Cutaneous Wound Model Research Articles

Estimation of Early Postmortem Interval from Long Noncoding RNA Gene Expression in the Incised Cutaneous Wound: An Experimental Study.

The assessment of alteration of postmortem RNA expression has forensic significance in estimating postmortem interval. To evaluate wound healing progression and the effect of different postmortem intervals, histopathological changes, immunohistochemical matrix metalloproteinase-9 (MMP-9) expression, and long noncoding fatty acid oxidation (lncFAO), RNA expression was assessed in the incised cutaneous wound model. A full-thickness cutaneous wound was inflicted on 75 rats. All 15 rats were sacrificed at different post-infliction intervals (0, 2, 4, 8 and 10 days), and the cutaneous wounds (n = 5) were excised at different postmortem intervals (0, 5, and 24 h after euthanasia). The maximal inflammatory healing stage was detected at day 4 post-infliction, while near complete healing, thick mature collagen deposition was detected at day 10 post-infliction. LncFAO expression was significantly over-expressed with increasing wound age. MMP-9 was detectable on injury day with continuous elevation until 8 days post-wounding, which later decreased. Although histopathological and immunohistochemical examinations within 24 h postmortem did not show any remarkable changes, lncFAO RNA expression showed a significant negative correlation with hours passed since death. The combined use of histopathological changes, immunohistochemical expression of MMP-9, and molecular expression of lncFAO could be appropriate in wound dating verification. Among these factors, lncFAO could be a reliable indicator in postmortem interval estimation.

Myeloid Wls expression is dispensable for skin wound healing and blood vessel regeneration.

Wnt signaling controls blood vessel growth, regression and patterning during embryonic and postnatal life. Macrophages are major producers of Wnt ligands and angiogenic growth factors. It regulates vascular development and specification during embryogenesis and wound healing. Macrophage dysregulation in wound healing impairs vessel regeneration and delay wound closure. During cutaneous wound healing, the endovascular progenitors (EVPs) proliferate and differentiate into mature endothelial (D) cells in response to signals produced by perivascular cells, including macrophages, governing blood vessels regeneration. However, the role of macrophage’s Wnt production on endothelial cells, especially the EVPs during wound healing is currently unknown. Here we used a cutaneous excisional wound model in mice with conditional deletion of Wnt secretion by myeloid cells (Wlsfl/flLysM-Cre+ ) to assess the kinetics of endothelial subpopulations (including EVP), myeloid infiltration, collagen deposition and wound closure. Deletion of Wls expression by myeloid cells did not affect wound closure and collagen deposition, indicating that myeloid Wls expression does not promote wound healing and regeneration. Myeloid-specific Wls deletion elevated the EVP population during the peak of angiogenesis, yet without affecting blood vessel density. Wounds in Wlsfl/flLysM-Cre+ animals showed unperturbed myeloid infiltration and differentiation. Overall, our data indicate that macrophage Wnt production shapes EVP kinetics without major relevance to wound healing. These findings extend the knowledge of macrophage and endothelial molecular crosstalk and position myeloid-derived Wnt production as a regulator of endovascular progenitor.

Human Umbilical Cord Lining-Derived Epithelial Cells: A Potential Source of Non-Native Epithelial Cells That Accelerate Healing in a Porcine Cutaneous Wound Model.

Human umbilical cord lining epithelial cells [CLECs) are naïve in nature and can be ethically recovered from cords that are routinely discarded. The success of using oral mucosal epithelial cells for cornea defects hints at the feasibility of treating cutaneous wounds using non-native CLECs. Herein, we characterized CLECs using flow cytometry (FC) and skin organotypic cultures in direct comparison with skin keratinocytes (KCs). This was followed by wound healing study to compare the effects of CLEC application and the traditional use of human skin allografts (HSGs) in a porcine wound model. While CLECs were found to express all the epidermal cell markers probed, the major difference between CLECs and KCs lies in the level of expression (in FC analysis) as well as in the location of expression (of the epithelium in organotypic cultures) of some of the basal cell markers probed. On the pig wounds, CLEC application promoted accelerated healing with no adverse reaction compared to HSG use. Though CLECs, like HSGs, elicited high levels of local and systemic immune responses in the animals during the first week, these effects were tapered off more quickly in the CLEC-treated group. Overall, the in vivo porcine data point to the potential of CLECs as a non-native and safe source of cells to treat cutaneous wounds.

