Full-thickness Cutaneous Wounds Research Articles

Biomimetic nanoengineered scaffold for enhanced full-thickness cutaneous wound healing

Wound healing is a complex process based on the coordinated signaling molecules and dynamic interactions between the engineered scaffold and newly formed tissue. So far, most of the engineered scaffolds used for the healing of full-thickness skin wounds do not mimic the natural extracellular matrix (ECM) complexity and therefore are not able to provide an appropriate niche for endogenous tissue regeneration [1]. To address this gap and to accelerate the wound healing process, we present biomimetic bilayer scaffolds compositing of gelatin nanofibers (GFS) and photocrosslinkable composite hydrogels loaded with epidermal growth factors (EGF). The nanofibers operate as the dermis layer, and EGF-loaded composite hydrogels acted as the epidermis matrix for the full-thickness wound healing application. The hydrogels are composed of gelatin metacryloyl (GelMA) modified with silicate nanoplatelets (Laponite). To overcome the challenges of transdermal delivery of EGF, including short half-life and lack of efficient formulation precise, controlled delivery was attained by immobilization of EGF on Laponite. It is shown that the addition of 1wt% silicate nanoplatelet increases the compressive modulus of the hydrogels by 170%. In vitro wound closure analysis also demonstrated improved adhesion of the scaffolds to the native tissue by 3.5 folds. Moreover, the tunable hemostatic ability of the scaffolds due to the negatively charged nanoplatelets is shown. In an established excisional full-thickness wound model, an enhanced wound closure (up to 93.1 ± 1.5%) after 14 days relative to controls (GFS and saline-treated groups) is demonstrated. The engineered adhesive and hemostatic scaffolds with sustained release of the growth factors have the potential to stimulate complete skin regeneration for full-thickness wound healing.

Platelets Facilitate the Wound-Healing Capability of Mesenchymal Stem Cells by Mitochondrial Transfer and Metabolic Reprogramming

Platelets are known to enhance the wound-healing activity of mesenchymal stem cells (MSCs). However, the mechanism by which platelets improve the therapeutic potential of MSCs has not been elucidated. Here, we provide evidence that, upon their activation, platelets transfer respiratory-competent mitochondria to MSCs primarily via dynamin-dependent clathrin-mediated endocytosis. We found that this process enhances the therapeutic efficacy of MSCs following their engraftment in several mouse models of tissue injury, including full-thickness cutaneous wound and dystrophic skeletal muscle. By combining invitro and invivo experiments, we demonstrate that platelet-derived mitochondria promote the pro-angiogenic activity of MSCs via their metabolic remodeling. Notably, we show that activation of the de novo fatty acid synthesis pathway is required for increased secretion of pro-angiogenic factors by platelet-preconditioned MSCs. These results reveal a new mechanism by which platelets potentiate MSC properties and underline the importance of testing platelet mitochondria quality prior to their clinical use.

Exosome loaded genipin crosslinked hydrogel facilitates full thickness cutaneous wound healing in rat animal model

Full thickness cutaneous wound therapy and regeneration remains a critical challenge in clinical therapeutics. Recent reports have suggested that mesenchymal stem cells exosomes therapy is a promising technology with great potential to efficiently promote tissue regeneration. Multifunctional hydrogel composed of both synthetic materials and natural materials is an effective carrier for exosomes loading. Herein, we constructed a biodegradable, dual-sensitive hydrogel encapsulated human umbilical cord-mesenchymal stem cells (hUCMSCs) derived exosomes to facilitate wound healing and skin regeneration process. The materials characterization, exosomes identification, and in vivo full-thickness cutaneous wound healing effect of the hydrogels were performed and evaluated. The in vivo results demonstrated the exosomes loaded hydrogel had significantly improved wound closure, re-epithelialization rates, collagen deposition in the wound sites. More skin appendages were observed in exosomes loaded hydrogel treated wound, indicating the potential to achieve complete skin regeneration. This study provides a new access for complete cutaneous wound regeneration via a genipin crosslinked dual-sensitive hydrogel loading hUCMSCs derived exosomes.

