RESUMEN
Adipose-derived stem cells (ADSCs) are mesenchymal stem cells with a great potential for self-renewal and differentiation. Exosomes derived from ADSCs (ADSC-exos) can imitate their functions, carrying cargoes of bioactive molecules that may affect specific cellular targets and signaling processes. Recent evidence has shown that ADSC-exos can mediate tissue regeneration through the regulation of the inflammatory response, enhancement of cell proliferation, and induction of angiogenesis. At the same time, they may promote wound healing as well as the remodeling of the extracellular matrix. In combination with scaffolds, they present the future of cell-free therapies and promising adjuncts to reconstructive surgery with diverse tissue-specific functions and minimal adverse effects. In this review, we address the main characteristics and functional properties of ADSC-exos in tissue regeneration and explore their most recent clinical application in wound healing, musculoskeletal regeneration, dermatology, and plastic surgery as well as in tissue engineering.
Asunto(s)
Tejido Adiposo , Exosomas , Células Madre Mesenquimatosas , Regeneración , Cicatrización de Heridas , Humanos , Exosomas/metabolismo , Tejido Adiposo/citología , Tejido Adiposo/metabolismo , Animales , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Ingeniería de Tejidos/métodos , Diferenciación Celular , Células Madre/metabolismo , Células Madre/citologíaRESUMEN
Desired orthopedic implant materials must have a good biological activity and possess appropriate mechanical property that correspond to those of human bone. Although polyetheretherketone (PEEK) has displayed a promising application prospect in musculoskeletal and dentistry reconstruction thanks to its non-biodegradability and good biocompatibility in the body, the poor osseointegration and insufficient mechanical strength have significantly limited its application in the repair of load-bearing bones and surgical operations. In this study, carbon nanotubes (CNT)/calcium silicate (CS)/polyetheretherketone ternary composites were fabricated for the first time. The addition of CS was mainly aimed at improving biological activities and surface hydrophilicity, but it inevitably compromised the mechanical strength of PEEK. CNT can reinforce the composites even when brittle CS was introduced and further upgraded the biocompatibility of PEEK. The CNT/CS/PEEK composites exhibited higher mechanical strengths in tensile and bending tests, 64% and 90% higher than those of brittle CS/PEEK binary composites. Besides, after incorporation of CNT and CS into PEEK, the hydrophilicity, surface roughness and ability to induce apatite-layer deposition were significantly enhanced. More importantly, the adhesion, proliferation, and osteogenic differentiation of mouse embryo osteoblasts were effectively promoted on CNT/CS/PEEK composites. In contrast to PEEK, these composites exhibited a more satisfactory biocompatibility and osteoinductive activity. Overall, these results demonstrate that ternary CNT/CS/PEEK composites have the potential to serve as a feasible substitute to conventional metal alloys in musculoskeletal regeneration and orthopedic implantation.
RESUMEN
Electrical phenomena play an important role in numerous biological processes including cellular signaling, early embryogenesis, tissue repair and remodeling, and growth of organisms. Electrical and magnetic effects have been studied on a variety of stimulation strategies and cell types regarding cellular functions and disease treatments. In this review, we discuss recent advances in using three different stimulation strategies, namely electrical stimulation via conductive and piezoelectric materials as well as magnetic stimulation via magnetic materials, to modulate cell and tissue properties. These three strategies offer distinct stimulation routes given specific material characteristics. This review will evaluate material properties and biological response for these stimulation strategies with respect to their potential applications in neural and musculoskeletal research.
