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Abstract: We utilized the hAM to provide the biological and the three dimensional (3D) topographic components of the prototype. The 3D nano-roughness of the hAM was characterized using surface electron microscopy and surface image analysis (ImageJ and SurfaceJ). We developed additional macro-scale and micro-scale versions of the platform which provided additional shear stress factors to simulate the fluid dynamics of the in vivo extracellular fluids.Three models of varying complexities of the prototype were assembled. A well-defined 3D surface modulation of the hAM in comparable to commercial 3D biomaterial culture substrates was achieved without complex fabrication and with significantly lower cost. Performance of the prototype was demonstrated through culture of primary human umbilical cord mononuclear blood cells (MNCs), human bone marrow mesenchymal stem cell line (hBMSC), and human breast cancer tissue.This study presents methods of assembling an integrated, flexible and low cost biomimetic cell culture platform for diverse cell culture applications.
Pub.: 10 Dec '16, Pinned: 02 Feb '17
Abstract: One major limitation of intervertebral disc (IVD) repair is that no ideal biomaterial has been developed that effectively mimics the angle-ply collagen architecture and mechanical properties of the native annulus fibrosus (AF). Furthermore, it would be beneficial to devise a simple, scalable process by which to manufacture a biomimetic biomaterial that could function as a mechanical repair patch to be secured over a large defect in the outer AF that will support AF tissue regeneration. Such a biomaterial would: (1) enable the employment of early-stage interventional strategies to treat IVD degeneration (i.e. nucleus pulposus arthroplasty); (2) prevent IVD re-herniation in patients with large AF defects; and (3) serve as a platform to develop full-thickness AF and whole IVD tissue engineering strategies. Due to the innate collagen fibre alignment and mechanical strength of pericardium, a procedure was developed to assemble multi-laminate angle-ply AF patches derived from decellularized pericardial tissue. Patches were subsequently assessed histologically to confirm angle-ply microarchitecture, and mechanically assessed for biaxial burst strength and tensile properties. Additionally, patch cytocompatibility was evaluated following seeding with bovine AF cells. This study demonstrated the effective removal of porcine cell remnants from the pericardium, and the ability to reliably produce multi-laminate patches with angle-ply architecture using a simple assembly technique. Resultant patches demonstrated their inherent ability to resist biaxial burst pressures reminiscent of intradiscal pressures commonly borne by the AF, and exhibited tensile strength and modulus values reported for native human AF. Furthermore, the biomaterial supported AF cell viability, infiltration and proliferation. Copyright © 2016 John Wiley & Sons, Ltd.
Pub.: 13 Dec '16, Pinned: 15 Dec '16
Abstract: Over the past years the progress in the development of a bioartificial liver (BAL) as an extracorporeal device or as a tissue engineered transplantable organ has been immense. However, many important BAL characteristics that are necessary to meet clinical demands, have not been sufficiently addressed. This review describes the existing challenges in the development of a BAL for clinical applications, highlighting multicellularity and sinusoidal microarchitecture as crucial BAL characteristics to fulfill various liver functions. We define currently available sources of non-parenchymal liver cells, such as endothelial cells, cholangiocytes and macrophages, used in BAL development. Also, we discuss the recent studies on the reconstruction of the complex liver sinusoid microarchitecture using various liver cell types. Moreover, we highlight some other aspects of a BAL, such as liver zonation and formation of a vascular as well as biliary network for an adequate delivery, biotransformation and removal of substrates and waste products. Finally, the benefits of a multicellular BAL for the pharmaceutical industry are briefly described as well.
Pub.: 13 Dec '16, Pinned: 15 Dec '16
Abstract: New health technologies are rapidly emerging from various areas of bioscience research, such as gene editing, regenerative medicine and synthetic biology. These technologies raise promising medical possibilities but also a range of ethical considerations. Apart from the issues involved in considering whether novel health technologies can or should become part of mainstream medical treatment once established, the process of research translation to develop such therapies itself entails particular ethical concerns. In this paper I use synthetic biology as an example of a new and largely unexplored area of health technology to consider the ways in which novel health technologies are likely to emerge and the ethical challenges these will present. I argue that such developments require us to rethink conventional attitudes towards clinical research, the roles of doctors/researchers and patients/participants with respect to research, and the relationship between science and society; and that a broader framework is required to address the plurality of stakeholder roles and interests involved in the development of treatments based on novel technologies.
