Skin Wound Healing Research Articles

Development and application of a mechanical arm-based in situ 3D bioprinting method for the repair of skin wounds

Current treatments for skin wounds typically involve multiple surgical procedures that require complex processes and expensive costs, making it difficult to achieve timely treatment in field environments. We developed an innovative in situ printing method, utilizing robotic arm control, to address the significant challenges of large-scale skin wound repair resulting from natural disasters such as earthquakes, fires, and explosions during relief efforts. Our portable 3D printing equipment, which integrates debridement, precise 3D scanning and modeling of wounds, and compatibility with cell-loaded bioink, facilitates rapid repair of large-area skin wounds in specialized field environments. Compared with traditional methods, this in situ printing method has significant advantages, including the ability to customize treatment according to the unique needs of the wound, achieve rapid healing, and the potential to reduce the total cost. We conducted experiments on rats with full-thickness dorsal skin defects and compared the performance of in situ bioprinting method with commercial skin defect repair dressings. Our results demonstrate that the in situ bioprinted skin achieved faster wound healing and more uniform re-epithelialization than the commercial dressing treatment. This study demonstrates the potential of in situ bioprinting method as a promising and effective strategy for rapid skin wound healing, especially for patients in remote environments where traditional wound treatment methods may not be readily available or practical.

MiR-494-3p regulates skin fibroblast activities by mediating fibromodulin production.

Skin wound healing is a well-coordinated process in which various cells and factors participate, during which fibroblast exhibits a critical role by exerting its multiple activities, including proliferation, migration, invasion, and differentiation. Previous studies have identified that fibromodulin (FMOD) could enhance dermal wound healing by promoting skin fibroblast activities, but little is known about its upstream regulator. We occasionally found that FMOD expression was downregulated in skin fibroblast by transforming growth factor-β1 treatment. It was hypothesized that microRNAs (miRNA) in skin fibroblast could downregulate FMOD production and blocking them would increase FMOD expression, as well as promote skin wound healing. Here, by utilizing combined analysis of miRNA microarray from the Gene Expression Omnibus database and miRNA targets prediction, we successfully identified a miRNA, termed miR-494-3p, could regulate FMOD production in human skin fibroblast (BJ fibroblast). The functional analysis revealed that miR-494-3p mimics could inhibit BJ fibroblast migration and invasion but not proliferation and differentiation, while miR-494-3p inhibition markedly promotes migration, invasion, and differentiation of BJ fibroblast. Moreover, we established FMOD overexpression (OE) and knockout BJ fibroblast. We found that FMOD OE could rescue the inhibitory effects of miR-494-3p mimics on the migration and invasion of BJ fibroblast. In contrast, the miR-494-3p inhibitor transfection could not enhance migration, invasion, and differentiation of FMOD KO BJ fibroblast. Together, our results suggest that miR-494-3p may be a potential target for skin wound management via regulating FMOD production.

GelMA loaded with platelet lysate promotes skin regeneration and angiogenesis in pressure ulcers by activating STAT3

Pressure ulcers (PU) are caused by persistent long-term pressure, which compromises the integrity of the epidermis, dermis, and subcutaneous adipose tissue layer by layer, making it difficult to heal. Platelet products such as platelet lysate (PL) can promote tissue regeneration by secreting numerous growth factors based on clinical studies on skin wound healing. However, the components of PL are difficult to retain in wounds. Gelatin methacrylate (GelMA) is a photopolymerizable hydrogel that has lately emerged as a promising material for tissue engineering and regenerative medicine. The PL liquid was extracted, flow cytometrically detected for CD41a markers, and evenly dispersed in the GelMA hydrogel to produce a surplus growth factor hydrogel system (PL@GM). The microstructure of the hydrogel system was observed under a scanning electron microscope, and its sustained release efficiency and biological safety were tested in vitro. Cell viability and migration of human dermal fibroblasts, and tube formation assays of human umbilical vein endothelial cells were applied to evaluate the ability of PL to promote wound healing and regeneration in vitro. Real-time polymerase chain reaction (PCR) and western blot analyses were performed to elucidate the skin regeneration mechanism of PL. We verified PL’s therapeutic effectiveness and histological analysis on the PU model. PL promoted cell viability, migration, wound healing and angiogenesis in vitro. Real-time PCR and western blot indicated PL suppressed inflammation and promoted collagen I synthesis by activating STAT3. PL@GM hydrogel system demonstrated optimal biocompatibility and favorable effects on essential cells for wound healing. PL@GM also significantly stimulated PU healing, skin regeneration, and the formation of subcutaneous collagen and blood vessels. PL@GM could accelerate PU healing by promoting fibroblasts to migrate and secrete collagen and endothelial cells to vascularize. PL@GM promises to be an effective and convenient treatment modality for PU, like chronic wound treatment.

