Roe-inspired stem cell microcapsules for inflammatory bowel disease treatment.

Mesenchymal stem cells (MSCs), which exert regulatory effects on various immune cells, have been a promising therapy for inflammatory bowel disease treatment. However, their therapeutic effects are limited by lack of nutritional supply, immune system attack, and low accumulation on the target site. Here, inspired by the natural incubation mechanism of roe, we present immune-isolating, wet-adhesive, and nutrient-rich microcapsules for therapeutic MSCs encapsulation. The adhesive shells were fabricated by ionic cross-linking of alginate and visible curing of epsilon-poly-L-lysine-graft-methacrylamide and dopamine methacrylamide, which encapsulated the liquid core of the MSCs and roe proteins. Due to the core-shell construction of the resultant microcapsules, the MSCs might escape from attack of the immune system while still maintaining immunomodulating functions. In addition, the roe proteins encapsulated in the core phase offered sufficient nutrient supply for MSCs' survival and proliferation. Furthermore, after intraperitoneal transplantation, the wet-adhesive radicals on the shell surface could immobilize the MSCs-encapsulating microcapsules onto the bowel. Based on these features, practical values of the roe-inspired microcapsules with MSCs encapsulation were demonstrated by applying them to treat dextran sulfate sodium (DSS)-induced colitis through increasing residence time, regulating immune imbalance, and relieving disease progression. We believe that the proposed roe-inspired microcapsules with MSCs encapsulation are potential for clinical application.

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.

3D-Printed Janus Piezoelectric Patches for 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 in vivo 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.

Living microecological hydrogels for wound healing.

Chronic hard-to-heal wounds draw great attention worldwide, as their treatments are limited by infections and hypoxia. Inspired by the natural oxygen production capacity of algae and the competitive advantage of beneficial bacteria over other microbes, we presented a living microecological hydrogel (LMH) with functionalized Chlorella and Bacillus subtilis encapsulation to realize continuous oxygen delivery and anti-infections for promoting chronic wound healing. As the hydrogel consisted of thermosensitive Pluronic F-127 and wet-adhesive polydopamine, the LMH could keep liquid at a low temperature while quickly solidifying and tightly adhering to the wound bed. It was demonstrated that by optimizing the proportion of the encapsulated microorganism, the Chlorella could continuously produce oxygen to relieve hypoxia and support the proliferation of B. subtilis, while B. subtilis could eliminate the colonized pathogenic bacteria. Thus, the LMH substantially promoted the healing of infected diabetic wounds. These features make the LMH valuable for practical clinical applications.

Pollen-Inspired Adhesive Multilobe Microparticles from Microfluidics for Intestinal Drug Delivery.

Microparticles (MPs)-based delivery systems have a demonstrated value in gastrointestinal administration. Research in this area is focusing on the development of multifunctional MPs to improve delivery effects. Herein, learning from the natural morphology of peony pollens, novel multilobe MPs delivery systems for target surface adhesion and durable drug release are pesented. Ascribing to the flexibility of microfluidic technology and the combination of selective hydrogel degradation methods, MPs with a series of multilobe structures can be obtained using alginate and methacrylated gelatin. Compared with spherical MPs, these multilobe MPs are elucidated to show excellent adhesion capacity due to their enhanced contact area. By encapsulating anti-inflammatory agent dexamethasone (DXM) into their matrix hydrogel, the resultant multilobe MPs delivery systems are verified to feature durable drug-release property and anti-inflammatory efficacy, which is further demonstrated in rats with inflammatory bowel disease. These results indicated that the biomimetic multilobe MPs are potentially ideal adhesive and durable drug-delivery vehicles for gastrointestinal drug administrations.

Bioadhesive Microcarriers Encapsulated with IL-27 High Expressive MSC Extracellular Vesicles for Inflammatory Bowel Disease Treatment.

