Interaction of vascular endothelial cells with hydrophilic fullerene nanoarchitectured structures in 2D and 3D environments.

The interaction between diverse nanoarchitectured fullerenes and cells is crucial for biomedical applications. Here, we detailed the preparation of hydrophilic self-assembled fullerenes by the liquid-liquid interfacial precipitation (LLIP) method and hydrophilic coating of the materials as a possible vascularization strategy. The interactions of vascular endothelial cells (ECs) with hydrophilic fullerene nanotubes (FNT-P) and hydrophilic fullerene nanowhiskers (FNW-P) were investigated. The average length and diameter of FNT-P were 16 ± 2 µm and 3.4 ± 0.4 µm (i.e. aspect ratios of 4.6), respectively. The average length and diameter of FNW-P were 65 ± 8 µm and 1.2 ± 0.2 µm (i.e. aspect ratios of 53.9), respectively. For two-dimensional (2D) culture after 7 days, the ECs remained viable and proliferated up to ~ 420% and ~ 400% with FNT-P and FNW-P of 50 µg/mL, respectively. Furthermore, an optimized chitosan-based self-healing hydrogel with a modulus of ~400 Pa was developed and used to incorporate self-assembled fullerenes as in vitro three-dimensional (3D) platforms to investigate the impact of FNT-P and FNW-P on ECs within a 3D environment. The addition of FNW-P or FNT-P (50 µg/mL) in the hydrogel system led to proliferation rates of ECs up to ~323% and ~280%, respectively, after 7 days of culture. The ECs in FNW-P hydrogel displayed an elongated shape with aligned morphology, while those in FNT-P hydrogel exhibited a rounded and clustered distribution. Vascular-related gene expressions of ECs were significantly upregulated through interactions with these fullerenes. Thus, the combined use of different nanoarchitectured self-assembled fullerenes and self-healing hydrogels may offer environmental cues influencing EC development in a 3D biomimetic microenvironment, holding promise for advancing vascularization strategy in tissue engineering.

Self-assembled fullerenes with large aspect ratios modulate the morphology and gene expression of endothelial cells within a soft biomimetic 3D microenvironment, representing a promising new vascularization strategy in tissue engineering.

Ultrafast Self-Healing, Superstretchable, and Ultra-Strong Polymer Cluster-Based Adhesive Based on Aromatic Acid Cross-Linkers for Excellent Hydrogel Strain Sensors.

Synthetic hydrogel strain sensors rarely exhibit a comprehensive combination of mechanical properties such as ultra-stretchability, ultrafast self-healing, and high sensitivity. Herein, seven small molecule enhanced mechanical behaviors of polymer-cluster based hydrogels are demonstrated. The oxidized polyethyleneimine/polymeric acrylic acid (ohPEI/PAA) hydrogels with aromatic formic acids as supramolecular cross-linkers are prepared by simultaneous formation of ohPEI polymer clusters and PAA upon the addition of ammonium persulfate. The optimized hydrogel adhesive exhibits comprehensive excellent properties, such as high extensibility (up to 12 298%), real-time mechanical self-healing capability (<1 s, 93% efficiency), high uniformity, underwater adhesivity, and water-sealing ability. The proper binding strength of hydrogel and skin (47 kPa) allows the hydrogel to be utilized as highly sensitive (gauge factor:16.08), highly conductive (2.58 mS cm-1 ), and underwater strain sensors. Specially, the adhesive strength of the adhesive to wood after dehydration is extremely high, reaching up to 29.59 MPa. Additionally, when glycerol is introduced, the obtained gel maintains the physical properties even at harsh-temperature conditions (-40 to 80 °C). It presents that multiple and hierarchical non-covalent interactions including multiple hydrogen bonding interactions, π-π stacking, electrostatic interactions, and dipole-dipole interactions of polymer clusters, allow for the energy dissipation and contribute to the excellent performance of the hydrogel.

