基于脱细胞后鱼皮细胞外基质的生物打印水凝胶纺织品用于创面修复

创面修复具有普遍性、治疗困难、患者众多和医疗负担沉重的特点,一直是临床研究的热点。为了满足特定需求,研究者投入了大量科研力量,致力于开发各种个性化需求和功能的伤口敷料。在这方面,我们提出了一种基于鱼皮脱细胞的细胞外基质(d ECM)水凝胶纺织品用于创面修复。鱼源的d ECM具有理想的生物相容性,并且通过生物打印技术制备的纺织品在细胞黏附和增殖方面表现出卓越的性能。此外,基于d ECM的水凝胶纺织品采用生物打印技术生成,因此具有可调节的多孔结构,使整个纺织品具备良好的透气性。而且,水凝胶骨架上的多孔结构高比表面积使其能够负载多种活性分子,从而提高创面愈合效果。通过体内研究结果,我们证明了这种制备的纺织品负载活性药物分子姜黄素(Cur)和碱性成纤维细胞生长因子(b FGF)能够显著加速慢性创面的修复过程。这些结果表明鱼皮d ECM纺织品在创面修复和生物医学工程领域具有潜在的价值。

Biomass Microcapsules with Stem Cell Encapsulation for Bone Repair

Bone defects caused by trauma,tumor,or osteoarthritis remain challenging due to the lack of effective treatments in clinic.Stem cell transplantation has emerged as an alternative approach for bone repair and attracted widespread attention owing to its excellent biological activities and therapy effect.The attempts to develop this therapeutic approach focus on the generation of effective cell delivery vehicles,since the shortcomings of direct injection of stem cells into target tissues.Here,we developed a novel core-shell microcapsule with a stem cell-laden core and a biomass shell by using all-aqueous phase microfluidic electrospray technology.The designed core-shell microcapsules showed a high cell viability during the culture procedure.In addition,the animal experiments exhibited that stem cell-laden core-shell microcapsules have good biocompatibility and therapeutic effect for bone defects.This study indicated that the core-shell biomass microcapsules generated by microfluidic electrospray have promising potential in tissue engineering and regenerative medicine.

Intelligent hydrogels for treating malignant melanoma

Malignant melanoma(MM)is an extremely aggressive and fatal form of skin cancer that primarily affects the bottom layer of the epidermis and is associated with poor clinical outcomes.Early-stage MM is typically treated through surgical removal,while chemotherapy and radiotherapy are common conventional treatment options that come with harmful side effects.Emerging therapies such as immunotherapy,photodynamic therapy,biologic therapy,and photothermal therapy present hopeful options for treatment due to their effective and secure drug delivery methods.To address the limitations of current treatment options,advanced methods of drug delivery for subcutaneous MM are being developed,with hydrogels emerging as a promising alternative.To date,significant advancements have been made in the treatment of MM through the use of hydrogels-based drug delivery systems through focal plastering,injection,implantation,and microneedles.Recent research on hydrogel-based drug delivery systems that integrate multiple therapies for the treatment of subcutaneous MM is discussed in this review.

Spatial tumor biopsy with fluorescence PCR microneedle array

Biopsy is the gold standard for tumor diagnosis,as this technology provides highly detailed and reliable information on tumorigenesis and progression.Resembling the discrete wettability of desert beetles,in this study,a fluorescence polymerase chain reaction(F-PCR)microneedle array(MNA)platform is developed for efficient spatial tumor biopsy.This MNA is fabricated by the coupled strategies of bottom-up self-assembly and top-down photolithography;it comprises a hydrophobic silica nanoparticle-assembled substrate and graphene aerogel-hydrogel hybrid microneedle peaks.Benefitting from the hydrophilicity and absorption capacity of its graphene hybrid microneedle peaks,MNA can easily penetrate tissue specimens and collect tumor nucleic acid biomarkers stereoscopically.In addition,because of the discrete wettability of the platform,both tissue fluids and PCR liquids can be easily removed from the substrate,and each microneedle peak is similar to an independent island for directly conducting F-PCR reactions for tumor marker discovery.Based on these advantages,the F-PCR-MNA platform is demonstrated to be ideal for detecting DNA biomarkers of lung carcinoma in standard solutions,mouse tissue samples,and clinical specimens,thus indicating its practical potential as an innovative tumor biopsy system.

