Regenerative Medicine

Extrusion-based bioprinting (EBB) is a rapidly growing technology that has made substantial progress during the last decade. It has great versatility in printing various biologics, including cells, tissues, tissue constructs, organ modules and microfluidic devices, in applications from basic research and pharmaceutics to clinics. Despite the great benefits and flexibility in printing a wide range of bioinks, including tissue spheroids, tissue strands, cell pellets, decellularized matrix components, micro-carriers and cellladen hydrogels, the technology currently faces several limitations and challenges. These include impediments to organ fabrication, the limited resolution of printed features, the need for advanced bioprinting solutions to transition the technology bench to bedside, the necessity of new bioink development for rapid, safe and sustainable delivery of cells in a biomimetically organized microenvironment, and regulatory concerns to transform the technology into a product. This paper, presenting a first-time comprehensive review of EBB, discusses the current advancements in EBB technology and highlights future directions to transform the technology to generate viable end products for tissue engineering and regenerative medicine.

Background: Several synthetic and natural matrices have been described for tissue engineering of bladder but there is little information on the effects of processing on their subsequent mechanical performance or interaction with human cells. Aim: Our aim was to assess the effects of delamination, decellularization and sterilization on the mechanical properties of porcine urinary bladder matrix (UBM) and to then assess the ability of the UBM to act as a scaffold for reconstruction with human bladder cells. Methods: A total of 20 porcine bladders were assessed before and after mechanical delamination and four porcine bladders were followed at every stage through a comparison of several decellularization and terminal sterilization methodologies examining histological and mechanical characteristics. The sterile UBM was seeded with normal human urothelial and bladder stromal cells either as a simultaneous coculture, or with stromal cells followed by urothelial cells. Results: Mechanical delamination, physical rinsing of the resulting bladder stroma in hypotonic buffer, 0.1% sodium dodecyl sulfate solution and 0.1% peracetic acid resulted in an UBM with acceptable mechanical properties capable of supporting urothelial and bladder stromal cells. Terminal sterilization with ethylene oxide resulted in considerable stiffening of the matrix simultaneous coculture and layered seeding of scaffolds with stromal cells followed by epithelial cells gave similar results with good initial urothelial attachment (followed by loss of cells later) and slow stromal cell penetration. Conclusion: We describe a decellularized sterilized porcine UBM with acceptable mechanical properties that shows promise as a scaffold for producing an in vitro tissue-engineered bladder patch material for lower urinary tract reconstruction. Future work now needs to focus on the conditions for achieving secure epithelial attachment.

Impaired endogenous stem cell repair capacity is hypothesized to be a biologic basis of frailty. Therapies that restore regenerative capacity may therefore be beneficial. This Phase 1 study evaluated the safety and potential efficacy of intravenous, allogeneic, human mesenchymal stem cell (allo-hMSC)-based therapy in patients with aging frailty. In this nonrandomized, dose-escalation study, patients received a single intravenous infusion of allo-hMSCs: 20-million (n = 5), 100-million (n = 5), or 200-million cells (n = 5). The primary endpoint was incidence of any treatment-emergent serious adverse events measured at 1 month postinfusion. The secondary endpoints were functional efficacy domains and inflammatory biomarkers, measured at 3 and 6 months, respectively. There were no treatment-emergent serious adverse events at 1-month postinfusion or significant donor-specific immune reactions during the first 6 months. There was one death at 258 days postinfusion in the 200-million group...

Tissue engineering is an interdisciplinary field that applies the principles and methods of engineering and the cell culture toward the development of biomaterials that restore, maintain or improve tissue function. The amalgamation of engineering and medicine has interested many scientists for at last two hundred years. What was the goal of cell culture? First, for progress in life sciences achievement and subsequent for virology and toxicology development. In vitro studies are done because of many problems with carrying out animal experiments. In this work the authors present the attempts of physicians, anatomopathologists, embryologists and biologists which contributed to fast development of new area in medicine--tissue engineering.

