Zwitterionic hydrogels, although highly biocompatible, are widely regarded as mechanically fragile, with typical tensile strengths below 0.1 MPa, which restricts their use in load-bearing applications. Here, we address this limitation by integrating a polyzwitterionic network with a poly(vinyl alcohol) (PVA) network through high-speed pregelation agitation that enhances chain entanglement and induces flow orientation. By exploiting the salt-driven conformational transition of zwitterionic chains, a controlled salting-out step generates uniformly dispersed nanoscale microdomains that act as reversible energy-dissipating units. At the same time, balanced hydrogen bonding between the two networks moderates PVA crystallinity, limiting embrittlement while preserving elasticity. The resulting double-network hydrogel shows an elongation of 890% and a toughness of 18.75 MJ m-3, representing a high combination of stiffness and toughness among zwitterionic-PVA hydrogels reported so far. Beyond materials optimization, this study demonstrates how molecular-scale chain hydration and collapse govern macroscopic mechanical reinforcement. These findings suggest that zwitterionic components can function as effective toughening motifs rather than mechanical liabilities and provide a cross-scale design principle for adaptive, high-strength hydrogels.

Critical-sized cranial defects present two sequential clinical challenges. These include an acute need for rapid hemostasis and a long-term requirement for vascularized bone regeneration. Current implants fail to address these sequential demands. To overcome this limitation, a bone marrow-mimetic composite hydrogel (FE-PDA@Fib/Gel-TG) is engineered. This system integrates transglutaminase crosslinked gelatin, rigid polydopamine-coated hydroxyapatite/poly(L-lactic acid) (HAp/PLLA) short fibers, and cell-free fat extract (FE). These components together recapitulate key biochemical and biomechanical features of native bone marrow. The hierarchically designed scaffold immediately achieves hemostasis through fiber-mediated mechanical sealing and catechol-assisted clot stabilization. Furthermore, the sustained release of FE establishes a pro-regenerative microenvironment. This milieu significantly enhances cell recruitment, endothelial network formation, and osteogenic differentiation. It also promotes heterotypic crosstalk between endothelial and osteoprogenitor cells. Transcriptomic analyses reveal that this vascular-bone coupling is driven by the convergent activation of VEGF/VEGFR-PI3K-AKT signaling pathways. In a critical-sized calvarial defect model, the hydrogel actively steers macrophage polarization toward an anti-inflammatory phenotype. Consequently, it induces the robust regeneration of morphologically mature, highly vascularized bone tissue. By successfully coupling rapid hemostatic control with spatiotemporally programmed osteo-angiogenesis, this multifunctional biomimetic platform represents a highly translatable advancement for effective cranial defect repair.

Despite extensive exploration of gelatin methacryloyl (GelMA)-based hydrogels for bone tissue engineering, their clinical translation is hindered by a critical trade-off: poor precursor stability leads to rapid sedimentation of bioactive fillers like hydroxyapatite (HAp), while formulations optimized for injectability often sacrifice mechanical integrity or handling precision. To overcome this challenge, we report a rheologically engineered, injectable composite hydrogel scaffold that integrates unmodified gelatin as a thermoresponsive viscosity modulator into a GelMA/HAp matrix. The incorporation of gelatin yields a stable, paste-like precursor at physiological temperature, which effectively prevents HAp sedimentation and enables precise, filamentous extrusion. Subsequent UV crosslinking locks the homogeneous structure in place, resulting in a mechanically robust scaffold with significantly enhanced compressive modulus. In vitro studies demonstrate that this biomimetic microenvironment not only supports high viability and proliferation of bone marrow stromal cells (BMSCs) but also potently enhances their osteogenic differentiation, as evidenced by upregulated alkaline phosphatase activity, Runx2 expression, and matrix mineralization. This simple, one-step strategy successfully reconciles injectability, structural fidelity, and bioactivity, offering a highly promising and clinically translatable platform for minimally invasive bone regeneration.

