Effect of TGF-ß3 on wound healing of bone cell monolayer in static and hydrodynamic shear stress conditions.

Introduction: Wound healing is characterized as a complicated and sophisticated biological process through which tissue heals and repairs itself after injury. However, the normal wound healing process relies on different growth factors as well as the presence of an accurate cytokine level to ensure appropriate cellular responses. In the case of wound healing, the effects of various growth factors have been studied, but the effects of transforming growth factor beta (TGF-ß) on wound healing have been found to be more significant because of its broad spectrum of impacts on healing the wounded tissues or skins. Methods: In the current study, the impact of TGF-ß3 in bone cells' wound healing was examined in vitro. Furthermore, the activities and characteristics of TGF-ß3, as well as those of related growth factors throughout this wound healing process, were studied under hydrodynamic shear stress conditions as well as static conditions of cultured bone cells. Results: We demonstrated that a positive outcome of TGF-ß3 treatment was found after 24 h under a static condition, while TGF-ß3 treatment was found to be effective under a dynamic condition for wound closure. In the case of the dynamic condition, a full wound closure was obtained after 18 h in both the control and TGF-ß3 treatment, while in the case of static conditions, wounds were found to remain open, even after 24 h, for both the control and TGF-ß3 treatment. Additionally, in the static condition, the wound closure rate with TGF-ß3 treatment was found to be quicker than that of the control flask, which implies that wound healing can be postponed in the static condition. In the dynamic condition, the wound healing process became more rapid in a cultured cell environment. Conclusion: The synergistic effect of TGF-ß3 and hydrodynamic shear stress conditions had a positive impact on increasing wound healing and improving the rate of wound closure.

New immunotherapy approaches as the most effective treatment for uveal melanoma.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Conventional methods of UM treatment are based on chemotherapy and radiotherapy, which have been able to control tumor growth in a limited way. But due to the inadequacy and many side effects of these treatments, many UM patients die during treatment, and approximately 50% of patients develop metastasis. Meanwhile, the 2-year survival rate of these patients from the time of metastasis is 8%. Since immunotherapy has the potential to be the most specific and efficient method in the treatment of tumors, it is considered an attractive and promising research field in the treatment of UM. This review highlights recent advances in UM immunotherapy and provides new immunological approaches on how to overcome the challenges of UM immunotherapy.

Processing and post-processing of fish skin as a novel material in tissue engineering.

As a natural material, fish skin contains significant amounts of collagen I and III, and due to its biocompatible nature, it can be used to regenerate various tissues and organs. To use fish skin, it is necessary to perform the decellularization process to avoid the immunological response of the host body. In the process of decellularization, it is crucial to conserve the extracellular matrix (ECM) three-dimensional (3D) structure. However, it is known that decellularization methods may also damage ECM strands arrangement and structure. Moreover, after decellularization, the post-processing of fish skin improves its mechanical and biological properties and preserves its 3D design and strength. Also, sterilization, which is one of the post-processing steps, is mandatory in pre-clinical and clinical settings. In this review paper, the fish skin decellularization methods performed and the various post-processes used to increase the performance of the skin have been studied. Moreover, multiple applications of acellular fish skin (AFS) and its extracted collagen have been reviewed.

Retinal Tissue Engineering: Regenerative and Drug Delivery Approaches.

In recent decades, the improvement of photoreceptor-cell transplantation has been used as an effective therapeutic approach to treat retinal degenerative diseases. In this review, the effect of different factors on the differentiation process and stem cells toward photoreceptors along with cell viability, morphology, migration, adhesion, proliferation, and differentiation efficiency is discussed. Scientists are researching to better recognize the reasons for retinal degeneration, as well as discovering novel therapeutic methods to restore lost vision. In this field, several procedures and treatments in the implantation of stem cells-derived retinal cells have been explored for clinical trials. However, the number of these clinical trials is too small to draw sound decisions about whether stem-cell therapies can offer a cure for retinal diseases. Nevertheless, future research directions have started for patients affected by retinal degeneration and promising findings have been obtained.

Recent Emerging Trend in Stem Cell Therapy Risk Factors.

Different types of stem cells have remarkable characteristics such as high proliferation rate, multi/pluripotency, self-renewal, and broad differentiation that can effectively treat diseases, cancers, and damage. Despite abundant therapeutic applications of stem cells in medical science, numerous risks threaten stem cell transplantation. Tumor development, immune response, cellular senescence, dosage effects, and administration timing are critical risks that should be considered in stem cell therapy. Hence, an investigation of possible risks is required before utilizing stem cell-based medicinal products in the clinical phase and human trials. This review aims to survey the literature and perspectives on the advantages and risks associated with pluripotent and multipotent stem cells.