Mesenchymal stem cell (MSC) therapy is a promising candidate for inflammatory bowel disease (IBD) treatment, while overcoming the limitations of naive seeding cells function and realizing efficient intestinal targeting remains a challenge. Here, a bioadhesive microparticle carrying interleukin-27 (IL-27) MSC-derived extracellular vesicles (MSCIL-27 EVs) is developed to treat IBD. The MSCIL-27 EVs prepared through lentivirus-mediated gene transfection technology show ideal anti-inflammatory and damage repair function. By encapsulating MSCIL-27 EVs into dopamine methacrylamide-modified hydrogel, a bioadhesive EVs microcarrier via microfluidic technology is fabricated. The resultant microcarriers exhibit ideal MSCIL-27 EVs sustained release effect and effective wet adhesion property. Furthermore, the therapeutic potential of MSCIL-27 EVs-loaded microcarriers in treating IBD is demonstrated. Through giving IBD rats a rectal administration, it is found that the microcarriers can firmly anchor to the surface of colon, reduce the inflammatory response, and repair the damaged barrier. Therefore, the bioadhesive MSCIL-27 EVs-loaded microcarriers provide a promising strategy for the biomedical application of MSC-derived EVs, and broaden the clinical potential of MSC therapy.

Microfluidic Templated Stem Cell Spheroid Microneedles for Diabetic Wound Treatment.

Wound dressing patches based on stem cells have demonstrated promising potential in the treatment of diabetic wounds, while their capabilities in the maintenance of cell stemness, effective exchange of cellular substance, and precise targeting of the stem cells remain to be promoted. Here, a novel stem cell spheroid loaded microneedle (MN@SPs) patch is presented using microfluidic templating technology. By leveraging the precise fluid manipulation capabilities of the microfluidic template, stem cell spheroids (SPs) with uniform size can be generated in situ. The resulting SPs exhibit advanced viability and cell functions, as evidenced by the overexpressed genes related to extracellular matrix organization and angiogenesis. By loading these SPs into the microneedles (MNs), the platform enables the precise delivery and exchange of multiple active substances, which contribute to advanced neovascularization, collagen deposition, and tissue reconstruction of diabetic wounds. Overall, this microfluidic-engineered stem cell therapy platform demonstrates significant promise in promoting wound healing.

Glucose metabolism-inspired catalytic patches for NIR-II phototherapy of diabetic wound infection.

Medical patches hold great prospects for diabetic wound administration, while their practical effects in diabetic wound management remain mired by the complexity of wound microenvironments. Here, inspired by the biological processes of glucose metabolism, we present a catalytic microneedle patch that encapsulates near-infrared-II responsive and dual-nanozyme active Au-Cu2MoS4 nanosheets (Au-CMS NSs) for treating diabetic wound infection. Since microneedle patches have great tissue penetration ability, the Au-CMS NSs can be delivered to deep tissues and fully interact with wound environments. Benefitting from the dual nanozyme activities (glucose oxidase and catalase) and near-infrared-II photothermal performances of Au-CMS NSs, the composited catalytic patch realizes in situ glucose consumption, oxygen generation, and bacterial elimination. Notably, their repeatability of near-infrared-II responsive antibacterial capability has been proved both in vitro and in diabetic mice against methicillin-resistant Staphylococcus aureus. The catalytic patch can find wide catalytic applications in wound care and infection prevention. STATEMENT OF SIGNIFICANCE: Effective treatment of diabetic wound infection remains still challenging in the clinic owing to the complex wound microenvironments. Herein, inspired by the biological processes of glucose metabolism in lives, we propose a novel strategy to treat wound infections by modulating the diabetic wound microenvironments. A near-infrared-II (NIR-II) responsive biocatalytic microneedle patch with both glucose oxidase- and catalase-like activities capable of killing bacteria, reducing glucose level, and supplying O2 is developed. The patch not only achieves efficient antibacterial outcomes in vitro, but also is a valuable wound patch for efficient treatment of MRSA-infected wounds in diabetic mice. We anticipate that this therapeutic strategy will provide the applications in chronic inflammation and infections.

