Deep learning large-scale drug discovery and repurposing.

Large-scale drug discovery and repurposing is challenging. Identifying the mechanism of action (MOA) is crucial, yet current approaches are costly and low-throughput. Here we present an approach for MOA identification by profiling changes in mitochondrial phenotypes. By temporally imaging mitochondrial morphology and membrane potential, we established a pipeline for monitoring time-resolved mitochondrial images, resulting in a dataset comprising 570,096 single-cell images of cells exposed to 1,068 United States Food and Drug Administration-approved drugs. A deep learning model named MitoReID, using a re-identification (ReID) framework and an Inflated 3D ResNet backbone, was developed. It achieved 76.32% Rank-1 and 65.92% mean average precision on the testing set and successfully identified the MOAs for six untrained drugs on the basis of mitochondrial phenotype. Furthermore, MitoReID identified cyclooxygenase-2 inhibition as the MOA of the natural compound epicatechin in tea, which was successfully validated in vitro. Our approach thus provides an automated and cost-effective alternative for target identification that could accelerate large-scale drug discovery and repurposing.

Decellularized Tumor Tissues Integrated with Polydopamine for Wound Healing.

Natural biomaterials have been showing extensive potential in wound healing; attempts therefore focus on productions achieving both antimicrobial and tissue regenerative abilities. Here, we construct a decellularized human colon tumor (DHCT)-derived scaffold for wound remolding via microfluidic bioprinting. The DHCT retains a series of growth factors, fibrin, and the collagen configuration, that favor tissue repair and reconstruction. Specifically, the scaffold shows superior abilities in cell migration and angiogenesis. The biocompatible scaffold is also imparted with tissue adhesion ability and photothermal effect due to the coating of biologically derived polydopamine on the surface. The strong photothermal effect under near-infrared irradiation also present the scaffold with an antibacterial rate exceeding 90%. Furthermore, in vivo experiments convinced that the polydopamine-integrated DHCT scaffold can markedly expedite the healing process of acute extensive wounds. These findings indicate that composite materials derived from natural tumors have substantial potential in pertinent clinical applications.

Hydrogel-Encapsulated Pancreatic Islet Cells as a Promising Strategy for Diabetic Cell Therapy.

Islet transplantation has now become a promising treatment for insulin-deficient diabetes mellitus. Compared to traditional diabetes treatments, cell therapy can restore endogenous insulin supplementation, but its large-scale clinical application is impeded by donor shortages, immune rejection, and unsuitable transplantation sites. To overcome these challenges, an increasing number of studies have attempted to transplant hydrogel-encapsulated islet cells to treat diabetes. This review mainly focuses on the strategy of hydrogel-encapsulated pancreatic islet cells for diabetic cell therapy, including different cell sources encapsulated in hydrogels, encapsulation methods, hydrogel types, and a series of accessorial manners to improve transplantation outcomes. In addition, the formation and application challenges as well as prospects are also presented.

Biopolymer-Assembled Porous Hydrogel Microfibers from Microfluidic Spinning for Wound Healing.

Hydrogels are considered as a promising medical patch for wound healing. Researches in this aspect are focused on improving their compositions and permeability to enhance the effectiveness of wound healing. Here, novel prolamins-assembled porous hydrogel microfibers with the desired merits for treating diabetes wounds are presented. Such microfibers are continuously generated by one-step microfluidic spinning technology with acetic acid solution of prolamins as the continuous phase and deionized water as the dispersed phase. By adjusting the prolamin concentration and flow rates of microfluidics, the porous structure and morphology as well as diameters of microfibers can be well tailored. Owing to their porosity, the resultant microfibers can be employed as flexible delivery systems for wound healing actives, such as bacitracin and vascular endothelial growth factor (VEGF). It is demonstrated that the resultant hydrogel microfibers are with good cell-affinity and effective drug release efficiency, and their woven patches display superior in vivo capability in treating diabetes wounds. Thus, it is believed that the proposed prolamins-assembled porous hydrogel microfibers will show important values in clinic wound treatments.

