Repair Therapy Research Articles

ApoSEVs-Mediated Modulation of Versatile Target Cells Promotes Diabetic Wound Healing: Unveiling a Promising Strategy.

Diabetic chronic wounds present a formidable challenge in clinical management, lacking effective treatment options. Mesenchymal stem cell (MSC) transplantation has emerged as a promising therapy for tissue repair and regeneration. However, transplanted MSCs often undergo rapid apoptosis, giving rise to heterogeneous extracellular vesicles (EVs), including apoptotic bodies (apoBDs) and apoptotic small extracellular vesicles (apoSEVs). The potential stimulatory role of these EVs in diabetic wound healing remains unknown. In this study, we investigated the effects of apoSEVs derived from adipose-derived mesenchymal/stromal cells (ADSCs) on the recovery of diabetic wounds by modulating the function of versatile target cells. First, we characterized the apoSEVs and apoBDs derived from apoptotic ADSCs. Subsequently, we evaluated the effects of apoSEVs and apoBDs on macrophages, endothelial cells, and fibroblasts, three essential cell types in wound healing, under high-glucose conditions. Furthermore, we developed a gelatin methacryloyl (GelMA) hydrogel for the sustained release of apoSEVs and investigated its therapeutic effects on wound healing in type 2 diabetic mice in vivo. apoSEVs facilitated the polarization of M1 phenotype macrophages to M2 phenotype, promoted proliferation, migration, and tube formation of endothelial cells, and enhanced fibroblast proliferation and migration. However, apoBDs failed to improve the function of endothelial cells and fibroblasts. In vivo, the apoSEVs-loaded GelMA effectively promoted wound healing by facilitating collagen fiber deposition, angiogenesis, and immune regulation. Our study elucidates the beneficial effects of apoSEVs on wound recovery in diabetes and introduces a novel strategy for diabetic wound treatment based on apoSEVs.

Nanomaterial payload delivery to central nervous system glia for neural protection and repair

Central nervous system (CNS) glia, including astrocytes, microglia, and oligodendrocytes, play prominent roles in traumatic injury and degenerative disorders. Due to their importance, active pharmaceutical ingredients (APIs) are being developed to modulate CNS glia in order to improve outcomes in traumatic injury and disease. While many of these APIs show promise in vitro, the majority of APIs that are systemically delivered show little penetration through the blood–brain barrier (BBB) or blood-spinal cord barrier (BSCB) and into the CNS, rendering them ineffective. Novel nanomaterials are being developed to deliver APIs into the CNS to modulate glial responses and improve outcomes in injury and disease. Nanomaterials are attractive options as therapies for central nervous system protection and repair in degenerative disorders and traumatic injury due to their intrinsic capabilities in API delivery. Nanomaterials can improve API accumulation in the CNS by increasing permeation through the BBB of systemically delivered APIs, extending the timeline of API release, and interacting biophysically with CNS cell populations due to their mechanical properties and nanoscale architectures. In this review, we present the recent advances in the fields of both locally implanted nanomaterials and systemically administered nanoparticles developed for the delivery of APIs to the CNS that modulate glial activity as a strategy to improve outcomes in traumatic injury and disease. We identify current research gaps and discuss potential developments in the field that will continue to translate the use of glia-targeting nanomaterials to the clinic.

Metal–Organic Frameworks for Nerve Repair and Neural Stem Cell Therapy

AbstractRecently, neurological disorders have led to a growing global burden of fatalities and disabilities. The limited capacity for natural self‐regeneration poses a significant challenge in repairing nervous system injuries, which is closely related to the complex microenvironment and nonregenerative nature of neurons. Metal–organic frameworks (MOFs), with their distinctive structure and properties including high surface area, porosity, tunability, stimuli‐responsive behavior, biocompatibility, and biodegradability, stand as an auspicious platform for devising therapeutic strategies aiming at nerve regeneration and repair. By taking advantage of these characteristics, researchers have the opportunity to explore innovative methods including endogenous stimulation, magnetic response therapy, phototherapy, ultrasound therapy, and drug delivery systems for the treatment of neurological diseases. Moreover, MOFs‐based stem cell therapy also is developed to inhibit neuroinflammation and oxidative stress, promote axon growth, regulate stem cell differentiation, promote nerve regeneration, and finally restore the function of injured nerves. In this paper, the preparation strategy and biological characteristics of MOFs, highlighting their applications in repairing nerve injuries and treating neural stem cells is presented. Finally, an outlook on the future development and challenges in the field of neuroscience concerning MOFs is provided.