Keratinocyte culture medium (KCM) has been used for the in vitro culture of keratinocytes and other types of epithelial cells, and the medium includes various ingredients. In this study, two modified KCMs were prepared. In the first, insulin, hydrocortisone and antibiotics that are normally included in KCM were replaced with clinically approved pharmaceutical agents, except transferrin and selenium; in the second, cholera toxin (CT) was replaced by L-isoproterenol (ISO). The modified KCMs were then compared to conventional KCM containing laboratory-grade reagents. Induced cell colony formations of canine oral mucosal epithelial cells cultured in both modified KCMs were found to be nearly equivalent to that in the control KCM, and there was no significant difference between the effect of CT and ISO. Canine oral mucosal cells proliferated to confluence in all three KCM formulations, with or without the use of 3T3 feeder layers. Cultured epithelial cells were harvested from temperature-responsive culture surfaces as an intact cell sheet, and the immunohistochemical analysis of the sheets showed that p63 and cytokeratin were expressed in the epithelial cell sheets cultured in all KCMs. Eventually, in the modified KCM formula, fetal bovine serum was replaced by autologous human serum, and the formula was found to be able to fabricate human oral mucosal epithelial cell sheets. These results indicated that the modified KCM was equally efficient as conventional KCM in the fabrication of transplantable stratified epithelial cell sheets.

Rapid advancements in the field of stem cell biology have led to many current efforts to exploit stem cells as therapeutic agents in regenerative medicine. However, current ex vivo cell manipulations common to most regenerative approaches create a variety of technical and regulatory hurdles to their clinical translation, and even simpler approaches that use exogenous factors to differentiate tissue-resident stem cells carry significant off-target side effects. We show that non-ionizing, low-power laser (LPL) treatment can instead be used as a minimally invasive tool to activate an endogenous latent growth factor complex, transforming growth factor-β1 (TGF-β1), that subsequently differentiates host stem cells to promote tissue regeneration. LPL treatment induced reactive oxygen species (ROS) in a dose-dependent manner, which, in turn, activated latent TGF-β1 (LTGF-β1) via a specific methionine residue (at position 253 on LAP). Laser-activated TGF-β1 was capable of differentiating hum...

Among the tools of regenerative medicine, induced pluripotent stem cells (iPSCs) are interesting because the donor genotype can be selected. The construction of banks of iPSC cell lines selected from human leukocyte antigen (HLA) homozygous donors has been proposed to be an effective way to match a maximal number of patients receiving cell therapy from iPSC lines. However, what effort would be required to constitute such a bank for a worldwide application has remained unexplored. We developed a probabilistic model to compute the number of donors to screen for constituting banks of best-chosen iPSC lines with homozygous HLA haplotypes (haplobanks) in four ancestry backgrounds. We estimated what percentage of the patients would be provided with single HLA haplotype matched cell lines. Genetic diversity leads to dif-ferent outcomes for the four sets in all terms. A bank comprising iPSC lines representing the 20 most frequent haplotypes in each population would request quite different number of donors to screen, between 26,000 for European Americans and 110,000 for African Americans. It would also match different fractions of the recipient population, namely, more than 50% of the European Americans and 22% of African Americans. Conversely, a bank comprising the 100 iPSC lines with the most frequent HLA in each population would leave out only 22% of the European Americans, but 37% of the Asians, 48% of the Hispanics, and 55% of the African Americans. The constitution of a haplobank of iPSC lines is achievable through a large-scale concerted worldwide collaboration. STEM

Introduction 5 Cell and Gene Therapy 9 Modification of splicing: Antisense oligonucleotides and small molecules 21 Tissue Engineering 24 Small trials, difficult statistics, difficult regulation and data reproducibility. 28 Health economics of regenerative medicine 31 Regulation of stem cell therapies and regenerative medicine 41 Ethics 43 Public engagement and trust 54 Conclusions 56

