[Introduction and Reflection on Novel Medical Device Regulatory Science Tool MDDT].

In recent years, emerging technology medical devices have developed rapidly. How to more scientifically and more efficiently regulate these novel medical devices so as to improve access to advanced medical technology while ensuring safety and effectiveness is a new challenge faced by regulatory authorities, and is also the core topic of regulatory science. New tools, new standards and new methods are important means to achieve regulatory science. "Medical Device Development Tool" proposed by the U.S. FDA is a novel medical device regulatory science tool, which can help medical device developers to predict and evaluate product performance more efficiently. It is also helpful for regulatory authorities to make regulatory decisions more efficiently. This study introduces the concept, qualification process, role of MDDT in medical device regulation and MDDT examples, and makes some discussion on the device evaluation from the perspective of reliability and validity. MDDT can facilitate the developing of novel medical device.

Emerging Effects of Resveratrol on Wound Healing: A Comprehensive Review.

Resveratrol (RSV) is a natural extract that has been extensively studied for its significant anti-inflammatory and antioxidant effects, which are closely associated with a variety of injurious diseases and even cosmetic medicine. In this review, we have researched and summarized the role of resveratrol and its different forms of action in wound healing, exploring its role and mechanisms in promoting wound healing through different modes of action such as hydrogels, fibrous scaffolds and parallel ratio medical devices with their anti-inflammatory, antioxidant, antibacterial and anti-ageing properties and functions in various cells that may play a role in wound healing. This will provide a direction for further understanding of the mechanism of action of resveratrol in wound healing for future research.

Novel prospects for scarless wound healing: The roles of myofibroblasts and adipocytes.

Disturbances or defects in the process of wound repair can disrupt the delicate balance of cells and molecules necessary for complete wound healing, thus leading to chronic wounds or fibrotic scars. Myofibroblasts are one of the most important cells involved in fibrotic scars, and reprogramming provides a potential avenue to increase myofibroblast clearance. Although myofibroblasts have long been recognized as terminally differentiated cells, recent studies have shown that myofibroblasts have the capacity to be reprogrammed into adipocytes. This review intends to summarize the potential of reprogramming myofibroblasts into adipocytes. We will discuss myofibroblast lineage tracing, as well as the known mechanisms underlying adipocyte regeneration from myofibroblasts. In addition, we investigated different changes in myofibroblast gene expression, transcriptional regulators, signalling pathways and epigenetic regulators during skin wound healing. In the future, myofibroblast reprogramming in wound healing will be better understood and appreciated, which may provide new ideas for the treatment of scarless wound healing.

Dual-Action Icariin-Containing Thermosensitive Hydrogel for Wound Macrophage Polarization and Hair-Follicle Neogenesis.

Bone morphogenetic protein (BMP) pathway is essential for M2 macrophage polarization and hair-follicle neogenesis. Icariin, a flavonoid derived from Epimedium, is a mediator of the BMP pathway. Here, we develop a hydrogel formulation functionalized with icariin for regulation of macrophage polarization to accelerate wound healing and hair-follicle neogenesis. Compared to skin defects without icariin treatment, those treated with icariin+PEG hydrogel healed faster and had new hair follicles. Results in vivo showed that icariin+PEG hydrogel induced a higher level of M2 phenotypic transformation of macrophages. Moreover, icariin+PEG hydrogel significantly accelerated wound-repair process by reducing the invasion of inflammation, excessive deposition of collagen, immoderate activation of myofibroblasts, and increasing the regeneration of hair follicles. Furthermore, studies in vitro demonstrated that the icariin+PEG hydrogel induced macrophages to polarize to the M2 phenotype and dermal papilla cell to hair follicles. Finally, molecular analysis demonstrated that the icariin+PEG hydrogel increased the expression of BMP4 and Smad1/5 phosphorylation in skin wounds. These results demonstrate the therapeutic potential of icariin-containing thermosensitive hydrogels for inducing M2 macrophage polarization to accelerate wound healing and promote hair-follicle neogenesis by regulating the BMP pathway.

Insight into the role of DPP-4 in fibrotic wound healing.

