Research advances in smart responsive-hydrogel dressings with potential clinical diabetic wound healing properties

The treatment of chronic and non-healing wounds in diabetic patients remains a major medical problem.Recent reports have shown that hydrogel wound dressings might be an effective strategy for treating diabetic wounds due to their excellent hydrophilicity,good drug-loading ability and sustained drug release properties.As a typical example,hyaluronic acid dressing(Healoderm)has been demonstrated in clinical trials to improve wound-healing efficiency and healing rates for diabetic foot ulcers.However,the drug release and degradation behavior of clinically-used hydrogel wound dressings cannot be adjusted according to the wound microenvironment.Due to the intricacy of diabetic wounds,antibiotics and other medications are frequently combined with hydrogel dressings in clinical practice,although these medications are easily hindered by the hostile environment.In this case,scientists have created responsive-hydrogel dressings based on the microenvironment features of diabetic wounds(such as high glucose and low pH)or combined with external stimuli(such as light or magnetic field)to achieve controllable drug release,gel degradation,and microenvironment improvements in order to overcome these clinical issues.These responsive-hydrogel dressings are anticipated to play a significant role in diabetic therapeutic wound dressings.Here,we review recent advances on responsive-hydrogel dressings towards diabetic wound healing,with focus on hydrogel structure design,the principle of responsiveness,and the behavior of degradation.Last but not least,the advantages and limitations of these responsive-hydrogels in clinical applications will also be discussed.We hope that this review will contribute to furthering progress on hydrogels as an improved dressing for diabetic wound healing and practical clinical application.

Porous nanofibrous dressing enables mesenchymal stem cell spheroid formation and delivery to promote diabetic wound healing

Delayed and nonhealing of diabetic wounds imposes substantial economic burdens and physical pain on patients.Mesenchymal stem cells(MSCs)promote diabetic wound healing.Particularly when MSCs aggregate into multicellular spheroids,their therapeutic effect is enhanced.However,traditional culture platforms are inadequate for the efficient preparation and delivery of MSC spheroids,resulting in inefficiencies and inconveniences in MSC spheroid therapy.In this study,a three-dimensional porous nanofibrous dressing(NFD)is prepared using a combination of electrospinning and homogeneous freeze-drying.Using thermal crosslinking,the NFD not only achieves satisfactory elasticity but also maintains notable cytocompatibility.Through the design of its structure and chemical composition,the NFD allows MSCs to spontaneously form MSC spheroids with controllable sizes,serving as MSC spheroid delivery systems for diabetic wound sites.Most importantly,MSC spheroids cultured on the NFD exhibit improved secretion of vascular endothelial growth factor,basic fibroblast growth factor,and hepatocyte growth factor,thereby accelerating diabetic wound healing.The NFD provides a competitive strategy for MSC spheroid formation and delivery to promote diabetic wound healing.

Single-cell sequencing technology in diabetic wound healing:New insights into the progenitors-based repair strategies

Diabetes mellitus(DM),an increasingly prevalent chronic metabolic disease,is characterised by prolonged hyperglycaemia,which leads to long-term health consequences.Although much effort has been put into understanding the pathogenesis of diabetic wounds,the underlying mechanisms remain unclear.The advent of single-cell RNA sequencing(scRNAseq)has revolutionised biological research by enabling the identification of novel cell types,the discovery of cellular markers,the analysis of gene expression patterns and the prediction of develop-mental trajectories.This powerful tool allows for an in-depth exploration of pathogenesis at the cellular and molecular levels.In this editorial,we focus on progenitor-based repair strategies for diabetic wound healing as revealed by scRNAseq and highlight the biological behaviour of various healing-related cells and the alteration of signalling pathways in the process of diabetic wound healing.ScRNAseq could not only deepen our understanding of the complex biology of diabetic wounds but also identify and validate new targets for inter-vention,offering hope for improved patient outcomes in the management of this challenging complication of DM.