Pub.: 13 Dec '16, Pinned: 15 Dec '16
Abstract: Clinical researches usually collected numerous intermediate variables besides treatment and outcome. These variables are often incorrectly treated as confounding factors and are thus controlled using a variety of multivariable regression models depending on the types of outcome variable. However, these methods fail to disentangle underlying mediating processes. Causal mediation analysis (CMA) is a method to dissect total effect of a treatment into direct and indirect effect. The indirect effect is transmitted via mediator to the outcome. The mediation package is designed to perform CMA under the assumption of sequential ignorability. It reports average causal mediation effect (ACME), average direct effect (ADE) and total effect. Also, the package provides visualization tool for these estimated effects. Sensitivity analysis is designed to examine whether the results are robust to the violation of the sequential ignorability assumption since the assumption has been criticized to be too strong to be satisfied in research practice.
Pub.: 13 Dec '16, Pinned: 15 Dec '16
Abstract: The concept of tissue regeneration is ancient; the earliest known written reference to it is found in Hesiod’s Theogony. Prometheus’ liver regenerated after being consumed. This type of tissue regeneration is known as regenerative hypertrophy. Regenerative biology advanced significantly in the 18th and 19th centuries and it was during this period that the first reference to the term “stem cell” was recorded; however, the term was used significantly differently than the definition it contains today (a clonal entity able to self-renew and displays asymmetric division). Although the history of regenerative medicine, regenerative biology, and tissue regeneration is ancient, significant findings have occurred in the 18th and 19th centuries, and recently, after a period of neglect, many findings of these time frames have resurfaced and changed the way the field experts understand regenerating tissue. This translates itself into regenerative medicine regarding how to think about the technologies available to the clinician practicing regenerative medicine. That is, basic science should guide the clinical use of available methods and tools used. The tools themselves (eg, cellular therapy) are not synonymous with the practice of regenerative medicine. Rather they are tools in the arsenal of the practicing physician. The goal of this article is to provide an overview of the history of regenerative biology and medicine, the progression of the basic science of regenerative biology, and to include discussions that are focused on translating the basic science of regenerative biology into regenerative medicine. This is not a structured and comprehensive review of all the history and aspects of regenerative biology and regenerative medicine, but merely incorporates several key points to provide evidence of the topics discussed in this article.
Pub.: 05 Dec '16, Pinned: 15 Dec '16
Abstract: Therapies using mesenchymal stem cell (MSC) seeded scaffolds may be applicable to various fields of regenerative medicine, including craniomaxillofacial surgery. Plastic compression of collagen scaffolds seeded with MSC has been shown to enhance the osteogenic differentiation of MSC as it increases the collagen fibrillary density. The aim of the present study was to evaluate the osteogenic effects of dense collagen gel scaffolds seeded with mesenchymal dental pulp stem cells (DPSC) on bone regeneration in a rat critical-size calvarial defect model. Two symmetrical full-thickness defects were created (5 mm diameter) and filled with either a rat DPSC-containing dense collagen gel scaffold (n = 15), or an acellular scaffold (n = 15). Animals were imaged in vivo by microcomputer tomography (Micro-CT) once a week during 5 weeks, whereas some animals were sacrificed each week for histology and histomorphometry analysis. Bone mineral density and bone micro-architectural parameters were significantly increased when DPSC-seeded scaffolds were used. Histological and histomorphometrical data also revealed significant increases in fibrous connective and mineralized tissue volume when DPSC-seeded scaffolds were used, associated with expression of type I collagen, osteoblast-associated alkaline phosphatase and osteoclastic-related tartrate-resistant acid phosphatase. Results demonstrate the potential of DPSC-loaded-dense collagen gel scaffolds to benefit of bone healing process.
Pub.: 10 Dec '16, Pinned: 15 Dec '16
Abstract: Ultrasound is critical in many areas of medicine including obstetrics, oncology, and cardiology with emerging applications in regenerative medicine. However, one critical limitation of ultrasound is the low contrast of target tissue over background. Here, we describe a novel cup-shaped silica nanoparticle that is reminiscent of exosomes and that has significant ultrasound impedance mismatch for labelling stem cells for regenerative medicine imaging. These exosome-like silica nanoparticles (ELS) were created through emulsion templating and the silica precursors bis(triethoxysilyl)ethane (BTSE) and bis(3-trimethoxysilyl-propyl)amine (TSPA). We found that 40% TSPA resulted in the exosome like-morphology and a positive charge suitable for labelling mesenchymal stem cells. We then compared this novel structure to other silica structures used in ultrasound including Stober silica nanoparticles (SSN), MCM-41 mesoporous silica nanoparticles (MSN), and mesocellular foam silica nanoparticles (MCF) and found that the ELS offered enhanced stem cell signal due to its positive charge to facilitate cell uptake as well as inherently increased echogenicity. The in vivo detection limits were <500 cells with no detectable toxicity at the concentrations used for labelling. This novel structure may eventually find utility in applications beyond imaging requiring an exosome-like shape including drug delivery.
