Regenerative Biomaterials最新文献

Extracorporeal shockwave (ESW) therapy is a noninvasive physical intervention widely applied in orthopedics for the treatment of musculoskeletal disorders such as plantar fasciitis, osteoarthritis, delayed fracture healing and tendinopathies. In recent years, accumulating evidence has suggested that ESW may also have beneficial effects on bone regeneration and local bone mineral density, particularly under osteoporotic conditions. However, the precise biological mechanisms underlying these effects remain incompletely elucidated. In this study, we systematically investigated the effects of different radial extracorporeal shockwave (r-ESW) intensities on osteoblasts derived from osteoporotic bone (OPOB), with a specific focus on osteogenic activity and the involvement of endoplasmic reticulum (ER) stress. Our in vitro results demonstrated that moderate-intensity r-ESW (3 bar) significantly enhanced osteoblast proliferation, upregulated the expression of osteogenic markers including Runx2, Col I, OPN and OCN and promoted matrix mineralization. Mechanistically, this was accompanied by mild ER stress and activation of the PERK-eIF2α-ATF4 signaling pathway, which contributed to improved osteogenic differentiation and alleviated cellular senescence. In contrast, high-intensity stimulation (5 bar) induced excessive ER stress, calcium overload and subsequent apoptosis and necrosis, ultimately impairing osteogenesis. Furthermore, in an ovariectomy (OVX)-induced osteoporotic rat model, 3 bar r-ESW treatment effectively increased bone mass, stimulated new bone formation and decreased osteoclast activity and senescence-associated markers in vivo. These findings collectively highlight the potential of moderate-intensity r-ESW as a promising nonpharmacological strategy for osteoporosis management, providing novel insights into the modulation of ER stress as a therapeutic target in OPOB remodeling.

Anoxia remains a challenging problem to effective graft implantation in bone tissue engineering for managing large-size bone defects. One promising strategy is to provide immediate oxygen required for cell viability and graft maturation by introducing oxygen-generating biomaterials. In this study, we present a novel composite oxygen-generating scaffold by integrating oxygen-generating microspheres (OMs) comprised of emulsified calcium peroxides (CPOs) encapsulated in poly (lactic-co-glycolic acid; PLGA) into the gelatin methacryloyl (GelMA) hydrogel. The in vitro results reveal that the scaffold encapsulating 2% (w/v) OMs (OM@GelMA) mildly sustained oxygen production for approximately 16 days, and hence, established hypoxic niches with low oxygen tension (10-46 mmHg) under anoxic culture condition (0.2% oxygen) for the viability of bone marrow-derived mesenchymal stem cells (BMSCs) and their enhanced osteogenic differentiation, which may be induced by activation of HIF-1/β-catenin signaling pathway by the compatibly hypoxic level as one of the underlying molecular mechanisms verified via transcriptome sequencing, western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) tests on in vitro samples. Moreover, the oxygen-generating hydrogel could enhance angiogenesis of human umbilical vein endothelial cells (HUVECs) under anoxia by preserving cell viability, accelerating cell migration, promoting tube formation and activating angiogenic genes and proteins expression. In vivo studies using rat cranial critical-size defect models demonstrated that OM@GelMA significantly enhanced bone regeneration, effectively promoting bone defect repair. In summary, the OM@GelMA, as a novel endogenously oxygen-generating scaffold, holds great potential to facilitate bone tissue regeneration subject to oxygen-deprived scenarios. This study provides a new insight for future research and clinical applications in bone tissue engineering, particularly for large bone defect repair.