Multiple Coordination-Derived Bioactive Hydrogel with Proangiogenic Hemostatic Capacity for Wound Repair.

Bioactive hydrogels with multifunctional properties have shown promising potential in promoting wound repair and skin tissue regeneration. The regulation on different stages of skin wound healing (hemostasis and inflammation) is important for wound repair. Herein, a multiple coordination-derived bioactive hydrogel (SGPA) with anti-inflammatory proangiogenic hemostatic capacity for wound repair is reported. The SGPA is prepared through a facile multiple metal coordination action based on the sodium alginate, metal ions (Gd3+ ), and bisphosphate functionalized polycitrate. The SGPA exhibits a large porous structure, good injectability, and self-healing performance, as well as controlled biodegradation. Furthermore, the SGPA has good cytocompatibility and hemocompatibility, and can further promote the migration of endothelial cells. The SGPA hydrogel presents good hemostasis capacity in a liver hemorrhage model in vivo. The full-thickness cutaneous wound model demonstrates that the SGPA hydrogel can effectively accelerate the wound repair through down-regulating the inflammatory factors and stimulating the angiogenesis around the wound beds. This work suggests that the multiple metal-organic coordination may be a good strategy to construct the multifunctional bioactive hydrogel for wound repair.

The assessment 1,2,3-Triazolo-[5,1-b]-1,3,4-thiadiazine derivative influence on restoration of the fibrous skin component during regeneration caused by burn injury

In this study, the stimulating effect of the 1,2,3-triazolo-1,3,4-thiadiazine derivative on the restoration of the fibrous skin component was evaluated on the burn cutaneous wound model of white male rats. The experiment included morphological and mechanical investigations. The animals of the experienced groups were taken out of the experiment on the 14th and 21st days to assess the regenerative process. Experimental animals received a third A grade burn injury. Treatment was carried out by applying an ointment containing the test substance to the affected area. Morphological analysis data indicate the stimulating effect of 1,2,3-triazolo-1,3,4-thiadiazine on the skin regeneration, particularly, the fibrous component restoration. By the 14th day of the experiment, all samples have weak mechanical characteristics. However, on the 21st day, samples from the "triazole" group demonstrate higher strength properties, stretching by 28,893 ± 4,548 % at a maximum load of 0,804 ± 0,129 MPa. Significant difference from the intact value (31,434 ± 4,921 % extension at a load of 5,082 ± 0,060 MPa) is probably associated with the contribution to the mechanical properties not only of the fibers thickness, but also the ways of fibers stacking in bundles, arrangement and interaction with other structural components of the tissue.

Hybrid Biomaterial Initiates Refractory Wound Healing via Inducing Transiently Heightened Inflammatory Responses.

Inflammation plays a crucial role in triggering regeneration, while inadequate or chronic inflammation hinders the regenerative process, resulting in refractory wounds. Inspired by the ideal regeneration mode in lower vertebrates and the human oral mucosa, realigning dysregulated inflammation to a heightened and acute response provides a promising option for refractory wound therapy. Neutrophils play important roles in inflammation initiation and resolution. Here, a hybrid biomaterial is used to stimulate transiently heightened inflammatory responses by precise tempospatial regulation of neutrophil recruitment and apoptosis. The hybrid biomaterial (Gel@fMLP/SiO2‐FasL) is constructed by loading of formyl‐met‐leu‐phe (fMLP) and FasL‐conjugated silica nanoparticles (SiO2‐FasL) into a pH‐responsive hydrogel matrix. This composition enables burst release of fMLP to rapidly recruit neutrophils for heightened inflammation initiation. After neutrophils act to produce acids, the pH‐responsive hydrogel degrades to expose SiO2‐FasL, which induces activated neutrophils apoptosis via FasL‐Fas signaling triggering timely inflammation resolution. Apoptotic neutrophils are subsequently cleared by macrophages, and this efferocytosis activates key signalings to promote macrophage anti‐inflammatory phenotypic transformation to drive regeneration. Ultimately, Gel@fMLP/SiO2‐FasL successfully promotes tissue regeneration by manipulating inflammation in critical‐sized calvarial bone defects and diabetic cutaneous wound models. This work provides a new strategy for refractory wound therapy via inducing transiently heightened inflammatory responses.

