Ascidian‐Inspired Fast‐Forming Hydrogel System for Versatile Biomedical Applications: Pyrogallol Chemistry for Dual Modes of Crosslinking Mechanism

Exploitation of unique biochemical and biophysical properties of marine organisms has led to the development of functional biomaterials for various biomedical applications. Recently, ascidians have received great attention, owing to their extraordinary properties such as strong underwater adhesion and rapid self‐regeneration. Specific polypeptides containing 3,4,5‐trihydroxyphenylalanine (TOPA) in the blood cells of ascidians are associated with such intrinsic properties generated through complex oxidative processes. In this study, a bioinspired hydrogel platform is developed, demonstrating versatile applicability for tissue engineering and drug delivery, by conjugating pyrogallol (PG) moiety resembling ascidian TOPA to hyaluronic acid (HA). The HA–PG conjugate can be rapidly crosslinked by dual modes of oxidative mechanisms using an oxidant or pH control, resulting in hydrogels with different mechanical and physical characteristics. The versatile utility of HA–PG hydrogels formed via different crosslinking mechanisms is tested for different biomedical platforms, including microparticles for sustained drug delivery and tissue adhesive for noninvasive cell transplantation. With extraordinarily fast and different routes of PG oxidation, ascidian‐inspired HA–PG hydrogel system may provide a promising biomaterial platform for a wide range of biomedical applications.     

Functional Nanomaterials on 2D Surfaces and in 3D Nanocomposite Hydrogels for Biomedical Applications

An emerging approach to improve the physicobiochemical properties and the multifunctionality of biomaterials is to incorporate functional nanomaterials (NMs) onto 2D surfaces and into 3D hydrogel networks. This approach is starting to generate promising advanced functional materials such as self‐assembled monolayers (SAMs) and nanocomposite (NC) hydrogels of NMs with remarkable properties and tailored functionalities that are beneficial for a variety of biomedical applications, including tissue engineering, drug delivery, and developing biosensors. A wide range of NMs, such as carbon‐, metal‐, and silica‐based NMs, can be integrated into 2D and 3D biomaterial formulations due to their unique characteristics, such as magnetic properties, electrical properties, stimuli responsiveness, hydrophobicity/hydrophilicity, and chemical composition. The highly ordered nano‐ or microscale assemblies of NMs on surfaces alter the original properties of the NMs and add enhanced and/or synergetic and novel features to the final SAMs of the NM constructs. Furthermore, the incorporation of NMs into polymeric hydrogel networks reinforces the (soft) polymer matrix such that the formed NC hydrogels show extraordinary mechanical properties with superior biological properties.     

In Vivo Examination of an Injectable Hydrogel System Crosslinked by Peptide–Oligosaccharide Interaction in Immunocompetent Nude Mice

Hydrogels can serve as matrices to mimic natural tissue function and be used for wide‐ranging applications such as tissue regeneration and drug delivery. Injectable hydrogels are particularly favorable because their uses are minimally invasive. However, creating moldable substance for injection often results in compromised function and stability. This study reports an injectable hydrogel system crosslinked by peptide–oligosaccharide noncovalent interaction. The dynamic network shows fast self‐healing, a property essential for injectability. Injected hydrogels in immunocompetent mice and release of encapsulated compound are monitored up to 9 months by magnetic resonance imaging (MRI) and optical imaging. This surprisingly stable hydrogel does not cause adverse inflammatory response, as analyzed by measuring cytokine levels, immunohistochemistry, and MRI. Hydrogel degradation is associated with invasion of macrophages and vascular formation. The facile synthesis, high biocompatibility, and stability of this injectable hydrogel can lead to various experimental and clinical applications in regenerative medicine and drug delivery.     

Biodegradable Polymer Crosslinker: Independent Control of Stiffness,Toughness, and Hydrogel Degradation Rate

