Magnetic Polysaccharide Mesenchymal Stem Cells Exosomes Delivery Microcarriers for Synergistic Therapy of Osteoarthritis.

Osteoarthritis (OA) is a prevalent degenerative disease that afflicts more than 250 million people worldwide, impairing their mobility and quality of life. However, conventional drug therapy is palliative. Exosomes (Exo), although with the potential to fundamentally repair cartilage, face challenges in their efficient enrichment and delivery. In this study, we developed magnetic polysaccharide hydrogel particles as microcarriers for synergistic therapy of OA. The microcarriers were composed of modified natural polysaccharides, hyaluronic acid (HAMA), and chondroitin sulfate (CSMA), and were generated from microfluidic electrospray in combination with a cryogelation process. Magnetic nanoparticles with spiny structures capable of capturing stem cell Exo were encapsulated within the microcarriers together with an anti-inflammatory drug diclofenac sodium (DS). The released DS and Exo from the microcarriers had a synergistic effect in alleviating the OA symptoms and promoting cartilage repair. The in vitro and in vivo results demonstrated the excellent performance of the microcarrier for OA treatment. We believe this work has potential for Exo therapy of OA and other related diseases.

Self-Healing Dynamic Hydrogel Microparticles with Structural Color for Wound Management.

Chronic diabetic wounds confront a significant medical challenge because of increasing prevalence and difficult-healing circumstances. It is vital to develop multifunctional hydrogel dressings, with well-designed morphology and structure to enhance flexibility and effectiveness in wound management. To achieve these, we propose a self-healing hydrogel dressing based on structural color microspheres for wound management. The microsphere comprised a photothermal-responsive inverse opal framework, which was constructed by hyaluronic acid methacryloyl, silk fibroin methacryloyl and black phosphorus quantum dots (BPQDs), and was further re-filled with a dynamic hydrogel. The dynamic hydrogel filler was formed by Knoevenagel condensation reaction between cyanoacetate and benzaldehyde-functionalized dextran (DEX-CA and DEX-BA). Notably, the composite microspheres can be applied arbitrarily, and they can adhere together upon near-infrared irradiation by leveraging the BPQDs-mediated photothermal effect and the thermoreversible stiffness change of dynamic hydrogel. Additionally, eumenitin and vascular endothelial growth factor were co-loaded in the microspheres and their release behavior can be regulated by the same mechanism. Moreover, effective monitoring of the drug release process can be achieved through visual color variations. The microsphere system has demonstrated desired capabilities of controllable drug release and efficient wound management. These characteristics suggest broad prospects for the proposed composite microspheres in clinical applications.

Flexible liquid-diode microtubes from multimodal microfluidics.

Directional transport of liquids is of great importance in energy saving, chemical/biomedical engineering, and microfluidics applications. Despite considerable progress in engineering different open surfaces to achieve liquid manipulation, the realization of diode-like liquid transport in enclosed spaces is still challenging. Here, a flexible diode microtube is presented for directional liquid transport within confined spaces using pulsed microfluidics. The microtubes exhibit sophisticated microstructures on the inner wall, replicated from a precisely controlled flow configuration in the microfluidic channel. Under the effect of asymmetric pinning and unbalanced Laplace pressure, such microtubes enable directional liquid transport in closed channels. More importantly, by integrating in situ flow lithography with the microfluidic system, segmented liquid diodes are fabricated as assembly units for the construction of fluidic-electronic circuits that perform logic operations. These results demonstrate the capacity of the present liquid-diode microtubes for flexible, directional, and programmable liquid transport. We believe that it can open an avenue for designing advanced fluidic circuit-based devices toward versatile practical applications.

Glucose Responsive Coacervate Protocells from Microfluidics for Diabetic Wound Healing.