Biomimetic Enzyme Cascade Structural Color Hydrogel Microparticles for Diabetic Wound Healing Management.

Hard-healing diabetic wound brings burgeoning physical and mental burdens to patients. Current treatment strategies tend to achieve multistage promotion and real-time reporting to facilitate wound management. Herein, a biomimetic enzyme cascade inverse opal microparticles system for wound healing, which is intergated with glucose oxidase (GOD) and copper peroxide (CP). Such microparticles are composed of biofriendly hyaluronic acid methacryloyl (HAMA) and pH-responsive acrylic acid (AA), which provided abundant binding sites and spaces for chemical immobilizing and physical doping of enzymes and metal bioinorganics. When the cascade catalytic system is applied on wound sites, hyperglycemia environment would serve as a hydrogen peroxide (H2 O2 ) generator through GOD catalysis, while acidic environment triggers the decomposition of CP, further catalyzing H2 O2 to generate reactive oxygen species (ROS). Additionally, the distinctive structural color of the microparticles can visually reflect the wound pH and intelligently estimate the healing state. It is demonstrated that such microparticle systems exhibit excellent broad-spectrum antibacterial and angiogenesis-promoting properties, as well as significant real-time reporting ability for wound healing. These features indicate that enzyme cascade structural color microparticles possess valuable potential in wound healing and related field.

Rocket-Inspired Effervescent Motors for Oral Macromolecule Delivery.

Oral administration is among the most convenient ways with good patient compliance for drug delivery; while it remains a challenge to achieve desirable bioavailability of most macromolecules due to the complex gastrointestinal barriers. Here, inspired by the structure and function of rocket, a novel micromotor delivery system is presented with scaled-down rocket-like architecture and effervescent-tablets-derived fuel for efficient oral macromolecule delivery by penetrating intestinal barrier. These rocket-inspired effervescent motors (RIEMs) are composed of sharp needle tips for both loading cargoes and efficient penetrating, and tail wings for loading effervescent powders and avoiding perforation. When exposed to a water environment, the effervescent fuel generates intensive CO2 bubbles to propel the RIEMs to move at high speed. Thus, the RIEMs with their sharp tip can inject into the surrounding mucosa for effective drug release. Furthermore, benefiting from their tail-wing design, perforation can be effectively avoided during the injection process, ensuring the safety of the RIEMs in gastrointestinal active delivery. Based on these advantages, it is demonstrated that the RIEMs can efficiently move and stab into the intestinal mucosa for insulin delivery, exhibiting efficacy in regulating blood sugar glucose in a diabetic rabbit model. These features indicate that these RIEMs are versatile and valuable for clinical oral delivery of macromolecules.

A Trilayer Dressing with Self-Pumping and pH Monitoring Properties for Promoting Abdominal Wall Defect Repair.

Due to abdominal infection, excessive wound exudation, and intestinal fistula formation, the treatment of full-thickness abdominal wall defects has become a difficult challenge for clinic doctors. This clinical problem cannot be resolved with existing biomaterials. To facilitate the repair of the abdominal wall, we developed a novel wound dressing with directional biofluid transport. We used electrospinning to spin a trilayer dressing consisting of hydrolyzed poly-acrylonitrile (HPAN)/Curcumin (CUR), polyurethane (PU), and polycaprolactone (PCL). In vitro results show that the three-layer wound dressing is biocompatible, capable of directional transport of excessive wound exudation, preventing reverse penetration, and monitoring the pH of the wound. Furthermore, in vivo results show the trilayer wound dressing improves the wound microenvironment, reduces inflammatory factors, promotes angiogenesis, and accelerates abdominal wall repair. Thus, we believe that the novel trilayer electrospinning dressing could facilitate abdominal wall defect repair.

Arrowhead Composite Microneedle Patches with Anisotropic Surface Adhesion for Preventing Intrauterine Adhesions.