Therapeutic application of mesenchymal stem cell-derived exosomes in skin wound healing.

Wound healing is a complicated obstacle, especially for chronic wounds. Mesenchymal stem cell-derived exosomes may be a promising cell-free approach for treating skin wound healing. Exosomes can accelerate wound healing by attenuating inflammation, promoting angiogenesis, cell proliferation, extracellular matrix production and remodeling. However, many issues, such as off-target effects and high degradation of exosomes in wound sites need to be addressed before applying into clinical therapy. Therefore, the bioengineering technology has been introduced to modify exosomes with greater stability and specific therapeutic property. To prolong the function time and the local concentration of exosomes in the wound bed, the use of biomaterials to load exosomes emerges as a promising strategy. In this review, we summarize the biogenesis and characteristics of exosomes, the role of exosomes in wound healing, and the therapeutic applications of modified-exosomes in wound healing. The challenges and prospects of exosomes in wound healing are also discussed.

Transdermal characteristic study of bovine sialoglycoproteins with anti-skin aging and accelerating skin wound healing.

Sialoglycoproteins play important roles in various biological processes, including cell adhesion, immune response, and cell signaling. Our previous studies indicated that the bovine sialoglycoproteins could be developed as a reagent against skin aging and as a new candidate for accelerating skin wound healing as well as inhibiting scar formation. However, transdermal characteristic of the bovine sialoglycoproteins is still unknown. This study investigated the transdermal permeation of the bovine sialoglycoproteins through porcine skin using the Franz diffusion cell method. Our study showed that the bovine sialoglycoproteins could penetrate through the porcine skin with a linear permeation pattern described by the regression equation N% = 11.49 t-3.858, with a high coefficient of determination (R2 = 0.9903). The histochemical results demonstrated the widespread distribution of the bovine sialoglycoproteins between the epidermal and dermal layers, which suggesting parts of the bovine sialoglycoproteins had ability to traverse the epidermal barrier. The results of the lectin microarrays indicated highly enriched glycopatterns on the bovine sialoglycoproteins, which also appeared in permeated porcine skin. The LC-MS/MS analysis further showed that the bovine sialoglycoproteins were composed of approximately 100 proteins with molecular weight ranging from 748.4 kDa to 10 kDa, and there were 23 specific bovine sialoglycoproteins with molecular weight ranging from 69.2 kDa to 10 kDa to be characterized in permeated porcine skin. Parts of the bovine sialoglycoproteins with molecular weight less than 69.2 kDa had ability to traverse the epidermal barrier. Understanding the permeation characteristics of the bovine sialoglycoproteins for developing innovative formulations with therapeutic benefits, contributing to advancements in cosmetic and dermatological fields.

Rhein-chitosan in situ hydrogel promotes wound healing in diabetic mice

Chronic inflammation and infection often lead to delayed healing in skin wounds of patients with diabetes, presenting a significant challenge in clinical wound repair. In an effort to tackle this issue, we explored the utilization of the natural compounds Rhein and chitosan in the creation of a crosslinked in situ gel. Developed as Rhein-chitosan in situ hydrogel (CS-Rh gel), this formulation has the ability to gel at body temperature, making it suitable for irregular wounds of varying shapes. Our experimental investigations have demonstrated its excellent biocompatibility, controlled release of Rhein, biodegradability, anti-inflammatory properties, antibacterial effect, as well as its ability to enhance keratinocyte proliferation and migration. Furthermore, in vivo studies have confirmed that CS-Rh gel can effectively mitigate tissue inflammation, promote collagen deposition, and significantly accelerate wound healing in diabetic mice within a short timeframe of two weeks. Consequently, this innovative approach holds promise as a viable therapeutic strategy for supporting the healing of diabetic wounds in a clinical setting.

