Mesenchymal stem cell-derived extracellular vesicles in skin wound healing:roles,opportunities and challenges

Skin wounds are characterized by injury to the skin due to trauma,tearing,cuts,or contusions.As such injuries are common to all human groups,they may at times represent a serious socioeconomic burden.Currently,increasing numbers of studies have focused on the role of mesenchymal stem cell(MSC)-derived extracellular vesicles(EVs)in skin wound repair.As a cell-free therapy,MSC-derived EVs have shown significant application potential in the field of wound repair as a more stable and safer option than conventional cell therapy.Treatment based on MSC-derived EVs can significantly promote the repair of damaged substructures,including the regeneration of vessels,nerves,and hair follicles.In addition,MSC-derived EVs can inhibit scar formation by affecting angiogenesis-related and antifibrotic pathways in promoting macrophage polarization,wound angiogenesis,cell proliferation,and cell migration,and by inhibiting excessive extracellular matrix production.Additionally,these structures can serve as a scaffold for components used in wound repair,and they can be developed into bioengineered EVs to support trauma repair.Through the formulation of standardized culture,isolation,purification,and drug delivery strategies,exploration of the detailed mechanism of EVs will allow them to be used as clinical treatments for wound repair.In conclusion,MSCderived EV-based therapies have important application prospects in wound repair.Here we provide a comprehensive overview of their current status,application potential,and associated drawbacks.

Clinical efficacy of endovascular revascularization combined with vacuum-assisted closure for the treatment of diabetic foot

BACKGROUND The diabetic foot is a common cause of disability and death,and comorbid foot infections usually lead to prolonged hospitalization,high healthcare costs,and a significant increase in amputation rates.And most diabetic foot trauma is complicated by lower extremity arteriopathy,which becomes an independent risk factor for major amputation in diabetic foot patients.AIM To establish the efficacy and safety of endovascular revascularization(ER)combined with vacuum-assisted closure(VAC)for the treatment of diabetic foot.METHODS Clinical data were collected from 40 patients with diabetic foot admitted to the Second Affiliated Hospital of Soochow University from April 2018 to April 2022.Diabetic foot lesions were graded according to Wagner’s classification,and blood flow to the lower extremity was evaluated using the ankle-brachial index test and computerized tomography angiography of the lower extremity arteries.Continuous subcutaneous insulin infusion pumps were used to achieve glycemic control.Lower limb revascularization was facilitated by percutaneous transluminal balloon angioplasty(BA)or stenting.Wounds were cleaned by nibbling debridement.Wound granulation tissue growth was induced by VAC,and wound repair was performed by skin grafting or skin flap transplantation.RESULTS Of the 35 cases treated with lower limb revascularization,34 were successful with a revascularization success rate of 97%.Of these,6 cases underwent stenting after BA of the superficial femoral artery,and 1 received popliteal artery stent implantation.In the 25 cases treated with infrapopliteal artery revascularization,39 arteries were reconstructed,7 of which were treated by drug-coated BA and the remaining 32 with plain old BA.VAC was performed in 32 wounds.Twenty-four cases of skin grafting and 2 cases of skin flap transplantation were performed.Two patients underwent major amputations,whereas 17 had minor amputations,accounting for a success limb salvage rate of 95%.CONCLUSION ER in combination with VAC is a safe and effective treatment for diabetic foot that can significantly improve limb salvage rates.The use of VAC after ER simplifies and facilitates wound repair.

