Chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor for neurotrophic keratopathy

Neurotrophic keratopathy is a persistent defect of the corneal epithelium,with or without stromal ulceration,due to corneal nerve deficiency caused by a variety of etiologies.The treatment options for neurotrophic keratopathy are limited.In this study,an ophthalmic solution was constructed from a chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor(CTH-mNGF).Its effectiveness was evaluated in corneal denervation(CD)mice and patients with neurotrophic keratopathy.In the preclinical setting,CTH-mNGF was assessed in a murine corneal denervation model.CTH-mNGF was transparent,thermosensitive,and ensured sustained release of mNGF for over 20 hours on the ocular surface,maintaining the local mNGF concentration around 1300 pg/mL in vivo.Corneal denervation mice treated with CTH-mNGF for 10 days showed a significant increase in corneal nerve area and total corneal nerve length compared with non-treated and CTH treated mice.A subsequent clinical trial of CTH-mNGF was conducted in patients with stage 2 or 3 neurotrophic keratopathy.Patients received topical CTH-mNGF twice daily for 8 weeks.Fluorescein sodium images,Schirmer’s test,intraocular pressure,Cochet-Bonnet corneal perception test,and best corrected visual acuity were evaluated.In total,six patients(total of seven eyes)diagnosed with neurotrophic keratopathy were enrolled.After 8 weeks of CTH-mNGF treatment,all participants showed a decreased area of corneal epithelial defect,as stained by fluorescence.Overall,six out of seven eyes had fluorescence staining scores<5.Moreover,best corrected visual acuity,intraocular pressure,Schirmer’s test and Cochet-Bonnet corneal perception test results showed no significant improvement.An increase in corneal nerve density was observed by in vivo confocal microscopy after 8 weeks of CTH-mNGF treatment in three out of seven eyes.This study demonstrates that CTH-mNGF is transparent,thermosensitive,and has sustained-release properties.Its effectiveness in healing corneal epithelial defects in all eyes with neurotrophic keratopathy suggests CTH-mNGF has promising application prospects in the treatment of neurotrophic keratopathy,being convenient and cost effective.

Nanozyme‑Engineered Hydrogels for Anti‑Inflammation and Skin Regeneration

Inflammatory skin disorders can cause chronic scarring and functional impairments,posing a significant burden on patients and the healthcare system.Conventional therapies,such as corticosteroids and nonsteroidal anti-inflammatory drugs,are limited in efficacy and associated with adverse effects.Recently,nanozyme(NZ)-based hydrogels have shown great promise in addressing these challenges.NZ-based hydrogels possess unique therapeutic abilities by combining the therapeutic benefits of redox nanomaterials with enzymatic activity and the water-retaining capacity of hydrogels.The multifaceted therapeutic effects of these hydrogels include scavenging reactive oxygen species and other inflammatory mediators modulating immune responses toward a pro-regenerative environment and enhancing regenerative potential by triggering cell migration and differentiation.This review highlights the current state of the art in NZ-engineered hydrogels(NZ@hydrogels)for anti-inflammatory and skin regeneration applications.It also discusses the underlying chemo-mechano-biological mechanisms behind their effectiveness.Additionally,the challenges and future directions in this ground,particularly their clinical translation,are addressed.The insights provided in this review can aid in the design and engineering of novel NZ-based hydrogels,offering new possibilities for targeted and personalized skin-care therapies.

Ionization Engineering of Hydrogels Enables Highly Efficient Salt‑Impeded Solar Evaporation and Night‑Time Electricity Harvesting