RESUMEN
The extracellular microenvironment regulates many of the mechanical and biochemical cues that direct musculoskeletal development and are involved in musculoskeletal disease. The extracellular matrix (ECM) is a main component of this microenvironment. Tissue engineered approaches towards regenerating muscle, cartilage, tendon, and bone target the ECM because it supplies critical signals for regenerating musculoskeletal tissues. Engineered ECM-material scaffolds that mimic key mechanical and biochemical components of the ECM are of particular interest in musculoskeletal tissue engineering. Such materials are biocompatible, can be fabricated to have desirable mechanical and biochemical properties, and can be further chemically or genetically modified to support cell differentiation or halt degenerative disease progression. In this review, we survey how engineered approaches using natural and ECM-derived materials and scaffold systems can harness the unique characteristics of the ECM to support musculoskeletal tissue regeneration, with a focus on skeletal muscle, cartilage, tendon, and bone. We summarize the strengths of current approaches and look towards a future of materials and culture systems with engineered and highly tailored cell-ECM-material interactions to drive musculoskeletal tissue restoration. The works highlighted in this review strongly support the continued exploration of ECM and other engineered materials as tools to control cell fate and make large-scale musculoskeletal regeneration a reality.
RESUMEN
The musculoskeletal system plays a critical role in providing the physical scaffold and movement to the mammalian body. Musculoskeletal disorders severely affect mobility and quality of life and pose a heavy burden to society. This new field of musculoskeletal tissue engineering has great potential as an alternative approach to treating large musculoskeletal defects. Natural and synthetic polymers are widely used in musculoskeletal tissue engineering owing to their good biocompatibility and biodegradability. Even more promising is the use of natural and synthetic polymer composites, as well as the combination of polymers and inorganic materials, to repair musculoskeletal tissue. Therefore, this review summarizes the progress of polymer-based scaffolds for applications of musculoskeletal tissue engineering and briefly discusses the challenges and future perspectives.
RESUMEN
Perspective: Musculoskeletal (MSK) tissues such as articular cartilage, menisci, tendons, and ligaments are often injured throughout life as a consequence of accidents. Joints can also become compromised due to the presence of inflammatory diseases such as rheumatoid arthritis. Thus, there is a need to develop regenerative approaches to address such injuries to heterogeneous tissues and ones that occur in heterogeneous environments. Such injuries can compromise both the biomechanical integrity and functional capability of these tissues. Thus, there are several challenges to overcome in order to enhance success of efforts to repair and regenerate damaged MSK tissues. Challenges: 1. MSK tissues arise during development in very different biological and biomechanical environments. These early tissues serve as a template to address the biomechanical requirements evolving during growth and maturation towards skeletal maturity. Many of these tissues are heterogeneous and have transition points in their matrix. The heterogeneity of environments thus presents a challenge to replicate with regard to both the cells and the ECM. 2. Growth and maturation of musculoskeletal tissues occurs in the presence of anabolic mediators such as growth hormone and the IGF-1 family of proteins which decline with age and are low when there is a greater need for the repair and regeneration of injured or damaged tissues with advancing age. Thus, there is the challenge of re-creating an anabolic environment to enhance incorporation of implanted constructs. 3. The environments associated with injury or chronic degeneration of tissues are often catabolic or inflammatory. Thus, there is the challenge of creating a more favorable in vivo environment to facilitate the successful implantation of in vitro engineered constructs to regenerate damaged tissues. Conclusions: The goal of regenerating MSK tissues has to be to meet not only the biological requirements (components and structure) but also the heterogeneity of function (biomechanics) in vivo. Furthermore, for many of these tissues, the regenerative approach has to overcome the site of injury being influenced by catabolism/inflammation. Attempts to date using both endogenous cells, exogenous cells and scaffolds of various types have been limited in achieving long term outcomes, but progress is being made.
RESUMEN
Recombinant adeno-associated viral (rAAV) vector-mediated gene delivery is a novel molecular therapeutic approach for musculoskeletal disorders which achieves tissue regeneration by delivering a transgene to the impaired tissue. In recent years, substantial scientific progress in rAAV gene therapy has led to several clinical trials for human musculoskeletal diseases. Nevertheless, there are still limitations in developing an optimal gene therapy model due to the low transduction efficiency and fast degradation of the gene vectors. To overcome the challenges of rAAV gene therapy, tissue engineering combined with gene therapy has emerged as a more promising alternative. An rAAV viral vector incorporated into a biomaterial has a more controlled gene expression, lower immune response, and higher efficiency. A number of biomaterials and architectures have been combined with rAAV viral vectors, each having its own advantages and limitations. This review aims to give a broad introduction to combinatorial therapy and the recent progress this new technology has offered.