Experimental Study of Moist Exposed Burn Therapy/Moist Exposed Burn Ointment Combined with Zhuang Medicine Detoxification for Chronic Refractory Wound Healing

Background: This is still a public problem that needs to be solved urgently: chronic and refractory wound healing with long course and complex pathological mechanism. At present, there is still a lack of effective clinical treatment. This study, therefore, aims at exploring moist exposed burn therapy/moist exposed burn ointment (MEBT/MEBO) combined with Zhuang medicine detoxification in the treatment of chronic refractory wound healing. Methodology: 100 SPF Wistar rats were randomly divided into blank control group, model control group, MEBO group, Zhuang medicine group and Combined group, with 20 rats in each group. Open wound model was established in blank control group, and chronic refractory wound model was established in other groups. Black control group and model control group were given food and water freely, MEBO group was given dressing change once a day, Zhuang medicine group was given intragastric administration once a day, and combined group was given dressing change and intragastric administration once a day. The effective rate of wound healing was observed after 12 days of continuous intervention. Conclusion: Skin regeneration medical technique combined with Zhuang medicine poison theory can effectively reduce the symptoms of bleeding and exudation, reduce the area of wound, shorten the healing time of wound, and achieve physiological healing of wound. It has a good effect on chronic refractory wound.

Endogenous bioelectric fields: a putative regulator of wound repair and regeneration in the central nervous system

Studies on a variety of highly regenerative tissues, including the central nervous system（CNS） in non-mammalian vertebrates, have consistently demonstrated that tissue damage induces the formation of an ionic current at the site of injury. These injury currents generate electric fields（EF） that are 100-fold increased in intensity over that measured for uninjured tissue. In vitro and in vivo experiments have convincingly demonstrated that these electric fields（by their orientation, intensity and duration） can drive the migration, proliferation and differentiation of a host of cell types. These cellular behaviors are all necessary to facilitate regeneration as blocking these EFs at the site of injury inhibits tissue repair while enhancing their intensity promotes repair. Consequently, injury-induced currents, and the EFs they produce, represent a potent and crucial signal to drive tissue regeneration and repair. In this review, we will discuss how injury currents are generated, how cells detect these currents and what cellular responses they can induce. Additionally, we will describe the growing evidence suggesting that EFs play a key role in regulating the cellular response to injury and may be a therapeutic target for inducing regeneration in the mammalian CNS.

Design of axial flaps with color Doppler flow imaging technique for repairing deep wounds of heels

To report the methods and effect of axial pattern flap on lower limb in repairing deep wounds of heels by using color Doppler flow imaging (CDFI) technique so as to solve the ever before problems that the vessel can not be displayed in designing axial flap.Methods Suitable axial flaps on lower limbs were selected according to the character of the wounds.There were 25 flaps including 10 cases of the distal-based sural neurovascular flap,nine medial sole flap and six medial leg flap.All the axial pattern flaps were designed on the basis of traditional design ways before operation;then,CDFI appliance with high resolution was used to examine the starting spot,exterior diameter,trail and length of the flap’s major artery.The flaps were redesigned according to the results of CDFI and transferred to cover the wounds.In the meantime,both the results of operation and examination were compared.Results The major artery’s starting spot,exterior diameter,trail and anatomic layers were displayed clearly,in consistency with the results of operation.The flaps survived completely and recovered well,with perfect appearance,color and arthral function.Conclusion CDFI is a simple,macroscopic and atraumatic method for designing the axial pattern flap on lower limb,can provide more scientific and accurate evidence for preoperative determination of flap transplantation and is worthy of clinical application.10 refs,4 figs,2 tabs.

Repairing small wounds around ankle by medial planta island flaps pedicled with anterior tibial artery perforator in front of inner malleolus

Objective To discuss the application of medial planta island flaps pedicled with anterior tibial artery perforator in front of inner malleolus for repairing small wounds around ankle Methods From Jan. 2005 to Jun. 2009,10 cases with small wounds around ankle