The stromal vascular fraction (SVF) is a heterogeneous population of stem/stromal cells isolated from perivascular and extracellular matrix (ECM) of adipose tissue complex (ATC). Administration of SVF holds a strong therapeutic potential for regenerative and wound healing medicine applications aimed at functional restoration of tissues damaged by injuries or chronic diseases. SVF is commonly divided into cellular stromal vascular fraction (cSVF) and tissue stromal vascular fraction (tSVF). Cellular SVF is obtained from ATC by collagenase digestion, incubation/isolation, and pellet-ized by centrifugation. Enzymatic disaggregation may alter the relevant biological characteristics of adipose tissue, while providing release of complex, multiattachment of cell-to-cell and cell-to-matrix, effectively eliminating the bioactive ECM and periadventitial attachments. In many countries , the isolation of cellular elements is considered as a "more than minimal" manipulation, and is most often limited to controlled clinical trials and subject to regulatory review. Several alternative , nonenzymatic methods of adipose tissue processing have been developed to obtain via minimal mechanical manipulation an autologous tSVF product intended for delivery, reducing the procedure duration, lowering production costs, decreasing regulatory burden, and shortening the translation into the clinical setting. Ideally, these procedures might allow for the integration of harvesting and processing of adipose tissue for ease of injection, in a single procedure utilizing a nonexpanded cellular product at the point of care, while permitting intraoperative autologous cellular and tissue-based therapies. Here, we review and discuss the options, advantages, and limitations of the major strategies alternative to enzymatic processing currently developed for minimal manipulation of adipose tissue. STEM CELLS TRANSLATIONAL MEDICINE 2019;8:1265–1271

Global research in the field of pharmacology has not yet found effective drugs to treat Alzheimer's disease (AD). Thus, alternative therapeutic strategies are under investigation, such as neurostimulation by physical means. Radio electric asymmetric conveyer (REAC) is one of these technologies and has, until now, been used in clinical studies on several psychiatric and neurological disorders with encouraging results in the absence of side effects. Moreover, studies at the cellular level have shown that REAC technology, with the appropriate protocols, is able to induce neuronal differentiation both in murine embryonic cells and in human adult differentiated cells. Other studies have shown that REAC technology is able to positively influence senescence processes. Studies conducted on AD patients and in transgenic mouse models have shown promising results, suggesting REAC could be a useful therapy for certain components of AD.

450 scientists, patient advocates, and stem cell research supporters from 14 countries registered for the conference. In addition to poster and platform presentations, the conference featured panels entitled "Road to the Clinic" and "The Future of Regenerative Medicine.

Extracellular vesicles (EV) consist of exosomes, which are released upon fusion of the multivesicular body with the cell membrane, and microvesicles, which are released directly from the cell membrane. EV can mediate cell-cell communication and are involved in many processes, including immune signaling, angiogenesis, stress response, senescence, proliferation, and cell differentiation. The vast amount of processes that EV are involved in and the versatility of manner in which they can influence the behavior of recipient cells make EV an interesting source for both therapeutic and diagnostic applications. Successes in the fields of tumor biology and immunology sparked the exploration of the potential of EV in the field of regenerative medicine. Indeed, EV are involved in restoring tissue and organ damage, and may partially explain the paracrine effects observed in stem cell-based therapeutic approaches. The function and content of EV may also harbor information that can be used in tissue engineering, in which paracrine signaling is employed to modulate cell recruitment, differentiation, and proliferation. In this review, we discuss the function and role of EV in regenerative medicine and elaborate on potential applications in tissue engineering.