The hyperglycemic pathophysiological environment in diabetic wounds is a major obstacle that impedes the healing process. Glucose-responsive wound healing materials are a promising approach to address this challenge. In this study, complex coacervate-based protocells are introduced for diabetic wound healing. By employing a microfluidic chip with an external mechanical vibrator, uniform coacervate microdroplets are generated via electrostatic interactions between diethylaminoethyl-dextran and double-stranded DNA. The spontaneous assembly of a phospholipid membrane on the droplet surface enhances its biocompatibility. Glucose oxidase and copper peroxide nanodots are integrated into microdroplets, enabling a glucose-responsive cascade that produces hydroxyl radicals as antibacterial agents. These features contribute to efficient antibacterial activity and wound healing in diabetic mice. The present protocells facilitate intelligent wound management, and the design of cascade catalytic coacervates can contribute to the development of various smart vehicles for drug delivery.

Microfluidic-based multifunctional microspheres for enhanced oral co-delivery of probiotics and postbiotics.

Probiotic-based therapies have shown great potential in the prevention and treatment of many diseases by positively regulating intestinal flora homeostasis. However, the efficacy of oral probiotics is severely limited due to the loss of bioactivity, short intestinal retention time, and insufficient therapeutic effect. Here, based on droplet microfluidics, we developed a hydrogel microsphere with colonic targeting and mucoadhesive capabilities as a multifunctional delivery platform, which can be used for co-delivery of probiotics (Escherichia coli Nissle 1917, EcN) and auxiliary molecules (indole-3-propionic acid, IPA), achieving synergistic therapeutic effects. In vivo studies shown that the integrated multifunctional microspheres can significantly reduce intestinal inflammation, repair intestinal barrier function, enhance probiotic colonization in the intestine, and modulate disordered intestinal flora, demonstrating enhanced therapeutic effects in a mouse model of colitis. This work reveals that microfluidic-based smart droplet microspheres can provide a versatile platform for advanced microbial therapies.

Microfluidics-derived hierarchical microparticles for the delivery of dienogest for localized endometriosis therapy.

Drug therapy is one of the most important strategies for treating gynecological diseases. Local drug delivery is promising for achieving optimal regional drug exposure, considering the complex anatomy and dynamic environment of the upper genital tract. Here, we present microparticle-based microcarriers with a hierarchical structure for localized dienogest (DNG) delivery and endometriosis treatment. The microparticles were fabricated by microfluidics and consisted of photo-crosslinked bovine serum albumin hydrogel particles (D@P-B MPs) encapsulating DNG-loaded PLGA (poly lactic-co-glycolic acid) microspheres. Such design enables the microparticles to have sustained release capacity and cell adhesion ability. Based on this, the microparticles were applied for the treatment of peritoneal endometriosis through intraperitoneal injection. The performance of the microparticles in inhibiting the growth of ectopic lesions as well as their anti-inflammatory, anti-angiogenesis, and pelvic pain-relieving effects are well demonstrated in vivo. These findings indicate that the present hierarchical microparticles are good candidates for localized treatment of endometriosis and are promising for the management of gynecological diseases. STATEMENT OF SIGNIFICANCE: We prepared photo-crosslinked bovine serum albumin hydrogel particles (D@P-B MPs) encapsulating DNG-loaded PLGA microspheres using microfluidic electrospray. Such hierarchical structure provided multiple functions of the particles as drug carriers. The hierarchical microparticles not only supported the sustained release of drugs but also provided adhesion to human ectopic endometrial stromal cells. The hierarchical microparticles represented a localized treatment method for endometriosis and is promising for the management of gynecological diseases.

Bioinspired Confined Assembly of Cellulosic Cholesteric Liquid Crystal Bubbles.

Construction of biomimetic models for structural color evolution not only gives new photonic phenomena but also provide cues for biological morphogenesis. Here, a novel confined self-assembly method is proposed for the generation of hydroxypropyl cellulose (HPC)-based cholesteric liquid crystals (CLCs) microbubbles. The assembly process relies on the combination of droplet microfluidics, solvent extraction, and a volume confined environment. The as-prepared HPC structural color microbubbles have a transparent shell, an orderly arranged cholesteric liquid crystal (CLC) middle layer, and an innermost bubble core. The size of the microbubble, shell thickness, and the color of the CLC layer can be adjusted by altering the microfluidic parameters. Intriguingly, benefited from the compartmentalization effect provided by droplet microfluidics, microbubbles with multiple cores of different color combinations are generated under precise control. The self-assembled CLCs microbubbles have bright structural color, suspending ability, and good temperature-sensitive characteristics, making them ideal underwater sensors. The present confined assembly approach will shed light on creating novel photonic structures and the HPC microbubble will find widespread applications in multifunctional sensing, optical display, and other related fields are believed.