Injectable antibacterial hydrogels based on oligolysines for wound healing

Generally, oligolysine has poor antibacterial effect and almost no antibacterial activity. Herein, low cost and easily available oligolysines were chosen to prepare injectable antibacterial hydrogel (PVAL-gel) for wound healing. The hydrogel network was formed by cross-linking vanillin acrylate-N, N-dimethylacrylamide copolymer P(VA-co-DMA), oligolysine and adipate dihydrazide through Schiff base bond. The obtained hydrogel PVAL-gel exhibited not only excellent self-healing capability and injectability, but also the efficient contact antibacterial ability and good inhibitory effects on E.coli and S.aureus. In vitro, 99.9 % of pathogenic bacteria was killed within 160 min. Furthermore, the injectable PVAL-gel could rapidly eradicate bacteria in infected wounds and notably enhance the healing of full-thickness skin wounds. Therefore, PVAL-gel is expected to be used as a high-end dressing for the treatment of infected skin wounds, which can promote wound healing.

Platelet-Rich Plasma in Aesthetic Dermatology: Current Evidence and Future Directions.

Platelet-rich plasma (PRP) has emerged as a promising treatment in aesthetic dermatology. This systematic review aims to evaluate the current evidence for PRP applications in skin rejuvenation, hair restoration, wound healing, and fat grafting. FollowingPreferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a comprehensive literature search was conducted across multiple databases and 13 studies meeting the inclusion criteria were selected for review. The Mixed Methods Appraisal Tool (MMAT) was used to assess the quality of included studies. The reviewed studies consistently reported positive outcomes for PRP across various applications. In skin rejuvenation, significant improvements in collagen density and overall skin appearance were observed. For hair restoration, studies showed mean increases of 18-27.7 hairs/cm² in treated areas. PRP demonstrated efficacy in accelerating wound healing across various wound types, including chronic ulcers. In fat grafting, PRP was associated with improved graft survival and integration. Patient satisfaction was generally high across all applications. However, there was significant heterogeneity in PRP preparation methods and treatment protocols among studies. This systematic review provides evidence supporting the efficacy of PRP in aesthetic dermatology, particularly in skin rejuvenation, hair restoration, wound healing, and fat grafting. PRP demonstrates a favorable safety profile across applications. However, the variability in study designs and PRP protocols highlights the need for standardization. Future research should focus on large-scale randomized controlled trials with standardized protocols and longer follow-up periods to solidify the evidence base for PRP in aesthetic dermatology.

The stress-responsive gene ATF3 drives fibroblast activation and collagen production through transcriptionally activating TGF-β receptor Ⅱ in skin wound healing.

Skin wound is an emerging health challenge on account of the high-frequency trauma, surgery and chronic refractory ulcer. Further study on the disease biology will help to develop new effective approaches for wound healing. Here, we identified a wound-stress responsive gene, activating transcription factor 3 (ATF3), and then investigated its biological action and mechanism in wound healing. In the full-thickness skin wound model, ATF3 was found to promote fibroblast activation and collagen production, resulted in accelerated wound healing. Mechanically, ATF3 transcriptionally activated TGF-β receptor Ⅱ via directly binding to its specific promoter motif, followed by the enhanced TGF-β/Smad pathway in fibroblasts. Moreover, the increased ATF3 upon skin injury was partly resulted from hypoxia stimulation with Hif-1α dependent manner. Altogether, this work gives novel insights into the biology and mechanism of stress-responsive gene ATF3 in wound healing, and provides a potential therapeutic target for treatment.

Exosome-mediated Advancements in Plastic Surgery: Navigating Therapeutic Potential in Skin Rejuvenation and Wound Healing.