Wound healing is a complex and long-term process consisting of hemostasis, inflammation, proliferation, and maturation/remodeling. These four stages overlap and influence each other; they affect wound healing in different ways, and if they do not function perfectly, they may cause scarring, proliferative scarring and keloid formation. A therapeutic target affecting wound healing in multiple ways will help the healing process proceed more effectively. DPP-4/CD26 is a multifunctional dimorphic glycoprotein widely distributed on the surface of a variety of cells, including fibroblasts and keratin-forming cells. It has been found to affect periwound inflammation, re-epithelialization, extracellular matrix secretion and skin fibrosis and is a potential target for promoting wound healing and inhibiting scar formation. After presenting a brief introduction of the wound healing process and DPP-4/CD26, this paper summarizes the effects of DPP-4/CD26 on cells involved in different stages of wound healing and discusses the feasibility of DPP-4/CD26 as a multifunctional target for the treatment of wound healing and inhibition of scar formation.

The ASIC3-M-CSF-M2 macrophage-positive feedback loop modulates fibroblast-to-myofibroblast differentiation in skin fibrosis pathogenesis.

Inflammation is one of the main pathological features leading to skin fibrosis and a key factor leading to the progression of skin fibrosis. Acidosis caused by a decrease in extracellular pH is a sign of the inflammatory process. Acid-sensing ion channels (ASICs) are ligand-gated ion channels on the cell membrane that sense the drop in extracellular pH. The molecular mechanisms by which skin fibroblasts are regulated by acid-sensing ion channel 3 (ASIC3) remain unknown. This study investigated whether ASIC3 is related to inflammation and skin fibrosis and explored the underlying mechanisms. We demonstrate that macrophage colony-stimulating factor (M-CSF) is a direct target of ASIC3, and ASIC3 activation promotes M-CSF transcriptional regulation of macrophages for M2 polarization. The polarization of M2 macrophages transduced by the ASIC3-M-CSF signal promotes the differentiation of fibroblasts into myofibroblasts through transforming growth factor ß1 (TGF-ß1), thereby producing an ASIC3-M-CSF-TGF-ß1 positive feedback loop. Targeting ASIC3 may be a new treatment strategy for skin fibrosis.

The uPA System Differentially Alters Fibroblast Fate and Profibrotic Ability in Skin Fibrosis.

Skin fibrosis is a common pathological feature of various diseases, and few treatment strategies are available because of the molecular pathogenesis is poorly understood. The urokinase-type plasminogen activator (uPA) system is the major serine protease system, and its components uPA, urokinase plasminogen activator receptor (uPAR) and plasminogen activator inhibitor-1(PAI-1) are widely upregulated in fibrotic diseases, including hypertrophic scars, keloids, and scleroderma. Here, we found that the successful binding of uPA and uPAR activates the downstream peroxisome proliferator-activated receptor (PPAR) signalling pathway to reduce the proliferation, migration, and contraction of disease-derived fibroblasts, contributing to the alleviation of skin fibrosis. However, increased or robust upregulation of the inhibitor PAI-1 inhibits these effects, suggesting of the involvement of PAI-1 in skin fibrosis. Subsequent in vivo studies showed that uPAR inhibitors increased skin fibrosis in mouse models, while uPA agonists and PAI-1 inhibitors reversed these effects. Our findings demonstrate a novel role for the uPA system and highlights its relationships with skin fibrosis, thereby suggesting new therapeutic approaches targeting the uPA system.

Insight into the role of dermal white adipose tissue loss in dermal fibrosis.

The loss of dermal white adipose tissue (dWAT) is vital to the formation of dermal fibrosis (DF), but the specific mechanism is not well understood. A few studies are reviewed to explore the role of dWAT in the formation of DF. Recent findings indicated that the adipocytes-to-myofibroblasts transition in dWAT reflects the direct contribution to the DF formation. While adipose-derived stem cells (ADSCs) contained in dWAT express antifibrotic cytokines, the loss of ADSCs leads to skin protection decreased, which indirectly exacerbates DF and tissue damage. Therefore, blocking or reversing the adipocytes-to-myofibroblasts transition or improving the survival of ADSCs in dWAT and the expression of antifibrotic cytokines may be an effective strategy for the treatment of DF.

The m6A RNA Modification Modulates Gene Expression and Fibrosis-Related Pathways in Hypertrophic Scar.