Studies on the Efficacy of Single and Twice Application of Mesenchymal Stem Cells in Full Thickness Cutaneous Wound Healing

Background: A lot of research has been done in the field of wound healing utilising stem cell therapy. This study was conducted to compare the efficacy of single and twice application of mesenchymal stem cells for cutaneous wound healing.Methods: The present study was done on 18 guinea pigs and a 2.5 X 2.5 cm2 full-thickness skin wound was created on the dorsum of each under standard anesthetic protocol. Animals were divided into 3 groups having 6 animals in each. The animals of group I were administered phosphate buffer saline (PBS) subcutaneously on day 0, group II received 1×106 mesenchymal stem cells (MSCs) in PBS subcutaneously on day 0 and group III received 1×106 MSCs in PBS subcutaneously on day 0 and again at day 3, at wound margins. Clinical, photographic, histopathological and histochemical parameters were recorded for each animal.Result: An overall gross and histopathological evaluation suggested early wound closer, better tissue granulation, early orientation of fibrocytes and collagen fibers, revealing a superior quality healing in animals of group III as compared to rest of the groups. From the above study it was concluded that twice application of MSCs leads to faster and qualitatively better healing.

Rifampicin-Loaded Alginate-Gelatin Fibers Incorporated within Transdermal Films as a Fiber-in-Film System for Wound Healing Applications.

The various biological and molecular cascades including different stages or phases such as inflammation, tissue proliferation, and remodeling phases, which significantly define the wound healing process. The natural matrix system is suggested to increase and sustain these cascades. Biocompatible biopolymers, sodium alginate and gelatin, and a drug (Rifampicin) were used for the preparation of fibers into a physical crosslinking solution using extrusion-gelation. The formed fibers were then loaded in transdermal films for wound healing applications. Rifampicin, an antibiotic, antibacterial agent was incorporated into fibers and afterwards the fibers were loaded into transdermal films. Initially, rifampicin fibers were developed using biopolymers including alginate and gelatin, and were further loaded into polymeric matrix which led to the formation of transdermal films. The transdermal films were coded as TF1, TF2, TF3 and TF4.The characterization technique, FTIR, was used to describe molecular transitions within fibers, transdermal films, and was further corroborated using SEM and XRD. In mechanical properties, the parameters, such as tensile strength and elongation-at-break (extensibility), were found to be ranged between 2.32 ± 0.45 N/mm2 to 14.32 ± 0.98 N/mm2 and 15.2% ± 0.98% to 30.54% ± 1.08%. The morphological analysis firmed the development of fibers and fiber-loaded transdermal films. Additionally, physical evaluation such as water uptake study, water transmission rate, swelling index, moisture content, and moisture uptake study were executed to describe comparative interpretation of the formulations developed. In vivo studies were executed using a full thickness cutaneous wound healing model, the transdermal films developed showed higher degree of contraction, i.e., 98.85% ± 4.04% as compared to marketed formulation (Povidone). The fiber-in-film is a promising delivery system for loading therapeutic agents for effective wound care management.

Injectable Adhesive Self-Healing Multicross-Linked Double-Network Hydrogel Facilitates Full-Thickness Skin Wound Healing.

