Adhesive hydrogels in osteoarthritis:from design to application

Osteoarthritis(OA)is the most common type of degenerative joint disease which affects 7%of the global population and more than 500 million people worldwide.One research frontier is the development of hydrogels for OA treatment,which operate either as functional scaffolds of tissue engineering or as delivery vehicles of functional additives.Both approaches address the big challenge:establishing stable integration of such delivery systems or implants.Adhesive hydrogels provide possible solutions to this challenge.However,few studies have described the current advances in using adhesive hydrogel for OA treatment.This review summarizes the commonly used hydrogels with their adhesion mechanisms and components.Additionally,recognizing that OA is a complex disease involving different biological mechanisms,the bioactive therapeutic strategies are also presented.By presenting the adhesive hydrogels in an interdisciplinary way,including both the fields of chemistry and biology,this review will attempt to provide a comprehensive insight for designing novel bioadhesive systems for OA therapy.

Adhesive hydrogels for bioelectronics

Benefiting from the unique advantages of superior biocompatibility,strong stability,good biodegradability,and adjustable mechanical properties,hydrogels have attracted extensive research interests in bioelectronics.However,due to the existence of an interface between hydrogels and human tissues,the transmission of electrical signals from the human tissues to the hydrogel electronic devices will be hindered.The adhesive hydrogels with adhesive properties can tightly combine with the human tissue,which can enhance the contact between the electronic devices and human tissues and reduce the contact resistance,thereby improving the performance of hydrogel electronic devices.In this review,we will discuss in detail the adhesion mechanism of adhesive hydrogels and elaborate on the design principles of adhesive hydrogels.After that,we will introduce some methods of performance evaluation for adhesive hydrogels.Finally,we will provide a perspective on the development of adhesive hydrogel bioelectronics.

Injectable Self‑Healing Adhesive pH‑Responsive Hydrogels Accelerate Gastric Hemostasis and Wound Healing

Endoscopic mucosal resection(EMR)and endoscopic submucosal dissection(ESD)are well-established therapeutics for gastrointestinal neoplasias,but complications after EMR/ESD,including bleeding and perforation,result in additional treatment morbidity and even threaten the lives of patients.Thus,designing biomaterials to treat gastric bleeding and wound healing after endoscopic treatment is highly desired and remains a challenge.Herein,a series of injectable pH-responsive selfhealing adhesive hydrogels based on acryloyl-6-aminocaproic acid(AA)and AA-g-N-hydroxysuccinimide(AA-NHS)were developed,and their great potential as endoscopic sprayable bioadhesive materials to efficiently stop hemorrhage and promote the wound healing process was further demonstrated in a swine gastric hemorrhage/wound model.The hydrogels showed a suitable gelation time,an autonomous and efficient self-healing capacity,hemostatic properties,and good biocompatibility.With the introduction of AA-NHS as a micro-cross-linker,the hydrogels exhibited enhanced adhesive strength.A swine gastric hemorrhage in vivo model demonstrated that the hydrogels showed good hemostatic performance by stopping acute arterial bleeding and preventing delayed bleeding.A gastric wound model indicated that the hydrogels showed excellent treatment effects with significantly enhanced wound healing with type I collagen deposition,α-SMA expression,and blood vessel formation.These injectable self-healing adhesive hydrogels exhibited great potential to treat gastric wounds after endoscopic treatment.

Natural polymer-based adhesive hydrogel for biomedical applications

Hydrogel is a polymer network system that can form a hydrophilic three-dimensional network structure through different cross-linking methods.In recent years,hydrogels have received considerable attention due to their good biocompatibility and biodegradability by introducing different cross-linking mechanisms and functional components.Compared with synthetic hydrogels,natural polymer-based hydrogels have low biotoxicity,high cell affinity,and great potential for biomedical fields;however,their mechanical properties and tissue adhesion capabilities have been unable to meet clinical requirements.In recent years,many efforts have been made to solve these issues.In this review,the recent progress in the field of natural polymer-based adhesive hydrogels is highlighted.The authors first introduce the general design principles for the natural polymer-based adhesive hydrogels being used as excellent tissue adhesives and the challenges associated with their design.Next,their usages in biomedical applications are summarised,such as wound healing,haemostasis,nerve repair,bone tissue repair,cartilage tissue repair,electronic devices,and other tissue repairs.Finally,the potential challenges of natural polymer-based adhesive hydrogels are presented.