Bio-inspired microvascular patches with MSC encapsulation for wound healing

Mesenchymal stem cells (MSCs) have been studied extensively for promoting wound healing, while their practical applications remain challenging due to the difficulty of promoting concurrent restoration of the granulation and vasculature. Inspired by densely vascularized human tissues, we propose a novel microvascular patch with MSC encapsulation as a new therapy for wound repair. A microfluidic system was employed to construct the engineered endothelialized micro-vessels, which were subsequently encapsulated into therapeutic MSCs-laden fibrinogen hydrogel to generate a pre-vascularized MSCs patch (EMV − MSCs patch). We demonstrate that the embedded flexible microfibers significantly enhanced the mechanical properties of the fibrinogen hydrogel. At the same time, the MSCs in the patch promoted endothelial cell migration and angiogenesis in the microfibers. Thus, the transplanted EMV-MSCs patch significantly promoted collagen deposition, granulated tissue formation and suppressed inflammation in and around the wound area. We believe such facile and fast fabrication of the engineered microvessels integrated MSCs patch makes it promising for many practical applications.

Application of Chitosan-Based Polysaccharide Biomaterials in Tissue Engineering

Chitosan-based polysaccharide biomaterials have gained interest as viable options in tissue engineering due to their distinctive properties and wide range of potential applications. Biomaterials play a crucial role in regenerative medicine because they foster an environment conducive to cell growth and tissue repair. The chitin-derived polysaccharide chitosan is superior than synthetic materials in several ways: it has a similar structure to the extracellular matrix, is biocompatible, biodegradable, antimicrobial, and can incorporate bioactive chemicals. In this article, check how chitosan can be used in tissue engineering as a scaffold for different types of tissue, a hydrogel for wound healing, and a carrier for gene therapy, stem cell culture, and drug delivery. Scaffolds made from chitosan have shown tremendous promise in tissue engineering for the neurological system, bone and cartilage transplantation, and skin regeneration. Hydrogels made from chitosan have been shown to be useful in treating wounds and stopping bleeding. Chitosan's medicinal potential in gene therapy, stem cell culture, and targeted medication administration is further enhanced by the addition of bioactive components such as growth factors, genes, or medicines. In addition, using chitosan in tissue engineering can pave the way for future developments in stem cell techniques, nanotechnology, biofabrication, and 3D bioprinting, among other areas of study. These advances may one day lead to individualized and highly effective therapies for tissue repair and regeneration. The use of chitosan in tissue engineering has the potential to advance regenerative medicine and address the growing demand for more effective techniques to heal damaged tissues. Tissue engineers can revolutionize the field of regenerative medicine and enhance patient outcomes by taking use of chitosan's adaptability and bioactivity to create cutting-edge biomaterials and therapeutic techniques.

Germ line variant GFI1-36N affects DNA repair and sensitizes AML cells to DNA damage and repair therapy

AbstractGrowth factor independence 1 (GFI1) is a DNA-binding transcription factor and a key regulator of hematopoiesis. GFI1-36N is a germ line variant, causing a change of serine (S) to asparagine (N) at position 36. We previously reported that the GFI1-36N allele has a prevalence of 10% to 15% among patients with acute myeloid leukemia (AML) and 5% to 7% among healthy Caucasians and promotes the development of this disease. Using a multiomics approach, we show here that GFI1-36N expression is associated with increased frequencies of chromosomal aberrations, mutational burden, and mutational signatures in both murine and human AML and impedes homologous recombination (HR)–directed DNA repair in leukemic cells. GFI1-36N exhibits impaired binding to N-Myc downstream-regulated gene 1 (Ndrg1) regulatory elements, causing decreased NDRG1 levels, which leads to a reduction of O6-methylguanine-DNA-methyltransferase (MGMT) expression levels, as illustrated by both transcriptome and proteome analyses. Targeting MGMT via temozolomide, a DNA alkylating drug, and HR via olaparib, a poly-ADP ribose polymerase 1 inhibitor, caused synthetic lethality in human and murine AML samples expressing GFI1-36N, whereas the effects were insignificant in nonmalignant GFI1-36S or GFI1-36N cells. In addition, mice that received transplantation with GFI1-36N leukemic cells treated with a combination of temozolomide and olaparib had significantly longer AML-free survival than mice that received transplantation with GFI1-36S leukemic cells. This suggests that reduced MGMT expression leaves GFI1-36N leukemic cells particularly vulnerable to DNA damage initiating chemotherapeutics. Our data provide critical insights into novel options to treat patients with AML carrying the GFI1-36N variant.

