Platelet-Derived Growth Factor Nanocapsules with Tunable Controlled Release for Chronic Wound Healing.

Chronic wounds have emerged as an increasingly critical clinical challenge over the past few decades, due to their increasing incidence and socioeconomic burdens. Platelet-derived growth factor (PDGF) plays a pivotal role in regulating processes such as fibroblast migration, proliferation, and vascular formation during the wound healing process. The delivery of PDGF offers great potential for expediting the healing of chronic wounds. However, the clinical effectiveness of PDGF in chronic wound healing is significantly hampered by its inability to maintain a stable concentration at the wound site over an extended period. In this study, a controlled PDGF delivery system based on nanocapsules is proposed. In this system, PDGF is encapsulated within a degradable polymer shell. The release rate of PDGF from these nanocapsules can be precisely adjusted by controlling the ratios of two crosslinkers with different degradation rates within the shells. As demonstrated in a diabetic wound model, improved therapeutic outcomes with PDGF nanocapsules (nPDGF) treatment are observed. This research introduces a novel PDGF delivery platform that holds promise for enhancing the effectiveness of chronic wound healing.

Therapeutic potential of silkworm sericin in wound healing applications.

Chronic wounds are characterised by an imbalance between pro and anti-inflammatory signals, which result in permanent inflammation and delayed re-epithelialization, consequently hindering wound healing. They are associated with bacterial infections, tissue hypoxia, local ischemia, reduced vascularization, and MMP-9 upregulation. The global prevalence of chronic wounds has been estimated at 40 million in the adult population, with an alarming annual growth rate of 6.6%, making it an increasingly significant clinical problem. Sericin is a natural hydrophilic protein obtained from the silkworm cocoon. Due to its biocompatibility, biodegradability, non-immunogenicity, and oxidation resistance, coupled with its excellent affinity for target biomolecules, it holds great potential in wound healing applications. The silk industry discards 50,000 tonnes of sericin annually, making it a readily available material. Sericin increases cell union sites and promotes cell proliferation in fibroblasts and keratinocytes, thanks to its cytoprotective and mitogenic effects. Additionally, it stimulates macrophages to release more therapeutic cytokines, thus improving vascularization. This review focuses on the biological properties of sericin that contribute towards enhanced wound healing process and its mechanism of interaction with important biological targets involved in wound healing. Emphasis is placed on diverse wound dressing products that are sericin based and the utilisation of nanotechnology to design sericin nanoparticles that aid in chronic wound management.

Silver@Prussian Blue Core-Satellite Nanostructures as Multimetal Ions Switch for Potent Zero-Background SERS Bioimaging-Guided Chronic Wound Healing.

Metal-organic framework-based metal ion therapy has attracted increasing attention to promote the cascade wound-healing process. However, multimetal ion synergistic administration and accurately controlled ion release are still the challenges. Herein, an aptamer-functionalized silver@cupriferous Prussian blue (ACPA) is established as a metal-based theranostic nanoagent for a chronic nonhealing diabetic wound treatment. Prussian blue offers a programmable nanoplatform to formulate metal ion prescriptions, achieving cooperative wound healing. Silver, copper, and iron ions are released from ACPA controlled by the near-infrared-triggered mild hyperthermia and then synergistically participate in antipathogen, cell migration, and revascularization. ACPA also demonstrates a unique core-satellite nanostructure which enables it with improved surface-enhanced Raman scattering (SERS) capability as potent bacteria-targeted Raman-silent nanoprobe to monitor the residual bacteria during wound healing with nearly zero background. The theranostic feature of ACPA allows high-performance SERS imaging-guided chronic wound healing in infectious diabetic skin and keratitis.

A pH/enzyme dual responsive PMB spatiotemporal release hydrogel promoting chronic wound repair.

Suppressing persistent multidrug-resistant (MDR) bacterial infections and excessive inflammation is the key for treating chronic wounds. Therefore, developing a microenvironment-responsive material with good biodegradability, drug-loading, anti-infection, and anti-inflammatory properties is desired to boost the chronic wounds healing process; however, using ordinary assembly remains a defect. Herein, we propose a pH/enzyme dual-responsive polymyxin B (PMB) spatiotemporal-release hydrogel (GelMA/OSSA/PMB), namely, the amount of OSSA and PMB released from GelMA/OSSA/PMB was closely related the wound pH and the enzyme concentration changing. The GelMA/OSSA/PMB showed better biosafety than equivalent free PMB, owing to the controlled release of PMB, which helped kill planktonic bacteria and inhibit biofilm activity in vitro. In addition, the GelMA/OSSA/PMB exhibited excellent antibacterial and anti-inflammatory properties. A MDR Pseudomonas aeruginosa caused infection was effectively resolved by the GelMA/OSSA/PMB hydrogel in vivo, thereby significantly boosting wound closure during the inflammatory phase. Furthermore, GelMA/OSSA/PMB accelerated the sequential phases of wound repair.

