Wound Healing Angiogenesis Research Articles

Alginate-chitosan hydrogel formulations for VEGFA expressed baculovirus delivery promoting angiogenesis for wound healing and revascularization

Abstract Background Baculoviruses, engineered to express growth factors, offer a promising avenue for short-term gene therapy, such as wound dressings, due to their safety and specificity. Encapsulation in natural polymers like alginate and chitosan addresses limitations like serum inactivation and fragility, while promoting sustained delivery and shielding from immune inactivation. Wound healing involves complex processes that can be enhanced by maintaining an antimicrobial, moist environment, which promotes cell migration and angiogenesis. Vascular endothelial cell growth factor A (VEGFA) is known to be one of the most potent pro-angiogenic factors and plays a key role in wound healing. Purpose This investigation seeks to enhance wound healing and angiogenesis, support the revascularization process, and provide anti-inflammatory and anti-microbial effects. Additionally, it aims to assess the preclinical efficacy and safety of the approach. Methods Ionic cross-linking was used for virus encapsulation under aseptic conditions. The capsules were assessed for their surface morphology, particle size, zeta potential, and in vitro release profile. Additionally, their therapeutic potential was studied using cell lines. The efficacy of hydrogel delivery of VEGFA-expressing baculoviruses in promoting cell migration and angiogenesis for wound healing applications was investigated on Human Umbilical Vein Endothelial Cells (HUVECs). Hydrogel morphology, swelling, and encapsulation efficiency were evaluated, along with endothelial tube formation assays and hemocompatibility studies on HUVECs. Results Encapsulation of baculovirus expressing the VEGFA gene in alginate and chitosan–alginate hydrogels achieve a high encapsulation efficiency of 99.9%. This allows for prolonged virus delivery and an increased therapeutic window. The encapsulated baculovirus maintains activity and is released over eight days, with a transduction efficiency of over 40%. This promotes tube formation, cell proliferation, and cell migration for angiogenesis, particularly beneficial for chronic wound-healing applications. The hydrogels also prevented E. coli and C. albicans growth directly below and inhibited C. albicans growth surrounding the alginate–chitosan hydrogels. The hydrogels demonstrated no cytotoxicity and good blood compatibility. Conclusion This proof of concept underscores the potential of encapsulated baculovirus delivery systems for various gene therapy applications including cardiovascular tissue regeneration and revascularization.

Nervonic acid as novel therapeutics initiates both neurogenesis and angiogenesis for comprehensive wound repair and healing

Rapid tissue reconstruction in acute and chronic injuries are challengeable, the inefficient repair mainly due to the difficulty in simultaneous promoting the regeneration of peripheral nerves and vascular, which are closely related. Main clinical medication strategy of tissue repair depends on different cytokines to achieve nerves, blood vessels or granulation tissue regeneration, respectively. However, their effect is still limited to single aspect with biorisk exists upon long-time use. Herein, for the first time, we have demonstrated that NA isolated from Malania oleifera has potential to simultaneously promote both neurogenesis and angiogenesis in vitro and in vivo. First, NA was identified by NMR and FTIR structural characterization analysis. In a model of oxidative stress in neural cells induced by hydrogen peroxide, the cells viability of RSC96 and PC12 were protected from oxidative stress injury by NA. Similarly, based on the rat wound healing model, effective blood vessel formation and wound healing can be observed in tissue staining under NA treatment. In addition, according to the identification of nerve and vascular related markers in the wound tissue, the mechanism of NA promoting nerve regeneration lies in the upregulation of the secretion NGF, NF-200 and S100 protein, and NA treatment was also able to up-regulate VEGF and CD31 to directly promote angiogenesis during wound healing. This study provides an important candidate drug molecules for acute or chronic wound healing and nerve vascular synchronous regeneration.

