Rapid-Fabricated and Recoverable Dual-Network Hydrogel with Inherently Anti-Bacterial Abilities for Potential Adhesive Dressings

To satisfy the ever-accelerated demands for advanced engineering biomaterials with excellent physicochemical properties, injectable and recoverable dual-network (DN) hydrogels based on poly(l -lysine)-graft-4-hydroxyphenylacetic acid (PLL-g-HPA) and Aga are constructed by simply mixing PLL-g-HPA/HRP and PLL-g-HPA/H₂O₂ in Aga through enzyme-catalyzed cross-linkage of PLL-g-HPA and temperature-adjusted sol-gel transition of Aga. The recoverable and injectable performances of hydrogels are attributed to the reversible sol-gel transitional feature of Aga and enzymatically cross-linked reaction of PLL-g-HPA. DN hydrogels have fast and adjusted gelation time, connective pore structure, superior formability, and good biocompatibility. The helically structural Aga network endows the hydrogels with good mechanical strength and superior stability in extreme condition. Schiff-base effect between amino in skin tissues and carbonyl formed by the oxidation of phenol groups in hydrogel imparts the hydrogels to promising tissue attachment. Bursting pressure assay illustrates that the bursting pressure (34.5 ± 2.4 kPa) for 13.6% DN hydrogel is much higher than arterial blood pressure (16 kPa). The incorporated cationic PLL-g-HPA gives the hydrogels remarkable antibacterial ability, which effectively prevents the bacterial infection. In conclusion, the DN hydrogel with good cytocompatibility, inherently antibacterial ability, tissue adhesion, and excellent stability in extreme environment is probably able to become a promising candidate as potential wound dressings.     

Surface-Triggered In Situ Gelation for Tunable Conformal Hydrogel Coating of Therapeutic Cells and Biomedical Devices

Hydrogel coatings have been proposed as a promising strategy to improve the biocompatibility of therapeutic cells and biomedical devices. However, developed coating methods are only applicable for simple geometries, typical sizes, and limited substrates. In addition, its applications in therapeutic cell encapsulation are hampered by inadequate construction of the hydrogel capsules such as off-center encapsulation, immense volume, and lack of control over the thickness of capsules. Here, a method called surface-triggered in situ gelation (STIG) for universal hydrogel coating of multiscale objects ranging from single cells to mini-organs to biomedical devices with arbitrary shapes and heterogeneous components is reported. By covering cells or devices with calcium carbonate particles, progressive propagation of alginate hydrogel from their surface under the stimulation of GDL is achieved. The thickness of the hydrogel layers can be easily controlled from several micrometers to hundreds of micrometers by adjusting the gelation time and the release rate of calcium ions. Importantly, STIG facilitates accurate, complete, and individual cell encapsulation, which potentially overcomes the pitfalls of conventional strategies. It is further proven that the low-cost and facile method can potentially lead to advances in different fields by rendering precisely controlled microscale alginate layers on a wide variety of biomedical substrates.     

Designing Microgels for Cell Culture and Controlled Assembly of Tissue Microenvironments

Micrometer‐sized hydrogels, termed microgels, are emerging as multifunctional platforms that can recapitulate tissue heterogeneity in engineered cell microenvironments. The microgels can function as either individual cell culture units or can be assembled into larger scaffolds. In this manner, individual microgels can be customized for single or multicell coculture applications, or heterogeneous populations can be used as building blocks to create microporous assembled scaffolds that more closely mimic tissue heterogeneities. The inherent versatility of these materials allows user‐defined control of the microenvironments, from the order of singly encapsulated cells to entire 3D cell scaffolds. These hydrogel scaffolds are promising for moving towards personalized medicine approaches and recapitulating the multifaceted microenvironments that exist in vivo.     

A Universal and Facile Approach for the Formation of a Protein Hydrogel for 3D Cell Encapsulation

A universal and facile approach to modifying proteins so that they can rapidly form hydrogel upon mixing with crosslinkers is presented. The concept of it is to introduce maleimide, which is highly reactive with dithiol‐containing crosslinkers via thiol‐ene click chemistry, onto proteins. Bovine serum albumin (BSA) is used as a model protein due to its good stability and low cost. The results here show that a protein hydrogel can be readily formed by blending modified BSA and resilin‐related peptide crosslinker solutions at a proper ratio. The hydrogel exhibits good elasticity and tunable mechanical as well as biochemical properties. Moreover, it allows convenient 3D cell encapsulation and shows good biocompatibility. Muscle cells embedded in the hydrogel are promoted to spread by incorporating arginyl‐glycyl‐aspartic acid (RGD)‐containing peptide into the system, thus warranting a bright future of it in regenerative medicine.     