Purpose: To systematically analyze the overall m6A modification pattern in hyperplastic scars (HS). Methods: The m6A modification patterns in HS and normal skin (NS) tissues were described by m6A sequencing and RNA sequencing, and subsequently bioinformatics analysis was performed. The m6A-related RNA was immunoprecipitated and verified by real-time quantitative PCR. Results: The appearance of 14,791 new m6A peaks in the HS sample was accompanied by the disappearance of 7,835 peaks. The unique m6A-related genes in HS were thus associated with fibrosis-related pathways. We identified the differentially expressed mRNA transcripts in HS samples with hyper-methylated or hypo-methylated m6A peaks. Conclusion: This study is the first to map the m6A transcriptome of human HS, which may help clarify the possible mechanism of m6A-mediated gene expression regulation.

Fibroblasts: Heterogeneous Cells With Potential in Regenerative Therapy for Scarless Wound Healing.

In recent years, research on wound healing has become increasingly in-depth, but therapeutic effects are still not satisfactory. Occasionally, pathological tissue repair occurs. Influencing factors have been proposed, but finding the turning point between normal and pathological tissue repair is difficult. Therefore, we focused our attention on the most basic level of tissue repair: fibroblasts. Fibroblasts were once considered terminally differentiated cells that represent a single cell type, and their heterogeneity was not studied until recently. We believe that subpopulations of fibroblasts play different roles in tissue repair, resulting in different repair results, such as the formation of normal scars in physiological tissue repair and fibrosis or ulcers in pathological tissue repair. It is also proposed that scarless healing can be achieved by regulating fibroblast subpopulations.

The Smad Dependent TGF-ß and BMP Signaling Pathway in Bone Remodeling and Therapies.

Bone remodeling is a continuous process that maintains the homeostasis of the skeletal system, and it depends on the homeostasis between bone-forming osteoblasts and bone-absorbing osteoclasts. A large number of studies have confirmed that the Smad signaling pathway is essential for the regulation of osteoblastic and osteoclastic differentiation during skeletal development, bone formation and bone homeostasis, suggesting a close relationship between Smad signaling and bone remodeling. It is known that Smads proteins are pivotal intracellular effectors for the members of the transforming growth factor-ß (TGF-ß) and bone morphogenetic proteins (BMP), acting as transcription factors. Smad mediates the signal transduction in TGF-ß and BMP signaling pathway that affects both osteoblast and osteoclast functions, and therefore plays a critical role in the regulation of bone remodeling. Increasing studies have demonstrated that a number of Smad signaling regulators have potential functions in bone remodeling. Therefore, targeting Smad dependent TGF-ß and BMP signaling pathway might be a novel and promising therapeutic strategy against osteoporosis. This article aims to review recent advances in this field, summarizing the influence of Smad on osteoblast and osteoclast function, together with Smad signaling regulators in bone remodeling. This will facilitate the understanding of Smad signaling pathway in bone biology and shed new light on the modulation and potential treatment for osteoporosis.

Insights into the role of adipose-derived stem cells: Wound healing and clinical regenerative potential.

The incidence of acute and chronic wound diseases is rising due to various reasons. With complicated pathogenesis, long course, difficult treatment and high disability, wound diseases have become a major burden for patients, their families, and society. Therefore, the focus of research is to identify new ideas and methods for treatment. Fat grafting has gained increased attention because of its effectiveness in wound treatment, and further analysis has uncovered that the stem cells derived from fat may be the main factor affecting wound healing. We summarize the function of adipose stem cells and analyze their possible mechanisms in tissue repair, helping to provide new ideas for the treatment of wound healing.

Efficient manufacturing of tissue engineered cartilage in vitro by a multiplexed 3D cultured method.

Cell culture has become an indispensable tool to uncover fundamental biophysical and biomolecular mechanisms of cells assembling into tissues. An important advancement in cell culture techniques was the introduction of three-dimensional (3D) culture systems. In this study, the mutual fusion of chondrocyte pellets was promoted in order to produce large-sized tissue-engineered cartilage by a multiplexed 3D hanging drop culture and agarose mold method to optimize the means of cultivation. Cell proliferation, aggregation, cell morphology maintenance as well as cartilage related gene expression and matrix secretion in vitro and subcutaneous implantation models were evaluated. These results indicated that the multiplexed 3D hanging drop culture involving the fusion of small pellets into a large structure enabled the efficient production of 3D tissue engineered cartilage that was closer to physiological cartilage tissue in comparison to that of the agarose mold method.

Chondrogenic differentiation of BMSCs encapsulated in chondroinductive polysaccharide/collagen hybrid hydrogels.