Macrophages:Key players in diabetic wound healing

In this editorial,we discuss the article by Wen et al published.Diabetic foot ulcers are prevalent and serious complications of diabetes,significantly impacting patients’quality of life and often leading to disability or death,thereby placing a heavy burden on society.Effective diabetic wound healing is hindered by an imbalance in macrophage polarization;many macrophages fail to transition from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype,which is crucial for tissue remodelling and repair.The wound healing process is both dynamic and complex.Healthy M1 macrophages,which have strong phagocytic abilities,are vital during the inflammatory phase of diabetic wound healing.However,the failure to transition to M2 macrophages during the proliferative phase hinders wound healing.We anticipate the development of new therapies that can repair damaged M1 macrophages during the inflammatory phase and promote M2 macrophage polarization during the proliferative phase,thereby enhancing the overall healing process.

Therapeutic role of growth factors in treating diabetic wound

Wounds in diabetic patients,especially diabetic foot ulcers,are more difficult to heal compared with normal wounds and can easily deteriorate,leading to amputation.Common treatments cannot heal diabetic wounds or control their many complications.Growth factors are found to play important roles in regulating complex diabetic wound healing.Different growth factors such as transforming growth factor beta 1,insulin-like growth factor,and vascular endothelial growth factor play different roles in diabetic wound healing.This implies that a therapeutic modality modulating different growth factors to suit wound healing can significantly improve the treatment of diabetic wounds.Further,some current treatments have been shown to promote the healing of diabetic wounds by modulating specific growth factors.The purpose of this study was to discuss the role played by each growth factor in therapeutic approaches so as to stimulate further therapeutic thinking.

Mesenchymal stem cell-derived exosomes: The dawn of diabetic wound healing

Chronic wound healing has long been an unmet medical need in the field of wound repair,with diabetes being one of the major etiologies.Diabetic chronic wounds(DCWs),especially diabetic foot ulcers,are one of the most threatening chronic complications of diabetes.Although the treatment strategies,drugs,and dressings for DCWs have made great progress,they remain ineffective in some patients with refractory wounds.Stem cell-based therapies have achieved specific efficacy in various fields,with mesenchymal stem cells(MSCs)being the most widely used.Although MSCs have achieved good feedback in preclinical studies and clinical trials in the treatment of cutaneous wounds or other situations,the potential safety concerns associated with allogeneic/autologous stem cells and unknown long-term health effects need further attention and supervision.Recent studies have reported that stem cells mainly exert their trauma repair effects through paracrine secretion,and exosomes play an important role in intercellular communication as their main bioactive component.MSC-derived exosomes(MSC-Exos)inherit the powerful inflammation and immune modulation,angiogenesis,cell proliferation and migration promotion,oxidative stress alleviation,collagen remodeling imbalances regulation of their parental cells,and can avoid the potential risks of direct stem cell transplantation to a large extent,thus demonstrating promising performance as novel"cell-free"therapies in chronic wounds.This review aimed to elucidate the potential mechanism and update the progress of MSC-Exos in DCW healing,thereby providing new therapeutic directions for DCWs that are difficult to be cured using conventional therapy.

Evolving spectrum of diabetic wound: Mechanistic insights and therapeutic targets

Diabetes mellitus is a chronic metabolic disorder resulting in an increased blood glucose level and prolonged hyperglycemia,causes long term health consequences.Chronic wound is frequently occurring in diabetes patients due to compromised wound healing capability.Management of wounds in diabetic patients remains a clinical challenge despite many advancements in the field of science and technology.Increasing evidence indicates that alteration of the biochemical milieu resulting from alteration in inflammatory cytokines and matrix metalloproteinase,decrease in fibroblast and keratinocyte functioning,neuropathy,altered leukocyte functioning,infection,etc.,plays a significant role in impaired wound healing in diabetic people.Apart from the current pharmacotherapy,different other approaches like the use of conventional drugs,antidiabetic medication,antibiotics,debridement,offloading,platelet-rich plasma,growth factor,oxygen therapy,negative pressure wound therapy,low-level laser,extracorporeal shock wave bioengineered substitute can be considered in the management of diabetic wounds.Drugs/therapeutic strategy that induce angiogenesis and collagen synthesis,inhibition of MMPs,reduction of oxidative stress,controlling hyperglycemia,increase growth factors,regulate inflammatory cytokines,cause NO induction,induce fibroblast and keratinocyte proliferation,control microbial infections are considered important in controlling diabetic wound.Further,medicinal plants and/or phytoconstituents also offer a viable alternative in the treatment of diabetic wound.The focus of the present review is to highlight the molecular and cellular mechanisms,and discuss the drug targets and treatment strategies involved in the diabetic wound.