Surface Modification of Transition Metal Dichalcogenide Nanosheets for Intrinsically Self-Healing Hydrogels with Enhanced Mechanical Properties.

Nanocomposites with enhanced mechanical properties and efficient self-healing characteristics can change how the artificially engineered materials' life cycle is perceived. Improved adhesion of nanomaterials with the host matrix can drastically improve the structural properties and confer the material with repeatable bonding/debonding capabilities. In this work, exfoliated 2H-WS2 nanosheets are modified using an organic thiol to impart hydrogen bonding sites on the otherwise inert nanosheets by surface functionalization. These modified nanosheets are incorporated within the PVA hydrogel matrix and analyzed for their contribution to the composite's intrinsic self-healing and mechanical strength. The resulting hydrogel forms a highly flexible macrostructure with an impressive enhancement in mechanical properties and a very high autonomous healing efficiency of 89.92%. Interesting changes in the surface properties after functionalization show that such modification is highly suitable for water-based polymeric systems. Probing into the healing mechanism using advanced spectroscopic techniques reveals the formation of a stable cyclic structure on the surface of nanosheets, mainly responsible for the improved healing response. This work opens an avenue toward the development of self-healing nanocomposites where chemically inert nanoparticles participate in the healing network rather than just mechanically reinforcing the matrix by slender adhesion.

Self-healing hydrogel as an injectable implant: translation in brain diseases.

Tissue engineering biomaterials are aimed to mimic natural tissue and promote new tissue formation for the treatment of impaired or diseased tissues. Highly porous biomaterial scaffolds are often used to carry cells or drugs to regenerate tissue-like structures. Meanwhile, self-healing hydrogel as a category of smart soft hydrogel with the ability to automatically repair its own structure after damage has been developed for various applications through designs of dynamic crosslinking networks. Due to flexibility, biocompatibility, and ease of functionalization, self-healing hydrogel has great potential in regenerative medicine, especially in restoring the structure and function of impaired neural tissue. Recent researchers have developed self-healing hydrogel as drug/cell carriers or tissue support matrices for targeted injection via minimally invasive surgery, which has become a promising strategy in treating brain diseases. In this review, the development history of self-healing hydrogel for biomedical applications and the design strategies according to different crosslinking (gel formation) mechanisms are summarized. The current therapeutic progress of self-healing hydrogels for brain diseases is described as well, with an emphasis on the potential therapeutic applications validated by in vivo experiments. The most recent aspect as well as the design rationale of self-healing hydrogel for different brain diseases is also addressed.

A Novel Multifunctional Crosslinking PVA/CMCS Hydrogel Containing Cyclic Peptide Actinomycin X2 and PA@Fe with Excellent Antibacterial and Commendable Mechanical Properties.

Bacterial infected environments and resulting bacterial infections have been threatening the human health globally. Due to increased bacterial resistance caused by improper and excessive use of antibiotics, antibacterial biomaterials are being developed as alternatives to antibiotics in some cases. Herein, an advanced multifunctional hydrogel with excellent antibacterial properties, enhanced mechanical properties, biocompatibility and self-healing performance, was designed through freezing-thawing method. This hydrogel network is composed of polyvinyl alcohol (PVA), carboxymethyl chitosan (CMCS), protocatechualdehyde (PA), ferric iron (Fe) and an antimicrobial cyclic peptide actinomycin X2 (Ac.X2). The double dynamic bonds among protocatechualdehyde (PA), ferric iron (Fe) and carboxymethyl chitosan containing coordinate bond (catechol-Fe) as well as dynamic Schiff base bonds and hydrogen bonds endowed the hydrogel with enhanced mechanical properties. Successful formation of hydrogel was confirmed through ATR-IR and XRD, and structural evaluation through SEM analysis, whereas mechanical properties were tested with electromechanical universal testing machine. The resulting PVA/CMCS/Ac.X2/PA@Fe (PCXPA) hydrogel has favorable biocompatibility and excellent broad-spectrum antimicrobial activity against both S. aureus (95.3 %) and E. coli (90.2 %) compared with free-soluble Ac.X2, which exhibited subpar performance against E. coli reported in our previous studies. This work provides a new insight on preparing multifunctional hydrogels containing antimicrobial peptides as antibacterial material.