RESUMEN
Traumatic musculoskeletal injuries are common in both the civilian and combat care settings. Significant barriers exist to repairing these injuries including fracture nonunion, muscle fibrosis, re-innervation, and compartment syndrome, as well as infection and inflammation. Recently, extracellular vesicles (EVs), including exosomes and microvesicles, have attracted attention in the field of musculoskeletal regeneration. These vesicles are released by different cell types and play a vital role in cell communication by delivering functional cargoes such as proteins and RNAs. Many of these cargo molecules can be utilized for repair purposes in skeletal disorders such as osteoporosis, osteogenesis imperfecta, sarcopenia, and fracture healing. There are, however, some challenges to overcome in order to advance the successful application of these vesicles in the therapeutic setting. These include large-scale production and isolation of exosomes, long-term storage, in vivo stability, and strategies for tissue-specific targeting and delivery. This paper reviews the general characteristics of exosomes along with their physiological roles and contribution to the pathogenesis of musculoskeletal diseases. We also highlight new findings on the use of synthetic exosomes to overcome the limitations of native exosomes in treating musculoskeletal injuries and disorders.
Asunto(s)
Vesículas Extracelulares , Comunicación Celular , Sistemas de Liberación de Medicamentos , Exosomas , Músculo Esquelético , RegeneraciónRESUMEN
Natural or synthetic materials designed to adhere to biological components, bioadhesives, have received significant attention in clinics and surgeries. As a result, there are several commercially available, FDA-approved bioadhesives used for skin wound closure, hemostasis, and sealing tissue gaps or cracks in soft tissues. Recently, the application of bioadhesives has been expanded to various areas including musculoskeletal tissue engineering and regenerative medicine. The instant establishment of a strong adhesion force on tissue surfaces has shown potential to augment repair of connective tissues. Bioadhesives have also been applied to secure tissue grafts to host bodies and to fill or seal gaps in musculoskeletal tissues caused by injuries or degenerative diseases. In addition, the injectability equipped with the instant adhesion formation may provide the great potential of bioadhesives as vehicles for localized delivery of cells, growth factors, and small molecules to facilitate tissue healing and regeneration. This review covers recent research progress in bioadhesives as focused on their applications in musculoskeletal tissue repair and regeneration. We also discuss the advantages and outstanding challenges of bioadhesives, as well as the future perspective toward regeneration of connective tissues with high mechanical demand.
Asunto(s)
Materiales Biocompatibles , Adhesivos Tisulares , Medicina Regenerativa , Ingeniería de Tejidos , Cicatrización de HeridasRESUMEN
The discovery of induced pluripotent stem cells (iPSCs) has revolutionized biomedicine. Although the potential of iPSCs for tissue regeneration, disease modeling and drug screening has been largely recognized, findings of iPSC research to date are mostly focused on neurology, cardiology and haematology. For orthopaedics, growing interest in the unique cell type has prompted more researchers to get involved in iPSC research. In this article, we introduce the brief history of cellular reprogramming and different reprogramming methods that have been developed, discuss the biology of iPSCs and review previously reported findings of iPSC studies in orthopaedics. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: Stem cell therapies hold great promise for treating orthopaedic diseases, manifested in recent study findings and results of clinical trials. iPSCs are a unique stem cell type derived from a patient's own cells while still possessing the embryonic stem cell-featured pluripotency for generation of all tissues in the body. The distinctive properties make iPSCs much desirable to fulfill the promise of regenerative medicine for clinical orthopaedics.