Total alkaloid fraction of Leonurus japonicus Houtt. Promotes angiogenesis and wound healing through SRC/MEK/ERK signaling pathway

Ethnopharmacological relevanceLeonurus japonicus Houtt., also known as motherwort, is a traditional Chinese medicine that was first identified in Shennong Bencao Jing, the first and essential pharmacy monograph in China. L. japonicus has been regarded as a good gynecological medicine since ancient times. It has been widely used in clinical settings for treatment of gynecological diseases and postnatal rehabilitation with good efficacy and low adverse effects. Aim of the studyThe main purpose of this study was to determine the angiogenic and wound healing effects of total alkaloid fraction from L. japonicus Houtt. (TALH) in vivo and in vitro. In addition, the main bioactive components of total alkaloids were to be identified and analyzed in this study. Materials and methodsFirst, the UHPLC/Q-TOF-MS method was used to identify and quantify the major components in the TALH extract. The wound healing activity was evaluated in vivo using a rat full-thickness cutaneous wound model. Histological study of wound healing in rat model was performed via immunohistochemistry and immunofluorescence. Cell proliferation was determined by MTT assay. Wound healing and transwell assays were used for detection of cell migration. The effect on tube formation was determined by tube formation assay in HUVECs. Western blot and RT-PCR were used to detect the expressions of relative proteins and genes respectively. Knock-down of SRC by siRNA was done to verify the crucial role of SRC in promotion of angiogenesis induced by TALH. ResultsSeven characteristic peaks were recognized in the UHPLC/Q-TOF-MS spectrum, while four of the main components were quantified. The wound model in rats showed that treatment of TALH promoted wound healing by stimulating cellular proliferation and collagen deposition. In vitro experiments showed that co-treatment of TALH and VEGF increased cell proliferation, migration and tube formation in HUVECs. Mechanistic studies suggested that the co-treatment increased gene expressions of SRC, MEK1/2 and ERK1/2, as well as the phosphorylation levels of these proteins. Furthermore, the effect of co-treatment was attenuated after SRC knockdown, suggesting that SRC plays an important role in angiogenesis and wound healing induced by TALH and VEGF co-treatment. ConclusionOur results showed that TALH was one of the main active components of L. japonicus that promoted angiogenesis and wound healing by regulating the SRC/MEK/ERK pathway. Our study provided scientific basis for better clinical application of L. japonicas.

Evaluation of the healing properties of Garcinia brasiliensis extracts in a cutaneous wound model