Cell-based therapies have the potential to treat a diversity of disease conditions, many representing significant and long-standing unmet medical needs. Certain properties of cell-based therapies, such as differentiation potential and proliferative potential, present safety concerns uniquely distinct from those of small molecule drugs and other macromolecule biologics. These cellular products carry risks associated with localized host tissue response, long-term persistence, ectopic tissue formation, differentiation to undesirable cell and tissue types, uncontrollable biodistribution, tumorigenicity, and immunogenicity. Such risks are generally evaluated in preclinical animal model studies as part of a comprehensive safety program prior to administration in humans. However, safety assessment for these products can be challenging because of inconsistent approaches to product characterization, inadequately defined product parameters that anticipate adverse events, and the lack of stand...

Repeatedly, when medical scientists propose the authorization of new biotechnologies, fears and hopes emerge alongside new impasses, legal frictions and uncertainties. This applies, for example, to cutting-edge therapies potentially capable of treating chronic diseases and, hence, of substituting pharmaceuticals that are currently in use (sometimes paradigmatically). While navigating between this scepticism towards regulatory authorities and reassurances of faith in science, which biopolitical agendas do proposed biotechnologies enact and disseminate in contemporary health innovation arenas? This panel aims to explore the impacts of new health technologies on different societies and how, in turn, multiple actors affect new biotechnologies, including their evaluation processes, design and related health policies. The panel invites contributions that address aspects of the development, circulation, and co-regulation of novel biotechnologies as relatable to forms of bionetworking (for instance judicialization, biohacking, infrastructuring, and digital activism). Bionetworking practices comprise collaborative relationships between scientists, patients, their caretakers, and other actors (including biological, legal, and entrepreneurial ones), to support and/or disqualify promising biotechnologies. In light of this, the panel provides a platform to discuss the actuality and uses of concepts linked to the STS-field of biocitizenship like: political economies of hope; life assemblages; and adoption space. It looks to discuss controversies in areas such as vaccinology, regenerative medicine, gene therapy, translational and precision medicine, microbiome-based therapies, and experimental therapies more broadly. A central point of reflection concerns how tensions between different ways of assessing the efficacy and innovativeness of proposed biotechnologies, and of co-producing medical evidence, might become co-constitutive of biosocialities.

Background: Type II diabetes mellitus (T2DM) is known as non-insulin dependent diabetes mellitus. Insulin impairment and insulin resistance are the major causes of type II diabetes mellitus. People with T2DM are more prone to macro-vascular and micro vascular impediments. Adult Autologous Adipose derived stem cells (ADSC) hold potential to develop into multilineages and they can secrete numerous growth factors that can regenerate the damaged neighboring cells. The chronic wound healing processes and diabetes-associated complications are reported to be treated by using stem cells by revascularization and by promoting the micro vascular remodeling. Objective: To evaluate the safety and efficacy of Adipose derived autologous stem cells and PRP in patients suffering from Type 2 Diabetes Mellitus (T2DM). Methods: We reported three cases aged 50, 69 and 72 years suffering from T2DM since 20, 10 and 20 years respectively. They were treated with Adult autologous ADSC and Platelets Rich Plasma (PRP). Results: Over a follow up of twelve months significant control in glycemia as well as stable glycosylated hemoglobin with decrease in pain on Visual Analogous scale (VAS) score has been observed.

Trisomy silencing is an important factor in curing Down syndrome. As per a study in various experiments, XIST Transgene transforms chromosome 21 in stem cells. This Transgene normalizes cell function and development upon transformation and its induction in Transgene clones corrects the overproduction of meakayo cytes, stem cells, iPS cells and erythrocytes keeping the balance of hemopoietic developments. Given all these to added knowledge, our study further advanced to CD4/CD43 progenitors cells demonstrating principle proof for epigenetic based investigative strategy in pathology. Chapter basic focuses on drug discovery, delivery of drugs, administration path, dosage and frequency of transplantation. Monitor tools of MRI, MSK and PET-CT scanners. Also, the cultivation of chromosome 21 cells trisomy to disomy is relevant without genetic manipulation, chemical treatment and exposure to irradiation. Disomy or diploid cells serve to the purpose of drug screening and raw material of regenerative medicine and cell-based therapy.