Sequential treatment for diabetic foot ulcers in dialysis patients:A case report

BACKGROUND Diabetic foot ulcers(DFUs)are common in patients with diabetes,especially those undergoing hemodialysis.In severe cases,these ulcers can cause damage to the lower extremities and lead to amputation.Traditional treatments such as flap transposition and transfemoral amputation are not always applicable in all cases.Therefore,there is a need for alternative treatment methods.CASE SUMMARY This report describes a 62-year-old female patient who was admitted to the hospital with plantar and heel ulcers on her left foot.The patient had a history of renal failure and was undergoing regular hemodialysis.Digital subtraction angiography showed extensive stenosis and occlusion in the left superficial femoral artery,left peroneal artery and left posterior tibial artery.Following evaluation by a multidisciplinary team,the patient was diagnosed with type 2 DFUs(TEXAS 4D).Traditional treatments were deemed unsuitable,and the patient was treated with endovascular surgery in the affected area,in addition to supportive medical treatment,local debridement,and sequential repair using split-thickness skin and tissue-engineered skin grafts combined with negative pressure treatment.After four months,the wound had completely healed,and the patient was able to walk with a walking aid.CONCLUSION This study demonstrates a new treatment method for DFUs was successful,using angioplasty,skin grafts,and negative pressure.

Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo

Extracellular lysophosphatidate （LPA） is a potent bioactive lipid that signals through six G-protein-coupled receptors. This signaling is required for embryogenesis, tissue repair and remodeling processes. LPA is produced from circulating lysophosphatidylcholine by autotaxin （ATX）, and is degraded outside cells by a family of three enzymes called the lipid phosphate phosphatases （LPPs）. In many pathological conditions, particularly in cancers, LPA concentrations are increased due to high ATX expression and low LPP activity. In cancers, LPA signaling drives tumor growth, angiogenesis, metastasis, resistance to chemotherapy and decreased efficacy of radiotherapy. Hence, targeting the ATX-LPA-LPP axis is an attractive strategy for introducing novel adjuvant therapeutic options. In this review, we will summarize current progress in targeting the ATX-LPA-LPP axis with inhibitors of autotaxin activity, LPA receptor antagonists, LPA monoclonal antibodies, and increasing low LPP expression. Some of these agents are already in clinical trials and have applications beyond cancer, including chronic inflammatory diseases.

Study on the Bidirectional Regulation of Skin Regeneration by Tension

Objective: To explore the related factors of tension on wound skin healing and its solution. Methods: According to the analysis and discussion of 60 trauma patients admitted to the emergency department of our hospital, they were randomly divided into two groups, 30 patients in each group (Observation and control group). The other group was systematically studied for the related factors affecting wound healing and we gave the relevant nursing measures to the control group. Results: The healing rate of the two groups were compared after treatment and nursing. The observation group was better than the control group, and the difference was statistically significant (P < 0.001). Conclusion: Effective reduction of wound tension can induce immune response and have obvious effect on skin repair and regeneration. On the other hand, the prevention and treatment of abnormal hyperplasia and scar were also improved. Avoid other factors affecting wound healing, strengthen postoperative management, reduce scar formation and promote skin regeneration.

Nanosilver alleviates foreign body reaction and facilitates wound repair by regulating macrophage polarization

Foreign body reactions induced by macrophages often cause delay or failure of wound healing in the application of tissue engineering scaffolds.This study explores the application of nanosilver(NAg)to reduce foreign body reactions during scaffold transplantation.An NAg hybrid collagen-chitosan scaffold(NAg-CCS)was prepared using the freeze-drying method.The NAg-CCS was implanted on the back of rats to evaluate the effects on foreign body reactions.Skin tissue samples were collected for histological and immunological evaluation at variable intervals.Miniature pigs were used to assess the effects of NAg on skin wound healing.The wounds were photographed,and tissue samples were collected for molecular biological analysis at different time points post-transplantation.NAg-CCS has a porous structure and the results showed that it could release NAg constantly for two weeks.The NAg-CCS group rarely developed a foreign body reaction,while the blank-CCS group showed granulomas or necrosis in the subcutaneous grafting experiment.Both matrix metalloproteinase-1(MMP-1)and tissue inhibitor of metalloproteinase-1(TIMP-1)were reduced significantly in the NAg-CCS group.The NAg-CCS group had higher interleukin(IL)-10 and lower IL-6 than the blank CCS group.In the wound healing study,M1 macrophage activation and inflammatory-related proteins inducible nitric oxide synthase(iNOS),IL-6,and interferon-(IFN-)were inhibited by NAg.In contrast,M2 macrophage activation and proinflammatory proteins(arginase-1),major histocompatibility complex-II(MHC-II),and found in inflammatory zone-1(FIZZ-1)were promoted,and this was responsible for suppressing the foreign body responses and accelerating wound healing.In conclusion,dermal scaffolds containing NAg suppressed the foreign body reaction by regulating macrophages and the expression of inflammatory cytokines,thereby promoting wound healing.

