Aug 2026· Advanced Healthcare Materials· pp.
e71513
· 0 citations· 36 references
Medicine
TL;DR
In vivo studies in diabetic Sprague-Dawley rats model demonstrated that CC-pMnO2-Vet@PNAA established a coordinated immune-mechanical microenvironment, achieving rapid and scar-free wound healing.
Abstract
Fibrosis remains a major challenge in wound repair due to the dual role of fibroblast in tissue regeneration and fibrotic deposition. Early fibroblast activation supports wound closure, whereas sustained activation during remodeling drives fibrosis, making precise temporal regulation a key challenge in advanced wound repair biomaterials design. Herein, a hierarchical hydrogel (CC-pMnO2-Vet@PNAA) was engineered to spatiotemporally regulate fibroblast behavior, achieving fibrosis suppression without compromising wound healing rate. The hydrogel matrix was constructed by reversibly reassembling irregular thermo-responsive PNAA microgels (LCST∼45°C) with caffeic acid (CA)-modified chitosan (CS-CA) via dynamic boronate ester linkages. Based on a hierarchical physical encapsulation architecture, CC-pMnO2-Vet@PNAA enabled the highly controllable, stage-specific release of polydopamine-modified MnO2 (pMnO2) and verteporfin nanoparticles (Vet NPs). During the early inflammatory phase, the hydrogel rapidly disassembled in response to pathological cues (low pH, high ROS), releasing pMnO2 and CS-CA to synergistically eliminate bacteria (>99%), neutralize oxidative stress, and restore immune homeostasis. Subsequently, in the remodeling phase, localized near-infrared (NIR) irradiation triggered microgel contraction for the on-demand release of Vet NPs, suppressing YAP signaling in fibroblasts to rebalance the mechanical microenvironment. In vivo studies in diabetic Sprague-Dawley (SD) rats model demonstrated that CC-pMnO2-Vet@PNAA established a coordinated immune-mechanical microenvironment, achieving rapid and scar-free wound healing.
Abnormal mechanical stimulation drives fibrotic scar formation in active wounds by sustaining mechanotransduction, promoting apoptotic cell accumulation and pro-fibrotic amplification that constrain functional regeneration. To address this challenge, we developed a mechanically adaptive hydrogel patch (Gel/VP) through the integration of an interpenetrating polymer network and CNC@PDA@ZIF8 dynamic nanofillers, in which the interpenetrating network provides structural load-bearing and adaptive deformation, while the nanofillers form a force-induced, reconfigurable dissipative network via hydrogen bonding and π-π interactions, collectively dissipating tensile energy upon pre-stretched application, establishing a reverse mechanical buffer at the wound interface, suppressing sustained Piezo1-YAP activation, restoring macrophage efferocytosis-mediated apoptotic cell clearance, and ultimately limiting fibrotic scar formation. The interpenetrating architecture endows the patch with a tunable elastic window matched to the mechanical environment of skin (elastic modulus of 7-15 kPa with twofold extensibility). Under reverse mechanical buffering, the macrophage phagocytic rate increases from 22.50% to 64.50%, significantly enhancing apoptotic cell clearance. In vivo, the patch achieves near-complete wound closure (>95%) within two weeks, markedly reduces α-SMA+ myofibroblast accumulation, promotes ordered collagen remodeling, and substantially decreases scar formation. Overall, by leveraging material-mediated reverse stress buffering to restore macrophage efferocytosis, this study targets apoptotic cell clearance at an early stage of fibrosis and provides a robust antifibrotic material strategy for the functional regeneration of active wounds. STATEMENT OF SIGNIFICANCE: Abnormal mechanical stretching during wound healing is a key yet underrecognized driver of fibrotic scar formation, and current therapies rarely address this physical cue. Here, we develop a stress-adapted hydrogel patch that forms a "reverse mechanical buffer" under pre-stretch, actively redistributing tensile forces at the wound interface. This buffering suppresses mechanotransduction (Piezo1-YAP signaling) while restoring macrophage-mediated clearance of apoptotic cells. By integrating an interpenetrating polymer network with dynamic nanofillers, the material achieves adaptive energy dissipation and mechanical compatibility with skin. This work establishes a mechanically guided, immunomodulatory approach to limit fibrosis, offering a promising biomaterials strategy for scarless healing and functional tissue regeneration.
