Healing Of Full-thickness Skin Wounds Research Articles

Injectable chitosan/xyloglucan composite hydrogel with mechanical adaptivity and endogenous bioactivity for skin repair

Delayed or chronic wound healing is one of severe clinical issues. Developing scaffold materials capable of supporting cells and inducing tissue regeneration remains a challenge. Here, a polysaccharide-based hydrogel is constructed for promoting full-thickness skin wound healing in mouse model. The engineering hydrogel consists of a dynamic crosslinking network formed by the Schiff base reaction between aldehyde-containing xyloglucan and methacrylated chitosan. Its reversible gel-sol-gel transition upon shearing force is highly beneficial to completely cover and fill irregular wound shape. The second covalent cross-linking network achieved by photo-initiated polymerization offers a feasible way to tune the mechanical property of hydrogel after injection, with an ideal mechanical adaptivity for clinical application. Remarkably, both in vitro and in vivo evaluations demonstrate that the hydrogel with endogenously bioactive galactoside units can promote cell spheroid formation and accelerate wound healing by expediting re-epithelialization, collagen deposition, angiogenesis as well as the formation of hair follicles.

Nature-Skin-Derived e-Skin as Versatile "Wound Therapy-Health Monitoring" Bioelectronic Skin-Scaffolds: Skin to Bio-e-Skin.

Electronic skins (e-skins) have the potential to turn into breakthroughs in biomedical applications. Herein, a novel acellular dermal matrix (ADM)-based bioelectronic skin (e-ADM) is used to fabricate versatile "wound therapy-health monitoring" tissue-nanoengineered skin scaffolds via a facile "one-pot" bio-compositing strategy to incorporate the conductive carbon nanotubes and self-assembled micro-copper oxide microspheres with a cicada-wing-like rough surface and nanocone microstructure. The e-ADM exhibits robust tensile strength (22MPa), flexibility, biodegradability, electroactivity, and antibacterial properties. Interestingly, e-ADM exhibits the pH-responsive ability for intelligent command between sterilization and wound repair . Additionally, e-ADM enables accurate real-time monitoring of human activities, providing a novel flexible e-skin sensor to record injury and motions. In vitro and in vivo experiments show that with electrical stimulation, e-ADM could prominently facilitate cell growth and proliferation and further promote full-thickness skin wound healing, providing a comprehensive therapeutic strategy for smart sensing and tissue repair, guiding the development of high-performance "wound therapy-health monitoring" bioelectronic skin-scaffolds.

Human adipose tissue-derived small extracellular vesicles promote soft tissue repair through modulating M1-to-M2 polarization of macrophages

BackgroundSuccessful regenerative medicine strategies need the manipulation and control of macrophages’ phenotypic switching. Our previous study indicated that rat and porcine adipose tissue-derived small extracellular vesicles could successfully promote soft tissue repair. However, whether human adipose tissue-derived small extracellular vesicles (h-sEV-AT) showed the same ability to promote soft tissue regeneration and whether adipose tissue-derived small extracellular vesicles (sEV-AT) contribute to modulating the polarization of macrophages were unknown.MethodsIn this study, we, for the first time, isolated h-sEV-AT from liposuction adipose tissue and characterized the morphology, size distribution, and marker protein. In vitro, we treated adipose-derived stromal/stem cells (ASCs), endothelial cells (ECs), and M1 macrophages with h-sEV-AT. In vivo, the ability of h-sEV-AT to promote soft tissue regeneration and polarize macrophages was investigated.ResultsThe results indicated that h-sEV-AT possessed the characteristics of small extracellular vesicles (sEVs). In vitro, an obvious increase in adipogenesis and angiogenesis was induced by h-sEV-AT. In vivo, h-sEV-AT successfully induced the regeneration of adipose tissue and effectively accelerated full-thickness skin wound healing. Besides, we found that h-sEV-AT showed the ability to increase the percentage of M2 macrophages both in vivo and in vitro, which had been reported to contribute to tissue repair and regeneration.ConclusionsTaken together, these results suggested that h-sEV-AT showed the ability to induce soft tissue repair supported by not only the differentiation of ASCs and ECs but also the polarization of macrophages. Considering the abundant sources, high yield, and guaranteed effectiveness, this study provided a cell-free strategy for soft tissue regeneration that directly isolated small extracellular vesicles from human liposuction adipose tissue.