Antibacterial hydrogel with pH-responsive microcarriers of slow-release VEGF for bacterial infected wounds repair

Bacterial infection causes wound inflammation and makes angiogenesis difficult.It is urgent to develop effectively antibacterial and pro-vascularizing dressings for wound healing.The hydrogel is developed with pH-responsive drug-releasing microcarriers which were loaded with vascular endothelial growth factor(VEGF)that promotes angiogenesis and actively respond to wound pH for control and prolong VEGF release.The surfaces of the microcarriers were coated with polydopamine which can reduce the silver nanoparticles(AgNPs)in situ,and dynamically crosslink with the polyacrylamide,which forms a stable slow-release system with different release behavior for the VEGF and AgNPs.The hydrogel inhib-ited bacterial formation and accelerated wound healing.With the hydrogel dressing,83.3%±4.29%of the wound heals at day 7,which is 40.9%±8.5%higher than the non-treatment group in defect infected model.The antibacterial properties of hydrogel down-regulate early inflammation-related cytokines,and the release of VEGF in the middle and late phases of wound healing in response to pH changes pro-motes angiogenesis and up-regulate the expression of angiogenesis-associated cytokine.The sequential release of antibacterial agents and pro-vascularizing agents in response to the change in wound microen-vironmental cues facilitate temporally controlled therapy that suites the need of different wound healing phases.Collectively,the hydrogel loaded with multifunctional microcarriers that enable controlled release of AgNPs and VEGF is an effective system for treating infected wounds.

Multi-layer-structured bioactive glass nanopowder for multistage-stimulated hemostasis and wound repair

Current treatments for full-thickness skin injuries are still unsatisfactory due to the lack of hierarchically stimulated dressings that can integrate the rapid hemostasis,inflammation regulation,and skin tissue remodeling into the one system instead of single-stage boosting.In this work,a multilayer-structured bioactive glass nanopowder(BGN@PTE)is developed by coating the poly-tannic acid andε-polylysine onto the BGN via facile layer-by-layer assembly as an integrative and multilevel dressing for the sequential management of wounds.In comparison to BGN and poly-tannic acid coated BGN,BGN@PTE exhibited the better hemostatic performance because of its multiple dependent approaches to induce the platelet adhesion/activation,red blood cells(RBCs)aggregation and fibrin network formation.Simultaneously,the bioactive ions from BGN facilitate the regulation of the inflammatory response while the poly-tannic acid and antibacterialε-polylysine prevent the wound infection,promoting the wound healing during the inflammatory stage.In addition,BGN@PTE can serve as a reactive oxygen species scavenger,alleviate the oxidation stress in wound injury,induce the cell migration and angiogenesis,and promote the proliferation stage of wound repair.Therefore,BGN@PTE demonstrated the significantly higher wound repair capacity than the commercial bioglass dressing Dermlin™.This multifunctional BGN@PTE is a potentially valuable dressing for full-thickness wound management and may be expected to extend to the other wounds therapy.

Research Progress and Cosmetic Application of Fibronectin

Fibronectin(FN)is a widely existed glycoprotein in human body fluid and plays an important role in the process of wound repair in human tissue.With the in-depth study on the molecular mechanism of fibronectin for wound repair,its applications in emerging biomedical fields are becoming more extensive,such as the field of skin wound repair and the field of tissue engineering materials,which are gradually extended to the field of beauty and skin care.In this paper,the domestic and foreign academic research and application of fibronectin were briefly reviewed.