Mesenchymal stem cell-derived exosomes as a new therapeutic strategy in the brain tumors.

Brain tumors are one of the most mortal cancers, leading to many deaths among kids and adults. Surgery, chemotherapy, and radiotherapy are available options for brain tumor treatment. However, these methods are not able to eradicate cancer cells. The blood-brain barrier (BBB) is one of the most important barriers to treat brain tumors that prevents adequate drug delivery to brain tissue. The connection between different brain parts is heterogeneous and causes many challenges in treatment. Mesenchymal stem cells (MSCs) migrate to brain tumor cells and have anti-tumor effects by delivering cytotoxic compounds. They contain very high regenerative properties, as well as support the immune system. MSCs-based therapy involves cell replacement and releases various vesicles, including exosomes. Exosomes receive more attention due to their excellent stability, less immunogenicity and toxicity compare to cells. Exosomes derived from MSCs can develop a powerful therapeutic strategy for different diseases and be a hopeful candidate for cell-based and cell-free regenerative medicine. These nanoparticles contain nucleic acid, proteins, lipids, microRNAs, and other biologically active substances. Many studies show that each microRNA can prevent angiogenesis, migration, and metastasis in glioblastoma. These exosomes can-act as a suitable nanoparticle carrier for therapeutic applications of brain tumors by passing through the BBB. In this review, we discuss potential applications of MSC and their produced exosomes in the treatment of brain tumors.

Promoting keratocyte stem like cell proliferation and differentiation by aligned polycaprolactone-silk fibroin fibers containing Aloe vera.

There is a long history behind applying biological macromolecules like Aloe vera (AV) in regenerative medicine; endowed with anti-inflammatory and antimicrobial activities besides improving immune activity, AV has always been of particular interest to regenerate/reconstruct injuries and burns. In the present study, aligned electrospun polycaprolactone (PCL)-silk fibroin (SF) fibers containing different percentages of AV (0, 2.5, 5, and 7.5%wt) were fabricated for stromal regeneration. The results illustrated that a uniform bead-free structure was obtained, and the AV incorporation decreased the mean fiber diameter from 552 down to 182 nm and led to more alignment in the fibers. The Young's modulus raised from 4.96 to 5.26 MPa by higher amount of AV up to 5%wt. It is noteworthy that both the fiber alignment and AV affected the scaffolds' transparency and water uptake to increase. The human stromal keratocyte cells (hSKC)s culture revealed that the addition of AV and morphological properties of scaffolds encouraged cell adhesion and proliferation. The mRNA expression level for keratocan and ALDH3A1 and immunocytochemistry F-actin revealed the positive effect of AV on hSKCs differentiation. Our study indicated the promising potential of AV as a biological macromolecule for stromal tissue regeneration.

Culture and maintenance of neural progressive cells on cellulose acetate/graphene­gold nanocomposites.

In this study, the first CA nanofibers were fabricated by electrospinning under optimal conditions: flow rate of 0.5 ml/h, a voltage of 20 kV, electrospinning distance of 15 cm, and an internal temperature of 25 °C, and humidity of 38%. The used Graphene/gold nanoparticles for CA performance improvement were examined by TGA, XRD, and SEM analysis. Then the CA/graphene­gold nanocomposite was synthesized under optimum electrospinning conditions: flow rate 3 ml/h, voltage 20 kV, electrospinning distance 15 cm, internal temperature 26 °C, and humidity 36%. The SEM images revealed that the nanofibers' thicknesses of Graphene­gold NPs (CA1) and Chitosan (CA2) were 350 and 120 nm, respectively. The XRD diagrams of CA0, CA1 and CA2 revealed the peaks at 2θ, 8°, and 21° with Miller indices of (001) and (110) are related to CA (CA0), which proves its presence in other scaffolds. The FTIR analysis of samples indicated the presence of graphene­gold NPs in scaffolding CA1 and CA2. The CA2 nanofibers exhibited a high-water absorption capacity of about 2500% with the water contact-angle and Swelling method. The antibacterial properties of this nanocomposite were also confirmed by an antibacterial test on Staphylococcus aureus bacteria. The growth of Schwann cells on three scaffolds showed the highest growth of cells on CA1 scaffolds.