The regeneration of diabetic bone defects faces significant challenges due to glycemic fluctuations, reactive oxygen species (ROS), and chronic inflammation. A combined diagnostic and therapeutic strategy utilizing advanced visualization techniques enables monitoring of bone inflammation and implant degradation, facilitating timely and precise interventions to enhance bone repair. This study developed a multifunctional diagnostic and therapeutic scaffold (SrHA/IH/GOx@G) using 3D printing technology. The scaffold incorporates an "all-in-one" nanofluorescent probe (ICG@HMnO2), Sr-doped hydroxyapatite (SrHA), methacrylated gelatin (GelMA), and glucose oxidase (GOx). GOx catalyzes glucose and oxygen into gluconic acid and H2O2, while H2O2 is scavenged by ICG@HMnO2, releasing Mn2+ for magnetic resonance imaging (MRI) and ICG for near-infrared (NIR) imaging. The scaffold tracks inflammation at bone defect sites for 14 days and monitors scaffold degradation in situ for up to 8 weeks. Moreover, releasing Sr and Ca ions from the scaffold promotes osteogenic differentiation and angiogenesis, significantly accelerating diabetic bone repair. This scaffold combines advanced diagnostic imaging, real-time visualization, and therapeutic effects, offering a promising integrated strategy for treating diabetic bone defects with diagnostic and therapeutic applications.

The repair of traumatic bone defects presents high demands for advanced biomaterials that can simultaneously provide anatomical conformability, dynamic mechanical stimulation, and stable fixation. Herein, a smart bandage system comprising a bilayer actuating substrate and a photothermally responsive 3D-printed hydrogel scaffold is engineered. The bilayer substrate enables temperature-dependent, reversible shape transformations, allowing adaptive and conformal fixation under physiological conditions, while the top scaffold effectively converts near-infrared (NIR) light into heat, triggering programmable shape morphing and promoting bone repair. In vitro studies demonstrated that the system enhances osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) by modulating the Wnt/Hippo signaling pathways. In vivo results confirmed that the smart bandage significantly enhanced bone regeneration, inducing a 3.9-fold more new bone formation compared to the control group. By closely mimicking the dynamic mechanical microenvironment of natural bone healing, this smart bandage offers an integrated strategy combining mechanical stimulation and secure fixation, highlighting its potential for advanced bone regenerative therapies.

To balance the requirement of high mechanical properties and convenient injectability for the hydrogel design of osteoporotic bone defects (OBD) repair, a hierarchical hydrogel stiffening strategy is proposed through the synergetic utilizing of rapidly formed dynamic hydrazone crosslinking, high-strength double-bond chemical crosslinking, and contraction of activated shape-memory short fibers (SMSFs). In detail, the Schiff Base reaction mediated first network enabled stable precursor retention at the injection site without compromising injectability. Subsequent radical polymerization by photocrosslinking enhanced the hydrogel stiffness from 9.27 ± 0.77 kPa to 26.49 ± 3.48 kPa. Lastly, the shape memory effect (SME) induced contraction of the thermally activated SMSFs further densified the hydrogel network, ultimately elevating the stiffness to 53.40 ± 3.40 kPa. In vitro and in vivo studies confirm that this hierarchically stiffened hydrogel exhibited excellent biocompatibility and promoted osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) through mechanotransduction related Ras homologgene family, member A (RhoA)/a Rho—associated coiled coil-forming protein kinase (ROCK) pathway. The simultaneous releasing of alendronate (ALN) further enhanced osteogenesis in BMSCs. Notably, osteogenically differentiated BMSCs also effectively suppressed the osteoclastogenesis of macrophages. Thus, this injectable hydrogel, integrating hierarchical stiffening and ALN delivery, presents a promising therapeutic strategy for restoring bone homeostasis to accelerate regeneration in osteoporotic defects.