Although BMSC-based therapy is one of the most front-line technologies for cartilage repair, it is still a big challenge to attain ideal niches for BMSC chondrogenic differentiation. In this study, we developed hyaluronate and chondroitin sulfate derivatives to prepare covalently crosslinked polysaccharide hydrogels. Based on these binary hydrogels, collagen was added to prepare ternary hybrid hydrogels and its effect on encapsulated BMSCs was studied. After culturing with different cell densities in vitro without the addition of growth factors for 3 weeks, the chondrogenesis of BMSCs was evaluated by CLSM, mechanical testing, histological staining, immunohistochemical staining and gene expression. The results indicated that BMSCs in high cell density (50 million per mL) cell-laden constructs had a more obvious chondrogenic phenotype than those in low cell density ones (5 million per mL). However, the components of hydrogels had a significant influence on chondrogenic differentiation. With the addition of collagen, the BMSCs in ternary hybrid hydrogels showed more significant chondrogenesis, possessing with more amounts of secreted glycosaminoglycans (GAGs) and type II collagen deposition, higher mechanical properties and chondrogenic gene expression over 3 weeks of culture in vitro. It can be concluded that the bioactive collagen is beneficial to the chondrogenesis of BMSCs. This hybrid hydrogels deserve further studies to have a prospective application in tissue engineering for cartilage defect repair.

Extracellular matrix powder from cultured cartilage-like tissue as cell carrier for cartilage repair.

Cartilage extracellular matrix (ECM) is a promising material for cartilage repair because of its bioactivity. However, the animal source of ECM unavoidably increases the risk of pathogen infection and the variability of product quality. In this study, we utilized a novel 3D culture method to prepare a new type of artificial decellularized matrix powder (DEMP) for the development of injectable, bioactive, biodegradable cell carriers for cartilage tissue engineering. This culture method combined hanging drop culture with suspension culture method, and was very efficient to produce cartilage-like tissue (CLT). By this method, an initial 2.3 × 106 chondrocyte generated as much as 58.22 mg wet weight CLT at two weeks, which proved to contain abundant glycoaminoglycans (GAGs), type II collagen, and BMP-2 and TGF-ß1 growth factors by staining techniques and biochemical analysis. Subsequently, the two-week-old CLT was decellularized to prepare the artificial DEMP. In an in vitro study, it was found that MSCs cultured on DEMP differentiated to chondrocytes very well and secreted rich GAGs and type II collagen at three weeks even without exogenous TGF-ß1. The in vivo study demonstrated that the DEMP not only facilitated regeneration of hyaline cartilage, which was implied by the intense staining of GAGs and type II collagen in rabbit subchondral defects at 1 month, but also benefited the regeneration of subchondral bone (bone ingrowth at 1 month: 48.22%) as shown in micro-CT data. Collectively, these results suggest that the artificial DEMP prepared by this culture method holds great potential as a novel ECM material for cartilage repair.

Effects of Composition and Mechanical Property of Injectable Collagen I/II Composite Hydrogels on Chondrocyte Behaviors.

Satisfactory repair of damaged articular cartilage is still a challenge, while tissue engineering provides a promising strategy. Collagen-based hydrogels have been widely applied in cartilage tissue engineering due to their biocompatibility. In this study, type I collagen and type II collagen were selected to prepare physically crosslinked composite hydrogels by self-assembly of collagen, and the effects of their physicochemical properties on chondrocyte phenotype maintenance and extracellular matrix (ECM) secretion were investigated. First, the microstructure of hydrogels was observed by a scanning electron microscope, and the compressive modulus was measured by a dynamic mechanical analyzer. Then, chondrocytes were encapsulated in hydrogels and detected by Live/Dead staining. The secretion of ECM was qualitatively estimated by histological staining and quantitatively analyzed by sulfated glycosaminoglycans and DNA content detection. Finally, cartilage-specific gene expression was analyzed by quantitative real-time polymerase chain reaction analysis. The results showed that the microstructure and mechanical property of hydrogels were relevant to the composition of composite hydrogels. The compressive modulus of hydrogels improved with the increase of type I collagen content in the hydrogels. Chondrocytes could maintain their round or oval morphology and secrete cartilage-specific ECM in the four groups of hydrogels, but higher the compressive modulus of composite hydrogels, the more ECM secretion of chondrocytes.