Multifunctional self-healing hydrogels for chronic wound repair: Design, mechanisms, and applications.

The adverse impact of chronic wounds is felt worldwide. The concerns for advanced wound care product are progressively increasing due to factors such as value for money spent in wound care products. Acute and Chronic wounds are managed in most health facilities in Ghana with sodium chloride (0.9%) infusion solution and povidone iodine fortified with metronidazole solution. The procedure is usually done by the nurse cleaning the wound with the saline solution wet gauze or cotton and then covered with the povidone iodine wet gauze for acute and chronic wounds. For chronic infected wounds, the wound is usually cleaned with saline solution and covered with wet gauze saline or currently with neomycin wound care spray or powdered antibiotics applied on the wounds. But it is popular as many wounds are covered with povidone iodine after wound cleaning in wound care practices in Ghana. Despite all these efforts, many wounds, especially chronic type wounds take a very long time to heal or sometimes fails to heal which reduce the quality of life of the people suffering from the menace. When it happens in this way, many resort to the use of local remedies to cause the wounds to heal but no avail, especially in Ghana where advanced treatment is scare. It is against this background that focal research in wound care was done in Ghana to come out with an innovative pharmaceutical wound care product effective for chronic and acute wounds healing to improve the quality of life of people as global burden of wounds escalates. In a Blind Observational Study for a period of five years in Ghana to observe the wound care products efficacy to heal wounds especially chronic types, the objective of the study was to examine a new product efficacy in chronic wound healing in the targeted population of patients with wounds. A product that has dual purpose of wound care as a cleaning and application agent, also has unique product pharmaceutical characteristics. A scalable, easy- to- use, multi-purpose, multi-use and cost-effective product, able to address the barriers or problems of wounds healing. The areas of consideration as far as wound care are concerned included: The study also sought to observe the product ability to control wound pains, control wound bleeding, control and prevent wound infection, remove wound debris, remove wound exudates effecting wounds healing at reduced healing time and with minimal scar in varied targeted patients’ population. Again, to observe the product with outcome of which to mitigate the long-term effect of chronic wounds like recurrent hospitalizations, financial burden, amputations, deformity, and frequent visit to hospital for wound care. One product, 9G Wound Solution (a cleaning and application product) manufactured by Pat J Health Company Limited, Ghana, was effective in wounds healing, especially, effective chronic wounds healing. The product was used to subject varied patients’ population with wounds on randomized basis, for wound care, and through observation the direct short, intermedial and long-term outcomes recorded of product effectiveness recorded. The outcome reported included control of wound pains, control of wound odor, control of bleeding, control of wound infection, removal of wounds exudates, removal of wound debris and ultimately reduced wound healing time to prevent wounds complications like amputations. The study was progressively extended across 10 regions in Ghana to cover 500 patient population with varied wounds. Patients’ population included those with Diabetic ulcers, Burns, pressure ulcers, venous ulcers, herpes zoster skin ulcers, Perineum wounds, Surgical abdomen-pelvic wounds, Traumatic wounds, Buruli Ulcers, gas gangrene wounds, and Mouth ulcers. The outcome of using the new wound care product were directly observed for the study period. By this observational study, the new product was observed to be superior to the controls as this product was able to heal 99% patients who had wounds, especially chronic wounds for many years, including 20years-old wound at reduced healing rate with no reoccurrence within the study period. The product scientifically readily released to the wound environment modulators capable to address the problems or barriers of wounds and simultaneously promoting modulators effective for wound healing. The product was not only effective in chronic wound healing at reduced time but also controlled wound pains shortly, controlled wound odor shortly, stopped wound bleeding, fought and controlled wound infection. However, using the product needed change of wound dressing every two days. The long-term effect of the product on target population not conclusively observed within the period of the research. We need to continuously observe the reported long-term effect of the product efficacy.