Moisture-Adaptive Contractile Biopolymer-Derived Fibers for Wound Healing Promotion.

The advancement in thermosensitive active hydrogels has opened promising opportunities to dynamic full-thickness skin wound healing. However, conventional hydrogels lack breathability to avoid wound infection and cannot adapt to wounds with different shapes due to the isotropic contraction. Herein, a moisture-adaptive fiber that rapidly absorbs wound tissue fluid and produces a large lengthwise contractile force during the drying process is reported. The incorporation of hydroxyl-rich silica nanoparticles in the sodium alginate/gelatin composite fiber greatly improves the hydrophilicity, toughness, and axial contraction performance of the fiber. This fiber exhibits a dynamic contractile behavior as a function of humidity, generating ≈15% maximum contraction strain or ≈24MPa maximum isometric contractile stress. The textile knitted by the fibers features excellent breathability and generates adaptive contraction in the target direction during the natural desorption of tissue fluid from the wounds. In vivo animal experiments further demonstrate the advantages of the textiles over traditional dressings in accelerating wound healing.

Peptide RL-QN15 promotes regeneration of epidermal nerve fibers and recovery of sensory function in diabetic skin wounds.

Epidermal nerve fiber regeneration and sensory function are severely impaired in skin wounds of diabetic patients. To date, however, research on post-traumatic nerve regeneration and sensory reconstruction remains scarce, and effective clinical therapeutics are lacking. In the current study, localized treatment with RL-QN15, considered as a drug candidate for intervention in skin wounds in our previous research, accelerated the healing of full-thickness dorsal skin wounds in diabetic mice and footpad skin wounds in diabetic rats. Interestingly, nerve density and axonal plasticity in the skin wounds of diabetic rats and mice, as well as plantar sensitivity in diabetic rats, were markedly enhanced by RL-QN15 treatment. Furthermore, RL-QN15 promoted the proliferation, migration, and axonal length of neuron-like PC12 cells, which was likely associated with activation of the phosphatidylinositol-3 kinase/protein kinase B (PI3K/Akt) signaling pathway. The therapeutic effects of RL-QN15 were partially reduced by blocking the PI3K/Akt signaling pathway with the inhibitor LY294002. Thus, RL-QN15 showed positive therapeutic effects on the distribution of epidermal nerve fibers and stimulated the recovery of sensory function after cutaneous injury. This study lays a solid foundation for the development of RL-QN15 peptide-based therapeutics against diabetic skin wounds.

Accelerating full-thickness skin wound healing using Zinc and Cobalt doped-bioactive glass-coated eggshell membrane

The quest to develop advanced wound dressing with excellent healing properties is an unending clinical challenge. Several biological molecules have shown promising results in this regard. We utilized eggshell membrane, a waste product generated from egg processing industries, and coated it with bioactive glass/ion-doped (Zn, Co) bioactive glass in the nanoscale range to develop four different types of wound dressing mats (ESM/BAG, ESM/ZnBAG, ESM/CoBAG, ESM/ZnCoBAG). All the mats were cytocompatible with human dermal fibroblasts and maintained cytoskeletal and nuclear morphology up to day 14 of culture. On application of these mats over the full-thickness skin wounds in the rabbit model, enhanced wound closure was observed especially with the eggshell membrane/ion-doped bioactive glass mats. These mats also demonstrated orderly and timely deposition of ECM components i.e., collagen, elastin, and reticulin. These wound remodeling and early healing features could be attributed to the bioactive properties of eggshell membranes along with the Zinc and Cobalt doped bioactive glass. These mats thus hold enormous potential as an economic wound dressing and also in biomedical applications.