Around 5 million annual births in EU and 131 million worldwide give a unique opportunity to collect lifesaving Wharton's jelly derived mesenchymal stem cells (WJ-MSC). Evidences that these cells possess therapeutic properties are constantly accumulating. Collection of WJ-MSC is done at the time of delivery and it is easy and devoid of side effects associated with collection of adult stem cells from bone marrow or adipose tissue. Likewise, their rate of proliferation, immune privileged status, lack of ethical concerns, nontumorigenic properties make them ideal for both autologous and allogeneic use in regenerative medicine applications. This review provides an outline of the recent findings related to WJ-MSC therapeutic effects and possible advantage they possess over MSC from other sources. Results of first clinical trials conducted to treat immune disorders are highlighted.

Nearly 20 years after murine embryonic stem cells (mESC) were isolated, the first report of the derivation of human embryonic stem cells (hESC) in 1998 spawned the field of hESC research [Evans MJ, Kaufman MH, Establishment in culture of pluripotential cells from mouse embryos. Nature 1981;292(5819): 154-6; Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic stem cell lines derived from human blastocysts. Science 1998;282(5391):1145-7].

Background Pathological scars occur following injuries and are often considered esthetically unattractive. Several strategies have been attempted to improve these types of scars using both surgical and nonsurgical methods. The most common treatments include cryotherapy, intralesional corticosteroid injections, 5-fluorouracil, bleomycin, interferon, and verapamil. Aims In this study, we aim to investigate the effectiveness of dermal autologous micrografts in the treatment of pathological scars resulting from burns, trauma, or any iatrogenic source. Methods We used a new clinical practice called Rigenera Protocol to obtain autologous micrografts which were in turn injectable in the patients. Results A significant improvement was observed in appearance and texture of the exaggerated scars in all cases following already 4 months of autologous micrograft treatment We have also shown that these micrografts are composed of mesenchymal stem cells and in addition, histological evaluation verified restoration of the structural layers immediately below the epidermis and a horizontal realignment of collagen fibers in the papillary dermis. Conclusion Our results clearly demonstrate the optimal outcomes obtained following treatment with dermal micrografts on exaggerated scars with different etiologies. However, further studies are required to confirm the efficacy of this new technique.

Cartilage reconstruction is a crucial issue for tissue engineering because of high damage frequency in connection with low regenerative capacity. Microfractures and shaving are the oldest and most commonly used practices. The newest techniques are: Autologous Chondrocyte Implantation, Matrix Associated Chondrocytes Implantation and their derivatives. Dedifferentiation of chondrocytes due to low proliferation rate and phenotype loss makes isolation and in vitro culture of normal human chondrocytes very complex. Therefore, obtaining mesenchymal stem cells from various sources and differentiating them into chondrocytes is another interesting approach.

It is known that cells proliferate and produce extracellular matrix in response to biochemical and mechanical stimuli. Constitutive models considering these phenomena are needed to quantitatively describe the process of tissue growth in the context of tissue engineering and regenerative medicine. In this paper we reexamine the theoretical framework provided by Ambrosi and Guana (2007) and Ambrosi and Guillou (2007). We show how a volumetric growth rate term can be obtained (both in a large and small strain setting), which is consistent with the laws of thermodynamics and then apply the model to a simple geometry of tissue growth within a circular pore. The model, despite its simplicity, is comparable with experimental measurements of tissue growth and highlights the contribution of the mechanical stresses produced during tissue growth on the growth rate itself.

The definitive treatment for end-stage organ failure is orthotopic transplantation. However, the demand for transplantation far exceeds the number of available donor organs. A promising tissue-engineering/regenerativemedicine approach for functional organ replacement has emerged in recent years. Decellularization of donor organs such as heart, liver, and lung can provide an acellular, naturally occurring three-dimensional biologic scaffold material that can then be seeded with selected cell populations. Preliminary studies in animal models have provided encouraging results for the proof of concept. However, significant challenges for three-dimensional organ engineering approach remain. This manuscript describes the fundamental concepts of whole-organ engineering, including characterization of the extracellular matrix as a scaffold, methods for decellularization of vascular organs, potential cells to reseed such a scaffold, techniques for the recellularization process and important aspects regarding bioreactor design to support this approach. Critical challenges and future directions are also discussed.