Hydrogels are being increasingly studied for use in various biomedical applications including drug delivery and tissue engineering. The successful use of a hydrogel in these applications greatly relies on a refined control of the mechanical properties including stiffness, toughness, and the degradation rate. However, it is still challenging to control the hydrogel properties in an independent manner due to the interdependency between hydrogel properties. Here it is hypothesized that a biodegradable polymeric crosslinker would allow for decoupling of the dependency between the properties of various hydrogel materials. This hypothesis is examined using oxidized methacrylic alginate (OMA). The OMA is synthesized by partially oxidizing alginate to generate hydrolytically labile units and conjugating methacrylic groups. It is used to crosslink poly(ethylene glycol) methacrylate and poly(N‐hydroxymethyl acrylamide) to form three‐dimensional hydrogel systems. OMA significantly improves rigidity and toughness of both hydrogels as compared with a small molecule crosslinker, and also controls the degradation rate of hydrogels depending on the oxidation degree, without altering their initial mechanical properties. The protein‐release rate from a hydrogel and subsequent angiogenesis in vivo are thus regulated with the chemical structure of OMA. Overall, the results of this study suggests that the use of OMA as a crosslinker will allow the implantation of a hydrogel in tissue subject to an external mechanical loading with a desired protein‐release profile. The OMA synthesized in this study will be, therefore, highly useful to independently control the mechanical properties and degradation rate of a wide array of hydrogels.     

Inherent Photodegradability of Polymethacrylate Hydrogels: Straightforward Access to Biocompatible Soft Microstructures

Hydrogels are important functional materials useful for 3D cell culture, tissue engineering, 3D printing, drug delivery, sensors, or soft robotics. The ability to shape hydrogels into defined 3D structures, patterns, or particles is crucial for biomedical applications. Here, the rapid photodegradability of commonly used polymethacrylate hydrogels is demonstrated without the need to incorporate additional photolabile functionalities. Hydrogel degradation depths are quantified with respect to the irradiation time, light intensity, and chemical composition. It can be shown that these parameters can be utilized to control the photodegradation behavior of polymethacrylate hydrogels. The photodegradation kinetics, the change in mechanical properties of polymethacrylate hydrogels upon UV irradiation, as well as the photodegradation products are investigated. This approach is then exploited for microstructuring and patterning of hydrogels including hydrogel gradients as well as for the formation of hydrogel particles and hydrogel arrays of well‐defined shapes. Cell repellent but biocompatible hydrogel microwells are fabricated using this method and used to form arrays of cell spheroids. As this method is based on readily available and commonly used methacrylates and can be conducted using cheap UV light sources, it has vast potential to be applied by laboratories with various backgrounds and for diverse applications.     

Spatiotemporally Controlled Photoresponsive Hydrogels: Design and Predictive Modeling from Processing through Application

Photoresponsive hydrogels (PRHs) are soft materials whose mechanical and chemical properties can be tuned spatially and temporally with relative ease. Both photo‐crosslinkable and photodegradable hydrogels find utility in a range of biomedical applications that require tissue‐like properties or programmable responses. Progress in engineering with PRHs is facilitated by the development of theoretical tools that enable optimization of their photochemistry, polymer matrices, nanofillers, and architecture. This review brings together models and design principles that enable key applications of PRHs in tissue engineering, drug delivery, and soft robotics, and highlights ongoing challenges in both modeling and application.     

Tailoring Hyaluronic Acid Hydrogels for Biomedical Applications

Hyaluronic acid (HA) is an attractive anionic polysaccharide polymer with inherent pharmacological properties and versatile chemical groups for modification. Due to their water retention ability, biocompatibility, biodegradation, cluster of differentiation-44 targeting, and highly designable capacity, HA hydrogels have been an emerging biomaterial, showing tailoring performance in terms of chemical modifications and hydrogel forms. Various preparation technologies have been developed for the fabrication of the tailoring HA hydrogels with unique structures and functions. They have been utilized in diverse biomedical applications like drug delivery and tissue engineering scaffolds. Herein, this review comprehensively summarizes the HA derivatives with different molecule weights and functional modifications. Then the various fabrication methods to obtain tailoring hydrogels in the forms of nanogel, nanofiber, microparticle, microneedle patch, injectable hydrogel, and scaffold are reviewed as well. The emphasis is focused on the shining biomedical applications of these tailoring HA hydrogels in anti-bacteria, anti-inflammation, wound healing, cancer treatment, regenerative medicine, psoriasis treatment, diagnosis, etc. The potentials and prospects are subsequently given to inspire further investigation, aiming at accelerating product translation from research to clinic.     