Transposition Flaps for Reconstruction of Perianal Skin Defects After Tumor Resection

Objective To investigate the application of transposition flaps in the reconstruction of perianal skin defects after tumor resection.Methods From September 2018 to December 2019,16 cases of perianal skin defects were repaired with unilateral or bilateral transposition flaps.The wound size before closure ranged from 4 cm×8 cm to 7 cm×10 cm.Fourteen patients achieved primary healing.Wound dehiscence occurred in one patient at the flap tip,whereas a slight infection occurred in another patient,which healed after a dressing change.During the follow-up period of 3–6 months,all patients were satisfied with the perianal area both aesthetically and functionally.Conclusion Transposition flaps are a promising option for the repair of perianal skin defects after tumor removal.Owing to the simplicity of the flap design,the wide popularity of this flap type among surgeons is anticipated.

Heparinized PGA host-guest hydrogel loaded with paracrine products from electrically stimulated adipose-derived mesenchymal stem cells for enhanced wound repair

The microenvironment of the wound bed is essential in the regulation of wound repair.In this regard,strategies that provide a repairing favorable microenvironment may effectively improve healing outcomes.Herein,we attempted to use electrical stimulation(ES)to boost the paracrine function of adipose-derived stem cells from rats(rASCs).By examining the concentrations of two important growth factors,VEGF and PDGF-AA,in the cell culture supernatant,we found that ES,especially 5𝜇A ES,stimulated rASCs to produce more paracrine factors(5𝜇A-PFs).Further studies showed that ES may modulate the paracrine properties of rASCs by upregulating the levels of TRPV2 and TRPV3,thereby inducing intracellular Ca^(2+) influx.To deliver the PFs to the wound to effectively improve the wound microenvironment,we prepared a heparinized PGA host-guest hydrogel(PGA-Hp hydrogel).Moreover,PGA-Hp hydrogel loaded with 5𝜇A-PFs effectively accelerated the repair process of the full-thickness wound model in rats.Our findings revealed the effects of ES on the paracrine properties of rASCs and highlighted the potential application of heparinized PGA host-guest hydrogels loaded with PFs derived from electrically stimulated rASCs in wound repair.

Activating proper inflammation for wound-healing acceleration via mesoporous silica nanoparticle tissue adhesive

Efficient initiation and resolution of inflammation are crucial for wound repair.However,with using tissue adhesives for wound repair,patients occasionally suffered from delayed healing process because slow elimination of those exogenous adhesives generally leads to chronic inflammation.As the demand for minimal invasive therapy continues to rise,desire for adhesive materials that can effectively reconnect surgical gaps and promote wound regeneration becomes increasingly urgent.Herein,by exploiting the inherent porous structure and performance of adhesion to tissue of mesoporous silica nanoparticles(MSNs),we demonstrate a tissue adhesive that can elicit acute inflammatory response and get eliminated after tissue reformation.With formation of nanocomposites in wound gaps,the injured tissues can get reconnected conveniently.The resultant accelerated healing process verifty that the strategy of exploiting unique properties of nanomaterials can effectively promote inflammation resolution and wound repair.This design strategy will inspire more innovative tissue adhesives for clinical applications.

