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1.
    
Photo-crosslinkable platelet lysate (PL)-based hydrogels have been proven to support human-derived cell cultures owing to their high content of bioactive molecules, such as cytokines and growth factors. As a unique self-maintained and biocompatible 3D scaffold, the recently reported self-feeding hydrogels with enzyme-empowered degradation capacity have shown high biological performance in vitro and in vivo. To take advantage of all features of both PL and self-feeding hydrogels, here UV responsive laminaran-methacrylate (LamMA) and PL-methacrylate (PLMA) derivatives plus glucoamylase (GA), which significantly improve the overall features of a 3D system, is coupled. This self-sustaining hybrid hydrogel emerges as a unique scaffold due to the sustained delivery of glucose produced via enzymatic degradation of laminaran while granting the release of growth factors through the presence of PL. This biomaterial is applied to fabricate high-throughput freestanding microgels with controlled geometric shapes. Furthermore, this multicomponent hybrid hydrogel is successfully implemented as the first reported glucose supplier bioink to manufacture intricate and precisely defined cell-laden structures using a support matrix. Finally, such hydrogels are utilized as a proof of concept to serve as 3D in vitro cancer models, with the aim of recapitulating the tumor microenvironment.  相似文献   

2.
    
“Organoid medicine” has rapidly progressed over the past decade as a new class of therapeutics with high functionality and complexity for addressing unmet medical needs such as effective treatment of patients suffering from chronic liver disease using liver organoids. Here, scalable and xeno-free integrated differentiation platforms are established to generate hepatic progenitors, mesenchymal stromal cells, and endothelial cells using individual human pluripotent stem cell lines as starting cell types for vascularized liver organoids generation. A scalable microfluidic system is developed to continuously generate cells-loaded microcapsules with self-biodegradable 4-arm-PEG-MMP1-sensitive peptide hydrogel as shell material, to support cells proliferation, self-condensation, and liver organoids generation through self-organization. Self-organized vascularized hepatobiliary organoids (VHOs) containing interconnected biliary networks and vascular structures are generated after optimizing the co-culture conditions inside hydrogel microcapsules and transferring the organoids to 3D dynamic suspension culture for further maturation. The VHOs show key functional features similar to the fetal and adult liver tissue including the expression of liver-specific marker genes, the ability to perform main liver metabolic functions, and inducing drug metabolism. The established platforms can be beneficial to the mass production of human liver organoids for liver organoid medicine and the development of safe, effective, and personalized drugs.  相似文献   

3.
    
Biological structures control cell behavior via physical, chemical, electrical, and mechanical cues. Approaches that allow us to build devices that mimic these cues in a combinatorial way are lacking due to there being no suitable instructive materials and limited manufacturing procedures. This challenge is addressed by developing a new conductive composite material, allowing for the fabrication of 3D biomimetic structures in a single manufacturing method based on two‐photon polymerization. The approach induces a combinatorial biostimulative input that can be tailored to a specific application. Development of the 3D architecture is performed with a chemically actuating photocurable acrylate previously identified for cardiomyocyte attachment. The material is made conductive by impregnation with multiwalled carbon nanotubes. The bioinstructive effect of 3D nano‐ and microtopography is combined with electrical stimulation, incorporating biochemical, and electromechanical cues to stimulate cells in serum‐free media. The manufactured architecture is combined with cardiomyocytes derived from human pluripotent stem cells. It is demonstrated that by mimicking biological occurring cues, cardiomyocyte behavior can be modulated. This represents a step change in the ability to manufacture 3D multifunctional biomimetic modulatory architectures. This platform technology has implications in areas spanning regenerative medicine, tissue engineering to biosensing, and may lead to more accurate models for predicting toxicity.  相似文献   

4.
    
