Electrically Conductive Hydrogel Nerve Guidance Conduits for Peripheral Nerve Regeneration

Peripheral nerve injuries are serious conditions, and surgical treatment has critical limitations. Therefore, nerve guidance conduits (NGCs) are proposed as an alternative. In this study, multifunctional NGCs are fabricated for the regeneration of injured peripheral nerves. Graphene oxide (GO) and gelatin‐methacrylate (GelMA) are polymerized and chemically reduced to form reduced (GO/GelMA) (r(GO/GelMA)). The prepared materials present good electrical conductivity, flexibility, mechanical stability, and permeability, which are suitable for use as NGCs. In vitro studies show 2.1‐ and 1.4‐fold promotion of neuritogenesis of PC12 neuronal cells on r(GO/GelMA) compared to GelMA and unreduced GO/GelMA, respectively. Animal studies using a rat sciatic nerve injury model with a 10 mm gap between the proximal and distal regions of the defect reveal that r(GO/GelMA) NGCs significantly enhance peripheral nerve regeneration, indicated by improved muscle weight increase, electro‐conduction velocity, and sciatic nerve function index. Specifically, r(GO/GelMA) NGCs are utilized to potentiate regrowth with myelination in rat sciatic nerves followed by histological, immunohistological, and morphometrical analyses. This study successfully shows the feasibility of electrically conductive hydrogel NGCs as functional conduits for improved nerve regeneration in a preclinical study, where these NGCs can not only mimic nerve tissues but also strongly promote nerve regeneration.     

Two-Dimensional-Germanium Phosphide-Reinforced Conductive and Biodegradable Hydrogel Scaffolds Enhance Spinal Cord Injury Repair

Developing biodegradable conductive hydrogels is of great importance for the repair of electroactive tissues, such as myocardium, skeletal muscle, and nerves. However, conventional conductive phase incorporation in composite hydrogels, such as polypyrrole, polyaniline, carbon nanotubes, graphene, and gold nanowires, which are non-degradable materials, will exist in the body as foreign matter. Herein, an injectable hydrogel based on the integration of conductive and biodegradable germanium phosphide (GeP) nanosheets into an adhesive hyaluronic acid-graft-dopamine (HA-DA) hydrogel matrix is explored, and the successful application of this biohybrid hydrogel in spinal cord injury (SCI) repair is demonstrated. The incorporation of polydopamine (PDA)-modified GeP nanosheets (GeP@PDA) into HA-DA hydrogel matrix significantly improves the conductivity of HA-DA/GeP@PDA hydrogels. The conductive HA-DA/GeP@PDA hydrogels can accelerate the differentiation of neural stem cells (NSC) into neurons in vitro. In a rat SCI complete transection model, the in vivo implanted HA-DA/GeP@PDA hydrogel is found to improve the recovery of locomotor function significantly. The immunohistofluorescence investigation suggests that the HA-DA/GeP@PDA hydrogels promote immune regulation, endogenous angiogenesis, and endogenous NSC neurogenesis in the lesion area. The strategy of integrating conductive and biodegradable GeP nanomaterials into an injectable hydrogel provides new insight into designing advanced biomaterials for SCI repair.     

Electroconductive and Immunomodulatory Natural Polymer-Based Hydrogel Bandages Designed for Peripheral Nerve Regeneration

Successful regeneration of the peripheral nerve relies on the collaborative efforts of neural cells and immune cells. Conductive hydrogels have yielded promising results in supporting axonal growth; however, their inability to regulate the immune response and their poor biological integration with tissues hinder the repair of injured peripheral nerves. Herein, an adhesive conductive immunomodulatory nerve hydrogel bandage is developed for nerve regeneration. The nerve bandage hydrogel is prepared from the bioactive material extracellular matrix (ECM), oxidized polysaccharides, and poly(3,4-ethylenedioxythiophene)/poly(styrenesulfonate) (PEDOT:PSS) by self-assembly and dynamic Schiff base cross-linking. The drug indole-3-propionic acid (IPA) is loaded into nerve bandages and contributes to the rapid chemotaxis of neutrophils in the dorsal root ganglia and modulation of the immune system. In addition, the conductive hydrogel bandage exhibits close conformal contact with the injured nerve, forming a stable and tightly coupled electrical bridge with the electroresponsive neural tissue. In summary, the nerve bandage effectively promote nerve regeneration and enable both anatomical and functional recovery of neural tissue while preventing muscle atrophy. This work provides a new strategy for peripheral nerve regeneration and may have critical clinical applications in the future.     