Wound healing is a complex process that can leave pathological scars, especially in case of infections from opportunistic microorganisms. In this context, herbal medicines open up great possibilities for investigation. One of the species of interest native to Brazil is Garcinia brasiliensis ("bacupari"). Traditionally known for treating wounds and ulcers, G. brasiliensis presents anti-inflammatory, antioxidant and antimicrobials properties. But, its wound healing profile in experimental models, in order to validate its efficacy, is still litle studied. Thus, the objective of this work was to evaluate, in an infected cutanous wound model, the potential of formulations incorporated with G. brasiliensis leaves extracts. Crude extract (CE), Ethyl Acetate Fraction (EAF) and Hexanic Fraction (HF) were submitted to phytochemical assays, high performance thin layer chromatography (HTPLC) and cytotoxicity studies. CE and EAF were also tested for microbicidal properties and incorporated in cream and gel formulations at 10% concentration. After stability testing, the gel formulations with CE or EAF at 10% were selected and applied to skin wounds infected or not with Staphylococcus aureus in Wistar rats. The healing potenttial of the extracts was verified by the expression of the protein Annexin A1 (AnxA1), related to the processes of inflammation and antifibrotic function, the cells immunostaining for Gasdermin-D (GSDM-D), a marker of pyroptotic cell death, and the dosage of interleukin-10 (IL-10) and monocyte chemotactic protein (MCP)-1 inflammatory mediators. Phytochemical studies indicated the presence of compounds of pharmacological interest, including Catechin, Quercetin and Berberine in addition to low cytotoxicity of CE and EAF at 10%. After the 6-day topical treatments, CE and EAF gel formulations demonstrated to control the pruritus formation process. The treatments decreased AnxA1 expression and the amount of cells immunostained for GSDM-D, and increased the expression of MCP-1 in infected wounds. Together, the results show important anti-inflammatory profile and skin healing potential of CE and EAF from G. brasiliensis leaves, even in infected lesions, with therapeutic perspectives.

Allantoin-functionalized silk fibroin/sodium alginate transparent scaffold for cutaneous wound healing

In clinical application, it's highly desirable for developing bio-functionalized cutaneous scaffold with transparent features for convenient observation, excellent biocompatibility, and high efficiency for promoting wound repair. Herein, allantoin-functionalized composite hydrogel was developed by coupling silk fibroin (SF) and sodium alginate (SA) for treatment of cutaneous wounds. The prepared allantoin-functionalized SF-SA composite scaffolds (AFAS) exhibited excellent mechanical properties, especially featured by similar ultimate tensile strength (UTS) and elongation at breaking to human skin. Besides, the solvent-casting method guaranteed the AFAS to obtain highly transparent properties with sufficient moisture permeability and excellent adhesion in wet state. In vitro cellular experiments demonstrated excellent biocompatibility of the scaffold that attachment and proliferation of NIH-3T3 fibroblast cells was promoted in the presence of AFAS. Furthermore, the scaffolds exhibited efficient hemostatic property, based on rat hepatic hemorrhage model. In a cutaneous excisional mouse wound model, the AFAS significantly improved the wound closure rate, compared with pure SF-SA scaffolds and blank control. Moreover, the histomorphological assessments showed that AFAS facilitated the integrity of skin and wound healing process by enhancing collagen deposition, re-epithelialization and vascularization at wound site. The results demonstrate that the novel allantoin-functionalized SF/SA transparent hydrogel has great potential for clinical treatment of cutaneous wound.

Urolithin A Promotes Angiogenesis and Tissue Regeneration in a Full-Thickness Cutaneous Wound Model

The treatment of chronic wound is an important topic of current clinical issue. Neovascularization plays a crucial role in skin wound healing by delivering fresh nutrients and oxygen to the wound area. The aim of this study was to investigate the mechanisms of urolithin A (UA) in angiogenesis during wound healing. The results of in vitro experiments showed that treatment with UA (5–20 μM) promoted the proliferation, migration, and angiogenic capacity of HUVECs. Furthermore, we investigated the effect of UA in vivo using a full-thickness skin wound model. Subsequently, we found that UA promoted the regeneration of new blood vessels, which is consistent with the results of accelerated angiogenesis in vitro experiments. After UA treatment, the blood vessels in the wound are rapidly formed, and the deposition and remodeling process of the collagen matrix is also accelerated, which ultimately promotes the effective wound healing. Mechanistic studies have shown that UA promotes angiogenesis by inhibiting the PI3K/AKT pathway. Our study provides evidence that UA can promote angiogenesis and skin regeneration in chronic wounds, especially ischemic wounds.

Retraction.