Interfacial solar evaporation holds immense potential for brine desalination with low carbon footprints and high energy utilization.Hydrogels,as a tunable material platform from the molecular level to the macroscopic scale,have been considered the most promising candidate for solar evaporation.However,the simultaneous achievement of high evaporation efficiency and satisfactory tolerance to salt ions in brine remains a challenging scientific bottleneck,restricting the widespread application.Herein,we report ionization engineering,which endows polymer chains of hydrogels with electronegativity for impeding salt ions and activating water molecules,fundamentally overcoming the hydrogel salt-impeded challenge and dramatically expediting water evaporating in brine.The sodium dodecyl benzene sulfonate-modified carbon black is chosen as the solar absorbers.The hydrogel reaches a ground-breaking evaporation rate of 2.9 kg m−2 h−1 in 20 wt%brine with 95.6%efficiency under one sun irradiation,surpassing most of the reported literature.More notably,such a hydrogel-based evaporator enables extracting clean water from oversaturated salt solutions and maintains durability under different high-strength deformation or a 15-day continuous operation.Meantime,on the basis of the cation selectivity induced by the electronegativity,we first propose an all-day system that evaporates during the day and generates salinity-gradient electricity using waste-evaporated brine at night,anticipating pioneer a new opportunity for all-day resource-generating systems in fields of freshwater and electricity.

Application of Optical Hydrogels in Environmental Sensing

The ever-increasing complexity of environmental pollutants urgently warrants the development of new detection technologies.Sensors based on the optical properties of hydrogels enabling fast and easy in situ detection are attracting increasing attention.In this paper,the data from 138 papers about different optical hydrogels(OHs)are extracted for statistical analysis.The detection performance and potential of various types of OHs in different environmental pollutant detection scenarios were evaluated and compared to those obtained using the standard detection method.Based on this analysis,the target recognition and sensing mechanisms of two main types of OHs are reviewed and discussed:photonic crystal hydrogels(PCHs)and fluorescent hydrogels(FHs).For PCHs,the environmental stimulus response,target receptors,inverse opal structures,and molecular imprinting techniques related to PCHs are reviewed and summarized.Furthermore,the different types of fluorophores(i.e.,compound probes,biomacromolecules,quantum dots,and luminescent microbes)of FHs are discussed.Finally,the potential academic research directions to address the challenges of applying and developing OHs in environmental sensing are proposed,including the fusion of various OHs,introduction of the latest technologies in various fields to the construction of OHs,and development of multifunctional sensor arrays.

Fluorescent Double Network Hydrogels with Ionic Responsiveness and High Mechanical Properties for Visual Detection

We developed a fluorescent double network hydrogel with ionic responsiveness and high mechanical properties for visual detection.The nanocomposite hydrogel of laponite and polyacrylamide serves as the first network,while the ionic cross-linked hydrogel of terbium ions and sodium alginate serves as the second network.The double-network structure,the introduction of nanoparticles and the reversible ionic crosslinked interactions confer high mechanical properties to the hydrogel.Terbium ions are not only used as the ionic cross-linked points,but also used as green emitters to endow hydrogels with fluorescent properties.On the basis of the “antenna effect” of terbium ions and the ion exchange interaction,the fluorescence of the hydrogels can make selective responses to various ions(such as organic acid radical ions,transition metal ions) in aqueous solutions,which enables a convenient strategy for visual detection toward ions.Consequently,the fluorescent double network hydrogel fabricated in this study is promising for use in the field of visual sensor detection.

White-light-induced synthesis of injectable alginate-based composite hydrogels for rapid hemostasis

Dear Editor,Timely and effective hemostasis is of great significance for reducing body damage and mortality of patients [1]. Alginate is generally considered to be an excellent hemostatic polymer-based biomaterial and has been approved by the Food and Drug Administration as Generally Recognized as Safe [2]. However, the violent crosslinking reaction and unstable structure at the wound site limit its clinical applications. Hence, we report a biocompatible and injectable composite hydrogel methacrylate alginate (Alg-AEMA)-based Eosin Y/N-phenylglycine (NPG)-initiated composite hydrogel (AEC) composed of photocrosslinkable alginate, viscosity modifiers and novel white light photoinitiator, namely Eosin Y/NPG system, for instant hemorrhage control.

Smart molecules in ophthalmology:Hydrogels as responsive systems for ophthalmic applications

This comprehensive review delves into a unique intersection of hydrogels as smart molecules and their transformative applications in ophthalmology.Beginning with the foundational definition,properties,and classification of hydrogels,the review explores their synthesis and responsive capabilities.Specific applications examined encompass topical drug delivery,contact lenses,intravitreal drug delivery,ocular adhesives,vitreous substitutes,and cell-based therapy.A methodical analysis,including an overview of relevant ocular structures and a comparative evaluation of hydrogel-based solutions against traditional treatments,is conducted.Additionally,potential constraints,translation challenges,knowledge gaps,and research areas are identified.Our methodical approach,guided by an extensive literature review from 2017 to 2023,illuminates the unprecedented opportunities offered by hydrogels,along with pinpointing areas for further inquiry to facilitate their transition into clinical practice.