Facile fabrication of self-healing, injectable and antimicrobial cationic guar gum hydrogel dressings driven by hydrogen bonds

Developing self-healing polysaccharide hydrogels offers a promising strategy for the healing of full-thickness skin wounds. However, the green and facile fabrication of self-healing polysaccharide hydrogel dressings is challenging. Herein, a novel hydrogen-bonded polysaccharide hydrogel consisting only of cationic guar gum (CG) and CuCl2 was developed by simply mixing CG and Cu2+ solution. A strong enough intermolecular hydrogen bonding could be formed between ipsilateral hydroxyl groups to induce rapid gelation. Benefiting from dynamic and reversible linkages, cationic guar gum-Cu2+ (CG-Cu) hydrogels exhibited self-healing, injectable and self-adaption. The CG-Cu hydrogels possessed favorable mechanical strength (compression strength: 50–89 kPa), excellent biocompatibility (cell viability: >95 %; hemolysis ratio: < 5 %) and satisfying antibacterial ability. In vivo degradation tests showed that the CG-Cu hydrogels could be completely degraded after 21 days. Furthermore, in-situ injected CG-Cu hydrogel dressings could perfectly cover wounds to reduce risk of infection and accelerated full-thickness skin generation. In conclusion, this study may provide a new simple and straightforward strategy to prepare self-healing polysaccharide hydrogels based on hydrogen bonding to expand its application in the field of biomedicine and tissue regeneration.

Application of 3D-printed tissue-engineered skin substitute using innovative biomaterial loaded with human adipose-derived stem cells in wound healing.

Large-scale skin injuries are usually accompanied by impaired wound healing, resulting in scar formation, or significant morbidity and mortality. The aim of this study is to explore the in vivo application of 3D-printed tissue-engineered skin substitute using innovative biomaterial loaded with human adipose-derived stem cells (hADSCs) in wound healing. Adipose tissue was decellularized, and extracellular matrix components were lyophilized and solubilized to obtain adipose tissue decellularized extracellular matrix (dECM) pre-gel. The newly designed biomaterial is composed of adipose tissue dECM pre-gel, methacrylated gelatin (GelMA), and methacrylated hyaluronic acid (HAMA). Rheological measurement was performed to evaluate the phase-transition temperature and the storage and loss modulus at this temperature. Tissue-engineered skin substitute loaded with hADSCs was fabricated by 3D printing. We used nude mice to establish full-thickness skin wound healing model and divided them into four groups randomly: (A) Full-thickness skin graft treatment group, (B) 3D-bioprinted skin substitute treatment group as the experimental group, (C) microskin graft treatment group, and (D) control group. The amount of DNA in each milligram of dECM was 24.5 ± 7.1 ng, fulfilling the currently accepted decellularization criteria. The solubilized adipose tissue dECM was thermo-sensitive biomaterial and underwent a sol-gel phase transition when temperature rises. The dECM-GelMA-HAMA precursor undergoes a gel-sol phase transition at 17.5°C, where the storage and loss modulus of the precursor is about 8 Pa. The scanning electron microscope showed that the interior of crosslinked dECM-GelMA-HAMA hydrogel is 3D porous network structure with suitable porosity and pore size. The shape of the skin substitute is stable with regular grid-like scaffold structure. Wound healing in the experimented animals was accelerated after being treated with 3D-printed skin substitute, which attenuate inflammatory response, increase blood perfusion around the wound, as well as promote re-epithelialization, collagen deposition and alignment, and angiogenesis. In summary, 3D-printed dECM-GelMA-HAMA tissue-engineered skin substitute loaded with hADSCs, which can be fabricated by 3D printing, can accelerate wound healing and improve healing quality by promoting angiogenesis. The hADSCs and the stable 3D-printed stereoscopic grid-like scaffold structure play a critical role in promoting wound healing.

A natural biological adhesive from snail mucus for wound repair

The discovery of natural adhesion phenomena and mechanisms has advanced the development of a new generation of tissue adhesives in recent decades. In this study, we develop a natural biological adhesive from snail mucus gel, which consists a network of positively charged protein and polyanionic glycosaminoglycan. The malleable bulk adhesive matrix can adhere to wet tissue through multiple interactions. The biomaterial exhibits excellent haemostatic activity, biocompatibility and biodegradability, and it is effective in accelerating the healing of full-thickness skin wounds in both normal and diabetic male rats. Further mechanistic study shows it effectively promotes the polarization of macrophages towards the anti-inflammatory phenotype, alleviates inflammation in chronic wounds, and significantly improves epithelial regeneration and angiogenesis. Its abundant heparin-like glycosaminoglycan component is the main active ingredient. These findings provide theoretical and material insights into bio-inspired tissue adhesives and bioengineered scaffold designs.

