Injectable,Micellar Chitosan Self-Healing Hydrogel for Asynchronous Dual-Drug Delivery to Treat Stroke Rats

Stroke is a common disease with high mortality worldwide. The endogenous neural regeneration during the intracerebral hemorrhage (ICH) stroke is restricted by the brain cavity, inflammation, cell apoptosis, and neural scar formation. Biomaterials serving as temporary supporting matrices are highly demanded as injectable implants for brain tissue regeneration. Herein, a chitosan micellar self-healing hydrogel (CM hydrogel) with comparable modulus (≈150 Pa) to brain, shape adaptability, and proper swelling (≈105%) is developed from phenolic chitosan (PC) and a micellar crosslinker (DPF). Two model drugs are individually packaged in the hydrophilic network and hydrophobic micelle cavities of CM hydrogel, and they feature asynchronous releasing kinetics, including a first-order rapid release for hydrophilic drug and a zero-order sustained release for hydrophobic drug. The dual-drug loaded CM (CMD) hydrogel delivers two clinical drugs corresponding to the anti-inflammatory and neurogenesis phases of the stroke to ICH rats through brain injection. The rats receiving CMD hydrogel show behavioral improvement (≈84% recovery) and balanced brain midline shift (≈0.98 left/right hemibrain ratio). Immunohistochemistry reveals neurogenesis (doublecortin- and nestin- positive cells) and evidence of angiogenesis (≈18 µm diameter vessels lined with CD31-positive cells). The injectable CMD hydrogel offers a novel asynchronous drug delivery platform for treating ICH stroke.     

Nanogel Encapsulated Hydrogels As Advanced Wound Dressings for the Controlled Delivery of Antibiotics

Biocompatible and degradable dual-delivery gel systems based on hyperbranched dendritic−linear−dendritic copolymers (HBDLDs) is herein conceptualized and accomplished via thiol-ene click chemistry. The elasticity of the hydrogels is tunable by varying the lengths of PEG (2, 6, 10 kDa) or the dry weight percentages (20, 30, 40 wt%), and are found to range from 2–14.7 kPa, comparable to human skin. The co-delivery of antibiotics is achieved, where the hydrophilic drug novobiocin sodium salt (NB) is entrapped within the hydrophilic hydrogel, while the hydrophobic antibiotic ciprofloxacin (CIP) is encapsulated within the dendritic nanogels (DNGs) with hydrophobic cores (DNGs-CIP). The DNGs-CIP with drug loading capacity of 2.83 wt% are then physically entrapped within the hybrid hydrogels through UV curing. The hybrid hydrogels enable the quick release of NB and prolonged released of CIP. In vitro cell infection assays showed that the antibiotic-loaded hybrid hydrogels are able to treat bacterial infections with significant bacterial reduction. Hybrid hydrogel band aids are fabricated and exhibited better antibacterial activity compared with commercial antimicrobial band aids. Remarkably, most hydrogels and hybrid hydrogels show enhanced human dermal cell proliferation and could be degraded into non-toxic constituents, showing great promise as wound dressing materials.     

Time Controlled Protein Release from Layer‐by‐Layer Assembled Multilayer Functionalized Agarose Hydrogels

Axons of the adult central nervous system exhibit an extremely limited ability to regenerate after spinal cord injury. Experimentally generated patterns of axon growth are typically disorganized and randomly oriented. Support of linear axonal growth into spinal cord lesion sites has been demonstrated using arrays of uniaxial channels, templated with agarose hydrogel, and containing genetically engineered cells that secrete brain‐derived neurotrophic factor (BDNF). However, immobilizing neurotrophic factors secreting cells within a scaffold is relatively cumbersome, and alternative strategies are needed to provide sustained release of BDNF from templated agarose scaffolds. Existing methods of loading the drug or protein into hydrogels cannot provide sustained release from templated agarose hydrogels. Alternatively, here it is shown that pH‐responsive H‐bonded poly(ethylene glycol)(PEG)/poly(acrylic acid)(PAA)/protein hybrid layer‐by‐layer (LbL) thin films, when prepared over agarose, provided sustained release of protein under physiological conditions for more than four weeks. Lysozyme, a protein similar in size and isoelectric point to BDNF, is released from the multilayers on the agarose and is biologically active during the earlier time points, with decreasing activity at later time points. This is the first demonstration of month‐long sustained protein release from an agarose hydrogel, whereby the drug/protein is loaded separately from the agarose hydrogel fabrication process.     

