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Hydrogels are well-suited for biomedical applications due to their numerous advantages, such as excellent bioactivity, versatile physical and chemical properties, and effective drug delivery capabilities. Recently, hydrogel coatings have developed to functionalize bone implants which are biologically inert and cannot withstand the complex bone tissue repair microenvironment. These coatings have shown promise in addressing unique and pressing medical needs. This review begins with the major functionalized performance and interfacial bonding strategy of hydrogel coatings, with a focus on the novel external field response properties of the hydrogel. Recent advances in the fabrication strategies of hydrogel coatings and their use in the treatment of pathologic bone regeneration are highlighted. Finally, challenges and emerging trends in the evolution and application of physiological environment-responsive and external electric field-responsive hydrogel coatings for bone implants are discussed.

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This study focuses on developing surface coatings with excellent antifouling properties, crucial for applications in the medical, biological, and technical fields, for materials and devices in direct contact with living tissues and bodily fluids such as blood. This approach combines thermoresponsive poly(2-alkyl-2-oxazoline)s, known for their inherent protein-repellent characteristics, with established antifouling motifs based on betaines. The polymer framework is constructed from various monomer types, including a novel benzophenone-modified 2-oxazoline for photocrosslinking and an azide-functionalized 2-oxazoline, allowing subsequent modification with alkyne-substituted antifouling motifs through copper(I)-catalyzed azide-alkyne cycloaddition. From these polymers surface-attached networks are created on benzophenone-modified gold substrates via photocrosslinking, resulting in hydrogel coatings with several micrometers thickness when swollen with aqueous media. Given that poly(2-alkyl-2-oxazoline)s can exhibit a lower critical solution temperature in water, their temperature-dependent solubility is compared to the swelling behavior of the surface-attached hydrogels upon thermal stimulation. The antifouling performance of these hydrogel coatings in contact with human blood plasma is further evaluated by surface plasmon resonance and optical waveguide spectroscopy. All surfaces demonstrate extremely low retention of blood plasma components, even with undiluted plasma. Notably, hydrogel layers with sulfobetaine moieties allow efficient penetration by plasma components, which can then be easily removed by rinsing with buffer.

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During the COVID-19 (Corona Virus Disease 2019) pandemic, traditional medical goggles are not only easy to attach bacteria and viruses in long-term exposure, but easy to fogged up, which increases the risk of infection and affects productivity. Bacterial adhesion and fog can be significantly inhibited through the hydrogel coatings, owing to super hydrophilic properties. On the one hand, hydrogel coatings are easy to absorb water and swell in wet environment, resulting in reduced mechanical properties, even peeling off. On the other hand, the hydrogel coatings don't have intrinsic antibacterial properties, which still poses a potential risk of bacterial transmission. Herein, an anti-swelling and antibacterial hydrogel coating is synthesized by 2-hydroxyethyl methacrylate (HEMA), acrylamide (AM), dimethylaminoethyl acrylate bromoethane (IL-Br), and poly(sodium-p-styrenesulfonate) (PSS). Due to the self-driven entropy reduction effect of polycation and polyanion, an ion cross-linking network is formed, which endows the hydrogel coating with excellent antiswelling performance. Moreover, because of the synergistic effect of highly hydrated surfaces and the active bactericidal effect from quaternary ammonium cations, the hydrogel coating exhibits outstanding antifouling performances. This work develops a facile strategy to fabricate anti-swelling, antifouling, and antifogging hydrogel coatings for the protection of medical goggles, and also for biomedical and marine antifouling fields.

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Hydrogels exhibit excellent moldability, biodegradability, biocompatibility, and extracellular matrix-like properties, which make them widely used in biomedical fields. Because of their unique three-dimensional crosslinked hydrophilic networks, hydrogels can encapsulate various materials, such as small molecules, polymers, and particles; this has become a hot research topic in the antibacterial field. The surface modification of biomaterials by using antibacterial hydrogels as coatings contributes to the biomaterial activity and offers wide prospects for development. A variety of surface chemical strategies have been developed to bind hydrogels to the substrate surface stably. We first introduce the preparation method for antibacterial coatings in this review, which includes surface-initiated graft crosslinking polymerization, anchoring the hydrogel coating to the substrate surface, and the LbL self-assembly technique to coat crosslinked hydrogels. Then, we summarize the applications of hydrogel coating in the biomedical antibacterial field. Hydrogel itself has certain antibacterial properties, but the antibacterial effect is not sufficient. In recent research, in order to optimize its antibacterial performance, the following three antibacterial strategies are mainly adopted: bacterial repellent and inhibition, contact surface killing of bacteria, and release of antibacterial agents. We systematically introduce the antibacterial mechanism of each strategy. The review aims to provide reference for the further development and application of hydrogel coatings.