A Single Component Conducting Polymer Hydrogel as a Scaffold for Tissue Engineering

Conducting polymers (CPs) have exciting potential as scaffolds for tissue engineering, typically applied in regenerative medicine applications. In particular, the electrical properties of CPs has been shown to enhance nerve and muscle cell growth and regeneration. Hydrogels are particularly suitable candidates as scaffolds for tissue engineering because of their hydrated nature, their biocompatibility, and their tissue‐like mechanical properties. This study reports the development of the first single component CP hydrogel that is shown to combine both electro‐properties and hydrogel characteristics. Poly(3‐thiopheneacetic acid) hydrogels were fabricated by covalently crosslinking the polymer with 1,1′‐carbonyldiimidazole (CDI). Their swelling behavior was assessed and shown to display remarkable swelling capabilities (swelling ratios up to 850%). The mechanical properties of the networks were characterized as a function of the crosslinking density and were found to be comparable to those of muscle tissue. Hydrogels were found to be electroactive and conductive at physiological pH. Fibroblast and myoblast cells cultured on the hydrogel substrates were shown to adhere and proliferate. This is the first time that the potential of a single component CP hydrogel has been demonstrated for cell growth, opening the way for the development of new tissue engineering scaffolds.     

Micropatterned Protein for Cell Adhesion through Phototriggered Charge Change in a Polyvinylpyrrolidone Hydrogel

Regulated immobilization of proteins on hydrogels allows for the creation of highly controlled microenvironments to meet the special requirements of cell biology and tissue engineering devices. Light is an ideal stimulus to regulate immobilization because it can be controlled in time, space, and intensity. Here, a photoresponsive hydrogel that enables the patterning of proteins by a combination of electrostatic adsorption and photoregulated charge change on a hydrogel is developed. It is based on a photosensitive cationic monomer ( CLA ), a coumarin caged lysine betaine zwitterion, incorporated into a polyvinylpyrrolidone ( PVP ) hydrogel, which can controllably change the charge from an adhesive positive state to an anti‐adhesive zwitterion state upon irradiation at 365 nm. With this strategy, the immobilization of proteins is regulated and cell adhesion is programmed on hydrogels on demand. This approach should open up new avenues for hydrogels in biomedical applications.     

Light-Activated Decellularized Extracellular Matrix-Based Bioinks for Volumetric Tissue Analogs at the Centimeter Scale

Tissue engineering requires not only tissue-specific functionality but also a realistic scale. Decellularized extracellular matrix (dECM) is presently applied to the extrusion-based 3D printing technology. It has demonstrated excellent efficiency as bioscaffolds that allow engineering of living constructs with elaborate microarchitectures as well as the tissue-specific biochemical milieu of target tissues and organs. However, dECM bioinks have poor printability and physical properties, resulting in limited shape fidelity and scalability. In this study, new light-activated dECM bioinks with ruthenium/sodium persulfate (dERS) are introduced. The materials can be polymerized via a dityrosine-based cross-linking system with rapid reaction kinetics and improved mechanical properties. Complicated constructs with high aspect ratios can be fabricated similar to the geometry of the desired constructs with increased shape fidelity and excellent printing versatility using dERS. Furthermore, living tissue constructs can be safely fabricated with excellent tissue regenerative capacity identical to that of pure dECM. dERS may serve as a platform for a wider biofabrication window through building complex and centimeter-scale living constructs as well as supporting tissue-specific performances to encapsulated cells. This capability of dERS opens new avenues for upscaling the production of hydrogel-based constructs without additional materials and processes, applicable in tissue engineering and regenerative medicine.     