Salvianolic-Acid-B-Loaded HA Self-Healing Hydrogel Promotes Diabetic Wound Healing through Promotion of Anti-Inflammation and Angiogenesis.

Inflammatory dysfunction and angiogenesis inhibition are two main factors leading to the delayed healing of diabetic wounds. Hydrogels with anti-inflammatory and angiogenesis-promoting effects have been considered as promising wound care materials. Herein, a salvianolic acid B (SAB)-loaded hyaluronic acid (HA) self-healing hydrogel (HA/SAB) with anti-inflammatory and pro-angiogenesis capacities for diabetic wound healing is reported. The HA hydrogel was prepared via the covalent cross-linking of aldehyde groups in oxidized HA (OHA) and hydrazide groups in adipic dihydrazide (ADH)-modified HA (HA-ADH) with the formation of reversible acylhydrazone bonds. The obtained HA hydrogel exhibited multiple favorable properties such as porous structures, excellent self-healing properties, a sustainable release capacity of SAB, as well as excellent cytocompatibility. In addition, the effects of the SAB-loaded HA self-healing hydrogel were investigated via a full-thickness skin defect model using diabetic rats. The HA/SAB hydrogel showed enhanced skin regeneration effects with accelerated wound closure, shorter remaining dermal space length, thicker granulation tissue formation, and more collagen deposition. Furthermore, reduced inflammatory response and enhanced vascularization were found with HA/SAB2.5 hydrogel-treated wounds, indicating that the hydrogel promotes diabetic wound healing through the promotion of anti-inflammation and angiogenesis. Our results suggest that the fabricated SAB-loaded HA self-healing hydrogel is promising as a wound dressing for the treatment of diabetic wounds.

Indocyanine Green Performance Enhanced System for Potent Photothermal Treatment of Bacterial Infection.

The instability in solution and aggregation-induced self-quenching of indocyanine green (ICG) have weakened its fluorescence and photothermal properties, thus inhibiting its application in practice. In this study, the cationic and anionic liposomes containing ICG were prepared based on 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-glycerol (DPPG), respectively. Molecular dynamics (MD) simulations demonstrate that ICG molecules are better distributed in the membranes of cationic DOTAP-based liposomes, leading to a superior fluorescence and photothermal performance. The liposomal ICG also shows the physical and photothermal stability during irradiation and long-term storage. On this basis, the prepared DOTAP-based liposomal ICG was encapsulated in the self-healing hydrogel formed by guar gum through the borate/diol interaction. The proposed liposomal ICG-loaded hydrogel can not only convert near-infrared (NIR) light into heat effectively but also repair itself without external assistance, which will realize potent photothermal therapy (PTT) against bacterial infection and provide the possibility for meeting the rapidly growing needs of modern medicine.

Irreversible and Self-Healing Electrically Conductive Hydrogels Made of Bio-Based Polymers.

Electrically conductive materials that are fabricated based on natural polymers have seen significant interest in numerous applications, especially when advanced properties such as self-healing are introduced. In this article review, the hydrogels that are based on natural polymers containing electrically conductive medium were covered, while both irreversible and reversible cross-links are presented. Among the conductive media, a special focus was put on conductive polymers, such as polyaniline, polypyrrole, polyacetylene, and polythiophenes, which can be potentially synthesized from renewable resources. Preparation methods of the conductive irreversible hydrogels that are based on these conductive polymers were reported observing their electrical conductivity values by Siemens per centimeter (S/cm). Additionally, the self-healing systems that were already applied or applicable in electrically conductive hydrogels that are based on natural polymers were presented and classified based on non-covalent or covalent cross-links. The real-time healing, mechanical stability, and electrically conductive values were highlighted.

