Regenerative Biomaterials最新文献

A healthy endometrium is crucial for embryo implantation and pregnancy maintenance. Thin endometrium, reduced glands and fibrosis resulting from infection or mechanical injury, are the primary causes of long-term infertility and poor pregnancy outcomes. Unfortunately, these issues have not been resolved by conventional clinical methods. Keratinocyte growth factor-2 (KGF-2) is an epithelial mitogen that regulates proliferation and migration of epithelial cells. Nitric oxide (NO) is involved in maintaining vascular homeostasis and angiogenesis. Poloxamer-407 (P) hydrogel is a promising topical drug delivery system due to its excellent solution-gel transition properties in response to body temperature. In this study, therapeutic NO gas was first prepared into stabilized microbubbles (NO-MBs). Subsequently, KGF-2 and NO-MBs were encapsulated into micelles of P hydrogel to form a multifunctional temperature-sensitive (28.9-31.8°C) hydrogel (KGF-NO-MBs-P hydrogel). This hydrogel not only exhibited suitable apparent viscosity, bio-adhesive and mechanical properties for application in situ but also showed sustained release of KGF-2 and NO. In vivo, KGF-NO-MBs-P hydrogel effectively restored endometrial morphology, increased the number of glands and endometrial thickness, reversed endometrial fibrosis and improved pregnancy outcomes by synergistic regulation of KGF-2 and NO. Repair of endometrial injury was closely related to promoting neovascularization, inducing endometrial cell proliferation and epithelialization, inhibiting apoptosis and inflammation and balancing collagen subtypes. Therefore, KGF-NO-MBs-P hydrogel may be useful in promoting endometrial regeneration and fertility restoration through in situ microinjection. This study represented a convenient, safe and promising method for repair of endometrial injury.

The development of advanced hydrogel dressings that integrate biocompatibility, antioxidant activity and dynamic adaptability remains critical for addressing the complex demands of modern wound management. In this study, we designed a multinetwork hydrogel (GHrCT) through synergistic strategies: A robust covalent network is constructed through photocrosslinked gelatin methacryloyl, while a secondary dynamic network formed via hydrogen bonds and electrostatic interactions is established among dopamine-modified hyaluronic acid (HD), tannic acid (TA) and recombinant collagen type III (rhCol III). Through a series of experiments, we systematically characterized key properties of the hydrogel, including its microscopic morphology, swelling behavior, rheological characteristics and mechanical strength. Biocompatibility was assessed through in vitro assays, while the wound healing efficacy was validated in vivo. In vitro experiments demonstrated that GHrCT hydrogel has interconnected porosity, excellent hemocompatibility and good cytocompatibility. Its strong antioxidant capacity (DPPH scavenging rate of 88.63%) can cope with the excessive accumulation of ROS in the wound microenvironment and reduce the damage caused by oxidative stress. Further, in vivo experiments showed that it could improve wound healing therapy by accelerating epithelial re-formation, angiogenesis and collagen deposition at full-thickness skin defects in SD rats. This study presents a strategy for functionalizing natural polymer hydrogels to enhance wound repair through the synergistic effect of scavenging ROS and promoting repair.

Enhancing the regeneration of cartilage defects remains a formidable challenge, as the dysregulated microenvironment and its crosstalk with chondrocytes play pivotal roles in impairing regeneration. In this study, we proposed a natural plant polysaccharides-derived injectable hydrogel (Exos@EKM) for adapting to irregular cartilage defects. By encapsulating stem cell-derived exosomes (Exos) into polyphenol modified methacryloylated konjac glucomannan (EKM), this hydrogel exerting a potent biological synergistic effect. First, the hydrogel demonstrates favorable biocompatibility and has the capability to modulate cellular behavior through the delivery of Exos. Additionally, it demonstrates significant chondroprotective effects and reprograms macrophages to the pro-healing state. Furthermore, konjac glucomannan and polyphenols in hydrogel synergistically activate the endogenous antioxidant capacity of chondrocytes through nuclear factor erythroid 2-related factor 2 (NRF2)-dependent pathway, thereby optimizing the biological function of Exos in regulating chondrocyte behavior and maintaining normal cartilage metabolism. In a full-thickness cartilage defect model, in vivo implantation of Exos@EKM hydrogel successfully improved cartilage regeneration and ultimately restoring knee joint functionalities. Overall, this combination of natural konjac glucomannan, polyphenols and Exos has resulted in the promotion the harmony between the microenvironment, chondrocyte and ECM. This study offers a novel approach for designing biomaterials for cartilage tissue engineering.

