Antibacterial Hydrogel Adhesives Based on Bifunctional Telechelic Dendritic-Linear-Dendritic Block Copolymers.

Antibiotic-resistant pathogens have been declared by the WHO as one of the major public health threats facing humanity. For that reason, there is an urgent need for materials with inherent antibacterial activity able to replace the use of antibiotics, and in this context, hydrogels have emerged as a promising strategy. Herein, we introduce the next generation of cationic hydrogels with antibacterial activity and high versatility that can be cured on demand in less than 20 s using thiol-ene click chemistry (TEC) in aqueous conditions. The approach capitalizes on a two-component system: (i) telechelic polyester-based dendritic-linear-dendritic (DLDs) block copolymers of different generations heterofunctionalized with allyl and ammonium groups, as well as (ii) polyethylene glycol (PEG) cross-linkers functionalized with thiol groups. These hydrogels resulted in highly tunable materials where the antibacterial performance can be adjusted by modifying the cross-linking density. Off-stoichiometric hydrogels showed narrow antibacterial activity directed toward Gram-negative bacteria. The presence of pending allyls opens up many possibilities for functionalization with biologically interesting molecules. As a proof-of-concept, hydrophilic cysteamine hydrochloride as well as N-hexyl-4-mercaptobutanamide, as an example of a thiol with a hydrophobic alkyl chain, generated three-component networks. In the case of cysteamine derivatives, a broader antibacterial activity was noted than the two-component networks, inhibiting the growth of Gram-positive bacteria. Additionally, these systems presented high versatility, with storage modulus values ranging from 270 to 7024 Pa and different stability profiles ranging from 1 to 56 days in swelling experiments. Good biocompatibility toward skin cells as well as strong adhesion to multiple surfaces place these hydrogels as interesting alternatives to conventional antibiotics.

Neurogenic and angiogenic poly(N-acryloylglycine)-co-(acrylamide)-co-(N-acryloyl-glutamate) hydrogel: preconditioning effect under oxidative stress and use in neuroregeneration.

Traumatic injuries, neurodegenerative diseases and oxidative stress serve as the early biomarkers for neuronal damage and impede angiogenesis and subsequently neuronal growth. Considering this, the present work aimed to develop a poly(N-acryloylglycine)-co-(acrylamide)-co-(N-acryloylglutamate) hydrogel [p(NAG-Ac-NAE)] with angiogenesis/neurogenesis properties. As constituents of this polymer modulate their vital role in biological functions, inhibitory neurotransmitter glycine regulates neuronal homeostasis, and glutamatergic signalling regulates angiogenesis. The p(NAG-Ac-NAE) hydrogel is a highly branched, biodegradable and pH-responsive polymer with a very high swelling behavior of 6188%. The mechanical stability (G', 2.3-2.7 kPa) of this polymeric hydrogel is commendable in the differentiation of mature neurons. This hydrogel is biocompatible (as tested in HUVEC cells) and helps to proliferate PC12 cells (152.7 ± 13.7%), whereas it is cytotoxic towards aggressive cancers such as glioblastoma (LN229 cells) and triple negative breast cancer (TNBC; MDA-MB-231 cells) and helps to maintain the healthy cytoskeleton framework structure of primary cortical neurons by facilitating the elongation of the axonal pathway. Furthermore, FACS results revealed that the synthesized hydrogel potentiates neurogenesis by inducing the cell cycle (G0/G1) and arresting the sub-G1 phase by limiting apoptosis. Additionally, RT-PCR results revealed that this hydrogel induced an increased level of HIF-1α expression, providing preconditioning effects towards neuronal cells under oxidative stress by scavenging ROS and initiating neurogenic and angiogenic signalling. This hydrogel further exhibits more pro-angiogenic activities by increasing the expression of VEGF isoforms compared to previously reported hydrogels. In conclusion, the newly synthesized p(NAG-Ac-NAE) hydrogel can be one of the potential neuroregenerative materials for vasculogenesis-assisted neurogenic applications and paramount for the management of neurodegenerative diseases.

Bioactive Metal Ion-Coordinated Dynamic Hydrogel with Antibacterial, Immunomodulatory, and Angiogenic Activities for Infected Wound Repair.