A CS-based composite scaffold with excellent photothermal effect and its application in full-thickness skin wound healing.

The development of natural polymer-based scaffolds with excellent biocompatibility, antibacterial activity, and blood compatibility, able to facilitate full-thickness skin wound healing, remains challenging. In this study, we have developed three chitosan (CS)-based porous scaffolds, including CS, CS/CNT (carbon nanotubes) and CS/CNT/HA (nano-hydroxyapatite, n-HA) using a freeze-drying method. All three scaffolds have a high swelling ratio, excellent antibacterial activity, outstanding cytocompatibility and blood compatibility in vitro. The introduction of CNTs exhibited an obvious increase in mechanical properties and exerts excellent photothermal response, which displays excellent healing performance as a wound dressing in mouse full-thickness skin wound model when compared to CS scaffolds. CS/CNT/HA composite scaffolds present the strongest ability to promote full-thickness cutaneous wound closure and skin regeneration, which might be ascribed to the synergistic effect of photothermal response from CNT and excellent bioactivity from n-HA. Overall, the present study indicated that CNT and n-HA can be engineered as effective constituents in wound dressings to facilitate full-thickness skin regeneration.

In Situ-Formed Fibrin Hydrogel Scaffold Loaded With Human Umbilical Cord Mesenchymal Stem Cells Promotes Skin Wound Healing

Healing of full-thickness skin wounds remains a major challenge. Recently, human umbilical cord mesenchymal stem cells (hUC-MSCs) were shown to possess an extraordinary potential to promote skin repair in clinical settings. However, their low survival rate after transplantation limits their therapeutic efficiency in treating full-thickness skin wounds. Hydrogels are considered an ideal cell transplantation vector owing to their three-dimensional mesh structure, good biosafety, and biodegradation. The objective of this study was to investigate the skin wound healing effect of a fibrin hydrogel scaffold loaded with hUC-MSCs. We found that the fibrin hydrogel had a three-dimensional mesh structure and low cytotoxicity and could prolong the time of cell survival in the peri-wound area. The number of green fluorescent protein (GFP)-labeled hUC-MSCs was higher in the full-thickness skin wound of mice treated with hydrogel–hUC-MSCs than those of mice treated with cell monotherapy. In addition, the combination therapy between the hydrogel and hUC-MSCs speed up wound closure, its wound healing rate was significantly higher than those of phosphate-buffered saline (PBS) therapy, hydrogel monotherapy, and hUC-MSCs monotherapy. Furthermore, the results showed that the combination therapy between hydrogel and hUC-MSCs increased keratin 10 and keratin 14 immunofluorescence staining, and upregulated the relative gene expressions of epidermal growth factor (EGF), transforming growth factor-β1 (TGF-β1), and vascular endothelial growth factor A (VEGFA), promoting epithelial regeneration and angiogenesis. In conclusion, the fibrin hydrogel scaffold provides a relatively stable sterile environment for cell adhesion, proliferation, and migration, and prolongs cell survival at the wound site. The hydrogel–hUC-MSCs combination therapy promotes wound closure, re-epithelialization, and neovascularization. It exhibits a remarkable therapeutic effect, being more effective than the monotherapy with hUC-MSCs or hydrogel.

Highly stretchable porous regenerated silk fibroin film for enhanced wound healing.

Silk fibroin (SF) has received interest in tissue engineering owing to its biocompatibility, biodegradability, and favorable mechanical properties. However, the complex preparation, brittleness, and lack of pores in the structure of the silk fibroin film limit its application. Herein, we show that facile dissolution of SF in aqueous phosphoric acid followed by regeneration in aqueous ammonium sulfate ((NH4)2SO4) could afford highly stretchable films with nano-pores formed in the nonsolvent-induced phase separation process. The named phase separation, which determines the morphology and mechanical properties of the regeneration silk fibroin (RSF) films, is highly dependent on the (NH4)2SO4 concentration as well as the initial concentration of the SF solution. Therefore, the RSF films exhibit a tunable pore size ranging from 230 to 510 nm and excellent stretchability with tensile strain up to 143 ± 16%. Most interestingly, the RSF films were shown to support the proliferation of human skin fibroblasts in vitro as well as speed up full-thickness skin wound healing in a rat model. This work establishes an easy and feasible method to access porous RSF membranes that can be used for wound dressing in clinical settings.