Recent advances on thermosensitive hydrogels-mediated precision therapy

Precision therapy has become the preferred choice attributed to the optimal drug concentration in target sites,increased therapeutic efficacy,and reduced adverse effects.Over the past few years,sprayable or injectable thermosensitive hydrogels have exhibited high therapeutic potential.These can be applied as cell-growing scaffolds or drug-releasing reservoirs by simply mixing in a free-flowing sol phase at room temperature.Inspired by their unique properties,thermosensitive hydrogels have been widely applied as drug delivery and treatment platforms for precision medicine.In this review,the state-of-theart developments in thermosensitive hydrogels for precision therapy are investigated,which covers from the thermo-gelling mechanisms and main components to biomedical applications,including wound healing,anti-tumor activity,osteogenesis,and periodontal,sinonasal and ophthalmic diseases.The most promising applications and trends of thermosensitive hydrogels for precision therapy are also discussed in light of their unique features.

Hierarchical Self‑Assembly of Injectable Alginate Supramolecular Nanofibril Hydrogels for Hemostasis In Vivo

Biomass-based supramolecular hydrogels are widely used in the biomedical field due to their favorable biocompatibility and outstanding mechanical properties.However,the preparation of injectable polysaccharide-based hydrogels has proven to be a significant challenge.Here we have employed a simple poor-solvent strategy to prepare alginate supramolecular hydrogels via a hierarchical self-assembly process,including micellization,micelles alignment to form nanofilament,and nanofibrils formation.The alginate supramolecular fibrillar hydrogels exhibit excellent mechanical properties and shear recoverability,meeting the requirements of injectable hydrogels.Furthermore,the presence of alginate and its fibrillar structures imparts superb hemostasis properties and the inherent biocompatibility to these hydrogels.Therefore,this simple and intriguing approach has the potential to develop polysaccharide-based hydrogels for hemostasis in wound within the biomedical fields.

Advances in Biomedical Applications of Hydrogels from Seaweed-Derived Sulfated Polysaccharides:Carrageenan,Fucoidan,and Ulvan

Sulfated polysaccharides extracted from seaweeds,including Carrageenan,Fucoidan and Ulvan,are crucial bioactive compounds known for their diverse beneficial properties,such as anti-inflammatory,antitumor,immunomodulatory,antiviral,and anticoagulant effects.These polysaccharides form hydrogels hold immense promise in biomedicine,particularly in tissue engineering,drug delivery systems and wound healing.This review comprehensively explores the sources and structural characteristics of the three important sulfated polysaccharides extracted from different algae species.It elucidates the gelation mechanisms of these polysaccharides into hydrogels.Furthermore,the biomedical applications of these three sulfated polysaccharide hydrogels in wound healing,drug delivery,and tissue engineering are discussed,highlighting their potential in the biomedicine.

Development of biomedical hydrogels for rheumatoid arthritis treatment

Rheumatoid Arthritis(RA)is an autoimmune disorder that hinders the normal functioning of bones and joints and reduces the quality of human life.Every year,millions of people are diagnosed with RA worldwide,particularly among elderly individuals and women.Therefore,there is a global need to develop new biomaterials,medicines and therapeutic methods for treating RA.This will improve the Healthcare Access and Quality Index and also relieve administrative and financial burdens on healthcare service providers at a global scale.Hydrogels are soft and cross-linked polymeric materials that can store a chunk of fluids,drugs and biomolecules for hydration and therapeutic applications.Hydrogels are biocompatible and exhibit excellent mechanical properties,such as providing elastic cushions to articulating joints by mimicking the natural synovial fluid.Hence,hydrogels create a natural biological environment within the synovial cavity to reduce autoimmune reactions and friction.Hydrogels also lubricate the articulating joint surfaces to prevent degradation of synovial surfaces of bones and cartilage,thus exhibiting high potential for treating RA.This work reviews the progress in injectable and implantable hydrogels,synthesis methods,types of drugs,advantages and challenges.Additionally,it discusses the role of hydrogels in targeted drug delivery,mechanistic behaviour and tribological performance for RA treatment.