Lina Huang, Chao Lin, Xiang Cui et al.· Acta Biomaterialia· 0 citations
Healing of diabetic wounds is severely hindered by a persistent vicious cycle of bacterial infection and metabolic disorders. Pathological microenvironments, characterized by high glucose levels and excessive reactive oxygen species (ROS), exacerbate chronic inflammation and impede the transition of macrophages toward a pro-healing phenotype. To address these challenges, we developed a multi-stimuli-responsive composite hydrogel platform (GHFA/Cu@TA) by integrating fulvic acid (FA) and copper-tannic acid nanozymes (Cu@TA NPs) into a dynamic covalent network composed of methacrylated gelatin (GelMA) and phenylboronic acid-modified hyaluronic acid (HA-PBA). This platform implements a self-feedback mechanism to restore metabolic homeostasis: glucose-triggered release of Cu@TA NPs effectively scavenges microenvironmental ROS to drive tissue microenvironment remodeling, thereby decelerating responsive hydrogel degradation upon homeostasis normalization to ensure synchronized on-demand drug delivery. Intelligently released FA promotes M2 macrophage polarization to reshape the immune microenvironment, while Cu@TA NPs achieve photothermal biofilm eradication under near-infrared (NIR) light. This "metabolic sensing-feedback regulation-homeostasis reconstruction" strategy offers a distinct therapeutic framework for addressing diabetic wound and contributes to the rational design of bioactive dressings with stimuli responsiveness.
Na Yang, Lingling Tang, Huanghe Zeng et al.· International Journal of Bio...· 0 citations
The diabetic-infected wound microenvironment, marked by elevated reactive oxygen species (ROS) levels, ongoing inflammation, and defective angiogenesis, interferes with the normal wound healing cascade and contributes to delayed and treatment-resistant repair. However, most existing wound dressings lack the capability to dynamically adapt to these spatiotemporally evolving conditions. Herein, a smart and microenvironment-programmable PVH-ST hydrogel is developed to achieve phased and spatiotemporally coordinated regulation of diabetic-infected wound healing. The hydrogel is engineered by integrating strontium (Sr)-tannic acid (ST) nanoparticles into a polyvinyl alcohol (PVA) and hyaluronic acid (HA) matrix through a boric acid-mediated multilevel dynamic crosslinking network, endowing the system with mechanical robustness suitable for daily motion. Upon wound occurrence, the PVH-ST hydrogel rapidly induces hemostasis and establishes a bioactive provisional matrix. In response to the ROS-enriched infected microenvironment, the dynamic borate bonds undergo on-demand dissociation, triggering controlled release of ST nanoparticles. Released ST nanoparticles integrate antibacterial and antioxidant functions and reduce inflammatory burden via modulation of NF-κB signaling and skewing macrophages toward an M2 pro-regenerative state. Concurrently, the sustained release of Sr2+ ions activates VEGF-associated angiogenic signaling and epithelialization pathways, thereby promoting vascularization and epithelial reconstruction for diabetic-infected wounds.