Sprayable Multifunctional Black Phosphorus Hydrogel with On-Demand Removability for Joint Skin Wound Healing.

Wound healing remains a critical challenge in regenerative engineering. Great efforts are devoted to develop functional patches for wound healing. Herein, a novel sprayable black phosphorus (BP)-based multifunctional hydrogel with on-demand removability is presented as a joints' skin wound dressing. The hydrogel is facilely prepared by mixing dopamine-modified oxidized hyaluronic acid, cyanoacetategroup-functionalized dextran containing black phosphorus, and the catalyst histidine. The catechol-containing dopamine can not only enhance tissue adhesiveness, but also endow the hydrogel with antioxidant capacity. In addition, benefiting from the photothermal conversion ability of the BP and thermally reversible performance of the formed C═C double bonds between aldehyde groups and cyanoacetate groups, the resulting hydrogel displays excellent antibacterial performance and on-demand dissolving ability under NIR irradiation. Moreover, by loading vascular endothelial growth factor into the hydrogel, the promoted migration and angiogenesis effects of endothelial cells can also be achieved. Based on these features, it is demonstrated that such sprayable BP hydrogels can effectively facilitate joint wounds healing by accelerating angiogenesis, alleviating inflammation, and improving wound microenvironment. Thus, it is believed that this NIR-responsive removable BP hydrogel dressing will put forward an innovative concept in designing wound dressings.

Preparation and Application of Hemostatic Hydrogels.

Hemorrhage remains a critical challenge in various medical settings, necessitating the development of advanced hemostatic materials. Hemostatic hydrogels have emerged as promising solutions to address uncontrolled bleeding due to their unique properties, including biocompatibility, tunable physical characteristics, and exceptional hemostatic capabilities. In this review, a comprehensive overview of the preparation and biomedical applications of hemostatic hydrogels is provided. Particularly, hemostatic hydrogels with various materials and forms are introduced. Additionally, the applications of hemostatic hydrogels in trauma management, surgical procedures, wound care, etc. are summarized. Finally, the limitations and future prospects of hemostatic hydrogels are discussed and evaluated. This review aims to highlight the biomedical applications of hydrogels in hemorrhage management and offer insights into the development of clinically relevant hemostatic materials.

Pearl Powder Hybrid Bioactive Scaffolds from Microfluidic 3D Printing for Bone Regeneration.

The development of bioactive scaffolds by mimicking bone tissue extracellular matrix is promising for bone regeneration. Herein, inspired by the bone tissue composition, a novel pearl powder (PP) hybrid fish gelatin methacrylate (GelMa) hydrogel scaffold loaded with vascular endothelial growth factor (VEGF) for bone regeneration is presented. With the help of microfluidic-assisted 3D printing technology, the composition and structure of the hybrid scaffold can be accurately controlled to meet clinical requirements. The combination of fish skin GelMa and PP also endowed the hybrid scaffold with good biocompatibility, cell adhesion, and osteogenic differentiation ability. Moreover, the controlled release of VEGF enables the scaffold to promote angiogenesis. Thus, the bone regeneration in the proposed scaffolds could be accelerated under the synergic effect of osteogenesis and angiogenesis, which has been proved in the rat skull defect model. These features indicate that the PP hybrid scaffolds will be an ideal candidate for bone regeneration in clinical applications.

Multiple Bio-Actives Loaded Gellan Gum Microfibers from Microfluidics for Wound Healing.

Wound healing, known as a fundamental healthcare issue worldwide, has been attracting great attention from researchers. Here, novel bioactive gellan gum microfibers loaded with antibacterial peptides (ABPs) and vascular endothelial growth factor (VEGF) are proposed for wound healing by using microfluidic spinning. Benefitting from the high controllability of microfluidics, bioactive microfibers with uniform morphologies are obtained. The loaded ABPs are demonstrated to effectively act on bacteria at the wound site, reducing the risk of bacterial infection. Besides, sustained release of VEGF from microfibers helps to accelerate angiogenesis and further promote wound healing. The practical value of woven bioactive microfibers is demonstrated via animal experiments, where the wound healing process is greatly facilitated because of the excellent circulation of air and nutritious substances. Featured with the above properties, it is believed that the novel bioactive gellan gum microfibers would have a remarkable effect in the field of biomedical application, especially in promoting wound healing.