[This corrects the article DOI: 10.1093/rb/rbaf011.].

Titanium-based materials are commonly utilized in bone tissue repair due to their exceptional physical and chemical properties. Surface modification of titanium dioxide (TiO₂) nanotubes effectively modulates cellular osteo-adipogenic balance, thereby promoting stem cells osteogenic differentiation. Sterol regulatory element-binding protein 1 (SREBP1), a pivotal transcriptional factor involved in lipid metabolism, plays a significant role in mechanotransduction. Nevertheless, it remains unclear whether SREBP1 also exerts a crucial influence on regulating the differentiation of bone marrow mesenchymal stem cells induced by TiO₂ nanotubes and its involvement in mechanotransduction during this process. Therefore, this study aimed to investigate the mechanistic role of SREBP1 in cell differentiation induced by TiO₂ nanotubes. The results demonstrated that TiO₂ nanotubes exerted regulatory control over SREBP1, enhancing the expression of regulatory factors that induce osteogenic differentiation while suppressing the expression of marker genes associated with adipogenic differentiation. Simultaneously, this regulation inhibited the transcription and translation of pivotal enzymes involved in fatty acid anabolism. Activated by the nanostructure, Lipin1 acted as an upstream target that negatively regulated the expression of SREBP1. The signaling pathway involving Lipin1/SREBP1 was regulated by stress fibers responding to mechanotransduction induced by TiO₂ nanotubes. Consequently, SREBP1 serves as a critical regulatory factor linking mechanotransduction mediated by TiO₂ nanotubes and maintaining homeostasis between stem cell osteo-adipogenic differentiation processes. This provides novel insights for designing biomaterials for bone repair.

PDAC cells perceive and respond to mechanical stimuli in their extracellular microenvironments (ECMs), playing a crucial role in chemoresistance, while the underlying mechanisms are not fully understood. The progression of various solid tumors is accompanied by metabolic reprogramming. RNA-seq and untargeted metabolomics analysis indicated that stiff substrate may regulate lipid metabolism. The expression of lipogenesis-related genes, including fatty acid synthase (FASN), ATP citrate lyase (ACLY) and acetyl-CoA carboxylase (ACC) was elevated, also the sum of lipid droplets and the triglyceride content. Herein, whether lipid metabolism is involved in matrix stiffness-mediated PDAC chemoresistance and the in-depth mechanism were further explored. Rescue with C75 (FASN inhibitor) validated that fatty acid synthesis participated in matrix stiffness-regulated chemoresistance. Simultaneously, the SCD1 expression was reinforced, consistent with PDAC tissues. The concurrent restraint SCD1 (with inhibitor CAY10566 or shSCD1) and addition of oleic acid confirmed that SCD1 is involved in matrix stiffness-mediated chemoresistance through fatty acid synthesis. In addition, Piezo1 regulated SCD1 expression through the augmentation of Ca²⁺ influx, and the PI3K/Akt pathway participated in this process. Taken together, our research sheds light on lipid metabolism exerts an essential role during matrix stiffness-mediated chemoresistance through Piezo1-elicited elevation of SCD1. Our findings delivered a supplement PDAC chemoresistance mechanism mediated by matrix stiffness from the perspective of lipid metabolic reprogramming, and provided a novel strategy for improving clinical therapies.

Research on myogenesis and myogenic pathologies has garnered significant attention in recent years. However, traditional in vitro modeling approaches have struggled to fully replicate the complex functions of skeletal muscle. This limitation is primarily due to the insufficient reconstruction of the muscle tissue microenvironment and the role of physical cues in regulating muscle cell activity. Recent studies have highlighted the importance of the microenvironment, which includes cells, extracellular matrix (ECM) and cytokines, in influencing myogenesis, regeneration and inflammation. This review focuses on advances in skeletal muscle construction toward a complete microphysiological system, such as organoids and muscle-on-a-chip technology, as well as innovative interventions like bioprinting and electrical stimulation. These advancements have enabled researchers to restore functional skeletal muscle tissue, bringing us closer to achieving a fully functional microphysiological system. Compared to traditional models, these systems allow for the collection of more comprehensive data, providing insights across multiple scales. Researchers can now study skeletal muscle and disease models in vitro with increased precision, enabling more advanced research into the physiological and biochemical cues affecting skeletal muscle activity. With these advancements, new applications are emerging, including drug screening, disease modeling and the development of artificial tissues. Progression in this field holds great promise for advancing our understanding of skeletal muscle function and its associated pathologies, offering potential therapeutic solutions for a variety of muscle-related diseases.