Immunomodulatory hydrogel orchestrates pro-regenerative response of macrophages and angiogenesis for chronic wound healing

Chronic wound healing often encounters challenges characterized by prolonged inflammation and impaired angiogenesis. While the immune response plays a pivotal role in orchestrating the intricate process of wound healing, excessive inflammation can hinder tissue repair. In this study, a bilayer alginate hydrogel system encapsulating polyelectrolyte complex nanoparticles (PCNs) loaded with anti-inflammatory cytokines and angiogenic growth factors is developed to address the challenges of chronic wound healing. The alginate hydrogel is designed using two distinct crosslinking methods to achieve differential degradation, thereby enabling precise spatial and temporal controlled release of PCNs. Initially, interleukin-10 (IL-10) is released to mitigate inflammation, while unsaturated PCNs bind and remove accumulated pro-inflammatory cytokines at the wound site. Subsequently, angiogenic growth factors, including vascular endothelial growth factor and platelet-derived growth factor, are released to promote vascularization and vessel maturation. Our results demonstrate that the bilayer hydrogel exhibits distinct degradation kinetics between the two layers, facilitating the staged release of multiple signaling molecules. In vitro experiments reveal that IL-10 can activate the Jak1/STAT3 pathway, thereby suppressing pro-inflammatory cytokines and chemokines while down-regulating inflammation-related genes. In vivo studies demonstrate that application of the hydrogel in chronic wounds using diabetic murine model promotes healing by positively modulating multiple integral reparative mechanisms. These include reducing inflammation, promoting macrophage polarization towards a pro-regenerative phenotype, enhancing keratinocyte migration, stimulating angiogenesis, and expediting wound closure. In conclusion, our hydrogel system effectively mitigates inflammatory responses and provides essential physiological cues by inducing a synergistic angiogenic effect, thus offering a promising approach for the treatment of chronic wounds.

The Optimal Effective Dose of Adipose-Derived Stem Cell Exosomes in Wound Healing.

Although the effect of adipose-derived mesenchymal stem cell exosomes (ADSC-exos) on wound healing with different doses are shown in various studies, efficient and sufficient doses of ADSC-exos are still unknown. The study aimed to determine the optimal dose of ADSC-exos in wound healing. The 45 Sprague-Dawley rats were randomly divided into five groups, with seven animals in each. After dorsal circular defects were created, each wound was injected as follows: group 1: saline, group 2: 10 μg/mL of ADSC-exos, group 3: 100 μg/mL of ADSC-exos, group 4: 200 μg/mL of ADSC-exos, and group 5: 400 μg/mL of ADSC-exos. The effects of ADSC-exos on epithelization, angiogenesis, and collagen formation were analyzed macroscopically, histopathologically, and immunohistochemically on day 14. A total of 200 μg/mL and 400 μg/mL ADSC-exos groups had higher epithelial tongue length, epithelial tongue area, and angiogenesis scores than the other groups. Although there was no statistical difference in fibrosis scores among groups, collagen fibers were becoming well-organized as the ADSC-exos doses increased. While the wound area was clinically smaller in the 200 μg/mL ADSC-exos group, there was no statistically significant difference among groups on day 14. A total of 200 μg/mL of ADSC-exos was found to be the adequate and effective dose for re-epithelialization and angiogenesis in cutaneous wound healing. Moreover, the collagen density increased with a more regular pattern in the 200 μg/mL group, which can be important in scar regulation.

Stepwise co-assembled biomimetic hydrogel with antibacterial, angiogenesis, and tissue regeneration acceleration for diabetic wound healing

Bacterial infections and inadequate tissue regeneration capacity are prevalent issues in diabetic wounds, impeding the healing process. To solve these problems, a biomimetic hydrogel combined with bacterial cellulose (BC), recombinant human collagen type III (RHC), and ε-poly-L-Lysine (EPL) is fabricated by stepwise co-assembly technology. Owing to the RHC and EPL modifications of BC, the biomimetic hydrogel exhibited antibacterial effects and promoted fibroblast proliferation and angiogenesis, which accelerated the healing of diabetic wounds. Biomimetic hydrogels exhibit good mechanical properties and excellent water absorption, that can protect wounds and provide a moist environment. In addition, in vitro studies have shown that the hydrogels exhibit excellent antibacterial activity and biocompatibility. In vivo studies on diabetic wound healing have shown that biomimetic hydrogels can promote angiogenesis, accelerate collagen deposition, and re-epithelialize wound sites to promote wound healing. This study provides a new and promising strategy for the treatment of diabetic wounds.

Self-Adapting Biomass Hydrogel Embodied with miRNA Immunoregulation and Long-Term Bacterial Eradiation for Synergistic Chronic Wound Therapy.