Engineering ultrasound-activated piezoelectric hydrogels with antibacterial activity to promote wound healing.

The development of nanocomposite hydrogel dressings with adhesion and superior mechanical and wound infection inhibition characteristics for wound repair and skin regeneration is urgently needed for clinical applications. In this study, the adhesive piezoelectric antibacterial hydrogels with high expansibility, degradability, and adjustable rheological properties were innovatively prepared by a simple assembly process with carboxymethyl chitosan (CMCS), tannic acid (TA), carbomer (CBM), and piezoelectric FeWO4 nanorods. As an exogenous mechanical wave, ultrasound can trigger the piezoelectric effect of FeWO4 and then effectively augment the generation of reactive oxygen species, exhibiting a superior antibacterial efficiency and preventing wound infection. In vitro and in vivo results have demonstrated that piezoelectric hydrogels can accelerate full-thickness skin wound healing in bacteria-infected mice by skin regeneration, inhibiting inflammatory response, increasing collagen deposition, and promoting angiogenesis. Such a discovery provides a representative paradigm for the rational design of piezoelectric hydrogel and effectively serves antibacterial and wound dressing fields.

Gelatin Microspheres Loaded with Wharton's Jelly Mesenchymal Stem Cells Promote Acute Full-Thickness Skin Wound Healing and Regeneration in Mice.

Objective: At present, there is an urgent need to develop a novel and practical therapeutic approach to accelerate the healing of acute wounds. Mesenchymal stem cell (MSC)-based therapy is emerging as a promising therapeutic approach for acute skin wounds. However, there are still challenges in clinical application of this strategy, such as low survivability, low retention time, and less engraftment in skin wounds. Approach: Wharton's jelly mesenchymal stem cells (WJMSCs) were seeded into three-dimensional (3D) gelatin microspheres (GMs) to identify the biocompatibility of GMs. WJMSCs were embedded in GMs and then encapsulated with Pluronic F-127 (PF-127) and sodium ascorbyl phosphate (SAP) combination to transplant onto acute full-thickness skin wound in mice. Histology, immunohistochemistry, and immunofluorescence assay were used to investigate the skin wound healing, dermis regeneration, collagen deposition, cell proliferation, and neovascularization. Results: Three-dimensional GM had strong biocompatibility, compared with two-dimensional adherent culturing, GM loading increased the cell viability and proliferation ability of WJMSCs. WJMSCs+GM+PF-127+SAP transplantation increased skin wound healing rate, dermis regeneration, and type III collagen deposition through improving macrophage polarization, cell proliferation, neovascularization, cell retention, and engraftment at skin wound site. Innovation: The effective 3D encapsulation technology for WJMSCs solved the main problems of cell activity and residence time during MSC transplantation. WJMSCs+GM+PF-127+SAP transplantation will be a new and effective MSC biomaterials-based therapeutic strategy for acute skin traumatic wounds. Conclusion: WJMSCs+GM+PF-127+SAP transplantation facilitated acute full-thickness skin wound healing and regeneration and might be a new and effective therapy for acute skin traumatic wounds.

Study of polydopamine-modified β-chitin nanofiber hydrogels for full-thickness wound healing

Developing natural polymer-based hydrogel with excellent injectability, suitable mechanical properties, and the ability to facilitate full-thickness skin wound healing is highly desirable in clinical application. Herein injectable hydrogels made of polydopamine (PDA) modified β-chitin nanofibers (β-ChNFs) were successfully prepared and applied for irregular wound healing. Compared with β-ChNFs hydrogels which were too weak to be used, the surface coating of PDA helped concentrate the β-ChNFs, and hydrogels with much higher strength were obtained and could be conveniently applied to the wound. The incorporation of chitosan oligosaccharide (COS) remarkably increased the hydrogels’ bioactivity. Shown as the biocompatibility measurement, ChNFs-PDA-COS hydrogels significantly promoted the proliferation of L929 cells. Demonstrated by the in vivo study in a rat full-thickness skin defect model, ChNFs-PDA-COS hydrogels with 1 % of COS significantly reduced inflammatory cell infiltration, improved the maturation of granulation tissue and well-organized collagen deposition, and regenerated thick dermis and epidermis with some cutaneous appendages at 9th post-operative day. All these contributed to the acceleration of wound closure and a better healing outcome as compared to the control group, indicating that the COS-incorporated ChNFs-PDA hydrogels are promising wound dressing for full-thickness skin tissue repair.