Nanoenzyme-Reinforced Injectable Hydrogel for Healing Diabetic Wounds Infected with Multidrug Resistant Bacteria.

Diabetic wound healing remains a critical challenge due to its vulnerability to multidrug-resistant (MDR) bacterial infection, as well as the hyperglycemic and oxidative wound microenvironment. Herein, an injectable multifunctional hydrogel (FEMI) was developed to simultaneously overcome these hurdles. The FEMI hydrogel was fabricated through a Schiff-based reaction between ε-polylysine (EPL)-coated MnO2 nanosheets (EM) and insulin-loaded self-assembled aldehyde Pluronic F127 (FCHO) micelles. Through a synergistic combination of EPL and "nanoknife-like" MnO2 nanosheets, the FEMI hydrogel exhibited extraordinary antimicrobial capacities against MDR bacteria. The MnO2 nanoenzyme reshaped the hostile oxidative wound microenvironment by decomposing the endogenous H2O2 into O2. Meanwhile, the pH/redox dual-responsive FEMI hydrogel achieved a sustained and spatiotemporal controlled release of insulin to regulate the blood glucose. Our FEMI hydrogel demonstrated an accelerated MDR bacteria-infected diabetic wound healing in vivo and represents a versatile strategy for healing a broad range of tissue damages caused by diabetes.

Self-healing hydrogel based on poly (vinyl alcohol)-poly (lysine)-gum arabic accelerates diabetic wound healing under photothermal sterilization.

Diabetic wounds are a significant clinical challenge. Developing effective antibacterial dressings is crucial for preventing wound ulcers caused by bacterial infections. In this study, a self-healing antibacterial hydrogel (polyvinyl alcohol (PVA)-polylysine-gum arabic, PLG hydrogels) with near-infrared photothermal response was prepared by linking PVA and a novel polysaccharide-amino acid compound (PG) through borate bonding combined with freeze-thaw cycling. Subsequently, the hydrogel was modified by incorporating inorganic nanoparticles (modified graphene oxide (GM)). The experimental results showed that the PLGM3 hydrogels (PLG@GM hydrogels, 3.0 wt%) could effectively kill bacteria and promote diabetic wound tissue healing under 808-nm near-infrared laser irradiation. Therefore, this hydrogel system provides a new idea for developing novel dressings for treating diabetic wounds.

Mussel-inspired tissue adhesive composite hydrogel with photothermal and antioxidant properties prepared from pectin for burn wound healing.

Biodegradable self-healing hydrogels with antibacterial property attracted growing attentions in biomedication as wound dressings since they can prevent bacterial infection and promote wound healing process. In this research, a biodegradable self-healing hydrogel with ROS scavenging performance and enhanced tissue adhesion was fabricated from dopamine grafted oxidized pectin (OPD) and naphthoate hydrazide terminated PEO (PEO NH). At the same time, Fe3+ ions were incorporated to endow the hydrogel with near-infrared (NIR) triggered photothermal property to obtain antibacterial activity. The composite hydrogel showed good hemostasis performance based on mussel inspired tissue adhesion with biocompatibility well preserved. As expected, the composition of FeCl3 improved conductivity and endowed photothermal property to the hydrogel. The in vivo wound repairing experiment revealed the 808 nm NIR light triggered photothermal behavior of the hydrogel reduced the inflammation response and promoted wound repairing rate. As a result, this composite FeCl3/hydrogel shows great potential to be an excellent wound dressing for the treatment of infection prong wounds with NIR triggers.

Multifunctional self-healing peptide hydrogel for wound healing.