Fluoroquinolones increase susceptibility to aortic aneurysm and aortic dissection: Molecular mechanism and clinical evidence.

Aortic aneurysm (AA) and aortic dissection (AD) are prevalent severe cardiovascular diseases that result in catastrophic complications and unexpected deaths. Owing to the lack of clinically established and effective medications, the only treatment options are open surgical repair or endovascular therapy. Most researchers have focused on the development of innovative medications or therapeutic targets to slow the progression of AA/AD or lower the risk of malignant consequences. Recent studies have shown that the use of fluoroquinolones (FQs) may increase susceptibility to AA/AD to some extent, especially in patients with aortic dilatation and those at a high risk of AD. Therefore, it is crucial for doctors, particularly those in cardiovascular specialties, to recognize the dangers of FQs and adopt alternatives. In the present review, the main clinical observational studies on the correlation between FQs and AA/AD in recent years are summarized, with an emphasis on the relative physiopathological mechanism incorporating destruction of the extracellular matrix (ECM), phenotypic transformation of vascular smooth muscle cells, and local inflammation. Although additional data are required, it is anticipated that the rational use of FQs will become the standard of care for the treatment of aortic diseases.

Re-WRAP (Remyelination for women at risk of axonal loss and progression): A phase II randomized placebo-controlled delayed-start trial of bazedoxifene for myelin repair in multiple sclerosis

IntroductionMultiple sclerosis (MS) is a major cause of disability in young and middle-aged people, and myelin repair therapies are needed to slow or potentially reverse this damage. Bazedoxifene (BZA) is a selective estrogen receptor modulator identified in a novel high-throughput unbiased screen for its remyelinating potential, and its remyelinating effects were demonstrated in pre-clinical models. MethodsThis is a single-center, double blind, randomized, controlled, delayed-start Phase 2 clinical trial (NCT04002934) investigating the remyelinating effects of BZA relative to placebo. Female patients with relapsing-remitting MS, aged 45–60 years (or > 40 if post-menopausal), and ambulatory status (EDSS 0–6 inclusive), will be recruited into a clinical trial with 2 arms of identical design, except that the “Chronic Optic Neuropathy” arm requires additional inclusion criteria of electrophysiological evidence of prior visual pathway demyelination. Clinical, electrophysiological, and imaging evaluations will occur at baseline, 3 months, and 6 months. The primary outcome is change in Myelin Water Fraction (MWF) on MRI within the corpus callosum. Secondary outcomes are: visual evoked potential (VEP) P100 latency, novel digital measures of cognition and activity, and patient reported outcomes. Tertiary outcomes are: safety and tolerability. DiscussionBZA has strong preclinical effects on myelin repair, and in the general population demonstrated benefits in treating postmenopausal osteoporosis. Together, these findings support the rationale for an RCT testing BZA in women with MS, evaluating established neuroimaging and neurovisual measures of myelin repair. Additionally, validating novel digital tools could increase sensitivity to change and inform the duration and design of future clinical trials.

Effectiveness of Mesenchymal Stem Cell Secretome on Wound Healing: A Systematic Review and Meta-analysis.

Secretome provides promising potential in replacing cell-based therapies in wound repair therapy. This study aimed to systematically review and conduct a meta-analysis on the effectiveness of secretome in promoting wound healing. To ensure the rigor and transparency of our study, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, as registered in PROSPERO with ID: CRD42023412671. We conducted a comprehensive search on four electronic databases to identify studies evaluating the effect of secretome on various clinical parameters of wound repair. In addition, we evaluated the risk of bias for each study using the Jadad and Newcastle-Ottawa scale. To synthesize the data, we employed a fixed-effects model and calculated the mean difference or odds ratio (OR) with a 95% confidence interval (CI). Based on six included articles, secretome is known to affect several clinical parameters in wound healing included the size and depth of ulcers during healing; the E´chelle d'évaluation clinique des cicatrices d'acne (ECCA) score, epidermal thickness, collagen fibers, abnormal elastic tissues, volume of atrophic acne scars, skin pore volume, and erythema during acne scar healing; and microcrust areas, erythema index, transepidermal water loss, volume of atrophic acne scars, erythema, and relative gene expression of procollagen type I, procollagen type III, and elastin were evaluated in wound healing after laser treatment. Meta-analysis studies showed that secretome reduced ulcer size (mean difference: 0.87, 95% CI of 0.37-1.38, p = 0.0007), decreased ulcer depth (mean difference: 0.18, 95% CI of 0.11-0.25, p < 0.00001), and provided patient satisfaction (odds ratio: 9.71, 95% CI of 3.47-21.17, p < 0.0001). However, secretome failed to reach significance in clinical improvement (OR 0.38, 95% CI 0.10, 1.53, p = 0.06). The secretome provides good effectiveness in accelerating wound healing through a mechanism that correlates with several clinical parameters of wound repair.