Exosomes, tiny extracellular vesicles derived from various cells such as adipose-derived stem cells, bone marrow-derived mesenchymal stem cells, and human umbilical cord mesenchymal stem cells, exhibit considerable potential in wound healing due to their ability to facilitate cell communication and modulate inflammatory responses. These exosomes contribute positively to collagen synthesis and scar reduction, and have shown efficacy in documented clinical cases of wound improvement. Although research indicates their potential in reducing hypertrophic scars and suppressing keloid fibroblasts, further clinical investigations are warranted. In plastic surgery, exosome application postsurgery can enhance wound healing, particularly in cases prone to swelling or poor healing conditions. This study incorporates five case reports of individuals undergoing exosome treatment (EXOP; Sihler Inc., and Exodew; Hyundaimeditech, Inc.) for wound healing, providing practical insights into the application of this therapeutic approach. The five case reports presented in this study demonstrate the practical applications and efficacy of exosome therapy in promoting wound healing and reducing scarring. Exosomes emerge as a promising avenue within the field of plastic surgery, showcasing their potential to enhance wound healing, reduce scarring, and improve overall outcomes in clinical settings. The findings from this study underscore the importance of further exploration into the therapeutic benefits of exosomes in wound management, paving the way for their widespread adoption in clinical practice.

Therapeutic potential of cannabis for surgical wound healing in rats.

This study was conducted to evaluate the wound-healing activities of a Cannabis sativa L. plant extract and cannabidiol on incision wounds. An incision was created and sutured in rats under anaesthesia. Routine wound care procedures were applied for 10 days, followed by histological wound examinations. The cellular bioactivities of the hemp extract and CBD were assessed for MCP-1, EGF, BFGF, IL-8, and COL-1 using ELISA on the rat skin wound healing activity. A one-way ANOVA was used for the data analysis. The EGF values in the plasma were similar in the povidone-iodine, hemp seed oil, and hemp essential oil groups (P > 0.05). However, the EGF levels were lower in the CBD group compared to the other groups (P < 0.001, P < 0.005). The MCP-1 values in the hemp seed oil, hemp essential oil, and CBD were similar (P > 0.05), whereas povidone iodine exhibited lower MCP-1 levels compared to the other groups (P < 0.001, P < 0.005). It was determined that the plasma BFGF, IL-8, and COL 1 values of the groups were similar (P > 0.05). To our knowledge, this study is the first to evaluate the effects of CBD, seed oil, and hemp leaf extract on incision wound healing. It demonstrates that hemp extract holds greater potential benefits for wound healing compared to CBD.

Electrospun collagen/chitosan composite fibrous membranes for accelerating wound healing

The protein-polysaccharide nanofibers have attracted intensive attention in promoting wound healing, due to their components and nanoscale fibrous structure that mimics the native extracellular matrix (ECM). For the full-thickness wounds, in addition to promoting healing, hemostatic property and antibacterial activity are also of critical importance. However, currently, protein-polysaccharide-based nanofiber membranes exhibit poor mechanical properties, lack inherent hemostatic and antibacterial capabilities, as well as the ability to promote tissue repair. In this study, we developed composited membranes, which were composed of collagen (Col) and chitosan (Chs), through solvent alteration and post-processing, the membranes showed enhanced stability under physiological conditions, proper hydrophilic performance and improved mechanical property. Appropriated porosity and water vapor transmission rate, which benefit to wound healing, were detected among all the membranes except for Col membrane. Aimed at wound dressing, hemocompatibility, antibacterial activity and cell proliferation of the electrospun membranes were evaluated. The results indicated that the Col/Chs composited membranes exhibited superior blood clotting capacity, and the membranes with Chs exceeding 60% possessed sufficient antibacterial activity. Moreover, compared with Chs nanofibers, significant increase in cell grow was detected in Col/Chs (1:3) membrane. Taken together, the electrospun membrane with multiple properties favorable to wound healing, superior blood coagulation, sufficient antibacterial performance and promoting cell proliferation property make it favorable candidate for full-thickness skin wound healing.

Reprogramming macrophages with R848-loaded artificial protocells to modulate skin and skeletal wound healing.