Retraction: "Paeoniflorin promotes angiogenesis and tissue regeneration in a full-thickness cutaneous wound model through the PI3K/AKT pathway", by Xiaoyu Dong, Zili He, Guangheng Xiang, Leyi Cai, Zhenjiang Xu, Cong Mao, and Yongzeng Feng, J Cell Physiol. 2020; 9933-9945: The above article, published online on 15 June 2020 in Wiley Online Library (https://doi.org/10.1002/jcp.29808), has been retracted by agreement between the authors, the journal's Editor in Chief, Prof. Dr. Gregg Fields, and Wiley Periodicals LLC. The retraction has been agreed after authors admitted substantial mistakes in the figures of this manuscript. Additionally, some image elements of the experimental data were published elsewhere in a different scientific context. As a result, the experiments in this article are considered unreliable and do not sufficiently support the conclusions.

Transplantation of decellularised human amniotic membranes seeded with mesenchymal stem cell-educated macrophages into animal models.

The reconstruction of chronic skin wounds remains a public health challenge in dermatology. Precisely controlling and monitoring the wound-healing process should result in enhanced outcomes for the patient. Cell-based therapies have shown great potential in medicine due to their immunomodulatory and healing properties. Herein, we produced activated macrophages by treating circulating monocytes with mesenchymal stem cell (MSC) supernatant. We also demonstrated the critical role of activated macrophages transplantation using amniotic membranes in accelerating wound healing in an animal wound model. The activated macrophages not only exhibited immunomodulatory cytokines like transforming growth factorβ (TGFβ) and interleukin 10 (and IL10) secretion but also showed attachment and proliferation ability on the amniotic membrane scaffold. Moreover, MSCs supernatant-treated cells also displayed significant ARG1, CD206, and IL 10 genes expression. Inspired by the in vitro results, we examined the in vivo therapeutic efficacy of the activated macrophage transplantation using an acellular amniotic membrane carrier in a full-thickness cutaneous wound model. The wound healing rate was significant in the group treated with macrophages generated via mesenchymal cell therapy seeded human amniotic membrane. There was less scarring in the wound sites after placing cell-scaffold constructs in the wound sites in the animal models. Overall, macrophages stimulated with mesenchymal cells' supernatant exhibited improved healing processes in incisional wounds by decreasing the inflammatory phase, increasing angiogenesis, and reducing scar tissue development.

Quercetin promotes cutaneous wound healing in mice through Wnt/β-catenin signaling pathway

Ethnopharmacological relevanceOxytropis falcata Bunge is a legume distributed in Northwest China, which is mainly used to treat knife wounds and inflammation. Quercetin is a bioactive flavonoid in O. falcata and becomes a promising healing compound for its angiogenic and anti-inflammatory activities. However, the healing mechanism of quercetin in cutaneous wound remains elusive. Aim of the studyThe purpose of this study was to evaluate the healing effect of quercetin on cutaneous wound models in vivo and in vitro, and to reveal the Wnt/β-catenin pathway and Telomerase reverse transcriptase (TERT) involved mechanisms. Materials and methodsThe effects of quercetin on the proliferation and migration of 4 kinds of skin cells were determined by CCK-8 and scratch assay. The wound-healing capacity of quercetin was evaluated in cutaneous wound model of C57BL/6 mice and the wound healing degree was observed by histological staining. The expressions of inflammatory factors, growth factors and the related proteins were detected via Western blot and RT-qPCR analyses. The molecular docking was adopted to evaluate the binding ability of quercetin and TERT. ResultsQuercetin could promote both proliferation and migration of fibroblasts, and enhance cutaneous wound healing capacity in mice. Compared to the control group, the wound healing rates in low (1.5 mg/mL), medium (3.0 mg/mL) and high dose (6.0 mg/mL) quercetin groups reached 94.67%, 97.31% and 98.42%, respectively. Moreover, the dermal structure in quercetin treated mice restored normal and the content of collagen fiber became abundant after administration. The levels of inflammatory factors, including tumor necrosis factor-α, interleukin-1β and interleukin-6 were significantly reduced after quercetin administration. Among which, the level of IL-1β in cutaneous wound was 0.007 times higher than that of the control group when treated with quercetin of high dose (6.0 mg/mL). The improved level of GSH in quercetin treated cutaneous wounds also indicated its higher antioxidant ability. In addition, dose-dependent positive associations were found in the expression levels of vascular endothelial growth factor, fibroblast growth factor and alpha smooth muscle actin in quercetin treated cutaneous wounds. The significantly upregulated protein levels of Wnt and β-catenin further indicated the important role of quercetin in promoting wound healing in mice. According to molecular docking analysis, the formed hydrogen bonds between quercetin and Ala195, Gln308, Asn369 and Lys372 residues of TERT also indicated the indispensable role of TERT in improving wound healing capacity. ConclusionQuercetin effectively promoted cutaneous wound healing by enhancing the proliferation and migration of fibroblasts, as well as inhibiting inflammation and increasing the expression of growth factors in mice via Wnt/β-catenin signaling pathway and TERT. It provides a basis for a more thorough understanding of mechanism of action of O. falcata Bunge in the treatment of knife wounds and burns.