A Hybrid Peptide Amphiphile Fiber PEG Hydrogel Matrix for 3D Cell Culture

Since the traditional 2D surface for cell growth has been shown to be increasingly insufficient in contemporary cell biology, more and more research is performed on 3D matrices that can better represent the natural extracellular matrix (ECM) in many aspects. To create such a complex nonuniform 3D matrix, four‐armed polyethylene glycol with azides and (1R,8S,9S)‐bicyclo[6.1.0]non‐4‐yn‐9‐yl groups is functionalized to form the hydrogel basis. Together with these, a matrix metalloproteinase cleavable peptide sequence as a functional motif is also built in to add degradability to the hydrogel. In addition, self‐assembled peptide amphiphile (PA) fibers containing a cellular binding peptide sequence (RGDS) are encapsulated in the hydrogel to mimic the natural fibrous structure of the ECM and to stimulate cell adhesion. Rheology studies confirm that the polymer dissolved in the PA fiber solution forms a stable hydrogel with acceptable mechanical properties (G′ = 3.8 kPa). In addition, it is shown that this hydrogel network is degradable under the action of a metalloproteinase enzyme. Finally, the hybrid hydrogel is used to culture and it is demonstrated that both HeLa cells and human mesenchymal stem cells show adherence, good viability, and a well‐spread shape inside the hybrid hydrogel after 5 days of incubation when all components are present.     

Tissue Adhesive Catechol‐Modified Hyaluronic Acid Hydrogel for Effective,Minimally Invasive Cell Therapy

Current hyaluronic acid (HA) hydrogel systems often cause cytotoxicity to encapsulated cells and lack the adhesive property required for effective localization of transplanted cells in vivo. In addition, the injection of hydrogel into certain organs (e.g., liver, heart) induces tissue damage and hemorrhage. In this study, we describe a bioinspired, tissue‐adhesive hydrogel that overcomes the limitations of current HA hydrogels through its improved biocompatibility and potential for minimally invasive cell transplantation. HA functionalized with an adhesive catecholamine motif of mussel foot protein forms HA‐catechol (HA‐CA) hydrogel via oxidative crosslinking. HA‐CA hydrogel increases viability, reduces apoptosis, and enhances the function of two types of cells (human adipose‐derived stem cells and hepatocytes) compared with a typical HA hydrogel crosslinked by photopolymerization. Due to the strong tissue adhesiveness of the HA‐CA hydrogel, cells are easily and efficiently transplanted onto various tissues (e.g., liver and heart) without the need for injection. Stem cell therapy using the HA‐CA hydrogel increases angiogenesis in vivo, leading to improved treatment of ischemic diseases. HA‐CA hydrogel also improved hepatic functions of transplanted hepatocytes in vivo. Thus, this bioinspired, tissue‐adhesive HA hydrogel can enhance the efficacy of minimally invasive cell therapy.     

All Biodisintegratable Hydrogel Biohybrid Neural Interfaces with Synergistic Performances of Microelectrode Array Technologies,Tissue Scaffolding,and Cell Therapy

Biohybrid neural interfaces (BHNIs) are a new class of neuromodulating devices that integrate neural microelectrode arrays (MEAs) and cell transplantation to improve treatment of nerve injuries and disorders. However, current BHNI devices are made from abiotic materials that are usually bio-passive, non-biodisintegratable, or rigid, which restricts encapsulated cell activity and host nerve reconstruction and frequently leads to local tissue inflammation. Herein, the first MEA composed of all disintegratable hydrogel tissue scaffold materials with synergistic performances of tissue conformal adhesiveness, MEA technologies, tissue scaffolding and stem cell therapy on a time scale appropriate for nerve tissue repair is proposed. In particular, the MEA conductive tracks are made from extracellular matrix (ECM)-based double-cross-linked dual-electrically conductive hydrogel (ECH) systems with robust tissue-mimicking chemical/physical properties, electrical conductivity, and an affinity for neural progenitor stem cells. Meanwhile, the MEA hydrogel substrate prepared from transglutaminase-incorporated gelatin/silk precursors simultaneously promotes gelation and interfacial adhesion between all MEA stacks, leading to rapid and scalable device integration. When the full hydrogel MEA is subjected to various mechanical stimuli and moisture, it is structurally stable with a low impedance (4 ± 3 kΩ) comparable to a recently reported benchmark. With seamless lamination around peripheral nerve fibers, the device permits successive neural signal monitoring for wound condition evaluation, while demonstrating synergistic effects of spatiotemporally controlled electrical stimulation and cell transplantation to accelerate restoration of motor function. This BHNI is completely degraded by 1 month thus eliminating the need for surgical retrieval to stably remain, interact, and further fuse with host tissues, successfully exhibiting compatible integration of biology and an implanted electrical system.     