Rationally Designed Dynamic Protein Hydrogels with Reversibly Tunable Mechanical Properties

Protein hydrogels have attracted considerable interest due to their potential applications in biomedical engineering. Creating protein hydrogels with dynamic mechanical properties is challenging. Here, the engineering of a novel, rationally designed protein‐hydrogel is reported that translates molecular level protein folding‐unfolding conformational changes into macroscopic reversibly tunable mechanical properties based on a redox controlled protein folding‐unfolding switch. This novel protein folding switch is constructed from a designed mutually exclusive protein. Via oxidation and reduction of an engineered disulfide bond, the protein folding switch can switch its conformation between folded and unfolded states, leading to a drastic change of protein's effective chain length and mechanical compliance. This redox‐responsive protein can be readily photochemically crosslinked into solid hydrogels, in which molecular level conformational changes (folding‐unfolding) can result in significant macroscopic changes in hydrogel's physical and mechanical properties due to the change of the effective chain length between two crosslinking points in the protein hydrogel network. It is found that when reduced, the hydrogel swells and is mechanically compliant; when oxidized, it swells to a less extent and becomes resilient and stiffer, exhibiting an up to fivefold increase in its Young's modulus. The changes of the mechanical and physical properties of this hydrogel are fully reversible and can be cycled using redox potential. This novel protein hydrogel with dynamic mechanical and physical properties could find numerous applications in material sciences and tissue engineering.     

Dopant‐Free Hydrogels with Intrinsic Photoluminescence and Biodegradable Properties

Photoluminescent hydrogels that function as both injectable scaffolds and fluorescent imaging probes hold great potential for therapeutics delivery and tissue engineering. Current fluorescent hydrogels are fabricated by either conjugating or doping a fluorescent dye, fluorescent protein, lanthanide chelate, or quantum dot into polymeric hydrogel matrix. Their biomedical applications are severely limited due to drawbacks such as photostability, carcinogenesis, and toxicity associated with the above‐mentioned dopants. Here, a successful development of dopant‐free photoluminescent hydrogels in situ formed by crosslinking of biocompatible polymer precursors is reported, which can be synthesized by incorporating an amino acid to a citric acid based polyester oligomer followed by functionalization of multivalent crosslinking group through a convenient transesterification reaction using Candida Antarctica Lipase B as a catalyst. It is demonstrated that the newly developed hydrogels possess tunable degradation, intrinsic photoluminescence, mechanical properties, and exhibit sustained release of various molecular weight dextrans. In vivo study shows that the hydrogels formed in situ following subcutaneous injection exhibit excellent biocompatibility and emit strong fluorescence under visible light excitation without the need of using any traditional organic dyes. Their in vivo degradation profiles are then depicted by noninvasively monitoring fluorescence intensity of the injected hydrogel implants.     

Supertough Hybrid Hydrogels Consisting of a Polymer Double‐Network and Mesoporous Silica Microrods for Mechanically Stimulated On‐Demand Drug Delivery

Despite their potential in various fields of bioapplications, such as drug/cell delivery, tissue engineering, and regenerative medicine, hydrogels have often suffered from their weak mechanical properties, which are attributed to their single network of polymers. Here, supertough composite hydrogels are proposed consisting of alginate/polyacrylamide double‐network hydrogels embedded with mesoporous silica particles (SBA‐15). The supertoughness is derived from efficient energy dissipation through the multiple bondings, such as ionic crosslinking of alginate, covalent crosslinking of polyacrylamide, and van der Waals interactions and hydrogen bondings between SBA‐15 and the polymers. The superior mechanical properties of these hybrid hydrogels make it possible to maintain the hydrogel structure for a long period of time in a physiological solution. Based on their high mechanical stability, these hybrid hydrogels are demonstrated to exhibit on‐demand drug release, which is controlled by an external mechanical stimulation (both in vitro and in vivo). Moreover, different types of drugs can be separately loaded into the hydrogel network and mesopores of SBA‐15 and can be released with different speeds, suggesting that these hydrogels can also be used for multiple drug release.     

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.     

Rational Design of Bioactive Hydrogels toward Periodontal Delivery: From Pathophysiology to Therapeutic Applications

Periodontitis is a biofilm-induced, host-mediated inflammatory disease that results in periodontal tissue destruction. The design of functional biomaterials based on disease pathophysiology is essential for enhancing their therapeutic effects in periodontitis treatment. As promising localized drug delivery systems and tissue engineering scaffolds, hydrogels have gained significant interest for controlled and sustained release of bioactive agents in periodontal applications. The rational design of bioactive hydrogels can facilitate bacterial control and modulate destructive host inflammation, thereby preventing the progression of periodontitis. In this review, the pathophysiological mechanisms underlying periodontitis as fundamental principles for the design of functional hydrogel systems are first introduced. In the following part, an overview is systematically provided of the types and functions of the bioactive hydrogel systems loaded with anti-bacterial and anti-inflammatory agents for periodontal delivery. Finally, the remaining challenges and future perspectives of hydrogel delivery systems for periodontal applications are proposed. It is believed that this review will inspire the rational design and development of innovative functional hydrogel biomaterials toward periodontal therapy.     