Surgical infection is one of the most important and important problems of modern medicine. The lack of a universal remedy and method of wound treatment, the difficulty of choosing universal tactics of management of patients with chronic wounds determines the need for further search for new treatments that stimulate reparative processes in chronic wounds, including morphological research methods. The role of cellular regulation in the pathogenesis of the restoration of the morphofunctional state of a chronic wound in the conditions of its damage remains undisclosed. Therefore, the aim of our study was to evaluate the role of myofibroblasts in the healing of chronic purulent-necrotic wounds in the treatment of mesenchymal stem cells using immunohistochemistry. In the experiment we obtained a model of chronic purulent-necrotic wound, which meets all the requirements for quality indicators in the study of morphological changes in chronic wounds and can then be used as a basis for preclinical research. The condition of chronic purulent-necrotic wounds in 120 rats was studied by histological and immunohistochemical methods. Chronic wound was modeled according to the original method of the author: during the formation of a standard skin defect in the interscapular area of the rat with a diameter of 1 cm, the surrounding tissue was superimposed ischemic metal structure to reduce blood flow in the wound area, which significantly slowed the delay. Treatment was started from 28 days from the beginning of wounding, which clinically and histologically corresponded to the chronicity of the wound process. Statistical processing of morphometric parameters was performed using the standard software package “Statistica 6.1”. It was found that the positive dynamics of healing of chronic wounds, using 0.025 % decasan solution, was observed mainly in the early stages (3-7 days), while mesenchymal stem cells (MSC) and MSC cloned in inert gases (MSC-IG) were effective at all stages of the study. The use of MSC and MSC-IG creates favorable conditions for the normal course of regenerative processes and epithelialization of wounds, providing anti-edema and anti-inflammatory effects with activation of myofibroblasts, which increases the healing efficiency of chronic purulent-necrotic wounds. Prospects for the use of MSC in the treatment of chronic wounds are shown.

Rationale: Chronic nonhealing diabetic wound therapy and complete skin regeneration remains a critical clinical challenge. The controlled release of bioactive factors from a multifunctional hydrogel was a promising strategy to repair chronic wounds.Methods: Herein, for the first time, we developed an injectable, self-healing and antibacterial polypeptide-based FHE hydrogel (F127/OHA-EPL) with stimuli-responsive adipose-derived mesenchymal stem cells exosomes (AMSCs-exo) release for synergistically enhancing chronic wound healing and complete skin regeneration. The materials characterization, antibacterial activity, stimulated cellular behavior and in vivo full-thickness diabetic wound healing ability of the hydrogels were performed and analyzed.Results: The FHE hydrogel possessed multifunctional properties including fast self-healing process, shear-thinning injectable ability, efficient antibacterial activity, and long term pH-responsive bioactive exosomes release behavior. In vitro, the FHE@exosomes (FHE@exo) hydrogel significantly promoted the proliferation, migration and tube formation ability of human umbilical vein endothelial cells (HUVECs). In vivo, the FHE@exo hydrogel significantly enhanced the healing efficiency of diabetic full-thickness cutaneous wounds, characterized with enhanced wound closure rates, fast angiogenesis, re-epithelization and collagen deposition within the wound site. Moreover, the FHE@exo hydrogel displayed better healing outcomes than those of exosomes or FHE hydrogel alone, suggesting that the sustained release of exosomes and FHE hydrogel can synergistically facilitate diabetic wound healing. Skin appendages and less scar tissue also appeared in FHE@exo hydrogel treated wounds, indicating its potent ability to achieve complete skin regeneration.Conclusion: This work offers a new approach for repairing chronic wounds completely through a multifunctional hydrogel with controlled exosomes release.

Flexible hydrogel sensors have expanded the applications of electronic devices due to their suitable mechanical properties and excellent biocompatibility. However, conventionally synthesized reduced graphene oxide (rGO) encounters limitations in reduction degree and dispersion, restricting the conductivity of graphene hydrogels and impeding the development of high-sensitivity flexible sensors. Moreover, hydrogels are susceptible to inflammation and bacterial infections, jeopardizing sensor stability over time. Thus, the challenge persists in designing conductive hydrogels that encompass high sensitivity, antibacterial efficacy, and anti-oxidative capabilities. In this study, GO was modified and reduced via a heparin-polydopamine (Hep-PDA) complex, yielding well-reduced and uniformly dispersed Hep-PDA-rGO nanosheets. Consequently, a hydrogel utilizing Hep-PDA-rGO was synthesized, showcasing commendable conductivity (3.63 S/m) and sensor performance, effectively applied in real-time motion monitoring. Notably, the hydrogel’s attributes extend to facilitating chronic diabetic wound healing. It maintained a suitable inflammatory environment credited to its potent antibacterial and antioxidative properties, while its inherent conductivity promoted angiogenesis. The multifunctional nature of this hydrogel highlight its potential not only as an epidermal sensor but also as a promising dressing candidate for chronic wound treatment.