Pub.: 08 Dec '16, Pinned: 15 Dec '16
Abstract: The essential idea of regenerative medicine is to fix or replace tissues or organs with alive and patient-specific implants. Pluripotent stem cells are able to indefinitely self-renew and differentiate into all cell types of the body which makes them a potent substantial player in regenerative medicine. The easily accessible source of induced pluripotent stem cells may allow obtaining and cultivating tissues in vitro. Reprogramming refers to regression of mature cells to its initial pluripotent state. One of the approaches affecting pluripotency is the usage of low molecular mass compounds that can modulate enzymes and receptors leading to the formation of pluripotent stem cells (iPSCs). It would be great to assess the general character of such compounds and reveal their new derivatives or modifications to increase the cell reprogramming efficiency. Many improvements in the methods of pluripotency induction have been made by various groups in order to limit the immunogenicity and tumorigenesis, increase the efficiency and accelerate the kinetics. Understanding the epigenetic changes during the cellular reprogramming process will extend the comprehension of stem cell biology and lead to potential therapeutic approaches. There are compounds which have been already proven to be or for now only putative inducers of the pluripotent state that may substitute for the classic reprogramming factors (Oct3/4, Sox2, Klf4, c-Myc) in order to improve the time and efficiency of pluripotency induction. The effect of small molecules on gene expression is dosage-dependent and their application concentration needs to be strictly determined. In this review we analysed the role of small molecules in modulations leading to pluripotency induction, thereby contributing to our understanding of stem cell biology and uncovering the major mechanisms involved in that process.
Pub.: 22 Nov '16, Pinned: 15 Dec '16
Abstract: Hydrogels of spatially controlled physicochemical properties are appealing platforms for tissue engineering and drug delivery. In this study, core-shell silk fibroin (SF) hydrogels of spatially controlled conformation were developed. The core-shell structure in the hydrogels was formed by means of soaking the preformed (enzymatically crosslinked) random coil SF hydrogels in methanol. When increasing the methanol treatment time from 1 to 10 min, the thickness of the shell layer can be tuned from about 200 to about 850 μm as measured in wet status. After lyophilization of the rehydrated core-shell hydrogels, the shell layer displayed compact morphology and the core layer presented porous structure, when observed by scanning electron microscopy. The conformation of the hydrogels was evaluated by Fourier transform infrared spectroscopy in wet status. The results revealed that the shell layer possessed dominant β-sheet conformation and the core layer maintained mainly random coil conformation. Enzymatic degradation data showed that the shell layers presented superior stability to the core layer. The mechanical analysis displayed that the compressive modulus of the core-shell hydrogels ranged from about 25 kPa to about 1.1 MPa by increasing the immersion time in methanol. When incorporated with albumin, the core-shell SF hydrogels demonstrated slower and more controllable release profiles compared with the non-treated hydrogel. These core-shell SF hydrogels of highly tuned properties are useful systems as drug-delivery system and may be applied as cartilage substitute. Copyright © 2016 John Wiley & Sons, Ltd.
Pub.: 07 Dec '16, Pinned: 13 Dec '16
Abstract: The Bioartificial Renal Epithelial Cell System (BRECS), is a cell-based device to treat acute kidney injury through renal cell therapy from an extracorporeal circuit. To enable widespread implementation of cell therapy, the BRECS was designed to be cryopreserved as a complete device, cryostored, cryoshipped to an end-use site, thawed as a complete device, and employed in a therapeutic extracorporeal hemofiltration circuit. This strategy overcomes storage and distribution issues that have been previous barriers to cell therapy. Previous BRECS housings produced by Computer Numerical Control (CNC) machining, a slow process taking hours to produce one bioreactor, was also prohibitively expensive (>$600/CNC-BRECS); major obstacles to mass production. The goal of this study was to produce a BRECS to be mass produced by injection molding (IM-BRECS), decreasing cost (<$20/unit) and improving manufacturing speed (hundreds of units/hr), while maintaining the same cell therapy function as the previous CNC-BRECS, first evaluated through prototypes produced by stereolithography (SLA-BRECS). The finalized IM-BRECS design had a significantly lower fill volume (10 mL), mass (49 g) and footprint (8.5 cm×8.5 cm×1.5 cm), and was demonstrated to outperform the previous BRECS designs with respect to heat transfer, significantly improving control of cooling during cryopreservation and reducing thaw times during warming. During in vitro culture, IM-BRECS performed similarly to previous CNC-BRECS with respect to cell metabolic activity (lactate production, oxygen consumption and glutathione metabolism) and amount of cells supported.