Tissue Beads: Tissue‐Specific Extracellular Matrix Microbeads to Potentiate Reprogrammed Cell‐Based Therapy

Microbeads have been utilized as efficient cell culture carriers and injectable scaffolds for cell transplantation. However, various polymers currently used to generate microbeads have limited applicability due to loss of biological functions and tissue‐specific effects. Here, a tissue bead platform is reported that can provide a tissue‐specific microenvironment to facilitate cell culture and potentiate cell therapy. Using a flow‐focusing microfluidic device, uniform‐sized tissue microbeads are fabricated with extracellular matrix (ECM) from various decellularized tissues. The tissue microbeads are tested for tissue‐specific encapsulation of induced hepatic (iHep), induced cardiac (iCar), and induced myogenic (iMyo) cells, which are directly reprogrammed from mouse primary fibroblasts. Tissue‐specific microbeads significantly enhanced the viability, lineage‐specific maturation, and functionality of each type of reprogrammed cell, as compared to functionality when using conventional microbeads from a single ECM component (collagen). Finally, tissue microbeads are confirmed to mediate the successful in vivo engraftment of reprogrammed cells (iHep and iMyo) after transplantation, potentiating cell therapy and promoting functional tissue regeneration in tissue defective animal models. The study suggests that the use of a decellularized tissue matrix combined with a microfluidic technique can be employed to produce tissue‐specific ECM microbeads with increased versatility and efficacy for reprogrammed cell‐based therapy.     

Dual Stimuli‐Responsive Supramolecular Polypeptide‐Based Hydrogel and Reverse Micellar Hydrogel Mediated by Host–Guest Chemistry

Versatile strategies are currently being discovered for the fabrication of synthetic polypeptide‐based hybrid hydrogels, which have potential applications in polymer therapeutics and regenerative medicine. Herein, a new concept—the reverse micellar hydrogel—is introduced, and a versatile strategy is provided for fabricating supramolecular polypeptide‐based normal micellar hydrogel and reverse micellar hydrogels from the same polypeptide‐based copolymer via the cooperation of host–guest chemistry and hydrogen‐bonding interactions. The supramolecular hydrogels are thoroughly characterized, and a mechanism for their self‐assembly is proposed. These hydrogels can respond to dual stimuli—temperature and pH—and their mechanical and controlled drug‐release properties can be tuned by the copolymer topology and the polypeptide composition. The reverse micellar hydrogel can load 10% of the anticancer drug doxorubicin hydrochloride (DOX) and sustain DOX release for 45 days, indicating that it could be useful as an injectable drug delivery system.     

pH‐Based Regulation of Hydrogel Mechanical Properties Through Mussel‐Inspired Chemistry and Processing

The mechanical holdfast of the mussel, the byssus, is processed at acidic pH yet functions at alkaline pH. Byssi are enriched in Fe³⁺ and catechol‐containing proteins, species with chemical interactions that vary widely over the pH range of byssal processing. Currently, the link between pH, Fe³⁺‐catechol reactions, and mechanical function is poorly understood. Herein, it is described how pH influences the mechanical performance of materials formed by reacting synthetic catechol polymers with Fe³⁺. Processing Fe³⁺‐catechol polymer materials through a mussel‐mimetic acidic‐to‐alkaline pH change leads to mechanically tough materials based on a covalent network fortified by sacrificial Fe³⁺‐catechol coordination bonds. These findings offer the first direct evidence of Fe³⁺‐induced covalent cross‐linking of catechol polymers, reveal additional insight into the pH dependence and mechanical role of Fe³⁺‐catechol interactions in mussel byssi, and illustrate the wide range of physical properties accessible in synthetic materials through mimicry of mussel‐protein chemistry and processing.     