Injectable bone cements are recognized as ideal solution for bone augmentation due to their minimally invasive introduction strategy. However, current clinical formulations and composites, while demonstrating improvements in certain areas, often fail to comprehensively address challenges, including rheological injectability, mechanical stability, interconnected porosity, degradability, and bioactivity. To overcome limitations, a novel bone cement comprising linear polyhydroxy PEGylated poly(glycerol sebacate) (L-PEGS) and calcium phosphate cement (CPC) is developed. The incorporation of L-PEGS enhances injectability and reinforces the mechanical weakness of CPC, resulting in improvement in compressive strength (increased by 16.7 folds) and fatigue resistance (1000 cycles). Owing to linear polyhydroxy backbone, L-PEGS initiates self-reinforcing cross-linking reaction synchronized with the hydration of CPC into hydroxyapatite. This hydration reinforcement is mediated by its abundant hydroxyl groups and high water absorption capacity, which accelerate hydration kinetics. Concurrently, the cross-linking reaction generates in situ carbon dioxide, resulting in porous microarchitecture that facilitates hydration process, enhances cement degradability, and promotes nutrient exchange and new bone ingrowth. In vitro and vivo studies confirmed that L-PEGS/CPC substantially enhances osteogenesis compared to clinical materials. Collectively, this injectable, hydration-driven, and self-reinforcing bone cement offers comprehensive solution to the challenges in current bone graft materials, holding promise for clinical bone repair.

Ionogels are emerging as promising electronics due to their exceptional ionic conductivity, stretchability, and high thermal stability. However, developing ionogels with enhanced mechanical properties without compromising conductivity and ion transport rates remains a significant challenge. Here, we report a zwitterionic cross-linker, 4-(2-(((2-(methacryloyloxy)ethyl)carbamoyl)oxy)ethyl)-4,14-dimethyl-8,13-dioxo-7,12-dioxa-4,9-diazapentadec-14-en-4-ium-1-propanesulfonate (MEPS) and utilized it to cross-link a variety of functional monomers, leading to the synthesis of conductive ionogels that exhibit both high mechanical strength and versatile applicability. Due to its abundant hydrogen bond donors/acceptors and zwitterionic moiety, MEPS exhibits several hundred times higher solubility in ionic liquids compared to conventional cross-linkers. As a proof-of-concept, the poly(acrylic acid-MEPS) ionogels demonstrate enhanced elongation, fracture toughness, and superior thermal stability, all while maintaining high conductivity due to the high affinity between ionic liquids and zwitterionic networks. Furthermore, MEPS-cross-linked poly(alpha-thioctic acid) electronics can be engineered as strain sensors, showing exceptional antifatigue properties and recyclability, remaining stable and functional over 300 consecutive cycles. This universal cross-linking strategy not only improves the overall performance of ionogels but also contributes to the development of next-generation soft electronics with enhanced functionality and durability.

Advanced bioadhesion techniques have offered unprecedented opportunities for life-saving internal surgical procedures. However, most existing bioadhesives failed to rapidly establish long-lasting reliable biointerface and effectively reconstruct normal physiological function in the body fluid-rich and inevitable dynamic internal environment. Herein, a PEGylated poly(glycerol sebacate)-based Janus adhesive patch (PEGS-based JAP) is developed by integrating physically crosslinked guanidinylated PEGS (PEGSG) and acryloylated PEGS-chemically crosslinked poly(acrylic acid)-N-hydrosuccinimide ester (PEGSA-crosslinked PAAc-NHS) with a single-sided zwitterionic polymer-interpenetrated layer. The dry JAP can rapidly absorb the unpleasant interfacial water and effectively form strong physical interactions with wet tissues. Benefiting from the amphiphilic nature of PEGSG and a simple spatial-confined drying process, the JAP is allowed to resist excessive swelling and limitedly swell along one direction to avoid deterioration of the as-established conformable patch-tissue interface. Moreover, covalent interactions formed subsequently can further improve the adhesive strength and ensure a long-lasting reliable adhesion. Meanwhile, the notch-insensitive and puncture-resistant JAP can achieve tough adhesion to adapt to the dynamic conditions owing to the highly efficient energy-dissipation mechanism of the physically cross-linked network. Combining the above ideal features with the desirable postoperative anti-adhesion ability, the PEGS-based JAP is demonstrated to be a promising candidate for internal tissue adhesion and function reconstruction.

