Induce Tissue Regeneration Research Articles

Tissue Regeneration: The Dark Side of Opioids.

Opioids are regarded as among the most effective analgesic drugs and their use for the management of pain is considered standard of care. Despite their systematic administration in the peri-operative period, their impact on tissue repair has been studied mainly in the context of scar healing and is only beginning to be documented in the context of true tissue regeneration. Indeed, in mammals, growing evidence shows that opioids direct tissue repair towards scar healing, with a loss of tissue function, instead of the regenerative process that allows for recovery of both the morphology and function of tissue. Here, we review recent studies that highlight how opioids may prevent a regenerative process by silencing nociceptive nerve activity and a powerful anti-inflammatory effect. These data open up new perspectives for inducing tissue regeneration and argue for opioid-restricted strategies for managing pain associated with tissue injury.

The Effect of a 7 Year-Long Cryopreservation on Stemness Features of Canine Adipose-Derived Mesenchymal Stem Cells (cAD-MSC).

Mesenchymal stem cells (MSCs) are used in therapy in animal models and veterinary medicine, due to their capacity of inducing tissue regeneration and immunomodulation. Their clinical application requires a ready off-the-shelf amount of viable therapeutics doses. For this purpose, it is useful to cryopreserve MSCs to gain a ready and controlled source of abundant autologous stem cells. We evaluated the effect of 7 years cryopreservation using 10% dimethyl sulfoxide (DMSO) with different fetal bovine serum (FBS) concentrations (from 10 to 90%) on different passages of MSCs isolated from canine adipose tissue (cAD-MSCs). The study aimed to evaluate the most adequate cell passage and FBS percentage for the long-term cryopreservation of cells by maintaining the stemness features. Phenotype morphology, cell viability, osteogenic and adipogenic differentiation potentials, proliferative potential and expression of pluripotency markers were analyzed in thawed cells and compared with fresh ones. We demonstrated that cells cryopreserved with at least 80% FBS maintain unaltered the stemness characteristics of the freshly isolated cells. In particular, cells of P0-P1 passages have to be expanded in vitro and subsequently cryopreserved and cells of P2-P4 passages should be considered in the studies on therapeutic application and in vitro study of cAD-MSCs.

Huaier Inhibits Cancer Progression and Induces Tissue Regeneration by Transcriptional Regulations of Pluripotency of Stem Cells

The induced normal tissue regeneration was the results of transcriptional control of iPS/ES cell production. Among the gene families to control iPS/ES production, especially c-my expression level played a major role among the other genes or gene families. These results provide a clue to clarify the Huaier effects not only for recovery from cancer, but also for the prevention of many related diseases and disorders caused by daily accumulation of environmental stresses and ageing by controlling normal tissue regeneration by stem cell control.

Development of plasma functionalized polypropylene wound dressing for betaine hydrochloride controlled drug delivery on diabetic wounds

Diabetes Mellitus is one of the most worrying issues among illnesses, and its chronic subsequences almost refer to inflammations and infections. The loading and local release of antioxidants to wounds may decrease inflammations. However, the low wettability of PolyPropylene (PP) restricts the drug from loading. So, to increase the adhesion of PP for loading an optimum amount of Betaine Hydrochloride (BET), plasma has been applied in two steps of functionalization and polymerization, which has been confirmed with FE-SEM, ATR-FTIR, and EDX. The new chemistry of the surface led to almost 80% of BET loaded. The drug-releasing ratio studied by HPLC approved the presence of a PEG-like layer, which was coated by polymerization of tetraglyme. To evaluate the wound healing potential of the application of PP meshes treated by plasma, 72 Wistar rats were subdivided into four groups. The skin injury site was removed and underwent biomechanical tests, stereological analysis, and RNA extraction. The results showed a significant improvement in the polymerized scaffold containing BET for skin injury. The present study suggests that the use of a modified PP mesh can induce tissue regeneration and accelerate wound healing at the skin injury site.