A comprehensive review on methods for promotion of mechanical features and biodegradation rate in amniotic membrane scaffolds.

Amniotic membrane (AM) is a biological tissue that surrounds the fetus in the mother's womb. It has pluripotent cells, immune modulators, collagen, cytokines with anti-fibrotic and anti-inflammatory effect, matrix proteins, and growth factors. In spite of the biological characteristics, some results have been released in preventing the adhesion on traumatized surfaces. Application of the AM as a scaffold is limited due to its low biomechanical resistance and rapid biodegradation. Therefore, for using the AM during surgery, its modification by different methods such as cross-linking of the membrane collagen is necessary, because the cross-linking is an effective way to reduce the rate of biodegradation of the biological materials. In addition, their cross-linking is likely an efficient way to increase the tensile properties of the material, so that they can be easily handled or sutured. In this regard, various methods related to cross-linking of the AM subsuming the composite materials, physical cross-linking, and chemical cross-linking with the glutraldehyde, carbodiimide, genipin, aluminum sulfate, etc. are reviewed along with its advantages and disadvantages in the current work.

Safety of Intraparenchymal Injection of Allogenic Placenta Mesenchymal Stem Cells Derived Exosome in Patients Undergoing Decompressive Craniectomy Following Malignant Middle Cerebral Artery Infarct, A Pilot Randomized Clinical Trial.

Background: Malignant middle cerebral artery infarct (mMCAI) largely contributes to high mortality and physical disability among adults. Surviving individuals may not have proper outcomes and suffer from severe lasting disabilities. Utilization of stem cells and paracrine factor for regenerative purposes is considered as a potential strategy for patients with neurological deficits. While preclinical stroke studies have shown that mesenchymal stem cells (MSCs) reduce post-treatment neurological deficits and prevent disability and also promote recovery, few randomized clinical trials (RCT) have assessed exosome therapy in humans. Methods: In this RCT, we assessed the safety of intraparenchymal injection placenta MSC-derived Exosome in mMCAI patients with average age of 62 years between January, 2019, till September, 2020. The study was done in a single-center as an open-label RCT, with a 3-months follow-up. Primary outcomes assessed the safety and also disability indexes were followed. Results: Five mMCAI patients were included with mean NIHSS: 17.6 ± 5.02. The mean MRS was 3.25 ± 0.95 in three patients. No serious adverse events were observed. Hematoma or local reaction as excessive edema were not seen at the site of injection. Conclusions: Intraparenchymal implantation of MSC-EXO showed no post-interventional adverse effects in five ischemic stroke patients. It is proposed Local injection Exosome treatment following mMCAI can be safe and in future, it would be applied as a supportive, restorative and preventive treatment in patients who suffer from acute ischemic stroke and post ischemic disability.

The effect of extracellular matrix remodeling on material-based strategies for bone regeneration: Review article.

Bone defects may cause by a number of acquired or inherited disorders. Tissue engineering strategies aim to induce functional bone regeneration through incorporating biomaterials and cells, which can potentially provide an efficient and personalized treatment option with reduced risk of rejection. Designing the appropriate scaffold for each tissue is critical because of the microenvironment where cell growth can occur. Various types of natural and synthetic polymers were studied in combination with active ceramic and metallic materials to form osteoconductive scaffolds. The purpose of producing composite scaffolds was to obtain a supporting structure with appropriate mechanical and surface properties to mimic the bone extracellular matrix (ECM). The ECM is a dynamic bio-environment that continuously undergoes remodeling to control tissue homeostasis. This process is mediated by specific proteases such as metalloproteinases (MMPs) that play an essential role in ECM degradation. The ECM is involved in regulating cell adhesion, proliferation, differentiation, and finally, the functional properties of the mature bone. Many substances have different effects on ECM, which in turn can be effective in bone regeneration. Imitation of ECM is one of the promising ways in designing materials for the bone regeneration. In this review, we investigated the effect of ECM remodeling on material-based strategies for bone regeneration.

Cell-based Therapy for Ocular Disorders: A Promising Frontier.