N RÉ SUMÉ Nanotechnology involves the creation and use of materials and devices at the size scale of intracellular structures and molecules, and involves systems and constructs in the order of ,100 nm. The aim of nanomedicine is the comprehensive monitoring, control, construction, repair, defence, and improvement of human biological systems at the molecular level, using engineered nanodevices and nanostructures that operate massively in parallel at the single-cell level, ultimately to achieve medical benefit. In this review we consider general principles of nanotechnology as applied to nanomedicine (e.g., biomimicry and pseudointelligence). Some applications of nanotechnology to ophthalmology are described (including treatment of oxidative stress; measurement of intraocular pressure; theragnostics; use of nanoparticles to treat choroidal new vessels, prevent scarring after glaucoma surgery, and treat retinal degenerative disease with gene therapy; prosthetics; and regenerative nanomedicine). Nanotechnology will revolutionize our approach to current therapeutic challenges (e.g., drug delivery, postoperative scarring) and will enable us to address currently unsolvable problems (e.g., sight-restoring therapy for patients with retinal degenerative disease). Obstacles to the incorporation of nanotechnology remain, such as safe manufacturing techniques and unintended biological consequences of nanomaterial use. These obstacles are not insurmountable, and revolutionary treatments for ophthalmic diseases are expected to result from this burgeoning field.

Small intestinal submucosa grafts for vascular regeneration have produced variable patency (0–100%) that has been concurrent with variability in fabrication techniques. We hypothesized that 1) preservation (P) or removal (R) of the stratum compactum layer of the intestine and 2) a dehydrated (D) or hydrated (H) state of the graft, affect early patency and tissue regeneration. We combined both parameters through a 2 2 factorial experimental design into four groups (PD, RD, PH, RH), and compared them in an in vivo early response predictive model (swine, ID 4.5 mm, 7d, n = 4). Patency, thrombogenicity, vascularization, fibroblast infiltration, macrophage polarization profile, endo-thelialization, and biaxial mechanics were assessed. PD grafts remained patent (4/4) but had scarce vascularization and fibro-blast infiltration. RD and RH had extensive vascularization and fibroblast infiltration, however, RD had sustained patency (4/4) and the highest number of regeneration-associated phenotype macrophages (M2), whereas RH had lower patency (3/4) and less M2 macrophages. PH had a modest cellular infiltration, but the lowest patency (2/4) and a dominant adverse macrophage phenotype. Elasticity of R grafts evolved toward that of native carotids (particularly RD), while P grafts kept their initial stiffness. We concluded that fabrication parameters drastically affected early patency and regeneration, with RD providing the best results. ASAIO Journal 2015; 61:596–604.

Stem cell-based therapies represent a potential pathway for a new era of 21st century regenerative medicine. In support of this new form of treatment, a global multibillion-dollar research endeavor is currently underway in an effort to establish a scientific evidence base for safe and effective clinical use of stem cells. At present, due to its early stages, only a few stem cell therapies are approved for use. Yet despite very limited evidence-based data, a proliferation of questionable and often illegal stem cell providers around the world are now offering unfettered access to largely experimental stem cell treatment claiming cures for virtually any disease or condition. These stem cell clinics promote their services globally to patients using unregulated Internet and forms of direct-to-consumer advertising. In this paper we examine marketing characteristics of these questionable stem cell clinics and discuss pathways of access through the globalization of medical tourism. We conclude with an examination of the similarities between unproven stem cell therapy access and illicit online pharmacies and explore possible lessons that can be learned to inform future global regulation and policymaking in this arena.