Fibroblast activation promotes remodeling of the extracellular matrix (ECM), and the fibrotic remodeling ECM further stimulating fibroblast activation and advancing pulmonary fibrosis (PF). syndecan-4 (SDC4) is the key mediator of ECM-cell signaling, but its action in PF remains unclear. Using decellularized lung ECM (dECM), this study found that fibrotic ECM enhanced fibroblast activation via SDC4-regulated integrin-αvβ1 expression and activation, and FAK/AKT phosphorylation. Meanwhile, SDC4 knockdown inhibited fibrotic ECM-induced TGF-β1 synthesis and PKCα activation. A Duolink-proximity ligation assay confirmed extracellular interactions between SDC4 and integrin-αvβ1, and the SDC4 blocking antibody Anti-SDC4_(93-121) prevented this interaction, resulting in an effect consistent with knockdown of SDC4. The interfering peptide SDC4_87-131 diminished the interaction between SDC4 and integrin-αvβ1, subsequently inhibited the activation of FAK/AKT, Smad2/3 and PKCα/NF-κB pathways and exhibited anti-PF activity comparable to that of SDC4 knockdown and Anti-SDC4_(93-121). A docking mode of SDC4_87-131 with the Calf-1/Calf-2 domain of integrin-αv was constructed by using the AlphaFold2-Multimer model, and peptide design was performed to obtain a novel polypeptide chain CS-9 with enhanced anti-PF effect. This study found that the biomaterial, lung ECM, regulates fibroblast activation through the collaboration of SDC4 and integrin-αvβ1, and obtained a novel SDC4_87-131-derived peptide that may prevent fibrotic ECM from promoting PF.

Pancreatic cancer is one of the most lethal malignancies, largely due to the limitations of current imaging technologies and treatment strategies, which hinder early diagnosis and effective disease management. Achieving precise theranostics for pancreatic cancer has become a priority, and recent advances have focused on the development of novel nanomaterials with enhanced imaging capabilities and therapeutic functionalities. These nanomaterials, through surface modifications, can significantly improve the targeting and precision of both diagnostic and therapeutic applications. Recent progress in nanomaterial design has led to the creation of multifunctional platforms that not only enhance imaging but also improve therapeutic efficacy. These innovations have spurred significant interest in the application of nanomaterials for pancreatic cancer theranostics. In this review, we highlight recent developments in the use of nanomaterials for diagnostic imaging and precision therapy in pancreatic cancer. Various applications, including magnetic, optical, acoustic and radiological imaging, as well as therapeutic strategies such as chemodynamic therapy, light-based therapy, sonodynamic therapy and gene therapy, are discussed. Despite the promising potential of these nanomaterials, several challenges remain. These include optimizing targeting mechanisms, enhancing nanomaterial stability in vivo, overcoming biological barriers and ensuring safe and effective translation to clinical settings. Addressing these challenges will require further research and innovation. With sustained efforts, nanomaterial-assisted diagnostics and therapeutics have the potential to revolutionize the management of pancreatic cancer, ultimately improving early detection and treatment outcomes. Continued progress in this field could significantly enhance the overall prognosis for pancreatic cancer patients, making it a more treatable disease in the future.

Natural bone is a naturally mineralized material with a nonhomogeneous porous structure, which is difficult to construct using conventional manufacturing methods. Triply periodic minimal surfaces (TPMS) have emerged as an excellent solution in recent years for constructing porous artificial bone structures, characterized by smooth surfaces, highly interconnected porous structures and mathematically controllable geometries. In this work, digital light processing (DLP) printing technology was used to construct a nonhomogeneous TPMS structure with strontium-doping 13-93 bioactive glass (Sr@BG) prepared by fusion method. The heterogeneous scaffolds were obtained by integrating high-strength I-wrapped package (I) and high-permeability Gyroid (G) units behaving a sufficient compressive strength of 5.8 ± 0.6 MPa, a porosity of ∼63% and a permeability of 0.97 × 10^-8 m², which matched the microstructural parameters of cancellous bone. Meanwhile, the biomimetic structure and Sr doping could cooperatively promote the adhesion, proliferation and differentiation of bone mesenchymal stem cells (BMSCs). In addition, the osteogenic ability of IG scaffolds was verified in rabbit's femoral condylar defect. In general, heterogeneous IG scaffolds possess desirable bioactivity and mechanical property which meet the functional and structural requirements of bone regeneration.