Breadmaking-Inspired Antioxidant Porous Yeast Microcarriers for Stem Cell Delivery in Diabetic Wound Treatment.

Stem cell-based therapies have exhibited significant promise in the treatment of diabetic ulcers (DU). Nevertheless, enhancing the survival rate and functionality of transplanted stem cells poses a substantial challenge. In this study, inspired by the breadmaking process, yeast microcarriers (YMC) are devised as vehicles for stem cells to address these challenges. The fabrication of YMC involves the amalgamation of microfluidic emulsification with yeast-mediated fermentation, yielding microcarriers with outstanding biocompatibility, high porosity, and antioxidant activity. Adipose-derived stem cells (ADSCs) seeded onto YMC display remarkable cell viability and retain their cellular functions effectively. Additionally, YMC boast a rich glutathione content and exhibit remarkable ROS scavenging ability, thus shielding the ADSCs from oxidative stress. In vivo experiments further substantiate that ADSC@YMC implementation significantly lowered ROS levels in diabetic wounds, resulting in enhanced stem cell retention and improved angiogenesis, collagen deposition, and tissue regeneration. These results highlight the potential of ADSC@YMC as a promising platform for delivering stem cell in the treatment of diabetic wounds.

Photothermal Responsive Microcarriers Encapsulated With Cangrelor and 5-Fu for Colorectal Cancer Treatment.

Localized chemotherapy is emerging as a potential strategy for cancer treatment due to its low systemic toxicity. However, the immune evasion of tumor cells and the lack of an intelligent design of the delivery system limit its clinical application. Herein, photothermal responsive microcarriers are designed by microfluidic electrospray for colorectal tumor treatment. The microcarriers loaded with Cangrelor, 5-FU and MXene (G-M@F/C+NIR) show sustained delivery of antiplatelet drug Cangrelor, thus inhibiting the activity of platelets, interactions of platelet-tumor cell, as well as the tumor cells invasion and epithelial-mesenchymal transition (EMT). In addition, the sustained delivery of chemotherapeutics 5-FU and the photothermal effect provided by MXene enable the microcarriers to inhibit tumor cells proliferation and migration. In vivo studies validate that the G-M@F/C+NIR microcarriers significantly inhibites tumor growth, decreased the expression of Ki-67 in tumor cells and vascular endothelial growth factor (VEGF) in the tumor microenvironment, while increased the expression of E-cadherin. It is believe that by means of the proposed photothermal responsive microcarriers, the synergistic strategy of platelet inhibition, chemotherapy, and photothermal therapy can find practical applications in cancer treatment.

Multi-Bioinspired MOF Delivery Systems from Microfluidics for Tumor Multimodal Therapy.

Metal-organic framework (MOF)-based drug delivery systems have demonstrated values in oncotherapy. Current research endeavors are centralized on the functionality enrichment of featured MOF materials with designed versatility for synergistic multimodal treatments. Here, inspired by the multifarious biological functions including ferroptosis pattern, porphyrins, and cancer cell membrane (CCM) camouflage technique, novel multi-biomimetic MOF nanocarriers from microfluidics are prepared. The Fe3+ , meso-tetra(4-carboxyphenyl)porphine and oxaliplatin prodrug are incorporated into one MOF nano-system (named FeTPt), which is further cloaked by CCM to obtain a "Trojan Horse"-like vehicle (FeTPt@CCM). Owing to the functionalization with CCM, FeTPt@CCM can target and accumulate at the tumor site via homologous binding. After being internalized by cancer cells, FeTPt@CCM can be activated by a Fenton-like reaction as well as a redox reaction between Fe3+ and glutathione and hydrogen peroxide to generate hydroxyl radical and oxygen. Thus, the nano-platform effectively initiates ferroptosis and improves photodynamic therapy performance. Along with the Pt-drug chemotherapy, the nano-platform exhibits synergistic multimodal actions for inhibiting cancer cell proliferation in vitro and suppressing tumor growth in vivo. These features indicate that such a versatile biomimetic MOF delivery system from microfluidics has great potential for synergistic cancer treatment.

