Regenerative Biomaterials最新文献

As the most feasible method to reconstruct long-distance peripheral nerve injuries, tissue-engineered nerves rely on biomaterials as a key driving factor. Chitooligosaccharides, intermediate products of chitosan degradation, have the ability to positively regulate nerve regeneration microenvironments. However, the impact of chitooligosaccharides on clearance of myelin debris during Wallerian degeneration is unrevealed. The focus is on exploring the role of chitooligosaccharides in myelin clearance, which is a crucial preparation stage for nerve regeneration. The effects of chitooligosaccharides on nerve regeneration were demonstrated through the morphological and functional evaluations. Then, the myelin lipids and proteins were analyzed using the morphological staining, and molecular and protein detection. The microstructure and ultrastructure observations of lysosomes and autophagosomes were performed. In addition, the proteomics and bioinformatics analysis of injured nerves treated with chitooligosaccharides. The interacting molecules and the regulatory network of Wipi1 were further predicted. On the basis of positive roles on peripheral nerve regeneration, it was illustrated that chitooligosaccharides accelerated the clearance of myelin. Furthermore chitooligosaccharides could regulate lysosomal and autophagic functions, and its role in promoting myelin clearance was mainly related to the enhanced autophagy of Schwann cells rather than macrophages. The big data analysis revealed that Wipi1 was notably upregulated in Schwann cells, mediating chitooligosaccharides to promote autophagy and myelin clearance. Meanwhile, as a potential therapeutic target, Wipi1 significantly accelerated myelin clearance and lipid metabolism after peripheral nerve injury. Our research deepens the comprehensive understanding of the positive regulatory role of chitosan and chitooligosaccharides; and it expands new content and ideas for designing and constructing better tissue-engineered nerves from the perspective of mutual communication and response between biomaterials and body tissues.

Treating bone defects is a critical challenge in regenerative medicine. Carbon nanomaterials, with their unique physicochemical properties, offer significant potential for enhancing bone regeneration. In this study, we developed tartaric acid (TA)-based carbon dots (CDs) by synthesizing TA with branched polyethyleneimine (bPEI). These TA-bPEI CDs were systematically evaluated to determine their effects on osteogenic differentiation in human bone marrow-derived mesenchymal stem cells (BMSCs) and their capacity to repair calvarial defects in an in vivo model. Characterization of TA-bPEI CDs revealed a size of approximately 10 nm and a positive surface charge. The CDs exhibited fluorescence emission peaks between 464 and 506 nm under excitation wavelengths of 340-440 nm. Cytotoxicity assays demonstrated that TA-bPEI CDs maintained BMSC viability at concentrations up to 250 μg/ml. However, at concentrations of 500 μg/ml and above, apoptosis was induced. Treatment with TA-bPEI significantly enhanced osteogenic differentiation in vitro, as evidenced by increased expression of osteogenic-specific proteins such as Runx2, ALP, OCN and OPN. In vivo, the application of TA-bPEI CDs in a mouse calvarial defect model promoted robust new bone formation, reduced defect gaps, and improved bone morphometric parameters, including bone volume fraction and trabecular thickness. These results suggest that TA-bPEI CDs enhance osteogenesis by directly stimulating osteogenic differentiation and upregulating osteogenesis-specific genes. This study demonstrates the high potential of TA-bPEI CDs as a novel nanomaterial for bone regeneration applications.