Wound microenvironment-responsive glucose consumption and hydrogen peroxide generation synergistic with azithromycin for diabetic wounds healing.

Rationale: Chronic wounds are one of the common complications of diabetes. Due to the physiological conditions of diabetic patients, these wounds are more susceptible to bacterial infections and the formation of bacterial biofilms, leading to the inefficiency of conventional antibiotic treatment.Methods: Here, hollow mesoporous silica nanoparticles (HMSN) were used as the nanocarriers for co-delivery of azithromycin (AZM) and glucose oxidase (GOX), achieving a remarkable synergistic effect in chronic diabetic wounds. GOX possesses the catalytic ability to consume glucose and produce H2O2 in the diabetic wound area. The down-regulation of local glucose could effectively improve the chronic diabetic wound microenvironment. Meanwhile, the generated H2O2 effectively inhibits bacterial growth and eradicates bacterial biofilms with the synergism of antibiotics AZM.Results: In the bacteria-infected diabetic cutaneous wound models, the reduction of glucose, generation of H2O2, and release of AZM could effectively reduce the bacterial infection and promote the wounds healing. Moreover, there is no obvious toxicity behavior after the treatment.Conclusions: Therefore, the designed nanosystem could effectively accelerate the diabetic wound healing process by the amelioration of the hyperglycemia microenvironment and the eradication of bacterial biofilms around the wounds, making them promising candidates for clinical transformation.

Exosomal lncRNA KLF3-AS1 derived from bone marrow mesenchymal stem cells stimulates angiogenesis to promote diabetic cutaneous wound healing

AimsWe focused on BMSC-derived exosomal lncRNA KLF3-AS1 and its significance in diabetic cutaneous wound healing. MethodsPotential interaction between KLF3-AS1 and miR-383, miR-383 and VEGFA were predicted using bioinformatic analysis and validated by luciferase reporter, RIP, and FISH assays. The proliferation, apoptosis, migration and tube formation of HUVECs were evaluated by CCK-8, flow cytometry, wound healing, and tube formation assays, respectively. A murine diabetic cutaneous wound model was used to investigate therapeutic effects of exosomal KLF3-AS1 in vivo. Histological alterations in skin tissues were examined using HE, Masson staining, and immunostaining of CD31. ResultsBMSC-derived exosomal KLF3-AS1 sufficiently promoted proliferation, migration, and tube formation, while inhibited apoptosis of HUVECs challenged by high glucose. The protective effects of exosomal KLF3-AS1 were achieved at least partially by down-regulating miR-383, and boosting the expression of its target, VEGFA. In vivo, exosomes from KLF3-AS1-expressing BMSCs demonstrated the best effects in promoting cutaneous wound healing in diabetic mice, which were associated with minimal weight loss, increased blood vessel formation, reduced inflammation, decreased miR-383 expression, and up-regulated VEGFA. ConclusionsExosomal lncRNA KLF3-AS1 derived from BMSCs induces angiogenesis to promote diabetic cutaneous wound healing.