Cryo-shocked cancer cell microgels for tumor postoperative combination immunotherapy and tissue regeneration.

Prevention of recurrence/metastasis and tissue regeneration are critical for post-surgery treatment of malignant tumors. Here, to address these needs, a novel type of microgel co-loading cryo-shocked cancer cells, immunoadjuvant, and immune checkpoint inhibitor is presented by microfluidic electrospray technology and liquid nitrogen treatment. Owing to the encapsulation of cryo-shocked cancer cells and immunoadjuvant, the microgels can recruit dendritic cells and activate them in situ, and evoke a robust immune response. Moreover, with the combination of the immune checkpoint inhibitor, the antitumor immune response is further enhanced by inhibiting the interaction of PD1 and PDL1. With this, the excellent anti-recurrence and anti-metastasis efficacy of the microgels are demonstrated in an orthotopic breast cancer mouse model. Besides, because of the excellent biocompatibility and appropriate degradation performance, the microgels can provide support for normal cell adhesion and growth, which is beneficial to tissue reconstruction. These properties indicate the great value of the cryo-shocked cancer cell microgels for efficient tumor postoperative combination immunotherapy and tissue regeneration.

Multi-Bioinspired Functional Conductive Hydrogel Patches for Wound Healing Management.

Many hydrogel patches are developed to solve the pervasive and severe challenge of complex wound healing, while most of them still lack satisfactory controllability and comprehensive functionality. Herein, inspired by multiple creatures, including octopuses and snails, a novel muti-functional hydrogel patch is presented with controlled adhesion, antibacterial, drug release features, and multiple monitoring functions for intelligent wound healing management. The patch with micro suction-cup actuator array and a tensile backing layer is composed of tannin grafted gelatin, Ag-tannin nanoparticles, polyacrylamide (PAAm) and poly(N-isopropylacrylamide) (PNIPAm). In virtue of the photothermal gel-sol transition of tannin grafted gelatin and Ag-tannin nanoparticles, the patches exert a dual anti-microbial effect and temperature-sensitive snail mucus-like features. In addition, as the "suction-cups" consisting of thermal responsive PNIPAm can undergo a contract-relax transformation, the medical patches can adhere to the objects reversibly and responsively, and release their loaded vascular endothelial growth factor (VEGF) controllably for wound healing. More attractively, benefiting from their fatigue resistance, self-healing ability of the tensile double network hydrogel, and electrical conductivity of Ag-tannin nanoparticles, the proposed patches can report multiple wound physiology parameters sensitively and continuously. Thus, it is believed that this multi-bioinspired patch has immense potential for future wound healing management.

Liquid Crystal Materials for Biomedical Applications.

Liquid crystal is a state of matter being intermediate between solid and liquid. Liquid crystal materials exhibit both orientational order and fluidity. While liquid crystals have long been highly recognized in the display industry, in recent decades, liquid crystals provide new opportunities into the cross-field of material science and biomedicine due to their biocompatibility, multifunctionality, and responsiveness. In this review, the latest achievements of liquid crystal materials applied in biomedical fields are summarized. The start is made by introducing the basic concepts of liquid crystals, and then shifting to the components of liquid crystals as well as functional materials derived therefrom. After that, the ongoing and foreseeable applications of liquid crystal materials in the biomedical field with emphasis put on several cutting-edge aspects, including drug delivery, bioimaging, tissue engineering, implantable devices, biosensing, and wearable devices are discussed. It is hoped that this review will stimulate ingenious ideas for the future generation of liquid crystal-based drug development, artificial implants, disease diagnosis, health status monitoring, and beyond.

Adhesive Composite Microspheres with Dual Antibacterial Strategies for Infected Wound Healing.