Chronic wound rescue is critical for diabetic patients but is challenging to achieve with a specific and long-term strategy. The prolonged bacterial inflammation is particularly prevalent in hyperglycemia-induced wounds, usually leading to severe tissue damage. Such a trend could further suffer from an environmental suitability provided by macrophages for persisting Staphylococcus aureus (S. aureus) and even deteriorate by their mutual reinforcement. However, the strategy of both suppressing bacteria growth and immunoreprogramming the inflammatory type of macrophages to break their vicious harm to wound healing is still lacking. Here, a self-adapting biomass carboxymethyl chitosan (CMC) hydrogel comprising immunomodulatory nanoparticles is reported to achieve Gram-negative/Gram-positive bacteria elimination and anti-inflammatory cytokines induction to ameliorate the cutaneous microenvironment. Mechanistically, antibacterial peptides and CMCs synergistically result in a long-term inhibition against methicillin-resistant S. aureus (MRSA) over a period of 7 days, and miR-301a reprograms the M2 macrophage via the PTEN/PI3Kγ/mTOR signaling pathway, consequently mitigating inflammation and promoting angiogenesis for diabetic wound healing in rats. In this vein, immunoregulatory hydrogel is a promising all-biomass dressing ensuring biocompatibility, providing a perspective to regenerate cutaneous damaged tissue, and repairing chronic wounds on skin.

Bioactive glass 1393 promotes angiogenesis and accelerates wound healing through ROS/P53/MMP9 signaling pathway

Compared to bioactive glass 45S5, bioactive glass 1393 has shown greater potential in activating tissue cells and promoting angiogenesis for bone repair. Nevertheless, the effect of bioactive glass 1393 in the context of wound healing remains extensively unexplored, and its mechanism in wound healing remains unclear. Considering that angiogenesis is a critical stage in wound healing, we hypothesize that bioactive glass 1393 may facilitate wound healing through the stimulation of angiogenesis. To validate this hypothesis and further explore the mechanisms underlying its pro-angiogenic effects, we investigated the impact of bioactive glass 1393 on wound healing angiogenesis through both in vivo and in vitro studies. The research demonstrated that bioactive glass 1393 accelerated wound healing by promoting the formation of granulation, deposition of collagen, and angiogenesis. The results of Western blot analysis and immunofluorescence staining revealed that bioactive glass 1393 up-regulated the expression of angiogenesis-related factors. Additionally, bioactive glass 1393 inhibited the expression of ROS and P53 to promote angiogenesis. Furthermore, bioactive glass 1393 stimulated angiogenesis through the P53 signaling pathway, as evidenced by P53 activation assays. Collectively, these findings indicate that bioactive glass 1393 accelerates wound healing by promoting angiogenesis via the ROS/P53/MMP9 signaling pathway.

Rutin encapsulated decellularized earthworm granulation hydrogel promotes angiogenesis in wound healing of diabetic rabbit model by inhibiting TRAF1/NF-κB pathway

Diabetic micro-vasculopathy is induced by accumulation of Reactive Oxygen Species (ROS) which results in delayed wound healing under hyperglycemic conditions. The classical practice of treating diabetic wound includes surgical debridement, hyperbaric oxygen therapy and use of antibiotics to control infection. The therapeutic interventions based on these classical practices have been found ineffective in management of diabetic wound healing and diabetic vasculopathy. Henceforth, engineered biomaterials with anti-oxidant activity have become research hotspots for their high biological activity, due to sustained release of active principles and weak immunogenicity. Based on these postulates, current study was conducted to evaluate diabetic wound healing potential of Rutin encapsulated decellularized earthworm granulation tissue (RdECM) with special reference on angiogenesis. The angiogenetic activity of RdECM was evaluated on cell line under hyperglycemic conditions and we found significant decline in ROS induced Deoxyribonucleic acid (DNA) damage and inhibition of Nuclear factor kappa B (NF-Kβ) pathway with subsequent aggregation of cells in tubular structure. Application of RdECM on diabetic wound resulted in accelerated wound healing, reduction in ROS induced DNA damage and down regulation of TNF receptor associated factor 1 (TRAF1). These changes results in inhibition of TRAF1-mediated NF-κB signal activation and subsequently angiogenesis in hyperglycemic conditions of diabetic wound. These findings support therapeutic utility of RdECM as angiogenetic agent and its potential use against diabetic wound healing.

Angiogenesis and Microvascular Permeability.