To face the increasing demand of self‐healing hydrogels with biocompatibility and high performances, a new class of cellulose‐based self‐healing hydrogels are constructed through dynamic covalent acylhydrazone linkages. The carboxyethyl cellulose‐graft‐dithiodipropionate dihydrazide and dibenzaldehyde‐terminated poly(ethylene glycol) are synthesized, and then the hydrogels are formed from their mixed solutions under 4‐amino‐DL‐phenylalanine (4a‐Phe) catalysis. The chemical structure, as well as microscopic morphologies, gelation times, mechanical and self‐healing performances of the hydrogels are investigated with 1H NMR, Fourier transform infrared spectroscopy, atomic force microscopy, rheological and compression measurements. Their gelation times can be controlled by varying the total polymer concentration or 4a‐Phe content. The resulted hydrogels exhibit excellent self‐healing ability with a high healing efficiency (≈96%) and good mechanical properties. Moreover, the hydrogels display pH/redox dual responsive sol‐gel transition behaviors, and are applied successfully to the controlled release of doxorubicin. Importantly, benefitting from the excellent biocompatibility and the reversibly cross‐linked networks, the hydrogels can function as suitable 3D culture scaffolds for L929 cells, leading to the encapsulated cells maintaining a high viability and proliferative capacity. Therefore, the cellulose‐based self‐healing hydrogels show potential applications in drug delivery and 3D cell culture for tissue engineering.  相似文献   

5.
    
Considering the variations in burns depending on the circumstances that caused them, the need for personalized medicine and care for burn victims is vital to ensure that optimal treatment is provided. With the level of accuracy and customization that 3D printing brings as a technology, there is potential in its use to fabricate wound dressings that can provide better treatment for burn patients, provided that the material of choice has good printability and can be customized while facilitating wound healing. In this study, the versatility of chitosan methacrylate as said material to be used to fabricate customizable wound dressings via 3D printing is investigated. Synthesized chitosan methacrylate is evaluated to be printable, biodegradable, and biocompatible during wound healing. Various drugs relevant to the treatment of burns are then loaded and different multimaterial wound dressing designs containing different dosages are fabricated via 3D printing. The incorporation of said drugs does not significantly affect the printability of chitosan methacrylate, and the incorporation of antimicrobial agents significantly improves its antimicrobial capabilities. Through in vivo models, these variations in wound dressing designs have good wound healing properties and do not cause any adverse effects in the process.  相似文献   

6.
    
Effective therapies capable of simultaneously inhibiting inflammation and promoting bone healing remain to be developed for inflammatory bone disease. Stem cell therapies hold great promise for a variety of diseases, but their translation is hampered by low cell survival, rapid clearance, and limited functional integration of transplanted stem cells in target tissues. Herein, a multifunctional hydrogel-based stem cell niche engineering strategy is reported for the treatment of inflammatory bone loss. By rationally integrating different functional modules, an injectable hydrogel-based stem niche is engineered, which possesses temperature-triggered gelling performance, inflammation/oxidative stress-resolving activity, stem-cell binding and survival-enhancing capacity, and osteogenesis-promoting capability. Using ectomesenchymal stem cells (EMSCs), effectiveness of this functionally advanced synthetic stem cell niche is demonstrated in rats with periodontitis, a representative inflammatory bone loss disease. Synergistic effects of the multifunctional hydrogel and EMSCs are also confirmed, with respect to normalizing the pathological microenvironment and improving alveolar bone regeneration in the periodontal tissue. Mechanistically, inflammation/oxidative stress-resolving and osteogenic differentiation promoting capacities of the synthetic stem cell niche are mainly achieved by an incorporated nanotherapy via the GDF15/Atf3/c-Fos axis of the MAPK signaling pathway. Besides periodontitis, the newly engineered hydrogel-stem cell therapies are promising for the treatment of other inflammatory bone defects.  相似文献   

7.
    
Human induced pluripotent stem cells (hiPSCs) are used for drug discoveries, disease modeling and show great potential for human organ regeneration. 3D culture methods have been demonstrated to be an advanced approach compared to the traditional monolayer (2D) method. Here, a self-healing universal peptide hydrogel is reported for manufacturing physiologically formed hiPSC spheroids. With 100 000 hiPSCs encapsulated in 500 µL hydrogel, ≈50 000 spheroids mL−1 (diameter 20–50 µm) are generated in 5 d. The spheroids in the universal peptide hydrogel are viable (85–96%) and show superior pluripotency and differentiation potential based on multiple biomarkers. Cell performance is influenced by the degradability of the hydrogel but not by gel strength. Without postprinting crosslinking aided by UV or visible lights or chemicals, various patterns are easily extruded from a simple star to a kidney-like organ shape using the universal peptide hydrogel bioink showing acceptable printability. A 20.0 × 20.0 × 0.75 mm3 sheet is finally printed with the universal peptide hydrogel bioink encapsulating hiPSCs and cultured for multiple days, and the hiPSC spheroids are physiologically formed and well maintained.  相似文献   

8.
    