The development of natural polymer-based hydrogels, combining outstanding injectability, self-healing, and tissue adhesion, with mechanical performance, able to facilitate full-thickness skin wound healing, remains challenging. We have developed an injectable micellar hydrogel (AF127/HA-ADH/OHA-Dop) with outstanding adhesive and self-healing properties able to accelerate full-thickness skin wound healing. Dopamine-functionalized oxidized hyaluronic acid (OHA-Dop), adipic acid dihydrazide-modified HA (HA-ADH), and aldehyde-terminated Pluronic F127 (AF127) were employed as polymer backbones. They were cross-linked in situ using Schiff base dynamic covalent bonds (AF127 micelle/HA-ADH network and HA-ADH/OHA-Dop network), hydrogen bonding, and π-π stacking interactions. The resulting multicross-linked double-network design forms a micellar hydrogel. The unique multicross-linked double-network structure endows the hydrogel with both improved injection abilities and mechanical performance while self-healing faster than single-network hydrogels. Inspired by mussel foot adhesive protein, OHA-Dop mimics the catechol groups seen in mussel proteins, endowing hydrogels with robust adhesion properties. We also demonstrate the potential of our hydrogels to accelerate full-thickness cutaneous wound closure and improve skin regeneration with reduced scarring. We anticipate that our hydrogel platform based on a novel multicross-linked double-network design will transform the future development of multifunctional wound dressings.

Evaluation of fish skin as a biological dressing for metacarpal wounds in donkeys

BackgroundThe use of biological dressings has recently emerged in the management of burns and wounds. The aim of the present study was to evaluate the Nile tilapia skin as a biological dressing for full-thickness cutaneous metacarpal wounds in donkeys. The study was conducted on nine clinically healthy donkeys (n = 9). Here, fish skin dressings were obtained from fresh Nile tilapia (Oreochromis niloticus and sterilized by immersion in silver nanoparticles (AgNPs) solution for 5 min, with no change in collagen content. Bilateral, circular full-thickness excisional skin wounds (2 cm in diameter) were created on the dorsal aspect of the mid-metacarpals of each donkey. Wounds on the right metacarpals (treated wounds, n = 9) were dressed with sterile fish skins, while wounds on the left metacarpals (control wounds, n = 9) were dressed with sterile non-adherent dressing pads without any topical applications. Wound dressings were changed weekly. Wounds were evaluated microbiologically, grossly, and histologically on days 7, 14, and 21 post-wound inductions.ResultsFish skin-dressed wounds showed a significant (P < 0.0001) reduction in microbial counts (Total viable bacterial count, Staphylococcal count, and Coliform count), a significant (P < 0.0001) decrease in the wound size, and a significant reduction (P < 0.0001) in the epithelial gap compared to the untreated wounds. No frequent dressing changes were needed.ConclusionsFish skin dressing accelerated the wound healing process and efficiently inhibited the local microbial activity and exuberant granulation tissue formation suggesting its reliable and promising application for metacarpal wounds of donkeys.

Curcumin-loaded, alginate-gelatin composite fibers for wound healing applications.

The wound healing process is characterized by varied biological and molecular cascades including inflammation, tissue proliferation, and remodeling phase. To augment and maintain these cascades, an all-natural matrix system is proposed. Biocompatible biopolymers, sodium alginate and gelatin, were employed to prepare microfibers via extrusion-gelation into a physical crosslinking solution. Curcumin, an anti-inflammatory, anti-oxidant and wound healing agent, was loaded into the fibers as a natural bioactive compound. Curcumin-loaded composite microfibers and blank microfibers were fabricated using biopolymers such as sodium alginate and gelatin. The formulation batches were coded as A1G9-A10G0 according to the varied concentrations of sodium alginate and gelatin. The molecular transitions within the composite microfibers were characterized using FTIR and were further corroborated using molecular mechanics analysis. In mechanical properties tensile strength and elongation-at-break (extensibility) were ranging between 1.08 ± 0.01 to 3.53 ± 0.41N/mm2 and 3.89 ± 0.18 to 0.61 ± 0.03%. The morphological analysis confirmed the formation and fabrication of the microfibers. In addition, physical evaluation including matrix degradation and entrapment efficiency was performed to give a comparative account of various formulations. The water uptake capacity of the blank and curcumin-loaded composite fibers was found to be in the range of 30.77 ± 2.17 to 100.00 ± 5.99 and 22.34 ± 1.11 to 56.34 ± 4.68, respectively. Composite microfibers presented a cumulative release of 85% in 72h, confirming the prolonged release potential of the composite fibers. The drug release followed an anomalous (non-Fickian) release behavior asserting the role of degradation and diffusion. In an in vivo full-thickness cutaneous wound model, the composite microfibers provided higher degree of contraction 96.89 ± 3.76% as compared to the marketed formulation (Vicco turmeric cream). In conclusion, this all-natural, alginate-gelatin-curcumin composite has the potential to be explored as a cost-effective wound healing platform.