Adhesive cryogel particles for bridging confined and irregular tissue defects

Background Reconstruction of damaged tissues requires both surface hemostasis and tissue bridging.Tissues with damage resulting from physical trauma or surgical treatments may have arbitrary surface topographies,making tissue bridging challenging.Methods This study proposes a tissue adhesive in the form of adhesive cryogel particles(ACPs) made from chitosan,acrylic acid,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide(EDC) and N-hydroxysuccinimide(NHS).The adhesion performance was examined by the 180-degree peel test to a collection of tissues including porcine heart,intestine,liver,muscle,and stomach.Cytotoxicity of ACPs was evaluated by cell proliferation of human normal liver cells(LO2)and human intestinal epithelial cells(Caco-2).The degree of inflammation and biodegradability were examined in dorsal subcutaneous rat models.The ability of ACPs to bridge irregular tissue defects was assessed using porcine heart,liver,and kidney as the ex vivo models.Furthermore,a model of repairing liver rupture in rats and an intestinal anastomosis in rabbits were established to verify the effectiveness,biocompatibility,and applicability in clinical surgery.Results ACPs are applicable to confined and irregular tissue defects,such as deep herringbone grooves in the parenchyma organs and annular sections in the cavernous organs.ACPs formed tough adhesion between tissues[(670.9±50.1) J/m^(2) for the heart,(607.6±30.0) J/m^(2) for the intestine,(473.7±37.0) J/m^(2) for the liver,(186.1±13.3) J/m^(2) for the muscle,and(579.3±32.3) J/m^(2) for the stomach].ACPs showed considerable cytocompatibility in vitro study,with a high level of cell viability for 3 d[(98.8±1.2)%for LO2 and(98.3±1.6)%for Caco-2].It has comparable inflammation repair in a ruptured rat liver(P=0.58 compared with suture closure),the same with intestinal anastomosis in rabbits(P=0.40 compared with suture anastomosis).Additionally,ACP-based intestinal anastomosis(less than 30 s) was remarkably faster than the conventional suturing process(more than 10 min).When ACPs degrade after surgery,the tissues heal across the adhesion interface.Conclusions ACPs are promising as the adhesive for clinical operations and battlefield rescue,with the capability to bridge irregular tissue defects rapidly.

Robust hydrogel adhesives for emergency rescue and gastric perforation repair

Development of biocompatible hydrogel adhesives with robust tissue adhesion to realize instant hemorrhage control and injury sealing,especially for emergency rescue and tissue repair,is still challenging.Herein,we report a potent hydrogel adhesive by free radical polymerization of N-acryloyl aspartic acid(AASP)in a facile and straightforward way.Through delicate adjustment of steric hindrance,the synergistic effect between interface interactions and cohesion energy can be achieved in PAASP hydrogel verified by X-ray photoelectron spectroscopy(XPS)analysis and simulation calculation compared to poly(N-acryloyl glutamic acid)(PAGLU)and poly(N-acryloyl amidomalonic acid)(PAAMI)hydrogels.The adhesion strength of the PAASP hydrogel could reach 120 kPa to firmly seal the broken organs to withstand the external force with persistent stability under physiological conditions,and rapid hemostasis in different hemorrhage models on mice is achieved using PAASP hydrogel as physical barrier.Furthermore,the paper-based Fe^(3+)transfer printing method is applied to construct PAASP-based Janus hydrogel patch with both adhesive and non-adhesive surfaces,by which simultaneous wound healing and postoperative anti-adhesion can be realized in gastric perforation model on mice.This advanced hydrogel may show vast potential as bio-adhesives for emergency rescue and tissue/organ repair.

Mussel-inspired nanozyme catalyzed conductive and self-setting hydrogel for adhesive and antibacterial bioelectronics

Adhesive hydrogels have broad applications ranging from tissue engineering to bioelectronics;however,fabricating adhesive hydrogels with multiple functions remains a challenge.In this study,a mussel-inspired tannic acid chelated-Ag(TA-Ag)nanozyme with peroxidase(POD)-like activity was designed by the in situ reduction of ultrasmall Ag nanoparticles(NPs)with TA.The ultrasmall TA-Ag nanozyme exhibited high catalytic activity to induce hydrogel self-setting without external aid.The nanozyme retained abundant phenolic hydroxyl groups and maintained the dynamic redox balance of phenol-quinone,providing the hydrogels with long-term and repeatable adhesiveness,similar to the adhesion of mussels.The phenolic hydroxyl groups also afforded uniform distribution of the nanozyme in the hydrogel network,thereby improving its mechanical properties and conductivity.Furthermore,the nanozyme endowed the hydrogel with antibacterial activity through synergistic effects of the reactive oxygen species generated via POD-like catalytic reactions and the intrinsic bactericidal activity of Ag.Owing to these advantages,the ultrasmall TA-Ag nanozyme-catalyzed hydrogel could be effectively used as an adhesive,antibacterial,and implantable bioelectrode to detect bio-signals,and as a wound dressing to accelerate tissue regeneration while preventing infection.Therefore,this study provides a promising approach for the fabrication of adhesive hydrogel bioelectronics with multiple functions via mussel-inspired nanozyme catalysis.