The repair of infected wounds is a complex physiopathologic process. Current studies on infected wound treatment have predominantly focused on infection treatment, while the factors related to delayed healing caused by vascular damage and immune imbalance are commonly overlooked. In this study, an extracellular matrix (ECM)-like dynamic and multifunctional hyaluronic acid (HA) hydrogel with antimicrobial, immunomodulatory, and angiogenic capabilities was designed as wound dressing for the treatment of infected skin wounds. The dynamic network in the hydrogel dressing was based on reversible metal-ligand coordination formed between sulfhydryl groups and bioactive metal ions. In our design, antibacterial silver and immunomodulatory zinc ions were employed to coordinate with sulfhydrylated HA and a vasculogenic peptide. In addition to the desired bioactivities for infected wounds, the hydrogel could also exhibit self-healing and injectable abilities. Animal experiments with infected skin wound models indicated that the hydrogel dressings enabled minimally invasive injection and seamless skin wound covering and then facilitated wound healing by efficient bacterial killing, continuous inflammation inhibition, and improved blood vessel formation. In conclusion, the metal ion-coordinated hydrogels with wound-infection-desired bioactivities and ECM-like dynamic structures represent a class of tissue bionic wound dressings for the treatment of infected and chronic inflammation wounds.

Screening of Short-Chain Antimicrobial Peptide LKARI with Broad-Spectrum Bactericidal Properties and Its Application in Promoting Wound Healing.

Due to the extensive use of antibiotics, many highly resistant bacteria and extensively resistant bacteria have been produced. In recent years, the increase of drug-resistant bacteria and the resulting proliferation of drug-resistant bacteria have increased the incidence of hospital-acquired infections and caused great harm to human health. Antimicrobial peptides (AMPs) are considered to be an innovative antibiotic and belong to the latest advances in this field. We designed a polypeptide and verified its low minimum inhibitory concentration and broad-spectrum activity against Gram-positive bacteria, Gram-negative bacteria, and fungi in microbiology and pharmacology. Several experiments have confirmed that the screened antimicrobial peptides have significant antidrug resistance and also show significant therapeutic properties in the treatment of systemic bacterial infections. In addition, through our experimental research, it was proved that the antibacterial hydrogel composed of poly(vinyl alcohol), sodium alginate, and antimicrobial peptides had excellent antibacterial properties and showed good wound healing ability.

Shape Self-Adaptive Liquid Embolic Agent for Ultrafast and Durable Vascular Embolization.

Minimally invasive embolization greatly decreases the mortality resulting from vascular injuries while still suffering from a high risk of recanalization and systematic thrombosis due to the intrinsic hydrophobicity and poor adhesion of the clinically used liquid embolic agent of Lipiodol. In this study, a shape self-adaptive liquid embolic agent was developed by mixing biocompatible poly(acrylic acid) (PAA), two-dimensional magnesium-aluminum layered double hydroxide (LDH), and poly(ethylene glycol)200 (PEG200). Upon contact with blood, the injectable PAA-LDH@PEG200 would quickly absorb water to form an adhesive and mechanically strong PAA-LDH thin hydrogel within 5 s, which could firmly adhere to the blood vessel wall for ultrafast and durable embolization. In addition, benefiting from the "positively charged nucleic center effect" of LDH nanosheets, the liquid PAA-LDH@PEG200 could avoid vascular distension by PAA overexpansion and possess high shock-resistant mechanical strength from the blood flow. Furthermore, both in vitro and in vivo embolization experiments demonstrated the complete embolic capacity of liquid PAA-LDH@PEG200 without the occurrence of recanalization for 28 days and also the great potential to act as a platform to couple with chemotherapeutic drugs for the minimized transcatheter arterial chemoembolization (TACE) treatment of VX2 tumors without recurrence for 18 days. Thus, liquid PAA-LDH@PEG200 developed here possesses great potential to act as a shape self-adaptive liquid embolic agent for ultrafast and durable vascular embolization.

Lignin-Based Antioxidant Hydrogel Patch for the Management of Atopic Dermatitis by Mitigating Oxidative Stress in the Skin.