Angiogenesis, the formation of new blood microvessels, is a necessary physiological process for tissue generation and repair. Sufficient blood supply to the tissue is dependent on microvascular density, while the material exchange between the circulating blood and the surrounding tissue is controlled by microvascular permeability. We thus begin this article by reviewing the key signaling factors, particularly vascular endothelial growth factor (VEGF), which regulates both angiogenesis and microvascular permeability. We then review the role of angiogenesis in tissue growth (bone regeneration) and wound healing. Finally, we review angiogenesis as a pathological process in tumorigenesis, intraplaque hemorrhage, cerebral microhemorrhage, pulmonary fibrosis, and hepatic fibrosis. Since the glycocalyx is important for both angiogenesis and microvascular permeability, we highlight the role of the glycocalyx in regulating the interaction between tumor cells and endothelial cells (ECs) and VEGF-containing exosome release and uptake by tumor-associated ECs, all of which contribute to tumorigenesis and metastasis.

Biomaterials-Based Strategies to Enhance Angiogenesis in Diabetic Wound Healing.

Amidst the present healthcare issues, diabetes is unique as an emerging class of affliction with chronicity in a majority of the population. To check and control its effects, there have been huge turnover and constant development of management strategies, and though a bigger part of the health care area is involved in achieving its control and the related issues such as the effect of diabetes on wound healing and care and many of the works have reached certain successful outcomes, still there is a huge lack in managing it, with maximum effect yet to be attained. Studying pathophysiology and involvement of various treatment options, such as tissue engineering, application of hydrogels, drug delivery methods, and enhancing angiogenesis, are at constantly developing stages either direct or indirect. In this review, we have gathered a wide field of information and different new therapeutic methods and targets for the scientific community, paving the way toward more settled ideas and research advances to cure diabetic wounds and manage their outcomes.

HucMSC-Exo Induced N2 Polarization of Neutrophils: Implications for Angiogenesis and Tissue Restoration in Wound Healing.

Neutrophils rapidly accumulate in large numbers at sites of tissue damage, exhibiting not only their well-known bactericidal capabilities but also playing crucial roles in angiogenesis and tissue repair. While exosomes derived from human umbilical cord mesenchymal stem cells (HucMSC-Exo) have emerged as a promising therapeutic tool, their exact mechanisms of action remain partly elusive. We hypothesize that HucMSC-Exo treatment may modulate neutrophil phenotypes, thereby significantly influencing wound healing outcomes. HucMSC-Exo were isolated via ultracentrifugation and subsequently administered through subcutaneous injection into full-thickness cutaneous wounds in mice. To determine the impact of host neutrophils on the healing effects of HucMSC-Exo in skin injuries, strategies including neutrophil depletion and adoptive transfer were employed. Flow cytometry was used to evaluate the proportion of N2 subtype neutrophils in both normal and diabetic wounds, and the effect of HucMSC-Exo on this proportion was assessed. Furthermore, the mitochondrial metabolic reprogramming driven by HucMSC-Exo during N2 polarization was investigated through JC1 staining, ATP quantification, fatty acid uptake assays, and assessment of FAO-related genes (Cpt1b, Acadm, and Acadl). Depleting host neutrophils strikingly dampened prohealing effect of HucMSC-Exo on skin injury, while adoptive transfer of bone marrow neutrophils rescued this process. During normal healing process, some neutrophils expressed N2 markers, in contrast, diabetic wounds exhibited a reduced expression of N2 markers. After treatment with HucMSC-Exo, most neutrophils increased the phosphorylation of STAT6, leading to mitochondrial metabolic reprogramming and thus acquired an N2 phenotype. These N2 neutrophils, polarized by HucMSC-Exo, boosted the release of proangiogenic factors, particularly BV8, a myeloid cell-derived proangiogenic factor, and induced angiogenesis thereby favoring tissue restoration. This research uniquely demonstrates the identification of N2 neutrophils in skin injury and shows that HucMSC-Exo could skew neutrophils toward N2 phenotype, enhancing our insight into how cells react to HucMSC-Exo.