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Amphiphilic hydrogels from mixtures of 2-hydroxyethyl methacrylate and 2-(diethylamino)ethyl methacrylate p(HEMA-co-DEAEMA) with specific pH sensitivity and hydrophilic/hydrophobic structures were designed and polymerized via plasma polymerization. The behavior of plasma-polymerized (pp) hydrogels containing different ratios of pH-sensitive DEAEMA segments was investigated concerning possible applications in bioanalytics. In this regard, the morphological changes, permeability, and stability of the hydrogels immersed in solutions of different pHs were studied. The physico-chemical properties of the pp hydrogel coatings were analyzed using X-ray photoelectron spectroscopy, surface free energy measurements, and atomic force microscopy. Wettability measurements showed an increased hydrophilicity of the pp hydrogels when stored in acidic buffers and a slightly hydrophobic behavior after immersion in alkaline solutions, indicating a pH-dependent behavior. Furthermore, the pp (p(HEMA-co-DEAEMA) (ppHD) hydrogels were deposited on gold electrodes and studied electrochemically to investigate the pH sensitivity of the hydrogels. The hydrogel coatings with a higher ratio of DEAEMA segments showed excellent pH responsiveness at the studied pHs (pH 4, 7, and 10), demonstrating the importance of the DEAEMA ratio in the functionality of pp hydrogel films. Due to their stability and pH-responsive properties, pp (p(HEMA-co-DEAEMA) hydrogels are conceivable candidates for functional and immobilization layers for biosensors.

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Device failure due to undesired biological responses remains a substantial roadblock in the development and translation of new devices into clinical care. Polyethylene glycol (PEG)-based hydrogel coatings can be used to confer antifouling properties to medical devices-enabling minimization of biological responses such as bacterial infection, thrombosis, and foreign body reactions. Application of hydrogel coatings to diverse substrates requires careful consideration of multiple material factors. Herein, we report a systematic investigation of two coating methods: (1) traditional photoinitiated hydrogel coatings; (2) diffusion-mediated, redox-initiated hydrogel coatings. The effects of method, substrate, and compositional variables on the resulting hydrogel coating thickness are presented. To expand the redox-based method to include high molecular weight macromers, a mechanistic investigation of the role of cure rate and macromer viscosity was necessary to balance solution infiltration and gelation. Overall, these structure-property relationships provide users with a toolbox for hydrogel coating design for a broad range of medical devices.

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Among biomedical community, great efforts have been realized to develop antibacterial coatings that avoid implant-associated infections. To date, conventional mono-functional antibacterial strategies have not been effective enough for successful long-term implantations. Consequently, researchers have recently focused their attention on novel bifunctional or multifunctional antibacterial coatings, in which two or more antibacterial mechanisms interact synergistically. Thus, in this work different chitosan-based (CHI) hydrogel coatings were created on Ti6Al4V surface using genipin (Ti-CHIGP) and polyethylene glycol (Ti-CHIPEG) crosslinking agents. Hydrogel coatings demonstrated an exceptional in vivo biocompatibility plus a remarkable ability to promote cell proliferation and differentiation. Lastly, hydrogel coatings demonstrated an outstanding bacteria-repelling (17-28 % of S. aureus and 33-43 % of E. coli repelled) and contact killing (186-222 % of S. aureus and 72-83 % of E. coli damaged) ability. Such bifunctional antibacterial activity could be further improved by the controlled release of drugs resulting in powerful multifunctional antibacterial coatings.