Multifunctional alginate based hydrogel beads dressing for chronic wound healing: A review.

Chronic wound repair is a clinical treatment challenge. The development of multifunctional hydrogels is of great significance in the key aspects of treating chronic wounds, including reducing oxidative stress, promoting angiogenesis, and improving the natural remodeling of extracellular matrix and immune regulation. In this study, we prepared a composite hydrogel, sodium alginate (SA)@MnO2/recombinant humanized collagen III (RHC)/mesenchymal stem cells (MSCs), composed of SA, MnO2 nanoparticles, RHC, and MSCs. The hydrogel has high mechanical properties and good biocompatibility. In vitro, SA@MnO2/RHC/MSCs hydrogel effectively enhanced the formation of intricate tubular structures and angiogenesis and showed synergistic effects on cell proliferation and migration. In vivo, the SA@MnO2/RHC/MSCs hydrogel enhanced diabetes wound healing, rapid re-epithelization, favorable collagen deposition, and abundant wound angiogenesis. These findings demonstrated that the combined effects of SA, MnO2, RHC, and MSCs synergistically accelerate healing, resulting in a reduced healing time. These observed healing effects demonstrated the potential of this multifunctional hydrogel to transform chronic wound care and improve patient outcomes.

Chronic wounds have gradually evolved into a global health challenge, comprising long-term non-healing wounds, local tissue necrosis, and even amputation in severe cases. Accordingly, chronic wounds place a considerable psychological and economic burden on patients and society. Chronic wounds have multifaceted pathogenesis involving excessive inflammation, insufficient angiogenesis, and elevated reactive oxygen species levels, with bacterial infection playing a crucial role. Hydrogels, renowned for their excellent biocompatibility, moisture retention, swelling properties, and oxygen permeability, have emerged as promising wound repair dressings. However, hydrogels with singular functions fall short of addressing the complex requirements associated with chronic wound healing. Hence, current research emphasises the development of multifunctional antibacterial hydrogels. This article reviews chronic wound characteristics and the properties and classification of antibacterial hydrogels, as well as their potential application in chronic wound management.

In vivo evaluation of bioactive glass-reinforced multifunctional composite hydrogel for thermal burn and chronic diabetic wound repair.

Macrophages are immune cells known to have a diverse array of functions dependant on the local tissue environment. This thesis aimed to investigate the role of macrophages in the skin. The first aim was to study if targeting inflammatory cytokines and cellular pathways was able to improve the rate of wound closure in acute and/or chronic wounds. These inflammatorypathways included the IL-17/IL-23 axis, the IL-33/ST2 pathway and the NLRP3 inflammasome. The next aim was to identify the role of macrophages in UV irradiation, specifically neonatal UV and the long-term effects in the skin and on local immune suppression. Finally, we aimed to identify the long-term effects of inflammation in the skin on the resident macrophage populations, studying the kinetics of their self-renewal.Macrophages play a vital role in wound healing, with either excessive or insufficient infiltration both causing to impaired healing responses. Current therapies for chronic wounds have poor prognosis and outcomes, and as such the development of alternative treatments are required. We found IL-17 and IL-23 inhibition improved wound closure in obese, diabetic mice by switching the macrophage phenotype from pro-inflammatory to pro-healing. IL-17 secreted from gamma delta T-cells significantly impaired wound closure, and the inhibition of IL-17 and its upstream regulator IL-23 by blocking antibodies was able to significantly improve chronic wound healing by increasing the percentage of alternatively activated, pro-healing macrophages.IL-33 is a molecule that can function as an alarmin through its receptor, ST2. We used ST2-/- mice to assess the action of IL-33 during wound healing. We found ST2-/- mice had impaired wound closure, reduced angiogenesis and altered collagen deposition/remodelling compared to BALB/C controls. There was increased neutrophilic infiltrate and altered macrophage polarisation in ST2-/- mice wounds. These results indicate that ST2 signalling is important for macrophage differentiation, which may improve wound closure, increase angiogenesis and delay or prevent scarring.The NLRP3 inflammasome has been implicated in a variety of inflammatory diseases. We used MCC950, a water-soluble small molecule inhibitor of NLRP3 in a chronic wound healing mouse model in an attempt to improve wound healing. We failed to identify any significant differences in the rate of wound healing, or angiogenesis in MCC950-treated mice compared to controls. Our results indicated that the NLRP3 inflammasome is not significantly involved in chronic wound healing.UVR has been repeatedly reported to induce immune suppression, one of the driving factors for tumour formation. Delayed-type contact hypersensitivity (CHS) is the leading mechanism for testing UVR-mediated immune suppression. We found the depletion of macrophages in neonates using clodronate liposomes before, during and after insult of a single burning dose of UVR was able to prevent a long-term local immune suppression, mediated by CD4+ regulatory T-cells. We also defined the changing resident myeloid cells in the skin as a response to UV exposure, and opened up new avenues of research to follow on from this work.Langerhans cells are a well-studied resident immune cell in the epidermis, with hundreds of publications identifying their origin, from the yolk-sac/foetal liver and their method of self-renewal under homeostatic conditions, and their ability to be renewed bymonocytes with the presence of chronic inflammation. A lesser studied resident macrophage population in the skin involves the resident dermal macrophages, which have been implicated in conditions such as wound healing and hair follicle cycling. We aimed to use a multicolour, fluorescent lineage-tracing model to investigate the mechanism of renewal of dermal macrophages in homeostasis, and inflammation. Unfortunately, the model chosen for this project was insufficient for this particular study and we were unable to gather any useful information from this project. This thesis has identified a list of molecules and cytokines that are either important or not for macrophage polarisation and the effects on wound healing in both chronic and acute wound healing scenarios. I have also identified a link between phagocytic myeloid cells and UV-induced immunosuppression and subsequent hapten-controlled inflammation in contact-hypersensitivity. Finally, a shift in long-term resident macrophages has also been identified following UV-irradiation, which may play a role in immune suppression and contact hypersensitivity.