Wound Healing Agents as Described by Avicenna in the Canon of Medicine

Topical wounds are common complications, and it is necessary to find new remedies and approaches for their treatment. In this study, Avicenna’s definitions of topical wounds and his treatment strategies are investigated and compared with contemporary findings. Data were extracted from the fourth chapter of the fourth volume of the Canon of Medicine and databases of PubMed, Scopus and Google Scholar using keywords of wound healing, Avicenna, Persian medicine, etc. Avicenna tries to clarify categorizations, semiology, pathophysiology, dressing, remedies and treatment strategies for wound. Many of his descriptions—like callus and the importance of angiogenesis in wound healing—are close to current definitions. He also mentioned to strategies like using gauze in dressing, control of bleeding and swelling (inflammation), washing and clearing wounds, using suture and surgery in some cases and also prescribing tonic foods. Furthermore, the efficacy of many natural remedies mentioned by Avicenna like Boswellia sacra Flück., Hordeum vulgare L., Prangos ferulacea Lindl., Quercus persica Jaub. & Spach, Brassica oleracea L., and Plantago major L. have been evaluated and approved by contemporary investigations. These results demonstrate the impact of Avicenna’s knowledge on wounds and wound healing process. Therefore, besides historical impact, it is important as a novel natural source to find new medicaments based on this ancient knowledge.

A Poloxamer 407/chitosan-based thermosensitive hydrogel dressing for diabetic wound healing via oxygen production and dihydromyricetin release

The current clinical treatment of diabetic wounds is still based on oxygen therapy, and the slow healing of skin wounds due to hypoxia has always been a key problem in the repair of chronic skin injuries. To overcome this problem, the oxygen-producing matrix CaO2NPS based on the temperature-sensitive dihydromyricetin-loaded hydrogel was prepared. In vitro activity showed that the dihydromyricetin (DHM) oxygen-releasing temperature-sensitive hydrogel composite (DHM-OTH) not only provided a suitable oxygen environment for cells around the wound to survive but also had good biocompatibility and various biological activities. By constructing a T2D wound model, we further investigated the repairing effect of DHM-OTH on chronic diabetic skin wounds and the mechanisms involved. DHM-OTH was able to reduce inflammatory cells and collagen deposition and promote angiogenesis and cell proliferation for diabetic wound healing. These in vitro and in vivo data suggest that DHM-OTH accelerates diabetic wound repair as a novel method to efficiently deliver oxygen to wound tissue, providing a promising strategy to improve diabetic wound healing.

Electrospun statin‐loaded nanofibers for treating diabetic wounds

AbstractThis study aims to develop, characterize, and evaluate the best statin‐loaded Collagen Silver nanoparticle‐coated polycaprolactone nanofibers by electrospinning technique. The characterization and evaluation results reveal that nanofibers had shown an aligned Collagen Silver nanoparticle‐coated polycaprolactone nanofibers distribution of fibers and aliment of collagen and silver nanoparticle coating material on the surface of the nanofibers. Furthermore, the electrospun nanofibers have shown no interaction between the drug and collagen and PCL polymeric material and have demonstrated controlled drug release for 360 h and significant degradation for 60 days of the study. In vitro, among the nanofiber treatment groups and the control groups, Pravastatin Collagen Silver nanoparticle‐coated polycaprolactone nanofibers have shown cell proliferation and migration of NHDF cells and blood vessel development in the CAM assay and potential anti‐bacterial activity against S. aureus and E. coli. In vivo, the Pravastatin Collagen Silver nanoparticle‐coated polycaprolactone nanofibers have demonstrated improved wound recovery, re‐epithelization, fibroblast cell proliferation, angiogenesis, and ECM remodeling and enhanced VEGF‐sprouting in the excised tissues of streptozotocin‐induced diabetic rats for 7, 14, and 21 days of the study. Therefore, the developed Pravastatin Collagen Silver nanoparticle‐coated polycaprolactone nanofibers could be a promising wound‐dressing platform for effectively treating and managing diabetic wounds.Highlights Nanofiber wound dressings provide numerous structural features in biomaterials. Polycaprolactone can release the repurposed statin molecules into the wound site in a controlled manner. In diabetic wounds, ECM tissue remodeling stimulates repair and vessel growth. Pravastatin has been demonstrated to improve angiogenesis and ECM secretion for wound healing in diabetic conditions.

MicroRNA-409-3p/BTG2 signaling axis improves impaired angiogenesis and wound healing in obese mice.