An Intelligent Transdermal Formulation of ALA-Loaded Copolymer Thermogel with Spontaneous Asymmetry by Using Temperature-Induced Sol–Gel Transition and Gel–Sol (Suspension) Transition on Different Sides

Aqueous solutions of some amphiphilic block copolymers undergo a sol–gel transition upon heating and are thus called thermogels. In the thermogel family, some systems also exhibit a gel–sol (suspension) transition at higher temperatures following the sol–gel transition, which is usually ignored in biomedical applications. Herein, for the first time, a case is reported employing both the sol–gel transition and the gel–sol (suspension) transition, which is found in the development of a transdermal hydrogel formulation containing 5-aminolevulinic acid for photodynamic therapy (PDT) of skin disease. Two poly(d ,l -lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(d ,l -lactide-co-glycolide) triblock copolymers of different block lengths are synthesized. The transition temperatures of the formulation can be easily adjusted to meet the condition of sol–gel transition temperature (T_gel) < room temperature (T_air) < gel–sol (suspension) temperature (T_{sol (suspension)}) < body temperature (T_body) via changing the blending ratio. Therefore, after applying to skin, formulation of spontaneous asymmetry with a hydrogel outside and a sol (suspension) inside can avoid free flowing and achieve rapid release to ensure an efficient PDT. This study demonstrates such a concept via characterizations of the “block blend” biomaterials and drug release profiles, and also via cell experiments, in vitro permeation, and in vivo transdermal delivery studies.     

Smart Hydrogels Co‐switched by Hydrogen Bonds and π–π Stacking for Continuously Regulated Controlled‐Release System

A series of hydrogels with continuously regulatable release behavior can be achieved by incorporating hydrogen bonding and π–π stacking co‐switches in polymers. A poly(nitrophenyl methacrylate‐co‐methacrylic acid) hydrogel (NPMAAHG) for control over drug release is fabricated by copolymerizing 4‐nitrophenyl methacrylate and methacrylic acid using ethylene glycol dimethacrylate as a crosslinker. The carboxylic acid groups and nitrylphenyl groups form hydrogen bonds and π–π stacking interactions, respectively, which act as switches to control the release of guest molecules from the polymers. As revealed by the simulated gastrointestinal tract drug release experiments, the as‐synthesized NPMAAHG hydrogels can be regulated to release only 4.7% of drugs after 3 h in a simulated stomach and nearly 92.6% within 43 h in the whole digestive tract. The relation between the release kinetics and structures and the mechanism of the smart release control are analyzed in terms of diffusion exponent, swelling interface number, drug diffusion coefficient, and velocity of the swelling interface in detail. The results reveal that the release of guest molecules from the hydrogels can be continuously regulated for systemic administration by controlling the ratio of the hydrophilic hydrogen bonds and the hydrophobic π–π stacking switches.     

Omniphobic ZIF‐8@Hydrogel Membrane by Microfluidic‐Emulsion‐Templating Method for Wound Healing

Bacterial adhesion and colonization can result in chronic non‐healing wounds. Current hydrophilic wound dressings can release antibacterial agents into the wound exudate, but may result in overhydrated wounds, bacterial overgrowth, and even tissue maceration. Hydrophobic dressings are anti‐fouling, though ineffective to encapsulate and release bactericidal agents. Combining the advantages of hydrophilic and hydrophobic dressings seems difficult, until the development of superwettability surfaces offers an opportunity for omniphobic dressings from intrinsic hydrophilic polymers. Herein, omniphobic porous hydrogel wound dressings loaded with a zinc imidazolate framework 8 (ZIF‐8) are fabricated by a microfluidic‐emulsion‐templating method. The fabricated porous hydrogel membrane with its reentrant architecture is repellent to blood and body fluids, though intrinsically hydrophilic. This unique combination not only reduces the adhesion of harmful microbes, but also enables the encapsulation and release of antibacterial ingredients to wounded sites from hydrophilic polymer networks. As such, the omniphobic metal‐organic frameworks (MOFs)@hydrogel porous wound dressing can inhibit bacteria invasion and enable the controlled release of the bactericidal, anti‐inflammatory, and nontoxic zinc ions. Furthermore, in vivo study of infected full‐thickness skin defect models demonstrates that the dressing also accelerates wound closure by promoting angiogenesis and collagen deposition. Therefore, the omniphobic MOFs@hydrogel porous wound dressings are potentially useful for clinical application.     