608 Neuroimmune control of adult mammalian scarless skin regeneration

Adult mammalian wounds, with rare exception, heal with fibrotic scars that severely disrupt tissue architecture and function. Regenerative medicine seeks methods to avoid scar formation and restore the original tissue structures. We show in three adult mouse models that pharmacologic activation of the nociceptor TRPA1 on cutaneous sensory neurons reduces scar formation and can also promote tissue regeneration. Local activation of TRPA1 induces tissue regeneration on distant untreated areas of injury, demonstrating a systemic effect. Activated TRPA1 stimulates local production of interleukin-23 (IL-23) by dermal dendritic cells, leading to activation of circulating dermal IL-17–producing gd T cells. Genetic ablation of TRPA1, IL-23, dermal dendritic cells, or gd T cells prevents TRPA1-mediated tissue regeneration. These results reveal a cutaneous neuroimmune-regeneration cascade triggered by topical TRPA1 activators that promotes adult mammalian tissue regeneration, presenting a new avenue for research and development of therapies for wounds and scars.

Carbon-Based Nanomaterials: Promising Antiviral Agents to Combat COVID-19 in the Microbial-Resistant Era.

Therapeutic options for the highly pathogenic human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the current pandemic coronavirus disease (COVID-19) are urgently needed. COVID-19 is associated with viral pneumonia and acute respiratory distress syndrome causing significant morbidity and mortality. The proposed treatments for COVID-19 have shown little or no effect in the clinic so far. Additionally, bacterial and fungal pathogens contribute to the SARS-CoV-2-mediated pneumonia disease complex. The antibiotic resistance in pneumonia treatment is increasing at an alarming rate. Therefore, carbon-based nanomaterials (CBNs), such as fullerene, carbon dots, graphene, and their derivatives constitute a promising alternative due to their wide-spectrum antimicrobial activity, biocompatibility, biodegradability, and capacity to induce tissue regeneration. Furthermore, the antimicrobial mode of action is mainly physical (e.g., membrane distortion), characterized by a low risk of antimicrobial resistance. In this Review, we evaluated the literature on the antiviral activity and broad-spectrum antimicrobial properties of CBNs. CBNs had antiviral activity against 13 enveloped positive-sense single-stranded RNA viruses, including SARS-CoV-2. CBNs with low or no toxicity to humans are promising therapeutics against the COVID-19 pneumonia complex with other viruses, bacteria, and fungi, including those that are multidrug-resistant.

Decellularization of Small Intestinal Submucosa.

Small intestinal submucosa (SIS) is the most studied extracellular matrix (ECM) for repair and regeneration of different organs and tissues. Promising results of SIS-ECM as a vascular graft, led scientists to examine its applicability for repairing other tissues. Overall results indicated that SIS grafts induce tissue regeneration and remodeling to almost native condition. Investigating immunomodulatory effects of SIS is another interesting field of research. SIS can be utilized in different forms for multiple clinical and experimental studies. The aim of this chapter is to investigate the decellularization process of SIS and its common clinical application.

Enamel Matrix Derivative in Diffusion Chamber Implanted Subcutaneously in Rat Induces Formation of Fibrous Connective Tissue Containing Abundant Blood Vessels.

Enamel matrix derivative (EMD) is widely used for regeneration therapy in dental clinical situations, but the mechanism of EMD bioactivity remains obscure. To clarify this mechanism, we focused on the formation of connective tissue and blood vessels. The aim of this study was to confirm whether EMD induces the formation of connective tissue and blood vessels by using the diffusion chamber (DC) technique. Individual DCs containing EMD (DC-EMD) or propylene glycol alginate (PGA) were implanted subcutaneously in rat dorsum. At 4 weeks after the implantation, histological analysis of DCs was performed using azan staining. DC-EMD induced the formation of much larger amounts of connective tissue containing abundant blood vessels than did DC-PGA. The results indicated that EMD can induce the formation of both connective tissue and blood vessels. This bioactivity may contribute to the mechanism whereby EMD induces tissue regeneration.

Phosphodiesterase-5 inhibition improves bone regeneration at the early stages of ischemic osteonecrosis of the femoral head in rats.