Osteoporosis is one of the most disabling consequences of aging, osteoporotic fractures and higher risk of the subsequent fractures leading to substantial disability and deaths, indicating both local fractures healing and the early anti-osteoporosis therapy are of great significance. Teriparatide is strong bone formation promoter effective in treating osteoporosis, while side effects limit clinical applications. Traditional drug delivery is lack of sensitive and short-term release, finding a new non-invasive and easily controllable drug delivery to not only repair the local fractures but also improve total bone mass has remained a great challenge. Thus, bioinspired by the natural bone components, we develop appropriate interactions between inorganic biological scaffolds and organic drug molecules, achieving both loaded with the teriparatide in the scaffold and capable of releasing on demand. Herein, biomimetic bone microstructure of mesoporous bioglass, a near-infrared ray triggered switch, thermosensitive liposomes based on a valve, and polydopamine coated as a heater is developed rationally for osteoporotic bone regeneration. Teriparatide is pulsatile released from intelligent delivery, not only rejuvenating osteoporotic bone defect, but also presenting strong systemic anti-osteoporosis therapy. This biomimetic bone carrying novel drug delivery platform is well worth expecting to be a new promising strategy and clinically commercialized to help patients survive from the osteoporotic fracture.

Age-related bone defects are a leading cause of disability and mortality in elderly individuals, and targeted therapy to delay the senescence of bone marrow-derived mesenchymal stem cells (MSCs) has emerged as a promising strategy to rejuvenate bone regeneration in aged scenarios. More specifically, activating the nicotinamide adenine dinucleotide (NAD+ )-dependent sirtuin 1 (SIRT1) pathway is demonstrated to effectively counteract MSC senescence and thus promote osteogenesis. Herein, based on an inventively identified senescent MSC-specific surface marker Kremen1, a senescence-targeted and NAD+ dependent SIRT1 activated nanoplatform is fabricated with a dual delivery of resveratrol (RSV) (SIRT1 promoter) and nicotinamide riboside (NR, NAD+ precursor). This targeting nanoplatform exhibits a strong affinity for senescent MSCs through conjugation with anti-Kremen1 antibodies and enables specifically responsive release of NR and RSV in lysosomes via senescence-associated β-galactosidase-stimulated enzymatic hydrolysis of the hydrophilic chain. Furthermore, this nanoplatform performs well in promoting aged bone formation both in vitro and in vivo by boosting NAD+ , activating SIRT1, and delaying MSC senescence. For the first time, a novel senescent MSC-specific surface marker is identified and aged bone repair is rejuvenated by delaying senescence of MSCs using an active targeting platform. This discovery opens up new insights for nanotherapeutics aimed at age-related diseases.

Developing a drug delivery platform that possesses universal drug loading capacity to meet various requirements of cancer treatment is a challenging yet interesting task. Herein, a self-assembled gelatin/silk fibroin composite (GSC) particle based drug delivery system is developed via microphase separation followed by desolvation process. Thanks to its preassembled microphase stage, this GSC system is suitable for varying types of drugs. The desolvation process fix drugs inside GSC rapidly and densify the GSC structure, thereby achieving efficient drug loading and providing comprehensive protection for loaded drugs. Actually, the size of this brand-new non-pore dependent drug delivery system can be easily adjusted from 100 nm to 20 µm to fit different scenarios. This work selects GSC with 3 µm diameter as the universal inhaled drug delivery platform, which shows an excellent transmucosal penetration and lung retention ability. Additionally, the MMP-9 sensitive degradation property of GSC enhances the targeted efficiency of drugs and reduces side effects. Intestinally, GSC can self-amplify the regulation of innate immunity to reverse the cancerous microenvironment into an antitumor niche, significantly improving the therapeutic effect of drugs. This study of GSC universal drug platform provides a new direction to develop the next-generation of drug delivery system for lung cancer.

Clinical therapies developed for estrogen-deficiency-driven postmenopausal osteoporosis (PMO) and related diseases, such as bone degeneration, show multiple adverse effects nowadays. Targeting senescent cells (SnCs) and the consequent senescence-associated secretory phenotype (SASP) with a combination of dasatinib and quercetin (DQ) is a recently developed novel therapy for multiple age-related diseases. Herein, we found that estrogen deficiency induced-bone loss was attributed to a pro-inflammatory microenvironment with SASP secretions and accelerated SnC accumulation, especially senescent mesenchymal stem cells (MSCs) characterized by exhaustion and dysfunction in middle aged rats. Systematically targeting SnCs with DQ strikingly ameliorated PMO and restored MSC function. Local administration of DQ and bone morphogenetic protein 2 (BMP2) in combination promoted osteogenic differentiation of MSCs and rejuvenated osteoporotic bone regeneration. Our results repurposed DQ as an attractive therapy for treating PMO and related diseases.