Pub.: 07 Dec '16, Pinned: 13 Dec '16
Abstract: Microfluidic technologies enable temporal and spatial control of cellular microenvironments by mimicking the complex biological functions of normal cellular interactions, opening new opportunities for cell-based drug screening. Microfluidic devices with large-scale integration, automatic operation and micro-sized scale offer many unique benefits including high throughputs, low cost and high efficiency in drug development. Here, we review the recent fundamental development of microfluidic three-dimensional (3D) cellular scaffolds and highlight the perspective of drug assay applications in relation to drug screening and nano-drug cytotoxicity analysis. In particular, we discuss the advances in diverse biomimetic strategies including microfabricated 3D cell culture systems, droplet-based 3D hydrogel scaffolds for cell encapsulation, and organs- and tissues-on-chips. A brief summary is also presented along with a perspective of this field in the future.
Pub.: 28 Nov '16, Pinned: 05 Dec '16
Abstract: Neovascularization has been a major challenge in many tissue regeneration strategies. Hyaluronic acid (HA) of 3–25 disaccharides is known to be angiogenic due to its interaction with endothelial cell receptors. This effect has been explored with HA-based structures but a transitory response is observed due to HA burst biodegradation. Herein we developed gellan gum (GG)-HA spongy-like hydrogels from semi-interpenetrating network hydrogels with different HA amounts. Enzymatic degradation was more evident in the GG-HA with high HA amount due to their lower mechanical stability, also resulting from the degradation itself, which facilitated the access of the enzyme to the HA in the bulk. GG-HA spongy-like hydrogels hyaluronidase-mediated degradation lead to the release of HA oligosaccharides of different amounts and sizes in a HA content-dependent manner which promoted in vitro proliferation of human umbilical cord vein endothelial cells (HUVECs) but not their migration. Although no effect was observed in human dermal microvascular endothelial cells (hDMECs) in vitro, the implantation of GG-HA spongy-like hydrogels in an ischemic hind limb mice model promoted neovascularization in a material-dependent manner, consistent with the in vitro degradation profile. Overall, GG-HA spongy-like hydrogels with a sustained release of HA oligomers are valuable options to improve tissue vascularization, a critical issue in several applications in the tissue engineering and regenerative medicine field.
Pub.: 18 Nov '16, Pinned: 05 Dec '16
Abstract: Launched in June 2011, CCRM is a unique, Canadian, not-for-profit group that is solely focused on developing and commercializing regenerative medicine, cell and gene therapy technologies. Its mission is to generate sustainable health and economic benefits through global collaborations, and its vision is to be the preferred destination for the best people and companies, technologies, clinical trials and investments in cell and gene therapies, and regenerative medicine.
Pub.: 03 Dec '16, Pinned: 05 Dec '16
Abstract: Alzheimer's disease (AD) without cure remains as a serious health issue in the modern society. The major neuropathological alterations in AD are characterized by chronic neuroinflammation and neuronal loss due to neurofibrillary tangles (NFTs) of abnormally hyperphosphorylated tau, plaques of β-amyloid (Aβ) and various metabolic dysfunctions. Due to the multifaceted nature of AD pathology and our limited understanding on its etiology, AD is difficult to be treated with currently available pharmaceuticals. This unmet need, however, could be met with stem cell technology that can be engineered to replace neuronal loss in AD patients. Although stem cell therapy for AD is only in its development stages, it has vast potential uses ranging from replacement therapy to disease modelling and drug development. Current progress with stem cells in animal model studies offers promising results for the new prospective treatment for AD. This review will discuss the characteristics of AD, current progress in stem cell therapy and remaining challenges and promises in its development.
Pub.: 03 Dec '16, Pinned: 05 Dec '16
Abstract: Few topics in regenerative medicine have inspired such impassioned debate as the immunogenicity of cell types and tissues differentiated from pluripotent stem cells. While early predictions suggested that tissues derived from allogeneic sources may evade immune surveillance altogether, the pendulum has since swung to the opposite extreme, with reports that the ectopic expression of a few developmental antigens may prompt rejection, even of tissues differentiated from autologous cell lines. Here we review the evidence on which these contradictory claims are based in order to reach an objective assessment of the likely magnitude of the immunological challenges ahead. Furthermore, we discuss how the inherent properties of pluripotent stem cells may inform strategies for reducing the impact of immunogenicity on the future ambitions of regenerative medicine.
Pub.: 03 Dec '16, Pinned: 05 Dec '16
Abstract: Cardiac remodeling is critical for effective tissue healing, however, excessive production and deposition of extracellular matrix components contribute to scarring and failing of the heart. Despite the fact that novel therapies have emerged, there are still no lifelong solutions for this problem. An urgent need exists to improve the understanding of adverse cardiac remodeling in order to develop new therapeutic interventions that will prevent, reverse, or regenerate the fibrotic changes in the failing heart. With recent advances in both disease biology and cardiac tissue engineering, the translation of fundamental laboratory research toward the treatment of chronic heart failure patients becomes a more realistic option. Here, the current understanding of cardiac fibrosis and the great potential of tissue engineering are presented. Approaches using hydrogel-based tissue engineered heart constructs are discussed to contemplate key challenges for modeling tissue engineered cardiac fibrosis and to provide a future outlook for preclinical and clinical applications.