Posttraumatic osteonecrosis of the femoral head (ONFH) affects patients at different ages and may lead to functional limitation and joint replacement, with total hip arthroplasty, which is a costly procedure. Proposed methods to optimize ischemic tissue regeneration have been reported. Phosphodiesterase-5 inhibitors act by inhibiting the degradation of guanosine 3',5'-cyclic monophosphate in the nitric oxide pathway, increasing its bioavailability and promoting vascular endothelial growth factor (VEGF)-mediated neovascular recruitment and the induction of tissue regeneration in the traumatized bone. Thirty male Sprague-Dawley rats (6 months old) were subjected to an experimental model of traumatic ONFH divided into two groups, according to the administration of 5 mg/kg sildenafil or water (control group). Rats were then killed at 7, 14, and 21 days. Histological (Goldner's trichrome), histochemical (periodic acid-Schiff [PAS]), and immunohistochemical (VEGF and osteopontin [OPN]) techniques were used to quantify bone and vascular responses. Higher levels of VEGF (p < 0.01) and OPN (p < 0.01) immunostaining in the epiphysis, the greater formation of osteoid tissue (p < 0.01 on Day 7; p < 0.05 on Day 14), and higher levels of PAS staining (p < 0.01 on Day 7) were observed in the sildenafil-treated group. The present study demonstrated that sildenafil optimized bone tissue regeneration by increasing VEGF signaling and OPN expression, with increased bone formation (osteoid and carbohydrate macromolecule deposition) in the early stages following traumatic ischemic insult. Thus, sildenafil treatment may improve the prognosis of patients with osteonecrosis.

The Effect of Physical Cues of Biomaterial Scaffolds on Stem Cell Behavior.

Stem cells have been sought as a promising cell source in the tissue engineering field due to their proliferative capacity as well as differentiation potential. Biomaterials have been utilized to facilitate the delivery of stem cells in order to improve their engraftment and long-term viability upon implantation. Biomaterials also have been developed as scaffolds to promote stem cell induced tissue regeneration. This review focuses on the latter where the biomaterial scaffold is designed to provide physical cues to stem cells in order to promote their behavior for tissue formation. Recent work that explores the effect of scaffold physical properties, topography, mechanical properties and electrical properties, is discussed. Although still being elucidated, the biological mechanisms, including cell shape, focal adhesion distribution, and nuclear shape, are presented. This review also discusses emerging areas and challenges in clinical translation.

Pulp repair response after the use of a dentin-pulp biostimulation membrane (BBio) in primary teeth: study protocol for a randomized clinical trial

BackgroundVital pulp therapy aims at maintaining the pulp tissue injured but vital. Thus, the use of capping materials that induce tissue regeneration is a great current trend. This study aims to evaluate clinically and radiographically the pulp repair after the use of dentin-pulp biostimulation membrane in primary teeth.MethodsFour hundred and sixty-eight teeth from children aged between 5 and 9 years old, both genders, with deep caries lesion with pulp involvement, but no furcal impairment and any sign of necrosis will be selected. The vital pulp therapy will be performed with mineral trioxide aggregate (control group) and dentin-pulp biostimulation chitosan membrane (BBio group). The clinical and radiographic outcomes will be assessed at 12 and 24 months after treatment. The thickness of the dentin barrier will be verified through Image J2 software. The Wilcoxon signed rank test and Mann-Whitney test will respectively compare the intra- and intergroup clinical and radiographic outcomes. Paired t test and independent t test will respectively compare the intra- and intergroup radiographic measurements. The logistic regression will be applied, and the degrees of this association will be measured using odds ratio (OR) and 95% confidence interval (95% CI).DiscussionTherefore, this study protocol aims at new perspectives of vital pulp therapy of primary teeth by employing new easy-handling, low-cost material to keep viable the pulp tissue capable of regenerating and maintain the physiological process of deciduous tooth exfoliation.Trial registrationBrazilian Registry of Clinical Trials RBR-6vr58b. Registered on 17 February 2019.

Multifunctional phosphate-based glass fibres prepared via electrospinning of coacervate precursors: controlled delivery, biocompatibility and antibacterial activity

There is an increasing demand for new biomaterials that both rapidly stimulate healing and prevent infections. Being bioresorbable, phosphate-glass fibres can simultaneously induce tissue regeneration and deliver therapeutic agents (e.g. antibacterial ions) in a controlled way. Here we present a series of copper-doped phosphate-based glass fibres in the P2O5-CaO-Na2O-(CuO)x system (x = 0, 1, 3, and 5 mol%) prepared for the first time via electrospinning of coacervate precursors. This method presents several advantages over the conventional high temperature melt spinning; the synthesis of the coacervate occurs at room temperature and in aqueous solution allowing the incorporation of temperature sensitive molecules. Moreover, electrospinning is an inexpensive, sustainable, easily scalable manufacturing process. The fibres produced are cotton-like, fully amorphous with an average diameter in the range 1–3 µm. Dissolution studies on cations (Ca2+, Na+ and Cu2+) and phosphate anions (PO43−, P2O74−, and P3O105−) show a gradual release of all species in solution over time, ideal for controlled drug delivery applications.The antibacterial activity against both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria was found to increase with increasing Cu2+ content and was found to be more effective against E. coli than against S. aureus. Interestingly, Cu2+ content seem to have a positive effect on cytocompatibility. Tests performed on osteoblast-like MG63 osteosarcoma cells have shown that the copper doped phosphate-glass fibres have a significantly better capacity to regenerate bone tissue than the undoped glass fibres. These findings suggest that phosphate-based glass fibres are promising multifunctional biomaterials for both antibacterial activity and tissue regeneration.