A Highly Elastic and Rapidly Crosslinkable Elastin‐Like Polypeptide‐Based Hydrogel for Biomedical Applications

Elastin‐like polypeptides (ELPs) are promising for biomedical applications due to their unique thermoresponsive and elastic properties. ELP‐based hydrogels have been produced through chemical and enzymatic crosslinking or photocrosslinking of modified ELPs. Herein, a photocrosslinked ELP gel using only canonical amino acids is presented. The inclusion of thiols from a pair of cysteine residues in the ELP sequence allows disulfide bond formation upon exposure to UV light, leading to the formation of a highly elastic hydrogel. The physical properties of the resulting hydrogel such as mechanical properties and swelling behavior can be easily tuned by controlling ELP concentrations. The biocompatibility of the engineered ELP hydrogels is shown in vitro as well as corroborated in vivo with subcutaneous implantation of hydrogels in rats. ELP constructs demonstrate long‐term structural stability in vivo, and early and progressive host integration with no immune response, suggesting their potential for supporting wound repair. Ultimately, functionalized ELPs demonstrate the ability to function as an in vivo hemostatic material over bleeding wounds.     

Delivery of iPS‐NPCs to the Stroke Cavity within a Hyaluronic Acid Matrix Promotes the Differentiation of Transplanted Cells

Stroke is the leading cause of adult disability with ≈80% being ischemic. Stem cell transplantation has been shown to improve functional recovery. However, the overall survival and differentiation of these cells is still low. The infarct cavity is an ideal location for transplantation as it is directly adjacent to the highly plastic peri‐infarct region. Direct transplantation of cells near the infarct cavity has resulted in low cell viability. Here, neural progenitor cells derived from induce pluripotent stem cells (iPS‐NPC) are delivered to the infarct cavity of stroked mice encapsulated in a hyaluronic acid hydrogel matrix to protect the cells. To improve the overall viability of transplanted cells, each step of the transplantation process is optimized. Hydrogel mechanics and cell injection parameters are investigated to determine their effects on the inflammatory response of the brain and cell viability, respectively. Using parameters that balanced the desire to keep surgery invasiveness minimal and cell viability high, iPS‐NPCs are transplanted to the stroke cavity of mice encapsulated in buffer or the hydrogel. While the hydrogel does not promote stem cell survival one week post‐transplantation, it does promote differentiation of the neural progenitor cells to neuroblasts.     

Light‐Induced Swelling‐Responsive Conductive,Adhesive, and Stretchable Wireless Film Hydrogel as Electronic Artificial Skin

Light‐induced wireless soft electronic skin hydrogels with excellent mechanical and electronic properties are important for several applications, such as soft robotics and intelligent wearable devices. Precise control of reversible stretchability and capacitive properties depending on intermolecular interaction and surface characteristics remains a challenge. Here, a thin‐film hydrogel is designed based on titanium oxide (TiO₂) polydopamine–perfluorosilica carbon dot‐conjugated chitosan–polyvinyl alcohol‐loaded tannic acid with controllable hydrophobic–hydrophilic transition in the presence of UV–vis light irradiation. The shifting of surface wettability from hydrophobic to hydrophilic by irradiation affects thin‐film water permeability and swelling ratio. This allows the penetration of water into the matrix to change its mechanical strength, electronic properties, and adhesive behavior. Specifically, the hydrogel displays mechanical strain as high as 278% in response to light stimuli and demonstrates the ability to regain its initial state determining the elasticity of the fabricated material. Moreover, the thin‐film hydrogel shows an increase in conductivity to 1.096 × 10^?3 and 1.026 × 10^?3 S cm^?1 when irradiated with UV and visible light, respectively. The hydrogel exhibits capacitive reversibility that follows finger motion which can be identified directly or remotely using wireless connection, indicative of its possible applications as an artificial electronic skin.     