Antioxidant and anti-inflammatory activities of Prussian blue nanozyme promotes full-thickness skin wound healing

Excessive reactive oxygen species (ROS) and unresolved inflammations are the major causes of impaired wound healing as they overwhelm the cellular antioxidant system and impede the healing process. In this study, we examined the application of Prussian blue (PB) nanozyme as a novel material for cutaneous wound healing through the alleviation of excessive ROS and inflammation modulation. The PB nanoparticles not only exhibited hydrogen peroxide (H2O2) degradation activity but also showed strong superoxide scavenging ability. PB nanozyme mitigated the intracellular ROS at a high oxidative stress environment, resulting in a pronounced cytoprotective effect. Moreover, PB nanozyme also displayed significant anti-inflammatory activity, as evident from the suppression of inflammatory mediators in the lipopolysaccharide (LPS) induced macrophage cells. Encouraged by the in vitro results, we evaluated the in vivo therapeutic efficacy of PB nanozyme in a full-thickness cutaneous wound model combined with LPS treatment to mimic bacterial infection. The beneficial effects of topically applied PB nanozyme on wound healing and tissue regeneration were evident compared to the control. The periodical administration of a low amount (50 μg × 4) of PB nanoparticles exhibited faster wound closure as well as collagen deposition, maturation, and organization. Moreover, the PB treatment effectively induced the differentiation of keratinocytes, enhanced the neovascularization, and reduced macrophage burden in the entire wound site. Thus, PB nanozyme not only accelerated the healing process in an infection-mimicking cutaneous wound model but also exhibited tissue regeneration characteristics owing to the synergistic effect of ROS-scavenging and anti-inflammatory activities.

Biomimetic Nanoengineered Scaffold for Enhanced Full-Thickness Cutaneous Wound Healing

Wound healing is a complex process which is based on the coordinated signaling molecules and dynamic interactions between the engineered scaffold and newly formed tissue. So far, most of the engineered scaffolds used for the healing of full-thickness skin wound do not mimic the natural extracellular matrix (ECM) complexity and therefore are not able to provide an appropriate niche for endogenous tissue regeneration. To address this gap and to accelerate the wound healing process, we present biomimetic bilayer scaffolds compositing of gelatin nanofibers (GFS) and photocrosslinkable composite hydrogels loaded with epidermal growth factors (EGF). The nanofibers operate as the dermis layer and EFG-loaded composite hydrogels acted as the epidermis matrix for the full-thickness wound healing application. The hydrogels are composed of gelatin metacryloyl (GelMA) modified with silicate nanoplatelets (Laponite). To overcome the challenges of transdermal delivery of EGF including short half-life and lack of efficient formulation precise, controlled delivery was attained by immobilization of EGF on Laponite. It is shown that the addition of 1wt% silicate nanoplatelet increases the compressive modulus of the hydrogels by 170%. In vitro wound closure analysis also demonstrated improved adhesion of the scaffolds to the native tissue by 3.5 folds. Moreover, the tunable hemostatic ability of the scaffolds due to the negatively charged nanoplatelets is shown. In an established excisional full-thickness wound model, an enhanced wound closure (up to 93.1 ± 1.54%) after 14 days relative to controls (GFS and saline-treated groups) is demonstrated. The engineered adhesive and hemostatic scaffolds with sustained release of the growth factors have the potential to stimulate complete skin regeneration for full-thickness wound healing.