Converse modulation of Wnt/β-catenin signaling during expansion and differentiation phases of Infrapatellar fat pad-derived MSCs for improved engineering of hyaline cartilage

Mesenchymal stem cells (MSCs) are potential candidates in cell-based therapy for cartilage repair and regeneration. However, during chondrogenic differentiation, MSCs undergo undesirable hypertrophic maturation. This poses a risk of ossification in the neo-tissue formed that eventually impedes the clinical use of MSCs for cartilage repair. TGF-β is a potent growth factor used for chondrogenic differentiation of MSCs, however, its role in hypertrophy remains ambiguous. In the present work, we decipher that TGF-β activates Wnt/β-catenin signaling through SMAD3 and increases the propensity of Infrapatellar fat pad derived MSCs (IFP-MSCs) towards hypertrophy. Notably, inhibiting TGF-β induced Wnt/β-catenin signaling suppresses hypertrophic progression and enhances chondrogenic ability of IFP-MSCs in plasma hydrogels. Additionally, we demonstrate that activating Wnt signaling during expansion phase, promotes proliferation and reduces senescence, while improving stemness of IFP-MSCs. Thus, conversely modulating Wnt signaling in vitro during expansion and differentiation phases generates hyaline-like cartilage with minimal hypertrophy. Importantly, pre-treatment of IFP-MSCs encapsulated in plasma hydrogel with Wnt modulators followed by subcutaneous implantation in nude mice resulted in formation of a cartilage tissue with negligible calcification. Overall, this study provides technological advancement on targeting Wnt/β-catenin pathway in a 3D scaffold, while maintaining the standard chondro-induction protocol to overcome the challenges associated with the clinical use of MSCs to engineer hyaline cartilage.

Efficacy and safety of immune checkpoint inhibitors in Proficient Mismatch Repair (pMMR)/ Non-Microsatellite Instability-High (non-MSI-H) metastatic colorectal cancer: a study based on 39 cohorts incorporating 1723 patients

PurposeThis study was designed to investigate the efficacy and safety of immune checkpoint inhibitors (ICIs)-based therapy in proficient mismatch repair (pMMR)/non-microsatellite instability-high (non-MSI-H) metastatic colorectal cancer (mCRC).MethodsElectronic databases were screened to identify relevant trials. The primary endpoints were pooled objective response rate (ORR) and disease control rate (DCR). Stratified analysis was accomplished on ICIs-based regimens, treatment lines and RAS status.ResultsTotally, 1723 mCRC patients from 39 cohorts were included. The pooled ORR, DCR, 12-month overall survival (OS) rate and 6-month progression-free survival (PFS) rate of ICIs-based therapy in pMMR/non-MSI-H mCRC were 8.5% (95% CI: 4.4%-13.5%), 48.2% (95% CI: 37.8%-58.6%), 52.3% (95% CI: 46.4%-58.1%) and 32.8% (95% CI: 23.5%-42.7%) respectively. As a whole, no significantly differences were shown between ICIs-based and non-ICIs-based therapy for pMMR/non-MSI-H mCRC in terms of both PFS (HR = 1.0, 95% CI: 0.9–1.1, P = 0.91) and OS (HR = 1.0, 95% CI: 0.9–1.2, P = 0.51). It was worth noting that the addition of ICIs to anti-vascular endothelial growth factor (VEGF) agent plus chemotherapy displayed excellent efficacy in pMMR/non-MSI-H mCRC (ORR = 42.4%, 95% CI: 10.0%-78.6%; DCR = 92.0%, 95% CI: 68.3%-100.0%; 12-month OS rate = 71.4%, 95% CI: 50.0%-89.1%; 6-month PFS rate = 55.2%, 95% CI: 24.8%-83.8%; and PFS (compared with non-ICIs-based therapy): HR = 0.9, 95% CI: 0.8–1.0, P = 0.02), especially served as first-line therapy (ORR = 74.2%, 95% CI: 61.4%-85.4%; DCR = 98.7%, 95% CI: 92.0%-100.0%); and without additional treatment related adverse events (TRAEs) were observed.ConclusionsICIs-based combination therapy, especially the addition of ICIs to first-line anti-VEGF agent plus chemotherapy, is promising in pMMR/non-MSI-H mCRC with good efficacy and controllable toxicity.