The accumulation of advanced glycation end products (AGEs) plays a crucial role in chronic inflammation and delayed wound healing in individuals with diabetes. In this context, fibronectin has been identified as a crucial protein that promotes the differentiation of human periodontal ligament stem cells (hPDLSCs) into myofibroblasts, which play a vital role in the repair of diabetic skin ulcers. This process is intimately associated with the integrin β1 receptor and the NF-κB signaling pathway, both crucial for cellular responses to fibronectin. To validate our hypothesis, we expressed rhFN₁₀₂₄, a recombinant protein containing the integrin β1 affinity-binding domain from human fibronectin segments 12-14. This protein was used to formulate a hydrogel for hPDLSCs. rhFN₁₀₂₄'s binding affinity to integrin β1 was confirmed by molecular docking and the cellular thermal shift assay (CETSA). We developed sh-ITGB1-hPDLSCs with stable ITGB1 knockdown using shRNA-ITGB1 and compared their proliferation, migration and adhesion to wild-type hPDLSCs. Morphological changes were observed via SEM, and α-SMA expression levels were measured in AGEs-damaged hPDLSCs. We created full-thickness wound models in diabetic mice to assess pharmacodynamics. The study showed that rhFN₁₀₂₄ stimulated hPDLSCs differentiation into myofibroblasts by boosting ITGB1 expression. rhFN₁₀₂₄ also reduced AGEs' negative effects on hPDLSCs, as seen through SEM analysis and α-SMA levels. In full-thickness wound models, hPDLSCs and rhFN₁₀₂₄ accelerated re-epithelialization and collagen synthesis. rhFN₁₀₂₄ is proposed to interact with the ITGB1 receptor on hPDLSCs, activating the NF-κB pathway to neutralize AGEs-induced pro-inflammatory cytokines. This study suggests rhFN₁₀₂₄ as a potential biomedical material for tissue repair.

While genetic engineering has offered new strategies for regulating stem cell differentiation, the efficacy varies in cells with different phenotypes or lineage commitments, leading to inconsistent differentiation outcomes and uncertainty in regenerative medicine. To address this issue, we employ a Y-shaped DNA (Y-DNA) as a nanomaterial to phenotype-specifically regulate differentiation of human mesenchymal stem cells (hMSCs). Y-DNA is composed of three DNA strands with complementary sequences and different roles. The Y-DNA designed in the present study can be uniquely activated by miR-106a-5p, a microRNA preferentially expressed in adipogenesis-biased hMSCs. Upon activation, the Y-DNA disassembles, releasing an antisense oligonucleotide that inhibits expression of cofilin, which serves as a key regulator to enhance adipogenic differentiation, and thus, prevents hMSCs from undergoing osteogenic differentiation. The key regulatory role of cofilin in hMSC differentiation is verified at the single-cell level on arginine-glycine-aspartate microislands under the nonfouling background of poly(ethylene glycol) hydrogels. Our strategy effectively redirects these cells towards osteogenic differentiation by inhibiting adipogenic differentiation, demonstrating dose dependence with high specificity, selectivity, and low toxicity. hMSCs cultured in a dual induction medium (a mixture of adipogenic medium and osteogenic medium) show enhanced osteogenic differentiation after transfection with the nanostructured Y-DNA. This approach addresses the challenge of cell heterogeneity in bone regeneration, offering a promising solution for precise control over stem cell fate. The ability of Y-DNA to specifically target cells with a propensity for adipogenic differentiation and to reprogram their lineage commitment has significant implications for the field of regenerative medicine, particularly in applications requiring enhanced purity of cell differentiation outcomes.

Postoperative atrial fibrillation (POAF) is the most prevalent form of secondary atrial fibrillation and increases the risk of adverse cardiovascular outcomes, such as stroke, heart failure and increased mortality. Herein, we designed an andrographolide (Andr)-loaded degradable polymer patch to deliver the drug directly to the atrial tissue for prevention of POAF. The sterile pericarditis (SP) rat model was adopted for highly relationship to clinical practice. The patch-released Andr effectively reduced the incidence of atrial fibrillation from 90 to 20%, and alleviated local atrial inflammation and oxidative stress in vivo, by using electrophysiological detection and histological analysis such as immunofluorescence, western blot and PCR. In HL-1 cells, we found the use of Andr-loaded patch could strongly inhibit the cell death, reactive oxygen species (ROS) generation and mitochondrial injury caused by LPS. Meanwhile, the use of Andr-loaded patch could effectively inhibited macrophages polarize towards M1. Mechanistically, we verified that the regulation of the cytoplasm and mitochondria Ca²⁺ and ROS dynamic balance was quite important both in vivo and in vitro. Our strategy proved by regulating the inflammatory microenvironment, ROS balance and Ca²⁺ homeostasis and the Andr-loaded atrial patch was effective for POAF in the SP rat model. The electrical signal of atrial stromal reentry in the case of this model was successfully mined, and the results of calcium channel were basically consistent with that of electrical signal channel. In addition, we have reported the infiltration and polarization of local inflammatory cells in the atrial of POAF at the tissue section level. Our study served as a new inspiration for the treatment of arrhythmic diseases and other ROS- and Ca²⁺- associated local illnesses.