The complete healing of wounds remains a challenge in clinical care. In addition, various complications such as inflammation and infection that may occur during skin wound healing can impede the healing process. Here, we constructed a multifunctional self-repairing hydrogel by utilizing Schiff base bonds. This hydrogel exhibited good self-healing properties and could cope with destructive external influences. The self-healing hydrogel was injectable, ensuring that the hydrogel dressing adhered to the wound. Carboxymethyl chitosan and oxidized chondroitin sulfate demonstrated good biocompatibility and multiple bioactivities and were successfully used to prepare self-healing hydrogels. Meanwhile, the SIKVAV biopeptide was less expensive and more morphologically stable than vascular endothelial growth factor and had a high pro-angiogenic activity. Thus, the SIKVAV biopeptide was cross-linked to the oxidized chondroitin sulfate of the hydrogel through covalent bonding to avoid rapid biopeptide degradation, achieving a slow release of the drug. This peptide hydrogel exhibited good biocompatibility and antimicrobial properties; moreover, experiments conducted on mice revealed that it could effectively promote angiogenesis and skin tissue repair. These findings suggest that the injectable self-repairing peptide hydrogel may facilitate skin wound healing and other applications.

Pectin based hydrogel with covalent coupled doxorubicin and limonin loading for lung tumor therapy.

Self-healing hydrogels have shown great application potential in drug delivery for anti-tumor therapy and tissue engineering. In this research, Doxorubicin (DOX) was coupled onto the oxidized pectin (pec-Ald) to prepare DOX grafted pec-AD and used to fabricate self-healing hydrogel for lung cancer therapy combined with novel herbal medicine extract limonin targeting lung cancer cells. The hydrogel was prepared with P(NIPAM195-co-AH54) cross-linking and the hydrazone bond cross-linked hydrogel showed good mechanical property and self-healing behavior. With pectin composition, the hydrogel was still biodegradable catalyzed by enzyme and in vivo. The hydrogel formed fast fit for injectable application and the hydrogel itself showed moderate lung cancer inhibition activity. With limonin loading, the hydrogel showed synergistic lung cancer therapy with the tumor growth greatly inhibited. The covalent coupling of DOX and loaded limonin in the hydrogel decreased in vivo toxicity and the hydrogel degraded on time. With biodegradability and improved lung cancer therapy efficiency, this DOX grafted self-healing hydrogel could find great potential application in cancer therapy in near future.

Exosomes-carried curcumin based on polysaccharide hydrogel promote flap survival.

Flap grafting is a common technique used to repair skin defects in orthopedics and plastic and reconstructive surgeries. However, oxidative stress injury caused by ischemia and ischemia-reperfusion injury at the distal end of the skin flap can cause flap necrosis. Curcumin is a natural compound with anti-inflammatory and antioxidant properties that tackle oxidative stress. However, its applicability is limited by its poor water solubility. Exosomes are membranous vesicles that can be loaded with hydrophobic drugs. They are widely studied in drug delivery applications and can be investigated to augment curcumin efficiency. In this study, a self-healing oxidized pullulan polysaccharide-carboxymethylated chitosan composite hydrogel was used as a curcumin-loaded exosome delivery system to evaluate its impact on the viability of skin flaps. The hydrogel exhibited good self-healing properties that allowed the continuous and stable release of drugs. It had anti-inflammatory and antioxidant properties that could reduce oxidative stress damage due to early ischemia and hypoxia of the skin flap in vitro. Moreover, this composite hydrogel attenuated inflammatory responses, promoted angiogenesis, and reduced the distal necrosis of the flap in vivo. Therefore, our hydrogel provides a novel strategy for skin flap graft protection with reduced necrosis and the potential for broad clinical applications.

Synthesis, properties, and applications of a polyampholyte hydroxypropyl chitosan derivative with the phenylboronic acid functional group.