Skin damage and infection pose a severe challenge to human health. Construction of a novel versatile dressing with good anti-infection and healing-promoting abilities is greatly expected. In this paper, nature-source-based composite microspheres with dual antibacterial mechanisms and bioadhesive features by microfluidics electrospray for infected wound healing is developed. The microspheres enable sustained release of copper ions, which not only show long-term antibacterial properties, but also play important role in wound-healing-related angiogenesis. Additionally, the microspheres are coated with polydopamine via self-polymerization, which renders the microspheres adhesive to the wound surface, and further enhance the antibacterial ability through photothermal energy conversion. Based on the dual antibacterial strategies provided by copper ions and polydopamine as well as the bioadhesive property, the composite microspheres exhibit excellent anti-infection and wound healing performances in a rat wound model. These results, along with the nature-source-based composition and biocompatibility, indicate the great potential of the microspheres in clinical wound repair.

Bioinspired Jellyfish Microparticles from Microfluidics.

Nonspherical particles have attracted increasing interest because of their shape anisotropy. However, the current methods to prepare anisotropic particles suffer from complex generation processes and limited shape diversity. Here, we develop a piezoelectric microfluidic system to generate complex flow configurations and fabricate jellyfish-like microparticles. In this delicate system, the piezoelectric vibration could evolve a jellyfish-like flow configuration in the microchannel and the in situ photopolymerization could instantly capture the flow architecture. The sizes and morphologies of the particles are precisely controlled by tuning the piezoelectric and microfluidic parameters. Furthermore, multi-compartmental microparticles with a dual-layer structure are achieved by modifying the injecting channel geometry. Moreover, such unique a shape endows the particles with flexible motion ability especially when stimuli-responsive materials are incorporated. On the basis of that, we demonstrate the capability of the jellyfish-like microparticles in highly efficient adsorption of organic pollutants under external control. Thus, it is believed that such jellyfish-like microparticles are highly versatile in potential applications and the piezoelectric-integrated microfluidic strategy could open an avenue for the creation of such anisotropic particles.

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.

DNA-Polyelectrolyte Composite Responsive Microparticles for Versatile Chemotherapeutics Cleaning.

Drug therapy is among the most widely used methods in disease treatment. However, there remains a trade-off problem between drug dosage and toxicity. Blood purification by adsorption of excessive drugs during clinical treatment could be a solution for enhancing therapeutic efficacy while maintaining normal body function. Here, inspired by the intrinsic action mechanism of chemotherapeutic agents in targeting DNA in the cell nucleus, we present DNA-polyelectrolyte composite responsive microparticles for chemotherapeutics cleaning. The presence of DNA in the microparticles enabled the adsorption of multiple common chemotherapy drugs. Moreover, the microparticles are endowed with a porous structure and a photothermal-responsive ability, both of which contribute to improved adsorption by enhancing the contact of the microparticles with the drug solution. On the basis of that, the microparticles are integrated into a herringbone-structured microfluidic chip. The fluid mixing capacity and the enhanced drug cleaning efficiency of the microfluidic platform are validated on-chip. These results indicate the value of the DNA-polyelectrolyte composite responsive microparticles for drug capture and blood purification. We believe the microparticle-integrated microfluidic platform could provide a solution for settling the dosage-toxicity trade-off problems in chemotherapy.

Liquid Metal Droplets-Based Elastomers from Electric Toothbrush-Inspired Revolving Microfluidics.

Liquid metal (LM)-based elastomers have a demonstrated value in flexible electronics. Attempts in this area include the development of multifunctional LM-based elastomers with controllable morphology, superior mechanical performances, and great stability. Herein, inspired by the working principle of electric toothbrushes, a revolving microfluidic system is presented for the generation of LM droplets and construction of desired elastomers. The system involves revolving modules assembled by a needles array and 3D microfluidic channels. LM droplets can be generated with controllable size in a high-throughput manner due to the revolving motion-derived drag force. It is demonstrated that by employing a poly(dimethylsiloxane) (PDMS) matrix as the collection phase, the generated LM droplets can act as conductive fillers for the construction of flexible electronics directly. The resultant LM droplets-based elastomers exhibit high mechanical strength, stable electrical performance, as well as superior self-healing property benefiting from the dynamic exchangeable urea bond of the polymer matrix. Notably, due to the flexible programmable feature of the LM droplets embedded within the elastomers, various patterned LM droplets-based elastomers can be easily achieved. These results indicate that the proposed microfluidic LM droplets-based elastomers have a great potential for promoting the development of flexible electronics.

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.