Nanofibrous Membrane Dressings Loaded With Sodium Hydrogen Sulfide/Endothelial Progenitor Cells Promote Wound Healing.

Hydrogen sulfide (H2S) has been identified as an important gasotransmitter. H2S donor can release H2S sustained and is used as wound dressing. Endothelial progenitor cells (EPCs), given their regenerative ability, have also been reported to enhance wound healing. However, effective drug carriers are missing for the clinical application of H2S and EPCs. In this study, we investigated a novel drug carrier nanofibrous membrane, which was prepared by blending the recombinant spider silk protein (rMaSp) and sodium hydrogen sulfide (NaHS) by electrospun. Our results show that the rMaSp/NaHS nanofibrous membrane is associated with high hemocompatibility and cytocompatibility and is capable of stably releasing H2S for a long period of time. We also tested the rMaSp/NaHS membrane loaded with EPCs in an in vivo cutaneous wound model. We showed that the rMaSp/NaHS/EPC system significantly enhances wound regeneration efficiency as compared to rMaSp membrane and rMaSp/NaHS membrane. This study provides key evidence supporting the clinical application of nanofibrous membrane in the field of skin tissue regeneration.

Copper metal-organic framework embedded carboxymethyl chitosan-g-glutathione/polyacrylamide hydrogels for killing bacteria and promoting wound healing

Bacterial infection and its induced oxidative stress as major clinical challenge during wound healing call for an urgent response for the development of medical dressings with multi-functions, such as antioxidant and antibacterial. To meet this demand, copper metal organic framework nanoparticles (HKUST NPs) and carboxymethyl chitosan-g-glutathione (CMCs-GSH) were synthesized and characterized. By embedding HKUST NPs into PAM/CMCs-GSH hydrogel (AOH), we developed a novel hydrogel dressing (HKUST-Hs) with dual effects of antibacterial and antioxidant. The morphology, swelling behavior, oxidation resistance and antibacterial properties of HKUST-Hs were investigated as well as the slow-release behavior of copper ions. Full-thickness cutaneous wound model of rats was created to assess the promoting effect of HKUST-Hs on wound healing. We found that HKUST NPs could be well dispersed in HKUST-Hs by shielding the positive charge of copper ions, and thus copper ions released were uniformly distributed and chelated with CMCs-GSH to promote the swelling stability of HKUST-Hs. Also, HKUST-Hs exhibited good free radical scavenging ability in vitro antioxidant assay. Meanwhile, a gradient sustained-release system of copper ions was formed in HKUST-Hs owing to the inhibition of HKUST NPs to copper release and the chelation of CMCs-GSH, which effectively inhibited the explosive release of copper ions and prolonged the release period, thereby reducing cytotoxicity. In vitro antibacterial test demonstrated there was synergistic antibacterial effect between the slow-released copper ions and CMCs-GSH, which improved the antibacterial activity and antibacterial persistence of HKUST-Hs. Finally, HKUST-Hs accelerated wound healing in vivo by continuously killing bacteria and inhibiting oxidative stress.

Suction Cups-Inspired Adhesive Patch with Tailorable Patterns for Versatile Wound Healing.

Medical patches play an important role in wound healing because of their tissue conformality, drug release capacity, and convenient operation. Great efforts have been devoted to developing new‐generation patches with distinctive features promoting wound healing. Here, inspired by the structure of octopus suction cups and the component of natural tissue, a biocompatible wound patch with selective adhesiveness and individualized design using a combined strategy of template‐replication and mask‐guided lithography is presented. Such patches are based on Ecoflex film with suction‐cup‐mimicking microstructures to adhere to normal skin and with biocompatible gelatin methacryloyl (GelMA) hydrogel to contact wounded areas. An ultraviolet mask with a tailorable pattern is employed to shape the GelMA hydrogel into customized geometry replicating individual wound areas, and thus both adhesion and antiadhesion properties are integrated into the same patch. In addition, vascular endothelial growth factor is loaded to accelerate the healing process. Based on these advantages, the authors demonstrate that the present patches not only adhere to different skin surfaces, but also promote the treatment of a rat cutaneous wound model. Thus, it is believed that this versatile patch can break through the limitation of traditional patches and be ideal candidates for wound healing and related biomedical applications.