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Today, the treatment of implant-associated infections with conventional mono-functional antibacterial coatings has not been effective enough for a prosperous long-term implantation. Therefore, biomedical industry is making considerable efforts on the development of novel antibacterial coatings with a combination of more than one antibacterial strategies that interact synergistically to reinforce each other. Therefore, in this work hyaluronic acid-based (HA) hydrogel coatings were created on the surface Ti6Al4V biomaterial with 1,4-butanediol diglycidyl ether (Ti-HABDDE) and divinyl sulfone (Ti-HADVS) crosslinking agents. Hydrogel coatings displayed an extraordinary in vivo biocompatibility, a remarkable ability to promote cell proliferation, differentiation and mineralization, and capability to sustainedly release drugs. Finally, HA-based hydrogel coatings demonstrated an outstanding multifunctional antibacterial activity: bacteria-repelling (51-55 % of S. aureus and 27-40 % of E. coli), bacteria-killing (82-119 % of S. aureus and 83-87 % of E. coli) and bactericide release killing (drug-loaded hydrogel coatings, R > 2).

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This patent review encapsulates information that could be used as a reference by researchers in the fields of coatings and interfaces, biofabrication, tissue engineering, biomaterials, and biomedical engineering, as well as those especially interested in the formulation of hydrogel coatings. The state has been reviewed by introducing what has been innovated, invented, and patented in relation to hydrogel coatings. A detailed analysis of the patentability of hydrogel applications, such as the coating of medical devices to enhance their clinical performance, has been provided. During a search, 2937 patent documents were found. 2012 was the year with the most patent documents (177). Based on the patent classification, all patent documents and most inventions are intended for biomaterials for coating prostheses characterized by their function or physical properties, such as macromolecular materials, hydrogels, and biologically active materials. Additionally, research based on medicinal formulations with unique physical forms is concentrated in the majority of patents, according to knowledge clusters and expert driving factors. Finally, to demonstrate the innovation trends in hydrogel-based coatings, a selection of relevant patent applications and granted patents is proposed at the end of this paper, along with some examples of commercial products based on the patented technologies.

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In biomedicine fields, biofouling can easily occur on devices such as sensors and catheters, causing some iatrogenic infections, which menace the lives and health of patients greatly. Therefore, it is of great significance to solve the problems of bacterial infection on the surfaces of medical devices. In this paper, "self-defensive" and antifouling zwitterionic hydrogel coatings were prepared by network interpenetration of the hydrogel and the polymeric substrates. The zwitterionic polysulfobetaine methacrylate (PSBMA) hydrogel coatings resisted most of the bacteria to adhere on the substrates. When a few bacteria were lucky to escape the antifouling defense and adhered to the coatings, gentamicin sulfate (GS) would be released under the trigger of a weakly acidic environment caused by bacterial metabolism to kill these bacteria. Simultaneously, the coatings of the bacteria-adhering sites would be degraded by hyaluronidase secreted by these bacteria and peeled off to remove the bacteria and renew the antifouling surfaces. The antifouling properties and mechanism of the self-defensive behavior of the hydrogel coatings on polymeric substrates were investigated. Furthermore, the in vitro and in vivo antibacterial performances, as well as the biocompatibility of the coatings, were demonstrated. The results suggested that the self-defensive antifouling zwitterionic hydrogel coatings hold great potential to be used on the surfaces of polymeric medical devices.

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Mucosa is a protective and lubricating barrier in biological tissue, which has a great clinical inspiration because of its slippery, soft, and hydrophilic surface. However, mimicking mucosal traits on complex surface remains an enormous challenge. Herein, a novel approach to create mucosa-like conformal hydrogel coating is developed. A thin conformal hydrogel layer mimicking the epithelial layer is obtained by first absorbing micelles, followed by forming covalent interlinks with the polymer substrate via interface-initiated hydrogel polymerization. The resulting coating exhibits uniform thickness (≈15 µm), mucosa-matched compliance (Young's modulus = 1.1 ± 0.1 kPa) and lubrication (coefficients of friction = 0.018 ± 0.003), robust interfacial bonding against peeling (peeling strength = 1218.0 ± 187.9 J m-2 ), as well as high water absorption capacity. It effectively resists adhesion of proteins and bacteria without compromising biocompatibility. As demonstrated by an in vivo cynomolgus monkey model and clinical trial, applications of the mucosa-like conformal hydrogel coating on the endotracheal tube significantly reduce intubation-related complications, such as invasive stimuli, mucosal lesions, laryngeal edema, inflammation, and postoperative pain. This work offers a promising prototype for surface decoration of biomedical devices and holds great prospects for clinical translation to enable interventional operations with minimally invasive impacts.