A Printable Photopolymerizable Thermosensitive p(HPMAm‐lactate)‐PEG Hydrogel for Tissue Engineering

Bioprinting is a new technology in regenerative medicine that allows the engineering of tissues by specific placement of cells in biomaterials. Importantly, the porosity and the relatively small dimensions of the fibers allow rapid diffusion of nutrients and metabolites. This technology requires the availability of hydrogels that ensure viability of encapsulated cells and have adequate mechanical properties for the preparation of structurally stable and well‐defined three‐dimensional constructs. The aim of this study is to evaluate the suitability of a biodegradable, photopolymerizable and thermosensitive A–B–A triblock copolymer hydrogel as a synthetic extracellular matrix for engineering tissues by means of three dimensional fiber deposition. The polymer is composed of poly(N‐(2‐hydroxypropyl)methacrylamide lactate) A‐blocks, partly derivatized with methacrylate groups, and hydrophilic poly(ethylene glycol) B‐blocks of a molecular weight of 10 kDa. Gels are obtained by thermal gelation and stabilized with additional chemical cross‐links by photopolymerization of the methacrylate groups coupled to the polymer. A power law dependence of the storage plateau modulus of the studied hydrogels on polymer concentration is observed for both thermally and chemically cross‐linked hydrogels. The hydrogels demonstrated mechanical characteristics similar to natural semi‐flexible polymers, including collagen. Moreover, the hydrogel shows suitable mechanical properties for bioprinting, allowing subsequent layer‐by‐layer deposition of gel fibers to form stable constructs up to at least 0.6 cm (height) with different patterns and strand spacing. The resulting constructs have reproducible vertical porosity and the ability to maintain separate localization of encapsulated fluorescent microspheres. Moreover, the constructs show an elastic modulus of 119 kPa (25 wt% polymer content) and a degradation time of approximately 190 days. Furthermore, high viability is observed for encapsulated chondrocytes after 1 and 3 days of culture. In summary, we conclude that the evaluated hydrogel is an interesting candidate for bioprinting applications.     

Tissue Tapes—Phenolic Hyaluronic Acid Hydrogel Patches for Off‐the‐Shelf Therapy

Hydrogels have been applied to improve stem cell therapy and drug delivery, but current hydrogel‐based delivery methods are inefficient in clinical settings due to difficulty in handling and treatment processes, and low off‐the‐shelf availability. To overcome these limitations, an adhesive hyaluronic acid (HA) hydrogel patch is developed that acts as a ready‐to‐use tissue tape for therapeutic application. The HA hydrogel patches functionalized with phenolic moieties (e.g., catechol, pyrogallol) exhibit stronger tissue adhesiveness, greater elastic modulus, and increased off‐the‐shelf availability, compared with their bulk solution gel form. With this strategy, stem cells are efficiently engrafted onto beating ischemic hearts without injection, resulting in enhanced angiogenesis in ischemic regions and improving cardiac functions. HA hydrogel patches facilitate the in vivo engraftment of stem cell–derived organoids. The off‐the‐shelf availability of the hydrogel patch is also demonstrated as a drug‐loaded ready‐made tissue tape for topical drug delivery to promote wound healing. Importantly, the applicability of the cross‐linker‐free HA patch is validated for therapeutic cell and drug delivery. The study suggests that bioinspired phenolic adhesive hydrogel patches can provide an innovative method for simple but highly effective cell and drug delivery, increasing the off‐the‐shelf availability—a critically important component for translation to clinical settings.     

Injectable Self-Healing Natural Biopolymer-Based Hydrogel Adhesive with Thermoresponsive Reversible Adhesion for Minimally Invasive Surgery

Biocompatible hydrogel adhesives with multifunctional properties, including injectability, fast self-healing, and suitable on-demand detachment, are highly desired for minimally invasive procedures, but such materials are still lacking. Herein, an injectable self-healing biocompatible hydrogel adhesive with thermoresponsive reversible adhesion based on two extracellular matrix-derived biopolymers, gelatin and chondroitin sulfate, is developed to be used as a surgical adhesive for sealing or reconnecting ruptured tissues. The resulting hydrogels present good self-healing and can be conveniently injected through needles. The strong tissue adhesion at physiological temperatures originates from the Schiff base and hydrogen bonding interactions between the hydrogel and tissue that can be weakened at low temperatures, thereby easily detaching the hydrogel from the tissue in the gelation state. In vivo and ex vivo rat model show that the adhesives can effectively seal bleeding wounds and fluid leakages in the absence of sutures or staples. Specifically, a proof of concept experiment in a damaged rat liver model demonstrates the ability of the adhesives to act as a suitable laparoscopic sealant for laparoscopic surgery. Overall, the adhesive has several advantages, including low cost and ease of production and application that make it an exceptional multifunctional tissue adhesive/sealant, effective in minimally invasive surgical applications.     