Angelica dahurica promoted angiogenesis and accelerated wound healing in db/db mice via the HIF-1α/PDGF-β signaling pathway

Impaired angiogenesis is crucial for impeding the wound healing process in diabetic foot ulcers (DFUs). In this study, we found that Angelica dahurica (A. dahurica) stimulated angiogenesis and benefited wound healing in genetic mouse models of diabetes. In HUVECs, A. dahurica promoted cell proliferation and tube formation, which was accompanied by increased nuclear translocation of HIF-1α under hypoxic conditions and led to elevated PDGF-β protein expression. A. dahurica activated the PI3K/AKT signaling pathway in human umbilical vein endothelial cells (HUVECs), which was abrogated by the PI3K inhibitor LY294002. Furthermore, the cellular expression of PDGF-β decreased significantly after treatment with a HIF-1α-siRNA, and PDGF-β expression was increased in HIF-1α-overexpressing cells. In a full-thickness cutaneous wound healing db/db mouse model, A. dahurica accelerated wound closure, which was reflected by a significantly reduced wound area and an increase in neovascularization, as well as by elevated PDGF-β expression and increased capillary formation. In addition, A. dahurica activated the PI3K/AKT signaling pathway and enhanced HIF-1α synthesis in wounds. In summary, A. dahurica promoted angiogenesis of HUVECs in vitro by promoting signaling via the HIF-1α/PDGF-β pathway, efficiently enhancing vascularization in regenerated tissue and facilitating wound healing in vivo. The results revealed that A. dahurica has potential as a therapy for vessel injury-related wounds.

Umbilical Cord-Derived Mesenchymal Stem Cell-Derived Exosomes Combined Pluronic F127 Hydrogel Promote Chronic Diabetic Wound Healing and Complete Skin Regeneration.

PurposeChronic refractory wounds are a multifactorial comorbidity of diabetes mellitus with the characteristic of impaired vascular networks. Currently, there is a lack of effective treatments for such wounds. Various types of mesenchymal stem cell-derived exosomes (MSC-exos) have been shown to exert multiple therapeutic effects on skin regeneration. We aimed to determine whether a constructed combination of human umbilical cord MSC (hUCMSC)-derived exosomes (hUCMSC-exos) and Pluronic F-127 (PF-127) hydrogel could improve wound healing.Materials and MethodsWe topically applied human umbilical cord-derived MSC (hUCMSC)-derived exosomes (hUCMSC-exos) encapsulated in a thermosensitive PF-127 hydrogel to a full-thickness cutaneous wound in a streptozotocin-induced diabetic rat model. The material properties and wound healing ability of the hydrogel and cellular responses were analyzed.ResultsCompared with hUCMSC-exos, PF-127-only or control treatment, the combination of PF-127 and hUCMSC-exos resulted in a significantly accelerated wound closure rate, increased expression of CD31 and Ki67, enhanced regeneration of granulation tissue and upregulated expression of vascular endothelial growth factor (VEGF) and factor transforming growth factor beta-1 (TGFβ-1).ConclusionThe efficient delivery of hUCMSC-exos in PF-127 gel and improved exosome ability could promote diabetic wound healing. Thus, this biomaterial-based exosome therapy may represent a new therapeutic approach for cutaneous regeneration of chronic wounds.