Novel Osteochondral Biotemplate Improves Long-term Cartilage Repair Compared With Microfracture in an Ovine Model

Background: Current cartilage repair therapies do not re-create the complex mechanical interface between cartilage and bone, which is critical for long-term repair durability. New biomaterial designs that include hard tissue–soft tissue interface structures offer promise to improve clinical outcomes. Purpose/Hypothesis: The purpose of this study was to evaluate the efficacy and safety of a naturally derived osteochondral biotemplate with a novel contiguous hard tissue–soft tissue interface in an ovine model as a regenerative solution for articular cartilage defects. It was hypothesized that the osteochondral biotemplate would produce structurally superior repair tissue compared with microfracture over a 13-month period. Study Design: Controlled laboratory study. Methods: Osteochondral biotemplates were manufactured from porcine cancellous bone. Skeletally mature sheep (N = 30) were randomly allocated to 3 groups: early healing stage (euthanasia at 4 months), 6-month treatment, and 13-month treatment. In the early healing stage group, an 8 mm–diameter by 5 mm–deep osteochondral defect was created on the medial femoral condyle and treated at the time of iatrogenic injury with an osteochondral biotemplate. The contralateral limb received the same treatment 2 months later. In the 6- and 13-month treatment groups, 1 limb received the same osteochondral procedure as the early healing stage group. In the contralateral limb, an 8 mm–diameter, full-thickness cartilage defect (1-2 mm deep) was created and treated with microfracture. Cartilage repair and integration were quantitatively and qualitatively assessed with gross inspection, histological evaluation, and magnetic resonance imaging (MRI). Wilcoxon signed-rank and McNemar tests were used to compare the treatments. Results: At 6 and 13 months after treatment, the biotemplate was not present histologically. At 13 months, the biotemplate treatment demonstrated statistically higher histological scores than microfracture for integration with surrounding cartilage (biotemplate: 74 ± 31; microfracture: 28 ± 39; P = .03), type 2 collagen (biotemplate: 72 ± 33; microfracture: 40 ± 38; P = .02), total cartilage (biotemplate: 71 ± 9; microfracture: 59 ± 9; P = .01), and total integration (biotemplate: 85 ± 15; microfracture: 66 ± 20; P = .04). The osteochondral biotemplate treatment produced a notable transient nonneutrophilic inflammatory response that appeared to approach resolution at 13 months. MRI results were not statistically different between the 2 treatments. Conclusion: Even with the inflammatory response, after 13 months, the osteochondral biotemplate outperformed microfracture in cartilage regeneration and demonstrated superiority in integration between the repair tissue and host tissue as well as integration between the newly formed cartilage and the underlying bone. Clinical Relevance: This work has demonstrated the clinical potential of a novel biomaterial template to regenerate the complex mechanical interface between cartilage and the subchondral bone.

Apelin-Overexpressing Neural Stem Cells in Conjunction with a Silk Fibroin Nanofiber Scaffold for the Treatment of Traumatic Brain Injury.