Bone defects that arise from trauma, skeletal diseases, or tumor resections have become the commonest and most thorny problems in orthopedic clinics. Recently, biocomposite materials used as artificial bone repair materials have provided a promising approach for bone regeneration. In this study, poly (l-lactide acid) (PLLA) and silk fibroin (SF) were used to fabricate nanofiber scaffolds by electrospinning technology. In order to simulate a biomimetic osteoblast microenvironment, decellularized extracellular matrix from osteoblasts was loaded into the biocomposite scaffolds (O-ECM/PLLA/SF). It was found that the O-ECM/PLLA/SF scaffolds were nontoxic for L929 cells and had good cytocompatibility. Their effects on mesenchymal stem cells derived from human-induced pluripotent stem cell (iPSC-MSC) behavior were investigated. As a result, the scaffolds with the addition of O-ECM showed enhanced alizarin red S (ARS) activity. In addition, higher expression of osteogenic gene markers such as runt-related transcription factor 2 (Runx2), collagen type I (Col-1), and osteocalcin (OCN) as well as upregulated expression of osteogenic marker protein osteopontin (OPN) and Col-1 further substantiated the applicability of O-ECM/PLLA/SF scaffolds for osteogenesis. Furthermore, the in vivo study also indicated maximal new bone formation in the skull defect model of Sprague Dawley (SD) rats treated with the O-ECM/PLLA/SF carried by human iPSC-MSCs. Hence, this study suggests that O-ECM/PLLA/SF scaffolds have a potential application in bone tissue engineering.

Zwitterionic materials and allochroic materials, as the two completely different materials, offer distinct properties and functions for different applications, where the former is well recognized as bio-inert materials with highly hydrophilic, antifouling, and biocompatible properties, while the latter is proven as stimuli-responsive discoloration materials with poor water solubility and high toxicity to cells. However, the development of zwitterionic, allochroic materials remains great challenging by integrating these oppositely properties into the same materials. Here, we designed and synthesized water-soluble, allochroic, and zwitterionic polymers of (pVPES) with built-in nonfouling and pH-responsive discoloration properties under in vitro and in vivo conditions. pVPES can serve as a versatile material platform for either self-polymerizing into different architectures (i.e., brushes, colloids, microgels, hydrogels,) or co-polymerization with other functional polymers to become different smart devices (i.e., colorimetric pollutant sensors, electrochromic smart windows, bilayer hydrogel actuators), all realizing the integration of antifouling and allochroic properties. More importantly, pVPES-based hydrogel patches enabled to not only accelerate wound healing of both chronic and acute wounds, but also distinguish chronic woundsfrom acutewounds in mice by color changes. This work opens new directions for the development of functional zwitterionic materials by integrating allochroic properties into inert materials for bio-optics applications.

Development of biomimetic hydrogel-based wound dressing is highly desirable for addressing life-threatening infectious skin injuries but has proved to be extremely challenging. However, poor tissue adhesive performance, stretchability and difficult fixation lead to conventional wound dressings failing to adapt to dynamic wounds with high-frequency movement or special fluctuant positions. Herein, we present a new biomimetic natural-synthetical combination by integrating Osteichthyes-extracted gelatins into hydrophilic polymeric networks to form unique tough, adhesive, self-healable composite hydrogels. The resultant Gelatin/PHEAA hydrogel without any growth factors/fungicides has high mechanical strength (~1.0 MPa), high interfacial toughness (>1000 J/m2), and remarkable antifouling activity, enabling the hydrogel to effectively inhibit bacterial proliferation and promote the wound healing. Moreover, due to the abundant hydrogen bonds in composite crosslinked networks, the Gelatin/PHEAA hydrogels maintain high, repeatable adhesion even in high dynamic cases, regardless of wet or dry environments and the types of solid nonporous substrates. Further in vitro and in vivo full-thickness skin defect model confirms that the Osteichthyes-extracted proteins can accelerate collagen deposition and vascular regeneration, leading to a faster wound closure efficiency. Ultimately, we believe that the designed tough Gelatin/PHEAA hydrogels can be high-value candidates for managing rapid wound healing, while the proposed structural biomimetic combination can inspire researchers to design more interesting and effective biomaterials for clinical translation and health care.