RESUMEN
The rise in the incidence of musculoskeletal diseases is attributed to an increasing ageing population. The debilitating effects of musculoskeletal diseases, coupled with a lack of effective therapies, contribute to huge financial strains on healthcare systems. The focus of regenerative medicine has shifted to pluripotent stem cells (PSCs), namely, human embryonic stem cells and human-induced PSCs, due to the limited success of adult stem cell-based interventions. PSCs constitute a valuable cell source for musculoskeletal regeneration due to their capacity for unlimited self-renewal, ability to differentiate into all cell lineages of the three germ layers and perceived immunoprivileged characteristics. This review summarizes methods for chondrogenic, osteogenic, myogenic and adipogenic differentiation of PSCs and their potential for therapeutic applications.
RESUMEN
Tissue regenerative medicine combines the use of cells, scaffolds, and molecules to repair damaged tissues. Different cell types are employed for musculoskeletal diseases, both differentiated and mesenchymal stromal cells (MSCs). In recent years, the hypothesis that cell-based therapy is guided principally by cell-secreted factors has become increasingly popular. The aim of the present literature review was to evaluate preclinical and clinical studies that used conditioned medium (CM), rich in cell-factors, for musculoskeletal regeneration. Thirty-one were in vitro, 12 in vivo studies, 1 was a clinical study, and 2 regarded extracellular vesicles. Both differentiated cells and MSCs produce CM that induces reduction in inflammation and increases synthetic activity. MSC recruitment and differentiation, endothelial cell recruitment and angiogenesis have also been observed. In vivo studies were performed with CM in bone and periodontal defects, arthritis and muscle dystrophy pathologies. The only clinical study was performed with CM from MSCs in patients needing alveolar bone regeneration, showing bone formation and no systemic or local complications. Platelet derived growth factor receptor ß, C3a, vascular endothelial growth factor, monocyte chemoattractant protein-1 and -3, interleukin 3 and 6, insulin-like growth factor-I were identified as responsible of cell migration, proliferation, osteogenic differentiation, and angiogenesis. The use of CM could represent a new regenerative treatment in several musculoskeletal pathologies because it overcomes problems associated with the use of cells and avoids the use of exogenous GFs or gene delivery systems. However, some issues remain to be clarified.
Asunto(s)
Terapia Biológica/métodos , Medios de Cultivo Condicionados/metabolismo , Células Madre Mesenquimatosas/metabolismo , Enfermedades Musculoesqueléticas/terapia , Sistema Musculoesquelético/metabolismo , Comunicación Paracrina , Regeneración , Medicina Regenerativa/métodos , Animales , Diferenciación Celular , Células Cultivadas , Humanos , Enfermedades Musculoesqueléticas/metabolismo , Enfermedades Musculoesqueléticas/fisiopatología , Sistema Musculoesquelético/fisiopatología , Fenotipo , Transducción de SeñalRESUMEN
Kartogenin (KGN) is a recently characterized small molecule that promotes the selective differentiation of mesenchymal stem cells into chondrocytes, and thus, KGN stimulates cartilage regeneration. KGN also possess chondro-protective effect. Furthermore, because it is a highly stable small molecule, KGN can be stored and transported at room temperature. These obvious superiorities over peptide growth factors make KGN a desirable chondrogenic agent for cartilage regeneration. Since its discovery, KGN has drawn much attention as a new chondrogenic drug for intraarticular (IA) treatment. Although it was originally developed with a focus on OA, it has been used to treat other conditions and to promote disc and bone-tendon junction regeneration. Our group has also developed several formulations for IA delivery of KGN including KGN-conjugated chitosan nano/microparticles, thermo-responsive polymeric nanospheres based on chitosan oligosaccharide conjugated pluronic F127, and hyluronate hydrogels containing polyethylene glycol (PEG/KGN) micelles. This review was undertaken to summarize current research on the action mechanism of KGN and the various formulations described in the literature that induce musculoskeletal regeneration. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1141-1148, 2018.