Multi-functional conductive hydrogels based on heparin-polydopamine complex reduced graphene oxide for epidermal sensing and chronic wound healing.

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.

Symbiotic Algae-Bacteria Dressing for Producing Hydrogen to Accelerate Diabetic Wound Healing.

Oxidative stress induced by hyperglycemia or chronic inflammation can limit diabetic wound healing, resulting in diabetic foot ulcers. Hydrogen has the potential to act as an antioxidant and scavenge reactive oxygen species, thereby attenuating inflammation in these chronic wounds. However, most of the reported H2 delivery systems for wound healing, including hydrogen gas, hydrogen-rich water, and hydrogen-rich saline, are very short-lived for the low solubility of hydrogen gas. Here, we introduce a hydrogen-producing hydrogel made of living Chlorella and bacteria within a cell-impermeable casing that can continuously produce hydrogen for 60 h. This microbe-hydrogel system can selectively reduce highly toxic •OH and ONOO- species and reduce inflammation. Additional experiments indicated that the microbe-hydrogel dressing could promote cell proliferation and diabetic wound healing by almost 50% at day 3. The symbiotic algae-bacteria hydrogel has excellent biocompatibility and reactive oxygen species scavenging features, indicating it has great promise for clinical use.

Targeting Signalling Pathways in Chronic Wound Healing.

Chronic wounds fail to achieve complete closure and are an economic burden to healthcare systems due to the limited treatment options and constant medical attention. Chronic wounds are characterised by dysregulated signalling pathways. Research has focused on naturally derived compounds, stem-cell-based therapy, small molecule drugs, oligonucleotide delivery nanoparticles, exosomes and peptide-based platforms. The phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT), Wingless-related integration (Wnt)/ß-catenin, transforming growth factor-ß (TGF-ß), nuclear factor erythroid 2-related factor 2 (Nrf2), Notch and hypoxia-inducible factor 1 (HIF-1) signalling pathways have critical roles in wound healing by modulating the inflammatory, proliferative and remodelling phases. Moreover, several regulators of the signalling pathways were demonstrated to be potential treatment targets. In this review, the current research on targeting signalling pathways under chronic wound conditions will be discussed together with implications for future studies.

Hydrogel Dressing Containing Basic Fibroblast Growth Factor Accelerating Chronic Wound Healing in Aged Mouse Model.

Due to the decreasing self-repairing ability, elder people are easier to form chronic wounds and suffer from slow and difficult wound healing. It is desirable to develop a novel wound dressing that can accelerate chronic wound healing in elderly subjects to decrease the pain of patients and save medical resources. In this work, Heparin and basic fibroblast growth factor(bFGF) were dissolved in the mixing solution of 4-arm acrylated polyethylene glycol and dithiothreitol to form hydrogel dressing in vitro at room temperature without any catalysts, which is convenient and easy to handle in clinic application. In vitro re-lease test shows the bFGF could be continuously released for at least 7 days, whereas the dressing surface integrity maintained for 3 days degradation in PBS solution. Three groups of treatments including bFGF-Gel, bFGF-Sol and control without any treatment were applied on the full-thickness wound on the 22 months old mice back. The wound closure rate and histological and immunohistochemical staining all illustrated that bFGF-Gel displayed a better wound healing effect than the other two groups. Thus, as-prepared hydrogel dressing seems supe-rior to current clinical treatment and more effective in elderly subjects, which shows promising potential to be applied in the clinic.

A molecular approach to maggot debridement therapy with Lucilia sericata and its excretions/secretions in wound healing.