干细胞球聚体微针促进糖尿病创面愈合

根据世界卫生组织统计,全球范围内有超过4亿人患有糖尿病^([1]).由于其发病机制涉及神经病变、血管病变和免疫功能受损等多个因素,患者易出现皮肤感觉减退、血液供应不足及免疫功能下降等问题^([2]).经统计,约15%~25%的糖尿病患者会并发难以愈合的皮肤溃疡,即糖尿病溃疡,好发于患者下肢、足部或其他容易受压的部位^([3]).

3D-Printed Janus Piezoelectric Patchesfor Sonodynamic Bacteria Elimination and Wound Healing

Management of infected wounds has raised worldwide concerns.Attempts in this field focus on the development of intelligent patches for improving the wound healing.Here,inspired by the cocktail treatment and combinational therapy stratagem,we present a novel Janus piezoelectric hydrogel patch via 3-dimensional printing for sonodynamic bacteria elimination and wound healing.The top layer of the printed patch was poly(ethylene glycol)diacrylate hydrogel with gold-nanoparticle-decorated tetragonal barium titanate encapsulation,which realizes the ultrasound-triggered release of reactive oxygen species without leaking nanomaterials.The bottom layer is fabricated with methacrylate gelatin and carries growth factors for the cell proliferation and tissue reconstruction.Based on these features,we have demonstrated invivo that the Janus piezoelectric hydrogel patch can exert substantial infection elimination activity under the excitation of ultrasound,and its sustained release of growth factors can promote tissue regeneration during wound management.These results indicated that the proposed Janus piezoelectric hydrogel patch had practical significance in sonodynamic infection alleviation and programmable wound healing for treating different clinical diseases.

Biomimetic Erythrocyte-Like Particles from Microfluidic Electrospray for Tissue Engineering

Microparticles have demonstrated value for regenerative medicine.Attempts in this field tend to focus on the development of intelligent multifunctional microparticles for tissue regeneration.Here,inspired by erythrocytes-associated self-repairing process in damaged tissue,we present novel biomimetic erythrocyte-like microparticles(ELMPs).These ELMPs,which are composed of extracellular matrix-like hybrid hydrogels and the functional additives of black phosphorus,hemoglobin,and growth factors(GFs),are generated by using a microfluidic electrospray.As the resultant ELMPs have the capacity for oxygen delivery and near-infrared-responsive release of both GFs and oxygen,they would have excellent biocompatibility and multifunctional performance when serving as microscaffolds for cell adhesion,stimulating angiogenesis,and adjusting the release profile of cargoes.Based on these features,we demonstrate that the ELMPs can stably overlap to fill a wound and realize controllable cargo release to achieve the desired curative effect of tissue regeneration.Thus,we consider our biomimetic ELMPs with discoid morphology and cargo-delivery capacity to be ideal for tissue engineering.

Bio-inspired clamping microneedle arrays from flexible ferrofluid-configured moldings

Microneedle(MN)arrays have demonstrated value for cosmetics,diagnosis,transdermal drug delivery,and other biomedical areas.Much effort has been devoted to developing simple stratagem for creating versatile moldings and generating functional MN arrays.Here,inspired by the serrated microstructure of mantises’forelegs,we present a novel serration-like clamping MN array based on ferrofluidconfigured moldings.Benefiting from the flexibility and versatility of ferrofluids,negative microhole array moldings with various sizes and angles toward the midline could be created easily.The corresponding biocompatible polymer MN arrays with both isotropic and anisotropic structures could then be produced feasibly and cost-effectively by simply replicating these moldings.It was found that the resultant serrated clamping MN arrays had the ability to adhere to skin firmly,enabling them to be used over a relatively long time and while the recipient was moving.This proposed technology performed well in minimally invasive drug administration and sustained glucocorticoids release during treatment for imiquimod-induced psoriasis in mice.These features indicated that such MN arrays could play important roles in wearable transdermal drug delivery systems and in other applications.

Immunotherapeutic silk inverse opal particles for post-surgical tumor treatment

Recurrence of malignant tumor after surgical resection is the main reason of cancer treatment failure.Here,a novel kind of silk inverse opal particles(SIOPs)for post-surgical tumor treatment is presented,and it is derived from colloid crystal bead templates by negatively replicating.Because of their abundant uniform nanopores,interconnected nanochannels and excellent biocompatibility,SIOPs could not only carry great amount of anti-tumor drugs for tumor therapy,but also could provide support for cell adhesion,proliferation and differentiation as the 3 D spherical scaffolds which is beneficial to the tissue repair at resection sites.It is demonstrated that the antibody drugs could maintain their high biological activity without any influences during the preparation of SIOPs and these particles were able to enhance the therapeutic efficacy and promote tissue regeneration after surgical resection with their multifunctional features.These prominent properties indicate the great potentials of SIOPs as a promising strategy for efficient postoperative cancer therapy.