Effect of Omega-3 on Induced Cutaneous Wounds Healing in Rabbits

The present study was designed to evaluate the effects of omega3 on full-thickness cutaneous wounds healing&#x0D; in rabbits. All animals were created wound (1.5 cm2) full-thickness in dorsal back region in (16) male adult&#x0D; rabbits, clinically healthy weighing from (1.3- 1.8 kg). Under the effect of intramuscular administration&#x0D; of a mixture of xylazine hydrochloride 5mg/kg with ketamine hydrochloride 35mg/kg of and 1 mg/kg of&#x0D; Diazepam. The treatment group was given 300 mg of omega3 orally daily with single dose (group A), while&#x0D; in group (B), the rabbits were left without treatment, as a control group. For clinical and histopathological&#x0D; evaluation, each group was divided into four subgroups (two wounds/subgroup) on 3, 7, 14 and 21th days&#x0D; post-wound creation and treatment. The result revealed, Clinically, the rate of wound healing was same in&#x0D; all groups, no differences when section taken from the edge of the wounds. The results histopathologically,&#x0D; shown the treated groups have greater cellularity with improved vasculature with the superiority of omega&#x0D; 3 -treated groups than those in untreated groups. Conclusion; the histopathologically and clinically results&#x0D; confirmed that given effects of omega3 to the treated groups leads to enhance and develop of cutaneous&#x0D; wound healing.

Highly Water-Preserving Zwitterionic Betaine-Incorporated Collagen Sponges With Anti-oxidation and Anti-inflammation for Wound Regeneration.

A core problem in wound healing – with both fundamental and technological significance – concerns the rational design of bioactive and moist microenvironments. Here, we design a new class of zwitterionic betaine-incorporated collagen sponges (BET@COL) with integrated anti-oxidation and anti-inflammatory properties for promoting wound healing in a full-thickness wound model. The presence of zwitterionic betaine in a 3D network structure of collagen enables tightly bound and locked water molecules inside sponges via ionic solvation and confinement effect, while the integration of this amino acid also empowers the sponge with anti-oxidation and anti-inflammatory functions. In vitro results demonstrated that BET@COL collagen sponges strongly preserved water content up to 33.78 ± 0.78% at the 80th min at 37°C (only 0.44 ± 0.18% in control), and also exhibited high cell biocompatibility. Further, BET@COL collagen sponges with different betaine contents were applied to a full-thickness cutaneous wound model in mice, followed by a systematical evaluation and comparison of the effect of preserved water on wound healing efficiency in vivo. The optimal BET@COL collagen sponges were able to maintain high water content (e.g., moist microenvironment), suppress oxidative stress, improve anti-inflammation, all of which impose synergetic healing effects to promote wound closure, granulation formation, re-epithelization, collagen deposition and angiogenesis. This work demonstrates a new material as a promising candidate for wound dressing.

Injectable human decellularized adipose tissue hydrogel containing stem cells enhances wound healing in mouse

Acellular matrix hydrogels have been extracted from a variety of tissues currently, which have been widely exploited for various applications. What is more, hydrogels derived from porcine myocardium matrix have entered clinical trials (NCT02305602) for the prevention and treatment of heart failure post-myocardial infarction. However, few scholars have analyzed the adipose acellular matrix hydrogels. Here we report an injectable hydrogel entirely from human decellularized adipose tissue (hDAT-gel) and explore the innovative application in wound healing combining with human adipose-derived stem cells (hASCs). We postulated that hDAT-gel could provide hASCs with a 3D vivo-like ecological niche necessary to enhance stem cell engraftment, survival as well as differentiation to improve the quality of wound healing. Consequently, a temperature-responsive hDAT-gel was successfully produced, which could undergo sol-gel transition at 37℃. In vitro, hASCs could survive and proliferate well in the self-assembled gel which retained important protein components. In vivo, when the hASCs-embedded hDAT-gels were injected into the full-thickness cutaneous wound of mice, the wound healed rapidly through obvious neovascularization especially within 7 days. Our study demonstrated that the hDAT-gel containing hASCs could accelerate the vascularization of the wound site and speed up the wound healing to some extent. It is a promising injectable biomaterial for stem cell delivery and wound repair.

The laminin-211-derived PPFEGCIWN motif accelerates wound reepithelialization and increases phospho-FAK-Tyr397 and Rac1-GTP levels in a rat excisional wound splinting model.