Concentrated growth factors (CGFs) hold great potentials for postoperative bone regeneration. This study attempted to investigate the effect of CGF scaffolds on guided bone regeneration after microsurgical endodontic surgery on teeth with periapical lesions. Microsurgical endodontic surgery was performed on 68 teeth with periapical lesions after complete root canal therapy. Autologous CGFs were administered to 38 teeth (the experimental group) while the remaining teeth received no CGF (the control group). The patients were followed for an average of 18 months. Postoperative pain, swelling and the duration were compared between the two groups. The bone volume ratios were quantitatively measured and statistically analyzed with Mimics software. Compared with the control group, the experimental group reported a lower incidence and shorter duration of postoperative pain and swelling, with mild to moderate swelling in the former and mild swelling in the latter. Both groups demonstrated good postoperative wound healing. The experimental group reported a significant reduction in bone volume ratio at postoperative month 3 (P < 0.05). Both groups reported a most active period of new bone formation between 3 and 6 postoperative months, after which the formation rate stabilized, and an insignificant decrease in bone volume ratio from 6 to 18 postoperative months. By 18 postoperative months, the bone defects were minimized, with the experimental group showing faster new bone formation. Marked differences in bone volume reduction and volume reduction rate were found between the two groups, with more significant bone defect repair and bone regeneration in the experimental group. These results evidence that in guided bone regeneration, the use of CGF scaffolds for teeth with periapical lesions can alleviate postoperative pain and swelling, promote faster bone defect repair and ensure satisfactory incision healing, highlighting it as a promising clinical approach.

Periodontitis, a chronic inflammatory disorder primarily induced by bacterial infection and exacerbated by excessive oxidative stress, leads to the destruction of alveolar bone. Diabetes mellitus intensifies this oxidative stress in periodontal tissues and disrupts the oral microbiome, thereby aggravating periodontal conditions and complicating the management of periodontitis. The development of materials that possess comprehensive therapeutic effects, including antibacterial, antioxidant and osteogenic properties, for the treatment of diabetic periodontitis (DP) remains at the forefront of research. In this study, we introduced a copper hydrogen phosphate (CuHP) composite hydrogel, which exhibited multi-enzymatic activities at varying pH levels. This hydrogel was synthesized by encapsulating CuHP within a commercially available sodium alginate (SA) matrix. In vitro analyses explored the pH-responsive enzymatic activities, biocompatibility and the antioxidant, osteogenic and antibacterial properties of the resultant SA/CuHP composite hydrogel. At neutral pH, the hydrogel primarily exhibited catalase-like activity, providing it with antioxidant capabilities that reduced the inhibitory effects of oxidative stress on osteogenesis in bone marrow mesenchymal stem cells. In mildly acidic conditions, the hydrogel displayed peroxidase-like activity, catalysing the production of more potent reactive oxygen species and exhibiting significant antibacterial efficacy against Aggregatibacter actinomycetemcomitans. Furthermore, the SA/CuHP hydrogel continuously released copper ions, which synergistically enhance its osteogenic and antimicrobial efficacies. In vivo studies demonstrated that this composite hydrogel significantly inhibited bacterial growth and promoted bone regeneration in a rat model of DP. These findings suggest that the SA/CuHP hydrogel holds substantial potential for the treatment of periodontitis in patients with diabetes.

The treatment of osteoporosis is urgently needed in the clinic. Hydroxyapatite (HAP) has a bone-inducing ability on osteogenic differentiation. Especially, the presence of strontium component in HAP nanoparticles may improve the positive effect on bone regeneration and avoid undesirable bone resorption. However, the incorporating concentrations of strontium still need to be elucidated to balance the osteogenic function and side effects. Herein, a series of strontium-incorporated HAP nanocomposites (Srx-HAP) with different Sr incorporating molar ratio concentrations (0%, 1%, 2%, 5%, 10%, 20%, 50%, 80% and 100%) have been prepared by a simple hydrothermal route. The Srx-HAP samples exhibited uniform and well-dispersed rod-like morphology, mesoporous structure, eminent degradability and good biocompatibility. In particular, Sr20-HAP exhibited prominent advantages in osteogenic differentiation and mineralization of pre-osteoblasts cell line MC3T3-E1. Sr20-HAP nanoparticles were highly effective in enhancing the bone formation in the rat model of postmenopausal osteoporosis compared to the ovariectomy group. In addition, Sr20-HAP nanoparticles could regulate macrophage polarization to M2 type in vivo and in vitro, providing an anti-inflammatory bone microenvironment and promoting bone repair and angiogenesis. This study provides a new insight of strontium-incorporated hydroxyapatite nanoparticles as competent anti-osteoporotic biomaterials for bone formation.

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.