Pub.: 01 Dec '16, Pinned: 02 Dec '16
Abstract: Periosteum is a smart mechanobiological material that serves as a habitat and delivery vehicle for stem cells as well as biological factors that modulate tissue genesis and healing. Periosteum's remarkable regenerative capacity has been harnessed clinically for over two hundred years. Scientific studies over the past decade have begun to decipher the mechanobiology of periosteum, which has a significant role in its regenerative capacity. This integrative review outlines recent mechanobiological insights that are key to modulating and translating periosteum and its resident stem cells in a regenerative medicine context.
Pub.: 30 Nov '16, Pinned: 01 Dec '16
Abstract: An injectable and self-healable hydrogel was synthesized using dynamic imine bonds as cross-links. The hydrogel was formed between glycol chitosan and a dibenzaldehyde terminated copolymer, poly(N-isopropylacrylamide)-co-poly(acrylic acid) (DF poly(NIPAM-co-AA)). The polymer gelator DF poly(NIPAM-co-AA) was synthesized by the polymerization of comonomers of NIPAM and AA using a dibenzaldehyde-terminated chain transfer agent (DF CTA). Besides its injectable and self-healable property, the hydrogel was also dual pH and temperature responsive following the properties of the polymer gelator, DF poly(NIPAM-co-AA). Drug-loaded hydrogels showed distinct release behaviours responsive to the surroundings of varied pH values and temperatures. Being non-cytotoxic, the hydrogel was also successfully applied for 3D cell cultivation of L929 cells, revealing the hydrogel's potential applications as carriers in drug delivery and cell therapy systems.
Pub.: 15 Nov '16, Pinned: 01 Dec '16
Abstract: Three-dimensional (3D) bioprinting is on the cusp of permitting the direct fabrication of artificial living tissue. Multicellular building blocks (bioinks) are dispensed layer by layer and scaled for the target construct. However, only a few materials are able to fulfill the considerable requirements for suitable bioink formulation, a critical component of efficient 3D bioprinting. Alginate, a naturally occurring polysaccharide, is clearly the most commonly employed material in current bioinks. Here, we discuss the benefits and disadvantages of the use of alginate in 3D bioprinting by summarizing the most recent studies that used alginate for printing vascular tissue, bone and cartilage. In addition, other breakthroughs in the use of alginate in bioprinting are discussed, including strategies to improve its structural and degradation characteristics. In this review, we organize the available literature in order to inspire and accelerate novel alginate-based bioink formulations with enhanced properties for future applications in basic research, drug screening and regenerative medicine.
Pub.: 30 Nov '16, Pinned: 30 Nov '16
Abstract: Spinal conditions related to intervertebral disc (IVD) degeneration cost billions of dollars in the US annually. Despite the prevalence and soaring cost, there is no specific treatment that restores the physiological function of the diseased IVD. Thus, it is vital to develop new treatment strategies to repair the degenerating IVD. Persons with IVD degeneration without back pain or radicular leg pain often do not require any intervention. Only patients with severe back pain related to the IVD degeneration or biomechanical instability are likely candidates for cell therapy.
Pub.: 28 Nov '16, Pinned: 30 Nov '16
Abstract: Abstract This review summarizes recent developments in biologic treatments—including growth factors, platelet-rich plasma (PRP), stem cells, and cell-seeded scaffolds—for tendon repair. Growth and differentiation faction-5 (GDF-5), insulin-related growth factor-1 (IGF-1), and basic fibroblast growth factor (bFGF) all improved extracellular matrix (ECM) production and tensile strength of treated tendons; however, no clinical trials were done on GDF-5. Platelet-derived growth factor-BB (PDGF-BB) improved proliferation and ECM production, but did not consistently improve mechanical properties. The literature was mixed on the efficacy of PRP for the treatment of chronic and acute tendinopathies. However, PRP did cause any complications, and its benefits may be enhanced once an ideal, standardized composition is developed. Therefore, PRP may be a valid treatment, especially once nonsurgical management options have failed. Mesenchymal stem cells (MSCs) significantly and substantially improved the quality of tendon repairs and demonstrated the ability to regenerate an enthesis. Adipose-derived stem cells (ADSCs) have similar effects and are easier to harvest. The periosteum may also regenerate the tendon–bone attachment. Tenocytes, meanwhile, may be ideal for midsubstance tendon repairs. Cell-seeded scaffolds—especially ECM-derived scaffolds—were demonstrated to improve ECM production, enhancing the healing abilities of tenocytes or stem cells while providing early mechanical support to healing tendons. Each of these treatments demonstrated enhanced healing compared to common surgical techniques; moreover, patient outcomes may be enhanced by combining these treatments. Lay Summary Tendon injuries are very prevalent and can be debilitating. Tendon