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.

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.

Nerve-on-a-Chip Derived Biomimicking Microfibers for Peripheral Nerve Regeneration.

Fibrous scaffolds have shown their advantages in tissue engineering, such as peripheral nerve regeneration, while most of the existing fiber-shaped scaffolds are with simple structures, and the in vitro performance for nerve regeneration lacks systematic analysis. Here, novel nerve-on-a-chip derived biomimicking microfibers for peripheral nerve regeneration are presented. The microfibers with controllable core-shell structures and functionalities are generated through capillary microfluidic devices. By integrating these microfibers into a multitrack-architectured chip, and coculturing them with nerve cells as well as gradient bioactive elements, the nerve-on-a-chip with the capabilities of systematically assessing the performances of nerve fiber formation in the hollow microfibers at in vitro level is constructed. Based on a rat sciatic nerve injury model, the rapid promotion ability is demonstrated of optimized microfibers in nerve regeneration and function recovery in vivo, which implies the credibility of the nerve-on-a-chip on biomimicking microfibers evaluation for peripheral nerve regeneration. Thus, it is convinced that the organ-on-a-chip will undoubtedly open up a new chapter in evaluating biological scaffolds for in vivo tissue engineering.

Erythrocyte-Inspired Functional Materials for Biomedical Applications.

Erythrocytes are the most abundant cells in the blood. As the results of long-term natural selection, their specific biconcave discoid morphology and cellular composition are responsible for gaining excellent biological performance. Inspired by the intrinsic features of erythrocytes, various artificial biomaterials emerge and find broad prospects in biomedical applications such as therapeutic delivery, bioimaging, and tissue engineering. Here, a comprehensive review from the fabrication to the applications of erythrocyte-inspired functional materials is given. After summarizing the biomaterials mimicking the biological functions of erythrocytes, the synthesis strategies of particles with erythrocyte-inspired morphologies are presented. The emphasis is on practical biomedical applications of these bioinspired functional materials. The perspectives for the future possibilities of the advanced erythrocyte-inspired biomaterials are also discussed. It is hoped that the summary of existing studies can inspire researchers to develop novel biomaterials; thus, accelerating the progress of these biomaterials toward clinical biomedical applications.

Microtubes with gradient decellularized porcine sciatic nerve matrix from microfluidics for sciatic nerve regeneration.

Long-range peripheral nerve defect is a severe and worldwide disease. With the increasing development of tissue engineering, the excellent ability of nerve extracellular matrix (ECM) in peripheral nerve injury (PNI) has been widely studied and verified. Here, we present a novel microtube that contains gradient decellularized porcine sciatic nerve ECM hydrogel (pDScNM-gel) from microfluidics for sciatic nerve regeneration. The pDScNM is confirmed to enhance cell proliferation and migration, and improve the axon growth of primary dorsal root ganglions (DRGs) in a concentration-related manner. These behaviors were also achieved when cells were co-cultured in a gradient pDScNM microtube. The in vivo sciatic nerve regeneration and functional recovery were also demonstrated by assembling the gradient pDScNM microtubes with a medical silicon tube. These results indicated that the microtubes with gradient pDScNM could act as a promising alternative for repairing peripheral nerve defects and showed great potential in clinical use.

Multifunctional GO Hybrid Hydrogel Scaffolds for Wound Healing.