Traumatic brain injury (TBI), especially moderate or severe TBI, is one of the most devastating injuries to the nervous system, as the existing therapies for neurological defect repair have difficulty achieving satisfactory results. Neural stem cells (NSCs) therapy is a potentially effective treatment option, especially after specific genetic modifications and when used in combination with biomimetic biological scaffolds. In this study, tussah silk fibroin (TSF) scaffolds with interconnected nanofibrous structures were fabricated using a top-down method. We constructed the apelin-overexpressing NSCs that were cocultured with a TSF nanofiber scaffold (TSFNS) that simulated the extracellular matrix in vitro. To verify the therapeutic efficacy of engineered NSCs in vivo, we constructed TBI models and randomized the C57BL/6 mice into three groups: a control group, an NSC-ctrl group (transplantation of NSCs integrated on TSFNS), and an NSC-apelin group (transplantation of apelin-overexpressing NSCs integrated on TSFNS). The neurological functions of the model mice were evaluated in stages. Specimens were obtained 24 days after transplantation for immunohistochemistry, immunofluorescence, and western blot experiments, and statistical analysis was performed. The results showed that the combination of the TSFNS and apelin overexpression guided extension and elevated the proliferation and differentiation of NSCs both in vivo and in vitro. Moreover, the transplantation of TSFNS-NSCs-Apelin reduced lesion volume, enhanced angiogenesis, inhibited neuronal apoptosis, reduced blood-brain barrier damage, and mitigated neuroinflammation. In summary, TSFNS-NSC-Apelin therapy could build a microenvironment that is more conducive to neural repair to promote the recovery of injured neurological function.

Human PSC-derived cardiac cells and their products: therapies for cardiac repair

Despite the dramatic improvements in the management of patients with chronic heart failure which have occurred over the last decades, some of them still exhaust conventional drug-based therapies without being eligible for more aggressive options like heart transplantation or implantation of a left ventricular assist device. Cell therapy has thus emerged as a possible means of filling this niche. Multiple cell types have now been tested both in the laboratory but also in the clinics and it is fair to acknowledge that none of the clinical trials have yet conclusively proven the efficacy of cell-based approaches. These clinical studies, however, have entailed the use of cells from various sources but of non-cardiac lineage origins. Although this might not be the main reason for their failures, the discovery of pluripotent stem cells capable of generating cardiomyocytes now raises the hope that such cardiac-committed cells could be therapeutically more effective. In this review, we will first describe where we currently are with regard to the clinical trials using PSC-differentiated cells and discuss the main issues which remain to be addressed. In parallel, because the capacity of cells to stably engraft in the recipient heart has increasingly been questioned, it has been hypothesized that a major mechanism of action could be the cell-triggered release of biomolecules that foster host-associated reparative pathways. Thus, in the second part of this review, we will discuss the rationale, clinically relevant advantages and pitfalls associated with the use of these PSC “products”.

Biodistribution of lentiviral transduced adipose-derived stem cells for "ex-vivo" regional gene therapy for bone repair.

Ex-vivo gene therapy has been shown to be an effective method for treating bone defects in pre-clinical models. As gene therapy is explored as a potential treatment option in humans, an assessment of the safety profile becomes an important next step. The purpose of this study was to evaluate the biodistribution of viral particles at the defect site and various internal organs in a rat femoral defect model after implantation of human ASCs transduced with lentivirus (LV) with two-step transcriptional activation (TSTA) of bone morphogenetic protein-2 (LV-TSTA-BMP-2). Animals were sacrificed at 4-, 14-, 56-, and 84-days post implantation. The defects were treated with either a standard dose (SD) of 5 million cells or a high dose (HD) of 15 million cells to simulate a supratherapeutic dose. Treatment groups included (1) SD LV-TSTA-BMP-2 (2) HD LV-TSTA-BMP-2, (3) SD LV-TSTA-GFP (4) HD LV-TSTA-GFP and (5) SD nontransduced cells. The viral load at the defect site and ten organs was assessed at each timepoint. Histology of all organs, ipsilateral tibia, and femur were evaluated at each timepoint. There were nearly undetectable levels of LV-TSTA-BMP-2 transduced cells at the defect site at 84-days and no pathologic changes in any organ at all timepoints. In conclusion, human ASCs transduced with a lentiviral vector were both safe and effective in treating critical size bone defects in a pre-clinical model. These results suggest that regional gene therapy using lentiviral vector to treat bone defects has the potential to be a safe and effective treatment in humans.