As the ocular disorders causing the long-term blindness or optical abnormalities of the ocular tissue entirely affect life quality, an insight into their corresponding pathogenesis and the expansion of attitudes authorizing earlier detection and treatment need more consideration. Though current therapeutics result in desirable outcomes, they do not offer an inclusive solution for hindrance of development of visual impairment to blindness. Accordingly, stem cells because of their particular competencies have attracted pronounced attention to be applied in regenerative medicine of ocular diseases. In the last decades, a wide spectrum of stem cells surrounding Mesenchymal Stem/Stromal Cells (MSC), Neural Stem Cells (NSCs), and embryonic/induced pluripotent stem cells (ESCs/iPSCs) accompanied by Müller glia, ciliary epithelia-derived stem cells, and Retinal Pigment Epithelial (RPE) stem cells have been widely investigated to report their safety and efficacy in preclinical models and also human subjects. In this regard and the first interventions, RPE cell suspensions were successfully utilized to ameliorate visual defects of the patients suffering from Age-related Macular Degeneration (AMD) after subretinal transplantation. Herein, we will explain the pathogenesis of ocular diseases and highlight the novel discoveries and recent findings in the context of stem cell-based therapies in these disorders, focusing on the last decade's in vivo reports.

Umbilical Cord Mesenchymal Stem/Stromal Cells Potential to Treat Organ Disorders; An Emerging Strategy.

Currently, Mesenchymal Stem/Stromal Cells (MSCs) have attracted growing attention in the context of cell-based therapy in regenerative medicine. Following the first successful procurement of human MSCs from Bone Marrow (BM), these cells isolation has been conducted from various origins, in particular, the Umbilical Cord (UC). Umbilical Cord-Derived Mesenchymal Stem/Stromal Cells (UC-MSCs) can be acquired by a non-invasive plan and simply cultured, and thereby signifies their superiority over MSCs derived from other sources for medical purposes. Due to their unique attributes, including self-renewal, multipotency, and accessibility concomitant with their immunosuppressive competence and lower ethical concerns, UC-MSCs therapy is described as encouraging therapeutic options in cell-based therapies. Regardless of their unique aptitude to adjust inflammatory response during tissue recovery and delivering solid milieu for tissue restoration, UC-MSCs can be differentiated into a diverse spectrum of adult cells (e.g., osteoblast, chondrocyte, type II alveolar, hepatocyte, and cardiomyocyte). Interestingly, they demonstrate a prolonged survival and longer telomeres compared with MSCs derived from other sources, suggesting that UC-MSCs are desired source to use in regenerative medicine. In the present review, we deliver a brief review of UC-MSCs isolation, expansion concomitantly with immunosuppressive activities, and try to collect and discuss recent pre-clinical and clinical researches based on the use of UC-MSCs in regenerative medicine, focusing on with special focus on in vivo researches.

Photo Cross-linkable Biopolymers for Cornea Tissue Healing.

Light can act as an effective and strong agent for the cross-linking of biomaterials and tissues and is recognized as a safe substitute for chemical cross-linkers to modify mechanical and physical properties and promote biocompatibility. This review focuses on the research about crosslinked biomaterials with different radiation sources such as Laser or ultraviolet (UV) that can be applied as scaffolds, controlled release systems,and tissue adhesives for cornea healing and tissue regeneration.

The interplay between extracellular matrix and progenitor/stem cells during wound healing: Opportunities and future directions.

Skin wound healing, a dynamic physiological process, progresses through coordinated overlapping phases to restore skin integrity. In some pathological conditions such as diabetes, wounds become chronic and hard-to-heal resulting in substantial morbidity and healthcare costs. Despite much advancement in understanding mechanisms of wound healing, chronic and intractable wounds are still a considerable challenge to nations' health care systems. Extracellular matrix (ECM) components play pivotal roles in all phases of wound healing. Therefore, a better understanding of their roles during wound healing can help improve wound care approaches. The ECM provides a 3D structure and forms the stem cell niche to support stem cell adhesion and survival and to regulate stem cell behavior and fate. Also, this dynamic structure reserves growth factors, regulates their bioavailability and provides biological signals. In various diseases, the composition and stiffness of the ECM is altered, which as a result, disrupts bidirectional cell-ECM interactions and tissue regeneration. Hence, due to the impact of ECM changes on stem cell fate during wound healing and the possibility of exploring new strategies to treat chronic wounds through manipulation of these interactions, in this review, we will discuss the importance/impact of ECM in the regulation of stem cell function and behavior to find ideal wound repair and regeneration strategies. We will also shed light on the necessity of using ECM in future wound therapy and highlight the potential roles of various biomimetic and ECM-based scaffolds as functional ECM preparations to mimic the native stem cell niche.

Will stem cells from fat and growth factors from blood bring new hope to female patients with reproductive disorders?