An adhesive and resilient hydrogel for the sealing and treatment of gastric perforation

Adhesive hydrogels have been recently proposed as a potential option to seal and treat gastric perforation(GP)which causes high mortality despite advancements in surgical treatments.However,to be effective,the hydrogels must have sufficient tissue adhesiveness,tough mechanical property,tunable biodegradability and ideally are easy to apply and form.Herein,we report an adhesive and resilient hydrogel for the sealing and treatment of gastric perforation.The hydrogel consists of a bioactive,transglutaminase(TG)-crosslinked gelatin network and a dynamic,borate-crosslinked poly-N-[Tris(hydroxymethyl)methyl]acrylamide(PTH)network.The hydrogel can be formed in situ,facilitating easy delivery to the GP and allowing for precise sealing of the defects.In vivo experiments,using a perforated stomach mouse model,shows that the adhesive hydrogel plug effectively seals GP defects and promotes gastric mucosa regeneration.Overall,this hydrogel represents a promising biomaterial for GP treatment.

O-alg-THAM/gel hydrogels functionalized with engineered microspheres based on mesenchymal stem cell secretion recruit endogenous stem cells for cartilage repair

Lacking self-repair abilities,injuries to articular cartilage can lead to cartilage degeneration and ultimately result in osteoarthritis.Tissue engineering based on functional bioactive scaffolds are emerging as promising approaches for articular cartilage regeneration and repair.Although the use of cell-laden scaffolds prior to implantation can regenerate and repair cartilage lesions to some extent,these approaches are still restricted by limited cell sources,excessive costs,risks of disease transmission and complex manufacturing practices.Acellular approaches through the recruitment of endogenous cells offer great promise for in situ articular cartilage regeneration.In this study,we propose an endogenous stem cell recruitment strategy for cartilage repair.Based on an injectable,adhesive and self-healable o-alg-THAM/gel hydrogel system as scaffolds and a biophysio-enhanced bioactive microspheres engineered based on hBMSCs secretion during chondrogenic differentiation as bioactive supplement,the as proposed functional material effectively and specifically recruit endogenous stem cells for cartilage repair,providing new insights into in situ articular cartilage regeneration.

Catch bond-inspired hydrogels with repeatable and loading rate-sensitive specific adhesion

Biological receptor-ligand adhesion governed by mammalian cells involves a series of mechanochemical pro-cesses that can realize reversible,loading rate-dependent specific interfacial bonding,and even exhibit a counterintuitive behavior called catch bonds that tend to have much longer lifetimes when larger pulling forces are applied.Inspired by these catch bonds,we designed a hydrogen bonding-meditated hydrogel made from acrylic acid-N-acryloyl glycinamide(AA-NAGA)copolymers and tannic acids(TA),which formed repeatable specific adhesion to polar surfaces in an ultra-fast and robust way,but hardly adhered to nonpolar materials.It demonstrated up to five-fold increase in shear adhesive strength and interfacial adhesive toughness with external loading rates varying from 5 to 500 mm min^(-1).With a mechanochemical coupling model based on Monte Carlo simulations,we quantitatively revealed the nonlinear dependence of rate-sensitive interfacial adhesion on external loading,which was in good agreement with the experimental data.Likewise,the developed hydrogels were biocompatible,possessed antioxidant and antibacterial properties and promoted wound healing.This work not only reports a stimuli-responsive hydrogel adhesive suitable for multiple biomedical applications,but also offers an innovative strategy for bionic designs of smart hydrogels with loading rate-sensitive specific adhesion for various emerging areas including flexible electronics and soft robotics.

Complex coacervate-derived hydrogel with asymmetric and reversible wet bioadhesion for preventing UV light-induced morbidities

Protecting the skin from UV light irradiation in wet and underwater environments is challenging due to the weak adhesion of existing sunscreen materials but highly desired.Herein we report a polyethyleneimine/thioctic acid/titanium dioxide(PEI/TA/TiO_(2))coacervate-derived hydrogel with robust,asymmetric,and reversible wet bioadhesion and effective UV-light-shielding ability.The PEI/TA/TiO_(2)complex coacervate can be easily obtained by mixing a PEI solution and TA/TiO_(2)powder.The fluid PEI/TA/TiO_(2)coacervate deposited on wet skin can spread into surface irregularities and subsequently transform into a hydrogel with increased cohesion,thereby establishing interdigitated contact and adhesion between the bottom surface and skin.Meanwhile,the functional groups between the skin and hydrogel can form physical interactions to further enhance bioadhesion,whereas the limited movement of amine and carboxyl groups on the top hydrogel surface leads to low adhesion.Therefore,the coacervate-derived hydrogel exhibits asymmetric adhesiveness on the bottom and top surfaces.Moreover,the PEI/TA/TiO_(2)hydrogel formed on the skin could be easily removed using a NaHCO3 aqueous solution without inflicting damage.More importantly,the PEI/TA/TiO_(2)hydrogel can function as an effective sunscreen to block UV light and prevent UV-induced MMP-9 overexpression,inflammation,and DNA damage in animal skin.The advantages of PEI/TA/TiO_(2)coacervate-derived hydrogels include robust,asymmetric,and reversible wet bioadhesion,effective UV light-shielding ability,excellent biocompatibility,and easy preparation and usage,making them a promising bioadhesive to protect the skin from UV light-associated damage in wet and underwater environments.