Hydrogel dressings have received extensive attention for the skin wound repair, while it is still a challenge to develop a smart hydrogel for adapting the dynamic wound healing process. Herein, we develop a novel graphene oxide (GO) hybrid hydrogel scaffold with adjustable mechanical properties, controllable drug release, and antibacterial behavior for promoting wound healing. The scaffold was prepared by injecting benzaldehyde and cyanoacetate group-functionalized dextran solution containing GO into a collection pool of histidine. As the GO possesses obvious photothermal behavior, the hybrid hydrogel scaffold exhibited an obvious stiffness decrease and effectively promoted cargo release owing to the breaking of the thermosensitive C=C double bond at a high temperature under NIR light. In addition, NIR-assisted photothermal antibacterial performance of the scaffold could be also achieved with the local temperature rising after irradiation. Therefore, it is demonstrated that the GO hybrid hydrogel scaffold with vascular endothelial growth factor (VEGF) encapsulation can achieve the adjustable mechanical properties, photothermal antibacterial, and angiogenesis during the wound healing process. These features indicated that the proposed GO hybrid hydrogel scaffold is potentially valuable for promoting wound healing and other biomedical application.

Hierarchical Microparticles Delivering Oxaliplatin and NLG919 Nanoprodrugs for Local Chemo-immunotherapy.

Chemo-immunotherapy shows promising antitumor therapeutic outcomes for many primary cancers. Research in this area has been focusing on developing an ideal formula that enables the potent efficacy of chemo-immunotherapy in combating various cancers with reduced systemic toxicity. Herein, we present novel hierarchical hydrogel microparticles (MDDP) delivering oxaliplatin and NLG919 nanoprodrugs for local chemo-immunotherapy with desired features. The oxaliplatin prodrug and NLG919 were efficiently loaded in the dual-drug polymeric nanoparticles (DDP NPs), which were further encapsulated into a MDDP by using microfluidic technology. When delivered to the tumor site, the DDP NPs will be sustainedly released from the MDDP and retained locally to reduce systemic toxicity. After being endocytosed by cancer cells, the cytotoxic oxaliplatin and NLG919 could be successfully triggered to release from DDP NPs in a chain-shattering manner, leading to the immunogenic cell death (ICD) of tumor cells and the suppression of intratumoral immunosuppressive Tregs, respectively. With the assistance of an immune modulator, the chemotherapeutics-induced ICD could trigger robust systemic antitumor immune responses, presenting superior synergistic antitumor efficacies. Thus, the hierarchical microparticles could substantially inhibit the growth of mouse subcutaneous colorectal tumors, breast tumors, and colorectal tumors with large initial sizes via synergized chemo-immunotherapy, showing great potential in the practical clinical application of oncotherapy.

Histidine-Triggered GO Hybrid Hydrogels for Microfluidic 3D Printing.

Graphene oxide (GO) hydrogels have provided tremendous opportunities in designing and fabricating complex constructs for diverse applications, while their 3D printing without photocuring is still a challenging task due to their low viscosity, uncontrollable gelation, and low interfacial tension. Here, we report a histidine-assisted printing strategy to prepare GO hybrid hydrogels through the microfluidic 3D printing technique. We found that the GO additive could significantly hamper the Knoevenagel condensation (KC) reaction between benzaldehyde and cyanoacetate group-functionalized polymers to form a hydrogel, while these GO mixed solutions were rapidly solidified into a hydrogel when histidine was added. This fascinating phenomenon enabled us to prepare low-viscosity GO mixed polymer solutions as printable inks and generate hydrogel microfibers in histidine solutions. The hydrogel fibers could support cell survival and be further constructed into complex 3D structures through microfluidic 3D printing techniques. Moreover, due to the addition of GO, the microfibers exhibited excellent electrical conductivity and could sense the motion changes and convert these stimuli as electrical resistance signals. This strategy adds an option for the design and application of 3D printable aqueous GO inks in many fields.

Photopolymerized 3D Printing Scaffolds with Pt(IV) Prodrug Initiator for Postsurgical Tumor Treatment.