A nano-conductive osteogenic hydrogel to locally promote calcium influx for electro-inspired bone defect regeneration

Conductive nano-materials and electrical stimulation (ES) have been recognized as a synergetic therapy for ordinary excitable tissue repair. It is worth noting that hard tissues, such as bone tissue, possess bioelectrical properties as well. However, insufficient attention is paid to the synergetic therapy for bone defect regeneration via conductive biomaterials with ES. Here, a novel nano-conductive hydrogel comprising calcium phosphate-PEDOT:PSS-magnesium titanate-methacrylated alginate (CPM@MA) was synthesized for electro-inspired bone tissue regeneration. The nano-conductive CPM@MA hydrogel has demonstrated excellent electroactivity, biocompatibility, and osteoinductivity. Additionally, it has the potential to enhance cellular functionality by increasing endogenous transforming growth factor-beta1 (TGF-β1) and activating TGF-β/Smad2 signaling pathway. The synergetic therapy could facilitate intracellular calcium enrichment, resulting in a 5.8-fold increase in calcium concentration compared to the control group in the CPM@MA ES + group. The nano-conductive CPM@MA hydrogel with ES could significantly promote electro-inspired bone defect regeneration in vivo, uniquely allowing a full repair of rat femoral defect within 4 weeks histologically and mechanically. These results demonstrate that our synergistic strategy effectively promotes bone restoration, thereby offering potential advancements in the field of electro-inspired hard tissue regeneration using novel nano-materials with ES.

Research advances on improving the therapeutic efficacy of mesenchymal stem cell-derived exosomes in wound repair

How to promote high-quality wound healing is a common problem for plastic surgery and burn physicians. In recent years, numerous animal studies have demonstrated that mesenchymal stem cell-derived exosomes promote wound repair through multiple mechanisms and are promising cell-free therapeutic agents with broad prospect of application. How to enhance the therapeutic efficacy of exosomes, optimize their drug delivery strategy, and improve their biological properties are the challenges to be overcome in order to move from basic research to clinical application of exosome therapy for wound repair. This article focuses on methods to improve the wound repair potential of mesenchymal stem cell-derived exosomes, and reviews the recent research advances on improving the therapeutic efficacy of mesenchymal stem cell-derived exosomes in wound repair from three aspects, including pretreatment of parental mesenchymal stem cells, hydrogel bio-scaffold loaded with exosomes, and engineered exosomes, to provide a reference for further clinical studies.

Fulfilling the Promise of RNA Therapies for Cardiac Repair and Regeneration.

The progressive appreciation that multiple types of RNAs regulate virtually all aspects of tissue function and the availability of effective tools to deliver RNAs in vivo now offers unprecedented possibilities for obtaining RNA-based therapeutics. For the heart, RNA therapies can be developed that stimulate endogenous repair after cardiac damage. Applications in this area include acute cardioprotection after ischemia or cancer chemotherapy, therapeutic angiogenesis to promote new blood vessel formation, regeneration to form new cardiac mass, and editing of mutations to cure inherited cardiac disease. While the potential of RNA therapeutics for all these conditions is exciting, the field is still in its infancy. A number of roadblocks need to be overcome for RNA therapies to become effective, in particular, related to the problem of delivering RNA medicines into the cells and targeting them specifically to the heart.

Development of an innovative minimally invasive primate spinal cord injury model: A case report.

Spinal cord injury(SCI) animal models have been widely created and utilized for repair therapy research, but more suitable experimental animals and accurate modeling methodologies are required to achieve the desired results. In this experiment, we constructed an innovative dorsal 1/4 spinal cord transection macaque model that had fewer severe problems, facilitating postoperative care and recovery. In essence, given that monkeys and humans share similar genetics and physiology, the efficacy of this strategy in a nonhuman primate SCI model basically serves as a good basis for its prospective therapeutic use in human SCI.

Cranial Neural Crest Cells Contribution to Craniofacial Bone Development and Regeneration.

This review aims to summarize (i) the latest evidence on cranial neural crest cells (CNCC) contribution to craniofacial development and ossification; (ii) the recent discoveries on the mechanisms responsible for their plasticity; and (iii) the newest procedures to ameliorate maxillofacial tissue repair. CNCC display a remarkable differentiation potential that exceeds the capacity of their germ layer of origin. The mechanisms by which they expand their plasticity was recently described. Their ability to participate to craniofacial bone development and regeneration open new perspectives for treatments of traumatic craniofacial injuries or congenital syndromes. These conditions can be life-threatening, require invasive maxillofacial surgery and can leave deep sequels on our health or quality of life. With accumulating evidence showing how CNCC-derived stem cells potential can ameliorate craniofacial reconstruction and tissue repair, we believe a deeper understanding of the mechanisms regulating CNCC plasticity is essential to ameliorate endogenous regeneration and improve tissue repair therapies.