The foundation of regenerative medicine is the investigation and progression of hypotheses and approaches for substituting, mending, reconstructing, or regenerating different tissues and organs within the human body. Nevertheless, due to the slender central segment and the entire unattached configuration of the meniscus, the efficacy of conventional therapies is unsatisfactory in reinstating meniscal health and functionality. To overcome these limitations, medical-type hydrogels have the potential to provide a solution for meniscus repair and regeneration. Their biocompatibility and modifiability enable safe implantations in vivo, effectively modifying the pathophysiology of cells and the surrounding microenvironment at the site of meniscal injury. This article reviews the usage of different implantable medical-type hydrogels in meniscal regeneration and repair. First, the structure and physiologic function of the meniscus are first briefly described. Following this, the use of varying hydrogels in meniscus repair is highlighted, alongside a discussion of different materials employed in constructing hydrogel implants. Lastly, an analysis of the issues and challenges associated with hydrogels in meniscus repair is presented.  相似文献   

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10.
    
Microphysiological systems (MPSs), based on microfabrication technologies and cell culture, can faithfully recapitulate the complex physiology of various tissues. However, 3D tissues formed using MPS have limitations in size and accessibility; their use in regenerative medicine is, therefore, still challenging. Here, an MPS-inspired scale-up vascularized engineered tissue construct that can be used in regenerative medicine is designed. Endothelial cell-laden hydrogels are sandwiched between two through-hole membranes. The microhole array in the through-hole membranes enables the molecular transport across the hydrogel layer, allowing long-term cell culture. Furthermore, the time-controlled delamination of through-hole membranes enables the harvesting of cell-cultured hydrogel constructs without damaging the capillary network. Importantly, when the tissue constructs are implanted in a mouse ischemic model, they protect against necrosis and promoted functional recovery to a greater extent than implanted cells, hydrogels, and simple gel–cell mixtures.  相似文献   

11.
    
3D‐printing is emerging as a technology to introduce microchannels into hydrogels, for the perfusion of engineered constructs. Although numerous techniques have been developed, new techniques are still needed to obtain the complex geometries of blood vessels and with materials that permit desired cellular responses. Here, a printing process where a shear‐thinning and self‐healing hydrogel “ink” is injected directly into a “support” hydrogel with similar properties is reported. The support hydrogel is further engineered to undergo stabilization through a thiol‐ene reaction, permitting (i) the washing of the ink to produce microchannels and (ii) tunable properties depending on the crosslinker design. When adhesive peptides are included in the support hydrogel, endothelial cells form confluent monolayers within the channels, across a range of printed configurations (e.g., straight, stenosis, spiral). When protease‐degradable crosslinkers are used for the support hydrogel and gradients of angiogenic factors are introduced, endothelial cells sprout into the support hydrogel in the direction of the gradient. This printing approach is used to investigate the influence of channel curvature on angiogenic sprouting and increased sprouting is observed at curved locations. Ultimately, this technique can be used for a range of biomedical applications, from engineering vascularized tissue constructs to modeling in vitro cultures.  相似文献   

12.
    
Emerging soft ionotronics better match the human body mechanically and electrically compared to conventional rigid electronics. They hold great potential for human-machine interfaces, wearable and implantable devices, and soft machines. Among various ionotronic devices, ionic junctions play critical roles in rectifying currents as electrical p–n junctions. Existing ionic junctions, however, are limited in electrical and mechanical performance, and are difficult to fabricate and degrade. Herein, the design, fabrication, and characterization of tough transient ionic junctions fabricated via 3D ionic microgel printing is reported. The 3D printing method demonstrates excellent printability and allows one to fabricate ionic junctions of various configurations with high fidelity. By combining ionic microgels, degradable networks, and highly charged biopolymers, the ionic junctions feature high stretchability (stretch limit 27), high fracture energy (>1000 Jm−2), excellent electrical performance (current rectification ratio >100), and transient stability (degrade in 1 week). A variety of ionotronic devices, including ionic diodes, ionic bipolar junction transistors, ionic full-wave rectifiers, and ionic touchpads are further demonstrated. This study merges ionotronics, 3D printing, and degradable hydrogels, and will motivate the future development of high-performance transient ionotronics.  相似文献   

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14.
    