Tuning mechanical behaviors of highly entangled hydrogels with the random distribution of mobile entanglements

Highly entangled hydrogels exhibit excellent mechanical properties,including high toughness,high stretchability,and low hysteresis.By considering the evolution of randomly distributed entanglements within the polymer network upon mechanical stretches,we develop a constitutive theory to describe the large stretch behaviors of these hydrogels.In the theory,we utilize a representative volume element(RVE)in the shape of a cube,within which there exists an averaged chain segment along each edge and a mobile entanglement at each corner.By employing an explicit method,we decouple the elasticity of the hydrogels from the sliding motion of their entanglements,and derive the stress-stretch relations for these hydrogels.The present theoretical analysis is in agreement with experiment,and highlights the significant influence of the entanglement distribution within the hydrogels on their elasticity.We also implement the present developed constitutive theory into a commercial finite element software,and the subsequent simulations demonstrate that the exact distribution of entanglements strongly affects the mechanical behaviors of the structures of these hydrogels.Overall,the present theory provides valuable insights into the deformation mechanism of highly entangled hydrogels,and can aid in the design of these hydrogels with enhanced performance.

Light-based 3D printing of stimulus-responsive hydrogels forminiature devices:recent progress and perspective

Miniature devices comprising stimulus-responsive hydrogels with high environmental adaptability are now considered competitive candidates in the fields of biomedicine,precise sensors,and tunable optics.Reliable and advanced fabricationmethods are critical formaximizing the application capabilities ofminiature devices.Light-based three-dimensional(3D)printing technology offers the advantages of a wide range of applicable materials,high processing accuracy,and strong 3D fabrication capability,which is suitable for the development of miniature devices with various functions.This paper summarizes and highlights the recent advances in light-based 3D-printed miniaturized devices,with a focus on the latest breakthroughs in lightbased fabrication technologies,smart stimulus-responsive hydrogels,and tunable miniature devices for the fields of miniature cargo manipulation,targeted drug and cell delivery,active scaffolds,environmental sensing,and optical imaging.Finally,the challenges in the transition of tunable miniaturized devices from the laboratory to practical engineering applications are presented.Future opportunities that will promote the development of tunable microdevices are elaborated,contributing to their improved understanding of these miniature devices and further realizing their practical applications in various fields.

Evaluation of different crosslinking methods in altering the properties of extrusion-printed chitosan-basedmulti-material hydrogel composites

Three-dimensional printing technologies exhibit tremendous potential in the advancing fields of tissue engineering and regenerative medicine due to the precise spatial control over depositing the biomaterial.Despite their widespread utilization and numerous advantages,the development of suitable novel biomaterials for extrusion-based 3D printing of scaffolds that support cell attachment,proliferation,and vascularization remains a challenge.Multi-material composite hydrogels present incredible potential in this field.Thus,in this work,a multi-material composite hydrogel with a promising formulation of chitosan/gelatin functionalized with egg white was developed,which provides good printability and shape fidelity.In addition,a series of comparative analyses of different crosslinking agents and processes based on tripolyphosphate(TPP),genipin(GP),and glutaraldehyde(GTA)were investigated and compared to select the ideal crosslinking strategy to enhance the physicochemical and biological properties of the fabricated scaffolds.All of the results indicate that the composite hydrogel and the resulting scaffolds utilizing TPP crosslinking have great potential in tissue engineering,especially for supporting neo-vessel growth into the scaffold and promoting angiogenesis within engineered tissues.