Dendron‐Based Micelles for Topical Delivery of Endoxifen: A Potential Chemo‐Preventive Medicine for Breast Cancer

Endoxifen (EDX) is an active metabolite of tamoxifen that has been proven effective in the prevention and treatment of estrogen‐positive breast cancer; however, oral administration of tamoxifen often causes severe side effects. Here, the topical delivery of EDX is explored using polymeric micelles to achieve localized drug delivery with potentially minimal side effects. EDX is encapsulated into dendron micelles (DM) with various surface groups (‐NH₂, ‐COOH, or ‐Ac) and into cationic liposomes as a control. End‐group modification significantly affects the drug loading, where the DM‐COOH micelles allow the most efficient encapsulation. Furthermore, unlike the burst release from the liposomes, all DMs show sustained release of EDX over 6 days. Each formulation is evaluated for its potential to deliver EDX across the skin layers. DMs substantially enhance the permeation of EDX through both mouse (up to 20‐fold) and human (up to 4‐fold) skin samples relative to ethanol, a chemical penetration enhancer. Franz diffusion cell experiments reveal that DM‐COOH induces the highest flux of EDX among all groups. The enhanced drug loading, controlled release profiles, and enhanced skin permeation all demonstrate that DMs are a useful platform for the topical delivery of EDX, offering a potential alternative administration route for chemoprevention.     

Thermo-Responsive Microcapsules with Tunable Molecular Permeability for Controlled Encapsulation and Release

Microcapsules with regulated transmembrane transport are of great importance for various applications. The membranes with a tunable cut-off threshold of permeation provide advanced functionality. Here, thermo-responsive microcapsules are designed, whose hydrogel membrane shows a tunable cut-off threshold of permeation with temperature. To produce the microcapsules, water-in-oil-in-water (W/O/W) double-emulsion droplets are microfluidically produced, whose oil shell contains oil-soluble hydrogel precursor of poly(N, N-diethylacrylamide) copolymerized with benzophenone (PDEAM-BP). The PDEAM hydrogels, crosslinked by BP, show volume-phase transition around 34 °C, which makes the microcapsules with the PDEAM hydrogel membrane thermo-responsive. The microcapsules show temperature-dependent changes in radius and membrane thickness. More importantly, the cut-off threshold of permeation can be reversibly adjusted by temperature control as the degree of swelling decreases with temperature. This enables the molecule-selective encapsulation and the controlled release of the encapsulants in a programmed manner by adjusting the temperature. The microcapsules can be rendered to be photo-responsive by encapsulating photothermal polydopamine nanoparticles during the microfluidic operation, which allows the control of the degree of swelling with near-infrared (NIR) irradiation. The thermo- and photo-responsive microcapsules with a tunable cut-off threshold are appealing as a new platform for drug carriers, microreactors, and microsensors.     

Magnetic Living Hydrogels for Intestinal Localization,Retention, and Diagnosis

Natural microbial sensing circuits can be rewired into new gene networks to build living sensors that detect and respond to disease-associated biomolecules. However, synthetic living sensors, once ingested, are cleared from the gastrointestinal (GI) tract within 48 h; retaining devices in the intestinal lumen is prone to intestinal blockage or device migration. To localize synthetic microbes and safely extend their residence in the GI tract for health monitoring and sustained drug release, an ingestible magnetic hydrogel carrier is developed to transport diagnostic microbes to specific intestinal sites. The magnetic living hydrogel is localized and retained by attaching a magnet to the abdominal skin, resisting the peristaltic waves in the intestine. The device retention is validated in a human intestinal phantom and an in vivo rodent model, showing that the ingestible hydrogel maintains the integrated living bacteria for up to seven days, which allows the detection of heme for GI bleeding in the harsh environment of the gut. The retention of microelectronics is also demonstrated by incorporating a temperature sensor into the magnetic hydrogel carrier.     