A cyclic heptapeptide-based hydrogel boosts the healing of chronic skin wounds in diabetic mice and patients

The combined use of peptides, nanomaterials, and hydrogels is a promising strategy for chronic skin wound healing, which remains a huge clinical challenge. Here, we optimized the RL-QN15 peptide, which was shown to be a pro-healing drug candidate in our previous research, to obtain the cyclic heptapeptide (CyRL-QN15) with considerable therapeutic potency against skin wounds. Furthermore, a Zn2+-crosslinked sodium alginate (ZA) hydrogel containing hollow polydopamine (HPDA) nanoparticles loaded with CyRL-QN15 (HPDAlCyRL-QN15/ZA hydrogel) was prepared and characterized, which significantly enhanced the pro-healing potency of CyRL-QN15. At the cellular level, this nontoxic hydrogel accelerated the proliferation, migration, tube formation, and scratch healing of skin cells, regulated the secretion of cytokines from macrophages, directly scavenged free radicals, and decreased reactive oxygen species. Moreover, the HPDAlCyRL-QN15/ZA hydrogel significantly accelerated the healing of full-thickness skin wounds in type 2 diabetic mice by promoting the transition of macrophages to the M2 phenotype to reduce inflammation and cause re-epithelialization, formation of granulation tissue, deposition of collagen, and angiogenesis. Of note, the hydrogel also facilitated wound healing of diabetic patient skin cultured ex vivo. Overall, the HPDAlCyRL-QN15/ZA hydrogel presents a novel therapeutic strategy for clinical chronic skin wound (diabetic ulcer) healing.

GDF11 promotes wound healing in diabetic mice via stimulating HIF-1ɑ-VEGF/SDF-1ɑ-mediated endothelial progenitor cell mobilization and neovascularization.

Non-healing diabetic wounds (DW) are a serious clinical problem that remained poorly understood. We recently found that topical application of growth differentiation factor 11 (GDF11) accelerated skin wound healing in both Type 1 DM (T1DM) and genetically engineered Type 2 diabetic db/db (T2DM) mice. In the present study, we elucidated the cellular and molecular mechanisms underlying the action of GDF11 on healing of small skin wound. Single round-shape full-thickness wound of 5-mm diameter with muscle and bone exposed was made on mouse dorsum using a sterile punch biopsy 7 days following the onset of DM. Recombinant human GDF11 (rGDF11, 50 ng/mL, 10 μL) was topically applied onto the wound area twice a day until epidermal closure (maximum 14 days). Digital images of wound were obtained once a day from D0 to D14 post-wounding. We showed that topical application of GDF11 accelerated the healing of full-thickness skin wounds in both type 1 and type 2 diabetic mice, even after GDF8 (a muscle growth factor) had been silenced. At the cellular level, GDF11 significantly facilitated neovascularization to enhance regeneration of skin tissues by stimulating mobilization, migration and homing of endothelial progenitor cells (EPCs) to the wounded area. At the molecular level, GDF11 greatly increased HIF-1ɑ expression to enhance the activities of VEGF and SDF-1ɑ, thereby neovascularization. We found that endogenous GDF11 level was robustly decreased in skin tissue of diabetic wounds. The specific antibody against GDF11 or silence of GDF11 by siRNA in healthy mice mimicked the non-healing property of diabetic wound. Thus, we demonstrate that GDF11 promotes diabetic wound healing via stimulating endothelial progenitor cells mobilization and neovascularization mediated by HIF-1ɑ-VEGF/SDF-1ɑ pathway. Our results support the potential of GDF11 as a therapeutic agent for non-healing DW.

Scaffolds Based on Silk Fibroin with Decellularized Rat Liver Microparticles: Investigation of the Structure, Biological Properties and Regenerative Potential for Skin Wound Healing.