Biofilm-inspired adhesive and antibacterial hydrogel with tough tissue integration performance for sealing hemostasis and wound healing

Uncontrolled bleeding and infection can cause significant increases in mortalities.Hydrogel sealants have attracted extensive attention for their ability to control bleeding.However,because interfacial water is a formidable barrier to strong surface bonding,a challenge remains in finding a product that offers robust tissue adhesion combined with anti-infection properties.Inspired by the strong adhesive mechanism of biofilm and mussels,we report a novel dual bionic adhesive hydrogel(DBAH)based on chitosan grafted with methacrylate(CS-MA),dopamine(DA),and N-hydroxymethyl acrylamide(NMA)via a facile radical polymerization process.CS-MA and DA were simultaneously included in the adhesive polymer for imitating the two key adhesive components:polysaccharide intercellular adhesin(PIA)of staphylococci biofilm and 3,4-dihydroxy-L-phenylalanine(Dopa)of mussel foot protein,respectively.DBAH presented strong adhesion at 34 kPa even upon three cycles of full immersion in water and was able to withstand up to 168 mm Hg blood pressure,which is significantly higher than the 60–160 mm Hg measured in most clinical settings.Most importantly,these hydrogels presented outstanding hemostatic capability under wet and dynamic in vivo movements while displaying excellent antibacterial properties and biocompatibility.Therefore,DBAH represents a promising class of biomaterials for high-efficiency hemostasis and wound healing.

Microfluidic Electrospray Niacin Metal-Organic Frameworks Encapsulated Microcapsules for Wound Healing

Niacin metal-organic frameworks(MOFs)encapsulated microcapsules with alginate shells and copper-/zinc-niacin framework cores were in situ synthesized by using a microfuidic electrospray approach for wound healing.As the alginate shells were bacteriaresponsively degradable,the niacin MOFs encapsulated microcapsules could intelligently,controllably,and programmably release calcium,copper,and zinc ions,depending on the degree of infections.Te released ions could not only kill microbes by destroying their membrane and inducing the outfow of nutrient substance,but also activate copper/zinc superoxide dismutase(Cu/ZnSOD)to eliminate oxygen free radicals and rescue the cells from oxidative stress injury.Furthermore,the simultaneously released niacin could promote hemangiectasis and absorption of functional metal ions.Tus,the niacin MOFs encapsulated microcapsules were imparted with outstanding antibacterial,antioxidant,and angiogenesis properties.Based on an in vivo study,we have also demonstrated that the chronic wound healing process of an infected full-thickness skin defect model could be signifcantly enhanced by using the niacin MOFs encapsulated microcapsules as therapeutic agent.Terefore,the microfuidic electrospray niacin MOFs encapsulated microcapsules are potential for clinical applications.

Bio-inspired natural platelet hydrogels for wound healing

Wound healing has invariably been a fundamental health concern,demanding manpower and materials and causing financial burdens.In this research,inspired by the hemostatic function of platelets,we proposed a novel bionic hydrogel by covalent amidation crosslinking natural platelet and alginate for wound healing.With the natural functional groups,the platelet-derived hydrogel exhibited outstanding biocompatibility and blood compatibility.By changing the addition ratio of platelets to alginates,the mechanical properties of the achieved hydrogel were variable to cater to different wound environments.Furthermore,silver nanoparticles could be loaded into the void space of the hydrogel which endowed the composites with superior anti-infective properties.We have demonstrated that the bio-inspired platelet hydrogel could promote hemostasis of acute tissue damage,prevent bacterial proliferation,and promote angiogenesis,collagen deposition,and granulation tissue formation in wound healing.These features signify the potential values of the bio-inspired platelet hydrogel in clinical applications.