Atopic dermatitis (AD), a chronic skin condition characterized by itching, redness, and inflammation, is closely associated with heightened levels of endogenous reactive oxygen species (ROS) in the skin. ROS can contribute to the onset and progression of AD through oxidative stress, which leads to the release of proinflammatory cytokines, T-cell differentiation, and the exacerbation of skin symptoms. In this study, we aim to develop a therapeutic antioxidant hydrogel patch for the potential treatment of AD using lignin, a biomass waste material. Lignin contains polyphenol groups that enable it to scavenge ROS and exhibit antioxidant properties. The lignin hydrogel patches, possessing optimized mechanical properties through the control of the lignin and cross-linker ratio, demonstrated high ROS-scavenging capabilities. Furthermore, the lignin hydrogel demonstrated excellent biocompatibility with the skin, exhibiting beneficial properties in protecting human keratinocytes under high oxidative conditions. When applied to an AD mouse model, the hydrogel patch effectively reduced epidermal thickness in inflamed regions, decreased mast cell infiltration, and regulated inflammatory cytokine levels. These findings collectively suggest that lignin serves as a therapeutic hydrogel patch for managing AD by modulating oxidative stress through its ROS-scavenging ability.

Enhancing bone regeneration and immunomodulation via gelatin methacryloyl hydrogel-encapsulated exosomes from osteogenic pre-differentiated mesenchymal stem cells.

Mesenchymal stem cell-derived exosomes (MSC-Exos) have emerged as promising candidates for cell-free therapy in tissue regeneration. However, the native osteogenic and angiogenic capacities of MSC-Exos are often insufficient to repair critical-sized bone defects, and the underlying immune mechanisms remain elusive. Furthermore, achieving sustained delivery and stable activity of MSC-Exos at the defect site is essential for optimal therapeutic outcomes. Here, we extracted exosomes from osteogenically pre-differentiated human bone marrow mesenchymal stem cells (hBMSCs) by ultracentrifugation and encapsulated them in gelatin methacryloyl (GelMA) hydrogel to construct a composite scaffold. The resulting exosome-encapsulated hydrogel exhibited excellent mechanical properties and biocompatibility, facilitating sustained delivery of MSC-Exos. Osteogenic pre-differentiation significantly enhanced the osteogenic and angiogenic properties of MSC-Exos, promoting osteogenic differentiation of hBMSCs and angiogenesis of human umbilical vein endothelial cells (HUVECs). Furthermore, MSC-Exos induced polarization of Raw264.7 cells from a pro-inflammatory phenotype to an anti-inflammatory phenotype under simulated inflammatory conditions, thereby creating an immune microenvironment conducive to osteogenesis. RNA sequencing and bioinformatics analysis revealed that MSC-Exos activate the p53 pathway through targeted delivery of internal microRNAs and regulate macrophage polarization by reducing DNA oxidative damage. Our study highlights the potential of osteogenic exosome-encapsulated composite hydrogels for the development of cell-free scaffolds in bone tissue engineering.

Alginate-gelatine hydrogel microspheres protect NK cell proliferation and cytotoxicity under hypoxic conditions.

AIMS: This study aimed to encapsulate natural killer (NK) cells in a hydrogel to sustain their function within the hypoxic tumour microenvironments. METHODS: An alginate-gelatine hydrogel was generated via electrospray technology. Hydrogel biocompatibility was assessed through cell counting kit-8 and Live/Dead assays to ascertain cell. Moreover, we analysed lactate dehydrogenase assays to evaluate the cytotoxicity against tumours and utilised RT-qPCR to analyse cytokine gene level. RESULTS: Alginate and gelatine formed hydrogels with diameters ranging from 489.2 ± 23.0 µm, and the encapsulation efficiency was 34.07 ± 1.76%. Encapsulated NK cells exhibited robust proliferation and tumour-killing capabilities under normoxia and hypoxia. Furthermore, encapsulation provided a protective shield against cell viability under hypoxia. Importantly, tumour-killing cytotoxicity through cytokines upregulation such as granzyme B and interferon-gamma was preserved under hypoxia. CONCLUSION: The encapsulation of NK cells not only safeguards their viability but also reinforces anticancer capacity, countering the inhibition of activation induced by hypoxia.

Sustained Release of Hydrogen and Magnesium Ions Mediated by a Foamed Gelatin-Methacryloyl Hydrogel for the Repair of Bone Defects in Diabetes.