Combination therapy of hydrogel and stem cells for diabetic wound healing

Diabetic wounds(DWs)are a common complication of diabetes mellitus;DWs have a low cure rate and likely recurrence,thus affecting the quality of patients’lives.As traditional therapy cannot effectively improve DW closure,DW has become a severe clinical medical problem worldwide.Unlike routine wound healing,DW is difficult to heal because of its chronically arrested inflammatory phase.Although mesenchymal stem cells and their secreted cytokines can alleviate oxidative stress and stimulate angiogenesis in wounds,thereby promoting wound healing,the biological activity of mesenchymal stem cells is compromised by direct injection,which hinders their therapeutic effect.Hydrogels form a three-dimensional network that mimics the extracellular matrix,which can provide shelter for stem cells in the inflammatory microenvironment with reactive oxygen species in DW,and maintains the survival and viability of stem cells.This review summarizes the mechanisms and applications of stem cells and hydrogels in treating DW;additionally,it focuses on the different applications of therapy combining hydrogel and stem cells for DW treatment.

Diabetic wounds and artificial intelligence:A mini-review

Diabetic wound takes longer time to heal due to micro and macro-vascular ailment.This longer healing time can lead to infections and other health complications.Foot ulcers are one of the most common diabetic wounds.These are one of the leading cause of amputations.Medical science is continuously striving for improving quality of human life.A recent trend of amalgamation of knowledge,efforts and technological advancement of medical science experts and artificial intelligence researchers,has made tremendous success in diagnosis,prognosis and treatment of a variety of diseases.Diabetic wounds are no exception,as artificial intelligence experts are putting their research efforts to apply latest technological advancements in the field to help medical care personnel to deal with diabetic wounds in more effective manner.The presented study reviews the diagnostic and treatment research under the umbrella of Artificial Intelligence and computational science,for diabetic wound healing.Framework for diabetic wound assessment using artificial intelligence is presented.Moreover,this review is focused on existing and potential contribution of artificial intelligence to improve medical services for diabetic wound patients.The article also discusses the future directions for the betterment of the field that can lead to facilitate both,clinician and patients.

Role of defensins in diabetic wound healing

The adverse consequences resulting from diabetes are often presented as severe complications.Diabetic wounds are one of the most commonly occurring complications in diabetes,and the control and treatment of this is costly.Due to a series of pathophysiological mechanisms,diabetic wounds remain in the inflammatory phase for a prolonged period of time,and face difficulty in entering the proliferative phase,thus leading to chronic non-healing wounds.The current consensus on the treatment of diabetic wounds is through multidisciplinary comprehensive management,however,standard wound treatment methods are still limited and therefore,more effective methods are required.In recent years,defensins have been found to play diverse roles in a variety of diseases;however,the molecular mechanisms underlying these activities are still largely unknown.Defensins can be constitutively or inductively produced in the skin,therefore,their local distribution is affected by the microenvironment of these diabetic wounds.Current evidence suggests that defensins are involved in the diabetic wound pathogenesis,and can potentially promote the early completion of each stage,thus making research on defensins a promising area for developing novel treatments for diabetic wounds.In this review,we describe the complex function of human defensins in the development of diabetic wounds,and suggest potential therapeutic benefits.

Progress and expectation of stem cell therapy for diabetic wound healing

Impaired wound healing presents great health risks to diabetics.Encouragingly,the current clinical successfully found out meaningful method to repair wound tissue,and stem cell therapy could be an effective method for diabetic wound healing with its ability to accelerate wound closure and avoid amputation.This minireview aims at introducing stem cell therapy for facilitating tissue repair in diabetic wounds,discussing the possible therapeutic mechanism and clinical application status and problems.