Phenylboronic acid (PBA) groups are effective in building glucose-responsive drug delivery systems. Chitosan (CS) offers distinct advantages in the construction of PBA-based biomaterials, such as biodegradability and biocompatibility. However, challenges still persist due to the limited solubility of CS. This study proposes an efficient approach to introduce PBA groups into CS chains within 1 h via the O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU)-mediated amidation between 3-carboxyphenylboronic acid (CPBA) and O-hydroxypropyl chitosan (HPCS). The results showed that a wide range of substitution degrees, from 0.15 to 0.78, could be finely controlled by the amount of CPBA added. Furthermore, the obtained novel carboxyphenylboronic acid-grafted hydroxypropyl chitosan (PBA-HPCS) derivative showed enhanced crystallinity and thermostability compared to HPCS, and it demonstrated solubility in an alkaline solution. Based on the reversible bonding between the boronic acid group and cis-1,2/1,3-diols, PBA-HPCS was successfully used as an efficient crosslinker for the preparation of hydrogels incorporating sorbitol and polyhydroxy polymers, such as guar gum and polyvinyl alcohol. These hydrogels exhibited rapid gelation, rapid self-healing, injectability, and responsiveness to glucose and pH. These findings suggest that PBA-HPCS holds promise for advancing the development of PBA-based biomaterials.

Glucose oxidase and ruthenium nanorods-embedded self-healing polyvinyl alcohol/polyethylene imine hydrogel for simultaneous photothermal/photodynamic/starvation therapy and skin reconstruction.

Tumor recurrence and wound healing represent significant burdens for tumor patients after the surgical removal of melanomas. Wound dressings with wound healing and anticancer therapeutic abilities could help to solve these issues. Thus, a hybrid hydrogel made of polyvinyl alcohol (PVA) and polyethylene imine (PEI) was prepared by cross-linking imine bond and boronic acid bond. This hydrogel was loaded with ruthenium nanorods (Ru NRs) and glucose oxidase (GOx) and named as nanocomposite hydrogel (Ru/GOx@Hydrogel), exhibiting remarkable photothermal/photodynamic/starvation antitumor therapy and wound repair abilities. Ru NRs are bifunctional phototherapeutic agents that simultaneously exhibit intrinsic photothermal and photodynamic functions. Three-dimensional composite hydrogel loaded with GOx can also consume glucose in the presence of O2 during tumor starvation therapy. Near-infrared (NIR) light-triggered hyperthermia can not only promote the consumption of glucose, but also facilitate the ablation of residual cancer cells. The antitumor effect of the Ru/GOx@Hydrogel resulted in significant improvements, compared to those observed with either phototherapy or starvation therapy alone. Additionally, the postoperative wound was substantially healed after treatment with Ru/GOx@Hydrogel and NIR irradiation. Therefore, the Ru/GOx@Hydrogel can be used as a multi-stimulus-responsive nanoplatform that could facilitate on-demand controlled drug release, and be used as a promising postoperative adjuvant in combination therapy.

Formation of Nanofibrillar Self-Healing Hydrogels Using Antimicrobial Peptides.

The rise of drug-resistant microorganisms has prompted the development of innovative strategies with the aim of addressing this challenge. Among the alternative approaches gaining increased attention are antimicrobial peptides (AMPs), a group of peptides with the ability to combat microbial pathogens. Here, we investigated a small peptide, KLVFF, derived from the Alzheimer's amyloid-ß (Aß) protein. While Aß has been associated with the development of neurodegenerative diseases, the core part of the Aß protein, namely the Aß 16-20 fragment, has also been exploited to obtain highly functional biomaterials. In this study we found that KLVFF is capable of self-assembling into a fibrillar network to form a self-healing hydrogel. Moreover, this small peptide can undergo a transition from a gel to a liquid state following application of shear stress, in a reversible manner. As an AMP, this material exhibited both antibacterial and antifungal properties while remaining highly biocompatible and noncytotoxic toward mammalian cells. The propensity of the KLVFF hydrogel to rapidly assemble into highly ordered macroscopic structures makes it an ideal candidate for biomedical applications necessitating antimicrobial activity, such as wound healing.

Motion Sensing by a Highly Sensitive Nanogold Strain Sensor in a Biomimetic 3D Environment.