Background: Chronic wounds are a growing problem internationally, termed a silent epidemic. To combat this epidemic, it is not sufficient to rely on traditional wound care treatments alone, but to look to innovative and alternative therapies. The indispensable role of oxygen in wound healing is well-discussed in the literature, and in the past two decades the topical application of oxygen has shown promising results in the healing of chronic wounds. However, the toxic effects of oxygen are usually not appreciated and can often lead to wound necrosis and gangrene in wounds with compromised blood supply. While wounds with adequate blood supply contain free radical quenchers (catalase, superoxide dismutase and reduced glutathione) which neutralize the free radicals (reactive oxygen species) released as a by-product of the Krebs cycle, wounds with deficient blood supply are deficient in free radical quenchers and are further damaged by exposure to oxygen as a result of reperfusion injury/oxygen toxicity. Topical hyperbaric oxygen (THOT&#174) uses low oxygen tensions in the hyperbaric range to stimulate angiogenesis, while preventing excessive oxygen toxicity. The result is the induction of marked angiogenesis, with increasing capacity for quenching reactive oxygen species, resulting in wound healing of ischemic wounds. Case Presentation: This case report describes a 95-year-old Caucasian female who presented with a stage IV chronic necrotic ulcer on her lower left leg. Surgical pathology results revealed calcifying vasculopathy, which is thought to be responsible for deficient blood supply to the leg, leading to a necrotic, chronic leg ulcer of her left leg. After traditional wound therapies were unsuccessful, she was considered for leg amputation. The introduction of adjunctive treatment with topical hyperbaric oxygen therapy saw complete healing of the wound within 15 weeks. The wound remained closed, without the presence of scar tissue, with no signs of wound breakdown at three-month and six-month follow-ups. Conclusions: Chronic hypoxic wounds with vascular insufficiency are considered “unlikely to heal” and tend to lead to limb amputation. The use of THOT&#174 technology, with low hyperbaric oxygen tensions to neutralize free radicals released by the Krebs cycle when oxygen contacts the wound, prevents oxygen toxicity and results in angiogenesis necessary for wound healing. In this way, THOT&#174 treatment was able to convert the hypoxic “unlikely to heal” wound considered for limb amputation into one which healed, with limb salvage. The results of this case report demonstrate the potential for complete healing of chronic hypoxic wounds even in complex cases with multiple confounding factors preventing wound healing, using a cost-effective treatment that is easily accessible to patients.