After tissue injury, inflammatory cells are rapidly recruited to the wound where they clear microbes and other debris, and coordinate the behaviour of other cell lineages at the repair site in both positive and negative ways. In this study, we take advantage of the translucency and genetic tractability of zebrafish to evaluate the feasibility of reprogramming innate immune cells in vivo with cargo-loaded protocells and investigate how this alters the inflammatory response in the context of skin and skeletal repair. Using live imaging, we show that protocells loaded with R848 cargo (which targets TLR7 and TLR8 signalling), are engulfed by macrophages resulting in their switching to a pro-inflammatory phenotype and altering their regulation of angiogenesis, collagen deposition and re-epithelialization during skin wound healing, as well as dampening osteoblast and osteoclast recruitment and bone mineralization during fracture repair. For infected skin wounds, R848-reprogrammed macrophages exhibited enhanced bactericidal activities leading to improved healing. We replicated our zebrafish studies in cultured human macrophages, and showed that R848-loaded protocells similarly reprogramme human cells, indicating how this strategy might be used to modulate wound inflammation in the clinic.

Potential Wound Healing and Anti-Melanogenic Activities in Skin Cells of Aralia elata (Miq.) Seem. Flower Essential Oil and Its Chemical Composition.

Aralia elata (Miq.) Seem. (AES; family Araliaceae) is a medicinal plant and has been reported to have various bioactivities, including anticancer and hepatotoxicity protective activities. However, no studies have investigated the biological activities of AES or its extracts on skin. To address this, we aimed to explore the effect of AES-flower-derived absolute-type essential oil (AESFEO) on skin-related biological activities, especially skin wound healing and whitening-related responses in skin cells (human-derived keratinocytes [HaCaT cells] and melanocytes [B16BL6 cells]) and to identify the components of AESFEO. Cell biological activities were analyzed using WST and BrdU incorporation assays, ELISA, or by immunoblotting. In HaCaT cells, AESFEO promoted proliferation, type IV collagen production, and enhanced the phosphorylations of Erk1/2, p38 MAPK, JNK, and Akt. In B16BL6 cells, AESFEO reduced serum-induced proliferation, α-MSH-stimulated increases in melanin synthesis and tyrosinase activity, and α-MSH-induced increases in MITF, tyrosinase, TRP-1, and TRP-2 expressions. In addition, AESFEO inhibited the phosphorylation of Erk1/2, p38 MAPK, and JNK in α-MSH-stimulated B16BL6 cells. Eighteen compounds were identified in AESFEO by GC/MS. These results suggest that AESFEO has beneficial effects on keratinocyte activities related to skin wound healing and melanocyte activities related to inhibition of skin pigmentation. AESFEO may serve as a useful natural substance for developing agents that facilitate skin wound healing and inhibit melanogenesis.

Recombinant human amelogenin promotes wound healing by enhancing angiogenesis

The first barrier of the human body is the skin, and more serious harm may occur when skin wound healing is delayed. One of the components of enamel matrix proteins is amelogenin, which inhibits inflammation and promotes periodontal tissue regeneration. However, its role in skin wound healing and angiogenesis is inconclusive. Thus, this study aimed to assess the therapeutic effect of recombinant human amelogenin (rhAM) on mouse skin wounds and to determine its effect on angiogenesis and its underlying mechanism. rhAM was expressed in Escherichia coli and purified using the optimized acetic acid method. A skin injury mouse model was established to explore the effects of rhAM on skin wound healing. After treatment with rhAM for 7 days, the wound healing rate was calculated, and the therapeutic effect of rhAM on skin wounds was assessed using hematoxylin & eosin (HE), Masson, and CD31 immunofluorescence staining. The expression of growth and inflammatory factors in wound tissues were detected using Western Blot. In addition, the rhAM effects on the proliferation and migration of human umbilical vein endothelial cells (HUVEC) and mouse fibroblasts (NIH 3T3) were studied in vitro using the Cell Counting Kit-8, cell scratch, cytoskeleton staining, and qPCR. The rhAM effect on HUVEC angiogenesis and its potential mechanism was studied using tube formation and Western Blot. The results showed that the purity of the obtained rhAM was more than 90 % using the optimized acetic acid method, and high-dose rhAM treatment could improve wound healing rate in mice. Additionally, more blood vessels and collagen were produced in the skin wound, and the expression of angiopoietin-related protein 2 (ANGPTL2) and transforming growth factor (TGF)-β1 was upregulated; however, that of interleukin-6 was down-regulated. We also found that rhAM promoted the proliferation and migration of HUVEC and NIH 3T3, the mRNA levels of vascular endothelial growth factor (VEGF), fibroblast growth factor, TGF-β1 and ANGPTL2 in HUVEC cells were upregulated, and expression of VEGF and phosphorylation of the p38 mitogen-activated protein kinase were activated. Therefore, rhAM could promote skin wound healing by upregulating angiogenesis and inhibiting inflammation.