We previously reported that the PPFEGCIWN motif (Ln2-LG3-P2-DN3), residues 2678-2686 of the human laminin α2 chain, promotes cell attachment of normal human epidermal keratinocytes (NHEKs) and dermal fibroblasts (NHDFs); however, its in vivo effects on cutaneous wound healing have not yet been examined. In this study, we sought to determine whether Ln2-LG3-P2-DN3 could promote full-thickness cutaneous wound healing by accelerating wound reepithelialization and wound closure in vivo. Ln2-LG3-P2-DN3 had significantly higher cell attachment and spreading activities than vehicle or scrambled peptide control in both NHEKs and NHDFs in vitro. The wound area was significantly smaller in rats treated with Ln2-LG3-P2-DN3 than in those treated with vehicle or scrambled peptide in the early phase of wound healing. Furthermore, Ln2-LG3-P2-DN3 significantly accelerated wound reepithelialization relative to vehicle or scrambled peptide and promoted FAK-Tyr397 phosphorylation and Rac1 activation. Collectively, our findings suggest that the PPFEGCIWN motif has potential as a therapeutic agent for cutaneous regeneration via the acceleration of wound reepithelization and wound closure.

S-nitrosated keratin composite mats with NO release capacity for wound healing

Wound repair is a dynamic and complex process that involves various interactions between repair cells, growth factors and the extracellular matrix. Nitric oxide (NO) plays a pivotal role in wound healing, including causing the contraction of wound surfaces, dilating blood vessels, participating in inflammation, and promoting collagen synthesis, angiogenesis, and fibroblast proliferation. Here, we prepared a novel keratin-based nitric oxide donor, called S-nitrosated keratin (KSNO). Then, KSNO was coelectrospun with polyurethane (PU) and gelatin (Gel) to produce PU/Gel/KSNO biocomposite mats. The prepared mats released NO without cytotoxicity, promoted the proliferation of L929 murine fibroblasts and human umbilical vein endothelial cells (HUVECs), and inhibited bacterial growth. These mats could also accelerate the cell adhesion and growth along the random arrangement of electrospun fibers, and simulate the structure of the natural extracellular matrix to provide good scaffolds for cell. The effect of PU/Gel/KSNO on promoting wound healing was investigated on a full-thickness excisional cutaneous wound model in rats. The results demonstrated that these mats accelerated wound healing without inflammatory reaction. In conclusion, PU/Gel/KSNO mats display excellent bioactivity and biocompatibility and have potential in the field of wound repair.

Injectable melatonin-loaded carboxymethyl chitosan (CMCS)-based hydrogel accelerates wound healing by reducing inflammation and promoting angiogenesis and collagen deposition

Carboxymethyl chitosan (CMCS)-based hydrogels have antibacterial activity, and have shown the abilities of preventing wound infection, promoting cell proliferation, accelerating collagen deposition, and stimulating hyaluronic acid formation during wound healing. As a hormone produced by the pineal gland in humans and animals, melatonin promotes skin wound healing by regulating the release of inflammatory mediators and accelerating the proliferation and migration of cells, angiogenesis, and collagen deposition. However, the combined effects of CMCS and melatonin on wound healing remain unclear. Injectable CMCS-based hydrogels containing melatonin were prepared, and their healing effects were evaluated using a full-thickness cutaneous wound model in rats. Compared with the control and the hydrogel with no melatonin groups, the melatonin-loaded hydrogel significantly increased the percentage of wound closure, promoted the proliferation of granulation tissue and re-epithelialization, and accelerated collagen deposition. Additionally, the melatonin-loaded hydrogel promoted angiogenesis and vascular endothelial growth factor receptor protein expression and increased the expression of cyclooxygenase-2 and inducible nitric oxide synthase. The melatonin-loaded hydrogel also markedly increased the expression of collagen III, α-smooth muscle actin, and transforming growth factor-β1 proteins and reduced collagen I expression. These results suggest that the melatonin-loaded hydrogel promoted granulation tissue formation and accelerated wound healing by reducing inflammation and promoting angiogenesis and collagen deposition.