The development of advanced biomaterials and constructs for accelerated recovery of damaged tissues is a key direction in regenerative medicine. Biocompatible scaffolds based on natural biopolymers are widely used for these tasks. Organ decellularization enables obtaining a cell-free extracellular matrix (ECM) with preserved composition and biological activity. The objectives of the present work were combining these two approaches for the development of a composite scaffold based on silk fibroin and ECM microparticles and assessing its structure, biological properties, and regenerative potential. ECM microparticles were obtained by grinding the decellularized matrix of Wistar rat liver in liquid nitrogen. Scaffolds in the form of films were prepared by the casting method. The sinuous and rough topography of the scaffold surface was assessed by the scanning probe nanotomography (SPNT) technique. The inclusion of ECM microparticles in the composition did not affect the elasticity and tensile strength of the scaffolds. The obtained scaffold was non-toxic to cells, maintained high levels of adhesion and proliferation of mouse 3T3 fibroblast and Hep-G2 cells, and showed high regenerative potential, which was studied in the experimental model of full-thickness rat skin wound healing. The wound healing was accelerated by 1.74 times in comparison with the control.

Mechanoactive Nanocomposite Hydrogel to Accelerate Wound Repair in Movable Parts.

Dynamic full-thickness skin wound healing remains an intricate problem due to the humid environment and frequent exercise. Recently, multifunctional hydrogels have a great promise in wound repair. However, traditional hydrogels only keep the wound moist, protect the wound from bacterial infection, and cannot actively drive dynamic wound closure. Inspired by embryo wound active closure, we constructed a double-sided thermoresponsive mechanoactive (DTM) hydrogel that combines good flexibility, self-healing, wet-tissue adhesion, and antibacterial functions. The strong adhesion of the hydrogel to biological tissues is attributed to "multiple hydrogen bonding clusters" without any chemical reaction. The contraction force triggered by temperature is quickly transmitted to dynamic wound edges to resist external mechanical forces and drive wound closure, which can effectively avoid damage to surrounding healthy tissue and reduce the risk of scarring, infection, and inflammation caused by sutures, staples, or clips. Strikingly, in vivo, this hydrogel bandage actively enhanced wound repair in a full-thickness skin defect model by promoting collagen deposition, facilitating angiogenesis, and accelerating wound re-epithelialization. This mechanoactive biological method will provide a facile strategy for joint wound management and demonstrates strong potential in tissue remodeling.

Injectable Carrier-Free Hydrogel Dressing with Anti-Multidrug-Resistant Staphylococcus aureus and Anti-Inflammatory Capabilities for Accelerated Wound Healing.

Antibacterial hydrogels have gradually become a powerful weapon to treat bacterially infected wounds and accelerate healing. In this paper, we designed a small-molecule self-healing antibacterial hydrogel containing 100% drug-loaded benzyl 3β-amino-11-oxo-olean-12-en-30-oate (GN-Bn), which was governed by π-π stacking, hydrogen bonding, and van der Waals forces. Due to the carrier-free design concept, the problems of interbatch variability during sample preparation and carrier-related toxicity can be effectively avoided. Moreover, the GN-Bn hydrogel exhibited promising antibacterial activities against multidrug-resistant Staphylococcus aureus (MRSA). The minimum inhibitory concentration (MIC) of the GN-Bn hydrogel was 1.5625 nmol/mL, which was lower than those against clinical agents such as norfloxacin, penicillin, and tetracycline. This is attributed to its unique antibacterial mechanism that aims at killing bacteria or preventing their growth by regulating arginine biosynthesis and metabolism through both transcriptomic (RNA-seq) analysis and quantitative polymerase chain reaction (qPCR) analysis. In addition, the GN-Bn hydrogel can also inhibit proinflammatory cytokines (TNF-α, IL-1β, and IL-6) to promote wound healing. Collectively, the GN-Bn hydrogel elicited dual therapeutic effects on an MRSA-infected full-thickness skin wound model through its antibacterial and anti-inflammatory activities, which is attributed to the fact that the GN-Bn hydrogel has multiple advantages including sufficient mechanical stability, biocompatibility, and unique antibacterial mechanisms, making it significantly accelerate MRSA-infected full-thickness skin wound healing as a wound dressing. In a word, the GN-Bn antibacterial hydrogel dressing with an anti-inflammatory and antibacterial bifunctional material holds great potential in clinical application.