Revolutionizing diabetic wound healing:The power of microneedles

Diabetic wounds significantly affect patient quality of life.Microneedles are a promising treatment to accelerate wound healing owing to their high drug-loading capacity and efficient drug delivery;however,few studies to date have comprehensively reviewed microneedles for diabetic wound healing.This up-to-date review summarizes the research progress in microneedles for diabetic wound healing,including manufacturing materials and techniques,structures,designs,release mechanisms,delivery substances,and their specific effects.This study showed that most microneedles designed for diabetic wounds are made of synthetic polymers and/or natural materials using polydimethylsiloxane micromolding.The geometric structure and design directly influence penetration ability and drug delivery capacity.Microneedles can deliver antibiotics,hypoglycemic agents,traditional Chinese medicines,metal ions,growth factors,exosomes,stem cells,and microorganisms,thus promoting diabetic wound healing through diverse mechanisms,such as antibacterial,anti-inflammatory,antioxidant,hypoglycemic,and angiogenic activities,at different stages of the healing process.In conclusion,microneedles are promising drug delivery systems for the treatment of diabetic wounds.

Multifunctional hydrogel combined with electrical stimulation therapy for promoting diabetic wound healing

Diabetic wounds, as a complication of diabetes, are slow to heal and seriously affect the quality of life of patients. Functional hydrogel dressing is an effective approach to improve diabetic wound healing. Electrical stimulation (ES) therapy is conducive to promoting cell migration and wound healing. In this work, a multifunctional PPTZ hydrogel wound dressing was developed by freeze-thaw method with polyvinyl alcohol (PVA), phytic acid (PA), tannic acid (TA), and Zinc chloride. The obtained PPTZ hydrogel has good mechanical properties (stress and strain of 700.03 kPa and 575.08%), light transmittance (close to 100%) and antibacterial rate (over 75%). With good biocompatibility, antioxidant abilities and conductivity, the PPTZ hydrogel could effectively promote the healing of diabetic wounds with two weeks under the action of electric field, which provides an auxiliary treatment strategy for diabetic patients.

Shikonin protects mitochondria through the NFAT5/AMPK pathway for the treatment of diabetic wounds

BACKGROUND Shikonin is a natural remedy that is effective at treating diabetic wounds.NFAT5 is a potential therapeutic target for diabetes,and mitochondrial function is essen-tial for wound healing.However,the relationship among Shikonin,NFAT5,and mitochondrial function has not been thoroughly studied.Here,we offer new per-spectives on the advantages of shikonin for managing diabetes.AIM To assess the therapeutic mechanism of shikonin in diabetic wounds,its rela-tionship with NFAT5,and its protection of mitochondrial function.METHODS Hypertonic cell and diabetic wound mouse models were established.NFAT5 expression was measured through western blotting and immunofluorescence,in vivo and in vitro.Mitochondrial function was evaluated using reactive oxygen species(ROS)detection and JC-1 and Calcein AM dyes.Mitochondrial structures were observed using transmission electron microscopy.The NFAT5/AMPK pathway was analyzed using a transfection vector and an inhibitor.The effect of shikonin on cells under hypertonic conditions via the NFAT5/AMPK pathway was assessed using western blotting.RESULTS Shikonin treatment preserved HaCaT cell viability,while significantly reducing cyclooxygenase-2 expression levels in a high-glucose environment(P<0.05).Additionally,shikonin maintained mitochondrial morphology,enhanced membrane potential,reduced membrane permeability,and decreased ROS levels in HaCaT cells under hyperosmolar stress.Furthermore,shikonin promoted wound healing in diabetic mice(P<0.05).Shikonin also inhibited NFAT5,in vivo and in vitro(P<0.05).Shikonin treatment reduced NFAT5 expression levels,subsequently inhibiting AMPK expression in vitro(P<0.05).Finally,shikonin inhibited several key downstream molecules of the NFAT5/AMPK pathway,including mammalian target of rapamycin,protein kinase B,nuclear factor kappa-light-chain-enhancer of activated B cells,and inducible nitric oxide synthase(P<0.05).CONCLUSION Shikonin protects mitochondria via the NFAT5/AMPK-related pathway and enhances wound healing in diabetes.