Chronic wounds caused by underlying physiological causes such as diabetic wounds, pressure ulcers, venous leg ulcers and infected wounds affect a significant portion of the population. In order to treat chronic wounds, a strong debridement, removal of necrotic tissue, elimination of infection and stimulation of granulation tissue are required. Maggot debridement therapy (MDT), which is an alternative treatment method based on history, has been used quite widely. MDT is an efficient, simple, cost-effective and reliable biosurgery method using mostly larvae of Lucilia sericata fly species. Larvae can both physically remove necrotic tissue from the wound site and stimulate wound healing by activating molecular processes in the wound area through the enzymes they secrete. The larvae can stimulate wound healing by activating molecular processes in the wound area through enzymes in their excretions/secretions (ES). Studies have shown that ES has antibacterial, antifungal, anti-inflammatory, angiogenic, proliferative, hemostatic and tissue-regenerating effects both in vivo and in vitro. It is suggested that these effects stimulate wound healing and accelerate wound healing by initiating a direct signal cascade with cells in the wound area. However, the enzymes and peptides in ES are mostly still undefined. Examining the molecular content of ES and the biological effects of these ingredients is quite important to illuminate the molecular mechanism underlying MDT. More importantly, ES has the potential to have positive effects on wound healing and to be used more as a therapeutic agent in the future, so it can be applied as an alternative to MDT in wound healing.

Recent advances in the induced pluripotent stem cell-based skin regeneration.

Skin regeneration has been a challenging clinical problem especially in cases of chronic wounds such as diabetic foot ulcers, and epidermolysis bullosa-related skin blisters. Prolonged non-healing wounds often lead to bacterial infections increasing the severity of wounds. Current treatment strategies for chronic wounds include debridement of wounds along with antibiotics, growth factors, and stem cell transplantation therapies. However, the compromised nature of autologous stem cells in patients with comorbidities such as diabetes limits the efficacy of the therapy. The discovery of induced pluripotent stem cell (iPSC) technology has immensely influenced the field of regenerative therapy. Enormous efforts have been made to develop integration-free iPSCs suitable for clinical therapies. This review focuses on recent advances in the methods and reprogramming factors for generating iPSCs along with the existing challenges such as genetic alterations, tumorigenicity, immune rejection, and regulatory hurdles for the clinical application of iPSCs. Furthermore, this review also highlights the benefits of using iPSCs for the generation of skin cells and skin disease modeling over the existing clinical therapies for skin regeneration in chronic wounds and skin diseases.

Differentiation of diabetic foot ulcer-derived induced pluripotent stem cells reveals distinct cellular and tissue phenotypes.

Diabetic foot ulcers (DFUs) are a major complication of diabetes, and there is a critical need to develop novel cell- and tissue-based therapies to treat these chronic wounds. Induced pluripotent stem cells (iPSCs) offer a replenishing source of allogeneic and autologous cell types that may be beneficial to improve DFU wound-healing outcomes. However, the biologic potential of iPSC-derived cells to treat DFUs has not, to our knowledge, been investigated. Toward that goal, we have performed detailed characterization of iPSC-derived fibroblasts from both diabetic and nondiabetic patients. Significantly, gene array and functional analyses reveal that iPSC-derived fibroblasts from both patients with and those without diabetes are more similar to each other than were the primary cells from which they were derived. iPSC-derived fibroblasts showed improved migratory properties in 2-dimensional culture. iPSC-derived fibroblasts from DFUs displayed a unique biochemical composition and morphology when grown as 3-dimensional (3D), self-assembled extracellular matrix tissues, which were distinct from tissues fabricated using the parental DFU fibroblasts from which they were reprogrammed. In vivo transplantation of 3D tissues with iPSC-derived fibroblasts showed they persisted in the wound and facilitated diabetic wound closure compared with primary DFU fibroblasts. Taken together, our findings support the potential application of these iPSC-derived fibroblasts and 3D tissues to improve wound healing.-Kashpur, O., Smith, A., Gerami-Naini, B., Maione, A. G., Calabrese, R., Tellechea, A., Theocharidis, G., Liang, L., Pastar, I., Tomic-Canic, M., Mooney, D., Veves, A., Garlick, J. A. Differentiation of diabetic foot ulcer-derived induced pluripotent stem cells reveals distinct cellular and tissue phenotypes.

An EGF- and Curcumin-Co-Encapsulated Nanostructured Lipid Carrier Accelerates Chronic-Wound Healing in Diabetic Rats.

Nanostructured lipid carriers (NLC) are capable of encapsulating hydrophilic and lipophilic drugs. The present study developed an NLC containing epidermal growth factor (EGF) and curcumin (EGF-Cur-NLC). EGF-Cur-NLC was prepared by a modified water-in-oil-in-water (w/o/w) double-emulsion method. The EGF-Cur-NLC particles showed an average diameter of 331.8 nm and a high encapsulation efficiency (81.1% and 99.4% for EGF and curcumin, respectively). In vitro cell studies were performed using two cell types, NIH 3T3 fibroblasts and HaCaT keratinocytes. The results showed no loss of bioactivity of EGF in the NLC formulation. In addition, EGF-Cur-NLC improved in vitro cell migration, which mimics the wound healing process. Finally, EGF-Cur-NLC was evaluated in a chronic wound model in diabetic rats. We found that EGF-Cur-NLC accelerated wound closure and increased the activity of antioxidant enzymes. Overall, these results reveal the potential of the NLC formulation containing EGF and curcumin to promote healing of chronic wounds.