Bio-Inspired Stimuli-Responsive Ti3C2Tx/PNIPAM Anisotropic Hydrogels for High-Performance Actuators

Near-infrared (NIR) light-responsive hydrogels have the advantages of high precision, remote control and excellent biocompatibility, which are widely used in soft biomimetic actuators. The process by which water molecules diffuse can directly affect the deformation of hydrogel. Therefore, it remains a serious challenge to improve the response speed of hydrogel actuator. Herein, an anisotropic photo-responsive conductive hydrogel is designed by a directional freezing method. Due to the anisotropy of the MXene-based PNIPAM/MXene directional (PMD) hydrogel, its mechanical properties and conductivity are enhanced in a specific direction. At the same time, with the presence of the internal directional channels and the assistance of capillary force, the PMD hydrogel can achieve a volume deswelling of 70% in 2 s under light irradiation, further building a hydrogel actuator with a fast response performance. Additionally, the hydrogel actuator can lift an object 40 times its weight by a distance of 6 mm, realizing the advantages of both rapid responsiveness and high driving strength, which makes the hydrogel actuator have important application significance in remote control, microflow valve, and soft robot.     

Superior Synergistic Osteogenesis of MXene-Based Hydrogel through Supersensitive Drug Release at Mild Heat

Near-infrared (NIR) responsive smart drug delivery systems could provide efficient osteogenesis through the synergy of heat and drugs. However, such systems are hampered by an inability to allow supersensitive drug release through mild heat. Here superior osteogenesis is demonstrated using a biocompatible dexamethasone (Dex)-loaded MXene-poly(N-isopropylacrylamide)-co-N-(Hydroxymethyl) acrylamide hydrogel capable of the supersensitive release of Dex at ≈42 °C upon NIR irradiation. Furthermore, the hydrogel can significantly promote bone regeneration under NIR irradiation due to the synergistic anti-apoptosis and osteogenic differentiation of bone-derived mesenchymal stem cells induced by the mild heat and supersensitive release of Dex. The resulting osteogenesis efficiency of hydrogels surpass efficiencies previously reported for heat and drug stimulation and their combination. The synergistic osteogenesis strategy is characterized by near-instantaneous, noninvasive, and precise treatment through temporal NIR irradiation.     

Multifunctional Nanoparticle Loaded Injectable Thermoresponsive Hydrogel as NIR Controlled Release Platform for Local Photothermal Immunotherapy to Prevent Breast Cancer Postoperative Recurrence and Metastases

For breast cancer patients who have undergone breast‐conserving surgery, effective treatments to prevent local recurrences and metastases is very essential. Here, a local injectable therapeutic platform based on a thermosensitive PLEL hydrogel with near‐infrared (NIR)‐stimulated drug release is developed to achieve synergistic photothermal immunotherapy for prevention of breast cancer postoperative relapse. Self‐assembled multifunctional nanoparticles (RIC NPs) are composed of three therapeutic components including indocyanine green, a photothermal agent; resiquimod (R848), a TLR‐7/8 agonist; and CPG ODNs, a TLR‐9 agonist. RIC NPs are physically incorporated into the thermosensitive PLEL hydrogel. The RIC NPs encapsulated PLEL hydrogel (RIC NPs@PLEL) is then locally injected into the tumor resection cavity for local photothermal therapy to ablate residue tumor tissues and produce tumor‐associated antigens. At the same time, NIR also triggers the release of immune components CPG ODNs and R848 from thermoresponsive hydrogels PLEL. The released immune components, together with tumor‐associated antigens, work as an in situ cancer vaccine for postsurgical immunotherapy by inducing effective and sustained antitumor immune effect. Overall, this work suggests that photothermal immunotherapy based on local hydrogel delivery system has great potential as a promising tool for the postsurgical management of breast cancer to prevent recurrences and metastases.     