heals poorly, and the scar tissue that forms is weak and susceptible to reinjury. A major focus of orthopedic research is regenerative medicine, encouraging the formation of healthy tendon rather than mechanically inferior scar tissue. This review summarizes the recent scientific literature on biologic treatments for tendon repair, such as growth factors, platelet-rich plasma, and stem cells. The purpose of which is to show which treatments are promising candidates for clinical use and research, helping to guide physicians and to lay out a path for future research. Abstract This review summarizes recent developments in biologic treatments—including growth factors, platelet-rich plasma (PRP), stem cells, and cell-seeded scaffolds—for tendon repair. Growth and differentiation faction-5 (GDF-5), insulin-related growth factor-1 (IGF-1), and basic fibroblast growth factor (bFGF) all improved extracellular matrix (ECM) production and tensile strength of treated tendons; however, no clinical trials were done on GDF-5. Platelet-derived growth factor-BB (PDGF-BB) improved proliferation and ECM production, but did not consistently improve mechanical properties. The literature was mixed on the efficacy of PRP for the treatment of chronic and acute tendinopathies. However, PRP did cause any complications, and its benefits may be enhanced once an ideal, standardized composition is developed. Therefore, PRP may be a valid treatment, especially once nonsurgical management options have failed. Mesenchymal stem cells (MSCs) significantly and substantially improved the quality of tendon repairs and demonstrated the ability to regenerate an enthesis. Adipose-derived stem cells (ADSCs) have similar effects and are easier to harvest. The periosteum may also regenerate the tendon–bone attachment. Tenocytes, meanwhile, may be ideal for midsubstance tendon repairs. Cell-seeded scaffolds—especially ECM-derived scaffolds—were demonstrated to improve ECM production, enhancing the healing abilities of tenocytes or stem cells while providing early mechanical support to healing tendons. Each of these treatments demonstrated enhanced healing compared to common surgical techniques; moreover, patient outcomes may be enhanced by combining these treatments. AbstractThis review summarizes recent developments in biologic treatments—including growth factors, platelet-rich plasma (PRP), stem cells, and cell-seeded scaffolds—for tendon repair. Growth and differentiation faction-5 (GDF-5), insulin-related growth factor-1 (IGF-1), and basic fibroblast growth factor (bFGF) all improved extracellular matrix (ECM) production and tensile strength of treated tendons; however, no clinical trials were done on GDF-5. Platelet-derived growth factor-BB (PDGF-BB) improved proliferation and ECM production, but did not consistently improve mechanical properties. The literature was mixed on the efficacy of PRP for the treatment of chronic and acute tendinopathies. However, PRP did cause any complications, and its benefits may be enhanced once an ideal, standardized composition is developed. Therefore, PRP may be a valid treatment, especially once nonsurgical management options have failed. Mesenchymal stem cells (MSCs) significantly and substantially improved the quality of tendon repairs and demonstrated the ability to regenerate an enthesis. Adipose-derived stem cells (ADSCs) have similar effects and are easier to harvest. The periosteum may also regenerate the tendon–bone attachment. Tenocytes, meanwhile, may be ideal for midsubstance tendon repairs. Cell-seeded scaffolds—especially ECM-derived scaffolds—were demonstrated to improve ECM production, enhancing the healing abilities of tenocytes or stem cells while providing early mechanical support to healing tendons.Each of these treatments demonstrated enhanced healing compared to common surgical techniques; moreover, patient outcomes may be enhanced by combining these treatments. Lay Summary Tendon injuries are very prevalent and can be debilitating. Tendon heals poorly, and the scar tissue that forms is weak and susceptible to reinjury. A major focus of orthopedic research is regenerative medicine, encouraging the formation of healthy tendon rather than mechanically inferior scar tissue. This review summarizes the recent scientific literature on biologic treatments for tendon repair, such as growth factors, platelet-rich plasma, and stem cells. The purpose of which is to show which treatments are promising candidates for clinical use and research, helping to guide physicians and to lay out a path for future research. Lay SummaryTendon injuries are very prevalent and can be debilitating. Tendon heals poorly, and the scar tissue that forms is weak and susceptible to reinjury. A major focus of orthopedic research is regenerative medicine, encouraging the formation of healthy tendon rather than mechanically inferior scar tissue. This review summarizes the recent scientific literature on biologic treatments for tendon repair, such as growth factors, platelet-rich plasma, and stem cells. The purpose of which is to show which treatments are promising candidates for clinical use and research, helping to guide physicians and to lay out a path for future research.