Bioinspired Adhesive and Antibacterial Microneedles for Versatile Transdermal Drug Delivery

Microneedles have attracted increasing interest among various medical fields due to their painless,noninvasive,and efficient way of drug delivery.However,practical applications of these microneedles in different epidermal locations and environments are still restricted by their low adhesion and poor antimicrobial activity.Here,inspired by the antibacterial strategy of Paenibacillus polymyxa and adhesion mechanisms of mussel byssi and octopus tentacles,we develop hierarchical microneedles with multifunctional adhesive and antibacterial abilities.With polydopamine hydrogel as the microneedle base and a loop of suctioncup-structured concave chambers encircling each microneedle,the generated microneedles can fit the skin well;keep strong adhesion in dry,moist,and wet environments;and realize self-repair after being split into two parts.Besides,as polymyxin is loaded into both the hydrogel tips and the polydopamine base,the microneedles are endowed with excellent ability to resist common bacteria during storage and usage.We have demonstrated that these microneedles not only showed excellent adhesion when applied to knuckles and ideal antibacterial activity but also performed well in drug-sustained release and treatment for the osteoarthritis rat model.These results indicate that bioinspired multifunctional microneedles will break through the limitation of traditional methods and be ideal candidates for versatile transdermal drug delivery systems.

MXene-Integrated Microneedle Patches with Innate Molecule Encapsulation for Wound Healing

Wound healing is a complex physiological process that involves coordinated phases such as inflammation and neovascularization.Attempts to promote the healing process tend to construct an effective delivery system based on different drugs and materials.In this paper,we propose novel MXene-integrated microneedle patches with adenosine encapsulation for wound healing.Owing to the dynamic covalent bonding capacity of boronate molecules with adenosine,3-(acrylamido)phenylboronic acid-(PBA-)integrated polyethylene glycol diacrylate(PEGDA)hydrogel is utilized as the host material of microneedle patches.Benefitting from photothermal conversion capacity of MXene,the release of loaded adenosine could be accelerated under NIR irradiation for maintaining the activation signal around injury site.In vitro cell experiments proved the effect of MXene-integrated microneedle patches with adenosine encapsulation in enhancing angiogenesis.When applied for treating animal models,it is demonstrated that the microneedle patches efficiently promote angiogenesis,which is conductive to wound healing.These features make the proposed microneedle patch potential for finding applications in wound healing and other biomedical fields.

Bio-inspired intestinal scavenger from microfluidic electrospray for detoxifying lipopolysaccharide

Lipopolysaccharide(LPS)plays an important role in metabolic syndrome(MetS)and other gut-derived diseases,and detoxifying LPS is considered to be a fundamental approach to prevent and treat these diseases.Here,inspired by the feeding behaviour of scavenger,novel microfluidic microcapsules with alkaline phosphatase(ALP)encapsulation and the scavenger-like molecular sieve shell are presented for cleaning intestinal LPS.Benefiting from the precisely controlled of the pore size and microfluidic electrospray,the generated microcapsules were imparted with porous molecular-sieve shells and ALP encapsulated active cores.These microcapsules could continuously work as an intestinal scavenger after colonized in intestine.It has been demonstrated that the microcapsules could englobe LPS while inhibit the permeation of digestive enzyme,and this ability contributes to promising ALP’s activity,protecting cells at the presence of LPS and reducing inflammation.In addition,this scavenger inspired microcapsule could effectively decrease the LPS in organs,reduce inflammation and regulating fat metabolism in vivo.These features make the ALP encapsulated microcapsules an ideal candidate for treating MetS and other LPS related diseases.

Responsive graphene oxide hydrogel microcarriers for controllable cell capture and release

Cell microcarriers have emerged as a powerful cell culture platform in biomedical areas, but their functions are usually limited to simply capturing and proliferating cells,because of the simplicity of their components. Thus, in this study, we developed a new near-infrared（NIR） light-responsive graphene oxide（GO） hydrogel microcarrier system for controllable cell culture. The microcarriers were generated by using capillary microfluidics to emulsify the GO dispersed poly（N-isopropylacrylamide）（pNIPAM） and gelatin methacrylate（GelMA） pre-gel solution. The composite GO hydrogel microcarriers exhibited photothermally responsive cell capture, as well as the capacity for proliferation and release due to the NIR absorption of GO, the thermally responsive shape transition of pNIPAM, and the high biocompatibility of Gel MA. It was found that the NIR-responsive GO hydrogel microcarriers could prevent the cultured cells from being attacked by the immune system and promote the formation of tumor models in immunocompetent mice, which is desired for tumor and drug research. These features make the NIR-responsive GO hydrogel microcarriers excellent functional materials for different biomedical applications.