Versatile Functionalization of the Micropatterned Hydrogel of Hyperbranched Poly(ether amine) Based on “Thiol‐yne” Chemistry

The functionalization of a hydrogel with target molecules is one of the key steps in its various applications. Here, a versatile approach is demonstrated to functionalize a micropatterned hydrogel, which is formed by “thiol‐yne” photo‐click reaction between the yne‐ended hyperbranched poly(ether amine) (hPEA‐yne) and thiol‐containing polyhedral oligomeric silsesquioxane (PEG‐POSS‐SH). By controlling the molar ratio between hPEA‐yne and PEG‐POSS‐SH, patterned hydrogels containing thiol or yne groups are obtained. A series of thiol‐based click chemistry such as “thiol‐epoxy”, “thiol‐halogen”, “thiol‐ene”, and “thiol‐isocyanate” are used to functionalize the thiol‐containing hydrogel (Gel‐1), while the yne‐containing hydrogel (Gel‐2) is functionalized through a typical copper‐catalysed alkyne‐azide reaction (CuAAC). FTIR, UV‐vis spectra and confocal laser scanning microscopy (CLSM) are used to trace these click reactions. Due to the selective adsorption to the hydrophilic dyes, the obtained patterned hydrogel of hPEA modified with fluorescence dye is further demonstrated in application for the recognition of guest molecules.     

Encapsulating a Hydrophilic Chemotherapeutic into Rod‐Like Nanoparticles of a Genetically Encoded Asymmetric Triblock Polypeptide Improves Its Efficacy

Encapsulating hydrophilic chemotherapeutics into the core of polymeric nanoparticles can improve their therapeutic efficacy by increasing their plasma half‐life, tumor accumulation, and intracellular uptake, and by protecting them from premature degradation. To achieve these goals, a recombinant asymmetric triblock polypeptide (ATBP) that self‐assembles into rod‐shaped nanoparticles, and which can be used to conjugate diverse hydrophilic molecules, including chemotherapeutics, into their core is designed. These ATBPs consist of three segments: a biodegradable elastin‐like polypeptide, a hydrophobic tyrosine‐rich segment, and a short cysteine‐rich segment, that spontaneously self‐assemble into rod‐shaped micelles. Covalent conjugation of a structurally diverse set of hydrophilic small molecules, including a hydrophilic chemotherapeutic—gemcitabine—to the cysteine residues also leads to formation of nanoparticles over a range of ATBP concentrations. Gemcitabine‐loaded ATBP nanoparticles have significantly better tumor regression compared to free drug in a murine cancer model. This simple strategy of encapsulation of hydrophilic small molecules by conjugation to an ATBP can be used to effectively deliver a range of water‐soluble drugs and imaging agents in vivo.     

CelloMOF: Nanocellulose Enabled 3D Printing of Metal–Organic Frameworks

3D printing is recognized as a powerful tool to develop complex geometries for a variety of materials including nanocellulose. Herein, a one‐pot synthesis of 3D printable hydrogel ink containing zeolitic imidazolate frameworks (ZIF‐8) anchored on anionic 2,2,6,6‐tetramethylpiperidine‐1‐oxylradical‐mediated oxidized cellulose nanofibers (TOCNF) is presented. The synthesis approach of ZIF‐8@TOCNF (CelloZIF8) hybrid inks is simple, fast (≈30 min), environmentally friendly, takes place at room temperature, and allows easy encapsulation of guest molecules such as curcumin. Shear thinning properties of the hybrid hydrogel inks facilitate the 3D printing of porous scaffolds with excellent shape fidelity. The scaffolds show pH controlled curcumin release. The synthesis route offers a general approach for metal–organic frameworks (MOF) processing and is successfully applied to other types of MOFs such as MIL‐100 (Fe) and other guest molecules as methylene blue. This study may open new venues for MOFs processing and its large‐scale applications.     

