Study on Preparation of Temperature-sensitive Injectable Hydrogel

To get a sort of new scaffold material for soft tissue reconstruction,we have prepared XLHA-PNIPAAm and XLHA-MC injectable hydrogels through blending crosslinked HA(XLHA) and two temperature-sensitive materials differed in degradation poly(N-isopropylacrylamide)(PNIPAAm) and methylcellulose(MC),respectively.We tested the injectablility,enzymatic biodegradability,temperature-sensitivity,structure cytotoxicity and hemolysis of the two injectable hydrogels.Our research has successfully obtained the preparation condition of XLHA-PNIPAAm injectable hydrogel,and verified that adding non-degradable material PNIPAAm can postpone the degradation of HA more effectively than degradable material MC.PNIPAAm prepared with 5 kGy dose radiation,MBAAm/NIPAAm(M/M)=0.015,monomer concentration=3% produced XLHA-PNIPAAm with slowest enzymatic biodegradability.DSC results showed that temperature-sensitivity of the XLHA-PNIPAAm was more stable than that of XLHA-MC.Two composite hydrogels were qualified in cytotoxicity and hemolysis tests and the biocompatibility of XLHA-PNIPAAm hydrogel showed better than XLHA-MC hydrogel.

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.

Bioinspired Injectable Self-Healing Hydrogel Sealant with Fault-Tolerant and Repeated Thermo-Responsive Adhesion for Sutureless Post-Wound-Closure and Wound Healing

Hydrogels with multifunctionalities,including sufficient bonding strength,injectability and self-healing capacity,responsive-adhesive ability,fault-tolerant and repeated tissue adhesion,are urgently demanded for invasive wound closure and wound healing.Motivated by the adhesive mechanism of mussel and brown algae,bioinspired dynamic bonds cross-linked multifunctional hydrogel adhesive is designed based on sodium alginate(SA),gelatin(GT)and protocatechualdehyde,with ferric ions added,for sutureless post-wound-closure.The dynamic hydrogel cross-linked through Schiff base bond,catechol-Fe coordinate bond and the strong interaction between GT with temperature-dependent phase transition and SA,endows the resulting hydrogel with sufficient mechanical and adhesive strength for efficient wound closure,injectability and self-healing capacity,and repeated closure of reopened wounds.Moreover,the temperature-dependent adhesive properties endowed mispositioning hydrogel to be removed/repositioned,which is conducive for the fault-tolerant adhesion of the hydrogel adhesives during surgery.Besides,the hydrogels present good biocompatibility,near-infrared-assisted photothermal antibacterial activity,antioxidation and repeated thermo-responsive reversible adhesion and good hemostatic effect.The in vivo incision closure evaluation demonstrated their capability to promote the post-wound-closure and wound healing of the incisions,indicating that the developed reversible adhesive hydrogel dressing could serve as versatile tissue sealant.

Injectable <i>in situ</i>crosslinkable hyaluronan-polyvinyl phosphonic acid hydrogels for bone engineering

A novel injectable hydrogel that was synthesized by in situ crosslinking of hyaluronan and polyvinyl phosphonic acid was proposed in this study. Fourier transform infrared spectrum (FT-IR) analysis, scanning electron microscope (SEM), pH measurement, and biodegradation test were used to confirm its characteristics. The results permitted to prove successful crosslinking, observe the inner morphology of hydrogel and pore sizes distribution, and determine the decomposition of hydrogel components during incubation time. Result of pH measurement showed that the pH scale of hydrogel decreased when volume of PVPA increased. As a consequence, it affected the cytotoxicity value, cell proliferation, and cell growth behaviors of each hydrogel. Optical microscope observation showed that chondroblasts cell proliferated well on HA-PVPA hydrogel. Therefore, these results suggest that the new injectable hydrogel is appropriate for bone/cartilage regeneration applications.

Synthesis and characteristics of pH-and temperature-sensitive hydrogels of poly （DMAEMA/NIPAAm）

A kind of novel copolymer hydrogel of poly（N, N-dimethylaminoethyl methacrylate-co-N-isopropylacrylamide） （poly[DMAEMA/NIPAAm]） was synthesized by the initiation of K2S2O8, N, N＇-methylene-bis（acrylamide） （Bis） was used as the crosslinker. The effects of monomer content, pH and temperature on swelling ratio of the hydrogel were investigated; the thermo-sensitivity in deionized water and in physiological saline was determined. It showed that the swelling ratio of the hydrogel could be changed by changing the temperature or pH alternately. Both swelling ratio and LCST （Lower Critical Solution Temperature） of the hydrogel decreased with the increase of NIPAAm in the co-polymer content.