Diabetic bone defects, exacerbated by hyperglycemia-induced inflammation and oxidative stress, present significant therapeutic challenges. This study introduces a novel injectable scaffold, MgH2@PLGA/F-GM, consisting of foamed gelatin-methacryloyl (GelMA) and magnesium hydride (MgH2) microspheres encapsulated in poly(lactic-co-glycolic acid) (PLGA). This scaffold is uniquely suited for diabetic bone defects, conforming to complex shapes and fostering an environment conducive to tissue regeneration. As it degrades, Mg(OH)2 is released and dissolved by PLGA's acidic byproducts, releasing therapeutic Mg2+ ions. These ions are instrumental in macrophage phenotype modulation, inflammation reduction, and angiogenesis promotion, all vital for diabetic bone healing. Additionally, hydrogen (H2) released during degradation mitigates oxidative stress by diminishing reactive oxygen species (ROS). This multifaceted approach not only reduces ROS and inflammation but also enhances M2 macrophage polarization and cell migration, culminating in improved angiogenesis and bone repair. This scaffold presents an innovative strategy for addressing the complexities of diabetic bone defect treatment.

Viscoelastic Supramolecular Hyaluronan-Peptide Cross-Linked Hydrogels.

Viscoelasticity plays a key role in hydrogel design. We designed a physically cross-linked hydrogel with tunable viscoelasticity, comprising supramolecular-assembled peptides coupled to hyaluronan (HA), a native extracellular matrix component. We then explored the structural and molecular mechanisms underlying the mechanical properties of a series of these HA-peptide hydrogels. By modifying the peptide sequence, we modulated both long- and short-time stress relaxation rates as a way to target viscoelasticity with limited impact on stiffness, leading to gels that relax up to 60% of stress in 10 min. Gels with the highest viscoelasticity exhibited large mesh sizes and ß-sheet secondary structures. The stiffness of the gel correlated with hydrogen bonding between the peptide chains. These gels are cytocompatible: highly viscoelastic gels that mimic the native skin microenvironment promote dermal fibroblast cell spreading. Moreover, HA-peptide gels enabled cell encapsulation, as shown with primary human T cells. Overall, these physically-cross-linked hydrogels enable tunable viscoelasticity that can be used to modulate cell morphology.

Antioxidative, Anti-Inflammatory, Antibacterial, Photo-Cross-Linkable Hydrogel of Gallic Acid-Chitosan Methacrylate: Synthesis, In Vitro, and In Vivo Assessments.

Chitosan (CS)-based photo-cross-linkable hydrogels have gained increasing attention in biomedical applications. In this study, we grafted CS with gallic acid (GA) by carbodiimide chemistry to prepare the GA-CS conjugate, which was subsequently modified with methacrylic anhydride (MA) modification to obtain the methacrylated GA-CS conjugate (GA-CS-MA). Our results demonstrated that the GA-CS-MA hydrogel not only exhibited improved physicochemical properties but also showed antibacterial, antioxidative, and anti-inflammatory capacity. It showed moderate antibacterial activity and especially showed a more powerful inhibitory effect against Gram-positive bacteria. It modulated macrophage polarization, downregulated pro-inflammatory gene expression, upregulated anti-inflammatory gene expression, and significantly reduced reactive oxygen species (ROS) and nitric oxide (NO) production under lipopolysaccharide (LPS) stimulation. Subcutaneously implanted GA-CS-MA hydrogels induced significantly lower inflammatory responses, as evidenced by less inflammatory cell infiltration, thinner fibrous capsule, and predominately promoted M2 polarization. This study provides a feasible strategy to prepare CS-based photo-cross-linkable hydrogels with improved physicochemical properties for biomedical applications.

Biomimetic and Wound Microenvironment-Modulating PEGylated Glycopolypeptide Hydrogels for Arterial Massive Hemorrhage and Wound Prohealing.

Despite great progress in the hydrogel hemostats and dressings, they generally lack resistant vascular bursting pressure and intrinsic bioactivity to meet arterial massive hemorrhage and proheal wounds. To address the problems, we design a kind of biomimetic and wound microenvironment-modulating PEGylated glycopolypeptide hydrogels that can be easily injected and gelled in ∼10 s. Those glycopolypeptide hydrogels have suitable tissue adhesion of ∼20 kPa, high resistant bursting pressure of ∼150 mmHg, large microporosity of ∼15 µm, and excellent biocompatibility with ∼1% hemolysis ratio and negligible inflammation. They performed better hemostasis in rat liver and rat and rabbit femoral artery bleeding models than Fibrin glue, Gauze, and other hydrogels, achieving fast arterial hemostasis of <20 s and lower blood loss of 5-13%. As confirmed by in vivo wound healing, immunofluorescent imaging, and immunohistochemical and histological analyses, the mannose-modified hydrogels could highly boost the polarization of anti-inflammatory M2 phenotype and downregulate pro-inflammatory tumor necrosis factor-α to relieve inflammation, achieving complete full-thickness healing with thick dermis, dense hair follicles, and 90% collagen deposition. Importantly, this study provides a versatile strategy to construct biomimetic glycopolypeptide hydrogels that can not only resist vascular bursting pressure for arterial massive hemorrhage but also modulate inflammatory microenvironment for wound prohealing.