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.     

Ultrafast Fabrication of Gradient Nanoporous All‐Polysaccharide Films as Strong,Superfast, and Multiresponsive Actuators

The design of smart hydrogel actuators fully constructed from natural polymers for assessing the biomedical applications is important but challenging. Herein, an extremely simple, green, and ultrafast strategy is presented for preparing robust gradient all‐polysaccharide polyelectrolyte complex hydrogel actuators. Driven by diffusing of low molecular weight chitosan into high molecular weight sodium alginate solution, a nanoporous, ultrastrong, and gradient chitosan/sodium alginate complex hydrogel film with adjustable thickness can be directly generated on the interface of two solutions within minutes. The as‐prepared film can provide superfast temperature, ionic strength, and pH‐triggered programmable deformations, and perform a distinct sequential double folding behavior due to the competitive effect between complexed and noncomplexed segments of polyelectrolyte. Besides, patterning Ca²⁺ to locally crosslink sodium alginate in the film enables various more complex shape transformations. This green and simple diffusion‐driven strategy provides significant guidance for fabricating bio‐friendly actuators with applications in drug delivery, tissue engineering, soft robotics, and active implants.     

Biomedical Applications of DNA‐Based Hydrogels

Nucleic acids are gaining significant attention as versatile building blocks for the next generation of soft materials. Due to significant advances in the chemical synthesis and biotechnological production, DNA becomes more widely available enabling its usage as bulk material in various applications. This has prompted researchers to actively explore the unique features offered by DNA‐containing materials like hydrogels. In this review article, recent developments in the field of hydrogels that feature DNA as a component either in the construction of the material or as functional unit within the construct and their biomedical applications are discussed in detail. First, different synthetic approaches for obtaining DNA hydrogels are summarized, which allows classification of DNA materials according to their structure. Then, new concepts, properties, and applications are highlighted such as DNA‐based biosensor devices, drug delivery platforms, and cell scaffolds. With the 2018 Nobel Prize in Physiology or Medicine being awarded to cancer immunotherapy underscoring the importance of this therapy, DNA hydrogel systems designed to modulate the immune system are introduced. This review aims to give the reader a timely overview of the most important and recent developments in this emerging class of therapeutically useful materials of DNA‐based hydrogels.     

Hydrophobized Hydrogels: Construction Strategies,Properties, and Biomedical Applications

Hydrogels, as 3D networks containing huge amount of water, display similarity to soft tissues, and thus they are of wide interest in tissue engineering. Hydrogels, due to biocompatibility and porous structure, are valuable therapeutic platforms for hydrophilic drugs. Over the last decade, there has been a strong emphasis on the development of hydrogel platforms with the ability to increase the solubility of hydrophobic drugs. However, the pronounced discrepancy between the hydrophilic character of hydrogels and the hydrophobic nature of numerous pharmacologically active compounds is problematic. In recent years, different strategies are applied using special polymer constructs or composite materials exploiting the advanced scientific knowledge in the area of polymer and lipid-based nano- and microcarriers hydrophobization of the hydrogel turns out to be not only valuable in terms of achieving the ability to dissolve poorly soluble drugs in water, but also proves to be crucial in obtaining bioadhesion in wet conditions, but also, unexpected abnormal water swelling behavior, as well as in mechanical properties such as the dissipation mechanism and self-healable hydrogel properties. This review is mainly focused on recent advances in the usage of hydrophobized hydrogels in biomedical applications.     

Degradable Self-healable Networks for Use in Biomedical Applications

Among biomaterials, 3D networks with capacities to absorb and retain large quantities of water (hydrogels) or withstand significant deformation and stress while recovering their initial structures at rest (elastomers) are largely used in biomedical applications. However, when damaged, they cannot recover their initial structures and properties. To overcome this limitation and satisfy the requirements of the biomedical field, self-healable hydrogels and elastomers designed using (bio)degradable or bioeliminable polymer chains have been developed and are becoming increasingly popular. This review presents the latest advances in the field of self-healing degradable/bioeliminable networks designed for use in health applications. The strategies used to develop such networks based on reversible covalent or physical cross-linking or their combination via dual/multi-cross-linking approaches are analyzed in detail. The key parameters of these hydrogels and elastomers, such as mechanical properties, repair and degradation times, and healing efficiencies, are critically considered in terms of their suitabilities in biomedical applications. Finally, their current and prospective uses as biomaterials in the fields of tissue engineering, drug/cell delivery, and medical devices are presented, followed by the remaining challenges faced to ensure the further success of degradable self-healable networks.     