Recent applications in tissue engineering and regenerative medicine have highlighted the utility of microfluidic fiber fabrication. On page 11 M. A. Daniele and team show how this process uses microflow shaping to generate a core-sheath profile, which can be subsequently solidified into microfibers of various shapes and chemistries, providing the capability to incorporate and organize both fragile biomolecules and cell-cultures within individual fibers and bioactive textiles.

Biofabrication holds the potential to generate constructs that more closely recapitulate the complexity and heterogeneity of tissues and organs than do currently available regenerative medicine therapies. Such constructs can be applied for tissue regeneration or as in vitro 3D models. Biofabrication is maturing and growing, and scientists with different backgrounds are joining this field, underscoring the need for unity regarding the use of terminology. We therefore believe that there is a compelling need to clarify the relationship between the different concepts, technologies, and descriptions of biofabrication that are often used interchangeably or inconsistently in the current literature. Our objective is to provide a guide to the terminology for different technologies in the field which may serve as a reference for the biofabrication community.

In recent years, the altitude acclimatization responses elicited by short-term intermittent exposure to hypoxia have been subject to renewed attention. The main goal of short-term intermittent hypobaric hypoxia exposure programs was originally to improve the aerobic capacity of athletes or to accelerate the altitude acclimatization response in alpinists, since such programs induce an increase in erythrocyte mass. Several model programs of intermittent exposure to hypoxia have presented efficiency with respect to this goal, without any of the inconveniences or negative consequences associated with permanent stays at moderate or high altitudes. Artificial intermittent exposure to normobaric hypoxia systems have seen a rapid rise in popularity among recreational and professional athletes, not only due to their unbeatable cost/efficiency ratio, but also because they help prevent common inconveniences associated with high-altitude stays such as social isolation, nutritional limitations, ...

Poor angiogenesis within tissue-engineered grafts has been identified as a main challenge limiting the clinical introduction of bone tissue-engineering (BTE) approaches for the repair of large bone defects. Thick BTE grafts often exhibit poor cellular viability particularly at the core, leading to graft failure and lack of integration with host tissues. Various BTE approaches have been explored for improving vascularisation in tissue-engineered constructs and are briefly discussed in this review. Recent investigations relating to co-culture systems of endothelial and osteoblast-like cells have shown evidence of BTE efficacy in increasing vascularization in thick constructs. This review provides an overview of key concepts related to bone formation and then focuses on the current state of engineered vascularized co-culture systems using bone repair as a model. It will also address key questions regarding the generation of clinically relevant vascularized bone constructs as well as potential directions and considerations for research with the objective of pursuing engineered co-culture systems in other disciplines of vascularized regenerative medicine. The final objective is to generate serious and functional long-lasting vessels for sustainable angiogenesis that will enable enhanced cellular survival within thick voluminous bone grafts, thereby aiding in bone formation and remodelling in the long term. However, more evidence about the quality of blood vessels formed and its associated functional improvement in bone formation as well as a mechanistic understanding of their interactions are necessary for designing better therapeutic strategies for translation to clinical settings. Figure 1. (A) Hierarchical structure of bone from a sub-nanostructure of collagen molecules to a nanostructure of cylindrically arranged microfibrils to lamellar layers forming the macrostructure of cortical bone (adapted from Rho et al. (1998). (B) Vascularised bone anatomy and microenvironmental influences such as biomechanical, microarchitectural and low oxygen tension factors Y. Liu et al.

Collagen-based devices, in various physical conformations, are extensively used for tissue engineering and regenerative medicine applications. Given that the natural cross-linking pathway of collagen does not occur in vitro, chemical, physical, and biological cross-linking methods have been assessed over the years to control mechanical stability, degradation rate, and immunogenicity of the device upon implantation. Although in vitro data demonstrate that mechanical properties and degradation rate can be accurately controlled as a function of the cross-linking method utilized, preclinical and clinical data indicate that cross-linking methods employed may have adverse effects on host response, especially when potent cross-linking methods are employed. Experimental data suggest that more suitable cross-linking methods should be developed to achieve a balance between stability and functional remodeling.