Black‐Phosphorus‐Incorporated Hydrogel as a Conductive and Biodegradable Platform for Enhancement of the Neural Differentiation of Mesenchymal Stem Cells

Conductive hydrogel scaffolds have important applications for electroactive tissue repairs. However, the development of conductive hydrogel scaffolds tends to incorporate nonbiodegradable conductive nanomaterials that will remain in the human body as foreign matters. Herein, a biodegradable conductive hybrid hydrogel is demonstrated based on the integration of black phosphorus (BP) nanosheets into the hydrogel matrix. To address the challenge of applying BP nanosheets in tissue engineering due to its intrinsic instability, a polydopamine (PDA) modification method is developed to improve the stability. Moreover, PDA modification also enhances interfacial bonding between pristine BP nanosheets and the hydrogel matrix. The incorporation of polydopamine‐modified black phosphorous (BP@PDA) nanosheets into the gelatin methacryloyl (GelMA) hydrogels significantly enhances the electrical conductivity of the hydrogels and improves the cell migration of mesenchymal stem cells (MSCs) within the 3D scaffolds. On the basis of the gene expression and protein level assessments, the BP@PDA‐incorporated GelMA scaffold can significantly promote the differentiation of MSCs into neural‐like cells under the synergistic electrical stimulation. This strategy of integrating biodegradable conductive BP nanomaterials within a biocompatible hydrogel provides a new insight into the design of biomaterials for broad applications in tissue engineering of electroactive tissues, such as neural, cardiac, and skeletal muscle tissues.     

A Double‐Layer Mechanochromic Hydrogel with Multidirectional Force Sensing and Encryption Capability

Hydrogel‐based soft mechanochromic materials that display colorimetric changes upon mechanical stimuli have attracted wide interest in sensors and display device applications. A common strategy to produce mechanochromic hydrogels is through photonic structures, in which mechanochromism is obtained by strain‐dependent diffraction of light. Here, a distinct concept and simple fabrication strategy is presented to produce luminescent mechanochromic hydrogels based on a double‐layer design. The two layers contain different luminescent species—carbon dots and lanthanide ions—with overlapped excitation spectra and distinct emission spectra. The mechanochromism is rendered by strain‐dependent transmittance of the top‐layer, which regulates light emission from the bottom‐layer to control the overall hydrogel luminescence. An analytical model is developed to predict the initial luminescence color and color changes as a function of uniaxial strain. Finally, this study demonstrates proof‐of‐concept applications of the mechanochromic hydrogel for pressure and contact force sensors as well as for encryption devices.     

Hydrogel Scaffolds of Amphiphilic and Acidic β‐Sheet Peptides

Amphiphilic and acidic β‐sheet‐forming peptides (AAβPs) having the sequence Pro‐Y‐(Z‐Y)₅‐Pro, Y = Glu or Asp and Z = Phe or Leu may assemble into hydrogel structures at near neutral pH values, several units higher than the intrinsic pKa of their acidic amino acid side chains. The bottom‐to‐top design strategy enables the rationally supported association between the peptides' amino acids composition and bulk pH hydrogelation. Hydrogen bonds between the acidic amino acids side chains in the β‐sheet structure are found to contribute substantially to the stabilization of AAβPs hydrogels. The negatively charged peptides are also found to form gels at lower concentration in presence of calcium ions. Bone forming cells may be cultured on two‐dimensional films of AAβPs hydrogels that form at physiological pH values as well as within three dimensional hydrogel matrices. These acidic‐rich peptides hydrogels may become advantageous in applications related to engineering of mineralized tissues providing controllable, multifunctional calcified scaffolds to affect both the biological activity and the inorganic mineralization.     

A Highly Stretchable Cross‐Linked Polyacrylamide Hydrogel as an Effective Binder for Silicon and Sulfur Electrodes toward Durable Lithium‐Ion Storage

Despite the recent advancement in the in‐practical active materials (e.g., silicon, sulfur) in the rechargeable lithium‐ion energy storage systems, daunting challenges still remain for these high‐capacity electrode material candidates to overcome the severe volume changes associated with the repeated lithiation/delithiation process. Herein, developing a room‐temperature covalently cross‐linked polyacrylamide (c‐PAM) binder with high stretchability and abundant polar groups targeting the construction of high‐performance Si and sulfur electrodes is focused on. The robust 3D c‐PAM binder network enables not only significant enhancement of the strain resistance for working electrodes but also strong affinity to bonding with nano‐Si surface as well as effective capture of the soluble Li₂S_n intermediates, thereby giving rise to remarkably improved cycling performances in both types of electrodes. This rational design of such an effective and multifunctional binder offers a pathway toward advanced energy storage implementations.     