Charge Booster Tags for Controlled Release of Therapeutics from a Therapeutic Carrier

Injectable hydrogels are promising delivery vehicles for the sustained release of therapeutic proteins. Electrostatic interactions between proteins and hydrogels often increase affinity to decelerate protein release. However, this approach is not suitable for weakly charged proteins. The current study shows that the genetic fusion of a highly charged protein segment (charge booster tag) with proteins can control their interactions with injectable gels. A positive or negative charge booster tag is introduced into urate oxidase (UOX), a therapeutic protein for gout, to generate UOX variants with varying net charges. When a positively-charged injectable hydrogel is used, both the in vitro release rate and in vivo serum half-life of UOX are correlated with the net negative charge. This modified delivery approach results in a serum half-life of over 106 h for the UOX variant, which is substantially longer than that of free UOX (3.3 h). Hence, charge booster tags can be used as a systematic strategy for controlling the release of therapeutic proteins.     

Reversible Phase Change-Induced Hardening and Softening for Conditions-Adaptive and Mechanics-Reconfigurable Applications

The mechanical soft–hard transition of hydrogels is desired in conditions-adaptive deformation and mechanics reconfiguration applications. However, highly efficient, stimuli-responsive, and reversible transition strategies are hard to achieve. Inspired by the supercooling of salt-aqueous solutions, solid and supersaturated hydrogels are prepared based on a hydrophilic polymer network and salt-aqueous solution. The inner crystallization- or melting-induced reversible phase-change realizes the switch between the soft hydrogel (modulus: 0.1 MPa) and rigid composite (modulus: 24.0 MPa). The soft and supersaturated hydrogels easily deform to achieve diverse new 3D models and the unfamiliar soft–hard transition makes temporary shapes be efficiently fixed (hardening). Interestingly, the initial hydrogel's shapes can be regenerated relying on the resilience of the polyacrylamide network when the crystal is melted (softening). Shape memory, complex surface morphology replication, rapid mold application, and self-supporting laminated glass are accomplished by this unique crystallization-melting introduced soft–hard transition. This phase change soft-hard switching strategy will broaden the functionalities of hydrogels.     

Universal Peptide Hydrogel for Scalable Physiological Formation and Bioprinting of 3D Spheroids from Human Induced Pluripotent Stem Cells

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.     

Multifunctional Nanobiomaterials for Neural Interfaces

Neural electrodes are designed to interface with the nervous system and provide control signals for neural prostheses. However, robust and reliable chronic recording and stimulation remains a challenge for neural electrodes. Here, a novel method for the fabrication of soft, low impedance, high charge density, and controlled releasing nanobiomaterials that can be used for the surface modification of neural microelectrodes to stabilize the electrode/tissue interface is reported. The fabrication process includes electrospinning of anti‐inflammatory drug‐incorporated biodegradable nanofibers, encapsulation of these nanofibers by an alginate hydrogel layer, followed by electrochemical polymerization of conducting polymers around the electrospun drug‐loaded nanofibers to form nanotubes and within the alginate hydrogel scaffold to form cloud‐like nanostructures. The three‐dimensional conducting polymer nanostructures significantly decrease the electrode impedance and increase the charge capacity density. Dexamethasone release profiles show that the alginate hydrogel coating slows down the release of the drug, significantly reducing the burst effect. These multifunctional materials are expected to be of interest for a variety of electrode/tissue interfaces in biomedical devices.     

Novel Biocompatible Polysaccharide‐Based Self‐Healing Hydrogel

A novel biocompatible polysaccharide‐based self‐healing hydrogel, CEC‐l‐OSA‐l‐ADH hydrogel (“l” means “linked‐by”), is developed by exploiting the dynamic reaction of N‐carboxyethyl chitosan (CEC) and adipic acid dihydrazide (ADH) with oxidized sodium alginate (OSA). The self‐healing ability, as demonstrated by rheological recovery, macroscopic observation, and beam‐shaped strain compression measurement, is attributed to the coexistence of dynamic imine and acylhydrazone bonds in the hydrogel networks. The CEC‐l‐OSA‐l‐ADH hydrogel shows excellent self‐healing ability under physiological conditions with a high healing efficiency (up to 95%) without need for any external stimuli. In addition, the CEC‐l‐OSA‐l‐ADH hydrogel exhibits good cytocompatibility and cell release as demonstrated by three‐dimensional cell encapsulation. With these superior properties, the developed hydrogel holds great potential for applications in various biomedical fields, e.g., as cell or drug delivery carriers.