Bio-inspired adhesive porous particles with human MSCs encapsulation for systemic lupus erythematosus treatment

Mesenchymal stem cells(MSCs)therapy is a promising treatment for Systemic lupus erythematosus(SLE)patients.However,this method is encumbered by suboptimal phenotype of MSCs used in clinical settings,and a short in vivo persistence time.Herein,inspired by the natural microstructure of the sand tower worm nest,we proposed novel adhesive porous particles with human MSCs encapsulation via microfluidic electrospray technology for SLE treatment.The porous microparticles were formed by immediate gelation reaction between sodium alginate(ALG)and poly-D-lysine(PDL),and then sacrificed polyethylene oxide(PEO)to form the pores.The resultant microparticles could protect MSCs from immune cells while maintain their immune modulating functions,and achieve rapid exchange of nutrients from the body.In addition,owing to the electrostatic adsorption and covalent bonding between PDL and tissues,the porous microparticles could adhere to the bowel surfaces tightly after intraperitoneal injection.Through in vivo imaging system(IVIS)methods and in vivo study,it was demonstrated that the MSCs-encapsulated porous adhesive microparticles could significantly increase the cellular half-life,turn activated inflammatory macrophages into an anti-inflammatory profile,and ameliorate disease progression in MRL/lpr mice.Thus,the MSCs-encapsulated porous microparticles showed distinctive functions in chronic SLE treatment,with additional potential to be used in a variety of biomedical applications.

MSCs-laden injectable self-healing hydrogel for systemic sclerosis treatment

As a novel cellular therapy, the anti-inflammatory and immunomodulatory virtues of mesenchymal stem cells (MSCs) make them promising candidates for systemic sclerosis (SSc) treatment. However, the clinical efficacy of this stratagem is limited because of the short persistence time, poor survival, and engraftment of MSCs after injection in vivo. Herein, we develop a novel MSCs-laden injectable self-healing hydrogel for SSc treatment. The hydrogel is prepared using N, O-carboxymethyl chitosan (CS-CM) and 4-armed benzaldehyde-terminated poly-ethylene glycol (PEG-BA) as the main components, imparting with self-healing capacity via the reversible Schiff-base connection between the amino and benzaldehyde groups. We demonstrate that the hydrogel laden with MSCs not only promoted the proliferation of MSCs and increased the cellular half-life in vivo, but also improve their immune-modulating functions. The tube formation assay indicates that the MSCs could significantly pro-mote angiopoiesis. Moreover, the MSCs-laden hydrogel could inhibit fibrosis by modulating the synthesis of collagen and ameliorate disease progression in SSc disease model mice after subcutaneous injection of bleo-mycin. All these results highlight this novel MSCs-laden hydrogel and its distinctive functions in treatment of chronic SSc, indicating the additional potential to be used widely in the clinic.

Living Bacterial Microneedles for Fungal Infection Treatment

Fungal infections are everlasting health challenges all over the world,bringing about great financial and medical burdens.Here,inspired by the natural competition law of beneficial bacteria against other microbes,we present novel living microneedles(LMNs)with functionalized bacteria encapsulation for efficient fungal infection treatment.The chosen beneficial bacterial components,Bacillus subtilis(B.subtilis),which are naturally found on the human skin and widely used for food processing,can get nutrients from the skin and escape from the immune system with the help of microneedles.Besides,the encapsulated B.subtilis can continuously produce and secrete various potential antifungal agents which can directly bind to fungal cell surfaceassociated proteins and destruct the cell membranes,thus avoiding drug resistance.After immobilization in the LMNs,the bacteria can stay within the LMNs without invasion and the encapsulated bacteria together with microneedles can be removed after application.Thus,the side effects,especially the risk for subsequent bacterial infections,are controlled to a minimum to ensure security.In addition,strong penetrability of the microneedles enhances penetration of antifungal agents,and their heights can be adjusted according to the infected depth to acquire better therapeutic effects.These features make the LMNs potentially valuable for clinical applications.

Omnipotent tissue adhesive

Suturing and stapling are the most comm on fixation procedures employed for wound closure after critical injuries or surgery[1,2].Such procedures require penetration in the tissues,thus may cause infections,induce strain and raise potential aesthetic issues[3,4].Sutureless approaches seem to be much more appropriate fixation methods through producing an adhesive con tact at the surface between tissues and adhesives under physiological conditions[5-7],The existing adhesives,such as liquids or hydrogels,mostly depend on introducing binding interactions between hydrogel molecules and the polymer networks of tissues through the interfacial water[8,9].