3D Printed Stem‐Cell Derived Neural Progenitors Generate Spinal Cord Scaffolds

A bioengineered spinal cord is fabricated via extrusion‐based multimaterial 3D bioprinting, in which clusters of induced pluripotent stem cell (iPSC)‐derived spinal neuronal progenitor cells (sNPCs) and oligodendrocyte progenitor cells (OPCs) are placed in precise positions within 3D printed biocompatible scaffolds during assembly. The location of a cluster of cells, of a single type or multiple types, is controlled using a point‐dispensing printing method with a 200 µm center‐to‐center spacing within 150 µm wide channels. The bioprinted sNPCs differentiate and extend axons throughout microscale scaffold channels, and the activity of these neuronal networks is confirmed by physiological spontaneous calcium flux studies. Successful bioprinting of OPCs in combination with sNPCs demonstrates a multicellular neural tissue engineering approach, where the ability to direct the patterning and combination of transplanted neuronal and glial cells can be beneficial in rebuilding functional axonal connections across areas of central nervous system (CNS) tissue damage. This platform can be used to prepare novel biomimetic, hydrogel‐based scaffolds modeling complex CNS tissue architecture in vitro and harnessed to develop new clinical approaches to treat neurological diseases, including spinal cord injury.     

Alginate Hydrogel Microencapsulation Inhibits Devitrification and Enables Large‐Volume Low‐CPA Cell Vitrification

Cryopreservation of stem cells is important to meet their ever‐increasing demand by the burgeoning cell‐based medicine. The conventional slow freezing for stem cell cryopreservation suffers from inevitable cell injury associated with ice formation and the vitrification (i.e., no visible ice formation) approach is emerging as a new strategy for cell cryopreservation. A major challenge to cell vitrification is intracellular ice formation (IIF, a lethal event to cells) induced by devitrification (i.e., formation of visible ice in previously vitrified solution) during warming the vitrified cells at cryogenic temperature back to super‐zero temperatures. Consequently, high and toxic concentrations of penetrating cryoprotectants (i.e., high CPAs, up to ≈8 m ) and/or limited sample volumes (up to ≈2.5 μL) have been used to minimize IIF during vitrification. It is revealed that alginate hydrogel microencapsulation can effectively inhibit devitrification during warming. The data show that if ice formation were minimized during cooling, IIF is negligible in alginate hydrogel microencapsulated cells during the entire cooling and warming procedure of vitrification. This enables vitrification of pluripotent and multipotent stem cells with up to ≈4 times lower concentration of penetrating CPAs (up to 2 m , low CPA) in up to ≈100 times larger sample volume (up to ≈250 μL, large volume).     

A Macroporous Hydrogel Dressing with Enhanced Antibacterial and Anti‐Inflammatory Capabilities for Accelerated Wound Healing

Here, a novel macroporous hydrogel dressing is presented that can accelerate wound healing and guard against bacteria‐associated wound infection. Carboxymethyl agarose (CMA) is successfully prepared from agarose. The CMA molecular chains are cross‐linked by hydrogen bonding to form a supramolecular hydrogel, and the hydroxy groups in the CMA molecules complex with Ag⁺ to promote hydrogel formation. This hydrogel composite exhibits pH‐responsiveness and temperature‐responsiveness and releases Ag⁺, an antibacterial agent, over a prolonged period of time. Moreover, this hydrogel exhibits outstanding cytocompatibility and hemocompatibility. In vitro and in vivo investigations demonstrate that the hydrogel has enhanced antibacterial and anti‐inflammatory capabilities and can significantly accelerate skin tissue regeneration and wound closure. Astonishingly, the hydrogel can cause the inflammation process to occur earlier and for a shorter amount of time than in a normal process. Given its excellent antibacterial, anti‐inflammatory, and physicochemical properties, the broad application of this hydrogel in bacteria‐associated wound management is anticipated.     