Macroporous and Antibacterial Hydrogels Enabled by Incorporation of Mg-Cu Alloy Particles for Accelerating Skin Wound Healing

Repair of severe skin tissue injury remains a great challenge and wound infection is still a formidable problem.In this study,new macroporous and antibacterial gelatin/alginate(SAG)-based hydrogels for wound repair were designed and developed based on in-situ gas foaming method and ion release strategy as a result of Mg-Cu particles degradation in the hydrogel matrix.The addition of Mg-Cu particles decreased the storage modulus of SAG,maintained its mechanical resilience and enhanced its water-absorbing capability.Moreover,the water vapor transmission rate of SAG added with 2 wt.%Mg-Cu(SAG-2 MC)was 124%of that of medical gauze and 804%of commercial Tegaderm^(TM)film dressing.The bacterial inhibition rates of SAG-2 MC against S.aureus.E.coli and P.aeruginosa reached 99.9%±0.1%,98.7%±1.2%and 98.0%±0.7%,respectively,significantly greater than those of the SAG hydrogel and Mg particle-modified hydrogels.In addition,SAG-2 MC hydrogel was biocompatible and promoted cell migration.In vivo experiment results indicated that SAG-2 MC significantly accelerated the skin wound healing in murine model as demonstrated by higher epidermis thickness,more collagen deposition and enhanced angiogenesis compared with SAG-OMC,SAG-2 M and TegadermTM film.In summary,Mg-Cu particles have great potential to modulate the physiochemical and biological properties of SAG hydrogels.Mg-Cu particle-modified SAG hydrogels reveal significant promise in the treatment of severe skin wound or other soft tissue lesions.

Chronic activation of MUC1-C in wound repair promotes progression to cancer stem cells

The mucin 1(MUC1)gene emerged in mammals to afford protection of barrier epithelial tissues from the external environment.MUC1 encodes a transmembrane C-terminal(MUC1-C)subunit that is activated by loss of homeostasis and induces inflammatory,proliferative,and remodeling pathways associated with wound repair.As a consequence,chronic activation of MUC1-C promotes lineage plasticity,epigenetic reprogramming,and carcinogenesis.In driving cancer progression,MUC1-C is imported into the nucleus,where it induces NF-κB inflammatory signaling and the epithelial-mesenchymal transition(EMT).MUC1-C represses gene expression by activating(i)DNA methyltransferase 1(DNMT1)and DNMT3b,(ii)Polycomb Repressive Complex 1(PRC1)and PRC2,and(iii)the nucleosome remodeling and deacetylase(NuRD)complex.PRC1/2-mediated gene repression is counteracted by the SWI/SNF chromatin remodeling complexes.MUC1-C activates the SWI/SNF BAF and PBAF complexes in cancer stem cell(CSC)models with the induction of genome-wide differentially accessible regions and expressed genes.MUC1-C regulates chromatin accessibility of enhancer-like signatures in association with the induction of the Yamanaka pluripotency factors and recruitment of JUN and BAF,which promote increases in histone activation marks and opening of chromatin.These and other findings described in this review have uncovered a pivotal role for MUC1-C in integrating lineage plasticity and epigenetic reprogramming,which are transient in wound repair and sustained in promoting CSC progression.

Application of metal-based biomaterials in wound repair

Wound repair,as one of the most intricate biological mechanisms,is essential to ensure the formation and integrity of the skin barrier.However,multiple factors can cause delays and severe debilitating effects in wound repair,which bring serious challenges.Metal elements such as calcium,copper,iron,and zinc serve irreplaceable roles in various regulatory pathways of the human body and directly or indirectly affect the orderly wound repair process.Biomaterials have proven to be an attractive strategy that can be applied to wound repair and have excellent potential to induce skin regeneration.In recent decades,with in-depth research on the regulatory mechanisms of metal elements involved in wound repair,metal-based biomaterials have been widely reported.Metal-based zero-dimensional(0D)biomaterials such as Angstrom-scale metallic materials and metal quantum dots,metal-based one-dimensional(1D)biomaterials such as nanorods,nanowires and nanofibers,metal-based two-dimensional(2D)biomaterials such as nanofilms and nanosheets,and metal-based three-dimensional(3D)biomaterials such as nanoframes have achieved remarkable results,which provide great support for accelerated wound repair.In this review,we systematically investigated the advances and impacts of various metal-based biomaterial platforms for wound repair to provide valuable guidance for future breakthroughs in wound treatment.