Bilayer hydrogels are attracting tremendous attention for their capability to integrate several different functions on the two sides of the gel, that is, imparting the gel with Janus characteristics, which is highly desired in many engineering and biomedical applications including soft actuators, hydrogel patches, and wearable electronics. However, the preparation process of the bilayer materials usually involves several complicated steps and is time-consuming, while the interfacial bonding is another main concern. Here, a simple and versatile method is proposed to obtain bilayer hydrogels within just one step based on the method of introducing viscosity contrast of the precursors for different layers. The bilayer structure can be well maintained during the whole preparation process with a constrained interfacial molecular exchange to ensure the strong bonding strength. The key requirements for forming distinct bilayer structures in situ are studied and discussed in detail. Bilayer hydrogels with different chemical designs are prepared via this strategy to tailor the good distribution of desired functions for soft actuators, wound healing patches, and wearable electronics. We believe that the strategy illustrated here will provide new insights into the preparation and application of bilayer materials.

As the forefront of the digestive system, a mouth in a high moist microenvironment is easy to breed bacteria and the inevitable injury from oral surgeries will cause a series of physiological disorders. The injectable hydrogels are promising biomaterials to solve this challenge, but the limited mechanical performance and weak mechanical adjustment are insufficient to fit in the whole healing process. Herein, we propose and design a new spatio-temporal self-strengthening injectable hydrogel via manipulating the time-dependent cross-linking effects after the Schiff base reaction. The resultant hydrogels possess various promising properties and functions, including rapid initial gelation efficiency (similar to 30 s), spatiotemporal adjustable mechanical strength, great antifouling property and biocompatibility, leading to effective promote oral tissue regeneration and bone repair. We believe both our concept and spatiotemporal self-strengthening injectable hydrogels will provide new insight into the hydrogel-based wound dressing and broaden the application of the bioinspired hydrogels in biomedical fields.

Bone tissue scaffolds with good bulk or surface osteoconductivity are always pursued by biomaterial scientists. In this paper, we design a tough and flexible amphoteric copolymerbased (AC) hydrogel with bioactive groups for bone regeneration. In detail, our hydrogels are copolymerized with N-acyl glycinamide (NAGA), anionic acrylate alendronate (AcAln), and cationic (2-(acryloyloxy)ethyl) trimethyl ammonium chloride (DMAEA-Q) by free radical polymerization. There are three kinds of synergetic physical cross-links among our polyamphion hydrogels: (1) double hydrogen bonds between amide groups in NAGA to provide toughness, (2) hydrogen bonds between dual bisphosphite groups in AcAln, and (3) weak ionic pairs between the anionic bisphosphite groups and the cationic quaternary ammonium groups in DMAEA-Q to offer flexibility. The AC hydrogel shows osteoid-like viscoelasticity, which makes the AC hydrogel osteogenesis inductive. During the repairing process, the bioactive bisphosphite groups accelerate the calcium fixation to expedite the mineralization of the new-formed bone. At the same time, the surface charge property of AC hydrogels also prevents fibrous cyst formation, thus guaranteeing osseointegration. Our in vitro data strongly demonstrate that the AC hydrogel is an excellent matrix to induce osteogenesis of rat bone marrow mesenchymal stem cells. More importantly, the following in vivo experiments further prove that the AC hydrogel can reach satisfactory bone regeneration without encapsulation of seed cells or application of external simulating cues. These exciting results demonstrate that our AC hydrogel is a promising scaffold for bone regeneration. Our work can also inspire the constituent and structure design of biomaterial scaffolds for tissue regeneration.