Pub.: 21 Nov '16, Pinned: 30 Nov '16
Abstract: Cellular therapies for immunomodulation in vascularized composite allotransplantation (VCA) have gained importance due to their potential minimization of immunosuppression. Adipose-derived mesenchymal stem cells (AD-MSCs) especially have shown encouraging potential. We investigated the influence of timing and frequency of AD-MSC-treatment on immunologic and graft survival as well as graft vasculopathy (GV) outcomes after VCA.Lewis (LEW) rats received full-mismatched Brown Norway (BN) rat hindlimb transplants. Recipient animals were assigned to groups receiving donor-derived AD-MSCs (10 cells/animal) either on postoperative day (POD) 1, POD 4, or repeatedly on POD 4, 8, and 15, and compared to untreated controls.While AD-MSC administration on POD 1 or POD 4,8,15 resulted in 50% long-term graft acceptance, recipients treated on POD 4 and controls rejected prior to POD 50. All treated animals revealed peripheral blood chimerism (4 weeks), most pronounced following repetitive cell administration (12.92% vs. 5.03% [POD 1] vs. 6.31% [POD 4]; p<0.05; all p<0.01 vs. Control 1.45%). Chimerism was associated with the generation of regulatory T cells (CD4CD25FoxP3).In vitro MLRs revealed modulation of the recipient immune response after AD-MSC treatment. Graft arteries at end point revealed significant differences of arterial intimal thickness between rejecting and AD-MSC-treated animals (p<0.01).Taken together, our results point to the potential for repetitive AD-MSC administration in improving outcomes after VCA. Future studies are warranted into optimization of the AD-MSC therapy dosing and frequency, combination with other cell therapies (such as HSC or BM-MSC or dendritic cells) as selection of appropriate conditioning or maintenance regimens.
Pub.: 29 Nov '16, Pinned: 30 Nov '16
Abstract: Soft tissue replacement and repair is crucial to the ever-developing field of reconstructive surgery as trauma, pathology, and congenital deficits cannot be adequately restored if soft tissue regeneration is deficient. Predominant approaches were sometimes limited to harvesting autografts, but through regenerative medicine and tissue engineering, the hope of fabricating custom constructs is now a feasible and fast-approaching reality. The breadth of this field includes tissues ranging from skin, mucosa, muscle, and fat and hopes to not only provide construct to replace a tissue but also to replace its function.
Pub.: 29 Nov '16, Pinned: 30 Nov '16
Abstract: A series of novel self-healing pH-sensitive biodegradable hydrogels based on cytosine (C) and guanosine (G) modified hyaluronic acid (HA) is prepared via hydrogen bonding under physiological conditions, with 1,6-hexamethylenediamine (HMDA) as a bridging unit between nucleobase and HA. The lowest gel concentration, gelling time, pH-sensitivity, self-healing behavior, rheological properties, morphology, swelling ratio, degradation kinetics, and drug delivery behavior of HA-HMDA-C, HA-HMDA-G, and HA-HMDA-C/G hydrogels are investigated. The results demonstrate that moderate gelation time and rheology properties are observed at a concentration of 10% (w/v) hyaluronic acid derivative hydrogels. Most of the properties of HA-HMDA-C/G hydrogel are superior to the properties found in HA-HMDA-C and HA-HMDA-G at the same concentration of hydrogel. Overall, the series of pH-responsive self-healing hydrogels exhibits suitable gelling time, good rheology properties, high swelling ratio, biodegradability, effective drug loading capacity, and sustained drug release ability under physiological conditions, signifying that these hydrogels could be attractive candidates for short-and medium-term injectable drug delivery systems, tissue engineering, cell scaffold materials, and regenerative medicine.
Pub.: 24 Nov '16, Pinned: 30 Nov '16
Abstract: A major goal of regenerative medicine is to devise strategies to restore structure and function of damaged or lost organs/tissues. Stem cell therapy has emerged as one of the most promising tools in regenerative medicine. The ability to self-renew and differentiate into multiple cell types positions stem cells as wonder drugs or cellular drugs of the future. Recent accomplishments in transforming terminally differentiated cells to stem cells by reprogramming have widened the scope of opportunities for regenerative medicine. On the other hand, stem cells are believed to have a causal role in the pathogenesis of some diseases such as cancers. These wide-ranging clinical implications have driven researchers to search different tissues and organs for the presence of stem cells and characterize them further for their differentiation potential. The endometrium or the inner lining of the uterus has also been explored for the presence of stem cells. Endometrial stem cells (ESCs) have gained importance, not only because of their multi-potent nature but also due to the ease of their availability through a natural event i.e. menstruation. The first evidence for the presence of stem cells in human endometrium arrived in 2004. Since then, ESCs displaying different molecular phenotypes have been identified in humans. ESCs have been shown to differentiate into the cells of different lineages. Further, ESCs have been investigated for their potential role in some uterine pathologies. This review provides a bird's eye-view of our current understanding pertaining to the role of stem cells in the pathogenesis of endometriosis.