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Controllably coating the surfaces of substrates/medical devices with hydrogels exhibits great application potential, but lacks universal techniques. Herein, a new method, namely ultraviolet-triggered surface catalytically initiated radical polymerization (UV-SCIRP) from a sticky initiation layer (SIL) (SIL@UV-SCIRP), is proposed for growing hydrogel coatings. The method involves three key steps: 1) depositing a sticky polydopamine/Fe3+ coating on the surface of the substrates-SIL, 2) reducing Fe3+ ions to Fe2+ ions as active catalysts by UV illumination with the assistance of citric acid, and 3) conducting SCIRP in a monomer solution at room temperature for growing hydrogel coatings. In this manner, practically any substrate's surface (natural or artificial materials) can be modified by hydrogel coatings with controllable thickness and diverse compositions. The hydrogel coatings exhibit good interface bonding with the substrates and enable easy changes in their wettability and lubrication performances. Importantly, this novel method facilitates the smooth growth of uniform hydrogel lubrication coatings on the surface of a range of medical devices with complex geometries. Finally, as a proof-of-concept, the slippery balls coated with hydrogel exhibited smooth movement within the catheter and esophagus. Hence, this method can prove to be a pioneering universal modification tool, especially in surface/interface science and engineering.

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Implant-associated bacterial infections significantly impair the integration between titanium and soft tissues. Traditional antibacterial modifications of titanium implants are able to eliminate bacteria, but the resulting pro-inflammatory reactions are usually ignored, which still poses potential risks to human bodies. Here, a dual drug-loading system on titanium has been developed via the adhesion of a catechol motif-modified methacrylated gelatin hydrogel onto TiO2 nanotubes. Then synthesized CaO2 nanoparticles (NPs) are embedded into the hydrogel, and interleukin-4 (IL-4) is loaded into the nanotubes to achieve both antibacterial and anti-inflammatory properties. The dual drug-loading system can eliminate Staphylococcus aureus (S. aureus) rapidly, attributed to the H2 O2 release from CaO2 NPs. The potential cytotoxicity of CaO2 NPs is also remarkably reduced after being embedded into the hydrogel. More importantly, with the gradual release of IL-4, the dual drug-loading system is capable of modulating pro-inflammatory reactions by inducing M2 phenotype polarization of macrophages. In a subcutaneous infection model, the S. aureus contamination is effectively resolved after 2 days, and the resulting pro-inflammatory reactions are also inhibited after 7 days. Finally, the damaged tissue is significantly recovered. Taken together, the dual drug-loading system exhibits great therapeutic potential in effectively killing pathogens and inhibiting the resulting pro-inflammatory reactions.

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Hydrogels-natural or synthetic polymer networks that swell in water-can be made mechanically, chemically and electrically compatible with living tissues. There has been intense research and development of hydrogels for medical applications since the invention of hydrogel contact lenses in 1960. More recently, functional hydrogel coatings with controlled thickness and tough adhesion have been achieved on various substrates. Hydrogel-coated substrates combine the advantages of hydrogels, such as lubricity, biocompatibility and anti-biofouling properties, with the advantages of substrates, such as stiffness, toughness and strength. In this review, we focus on three aspects of functional hydrogel coatings: (i) applications and functions enabled by hydrogel coatings, (ii) methods of coating various substrates with different functional hydrogels with tough adhesion, and (iii) tests to evaluate the adhesion between functional hydrogel coatings and substrates. Conclusions and outlook are given at the end of this review.