Biomedical patches are considered as a promising strategy to help tissue repair and regeneration, prevent tissue adhesion, and reduce neighboring friction. Here, novel arrowhead composite microneedle patches (MNPs) are presented with anisotropic surface adhesion and growth factor encapsulation using a heterogeneous template replication approach for endometrium repair and intrauterine adhesions (IUAs) prevention. The arrowhead structures bring about interlocking between the microneedle (MN) tips and tissues, allowing these MNPs to steadily adhere to the tissues. Besides, benefitting from the cytoadhesive needle-tip material and the antiadhesive base material, these MNPs possess anisotropic surface adhesion and can facilitate cell adhesion on one surface to repair damaged tissues while restrain tissue contact on the other to prevent adverse adhesion. In the meanwhile, the encapsulated growth factor can be delivered through the MNs to the deep tissue, further accelerating tissue repair. Additionally, as the bases are soft and their patterns are highly tunable, the MNPs can change their shapes flexibly to adjust to the irregular morphology of uteri. It is demonstrated that these MNPs show good performances in treating injured endometrium and preventing IUAs of a rat model, indicating their great potential in versatile postoperative adhesion prevention and other clinical applications.

Corrigendum to "Bio-inspired intestinal scavenger from microfluidic electrospray for detoxifying lipopolysaccharide" [Bioact. Mater. 6 (2020) 1653-1662].

[This corrects the article DOI: 10.1016/j.bioactmat.2020.11.017.].

Structural Color Ionic Hydrogel Patches for Wound Management.

Ionic hydrogels have attracted extensive attention because of their wide applicability in electronic skins, biosensors, and other biomedical areas. Tremendous effort is dedicated to developing ionic hydrogels with improved detection accuracy and multifunctionality. Herein, we present an inverse opal scaffold-based structural color ionic hydrogel with the desired features as intelligent patches for wound management. The patches were composed of a polyacrylamide-poly(vinyl alcohol)-polyethylenimine-lithium chloride (PAM-PVA-PEI-LiCl) inverse opal scaffold and a vascular endothelial growth factor (VEGF) mixed methacrylated gelatin (GelMA) hydrogel filler surface. The scaffold imparted the composite patches with brilliant structural color, conductive property, and freezing resistance, while the VEGF-GelMA surface could not only prevent the ionic hydrogel from the interference of complex wound conditions but also contribute to the cell proliferation and tissue repair in the wounds. Thus, the hydrogel patches could serve as electronic skins for in vivo wound healing and monitoring with high accuracy and reliability. These features indicate that the proposed structural color ionic hydrogel patches have great potential for clinical applications.

Dip-Printed Microneedle Motors for Oral Macromolecule Delivery.

Micromotors have demonstrated values in drug delivery, and recent attempts focus on developing effective approaches to generate functional micromotors to improve this area. Here, with the integration of microfluidic droplet printing and wettability-induced drawing photolithography, we present an innovative spatiotemporal serial multistep dip-printing strategy to generate novel independent microneedle motors (IMNMs) for orally delivering macromolecular drugs. As the strategy combines the advantages of the hydrophilic wettability, extension effects, and capillary effects, the IMNMs with an oblate basement and a needle-shaped head or a core-shell structured multicomponent head can be created by simply printing pregel droplets layer by layer, following with simultaneous wiredrawing and solidification. Owing to the polarized magnetic particles in the bottom basement and the rapidly dissolvable polymers as the middle basement, the resultant IMNMs can respond to magnetic fields, move to desired places under a magnet, penetrate tissue-like substrates, induce head-basement separation, and leave only the needles for cargo release. Based on these features, we have demonstrated that these IMNMs can deliver insulin via intestinal tracts to realize effective blood glucose control of diabetic rabbit models. These results indicate the practical values and bright future of the dip-printing stratagem and these IMNMs in 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.

Mesenchymal Stem Cell Exosomes Encapsulated Oral Microcapsules for Acute Colitis Treatment.