Double hits with bioactive nanozyme based on cobalt-doped nanoglass for acute and diabetic wound therapies through anti-inflammatory and pro-angiogenic functions

Regeneration of pathological wounds,such as diabetic ulcers,poses a significant challenge in clinical settings,despite the widespread use of drugs.To overcome clinical side effects and complications,drug-free therapeutics need to be developed to promote angiogenesis while overcoming inflammation to restore regenerative events.This study presents a novel bioactive nanozyme based on cobalt-doped nanoglass(namely,CoNZ),which exhibits high enzymatic/catalytic activity while releasing therapeutic ions.Cobalt oxide“Co3O4”tiny crystallites produced in situ through a chemical reaction with H2O2 within CoNZ nanoparticles play a crucial role in scavenging ROS.Results showed that CoNZ-treatment to full-thickness skin wounds in mice significantly accelerated the healing process,promoting neovascularization,matrix deposition,and epithelial lining while reducing pro-inflammatory signs.Notably,CoNZ was highly effective in treating pathological wounds(streptozotocin-induced diabetic wounds).Rapid scavenging of ROS by CoNZ and down-regulation of pro-inflammatory markers while up-regulating tissue healing signs with proliferative cells and activated angiogenic factors contributed to the observed healing events.In vitro experiments involving CoNZ-cultures with macrophages and endothelial cells exposed to high glucose and ROS-generating conditions further confirmed the effectiveness of CoNZ.CoNZ-promoted angiogenesis was attributed to the release of cobalt ions,as evidenced by the comparable effects of CoNZ-extracted ionic medium in enhancing endothelial migration and tubule formation via activated HIF-1α.Finally,we compared the in vivo efficacy of CoNZ with the clinically-available drug deferoxamine.Results demonstrated that CoNZ was as effective as the drug in closing the diabetic wound,indicating the potential of CoNZ as a novel drug-free therapeutic approach.

A nanoenzyme-modified hydrogel targets macrophage reprogramming-angiogenesis crosstalk to boost diabetic wound repair

Diabetic wounds has a gradually increasing incidence and morbidity.Excessive inflammation due to immune imbalance leads to delayed wound healing.Here,we reveal the interconnection between activation of the NLRP3 inflammatory pathway in endotheliocyte and polarization of macrophages via the cGAS-STING pathway in the oxidative microenvironment.To enhance the immune-regulation based on repairing mitochondrial oxidative damage,a zeolitic imidazolate framework-8 coated with cerium dioxide that carries Rhoassociated protein kinase inhibition Y-27632(CeO_(2)-Y@ZIF-8)is developed.It is encapsulated in a photocross-linkable hydrogel(GelMA)with cationic quaternary ammonium salt groups modified to endow the antibacterial properties(CeO_(2)-Y@ZIF-8@Gel).CeO_(2)with superoxide dismutase and catalase activities can remove excess reactive oxygen species to limit mitochondrial damage and Y-27632 can repair damaged mitochondrial DNA,thus improving the proliferation of endotheliocyte.After endotheliocyte uptakes CeO_(2)-Y@ZIF-8 NPs to degrade peroxides into water and oxygen in cells and mitochondria,NLRP3 inflammatory pathway is inhibited and the leakage of oxidatively damaged mitochondrial DNA(Ox-mtDNA,a damage-associated molecular pattern)through mPTP decreases.Futhermore,as the cGAS-STING pathway activated by Ox-mtDNA down-regulated,the M_(2)phenotype polarization and anti-inflammatory factors increase.Collectively,CeO_(2)-Y@ZIF-8@Gel,through remodulating the crosstalk between macrophage reprogramming and angiogenesis to alleviate inflammation in the microenvironment and accelerates wound healing.

Hypoxia endothelial cells-derived exosomes facilitate diabetic wound healing through improving endothelial cell function and promoting M2 macrophages polarization