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Ideal percutaneous titanium implants request both antibacterial ability and soft tissue compatibility. ZnO structure constructed on titanium has been widely proved to be helpful to combat pathogen contamination, but the biosafety of ZnO is always questioned. How to maintain the remarkable antibacterial ability of ZnO and efficiently reduce the corresponding toxicity is still challenging. Herein, a hybrid hydrogel coating was constructed on the fabricated ZnO structure of titanium, and the coating was proved to be enzymatically-degradable when bacteria exist. Then the antibacterial activity of ZnO was presented. When under the normal condition (no bacteria), the hydrogel coating was stable and tightly adhered to titanium. The toxicity of ZnO was reduced, and the viability of fibroblasts was largely improved. More importantly, the hydrogel coating provided a good buffer zone for cell ingrowth and soft tissue integration. The curbed Zn ion release was also proved to be useful to regulate fibroblast responses such as the expression of CTGF and COL-I. These results were also validated by in vivo studies. Therefore, this study proposed a valid self-adaptive strategy for ZnO improvement. Under different conditions, the sample could present different functions, and both the antibacterial ability and soft tissue compatibility were finely preserved.

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Hydrogels have long been explored as attractive materials for biomedical applications given their outstanding biocompatibility, high water content, and versatile fabrication platforms into materials with different physiochemical properties and geometries. Nonetheless, conventional hydrogels suffer from weak mechanical properties, restricting their use in persistent load-bearing applications often required of materials used in medical settings. Thus, the fabrication of mechanically robust hydrogels that can prolong the lifetime of clinically suitable materials under uncompromising in vivo conditions is of great interest. This review focuses on design considerations and strategies to construct such tough hydrogels. Several promising advances in the proposed use of specialty tough hydrogels for soft actuators, drug delivery vehicles, adhesives, coatings, and in tissue engineering settings are highlighted. While challenges remain before these specialty tough hydrogels will be deemed translationally acceptable for clinical applications, promising preliminary results undoubtedly spur great hope in the potential impact this embryonic research field can have on the biomedical community.

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Brain machine interfaces (BMIs), introduced into the daily lives of individuals with injuries or disorders of the nervous system such as spinal cord injury, stroke, or amyotrophic lateral sclerosis, can improve the quality of life. BMIs rely on the capability of microelectrode arrays to monitor the activity of large populations of neurons. However, maintaining a stable, chronic electrode-tissue interface that can record neuronal activity with a high signal-to-noise ratio is a key challenge that has limited the translation of such technologies. An electrode implant injury leads to a chronic foreign body response that is well-characterized and shown to affect the electrode-tissue interface stability. Several strategies have been applied to modulate the immune response, including the application of immunomodulatory drugs applied both systemically and locally. While the use of passive drug release at the site of injury has been exploited to minimize neuroinflammation, this strategy has all but failed as a bolus of anti-inflammatory drugs is released at predetermined times that are often inconsistent with the ongoing innate inflammatory process. Common strategies do not focus on the proper anchorage of soft hydrogel scaffolds on electrode surfaces, which often results in delamination of the porous network from electrodes. In this study, we developed a microwire platform that features a robust yet soft biocompatible hydrogel coating, enabling long-lasting drug release via formation of drug aggregates and dismantlement of hydrophilic biodegradable three-dimensional polymer networks. Facile surface chemistry is developed to functionalize polyimide-coated electrodes with the covalently anchored porous hydrogel network bearing large numbers of highly biodegradable ester groups. Exponential long-lasting drug release is achieved using such hydrogels. We show that the initial state of dexamethasone (Dex) used to formulate the hydrogel precursor solution plays a cardinal role in engineering hydrophilic networks that enable a sustained and long-lasting release of the anti-inflammatory agent. Furthermore, utilization of a high loading ratio that exceeds the solubility of Dex leads to the encapsulation of Dex aggregates that regulate the release of this anti-inflammatory agent. To validate the anti-inflammatory effect of the hydrogel-functionalized Dex-loaded microwires, an in vivo preliminary study was performed in adult male rats (n = 10) for the acute time points of 48 h and 7 days post implant. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to assess the mRNA expression of certain inflammatory-related genes. In general, a decrease in fold-change expression was observed for all genes tested for Dex-loaded wires compared with controls (functionalized but no drug). The engineering of hybrid microwires enables a sustained release of the anti-inflammatory agent over extended periods of time, thus paving the way to fabricate neuroprosthetic devices capable of attenuating the foreign body response.