Recent advancements in flexible electronics have highlighted their potential in biomedical applications, primarily due to their human-friendly nature. This study introduces a new flexible electronic system designed for motion sensing in a biomimetic three-dimensional (3D) environment. The system features a self-healing gel matrix (chitosan-based hydrogel) that effectively mimics the dynamics of the extracellular matrix (ECM), and is integrated with a highly sensitive thin-film resistive strain sensor, which is fabricated by incorporating a cross-linked gold nanoparticle (GNP) thin film as the active conductive layer onto a biocompatible microphase-separated polyurethane (PU) substrate through a clean, rapid, and high-precision contact printing method. The GNP-PU strain sensor demonstrates high sensitivity (a gauge factor of ∼50), good stability, and waterproofing properties. The feasibility of detecting small motion was evaluated by sensing the beating of human induced pluripotent stem cell (hiPSC)-derived cardiomyocyte spheroids embedded in the gel matrix. The integration of these components exemplifies a proof-of-concept for using flexible electronics comprising self-healing hydrogel and thin-film nanogold in cardiac sensing and offers promising insights into the development of next-generation biomimetic flexible electronic devices.

Black Phosphorus-Based Dynamic Self-Healing Hydrogel to Integrate Demineralized Bone Matrix and Noggin-Targeting siRNA for Synergistic Osteogenesis.

Although a demineralized bone matrix (DBM) is often used as an alternative to an autologous bone graft, its clinical application is still hampered by easy dispersion of DBM particles and insufficient osteoinductivity in the defect site. Herein, we designed a self-healing hydrogel for DBM that can rapidly restore its structural integrity after damage based on amino-rich black phosphorus (BP) nanosheets and aldehyde-functionalized hyaluronic acid (AHA). Given the increased expression of bone morphogenetic protein (BMP) antagonists by DBM stimulation, the osteogenic potency of DBM in the hydrogel carrier was further enhanced by abrogating the BMP antagonism. The BP/AHA hydrogel provided dynamic polymer-nanosheet networks that combine injectability, modability, and physical stability with high DBM loading, where the BP nanosheets served as osteogenic cross-linkers to promote biomineralization and deliver siRNA to suppress undesirable expression of BMP antagonist noggin by DBM. As a result, the BP/AHA hydrogel integrated with DBM and noggin-targeting siRNA synergistically promoted osteogenic differentiation of mesenchymal stem cells by enhancing BMP/Smad signaling. This work demonstrates a promising strategy to improve the efficacy of bone regeneration using bone graft.

A multifunctional silk-hyaluronic acid self-healing hydrogel laden with alternatively activated macrophage-derived exosomes reshape microenvironment of diabetic wound and accelerate healing.

The impairment of phenotype switching of pro-inflammatory M1 to pro-healing M2 macrophage induced by hyperglycemic microenvironment often elevates oxidative stress, impairs angiogenesis, and leads to chronic non-healing wounds in diabetic patients. Administration of M2 macrophage-derived exosomes (M2Exo) at wound site is known to polarize M1 to M2 macrophage and can accelerate wound healing by enhancing collagen deposition, angiogenesis, and re-epithelialization. In the present study, M2Exo were conjugated with oxidized hyaluronic acid and mixed with PEGylated silk fibroin to develop self-healing Exo-gel to achieve an efficient therapy for diabetic wounds. Exo-gel depicted porous networked morphology with self-healing and excellent water retention behaviour. Fibroblast cells treated with Exo-gel showed significant uptake of M2Exo that increased their proliferation and migration in vitro. Interestingly, in a diabetic wound model of wistar rats, Exo-gel treatment induced 75 % wound closure within 7 days with complete epithelial layer regeneration by modulating cytokine levels, stimulating fibroblast-keratinocyte interaction and migration, angiogenesis, and organized collagen deposition. Taken together, this study suggests that Exo-gel depict properties of an excellent wound healing matrix and can be used as a therapeutic alternative to treat chronic non-healing diabetic wounds.