Mesenchymal stem cells derived exosomes (MSC-exos) exhibit an intrinsic and directed efficiency for multiple diseases, while their versatile and effective delivery to the target site is still a challenge. Herein, inspired by the acids and enzymes resistant property of sealing gelatin capsules, novel MSC-exo-encapsulated oral microcapsules are presented for colitis treatment. Based on a microfluidic electrospray technique, MSC-exos are first encapsulated in sodium alginate (SA) hydrogel microspheres with sustainable bioactivity. The resultant SA microspheres are then coated with a middle gelatin layer to protect MSC-exos from degradation. Especially, with an enteric coating-Eudragit FS30D on the outer layer, the resistance of the microcapsules in gastric juice is further enhanced. The prepared microcapsules maintain the stability and bioactivity of the MSC-exos during storage, protect them from the harsh conditions in the gastrointestinal tract, and enable the release of actives in the suitable sites for exerting their biological functions. In addition, these MSC-exos encapsulated microcapsules reduce the proinflammatory cytokines levels of inflammatory macrophages and impaired colonic epithelial cells, which exhibit superior damage repair ability in injured colon sites. Thus, it is believed that the proposed oral MSC-exos encapsulated microcapsules are valuable for many practically clinical treatments.

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 polyethylene 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 promote 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 bleomycin. 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.

Microfluidic encapsulated manganese organic frameworks as enzyme mimetics for inflammatory bowel disease treatment.

Metal organic frameworks (MOFs) with physicochemical properties and adjustable structures have been proposed as very attractive materials. The studies on development of such functional materials tended to fabricate featured MOF objects with fascinating catalytic capabilities to utilize their biomedical values. In this paper, we present novel biocompatible manganese metal organic framework (Mn-MOF)-based catalase mimetics with microfluidic microcapsule encapsulation for intravital inflammatory bowel disease (IBD) treatment. Phosphoserine, a component of the cell membrane, served as an organic ligand to ensure biocompatibility of Mn-MOF. Owing to the core-shell structure of the microcapsule, the Mn-MOF exhibited a well-organized distribution and controlled release features, which could protect them from gastric juice and provide function in the intestine. Upon reaching the sites of the inflammatory bowel, Mn-MOF could effectively scavenge reactive oxygen species (ROS) over-produced by neutrophils and macrophages under various gastrointestinal pH environments, protecting intestinal epithelial cells from ROS damage. The Mn-MOF-encapsulated microcapsules exhibited high performances in treating spontaneous IBD in interleukin-10-deficient mice by relieving the oxidative stress, reducing the inflammation, and restoring the intestinal barrier. These results indicate that the functional Mn-MOF-encapsulated microcapsules have practical applications in the treatment of ROS-associated diseases.

Multifunctional hydrogel based on dopamine-modified hyaluronic acid, gelatin and silver nanoparticles for promoting abdominal wall defect repair.

Abdominal wall defects are often accompanied by severe infections and complications, creating a significant challenge for clinicians. There is an urgent need to develop a novel wound dressing that can effectively prevent intra-abdominal infection and promote the healing of defective abdominal walls. Based on a hydrogel dressing containing hyaluronic acid (HA) and gelatin (GT), herein we integrated dopamine with a catechol structure to enhance its antioxidant and adherent properties. HA is oxidized to form an aldehyde group, and subsequently grafted with dopamine. The dopamine-modified HA undergoes amidation reaction with GT at different concentrations. In addition, silver nanoparticles (AgNPs) were introduced to the hydrogel to enhance the antibacterial properties. The in vitro studies on GT/DA-HA demonstrated excellent physical and chemical properties, biodegradability, and biocompatibility. In a rat full-thickness skin defect model and a full-thickness abdominal wall defect model, the GT/DA-HA hydrogel could accelerate the healing process by improving wet adhesion, reducing wound inflammation, and promoting angiogenesis and formation of granulation tissues. The multifunctional hydrogel developed in this study shows great potential for treating full-thickness abdominal wall defects.