Use of concentrate growth factors gel or membrane in chronic wound healing: Description of 18 cases.

Treating chronic skin wounds in patients with diabetes, bed sores, or stasis dermatitis is typically a time-consuming and costly process, and the outcome is not always promising. Concentrated growth factor (CGF) obtained from the autologous venous blood of patients via fractional centrifugation is employed for producing a CGF gel or membrane that can be applied to expedite self-regeneration of skin wounds. In this case report, we presented the results from 18 patients with chronic skin wounds treated with a CGF gel or membrane produced from autologous venous blood. Noticeable granulation tissue and regenerated epidermal coverage were observed in 16 patients who received CGF treatment over various time courses, thereby demonstrating the significant therapeutic effects of CGF treatment in overall wound healing. The other two patients with stasis ulcers in their calves failed to respond to the treatment because of the comorbidity of iliac vein thrombosis. In addition, by culturing HaCaT keratinocytes using CGF membrane as the foundation, we observed that HaCaT cells attached to the CGF membrane migrated and proliferated to form an epithelium-like structure. Comprehensively, the clinical results infer that CGF gel can expedite the regeneration of the soft tissue at the wound, whereas CGF membrane may facilitate its marginal re-epithelialisation. The combination of the two can promote autologous regeneration of both deep and superficial wounds effectively and safely.

Interleukin-23 regulates interleukin-17 expression in wounds, and its inhibition accelerates diabetic wound healing through the alteration of macrophage polarization.

Inflammation is a critical phase in the healing of skin wounds. Excessive inflammation and inflammatory macrophages are known to cause impaired wound closure and outcome. This prompted us to test the role of IL-23 in IL-17 expression and in modulating wound inflammation and macrophage polarization. Full-thickness wounds (4 × 6 mm) were created on the dorsal surface of multiple genetically modified mouse models. Obese diabetic mouse wounds were treated with anti-IL-17A, anti-IL-23, or isotype-matched antibodies. We found IL-23- but not IL-12-deficient mice displayed significantly reduced IL-17 expression in wounds. This was rescued by delivery of recombinant IL-23. IL-23- and IL-17-deficient mice showed a significant increase in noninflammatory macrophages. Obese diabetic mice treated with anti-IL-17A and anti-IL-23p19 blocking antibodies had significantly improved wound reepithelialization. Similarly, IL-17-/- obese mice had accelerated wound closure, resulting in reduced iNOS expression and inflammatory macrophages while maintaining prohealing CD206 and lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE1)-expressing macrophages. This study highlights the importance of the IL-17 pathway in wound closure offering new possibilities of therapeutic intervention in chronic wounds.-Lee, J., Rodero, M. P., Patel, J., Moi, D., Mazzieri, R., Khosrotehrani, K. Interleukin-23 regulates interleukin-17 expression in wounds, and its inhibition accelerates diabetic wound healing through the alteration of macrophage polarization.

The Small Molecule NLRP3 Inflammasome Inhibitor MCC950 Does Not Alter Wound Healing in Obese Mice.

The incidence of chronic wounds is escalating, and the associated healing process is especially problematic in an aging population with increased morbidity. Targeting increased inflammation in chronic wounds is a promising but challenging therapeutic strategy. Indeed, inflammation and especially macrophages are required for wound healing. As the NLRP3 inflammasome has been implicated with various other inflammatory diseases, in this study, we used MCC950-a selective NLRP3 small molecule inhibitor-on murine models of both acute and chronic wounds. This molecule, while tested for other inflammatory conditions, has never been investigated to reduce topical inflammation driving chronic wounds. We found that there were no significant differences when the treatment was applied either topically or orally in wild-type C57Bl/6 mice and that it even impaired wound healing in obese mice. The treatment was also unable to improve re-epithelialisation or angiogenesis, which are both required for the closure of wounds. We are inclined to believe that MCC950 may inhibit the closure of chronic wounds and that it does not alter wound-associated macrophage polarisation.