Stem cell–based therapies hold great promise in providing desirable solutions for diseases that cannot be effectively cured by conventional therapies. To maximize the therapeutic potentials, advanced cell tracking probes are essential to understand the fate of transplanted stem cells without impairing their properties. Herein, conjugated polymer (CP) nanodots are introduced as noninvasive fluorescent trackers with high brightness and low cytotoxicity for tracking of mesenchymal stem cells (MSCs) to reveal their in vivo behaviors. As compared to the most widely used commercial quantum dot tracker, CP nanodots show significantly better long‐term tracking ability without compromising the features of MSCs in terms of proliferation, migration, differentiation, and secretome. Fluorescence imaging of tissue sections from full‐thickness skin wound–bearing mice transplanted with CP nanodot‐labeled MSCs suggests that paracrine signaling of the MSCs residing in the regenerated dermis is the predominant contribution to promote skin regeneration, accompanied with a small fraction of endothelial differentiation. The promising results indicate that CP nanodots could be used as next generation of fluorescent trackers to reveal the currently ambiguous mechanisms in stem cell therapies through a facile and effective approach.  相似文献   

15.
    
Bone formation (osteogenesis) is a complex process in which cellular differentiation and the generation of a mineralized organic matrix are synchronized to produce a hybrid hierarchical architecture. To study the mechanisms of osteogenesis in health and disease, there is a great need for functional model systems that capture in parallel, both cellular and matrix formation processes. Stem cell-based organoids are promising as functional, self-organizing 3D in vitro models for studying the physiology and pathology of various tissues. However, for human bone, no such functional model system is yet available. This study reports the in vitro differentiation of human bone marrow stromal cells into a functional 3D self-organizing co-culture of osteoblasts and osteocytes, creating an organoid for early stage bone (woven bone) formation. It demonstrates the formation of an organoid where osteocytes are embedded within the collagen matrix that is produced by the osteoblasts and mineralized under biological control. Alike in in vivo osteocytes, the embedded osteocytes show network formation and communication via expression of sclerostin. The current system forms the most complete 3D living in vitro model system to investigate osteogenesis, both in physiological and pathological situations, as well as under the influence of external triggers (mechanical stimulation, drug administration).  相似文献   

16.
    
Many soft natural tissues display a fascinating set of mechanical properties that remains unmatched by manmade counterparts. These unprecedented mechanical properties are achieved through an intricate interplay between the structure and locally varying the composition of these natural tissues. This level of control cannot be achieved in soft synthetic materials. To address this shortcoming, a novel 3D printing approach to fabricate strong and tough soft materials is introduced, namely double network granular hydrogels (DNGHs) made from compartmentalized reagents. This is achieved with an ink composed of microgels that are swollen in a monomer-containing solution; after the ink is additive manufactured, these monomers are converted into a percolating network, resulting in a DNGH. These DNGHs are sufficiently stiff to repetitively support tensile loads up to 1.3 MPa. Moreover, they are more than an order of magnitude tougher than each of the pure polymeric networks they are made from. It is demonstrated that this ink enables printing macroscopic, strong, and tough objects, which can optionally be rendered responsive, with high shape fidelity. The modular and robust fabrication of DNGHs opens up new possibilities to design adaptive, strong, and tough hydrogels that have the potential to advance, for example, soft robotic applications.  相似文献   

17.
    
Progress in the discovery of potent antibodies for therapeutic and research purposes has been accelerated by mining the antibody repertoire of plasma cells and plasmablasts. Magnetic activated cell sorting (MACS) is a well recognized method for cell sorting, however, secreted IgGs rapidly diffuse away from cells, therefore requiring specialized technique to compartmentalize individual cells and capture their secretions for MACS isolation. To this end, a scalable method to prepare hydrogel-based microcontainers for single cell culture and subsequent sorting based on their secreted IgG products at high-throughput level are described. In situ crosslinkable microgels featuring tunable viscosity are fabricated to act as soft compartments that accommodate delicate primary cells and capture secreted proteins, while providing solid supports after solgel transition to enable immune recognition with chemically functionalized magnetic nanorods in aqueous medium for MACS separation. Splenocytes are sorted based on antigen-specific IgG production from mice immunized with an antibiotic target ceftriaxone sodium, enriching a population of 220 000 000 to 800 000 prevalence following sorting. This enrichment ratio is substantially higher than conventional fluorescence activated cell sorting (FACS) methods, likely due to the multivalency of the antigen-conjugated magnetic nanorods.  相似文献   

18.
    