Organoids are three-dimensional tissue analogues grown in vitro. Although they are not human organs in the strict sense, they can mimic the structure and function of tissues in vivo to the maximum extent, and have broad application prospects in the fields of organ development, personalized medicine, regenerative medicine, disease modeling, drug screening, gene editing, etc. There is even hope that organoids can replace experimental animals for preclinical testing, which will greatly shorten the cycle of preclinical testing and improve its efficiency. Nowadays, Matrigel remains the predominant substitute for organoid culture systems. At the same time, new extracellular matrix or inspired polymer materials with tunable and optimized biochemical and biophysical properties continue to emerge, which are of great significance for efficient and high-level cultivation of organoids. In this review, we critically evaluate how mechanobiological signaling dynamics at the cell-matrix interface inform the rational engineering of biomimetic extracellular matrices to achieve standardized and phenotypically regulated patient-derived organoid cultures. Then, we systematically classify hydrogel-based matrices encompassing natural, biohybrid, synthetic, protein-engineered and DNA crosslinked matrix systems by their biocompatibility and functional compatibility. Focusing on cancer oncogenesis and progression research, drug development and personalized medicine, we highlight biomimetic hydrogel innovations that recapitulate tumor organoids development. By summarizing the obstacles that hinder the development of organoid hydrogels, we hope to provide an outlook on the future directions for the development of organoid hydrogels and promote the application of organoids in the field of biomedicine.

A big diameter bioresorbable scaffold is expected to be used for treatment of vessel stenosis of children with congenital heart disease to adapt the growth characteristics of vessel of children and avoid the late adverse events of permanent stent implanted in children. However, it is challenging to fabricate a big diameter bioresorbable scaffold that is appropriate for percutaneous implantation with enough mechanical performance and can be smoothly delivered in children's small vessel. In this study, a novel iron big and bioresorbable Scaffold (BBS) for pulmonary artery stenosis of children with congenital cardiovascular diseases was fabricated and evaluated. The BBS was made of nitrided iron tube and processed by laser cutting and polishing. The testing results of radial strength, recoil, shortening, maximal expansion diameter and side-branch accessability illustrated the BBS has good mechanical performance. The animal study showed that the percentage of area stenosis of BBSs was 18.1 ± 8.6%, 20.2 ± 5.9% and 20.4 ± 6.1% at 28, 90 and 180 days after implantation in 17 rabbits, and no malposition, thrombus, dissection or tissue necrosis in the rabbit model was detected by micro-CT, STEM and histological examinations. An φ8 × 23 mm BBS was implanted into a 55-month-old child with left pulmonary stenosis, and multiple spiral CT was conducted. No lumen area loss appeared at 1- and 2-year follow-ups in this first-in-man study. It suggested that the BBS might be a new strategy for the therapy of pulmonary artery stenosis in children.