Wound healing is facilitated by neoangiogenesis, a complex process that is essential to tissue repair in response to injury. MicroRNAs are small, noncoding RNAs that can regulate the wound healing process including stimulation of impaired angiogenesis that is associated with type-2 diabetes (T2D). Expression of miR-409-3p was significantly increased in the nonhealing skin wounds of patients with T2D compared to the non-wounded normal skin, and in the skin of a murine model with T2D. In response to high glucose, neutralization of miR-409-3p markedly improved EC growth and migration in human umbilical vein endothelial cells (HUVECs), promoted wound closure and angiogenesis as measured by increased CD31 in human skin organoids, while overexpression attenuated EC angiogenic responses. Bulk mRNA-Seq transcriptomic profiling revealed BTG2 as a target of miR-409-3p, where overexpression of miR-409-3p significantly decreased BTG2 mRNA and protein expression. A 3' untranslated region (3'-UTR) luciferase assay of BTG2 revealed decreased luciferase activity with overexpression of miR-409-3p, while inhibition had opposite effects. Mechanistically, in response to high glucose, miR-409-3p deficiency in ECs resulted in increased mTOR phosphorylation, meanwhile BTG-anti-proliferation factor 2 (BTG2) silencing significantly decreased mTOR phosphorylation. Endothelial-specific and tamoxifen-inducible miR-409-3p knockout mice (MiR-409IndECKO ) with hyperglycemia that underwent dorsal skin wounding showed significant improvement of wound closure, increased blood flow, granulation tissue thickness (GTT), and CD31 that correlated with increased BTG2 expression. Taken together, our results show that miR-409-3p is a critical mediator of impaired angiogenesis in diabetic skin wound healing.

A multifunctional composite nanoparticle with antibacterial activities, anti-inflammatory, and angiogenesis for diabetic wound healing

The treatment of chronic diabetic wounds remains challenging due to the rapid bacterial infection, severe inflammation, and insufficient angiogenesis. To address these challenges, a novel multifunctional composite nanoparticle is developed by co-assembling antisolvent-induced co-assembling silk-fibroin ε-poly-l-Lysine nanoparticles (nSF-EPL) and further assembling nSF-EPL with polydeoxyribonucleotide (PDRN) and exosome derived from human umbilical mesenchymal stem cells (Exo). Owing to the modification of EPL, PDRN and Exo, composite nanoparticles exhibited synergistic antibacterial action, anti-inflammatory and angiogenesis, which can significantly benefit for promoting wound healing. Release results show that the composite nanoparticles exhibit long-term sustained PDRN and Exo release profiles as well as outstanding release efficiency. Furthermore, in vitro studies show that the composite nanoparticles exhibit effective antibacterial activity, thus inducing an anti-inflammatory M2 macrophages phenotype and promoting angiogenesis. In vivo research results of investigations pertaining to diabetic wound healing show that the composite nanoparticles have good anti-inflammatory and angiogenesis capabilities, which can promote granulation tissue formation, collagen deposition, wound tissue epithelialization, and significantly accelerate skin healing. This study presents a promising strategy for the clinical treatment of chronic diabetic wounds.

Recent Approach for Speeding up the Wound Healing

Healing wounds is an important physiological process in the body followed by trauma, burn injuries, post-surgery complications or different diseases that can damage the skin and tissues. Millions of people struggle with their healing process every year and some of them pass away according to the World Health Organization (WHO). Wound healing is done by different processes that are divided into hemostasis/inflammation phase, proliferation phase, and remodeling phase. The pathophysiology of these processes and the factors affecting them is explained. There are two general factors including systemic and local factors contributing, both explained in this research. Many resources have been reviewed regarding the factors that can enhance the healing process. All the information collected to fulfill one of the important purposes of this research. The enhancing factors which are discussed include therapeutic strategies for enhancing angiogenesis in wound healing like using growth Factors, Non-Growth Factor Protein Delivery, gene, and nucleic Acid-Based therapies for wound angiogenesis. Stem cells therapy one of the most recent topics that is being researched a lot in the wound healing subject and potentially gives hopes to healing enhancement, although more clinical trial and experiments need to be done especially on the human body to be able to get more specific results, hopefully can be proved and used to benefit the people who suffer from this problem around the world.

Exosome-mimetic vesicles derived from fibroblasts carrying matrine for wound healing.