Advanced Nanocomposite Arabic Gum Polyacrylic Acid Hydrogels for Flexible Supercapacitors

In this work,the fabrication and characterization of the nanocomposite hydrogel,as a solid electrode in electro-chemical cell and gel electrolyte material using Indium titanium oxide/polyethylene terephthalate(ITO/PET)flex-ible substrate for double-layer supercapacitors have been reported.The nanocomposite hydrogel composed of Arabic gum(AG),Acrylic acid(AA),reduced graphene oxide(RGO),and silver nanoparticles(AgNPs)was fab-ricated via a physical cross-linked polymerization reaction,in which the ascorbic acid was used as a reducing agent to generate AgNPs and to convert Graphene oxide(GO)to RGO during the polymerization reaction.The morphology and structural characteristics of nanocomposite hydrogel were investigated using atomic force microscopy(AFM),scanning electron microscope(SEM),Fourier transfer infrared(FTIR),and X-rayfluores-cence(XRF).Additionally,the effect of RGO and AgNPs on hydrogel stability was assessed through Thermogra-vimetric analysis(TGA)and differential scanning calorimetry(DSC),while its mechanical properties were studied using the nanoindentation test.Electrochemical impedance spectroscopy(EIS),and cyclic voltammetry(CV)were also conducted to study the electrochemical properties of the prepared hydrogel.The effects of AgNPs,RGO,and water content were all considered in the study of supercapacitor performance.The microstructural tests showed that the nanocomposite hydrogel has a relatively high swelling rate,which has a crucial effect on the capa-citance.Furthermore,the effects of increasing AgNP concentration and water content in the hydrogel matrix showed a significant improvement in its electrochemical performance,compared with that for Arabic gum poly acrylic acid(AGPAA)hydrogel itself,were the specific capacitance exhibited a significant enhancement,convert-ing from a low value to a substantially higher capacitance value.Moreover,when the nanocomposite hydrogel was used as the working electrode in an electrochemical cell with a hydrochloric acid(HCl)electrolyte solution,it exhibited good electrode performance.Additionally,using(ITO/PET)as aflexible substrate for nanocomposite hydrogel shows an improvement in their suitability for supercapacitor applications.Therefore,it is suggested that the fabricated hydrogel supercapacitor has potential applications in thefield of renewable and clean energy harvesting.

Thermosensitive and Wound-Healing Gelatin-Alginate Biopolymer Hydrogels Modified with Humic Acids

The main goal of the article is the creation and study of thermosensitive and wound-healing gelatin-alginate bio-polymer hydrogels modified with humic acids.Their rheological properties,swelling and contraction behavior were experimentally investigated,elucidated using Fourier transform infrared spectroscopy and used to achieve the physiological melting point,which is necessary for successful drug delivery.It has been shown that in the gelatin-alginate-humic acid biopolymer hydrogels systems,it is possible to obtain a gel-sol transition temperature close to the physiological temperature of 37℃,which is important for drug delivery in the treatment of wounds.By changing the type and concentration of humic acids in the gelatin-alginate hydrogel,it turned out to be achiev-able to regulate the softening time of the gel on the human body in the range from 6 to 20 min,which provides the possibility of controlled prolonged delivery of drugs.Based on the study of the influence of calcium ions on the properties of humic acids and ion exchange,as well as the interaction of humic acids,sodium alginate and gelatin with the formation of tighter gel networks,approaches to regulate the rate of softening of hydrogels at physiological temperature and their swelling,which simulates the absorption of exudate,were proposed and implemented.In addition,low shrinkage of the hydrogel surface due to cross-linking of gelatin-alginate networks when modified with humic acids was experimentally confirmed,which is important for avoiding problems of wound contracture and contour deformations when using dressings for wound healing.Thus,the developed opti-mized innovative biopolymer hydrogels synergistically combine the outstanding properties of natural molecular polymers and humic acids and are promising for the creation of effective medicines for wound healing.

Biomimetic fibril-like injectable hydrogels for wound management

Soft tissue repair and regeneration present a significant clinical challenge.Soft hydrogels have emerged as a promising solution for promoting stem cell differentiation and facilitating soft tissue formation[1].Various materials,including synthetic polymers like polydimethyl siloxane and natural polymers like proteins,have been be used as hydrogel matrix for hydrogel preparation[2,3].However,the limited biodegradability,inhomogeneous network structure,and inadequate mechanical properties of these hydrogels hinder their long-term application in complex environments in vivo.Inspired by the nanostructure of collagen fibrils,Li et al.developed a strategy for creating injectable nanofibrillar hydrogels by combining self-assembly and chemical crosslinking of nanoparticles[4].Moreover,injectable hydrogels offer advantages as implantable materials,including better defect filling and reduced risk of infection compared to prefabricated hydrogels[5].

