group 3, TCP soaked in BMSCs was placed in CSD and covered with CM. All defects were closed using resorbable sutures. Bone volume and bone mineral density of newly formed bone (NFB) and remaining TCP particles and rate of new bone formation was determined at baseline, 2, 4, 6, and 10 weeks using in vivo µCT. At the 10th week, the rats were killed and calvarial segments were assessed histologically. The results showed that the hardness of NFB was similar to that of the native bone in groups 1 and 2 as compared to the NFB in group 3. Likewise, values for the modulus of elasticity were also significantly higher in group 3 compared to groups 1 and 2. This suggests that TCP when used in combination with BMSCs and without CM was unable to form bone of significant strength that could possibly provide mechanical “lock” between the natural bone and NFB. The use of BMSCs as adjuncts to conventional GBR initiated new bone formation as early as 2 weeks of treatment compared to when GBR is attempted without adjunct BMSC therapy.

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  • The effect of sub-epineural platelet-rich plasma (PRP) on regeneration of the sciatic nerve in a rat model

    Abstract:

    Background: Peripheral nerve injury is one of the most challenging of modern surgical problem. Recent advances in understanding the physiological and molecular pathways demonstrated the important role of growth factors in peripheral nerve regeneration. Platelet-rich plasma (PRP) is a biological product that has many growth factors. The aim of this study was to investigate the effect of PRP in the regeneration of sciatic nerve crush in the rat model.Methods: In this experimental study that established in the animal lab of the Hazrat Fatemeh Hospital in Tehran from September to October 2013, Twenty-four healthy male Sprague-Dawley rats (200-250 g) were randomly divided into two groups. In all rats the sciatic nerve was cut and then carefully repaired by the tension free method under a light microscope. In group 1, after the repair, 0.05

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  • Short term results comparison of intraarticular platelet-rich plasma (prp) and hyaluronic acid (ha) applications in early stage of knee osteoarthritis

    Abstract

    Objective:

    The aim of this study is to compare the short-term results of intra-articular platelet-rich plasma (PRP) and hyaluronic acid (HA) administrations in early knee osteoarthritis. Materials and methods: One hundred and eighteen patients (mean age: 59.3

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