BMSC loaded photo-crosslinked hyaluronic acid/collagen hydrogel incorporating FG4592 for enhanced cell proliferation and nucleus pulposus differentiation.

Intervertebral disc degeneration arises from damage or degeneration of the nucleus pulposus (NP). In this study, we developed a photo-crosslinkable hydrogel incorporating FG4592 to support the growth and differentiation of bone-marrow-derived mesenchymal stem cells (BMSC). Initially, hyaluronic acid was modified with tyramine and combined with collagen to introduce riboflavin as a photo-crosslinker. This hydrogel transitioned from liquid to gel upon exposure to blue light in 3 min. The results showed that the hydrogel was biodegradable and had mechanical properties comparable to those of human NP tissues. Scanning electron microscopy after BMSC seeding in the hydrogel revealed an even distribution, and cells adhered to the collagen fibers in the hydrogel with minimal cell mortality. The effect of FG4592 on BMSC proliferation and differentiation was examined, revealing the capability of FG4592 to promote BMSC proliferation and direct differentiation resembling human NP cells. After cultivating BMSCs in the photo-crosslinked hydrogel, there was an upregulation in the expression of glycosaminoglycans, aggrecan, type II collagen, and keratin 19 proteins. Cross-species analyses of rat and human BMSCs revealed consistent results. For potential clinical applications, BMSC loaded with photo-crosslinked hydrogels can be injected into damaged intervertebral disc to facilitate NP regeneration.

Highly swellable, cytocompatible and biodegradeable guar gum-based hydrogel system for controlled release of bioactive components of liquorice (Glycyrrhiza glabra L.): Synthesis and evaluation.

Glycyrrhiza glabra Linn (liquorice) has been widely used for therapeutic purposes to treat digestive disorders, immunomodulatory disorders, inflammatory disorders, diabetes, viral infections, and cancer. Liquorice contains a wide variety of bioactive compounds, including glycyrrhizin, flavonoids, and terpenoids. Several factors compromise their therapeutic efficacy, such as poor pharmacokinetic profiles and physicochemical properties. Therefore, to improve its overall effectiveness, liquorice solid dispersion (LSD) was incorporated into biopolymer-based guar gum-grafted-2-acrylamido-2-methylpropane sulfonic acid (Guar gum-g-AMPS) hydrogels designed for controlled delivery via the oral route and characterized. The qualitative analysis of LSD revealed 51 compounds. Hydrogel structural properties were assessed for their effect on swelling and release. The highest swelling ratio (6413 %) and drug release (84.12 %) occurred at pH 1.2 compared to pH 7.4 (swelling ratio of 2721 % and drug release of 79.36 %) in 48 h. The hydrogels exhibited high porosity (84.23 %) and biodegradation (9.30 % in 7 days). In vitro hemolysis tests have demonstrated the compatibility of the hydrogel with blood. CCK-8 assay confirmed the biocompatibility of the synthesized hydrogel using osteoblasts and RIN-m5f cells. LSD exhibited good anti-inflammatory activity when loaded into hydrogels after being subjected to protein denaturation experiments. Moreover, LSD-loaded hydrogels have good antioxidant and antibacterial properties.

Carbene-mediated gelatin and hyaluronic acid hydrogel paints with ultra adhesive ability for arthroscopic cartilage repair.