How to Keep Myofibroblasts under Control: Culture of Mouse Skin Fibroblasts on Soft Substrates

During the physiological healing of skin wounds, fibroblasts recruited from the uninjured adjacent dermis and deeper subcutaneous fascia layers are transiently activated into myofibroblasts to first secrete and then contract collagen-rich extracellular matrix into a mechanically resistant scar. Scar tissue restores skin integrity after damage but comes at the expense of poor esthetics and loss of tissue function. Stiff scar matrix also mechanically activates various precursor cells into myofibroblasts in a positive feedback loop. Persistent myofibroblast activation results in pathologic accumulation of fibrous collagen and hypertrophic scarring, called fibrosis. Consequently, the mechanisms of fibroblast-to-myofibroblast activation and persistence are studied to develop antifibrotic and prohealing treatments. Mechanistic understanding often starts in a plastic cell culture dish. This can be problematic because contact of fibroblasts with tissue culture plastic or glass surfaces invariably generates myofibroblast phenotypes in standard culture. We describe a straight-forward method to produce soft cell culture surfaces for fibroblast isolation and continued culture and highlight key advantages and limitations of the approach. Adding a layer of elastic silicone polymer tunable to the softness of normal skin and the stiffness of pathologic scars allows to control mechanical fibroblast activation while preserving the simplicity of conventional 2-dimensional cell culture.

Composite hydrogels fabricated from CMC-PVA-GG incorporated with ZiF-8 for wound healing applications

The skin is at risk for injury to external factors since it serves as the body’s first line of defense against the external environment. Hydrogels have drawn much interest due to their intrinsic extracellular matrix (ECM) properties and their biomimetic, structural, and durable mechanical characteristics. Hydrogels have enormous potential use in skin wound healing due to their ability to deliver bioactive substances easily. In this study, composite hydrogels were developed by blending guar gum (GG), polyvinyl alcohol (PVA), and carboxymethyl cellulose (CMC) with crosslinker TEOS for skin wound treatment. The structural, surface morphology, surface roughness, and stability features of the composite hydrogels were characterized by several techniques, such as FTIR, SEM-EDX, AFM, and DSC. The increasing ZiF-8 causes more surface roughness, with decreased swelling in different media (Aqueous > PBS > NaCl). The increasing ZiF-8 amount causes less hydrophilic behavior and biodegradation with increasing gel fraction. The cytocompatibility of Zinc imidazolate framework-8 (ZiF-8) based composites was evaluated against fibroblast cell lines by cell viability, proliferation, and cell morphology. The increasing ZiF-8 caused more cell viability and proliferation with proper cell morphology. Hence, the results show that synthesized composite hydrogels may be a potential candidate for numerous wound repair applications.

Eosinophils Respond to Extracellular Matrix Treated Muscle Injuries but are Not Required for Macrophage Polarization.