Female reproductive system disorders (FRSD) with or without infertility are prevalent women's health problems with a variety of treatment approaches including surgery and hormone therapy. It currently considering to sub-branch of regenerative medicine including stem cells or growth factors injection-based delivery treatment might be improved female reproductive health life. The most common products used for these patients treatment are autologous cell or platelet-based products from patients, including platelet-rich plasma, plasma rich in growth factor, platelet-rich fibrin, and stromal vascular fraction. In this review, we discuss each of the above products used in treatment of FRSD and critically evaluate the clinical outcome.

Synthesis of thermogel modified with biomaterials as carrier for hUSSCs differentiation into cardiac cells: Physicomechanical and biological assessment.

One of the major challenges in cardiac cell therapy is cell death and low rate of cardiac differentiation. In this regard, a series of thermosensitive and injectable hydrogels with similar physicomechanical properties of cardiac tissue can be an ideal candidate for delivering human unrestricted somatic stem cells (hUSSCs) and improve the quality of cell therapy. Here, we designed N-isopropylacrylamide/acrylic acid/N-acryloxysuccinimide/2-hydroxyethyl methacrylate-poly lactide (NIPAAm/AAc/NAS/HEMAPLA) hydrogel via ring-opening polymerization for encapsulation of the cells. To improve biological activities, biomaterials like hyaluronic acid (HA), Aloe vera (AV), and silk fibroin (SF) were added with pure hydrogel (Pgel). The modulus of hydrogels was estimated between 68.1 and 74.63 kPa that was similar to the normal cardiac modulus. Moreover, the elastic region increased by adding biomaterials to Pgel. The results of RT-PCR and ICC demonstrated that the most expression of early genes (GATA4, NKX2.5) was related to Pgel/AV/SF group. In contrast, the highest expression of other genes (GJA1, TNNI3, MYH6) was observed in Pgel/HA/SF. The presence of biomaterials in the structure of hydrogel can play a key role in cell fate and the induction of cell differentiation as a factor influencing mechanotransduction. These hydrogels hold an excellent promise to deliver hUSSCs into damaged tissue for cardiac regeneration.

The promise of regenerative medicine in the treatment of urogenital disorders.

Polymers and scaffolds are the most significant tools in regenerative medicine. Urogenital disorders are an important group of diseases that greatly affect the patient's life expectancy and quality. Reconstruction of urogenital defects is one of the current challenges in regenerative medicine. Regenerative medicine, as well as tissue engineering, may offer suitable approaches, while the tools needed are appropriate materials and cells. Autologous urothelial cells obtained from biopsy, bone marrow-derived stem cells, adipose stem cells and urine-derived stem cells that expressed mesenchymal cell markers are the cells that mainly used. In addition, two main types of biomaterials mainly exist; synthetic polymers and composite scaffolds that are biodegradable polymers with controllable properties and naturally derived biomaterials such as extracellular matrix components and acellular tissue matrices. In this review, we present and evaluate the most appropriate and suitable scaffolds (naturally derived and synthetic polymers) and cells applied in urogenital reconstruction.

The effect of the carbodiimide cross-linker on the structural and biocompatibility properties of collagen-chondroitin sulfate electrospun mat.

BACKGROUND: Collagen and chondroitin sulfate (CS) are an essential component of the natural extracellular matrix (ECM) of most tissues. They provide the mechanical stability to cone the compressive forces in ECM. In tissue engineering, electrospun nanofibrous scaffolds prepared by electrospinning technique have emerged as a suitable candidate to imitate natural ECM functions. Cross-linking with 1-ethyl-3-(3-dimethyl-aminopropyl)-1-carbodiimide hydrochloride/N-hydroxy succinimide can overcome the weak mechanical integrity of the engineered scaffolds in addition to the increased degradation stability under physiological conditions. MATERIALS AND METHODS: This study has synthesized nanofibrous collagen-CS scaffolds by using the electrospinning method. RESULTS: The results have shown that incorporation of CS in higher concentration, along with 1-ethyl-3-(3-dimethyl-aminopropyl)-1-carbodiimide hydrochloride/N-hydroxy succinimide, enhanced mechanical stability. Scaffolds showed more resistance to collagenase digestion. Fabricated scaffolds showed biocompatibility in corneal epithelial cell attachment. CONCLUSION: These results demonstrate that cross-linked electrospun CO-CS mats exhibited a uniform nanofibrous and porous structure, especially for lower concentration of the cross-linker and may be utilized as an alternative effective substrate in tissue engineering.