In articular cartilage defect, particularly in arthroscopy, regenerative hydrogels are urgently needed. It should be able to firmly adhere to the cartilage tissue and maintain sufficient mechanical strength to withstand approximately 10 kPa of arthroscopic hydraulic flushing. In this study, we report a carbene-mediated ultra adhesive hybrid hydrogel paints for arthroscopic cartilage repair, which combined the photo initiation of double crosslinking system with the addition of diatomite, as a further reinforcing agent and biological inorganic substances. The double network consisting of ultraviolet initiated polymerization of hyaluronic acid methacrylate (HAMA) and carbene insertion chemistry of diazirine-grafted gelatin (GelDA) formed an ultra-strong adhesive hydrogel paint (H2G5DE). Diatomite helped the H2G5DE hydrogel paint firmly adhere to the cartilage defect, withstanding nearly 100 kPa of hydraulic pressure, almost 10 times that in clinical arthroscopy. Furthermore, the H2G5DE hydrogel supported cell growth, proliferation, and migration, thus successfully repairing cartilage defects. Overall, this study demonstrates a proof-of-concept of ultra-adhesive polysaccharide hydrogel paints, which can firmly adhere to the articular cartilage defects, can resist continuous hydraulic pressure, can promote effective cartilage regeneration, and is very suitable for minimally invasive arthroscopy.

Multi-dynamic-bond cross-linked antibacterial and adhesive hydrogel based on boronated chitosan derivative and loaded with peptides from Periplaneta americana with on-demand removability.

The design and development of a bio-adhesive hydrogel with on-demand removability and excellent antibacterial activities are meaningful to achieve high wound closure effectiveness and post-wound-closure care, which is desirable in clinical applications. In this work, a series of adhesive antioxidant antibacterial hydrogels containing peptides from Periplaneta americana (PAP) were prepared through multi-dynamic-bond cross-linking among 3,4-dihydroxybenzaldehyde (DBA) containing catechol and aldehyde groups and chitosan grafted with 3-carboxy-4-fluorophenylboronic acid (CS-FPBA) to enable the effective adhesion of skin tissues and prevention of bacterial infection of wound. PAP was derived from alcohol-extracted residues generated during the pharmaceutical process, aiming to minimize resource wastage and achieve the high-value development of such a medicinal insect. The hydrogel was prepared by freezing-thawing with no toxic crosslinkers. The multi-dynamic-bond cross-linking of dynamic borate ester bonds and dynamic Schiff base bonds can achieve reversible breakage and re-formation and the adhesive strength of CS-FPBA-DBA-P-gel treated with a 20 % glucose solution dramatically decreased from 3.79 kPa to 0.35 kPa within 10 s. Additionally, the newly developed hydrogel presents ideal biocompatibility, hemostasis and antibacterial activity against Staphylococcus aureus and Escherichia coli compared to commercial chitosan gel (approximately 50 % higher inhibition rate), demonstrating its great potential in dealing with infected full-thickness skin wounds.

Multifunctional pH-responsive hydrogel dressings based on carboxymethyl chitosan: Synthesis, characterization fostering the wound healing.

Antibiotic abuse is increasing the present rate of drug-resistant bacterial wound infections, producing a significant healthcare burden globally. Herein, we prepared a pH-responsive CMCS/PVP/TA (CPT) multifunctional hydrogel dressing by embedding the natural plant extract TA as a nonantibiotic and cross-linking agent in carboxymethyl chitosan (CMCS) and polyvinylpyrrolidone (PVP) to prompt wound healing. The CPT hydrogel demonstrated excellent self-healing, self-adaptive, and adhesion properties to match different wound requirements. Importantly, this hydrogel showed pH sensitivity and exhibited good activity against resistant bacteria and antioxidant activity by releasing TA in case of bacterial infection (alkaline). Furthermore, the CPT hydrogel exhibited coagulant ability and could rapidly stop bleeding within 30 s. The biocompatible hydrogel effectively accelerated wound healing in a full-thickness skin defect model by thickening granulation tissue, increasing collagen deposition, vascular proliferation, and M2-type macrophage polarization. In conclusion, this study demonstrates that multifunctional CPT hydrogel offers a candidate material with potential applications for infected skin wound healing.

Extracellular Matrix Mimicking Wound Microenvironment Responsive Amyloid-Heparin@TAAgNP Co-Assembled Hydrogel: An Effective Conductive Antibacterial Wound Healing Material.