Biomedical scaffolds have shown great success in postsurgical tumor treatment; their current efforts are focusing on eradicating residual tumor cells and circulating tumor cells and simultaneously repairing postoperative tissue defects. Herein, we report a novel photopolymerized 3D scaffold with Pt(IV) prodrug initiator to achieve the desired features for tumor comprehensive therapy. The Pt-GelMA scaffold was fabricated from the microfluidic 3D printing of methacrylate gelatin (GelMA) bioinks through a Pt(IV)-induced photocrosslinked process without any other additional photoinitiator and chemotherapeutic drug. Thus, the resultant scaffold displayed efficient cell killing ability against breast cancer cells in vitro and significantly inhibited the local tumor growth and distant metastases on an orthotopic postoperative breast cancer model in vivo. Besides, benefiting from their ordered porous structures and favorable biocompatibility, the scaffolds supported the cell attachment, spreading, and proliferation of normal cells in vitro; could facilitate the nutrient transportation; and induced new tissue ingrowth for repairing tissue defects caused by surgery. These properties indicate that such 3D printing scaffold is a promising candidate for efficient postoperative tumor treatment in the practical application.

Microfluidic electrospray generation of porous magnetic Janus reduced graphene oxide/carbon composite microspheres for versatile adsorption.

HYPOTHESIS: Graphene-based microparticles materials are broadly utilized in all sorts of fields owing to their outstanding properties. Despite great progress, the present graphene microparticles still face challenges in the aspects of size uniformity, motion flexibility, and tailorable surface chemistry, which limit their application in some specific fields, such as versatile adsorption. Hence, the development of novel graphene microparticles with the aforementioned characteristics is urgently required. EXPERIMENTS: We presented a simple microfluidic electrospray strategy to generate magnetic Janus reduced graphene oxide/carbon (rGO/C) composite microspheres with a variety of unique features. Specifically, the microfluidic electrospray method endowed the obtaiend microspheres with sufficient size uniformity as well as magnetic responsive motion ability. Additionally, magnetic-mediated surface assembly of phase transition lysozyme (PTL) nanofilm on the microspheres rendered the deposited area hydrophilic while non-deposited area hydrophobic. FINDINGS: Such magnetic Janus rGO/C composite microspheres with regionalized wettability characteristics not only showed prominent performance in adsorbing organic liquids with high adsorption capacity and remarkable reusability but also displayed satisfying biocompatibility for the efficient uptake of bilirubin. More encouragingly, the microspheres could serve as adsorbents in a simulative hemoperfusion setup, which further demonstrated the clinical application potential of the magnetic Janus rGO/C microspheres. Thus, we anticipate that the obtained magnetic Janus rGO/C composite microspheres could show multifunctional properties toward water treatment and blood molecule cleaning.

Dynamically Responsive Scaffolds from Microfluidic 3D Printing for Skin Flap Regeneration.

Biological scaffolds hold promising perspectives for random skin flap regeneration, while the practical application is greatly limited by their insufficient vascularization ability and the lack of responsiveness during the dynamical healing process. Herein, a novel MXene-incorporated hollow fibrous (MX-HF) scaffold with dynamically responsive channels is presented for promoting vascularization and skin flap regeneration by using a microfluidic-assisted 3D printing strategy. Benefiting from the photothermal conversion capacity of the MXene nanosheets and temperature-responsive ability of poly(NIPAM) hydrogels in the MX-HF scaffolds, they display a near-infrared (NIR)-responsive shrinkage/swelling behavior, which facilitates the cell penetration into the scaffold channels from the surrounding environment. Moreover, by incorporating vascular endothelial growth factor (VEGF) into the hydrogel matrix for controllable delivery, the MX-HF scaffolds can achieve promoted proliferation, migration, and proangiogenic effects of endothelial cells under NIR irradiation. It is further demonstrated in vivo that the NIR-responsive VEGF@MX-HF scaffolds can effectively improve skin flap survival by promoting angiogenesis, decreasing inflammation, and attenuating apoptosis in skin flaps. Thus, it is believed that such responsive MX-HF scaffolds are promising candidates for clinical random skin flap regeneration as well as other diverse tissue engineering applications.