Mechanical properties modulation and biological applications of DNA hydrogels

DNA hydrogels are three-dimensional polymer networks constructed using DNA as the structural building block.Due to the tight binding between hydrophilic groups on DNA chains and water molecules,they exhibit outstanding plasticity and fluid thermodynamic properties,making them one of the best choices for mimicking natural biological tissues.By controlling the backbone building blocks,gelation conditions,and cross-linking methods of DNA hydrogels,hydrogels with different mechanical strengths can be obtained,thus expanding their applications in the field of biology.This review first introduces the relationship between the mechanical properties of DNA hydrogels and their structure,elucidates the approaches and strategies for mechanical property modulation,and focuses on the scheme of controllable design to modulate the mechanical properties of DNA hydrogels for applications in biosensing,cellular function regulation,and bone tissue engineering.Furthermore,this review outlines the future development directions and challenges faced in the mechanical property modulation of DNA hydrogels,providing useful information for the precise design of DNA hydrogels for biological research.

3D Printing of Tough Hydrogel Scaffolds with Functional Surface Structures for Tissue Regeneration

Hydrogel scaffolds have numerous potential applications in the tissue engineering field.However,tough hydrogel scaffolds implanted in vivo are seldom reported because it is difficult to balance biocompatibility and high mechanical properties.Inspired by Chinese ramen,we propose a universal fabricating method(printing-P,training-T,cross-linking-C,PTC&PCT)for tough hydrogel scaffolds to fill this gap.First,3D printing fabricates a hydrogel scaffold with desired structures(P).Then,the scaffold could have extraordinarily high mechanical properties and functional surface structure by cycle mechanical training with salting-out assistance(T).Finally,the training results are fixed by photo-cross-linking processing(C).The tough gelatin hydrogel scaffolds exhibit excellent tensile strength of 6.66 MPa(622-fold untreated)and have excellent biocompatibility.Furthermore,this scaffold possesses functional surface structures from nanometer to micron to millimeter,which can efficiently induce directional cell growth.Interestingly,this strategy can produce bionic human tissue with mechanical properties of 10 kPa-10 MPa by changing the type of salt,and many hydrogels,such as gelatin and silk,could be improved with PTC or PCT strategies.Animal experiments show that this scaffold can effectively promote the new generation of muscle fibers,blood vessels,and nerves within 4 weeks,prompting the rapid regeneration of large-volume muscle loss injuries.

A matrix metalloproteinase-responsive hydrogel system controls angiogenic peptide release for repair of cerebral ischemia/reperfusion injury

Vascular endothelial growth factor and its mimic peptide KLTWQELYQLKYKGI(QK)are widely used as the most potent angiogenic factors for the treatment of multiple ischemic diseases.However,conventional topical drug delivery often results in a burst release of the drug,leading to transient retention(inefficacy)and undesirable diffusion(toxicity)in vivo.Therefore,a drug delivery system that responds to changes in the microenvironment of tissue regeneration and controls vascular endothelial growth factor release is crucial to improve the treatment of ischemic stroke.Matrix metalloproteinase-2(MMP-2)is gradually upregulated after cerebral ischemia.Herein,vascular endothelial growth factor mimic peptide QK was self-assembled with MMP-2-cleaved peptide PLGLAG(TIMP)and customizable peptide amphiphilic(PA)molecules to construct nanofiber hydrogel PA-TIMP-QK.PA-TIMP-QK was found to control the delivery of QK by MMP-2 upregulation after cerebral ischemia/reperfusion and had a similar biological activity with vascular endothelial growth factor in vitro.The results indicated that PA-TIMP-QK promoted neuronal survival,restored local blood circulation,reduced blood-brain barrier permeability,and restored motor function.These findings suggest that the self-assembling nanofiber hydrogel PA-TIMP-QK may provide an intelligent drug delivery system that responds to the microenvironment and promotes regeneration and repair after cerebral ischemia/reperfusion injury.