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In this work, a novel biomimetic surface-attachable initiator is successfully synthesized by the conjugation of 3,4-dihydroxyphenylacetic acid and thermal 2,2'-azobis(2-methylpropionamide) dihydrochloride (V-50). The synthesized initiator (DOPV) can adhere to various material surfaces in a mussel-inspired way and initiate the surface grafting polymerization. Hydrogel coatings are facilely prepared by the thermal-initiated radical copolymerization of antimicrobial polyhexamethylene guanidine and antifouling polyethylene glycol oligomers. The developed hydrogel coatings not only show antimicrobial activity toward gram-negative and gram-positive bacteria but also demonstrate protein resistance, antibiofilm efficacy, hemocompatibility, and low cytotoxicity in vitro. Most importantly, the hydrogel coatings reveal excellent antimicrobial efficacy with a log reduction above 5 in a rodent subcutaneous infection model. These results demonstrate the potential fabrication of bio-functional coatings for biomedical devices or implants through an inexpensive, facile, and environmentally friendly mussel-inspired technique.

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The development of versatile generalized strategies for easy surface modification is of immense scientific interest. Herein, a novel mechanism to form functional hydrogel coatings on a wide variety of substrate materials including polymers, polymeric resins, ceramics, and intermetallic compounds, enabling easy change of the surface wettability and lubrication property, is reported. In situ polymerization and hydrogel coating formation is initiated by free radicals generated through the redox reaction between Fe2+ and S2 O8 2- at the solid-liquid interface, which shows controllable growth kinetics. Hydrogel modification is fast, controllable, and performed in mild conditions at room temperature. The chemical components, thickness, and network structure of the hydrogel coating can be well controlled. The surface catalytically initiated radical polymerization method allows reinitiation of the polymerization when the grafted hydrogel coating is polished away, and allows continuous surface polymerization to form multi-interpenetrating network hydrogel coatings. Interestingly, it is fully compatible with 3D-printing technology, and by using 3D-printed composites as the catalytic template, it demonstrates an extreme advantage for engineering 3D hollow hydrogel objects with various complex structures. The versatility of this method makes it generate potential applications in the field of surface/interface and biological engineering.

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UNLABELLED: For surface-based diagnostic devices to achieve reliable biomarker detection in complex media such as blood, preventing nonspecific protein adsorption and incorporating high loading of biorecognition elements are paramount. In this work, a novel method to produce nonfouling zwitterionic hydrogel coatings was developed to achieve these goals. Poly(carboxybetaine acrylamide) (pCBAA) hydrogel thin films (CBHTFs) prepared with a carboxybetaine diacrylamide crosslinker (CBAAX) were coated on gold and silicon dioxide surfaces via a simple spin coating process. The thickness of CBHTFs could be precisely controlled between 15 and 150nm by varying the crosslinker concentration, and the films demonstrated excellent long-term stability. Protein adsorption from undiluted human blood serum onto the CBHTFs was measured with surface plasmon resonance (SPR). Hydrogel thin films greater than 20nm exhibited ultra-low fouling (<5ng/cm(2)). In addition, the CBHTFs were capable of high antibody functionalization for specific biomarker detection without compromising their nonfouling performance. This strategy provides a facile method to modify SPR biosensor chips with an advanced nonfouling material, and can be potentially expanded to a variety of implantable medical devices and diagnostic biosensors. STATEMENT OF SIGNIFICANCE: In this work, we developed an approach to realize ultra-low fouling and high ligand loading with a highly-crosslinked, purely zwitterionic, carboxybetaine thin film hydrogel (CBHTF) coating platform. The CBHTF on a hydrophilic surface demonstrated long-term stability. By varying the crosslinker content in the spin-coated hydrogel solution, the thickness of CBHTFs could be precisely controlled. Optimized CBHTFs exhibited ultra-low nonspecific protein adsorption below 5ng/cm(2) measured by a surface plasmon resonance (SPR) sensor, and their 3D architecture allowed antibody loading to reach 693ng/cm(2). This strategy provides a facile method to modify SPR biosensor chips with an advanced nonfouling material, and can be potentially expanded to a variety of implantable medical devices and diagnostic biosensors.

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