Calreticulin exploits TGF-β for extracellular matrix induction engineering a tissue regenerative process.

Topical application of extracellular calreticulin (eCRT), an ER chaperone protein, in animal models enhances wound healing and induces tissue regeneration evidenced by epidermal appendage neogenesis and lack of scarring. In addition to chemoattraction of cells critical to the wound healing process, eCRT induces abundant neo-dermal extracellular matrix (ECM) formation by 3days post-wounding. The purpose of this study was to determine the mechanisms involved in eCRT induction of ECM. In vitro, eCRT strongly induces collagen I, fibronectin, elastin, α-smooth muscle actin in human adult dermal (HDFs) and neonatal fibroblasts (HFFs) mainly via TGF-β canonical signaling and Smad2/3 activation; RAP, an inhibitor of LRP1 blocked eCRT ECM induction. Conversely, eCRT induction of α5 and β1 integrins was not mediated by TGF-β signaling nor inhibited by RAP. Whereas eCRT strongly induces ECM and integrin α5 proteins in K41 wild-type mouse embryo fibroblasts (MEFs), CRT null MEFs were unresponsive. The data show that eCRT induces the synthesis and release of TGF-β3 first via LRP1 or other receptor signaling and later induces ECM proteins via LRP1 signaling subsequently initiating TGF-β receptor signaling for intracellular CRT (iCRT)-dependent induction of TGF-β1 and ECM proteins. In addition, TGF-β1 induces 2-3-fold higher level of ECM proteins than eCRT. Whereas eCRT and iCRT converge for ECM induction, we propose that eCRT attenuates TGF-β-mediated fibrosis/scarring to achieve tissue regeneration.

OVARIAN RESERVE PARAMETERS AND IVF OUTCOMES IN 510 WOMEN WITH POOR OVARIAN RESPONSE (POR) TREATED WITH INTRAOVARIAN INJECTION OF AUTOLOGOUS PLATELET RICH PLASMA (PRP)

Poor ovarian response (POR) accounts for 15% of all assisted reproductive technologies (ART) cycles performed in 2017 and 2018 in the United States, and is associated with increased rate of cycle cancellation, lower number of embryos available for transfer, and overall lower pregnancy rates. Platelet-rich plasma (PRP) is rich in growth factors and cytokines and has been used as an agent that induces tissue regeneration. PRP also promotes follicle development in vitro and has been utilized in small case series as a potential treatment for women with POR.

The Application and Mechanism of Action of External Volume Expansion in Soft Tissue Regeneration.

The reconstruction of large-volume soft tissue defects is a major problem in plastic surgery. Many plastic surgeons have focused on external volume expansion (EVE) because of its capacity to promote regeneration of soft tissues, including breast, subcutaneous fat, and skin. EVE is a minimally invasive and less costly tissue engineering approach that has shown great clinical potential. However, many challenges still need to be addressed before such technology can become a common clinical practice. Basic in vivo and in vitro studies have been performed to determine the possible mechanisms by which EVE promotes tissue regeneration and to design optimized animal models. EVE application was found to facilitate cell proliferation and migration, enhance adipogenesis, improve angiogenesis, and provide available space for soft tissue growth. Understanding the mechanical and chemical signals associated with EVE during tissue regeneration may enable the clinical adaptation of this technology. This article reviews the clinical application of EVE techniques, describes preclinical animal models, and evaluates the possible mechanisms by which EVE induces tissue regeneration. Impact statement The reconstruction of large-volume soft tissue defects is a major problem in plastic surgery. External volume expansion (EVE) is a minimally invasive and less costly tissue engineering approach that has shown promise in clinical applications. This article reviews the clinical application of EVE techniques, describes preclinical animal models, and evaluates the possible mechanisms by which EVE induces tissue regeneration.

Collagen-Inspired Helical Peptide Coassembly Forms a Rigid Hydrogel with Twisted Polyproline II Architecture.