Paeoniflorin promotes angiogenesis and tissue regeneration in a full-thickness cutaneous wound model through the PI3K/AKT pathway.

The treatment of wounds remains a clinical challenge because of poor angiogenesis under the wound bed, and increasingly, the patients' need for functional and aesthetically pleasing scars. For the wound healing process, new blood vessels which can deliver nutrients and oxygen to the wound area are necessary. In this study, we investigated the pro-angiogenesis ability and mechanism in wound healing of paeoniflorin (PF), which is a traditional Chinese medicine. In our in vitro results, the ability for proliferation, migration and in vitro angiogenesis in human umbilical vein endothelial cells was promoted by coculturing with PF (1.25-5 μM). Meanwhile, molecular docking studies revealed that PF has excellent binding abilities to phosphatidylinositol-3-kinase (PI3K) and protein kinase B (AKT), and consistent with our western blot results, that PF suppressed PI3K and AKT phosphorylation. Furthermore, to investigate the healing effect of PF in vivo, we constructed a full-thickness cutaneous wound model in rats. PF stimulated the cellular proliferation status, collagen matrix deposition and remodeling processes in vitro and new blood vessel formation at the wound bed resulting in efficient wound healing after intragastric administration of 10 mg·kg-1 ·day-1 in vivo. Overall, PF performed the pro-angiogenetic effect in vitro and accelerating wound healing in vivo. In summary, the capacity for angiogenesis in endothelial cells could be enhanced by PF treatment via the PI3K/AKT pathway in vitro and could accelerate the wound healing process in vivo through collagen deposition and angiogenesis in regenerated tissue. This study provides evidence that application of PF represents a novel therapeutic approach for the treatment of cutaneous wounds.

Accelerated healing by topical administration of Salvia officinalis essential oil on Pseudomonas aeruginosa and Staphylococcus aureus infected wound model

BackgroundSalvia officinalis L. (Lamiaceae) is known to have antibacterial properties possibly conducive to the healing process of infected wounds. PurposeThe present study aimed to evaluate the effects of an ointment containing Salvia officinalis essential oil (SOO) on an infected wound model. MethodsEssential oil hydrodistillated from the dried leaves of the plant was analyzed by GC-FID and GC–MS. After creating two full-thickness cutaneous wounds, mice were classified into four groups, control, and animals treated with 2 % mupirocin® (standard positive drug), and 2 % and 4 % (w/w) of SOO. In order to evaluate the effects of SOO on the wound healing phases, the expression levels of interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), cyclin-D1, Bcl-2, fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factors (VEGF) were analyzed using qRT-PCR. Immunohistochemistry analysis, tissue total antioxidant capacity (TAC) and malondialdehyde (MDA) were further assessed in all groups. ResultsConcerning essential oil, the main compounds were found to be cis-thujone (26.8 %), camphor (16.4 %), trans-thujone (14.1 %) and 1,8-cineole (10.8 %). Our findings showed that the topical application of SOO was able to shorten the inflammatory phase and accelerate the cellular proliferation, re-vascularization, collagen deposition and re-epithelialization in comparison to the control group (p < 0.05). Moreover, increased mRNA levels of FGF-2 and VEGF, and up-regulation of cyclin-D1 and Bcl-2 were observed following the topical application of SOO compared to the control group (p < 0.05). The expression levels of IL-6, IL-1β and TNF-α were reduced in animals treated with SOO on days 3, 7 and 14 (p < 0.05). ConclusionsAdministration of SOO increased the TAC level and reduced the MDA content and levels of IL-1β and TNF-α. It is concluded that SOO is able to accelerate the wound healing process by regulating the expression of pro-inflammatory cytokines, growth factors, and antioxidant properties.