Ultrasensitive,Low‐Voltage Operational,and Asymmetric Ionic Sensing Hydrogel for Multipurpose Applications

Current artificial tactile sensors mostly exploit a variety of electron‐related physical mechanisms to obtain high sensitivity and low detection force. However, these mechanisms are still distinct from the ion‐related biological processes of human's tactile sensation, and are therefore away from the goal of bionic applications. In the past few years, only several types of ionic tactile sensors have been proposed, and they are still subject to low sensitivity. Here, a novel type of ultrasensitive hydrogel tactile sensor is reported based on asymmetric ionic charge injection as the working mechanism, named as asymmetric ionic sensing hydrogel (AISH). With a small external working voltage of only tens of millivolts, these AISH devices show an extremely low detection force of 0.075 Pa, ultrahigh sensitivity of 57–171 kPa^?1, and excellent cycling reliability upon pressing. Applications of these ultrasensitive tactile sensors in fingerprint identification of voice, monitoring of pulse waves, and detection of underwater wave signals are experimentally demonstrated. Combining the merits of simple fabrication process, ionic‐type detection mechanism, and ion injection procedure, such AISH sensors not only reveal a new strategy toward highly sensitive tactile sensors, but also show realistic potential applications in future wearable electronic and bioelectronic devices.     

Wet‐Responsive,Reconfigurable, and Biocompatible Hydrogel Adhesive Films for Transfer Printing of Nanomembranes

This study presents a wet‐responsive and biocompatible smart hydrogel adhesive that exhibits switchable and controllable adhesions on demand for the simple and efficient transfer printing of nanomembranes. The prepared hydrogel adhesives show adhesion strength as high as ≈191 kPa with the aid of nano‐ or microstructure arrays on the surface in the dry state. When in contact with water, the nano/microscopic and macroscopic shape reconfigurations of the hydrogel adhesive occur, which turns off the adhesion (≈0.30 kPa) with an extremely high adhesion switching ratio (>640). The superior adhesion behaviors of the hydrogels are maintained over repeating cycles of hydration and dehydration, indicating their ability to be used repeatedly. The adhesives are made of a biocompatible hydrogel and their adhesion on/off can be controlled with water, making the adhesives compatible with various materials and surfaces, including biological substrates. Based on these smart adhesion capabilities, diverse metallic and semiconducting nanomembranes can be transferred from donor substrates to either rigid or flexible surfaces including biological tissues in a reproducible and robust fashion. Transfer printing of a nanoscale crack sensor onto a bovine eye further demonstrates the potential of the reconfigurable hydrogel adhesive for use as a stimuli‐responsive, smart, and versatile functional adhesive for nanotransfer printing.     

A Biomimetic Mussel‐Inspired ε‐Poly‐l‐lysine Hydrogel with Robust Tissue‐Anchor and Anti‐Infection Capacity

In situ hydrogels have attracted considerable attention in tissue engineering because of their minimal invasiveness and ability to match the irregular tissue defects. However, hydrous physiological environments and the high level of moisture in hydrogels severely hamper binding to the target tissue and easily cause wound infection, thereby limiting the effectiveness in wound care management. Thus, forming an intimate assembly of the hydrogel to the tissue and preventing wound infecting still remains a significant challenge. In this study, inspired by mussel adhesive protein, a biomimetic dopamine‐modified ε‐poly‐l ‐lysine‐polyethylene glycol‐based hydrogel (PPD hydrogel) wound dressing is developed in situ using horseradish peroxidase cross‐linking. The biomimetic catechol–Lys residue distribution in PPD polymer provides a catechol–Lys cooperation effect, which endows the PPD hydrogels with superior wet tissue adhesion properties. It is demonstrated that the PPD hydrogel can facilely and intimately integrate with biological tissue and exhibits superior capacity of in vivo hemostatic and accelerated wound repair. In addition, the hydrogels exhibit outstanding anti‐infection property because of the inherent antibacterial ability of ε‐poly‐l ‐lysine. These findings shed new light on the development of mussel‐inspired tissue‐anchored and antibacterial hydrogel materials serving as wound dressings.