High Voltage Monophasic Pulsed Current (HVMPC) for stage II-IV pressure ulcer healing. A systematic review and meta-analysis.

This review was conducted to determine and quantify the efficacy of high-voltage monophasic pulsed current (HVMPC) in the treatment of stage II-IV pressure ulcers (PrUs), identify the details of HVMPC intervention parameters and the superior protocol, and ascertain other potential benefits and the safety of HVMPC intervention. Eleven studies, nine randomized controlled trials (RCTs) and two case series studies, matched the criteria and were included in the systematic review, whereas, only level 1 evidence RCTs were included in the meta-analysis. The percentage of wound surface area reduction per week was 12.39%; 95% CI, [10.43-14.37] for HVMPC plus standard wound care (SWC) and 6.96%; 95% CI, [5.56-8.38] for SWC alone or SWC plus sham HVMPC. The net effect of HVMPC was 5.4% per week (an increase of 78% greater than SWC alone or SWC plus sham HVMPC). Level 1, 2 and 4 evidence studies have consistently indicated that HVMPC plus SWC were more effective than SWC alone or SWC plus sham HVMPC in treating stage II-IV PrUs. Level 1 evidence studies showed that HVMPC intervention improved the healing of PrUs (reduced wound surface area), and combined with SWC, increased the probability of complete healing and almost eliminated the probability of worsening of healing. HVMPC intervention was shown to be relatively safe, with rare adverse reactions.

A review of genetic engineering biotechnologies for enhanced chronic wound healing.

Traditional methods for addressing chronic wounds focus on correcting dysfunction by controlling extracellular elements. This review highlights technologies that take a different approach - enhancing chronic wound healing by genetic modification to wound beds. Featured cutaneous transduction/transfection methods include viral modalities (ie adenoviruses, adeno-associated viruses, retroviruses and lentiviruses) and conventional non-viral modalities (ie naked DNA injections, microseeding, liposomal reagents, particle bombardment and electroporation). Also explored are emerging technologies, focusing on the exciting capabilities of wound diagnostics such as pyrosequencing as well as site-specific nuclease editing tools such as CRISPR-Cas9 used to both transiently and permanently genetically modify resident wound bed cells. Additionally, new non-viral transfection methods (ie conjugated nanoparticles, multi-electrode arrays, and microfabricated needles and nanowires) are discussed that can potentially facilitate more efficient and safe transgene delivery to skin but also represent significant advances broadly to tissue regeneration research.

Noninvasive red and near-infrared wavelength-induced photobiomodulation: promoting impaired cutaneous wound healing.

The innumerable intricacies associated with chronic wounds have made the development of new painless, noninvasive, biophysical therapeutic interventions as the focus of current biomedical research. Red and near-infrared light-induced photobiomodulation therapy appears to emerge as a promising drug-free approach for promoting wound healing, reduction in inflammation, pain and restoration of function owing to penetration power in conjunction with their ability to positively modulate the biochemical and molecular responses. This review will describe the physical properties of red and near-infrared light and their interaction with skin and highlight their efficacy of wound repair and regeneration. Near-infrared (800-830 nm) was found to be the most effective and widely studied wavelength range followed by red (630-680 nm) and 904 nm superpulsed light exhibiting beneficial photobiomodulatory effects on impaired dermal wound healing.

In vitro assessment of a novel, hypothermically stored amniotic membrane for use in a chronic wound environment.

Chronic wounds require extensive healing time and place patients at risk of infection and amputation. Recently, a fresh hypothermically stored amniotic membrane (HSAM) was developed and has subsequently shown promise in its ability to effectively heal chronic wounds. The purpose of this study is to investigate the mechanisms of action that contribute to wound-healing responses observed with HSAM. A proteomic analysis was conducted on HSAM, measuring 25 growth factors specific to wound healing within the grafts. The rate of release of these cytokines from HSAMs was also measured. To model the effect of these cytokines and their role in wound healing, proliferation and migration assays with human fibroblasts and keratinocytes were conducted, along with tube formation assays measuring angiogenesis using media conditioned from HSAM. Additionally, the cell-matrix interactions between fibroblasts and HSAM were investigated. Conditioned media from HSAM significantly increased both fibroblast and keratinocyte proliferation and migration and induced more robust tube formation in angiogenesis assays. Fibroblasts cultured on HSAMs were found to migrate into and deposit matrix molecules within the HSAM graft. These collective results suggest that HSAM positively affects various critical pathways in chronic wound healing, lending further support to promising qualitative results seen clinically and providing further validation for ongoing clinical trials.