A Review of Design and Fabrication Methods for Nanoparticle Network Hydrogels for Biomedical,Environmental, and Industrial Applications

Nanoparticle network hydrogels (NNHs) in which nanoparticles are used as a key building block to build the gel network have attracted significant interest given their potential to leverage the favorable properties of both hydrogels (e.g., hydrophilicity, tunable pore sizes, mechanics, etc.) and a variety of different nanoparticles (e.g., high surface area, chemical activity, independently tunable porosity, mechanics) to create new functional materials. Herein, recent progress in the design and use of NNHs is comprehensively reviewed, with an emphasis on defining the typical gel morphologies/architectures that can be achieved with NNHs, the typical crosslinking approaches used to fabricate NNHs, the fundamental properties and functional benefits of NNHs, and the reported applications of NNHs in electronics (flexible electronics, sensors), environmental (sorbents, separations), agriculture, self-cleaning-materials, and biomedical (drug delivery, tissue engineering) applications. In particular, the way in which the NNH structure is applied to improve the performance of the hydrogel in each application is emphasized, with the aim to develop a set of principles that can be used to rationally design NNHs for future uses.     

Injectable Polypeptide‐Protein Hydrogels for Promoting Infected Wound Healing

Protein is the key composition of all tissues, which has also been widely used in tissue engineering due to its superior biocompatibility and low immunogenicity. However, natural protein usually lacks active functions such as vascularization, osteo‐induction, and neural differentiation, which limits its further applications as a functional biomaterial. Here, based on the mimetic extracellular matrix feature of bovine serum albumin, injectable polypeptide‐protein hydrogels with vascularization and antibacterial abilities are constructed successfully via coordinative cross‐linking of sulfydryl groups with silver ions (Ag+) for the regeneration of infected wound. In this protein hydrogel system, (Ag+), acting as crosslinkers, can not only provide a sterile microenvironment and a strong and robust antibacterial ability but also introduce K₂(SL)₆K₂ (KK) polypeptide, which endows the hydrogel with vascularization behavior. Furthermore, the in vivo data show that the polypeptide‐protein hydrogel has a considerable collagen deposition and vascularization abilities in the early stage of wound healing, resulting in rapid new tissue regeneration featured with newly appeared hair follicles. Altogether, this newly developed multifunctional 3D polypeptide‐protein hydrogel with vascularization, antibacterial properties, and hair follicle promotion can be a promising approach in biomedical fields such as infected wound healing.     

Recent Advances in Design of Functional Biocompatible Hydrogels for Bone Tissue Engineering

Bone related diseases have caused serious threats to human health owing to their complexity and specificity. Fortunately, owing to the unique 3D network structure with high aqueous content and functional properties, emerging hydrogels are regarded as one of the most promising candidates for bone tissue engineering, such as repairing cartilage injury, skull defect, and arthritis. Herein, various design strategies and synthesis methods (e.g., 3D-printing technology and nanoparticle composite strategy) are introduced to prepare implanted hydrogel scaffolds with tunable mechanical strength, favorable biocompatibility, and excellent bioactivity for applying in bone regeneration. Injectable hydrogels based on biocompatible materials (e.g., collagen, hyaluronic acid, chitosan, polyethylene glycol, etc.) possess many advantages in minimally invasive surgery, including adjustable physicochemical properties, filling irregular shapes of defect sites, and on-demand release drugs or growth factors in response to different stimuli (e.g., pH, temperature, redox, enzyme, light, magnetic, etc.). In addition, drug delivery systems based on micro/nanogels are discussed, and its numerous promising designs used in the application of bone diseases (e.g., rheumatoid arthritis, osteoarthritis, cartilage defect) are also briefed in this review. Particularly, several key factors of hydrogel scaffolds (e.g., mechanical property, pore size, and release behavior of active factors) that can induce bone tissue regeneration are also summarized in this review. It is anticipated that advanced approaches and innovative ideas of bioactive hydrogels will be exploited in the clinical field and increase the life quality of patients with the bone injury.