It is imperative to develop and implement newer,more effective strategies to address refractory diabetic wounds.As of now,there is currently no optimal solution for these wounds.Hypoxic human umbilical vein endothelial cells(HUVECs)-derived exosomes have been postulated to promote diabetic wound healing,however,its effect and molecular mechanism need further study.In this study,we aimed to investigate whether hypoxic exosomes enhance wound healing in diabetics.Based on our high-throughput sequencing,differentially expressed lncRNAs(including 64 upregulated lncRNAs and 94 downregulated lncRNAs)were found in hypoxic exosomes compared to normoxic exosomes.Interestingly,lncHAR1B was one of the prominently upregulated lncRNAs in hypoxic exosomes,showing a notable correlation with diabetic wound healing.More specifically,hypoxic exosomes were transmitted to surrounding cells,which resulted in a significant increase in lncHAR1B level,thereby relieving the dysfunction of endothelial cells and promoting the switch from M1 to M2 macrophages under high glucose conditions.Mechanistically,lncHAR1B directly interacted with the transcription factor basic helix-loop-helix family member e23(BHLHE23),which subsequently led to its binding to the KLF transcription factor 4(KLF4)and promoted KLF4 expression.In our in vivo experiments,the use of hypoxic exosomes-loaded HGM-QCS hydrogels(Gel-H-Exos)resulted in rapid wound healing compared to that of normoxic exosomes-loaded HGM-QCS hydrogels(Gel-N-Exos)and diabetic groups.Consequently,our study provides potentially novel therapeutic approaches aimed at accelerating wound healing and developing a practical exosomes delivery platform.

Chlorogenic acid supported strontium polyphenol networks ensemble microneedle patch to promote diabetic wound healing

Delayed or non-healing of diabetic wounds is a significant complication,often attributed to high glucose-induced M1 macrophage accumulation,impaired angiogenesis,and reactive oxygen species(ROS)buildup.Addressing this,we introduced a strontium polyphenol network microneedle patch(SrC-MPNs@MN-PP)for percutaneous drug delivery.This patch,formulated with polymer poly(γ-glutamic acid)(γ-PGA)and epsilon-poly-l-lysine(ε-PLL),incorporates strontium polyphenol networks(SrC-MPNs).The release of chlorogenic acid(CGA)from SrC-MPNs not only neutralizes ROS,but strontium ions also foster angiogen-esis.Consequently,SrC-MPNs@MN-PP can ameliorate the diabetic wound microenvironment and expedite healing.

A mechanically stable self-pumping organohydrogel dressing with aligned microchannels for accelerated diabetic wound healing

Self-pumping dressings(SPDs)have been developed as a new type of effective material for the drainage of excessive wound exudates based on the structure of asymmetric wettability.However,current SPDs are easy to lose their asymmetric wettability due to the weak interfacial mechanical stability between the hydrophobic and hydrophilic layers.Herein,we report an integrated self-pumping organohydrogel dressing with aligned microchannels(SPD-AM),prepared by an ice-templating-assisted wetting-enabled-transfer(WET)polymerization strategy,that can accelerate the healing process of diabetic wounds.The WET polymerization strategy enables strong interfacial mechanical stability between the hydrophobic organogel and hydrophilic hydrogel layers.The aligned microchannels greatly improve the draining capability of SPDs.Taking a diabetic rat model as an example,the SPD-AM can significantly reduce the bacterial colonization with low inflammatory responses,enhance dermal remodeling by about 47.31%,and shorten wound closure time by about 1/5 compared with other dressings,ultimately accelerating diabetic wound healing.This study is valuable for developing next-generation SPDs with stable mechanical performance for clinical applications.

Harnessing cytokine-induced killer cells to accelerate diabetic wound healing:an approach to regulating post-traumatic inflammation

Impaired immunohomeostasis in diabetic wounds prolongs infiammation and cytokine dysfunction,thus,delaying or pre-venting wound-surface healing.Extensive clinical studies have been conducted on cytokine-induced killer(CIK)cells recently,as they can be easily proliferated using a straightforward,inex-pensive protocol.Therefore,the function of CIK cells in regulat-ing inflammatory environments has been drawing attention for clinical management.Throughout the current investigation,we discovered the regenerative capacity of these cells in the chal-lenging environment of wounds that heal poorly due to diabe-tes.We demonstrated that the intravenous injection of CIK cells can re-establish a proregenerative inflammatory microenviron-ment.promote larizationand.ultimatel accelerateskin healing in diabetic mice.The results indicated that CIK cell treatment affects macrophage polarization and restores the function regenerative cells under hyperglycemic conditions.This novel cellular therapy offers a promising intervention for clinical applic tions through specific inflammatory regulation functions.