Smart Asymmetric Hydrogel with Integrated Multi-Functions of NIR-Triggered Tunable Adhesion, Self-Deformation, and Bacterial Eradication.

Multifunctional hydrogels acting as wound dressing have received extensive attention in soft tissue repair; however, it is still a challenge to develop a non-antibiotic-dependent antibacterial hydrogel that has tunable adhesion and deformation to achieve on-demand removal. Herein, an asymmetric adhesive hydrogel with near-infrared (NIR)-triggered tunable adhesion, self-deformation, and bacterial eradication is designed. The hydrogel is prepared by the crosslinking polymerization of N-isopropylacrylamide and acrylic acid, during the sedimentation of conductive PPy-PDA nanoparticles based on the polymerization of pyrrole (Py) and dopamine (DA). Due to the conversion capacity from NIR light into heat for PPy-PDA NPs, the formed temperature-sensitive hydrogel exhibits tissue adhesive as well as NIR-triggered tunable adhesion and self-deformation property, which can achieve an on-demand dressing refreshing. Systematically in vitro/in vivo antibacterial experiments indicate that the hydrogel shows excellent disinfection capability to both Gram-negative and Gram-positive bacteria. The in vivo experiments in a full-layer cutaneous wound model demonstrate that the hydrogel has a good treatment effect to promote wound healing. Overall, the asymmetric hydrogel with tunable adhesion, self-deformation, conductive, and photothermal antibacterial activity may be a promising candidate to fulfill the functions of adhesion on skin tissue, easy removing on-demand, and accelerating the wound healing process.

Conditioned medium from induced pluripotent stem cell-derived mesenchymal stem cells accelerates cutaneous wound healing through enhanced angiogenesis

BackgroundMesenchymal stem cells (MSCs) can improve cutaneous wound healing via the secretion of growth factors. However, the therapeutic efficacy of MSCs varies depending upon their source. Induced pluripotent stem cells are emerging as a promising source of MSCs with the potential to overcome several limitations of adult MSCs. This study compared the effectiveness of conditioned medium of MSCs derived from induced pluripotent stem cells (iMSC-CdM) with that derived from umbilical cord MSCs (uMSC-CdM) in a mouse cutaneous wound healing model. We also investigated the mechanisms of protection.MethodsThe iMSC-CdM or uMSC-CdM were topically applied to mice cutaneous wound model. The recovery rate, scar formation, inflammation and angiogenesis were measured. We compared angiogenesis cytokine expression between iMSC-CdM and uMSC-CdM and their protective effects on human umbilical vein endothelial cells (HUVECs) under H2O2-induced injury. The effects of iMSC-CdM on energy metabolism, mitochondria fragmentation and apoptosis were measured.ResultsTopical application of iMSC-CdM was superior to the uMSC-CdM in accelerating wound closure and enhancing angiogenesis. Expression levels of angiogenetic cytokines were higher in iMSC-CdM than they were in uMSC-CdM. The iMSC-CdM protected HUVECs from H2O2 induced injury more effectively than uMSC-CdM did. Administration of iMSC-CdM stimulated HUVEC proliferation, tube formation and energy metabolism via the ERK pathway. Mechanistically, iMSC-CdM inhibited H2O2-induced mitochondrial fragmentation and apoptosis of HUVECs.ConclusionCollectively, these findings indicate that iMSC-CdM is more effective than uMSC-CdM in treating cutaneous wounds, and in this way, iMSC-CdM may serve as a more constant and sustainable source for cell-free therapeutic approach.Graphical abstract