Intervertebral disc degeneration is a significant contributor to the development of spinal disorders. Previous studies have shown that the senescence of nucleus pulposus cells can worsen the degradation of intervertebral disks. Therefore, targeting the senescence of nucleus pulposus cells may be a promising therapeutic approach for the treatment of intervertebral disc degeneration. This study investigated the use of exosomes from hypoxic umbilical cord-derived mesenchymal stem cells to reverse nucleus pulposus cells senescence and delay intervertebral disc degeneration progression. MicroRNA sequencing of hypoxic umbilical cord-derived mesenchymal stem cells revealed the presence of functional microRNAs, with the p53 signalling pathway identified as a key factor. To enhance the release time of hypoxic umbilical cord-derived mesenchymal stem cells in vivo, hyaluronic acid methacryloyl hydrogel was used to load hypoxic umbilical cord-derived mesenchymal stem cells and create a sustained-release system. This system effectively repaired the degradation of the extracellular matrix, reversed nucleus pulposus cells senescence and alleviated intervertebral disc degeneration progression in a rat model. Overall, this study highlights the potential of hypoxic umbilical cord-derived mesenchymal stem cells in reducing nucleus pulposus cell senescence and suggests the possibility of combining it with a sustained-release system as a novel therapeutic strategy for intervertebral disc degeneration.

The immature state of in vitro engineered cartilage (IVEC) hinders its clinical translation, highlighting the need for optimized scaffold platforms and cultivation models. Our previous work demonstrated that Wharton's jelly (WJ) contains an extracellular matrix (ECM) whose composition closely resembles that of native cartilage and includes several bioactive factors that promote chondrogenic induction. Furthermore, earlier studies have shown that photo-crosslinkable hydrogels are ideal carrier scaffolds for cartilage tissue engineering and that bioreactors improve nutrient and waste exchange between scaffolds and the culture medium. Based on these findings, we employed a dynamic bioreactor in combination with a WJ-derived photo-crosslinkable hydrogel to enhance IVEC maturity. Our results indicate that the decellularized WJ matrix (DWJM) effectively retains its native chondrogenic ECM components and bioactive factors. The photo-crosslinkable ADWJM hydrogel-produced by modifying DWJM with methacrylate anhydride-demonstrated excellent gelation capacity as well as tunable rheological properties, swelling ratios and degradation rates across different DWJM concentrations. In addition, the ADWJM hydrogel exhibited outstanding biocompatibility by providing a favorable 3D microenvironment for chondrocyte survival and proliferation. Most importantly, the dynamic bioreactor markedly promoted IVEC maturation. Constructs cultured under dynamic conditions displayed increased thickness, wet weight and volume; enhanced mechanical strength; more typical lacunae structures; and uniform deposition of cartilage-specific ECM compared to constructs maintained in static conditions or within a static bioreactor. Moreover, in vivo subcutaneous implantation of IVEC in goats further validated these findings, as the implanted constructs exhibited cartilage components and mechanical properties closely resembling those of natural cartilage. These results offer a promising approach for enhancing IVEC maturity and support its future clinical translation.

Postmenopausal osteoporosis (PMOP) is a predominant form of clinical osteoporosis. It has led to significant health and social burdens for older patients. Reestablishing the balance between osteogenic and osteoclastic is a crucial strategy for treating PMOP. Curcumin (Cur), a naturally derived polyphenolic substance, has gained recognition as a viable option for treating osteoporosis. Despite its potential, the clinical use of Cur is hindered by its limited bioavailability and the presence of side effects. Nanoparticles modified with aspartic acid octapeptide (ASP8) exhibit a strong affinity for bone tissue, facilitating targeted delivery. This study presents novel acid-responsive zeolite imidazolate framework-8 (ZIF) nanoparticles modified with ASP8 and loaded with Cur (Cur@ZIF@ASP8, CZA). Upon delivery by this nanoparticle drug delivery system, Cur can effectively regulate bone homeostasis, offering a potential therapeutic strategy for osteoporosis. This study demonstrated that CZA nanoparticles could successfully transport Cur to bone tissue without significant toxicity. Furthermore, nanoparticles promote bone formation and inhibit osteoclast activity. They also modify the expression of related genes and proteins, such as OCN, ALP, CTSK and MMP9. Significant evaluations utilizing microcomputed tomography, Masson's staining, hematoxylin and eosin staining and immunofluorescence staining demonstrated that intravenous CZA administration in ovariectomized mice resulted in bone destruction while simultaneously reducing overall bone loss. In conclusion, CZA nanoparticles hold promise as a therapeutic option for osteoporosis.