Biomimetic scaffolds mimic important features of the extracellular matrix (ECM) architecture and can be finely controlled at the nano‐ or microscale for tissue engineering. Rational design of biomimetic scaffolds is based on consideration of the ECM as a natural scaffold; the ECM provides cells with a variety of physical, chemical, and biological cues that affect cell growth and function. There are a number of approaches available to create 3D biomimetic scaffolds with control over their physical and mechanical properties, cell adhesion, and the temporal and spatial release of growth factors. Here, an overview of some biological features of the natural ECM is presented and a variety of original engineering methods that are currently used to produce synthetic polymer‐based scaffolds in pre‐fabricated form before implantation, to modify their surfaces with biochemical ligands, to incorporate growth factors, and to control their nano‐ and microscale geometry to create biomimetic scaffolds are discussed. Finally, in contrast to pre‐fabricated scaffolds composed of synthetic polymers, injectable biomimetic scaffolds based on either genetically engineered‐ or chemically synthesized‐peptides of which sequences are derived from the natural ECM are discussed. The presence of defined peptide sequences can trigger in situ hydrogelation via molecular self‐assembly and chemical crosslinking. A basic understanding of the entire spectrum of biomimetic scaffolds provides insight into how they can potentially be used in diverse tissue engineering, regenerative medicine, and drug delivery applications.  相似文献   

19.
    
Advanced forms of hydrogels have many inherently desirable properties and can be designed with different structures and functions. In particular, bioresponsive multifunctional hydrogels can carry out sophisticated biological functions. These include in situ single-cell approaches, capturing, analysis, and release of living cells, biomimetics of cell, tissue, and tumor-specific niches. They can allow in vivo cell manipulation and act as novel drug delivery systems, allowing diagnostic, therapeutic, vaccination, and immunotherapy methods. In the present review of multitasking hydrogels, new approaches and devices classified into point-of-care testing (POCT), microarrays, single-cell/rare cell approaches, artificial membranes, biomimetic modeling systems, nanodoctors, and microneedle patches are summarized. The potentials and application of each format are critically discussed, and some limitations are highlighted. Finally, how hydrogels can enable an “all-in-one platform” to play a key role in cancer therapy, regenerative medicine, and the treatment of inflammatory, degenerative, genetic, and metabolic diseases is being looked forward to.  相似文献   

20.
    
Exploration of efficient antioxidase-like reactive oxygen nanobiocatalysts (ROBCs) is a major challenge in combating oxidative stress-related diseases. Herein, the molecularly well-defined Ru-porphyrin-networks (Ru-Por-Net)-based ROBCs with ultrafast and reversible redox-centers for catalytic elimination of reactive oxygen species (ROS) are reported. Owing to the large π-conjugated networks, Ru–N coordination structures, and unique electronic and redox properties of atomic Ru sites, the Ru-Por-Net-based ROBCs exhibit exceptional catalytic ROS-scavenging activities. It is considerably more efficient than recently reported state-of-the-art anti-ROS biocatalysts. Notably, a new nucleophilic attack pathway to eliminate H2O2 and produce O2 is proposed via theoretical calculations, and the desorption of the OO* process is identified as the rate-determining step of atomic Ru centers. Cellular studies reveal that the new ROBCs can efficiently secure the survival, adhesion, spreading, and differentiation of the stem cells in high-ROS-level microenvironments. In vivo rat periodontitis treatments further demonstrate their superior anti-ROS therapeutic effects. This study provides significant insights into the crucial functions of Ru–N coordinated porphyrin-networks in catalytic ROS-scavenging and offers a new strategy to engineer high-performance antioxidase-like nanobiocatalysts for stem cell-based therapies and inflammatory diseases.  相似文献   

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