A Self-Powered,Rechargeable, and Wearable Hydrogel Patch for Wireless Gas Detection with Extraordinary Performance

Flexible gas sensors play an indispensable role in diverse applications spanning from environmental monitoring to portable medical electronics. Full wearable gas monitoring system requires the collaborative support of high-performance sensors and miniaturized circuit module, whereas the realization of low power consumption and sustainable measurement is challenging. Here, a self-powered and reusable all-in-one NO₂ sensor is proposed by structurally and functionally coupling the sensor to the battery, with ultrahigh sensitivity (1.92%/ppb), linearity (R² = 0.999), ultralow theoretical detection limit (0.1 ppb), and humidity immunity. This can be attributed to the regulation of the gas reaction route at the molecular level. The addition of amphiphilic zinc trifluoromethanesulfonate (Zn(OTf)₂) enables the H₂O-poor inner Helmholtz layer to be constructed at the electrode–gel interface, thereby facilitating the direct charge transfer process of NO₂ here. The device is then combined with a well-designed miniaturized low-power circuit module with signal conditioning, processing and wireless transmission functions, which can be used as wearable electronics to realize early and remote warning of gas leakage. This study demonstrates a promising way to design a self-powered, sustainable, and flexible gas sensor with high performance and its corresponding wireless sensing system, providing new insight into the all-in-one system of gas detection.     

4D Printing of a Bioinspired Microneedle Array with Backward‐Facing Barbs for Enhanced Tissue Adhesion

Microneedle (MN), a miniaturized needle with a length‐scale of hundreds of micrometers, has received a great deal of attention because of its minimally invasive, pain‐free, and easy‐to‐use nature. However, a major challenge for controlled long‐term drug delivery or biosensing using MN is its low tissue adhesion. Although microscopic structures with high tissue adhesion are found from living creatures in nature (e.g., microhooks of parasites, barbed stingers of honeybees, quills of porcupines), creating MNs with such complex microscopic features is still challenging with traditional fabrication methods. Here, a MN with bioinspired backward‐facing curved barbs for enhanced tissue adhesion, manufactured by a digital light processing 3D printing technique, is presented. Backward‐facing barbs on a MN are created by desolvation‐induced deformation utilizing cross‐linking density gradient in a photocurable polymer. Barb thickness and bending curvature are controlled by printing parameters and material composition. It is demonstrated that tissue adhesion of a backward‐facing barbed MN is 18 times stronger than that of barbless MN. Also demonstrated is sustained drug release with barbed MNs in tissue. Improved tissue adhesion of the bioinspired MN allows for more stable and robust performance for drug delivery, biofluid collection, and biosensing.     

A Self-Sustaining Hydrogels with Autonomous Supply of Nutrients and Bioactive Domains for 3D Cell Culture

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.     

A Novel Double‐Crosslinking‐Double‐Network Design for Injectable Hydrogels with Enhanced Tissue Adhesion and Antibacterial Capability for Wound Treatment

Most photocrosslinkable hydrogels have inadequacy in either mechanical performance or biodegradability. This issue is addressed by adopting a novel hydrogel design by introducing two different chitosan chains (catechol‐modified methacryloyl chitosan, CMC; methacryloyl chitosan, MC) via the simultaneous crosslinking of carbon–carbon double bonds and catechol‐Fe³⁺ chelation. This leads to an interpenetrating network of two chitosan chains with high crosslinking‐network density, which enhances mechanical performance including high compressive modulus and high ductility. The chitosan polymers not only endow the hydrogels with good biodegradability and biocompatibility, they also offer intrinsic antibacterial capability. The quinone groups formed by Fe³⁺ oxidation and protonated amino groups of chitosan polymer further enhance antibacterial property of the hydrogels. Serving as one of the two types of crosslinking mechanisms, the catechol‐Fe³⁺ chelation can covalently link with amino, thiol, and imidazole groups, which substantially enhance the hydrogel's adhesion to biological tissues. The hydrogel's adhesion to porcine skin shows a lap shear strength of 18.1 kPa, which is 6‐time that of the clinically established Fibrin Glue's adhesion. The hydrogel also has a good hemostatic performance due to the superior tissue adhesion as demonstrated with a hemorrhaging liver model. Furthermore, the hydrogel can remarkably promote healing of bacteria‐infected wound.