Tissue engineering and regenerative medicine are interdisciplinary fields that apply principles of engineering and life sciences to develop biological substitutes, typically composed of biological and synthetic components, that restore, maintain or improve tissue function. Many tissue engineering technologies are still at a laboratory or pre-commercial scale. The short review paper describes the most significant manufacturing and bio-process challenges inherent in the commercialisation and exploitation of the exciting results emerging from the biological and clinical laboratories exploring tissue engineering and regenerative medicine. A three-generation road map of the industry has been used to structure a view of these challenges and to define where the manufacturing community can contribute to the commercial success of the products from these emerging fields. The first-generation industry is characterised by its demonstrated clinical applications and products in the marketplace, the second is characterised by emerging clinical applications, and the third generation is characterised by aspirational clinical applications. The paper focuses on the cost reduction requirement of the first generation of the industry to allow more market penetration and consequent patient impact. It indicates the technological requirements, for instance the creation of three-dimensional tissue structures, and value chain issues in the second generation of the industry. The third-generation industry challenges lie in fundamental biological and clinical science. The paper sets out a road map of these generations to identify areas for research.

Liver transplantation is still the only effective treatment for end-stage liver disease. However, because of the serious worldwide shortage of donated organs, an alternative cellular therapy would be desirable. Animal studies and preclinical trials have indicated that hepatocyte transplantation can serve as an alternative to liver transplantation. Unfortunately, however, the harvesting of hepatocytes is associated with the same problem as organ transplantation, i.e., a lack of a suitable cell source. Therefore, current stem cell technology, which is attempting to establish an unlimited supply of hepatocytes, would facilitate the clinical application of hepatocyte transplantation. This review summarizes current knowledge of embryonic and adult stem cell differentiation into hepatocytes and discusses how liver stem cells could be applied clinically in the future.

Platelet-rich plasma (PRP) contains at least seven growth factors including epidermal, platelet-derived, transforming, vascular endothelial, fibroblast, insulin-like and keratinocyte growth factor. The therapeutic effect of PRP occurs because of the high concentration of these growth factors compared with those found in normal plasma. In recent years, PRP is widely used across many clinical fields, especially in regenerative medicine. This review aimed at presenting an overview of the applications of PRP in regenerative medicine. The mechanisms of PRP effects on healing are also stated in this review.

Background: Among the types of adult stem cells, those derived from tooth structures have been receiving the attention of researchers over the past decade and inspiring hope for practical applications in the future. Dental stem cells are a valuable source of stem cells and are found in teeth with healthy pulp.
Till date five different human dental stem cells have been isolated and characterized: Dental Pulp Stem Cells (DPSCs), Stem Cells From Exfoliated Deciduous Teeth (SHED), Periodontal Ligament Stem Cells (PDLSCs), Stem Cells From Apical Papilla (SCAP), and Dental Follicle Progenitor Cells (DFPCs). The discovery of dental stem cells and recent advances in cellular and molecular biology have led to the development of novel therapeutic strategies that aim at the regeneration of oral tissues that were injured by disease or trauma.
Dental Stem cells research has given newer conceptual approach to therapy of various diseases, named “regenerative dentistry” and it will have its place in the clinical practice of dentistry in the future. This review discusses the types of dental stem cells, their banking and their possible application in treatment of diseases in future.

Kinazlar, onkogenik Transkripsiyon Faktörleridir Kinazlar; Glikoliz,Yağ Sentezi,Protein Sentezini uyararak Hücre metabolizmasını aktifler.Elde edilen ATP'deki P'ı kullanan kinazlar da metabolizmadan faydalanmıĢ olur. Tm.supresor genler ise bu kinaz bağımlı yolakları baskılayarak hücre metabolizmasını bastırmaya çalıĢır.