Pub.: 18 Nov '16, Pinned: 30 Nov '16
Abstract: Adoptive immunotherapy using cytokine-induced killer (CIK) cells has shown potential antitumor ability against several kinds of cancers, including melanoma. However, little is known about the achievable outcome of CIK cells in melanoma patients at different pathological stages. Here we recruited 55 patients treated with conventional therapy plus CIK cells as the CIK group, and 49 patients treated with conventional therapy alone as the control group. The pathological characteristics were comparable between two groups, with a follow-up period up to 40 months. Survival data and immune responses were evaluated after CIK cell treatment. In this study, CIK cells were successfully generated from peripheral blood of melanoma patients after in vitro culture for 14 days. The cultured CIK cells not only produced high levels of pro-inflammatory cytokines upon in vitro stimulation but also efficiently killed human melanoma cell lines. No serious side events were observed in all patients treated with CIK cells. Furthermore, infusions of CIK cells improved the quality of life in some patients, including advanced cases. More importantly, the CIK group exhibited better survival rates compared to the control group among early-stage melanoma patients, in consistent with the increased frequency of peripheral CD4(+) T cells. However, the patients with advanced-stage melanoma did not benefit from the CIK cell therapy in terms of survival rate. In conclusion, CIK cells combined with conventional treatments may prolong the survival of early-stage melanoma patients and improve the quality of life for some advanced cases in a safe way.
Pub.: 28 Nov '16, Pinned: 30 Nov '16
Abstract: Current best practices in regenerative medicine use cell and platelet preparations derived from a patient׳s blood or bone marrow aspirate, concentrated at the point of care, and returned to the patient during a single surgical or clinical event. As a field in its infancy, there is great confusion among many physicians, patients, regulatory agencies, and the media about what these therapies represent, their safety and efficacy, and how they are properly administered. Advances in bone marrow aspiration technique and concentration technologies have resulted in consistent significant increases in mesenchymal stem cell content in pursuit of threshold or minimum progenitor concentrations for successful outcomes described by clinical studies treating bone and soft tissues. This report reviews current preclinical and clinical data on the acquisition, processing, and administration techniques of platelet-rich plasma and bone marrow concentrate while discussing the regulatory environment around these and other cellular and regenerative medicine products.
Pub.: 22 Nov '16, Pinned: 30 Nov '16
Abstract: Zhen Wang, Hongwei Yang, Xin Wang, Liang Wang, Yingduan Cheng, Yongsheng Zhang, Yanyang Tu Cancer Translational Medicine 2016 2(5):147-153 Malignant cancer is among the top of the life-threatening conditions, challenging humanity for a long time. Traditional methods of cancer therapy include surgery, chemotherapy, and radiotherapy, which aim to remove/destroy cancer cells. Although theoretically very promising, none of these methods can effectively eradicate cancer, the reason for which can be attributed to our incomplete understanding of the mechanism of cancer metastasis and recurrence. In recent years, researchers have proposed the theory of cancer stem cell (CSC). CSC is a small population of tumor cells that have unlimited self-renewal ability, exhibit a strong resistance to chemotherapy and radiotherapy, and have been proved to be the core reason of cancer metastasis and recurrence. CSC theory provides a deep insight into malignant tumorigenesis that brings new hope for tumor therapy. In this paper, we intend to discuss the development of CSC theory and summarize the regulatory pathways involved in CSC origin and self-renewal, which might be of assistance in the future development of malignant cancer therapy.
Pub.: 24 Oct '16, Pinned: 30 Nov '16
Abstract: The healing of chronic wounds remains a key challenge in regenerative medicine. To promote wound healing, a bioactive wound dressing is required. In this study, a functionalized silk fibroin dressing with topical bioactive insulin release was prepared for the treatment of chronic wounds. For this purpose, insulin-encapsulated silk fibroin (SF) microparticles were prepared by coaxial electrospraying of aqueous SF solution under mild processing conditions. Insulin was successfully encapsulated in the inner layer of SF microparticles, providing a sustained insulin release for up to 28 days. It was found that the insulin released from the microparticles could maintain original molecular conformation. Moreover, the cell migration assay based on human keratinocyte and endothelial cells confirmed that the insulin released from SF microparticles retained its native bioactivity. Furthermore, the insulin-encapsulated microparticles were loaded into SF sponge, functioned as a bioactive wound dressing, and in vivo therapeutic effect of the sponge dressing was evaluated on dorsal full thickness wounds of diabetic Sprague-Dawley rats. The results showed that insulin-functionalized SF dressing accelerated wound closure, collagen deposition and vascularization, thus, significantly promoted wound healing. The insulin-functionalized SF dressing provides new treatment options for chronic wounds.
Pub.: 24 Nov '16, Pinned: 30 Nov '16