Stalled healing in chronic wounds is a challenging problem for providers and remains multifactorial in etiology. Older adults with insulin-dependent diabetes are at very high risk. In this case report, two patients with large nonhealing wounds were considered for treatment with daily jet lavage irrigation in an attempt to remove the inflammatory products of their respective chronic wounds and eliminate the persisting biofilm bacteria. Several attempts were made to reduce treatments to two to three times per week, and negative-pressure wound therapy was initiated in both cases only to see the return of inflammation and necrosis of the wound bed. In both cases, the daily jet lavage irrigation was successful in creating a granulating wound bed that slowly healed over many months. One patient died with an open sacral pressure injury, and the other patient died 4 months after complete healing of a large heel pressure injury. The interesting observation is the necessity of daily high-intensity wound irrigation to correct the chronic infectious process. Diabetic chronic wounds in high-risk older adults are recalcitrant to standard wound treatments, and providers should consider daily jet lavage wound irrigation to deal with this problem.

While qualitative aspects of dermal repair differ in wounds of different types, duration, and depths, all wounds must be resurfaced by epidermal keratinocytes before they can be deemed “healed.” Epidermal keratinocytes undergo a series of activation steps in acute wound healing, which are likely to be regulated by autocrine growth control mechanims. The state of epidermal keratinocyte activation in chronic venous wounds is examined in this study in relationship to the correct expression of these changes in acute wound healing. The expression of endogenous growth factor pathways in chronic wounds is presented and changes in the growth activation associated with healing of chronic wounds are studied. The results of this study establish that growth activation of the epidermis is not defective in chronic wounds. The activation of epidermis is likely to be regulated by endogenous keratinocyte cytokine and receptor pathways, suggesting that addition of exogenous epidermal mitogens to chronic wounds is unlikely to further alter epidermal healing. In contrast, some of the therapeutic benefits of hydrocolloid dressings in promoting healing of chronic wounds may be related to their ability to suppress excessive keratinocyte proliferation and activation in chronic wounds.

Temperature-responsive self-contraction nanofiber/hydrogel composite dressing facilitates the healing of diabetic-infected wounds

Currently, the treatment of persistent non-healing wounds is among the most difficult clinical issues. We studied 20 samples of normal human skin, 10 specimens from patients with acute trauma, and 9 samples from the patients with chronic wounds that did not heal within 2 months. Using multicolor flow cytometry, we found that the resident T lymphocytes (CD3++ and CD3++) are able to locally produce biologically active substances, normalize human skin homeostasis, thus promoting the wound healing. The data obtained indicate that the blood contains mainly +T lymphocytes (p 0.001), while the +T cells detected in wounds represent a population similar to skin cells. We found no difference in the ratio of resident T cells in chronic and acute wounds, and healthy epithelium. Accordingly, non-healing of wounds and chronic clinical course may be caused by dysfunction of T cells. CD69 regulates T cell secretion of growth factors, IFN, IL-17 and IL-22. The relative number of CD69-expressing T cells from the patients with acute wounds was significantly increased, if compared with cells from normal epidermis and chronic wounds (10.5%2.3, 7.6%1.24, and 3.0%1.05, respectively. p 0.001). The number of cells with the CD3++CD69+ phenotype did not differ significantly between all three groups under comparison. Dysregulation of T cell-mediated healing in chronic wounds is caused by reduced production of IGF-1 by resident CD3++T lymphocytes (1.7%0.9 (p 0.001), and CD3++ (0.44%0.02, p 0.001) compared to CD3++T cells derived from acute wounds (13.6%5.6) and CD3++ (8.9%3.1). The + and + T cells isolated from non-healing chronic wounds did not respond to mitogenic stimuli, unlike the cells obtained from acute wounds and healthy skin. In vitro analysis of cytokine secretion by the CD69-deficient dermal T cells showed a lower spontaneous secretion of IL-22 (4.56%2.3 and 23.9%1.05 and 10.6%1.24, respectively; p 0.001) and IL-2 (0.9%0.08 and 22.6%2.5 and 3.9%1.0, and respectively; p 0.01). When analyzing the number of resident skin T cells secreting IL-17, we obtained the following differences for healthy skin (1.4%0.08), acute wounds (11.3%3.2) and chronic wounds (31.7%11.8), thus showing a significant intergroup difference (p 0.001). T lymphocytes in chronic wounds exhibit some functional disorders and are not able to produce biologically active substances that promote physiological tissue regeneration. The results suggest a role of resident T cells in human skin in wound healing processes and provide new insights into the pathogenesis of chronic wounds.

A multi-functional oxidative konjac glucomannan/ε-poly-l-lysine hydrogel with antibacterial, haemostatic, and chronic diabetic wound-treating properties.