Chronic skin wounds are a leading cause of hospital admissions and reduced life expectancy among older people and individuals with diabetes. Delayed wound healing is often attributed to a series of cellular abnormalities. Matrine, a well-studied component found in Sophora flavescens, is recognized for its anti-inflammatory effects. However, its impact on wound healing still remains uncertain. This study aims to explore the potential of matrine in promoting wound healing. In this study, we utilized gradient extrusion to produce fibroblast-derived exosome-mimetic vesicles as carriers for matrine (MHEM). MHEM were characterized using transmission electron microscopy and dynamic light scattering analysis. The therapeutic effect of MHEM in wound healing was explored in vitro and in vivo. Both matrine and MHEM enhanced the cellular activity as well as the migration of fibroblasts and keratinocytes. The potent anti-inflammatory effect of matrine diluted the inflammatory response in the vicinity of wounds. Furthermore, MHEM worked together to promote angiogenesis and the expression of transforming growth factor β and collagen I. MHEM contained growth factors of fibroblasts that regulated the functions of fibroblasts, keratinocytes and monocytes, which synergistically promoted wound healing with the anti-inflammatory effect of matrine. MHEM showed enhanced therapeutic efficacy in the inflammatory microenvironment, for new tissue formation and angiogenesis of wound healing.

Micro-environment triple-responsive hyaluronic acid hydrogel dressings to promote antibacterial activity, collagen deposition, and angiogenesis for diabetic wound healing.

The clinical treatment of chronic diabetic wounds is a long-standing thorny issue. Strategies targeting the diabetic micro-environment have been developed to promote wound healing. However, it remains challenging to reverse the adverse conditions and re-activate tissue regeneration and angiogenesis. In this work, we develop injectable hydrogels that are responsive to acidic conditions, reactive oxygen species (ROS), and high glucose levels in a diabetic wound micro-environment to sustainably deliver tannic acid (TA) to augment antibacterial, anti-inflammatory, and anti-oxidative activities. This triple-responsive mechanism is designed by introducing dynamic acylhydrazone and phenylboronic ester bonds to crosslink modified hyaluronic acid (HA) chains. At a diabetic wound, the acylhydrazone bonds may be hydrolyzed at low pH. Meanwhile, glucose may compete with TA, and ROS may oxidize the C-B bond to release TA. Thus, sustained release of TA is triggered by the diabetic micro-environment. The released TA effectively scavenges ROS and kills bacteria. In vivo experiments on diabetic mice demonstrate that the hydrogel dressing highly promotes angiogenesis and extracellular matrix (ECM) deposition, leading to eventual full healing of diabetic skin wounds. This micro-environment-triggered triple-responsive drug release provides a promising method for chronic diabetic wound healing.

Evaluation of the Effectiveness of Medical-Grade Honey and Hypericum Perforatum Ointment on Second-Intention Healing of Full-Thickness Skin Wounds in Cats.

This study aimed to determine the effects of two topical treatments on second-intention wound healing in cats. Eight 2 × 2 cm full-thickness wounds were created, four on each side of the dorsal midline of eight laboratory cats, to receive either medical-grade honey ointment (MGH) and its control (HC), or Hypericum-based ointment (HP) and its control (HPC). MGH or HP ointment was applied to four wounds on the same side, while the remaining four were used as controls, chosen at random. Planimetry, laser Doppler flowmetry, daily physical examinations, and histologic examinations on days 0, 7, 14, and 25 were used to assess the healing of wounds. Tissue perfusion was better in the MGH-treated (2.14 ± 0.18 mm/s) and HP-treated wounds (2.02 ± 0.13 mm/s) than in the untreated controls HC (1.59 ± 0.11 mm/s) and HPC (1.60 ± 0.05 mm/s), respectively (p = 0.001). Histopathology revealed that the median edema score was lower in the MGH-treated (2; range 1-4) compared to the HC-treated wounds (3; range 2-4) on day 7 (p < 0.05). The median angiogenesis score was higher on day 7 in the MGH-treated (2; range 1-3) compared to the HP-treated wounds (2; range 1-2) (p = 0.046). The fibroblast concentration was increased in the MGH-treated wounds (3.5; range 3-4) compared to the HP-treated wounds (3; range 2-4) on day 25 (p = 0.046). MGH and HP increased tissue perfusion compared to the untreated controls. The MGH-treated wounds had histologic parameters superior to the HP-treated wounds regarding angiogenesis and fibroblast concentration in cutaneous wound healing in cats. Topical application of MGH and HP did not accelerate the healing process of feline cutaneous wounds.