Bioengineered composite hydrogel platforms made of a supramolecular coassembly have recently garnered significant attention as promising biomaterial-based healthcare therapeutics. The mechanical durability of amyloids, in conjunction with the structured charged framework rendered by biologically abundant key ECM component glycosaminoglycan, enables us to design minimalistic customized biomaterial suited for stimuli responsive therapy. In this study, by harnessing the heparin sulfate-binding aptitude of amyloid fibrils, we have constructed a pH-responsive extracellular matrix (ECM) mimicking hydrogel matrix. This effective biocompatible platform comprising heparin sulfate-amyloid coassembled hydrogel embedded with polyphenol functionalized silver nanoparticles not only provide a native skin ECM-like conductive environment but also provide wound-microenvironment responsive on-demand superior antibacterial efficacy for effective diabetic wound healing. Interestingly, both the cytocompatibility and antibacterial properties of this bioinspired matrix can be fine-tuned by controlling the mutual ratio of heparin sulfate-amyloid and incubated silver nanoparticle components, respectively. The designed biomaterial platform exhibits notable effectiveness in the treatment of chronic hyperglycemic wounds infected with multidrug-resistant bacteria, because of the integration of pH-responsive release characteristics of the incubated functionalized AgNP and the antibacterial amyloid fibrils. In addition to this, the aforementioned assemblage shows exceptional hemocompatibility with significant antibiofilm and antioxidant characteristics. Histological evidence of the incised skin tissue sections indicates that the fabricated composite hydrogel is also effective in controlling pro-inflammatory cytokines such as IL6 and TNFα expressions at the wound vicinity with significant upregulation of angiogenesis markers like CD31 and α-SMA.

Lithium Promotes Osteogenesis via Rab11a-Facilitated Exosomal Wnt10a Secretion and ß-Catenin Signaling Activation.

Both bone mesenchymal stem cells (BMSCs) and their exosomes suggest promising therapeutic tools for bone regeneration. Lithium has been reported to regulate BMSC function and engineer exosomes to improve bone regeneration in patients with glucocorticoid-induced osteonecrosis of the femoral head. However, the mechanisms by which lithium promotes osteogenesis have not been elucidated. Here, we demonstrated that lithium promotes the osteogenesis of BMSCs via lithium-induced increases in the secretion of exosomal Wnt10a to activate Wnt/ß-catenin signaling, whose secretion is correlated with enhanced MARK2 activation to increase the trafficking of the Rab11a and Rab11FIP1 complexes together with exosomal Wnt10a to the plasma membrane. Then, we compared the proosteogenic effects of exosomes derived from lithium-treated or untreated BMSCs (Li-Exo or Con-Exo) both in vitro and in vivo. We found that, compared with Con-Exo, Li-Exo had superior abilities to promote the uptake and osteogenic differentiation of BMSCs. To optimize the in vivo application of these hydrogels, we fabricated Li-Exo-functionalized gelatin methacrylate (GelMA) hydrogels, which are more effective at promoting osteogenesis and bone repair than Con-Exo. Collectively, these findings demonstrate the mechanism by which lithium promotes osteogenesis and the great promise of lithium for engineering BMSCs and their exosomes for bone regeneration, warranting further exploration in clinical practice.

Self-Healing Conductive Hydrogels with Dynamic Dual Network Structure Accelerate Infected Wound Healing via Photothermal Antimicrobial and Regulating Inflammatory Response.

Wound infections are an escalating clinical challenge with continuous inflammatory response and the threat of drug-resistant bacteria. Herein, a series of self-healing conductive hydrogels were designed based on carboxymethyl chitosan/oxidized sodium alginate/polymerized gallic acid/Fe3+ (CMC/OSA/pGA/Fe3+, COGFe) for promoting infected wound healing. The Schiff base and catechol-Fe3+ chelation in the dynamical dual network structure of the hydrogels endowed dressings with good toughness, conductivity, adhesion, and self-healing properties, thus flexibly adapting to the deformation of skin wounds. In terms of ultraviolet (UV) resistance and scavenging of reactive oxygen species (ROS), the hydrogels significantly reduced oxidative stress at the wound site. Additionally, the hydrogels with photothermal therapy (PTT) achieved a 95% bactericidal rate in 5 min of near-infrared (NIR) light radiation by disrupting the bacterial cell membrane structure through elevated temperature. Meanwhile, the inherent antimicrobial properties of GA could reduce healthy tissue damage caused by excessive heat. The composite hydrogels could effectively promote the proliferation and migration of fibroblasts and possess good biocompatibility and hemostatic effect. In full-thickness infected wound repair experiments in rats, the COGFe5 hydrogel combined with NIR effectively killed bacteria, modulated macrophage polarization (M1 to M2 phenotype) to improve the immune microenvironment of the wound, and shortened the repair time by accelerating the expression of collagen deposition (TGF-ß) and vascular factors (CD31). This combined therapy might provide a prospective strategy for infectious wound treatment.