Aihong Chen, Xiaoran Liu, Xiaoqiang Wang et al.· Advanced Healthcare Material...· 0 citations
Chronic diabetic wounds require continuous modulation of the hyperglycemia-induced pathological microenvironment. Although glucose-responsive biomaterials show promise for diabetic wound treatment, intelligent wound management with tissue specificity and multifactorial repair capacity remains urgently needed. Here, we develop a tissue-homologous, glucose-responsive hydrogel based on epidermis-derived keratin functionalized with phenylboronic acid (Keratin-PBA), which is crosslinked with oxidized sodium alginate (OSA) to form a double-network hydrogel (cOK) and integrated with bioactive nanomicelles for adaptive wound microenvironment regulation. Co-assembled nanomicelles (OA-PG NMs), composed of oleanolic acid (OA) and propyl gallate (PG), exhibit glucose-triggered release and complementary bioactivities targeting oxidative stress, inflammation, macrophage polarization, angiogenesis, fibroblast behavior, antibacterial activity, and MMP regulation. Notably, OA promotes angiogenesis via the TGR5-Akt-eNOS-NO signaling pathway. The resulting cOK@NM hydrogel enables spatiotemporally controlled nanomicelle release and significantly accelerates diabetic wound healing in vivo, as evidenced by rapid wound closure, enhanced M2 macrophage polarization, robust neovascularization, improved collagen remodeling, reduced AGEs, broad-spectrum antibacterial effects against E. coli and S. aureus, and increased granulation tissue formation. This work presents a tissue-homologous, intelligently adaptive platform integrating intrinsic regenerative bioactivity with glucose-responsive therapeutic adaptability.
Luyao Wang, Shengchao Wang, I. Ullah et al.· Small· 0 citations
ABSTRACT During skin wound healing, complex interactions among multiple cell types and dynamic phase evolution make it difficult for biomaterial scaffolds to balance late‐healing and over‐healing, often resulting in delayed wound healing, persistent inflammatory responses, and hypertrophic scars due to spatiotemporal mismatch. Precise regulation of fibroblast‐to‐myofibroblast transformation and macrophage polarization is therefore essential yet challenging. Fibroblast activation protein (FAP) has been identified as a key bio‐cue in pulmonary and hepatic fibrosis, but whether FAP‐targeting peptide (FTP) within a biomimetic system can address this dilemma remains unclear. Here, a methacrylated hyaluronic acid hydrogel microneedle patch (CAF@MN) integrating a dual‐targeting biomimetic nanozyme system (Cu‐CeO2@ABs‐FTP) modified with apoptotic bodies (ABs) membranes and FTP is developed. Cu‐CeO2 nanocomposites activate fibroblast functions and exhibit anti‐inflammatory, antibacterial, antioxidant, and pro‐angiogenic activities. The ABs membrane enables macrophage targeting and M2 polarization, while FTP specifically modulates myofibroblast activation. The microneedle architecture enhances deep local delivery and nanozyme utilization. In mouse and rabbit full‐phase wound models, the system achieves accelerated wound healing, reduced inflammation, and attenuated hypertrophic scars. Single‐cell RNA sequencing further elucidates the dual‐targeted regulatory mechanisms underlying anti‐inflammation and scar suppression.
Hongyi Zhang, Jinwei Li, S. Hua et al.· Advancement of science· 0 citations
Effective tissue regeneration requires precise spatiotemporal therapeutic delivery while maintaining scaffold mechanical integrity, which remains a major challenge in regenerative medicine. Here, we present an ultrasound (US)-activated tissue regeneration platform based on engineered osteogenic microbubbles (MMB-BMPs) embedded in a dynamic hyaluronic acid hydrogel (dHA), forming a mechanically robust scaffold (dHAMBH). Upon repeated US stimulation at the resonant frequency, MMB-BMPs underwent stable oscillation within the hydrogel, enabling stepwise, on-demand release of iron oxide nanoparticles (IONPs) and bone morphogenetic protein-2 (BMP-2), while maintaining scaffold integrity after multiple stimulations cycles. This controlled co-delivery enhances osteogenic differentiation of human bone marrow-derived mesenchymal stromal cells (hMSCs). In a mouse critical-sized calvarial defect model, the dHAMBH hydrogel combined with US stimulation accelerated bone regeneration, achieving a 1.7-fold increase in new bone volume compared with the non-US stimulated control. Overall, this work establishes a US-activated platform that enables precise, repeatable therapeutic delivery to enhance tissue regeneration.
Lili Ren, Jingyi Su, Yuxuan Chen et al.· Nano Reseach· 0 citations