The immune response to decellularized extracellular matrix (ECM) muscle injury is characterized by Th2 T cells, Tregs, M2-like macrophages, and an abundance of eosinophils. Eosinophils have previously been described as mediators of muscle regeneration but inhibit skin wound healing. In addition to response to wounding, a large number of eosinophils respond to biomaterial-treated muscle injury, specifically in response to decellularized ECM. ECM treatment of muscle wounds has been associated with positive outcomes in tissue regeneration, but the detailed mechanisms of action are still being evaluated. Here, this work investigates the role of these eosinophils in terms of their immunologic phenotype and subsequent effect on the local tissue microenvironment. These cells have a mixed phenotype showing both type-2 and regulatory gene upregulation and but are not required for macrophage polarization. Beyond the local tissue, ECM treatment is seen to induce a transient flux of eosinophils to the lungs but prevented a trauma-associated neutrophilia in the lungs of injured mice. This work believes this local and systemic immunomodulation contributes to the regenerative effects of the material and such distal tissue effects should be considered in therapeutic design and implementation.

Advances and Challenges in Immune-Modulatory Biomaterials for Wound Healing Applications.

Wound healing progresses through three distinct stages: inflammation, proliferation, and remodeling. Immune regulation is a central component throughout, crucial for orchestrating inflammatory responses, facilitating tissue repair, and restraining scar tissue formation. Elements such as mitochondria, reactive oxygen species (ROS), macrophages, autophagy, ferroptosis, and cytokines collaboratively shape immune regulation in this healing process. Skin wound dressings, recognized for their ability to augment biomaterials' immunomodulatory characteristics via antimicrobial, antioxidative, pro- or anti-inflammatory, and tissue-regenerative capacities, have garnered heightened attention. Notwithstanding, a lack of comprehensive research addressing how these dressings attain immunomodulatory properties and the mechanisms thereof persists. Hence, this paper pioneers a systematic review of biomaterials, emphasizing immune regulation and their underlying immunological mechanisms. It begins by highlighting the importance of immune regulation in wound healing and the peculiarities and obstacles faced in skin injury recovery. This segment explores the impact of wound metabolism, infections, systemic illnesses, and local immobilization on the immune response during healing. Subsequently, the review examines a spectrum of biomaterials utilized in skin wound therapy, including hydrogels, aerogels, electrospun nanofiber membranes, collagen scaffolds, microneedles, sponges, and 3D-printed constructs. It elaborates on the immunomodulatory approaches employed by these materials, focusing on mitochondrial and ROS modulation, autophagic processes, ferroptosis, macrophage modulation, and the influence of cytokines on wound healing. Acknowledging the challenge of antibiotic resistance, the paper also summarizes promising plant-based alternatives for biomaterial integration, including curcumin. In its concluding sections, the review charts recent advancements and prospects in biomaterials that accelerate skin wound healing via immune modulation. This includes exploring mitochondrial transplantation materials, biomaterial morphology optimization, metal ion incorporation, electrostimulation-enabled immune response control, and the benefits of composite materials in immune-regulatory wound dressings. The ultimate objective is to establish a theoretical foundation and guide future investigations in the realm of skin wound healing and related materials science disciplines.

A simple and universal approach for fabricating bioactive self-stacked hydrogels with enhanced therapeutic efficacy

Despite significant advancements in self-stacked hydrogels of herbal small molecules in recent years, the emergence of new pharmacological small molecule self-stacked hydrogel systems remains largely reliant on serendipity and painstaking efforts. To address this challenge, we proposed a ‘bioactive bivalent metal ions-coordinated pharmacological small molecules’ strategy. This approach enabled the preparation of triterpenoid betulinic acid-based self-stacked hydrogels with excellent injectable and self-healing properties via a simple two-step method. We extended this strategy to self-stacking hydrogels based on other pentacyclic triterpene small molecules, anthraquinone small molecules, flavonoid small molecules and synthetic steroid small molecules. This universal strategy is capable of extracting hydrophobic pharmacological small molecules to construct novel self-stacked biomaterials in a cost-effective, efficient, large-scale, and environmentally friendly manner. Importantly, we successfully synthesized Mg2+-coordinated betulinic acid (BA-Mg) self-stacked hydrogel at low concentrations in the bacterial cellulose (termed BC) hydrogel network, overcoming the mechanical limitations of self-stacked hydrogels for biomedical applications. The BA-Mg/BC hybrid hydrogel demonstrated exceptional biocompatibility, anti-inflammatory, and angiogenic properties, significantly accelerating the skin wound healing process through the synergistic pharmacological effects of Mg2+ and BA.