Collagen, the most abundant protein in mammals, possesses notable cohesion and elasticity properties and efficiently induces tissue regeneration. The Gly-Pro-Hyp canonical tripeptide repeating unit of the collagen superhelix has been well-characterized. However, to date, the shortest tripeptide repeat demonstrated to attain a helical conformation contained 3–10 peptide repeats. Here, taking a minimalistic approach, we studied a single repeating unit of collagen in its protected form, Fmoc-Gly-Pro-Hyp. The peptide formed single crystals displaying left-handed polyproline II superhelical packing, as in the native collagen single strand. The crystalline assemblies also display head-to-tail H-bond interactions and an “aromatic zipper” arrangement at the molecular interface. The coassembly of this tripeptide, with Fmoc-Phe-Phe, a well-studied dipeptide hydrogelator, produced twisted helical fibrils with a polyproline II conformation and improved hydrogel mechanical rigidity. The design of these peptides illustrates the possibility to assemble superhelical nanostructures from minimal collagen-inspired peptides with their potential use as functional motifs to introduce a polyproline II conformation into hybrid hydrogel assemblies.

Development of DNA polymer films as a drug delivery system for the treatment of oral cancer.

DNA polymer films (DNA-PFs) hold promise for use in drug delivery systems (DDS). In this study, the growth pattern of oral squamous cell carcinoma (OSCC) cells was evaluated on DNA-PFs incorporated with a photoactive compound chlorine aluminum phthalocyanine (DNA-PFs-AlClPc) and the efficacy of DNA-PFs-AlClPc as a DDS for photodynamic therapy (PDT) for the treatment of mucosal cancer. Flow cytometry was used to evaluate cell viability following application of DNA-PFs-AlClPc during PDT; the results demonstrated a positive response to photo stimulation within the range of light doses used (300, 600, and 1200mJ/cm2). Reduced viability and increased cell death were observed with increasing doses than in the controls. As expected, the viability was reduced by more than 30% at the highest dose (1200mJ/cm2). Flow cytometry revealed that the main mechanism of cell death induction was apoptosis (early and late apoptosis). These results demonstrate the potential of applying DNA-PFs-AlClPc as a DDS for other active molecules in the treatment of other pathologies. Furthermore, this system allows other drugs to be associated with DNA-PFs, indicating the potential use of this nanostructure in novel ways for the treatment of different neoplasms, such as oral cancer. Additionally, DNA nanostructured films may be used to support cell growth and subsequently as a "curative material" incorporated with an active or photoactive compound that can induce tissue regeneration. Graphical abstract .

It Takes Two to Regenerate: Optimizing Custom Wnt Surrogates

In this issue of Cell Chemical Biology, Chen etal. (2020) present an antibody-based platform to generate Wnt agonists, offering multiple design principles for systematic investigation of Wnt activation. This study lays the groundwork to develop potent Wnt agonists for applications in regenerative medicine.

Mesoporous Strontium-Doped Phosphate-Based Sol-Gel Glasses for Biomedical Applications.

Mesoporous phosphate-based glasses have great potential as biomedical materials being able to simultaneously induce tissue regeneration and controlled release of therapeutic molecules. In the present study, a series of mesoporous phosphate-based glasses in the P2O5-CaO-Na2O system, doped with 1, 3, and 5 mol% of Sr2+, were prepared using the sol-gel method combined with supramolecular templating. A sample without strontium addition was prepared for comparison. The non-ionic triblock copolymer EO20PO70EO20 (P123) was used as a templating agent. Scanning electron microscopy (SEM) images revealed that all synthesized glasses have an extended porous structure. This was confirmed by N2 adsorption-desorption analysis at 77 K that shows a porosity typical of mesoporous materials. 31P magic angle spinning nuclear magnetic resonance (31P MAS-NMR) and Fourier transform infrared (FTIR) spectroscopies have shown that the glasses are mainly formed by Q1 and Q2 phosphate groups. Degradation of the glasses in deionized water assessed over a 7-day period shows that phosphate, Ca2+, Na+, and Sr2+ ions can be released in a controlled manner over time. In particular, a direct correlation between strontium content and degradation rate was observed. This study shows that Sr-doped mesoporous phosphate-based glasses have great potential in bone tissue regeneration as materials for controlled delivery of therapeutic ions.

Public Health Approach of Ayurveda and Yoga for COVID-19 Prophylaxis.

Public Health Approach of Ayurveda and Yoga for COVID-19 Prophylaxis.