Asunto(s)
Anilidas/farmacología , Sistema Musculoesquelético/efectos de los fármacos , Ácidos Ftálicos/farmacología , Regeneración/efectos de los fármacos , Animales , Huesos/patología , Humanos , Tendones/patología , Cicatrización de HeridasRESUMEN
Stem cell treatment and platelet-rich plasma (PRP) therapy are two significant issues in regenerative medicine. Stem cells such as bone marrow mesenchymal stem cells, adipose-derived stem cells and periodontal ligament stem cells can be successfully applied in the field of tissue regeneration. PRP, a natural product isolated from whole blood, can secrete multiple growth factors (GFs) for regulating physiological activities. These GFs can stimulate proliferation and differentiation of different stem cells in injury models. Therefore, combination of both agents receives wide expectations in regenerative medicine, especially in bone, cartilage and tendon repair. In this review, we thoroughly discussed the interaction and underlying mechanisms of PRP derived GFs with stem cells, and assessed their functions in cell differentiation for musculoskeletal regeneration.
RESUMEN
This review focuses on the current status of research that utilizes the application of pharmacological sciences to accelerate, optimize and characterize the development, maturation and function of bioengineered and regenerating tissues. These regenerative pharmacologic approaches have been applied to diseases of the urogenital tract, the heart, the brain, the musculoskeletal system and diabetes. Approaches have included the use of growth factors (such as VEGF and chemokines (stromal-derived factor - CXCL12) to mobilize cell to the sights of tissue loss or damage. The promise of this approach is to bypass the lengthy and expensive processes of cell isolation and implant fabrication to stimulate the body to heal itself with its own tissue regenerative pathways.
Asunto(s)
Materiales Biocompatibles/química , Farmacología , Medicina Regenerativa , Ingeniería de Tejidos/métodos , Animales , Humanos , Trasplante de Células MadreRESUMEN
Cells interact with various nanoscaled topographical and biochemical cues in their cellular macromolecular environment. Nanotopography recreates or mimic the cellular macromolecular environment in vitro. The influence of material surface topography on the behavior of adherent cells has been studied. Current techniques enable various kinds of nanopatterned surface to be generated and applied to cells. The purpose of this review is to provide an overview of nanotopography and its surface patterns, and introduce nanotopography effects on cell behavior including cell attachment, proliferation, and cell differentiation with particular emphasis on musculoskeletal regeneration.
Asunto(s)
Diferenciación Celular , Proliferación Celular , Nanoestructuras/química , Nanotecnología , Regeneración , Células Madre/metabolismo , Animales , Adhesión Celular , Humanos , Células Madre/citologíaRESUMEN
The purpose of this study was to develop single walled carbon nanotubes (SWCNT) and poly lactic-co-glycolic acid (PLAGA) composites for orthopedic applications and to evaluate the interaction of human stem cells (hBMSCs) and osteoblasts (MC3T3-E1 cells) via cell growth, proliferation, gene expression, extracellular matrix production and mineralization. PLAGA and SWCNT/PLAGA composites were fabricated with various amounts of SWCNT (5, 10, 20, 40, and 100 mg), characterized and degradation studies were performed. Cells were seeded and cell adhesion/morphology, growth/survival, proliferation and gene expression analysis were performed to evaluate biocompatibility. Imaging studies demonstrated uniform incorporation of SWCNT into the PLAGA matrix and addition of SWCNT did not affect the degradation rate. Imaging studies revealed that MC3T3-E1 and hBMSCs cells exhibited normal, non-stressed morphology on the composites and all were biocompatible. Composites with 10 mg SWCNT resulted in highest rate of cell proliferation (p < 0.05) among all composites. Gene expression of alkaline phosphatase, collagen I, osteocalcin, osteopontin, Runx-2, and Bone Sialoprotein was observed on all composites. In conclusion, SWCNT/PLAGA composites imparted beneficial cellular growth capabilities and gene expression, and mineralization abilities were well established. These results demonstrate the potential of SWCNT/PLAGA composites for musculoskeletal regeneration and bone tissue engineering (BTE) and are promising for orthopedic applications.