Injectable hydrogel wound dressing based on strontium ion cross-linked starch

Severe skin wounds cause great problems and sufferings to patients.In this study,an injectable wound dressing based on strontium ion cross-linked starch hydrogel(SSH)was developed and evaluated.The good inject-ability of SSH made it easy to be delivered onto the wound surface.The good tissue adhesiveness of SSH ensured a firm protection of the wound.Besides,SSH supported the proliferation of NIH/3T3 fibroblasts and facilitated the migration of human umbilical vein endothelial cells(HUVECs).Importantly,SSH exhibited strong antibacterial effects on Staphylococcus aiireiis(S.ai/rec/s),which could prevent wound infection.These results demonstrate that SSH is a promising wound dressing material for promoting wound healing.

Polyphenol-based hydrogels: Pyramid evolution from crosslinked structures to biomedical applications and the reverse design

As a kind of nature-derived bioactive materials, polyphenol-based hydrogels possess many unique and outstanding properties such as adhesion, toughness, and self-healing due to their specific crosslinking structures, which have been widely used in biomedical fields including wound healing, antitumor, treatment of motor system injury, digestive system disease, oculopathy, and bioelectronics. In this review, starting with the classi-fication of common polyphenol-based hydrogels, the pyramid evolution process of polyphenol-based hydrogels from crosslinking structures to derived properties and then to biomedical applications is elaborated, as well as the efficient reverse design considerations of polyphenol-based hydrogel systems are proposed. Finally, the existing problems and development prospects of these hydrogel materials are discussed. It is hoped that the unique perspective of the review can promote further innovation and breakthroughs of polyphenol-based hydrogels in the future.

Dendrimer-based Hydrogels with Controlled Drug Delivery Property for Tissue Adhesion

In recent years,the hydrogel-based tissue adhesives have been extensively investigated for their excellent biocompatibility and the ability to be administered directly within the adherent tissue.To meet the requirement for more controllable release in various physiological settings,the components of hydrogel adhesive should be more precisely tailored.In this work,the POSS-ace-PEG hydrogel adhesive was fabricated with the polyacetal dendrimer G1’-[NH3 Cl]16 and poly(ethylene glycol)succinimidyl carbonate(PEG-SC)due to the regular peripheral amino structure of G1’-[NH3 Cl]16.Rheological and adhesion tests demonstrated that the hydrogel adhesive had good mechanical and adhesive properties,which could effectively adhere to the pigskin and severed nerves.Moreover,the tissue adhesive exhibited good stability under neutral conditions and the rapid degradation under acidic conditions,allowing for the release of doxycycline hydrochloride(DOX)drug in response to pH.Together,these results suggested that the POSS-ace-PEG adhesive had the potential to provide an alternative to tissue adhesives for applications in pathological environments(inflammation,tumors,etc.).

Mechano-active biomaterials for tissue repair and regeneration

There is a lack of effective tissue repair and regeneration strategies in current clinical practices.Numerous studies have suggested that smart or responsive biomaterials possessing the ability to respond to endogenous stimuli in vivo may positively mediate the tissue micro-environment towards a tissue repair or regeneration.Mechanical stimuli,which constantly exist in a wide range of biological systems and are involved in almost all the physiological processes,belong to such stimuli to which responsive biomaterials can respond.In recent studies,a new type of smart biomaterials,which can dynamically adapt to the mechanical stimuli in vivo and thus has specific functionality consistently mediated by such mechanical stimuli,has emerged.In contrast to common biomaterials that passively react to the mechanical environment of an implantation site,such mechano-active biomaterials have enabled various active or automatic strategies for tissue repair or regeneration,such as providing precise spatial-temporal controls on delivery of drugs or cells in the organs of the musculoskeletal and the circulatory systems;in situ reconstructing the original or a favorable mechanical environment at a lesion site;and accelerating the tissue remodeling or healing process via a mechanobiological effect.This article elucidates a perspective of perfecting tissue repair or regeneration using mechano-active biomaterials,especially highlighting the rationale behind the concept of mechano-active biomaterials and their potential in the repair or regeneration of musculoskeletal and cardiovascular tissues.Albeit outstanding challenges and unknowns,the emergence of mechano-active biomaterials has become a new avenue for tissue engineering and regenerative medicine.