Finite deformation swelling of a temperature-sensitive hydrogel cylinder under combined extension-torsion

The swelling behavior of a temperature-sensitive poly-N-isopropylacrylamide(PNIPAM) hydrogel circular cylinder is studied subjected to combined extension-torsion and varied temperature. In this regard, a semi-analytical solution is proposed for general combined loading. A finite element(FE) analysis is conducted, subjecting a hydrogel cylinder to the combined extension-torsion and the varied temperature to evaluate the validity and accuracy of the solution. A user-defined UHYPER subroutine is developed and verified under free and constrained swelling conditions. The FE results illustrate excellent agreement with the semi-analytical solution. Due to the complexity of the problem, some compositions and applied loading factors are analyzed. It is revealed that for larger cross-linked density and larger ending temperature, the cylinder yields higher stresses and smaller radial swelling deformation. Besides, the radial and hoop stresses increase by applying larger twist and axial stretch. The hoop stresses intersect at approximately R/Rout = 0.58, where the hoop stress vanishes. Besides, the axial force has direct and inverse relationships with the axial stretch and the twist, respectively. However, the resultant torsional moment behavior is complex, and the position of the maximum point varies significantly by altering the axial stretch and the twist.

Preparation and Evaluation of an Injectable Chitosan-Hyaluronic Acid hydrogel for Peripheral Nerve Regeneration

The aim of this study was to obtain the fillers in the lumen of hollow nerve conduits（NCs） to improve the microenvironment of nerve regeneration. A p H-induced injectable chitosan（CS）-hyaluronic acid（HA） hydrogel for nerve growth factor（NGF） sustained release was developed. Its properties were characterized by gelation time, FT-IR, SEM, in vitro swelling and degradation. Furthermore, the in vitro NGF release profiles and cell biocompatibility were also investigated. The experimental results show that the CS-HA aqueous solution can undergo a rapid gelation 3 minutes after its environmental p H is changed to 7.4. The CSHA hydrogel has interconnected channels with a controllable pore diameter and with a porosity of about 80%. It has a favorable swelling behavior and can be degraded by about 70% within 8 weeks in vitro and is suitable for NGF release. The CS-HA/NGF hydrogel exhibits a lower cytotoxicity and is in favor of the adhesion and proliferation of the BMMSCs cells. It is indicated that the CS-HA/NGF will be a promising candidate for neural tissue engineering.

Preparation of Thermosensitive Chitosan Formulations Containing 5-Fluorouracil/Poly-3-hydroxybutyrate Microparticles Used as Injectable Drug Delivery System

The auto-gelling and drug release properties of the thermosensitive chitosan-β-glycerophosphate formulation were investigated. According to rheological study, gelation lag time of chitosan/β-glycerophosphate （GP） solutions varied from 2 to 60min with different deacetylation degree of chitosan, pH, gelation temperature, and the particles in the sol. The gelation properties were also found to influence the release profilles of a hydrophilic drug, 5-fluorouracil （5-FU）. Morphological examination by scanning electron microphotography demonstrated that large ＂pores＂ occurred during the gel-forming process, which created hydrophilic environment and led to the rapid initial release of the drug （85% in f＇LrSt 8h）. Poly-3-hydroxybutyrate （PHB）, a biodegradable material, was applied here as scaffold to capture 5-FU into microparticles with high encapsulation efficiency by solvent-nonsolvent method. Combination of these microparticles into the chitosan-β-GP formulation could drop the rapid initial release from 85% down to 29% in the optimized PHB content （75%, by mass）. The release could sustain for about 10 months. Tiffs study provided an understanding of the potential of injectable implant using thermosensitive chitosan-β-GP formulation containing PHB based particles for the water soluble drugs that need the property of long-term delivery.

Intratympanic injection of hydrogel nanodrug for the prevention and treatment of sensorineural hearing loss

Safe and efficient drug delivery to the inner ear has always been the focus of prevention and treatment of sensorineural deafness.The rapid development of nanodrug delivery systems based on hydrogel has provided a new opportunity.Among them,thermo-sensitive hydrogels promote the development of new dosage form for intratympanic injection.This smart biomaterial could transform to semisolid phase when the temperature increased.Thermo-sensitive hydrogel nanodrug delivery system is expected to achieve safe,efficient,and sustained inner ear drug administration.This article introduces the key techniques and the latest progress in this field.

Photo-responsive Carboxymethyl Chitosan/Laponite Hydrogel as a Potential Spinal Cord Injury Scaffold:Characterization and Cytocompatibility Study

We synthesized photo-responsive carboxymethyl chitosan(CMC-MA)via free radical polymerization and utilized nanoclay laponite(LAP)as an inorganic crosslinking agent to develop an injectable and 3D-printable CMC-MA/LAP hydrogel.We determined the optimal ratio of 2.5 w/v%CMC-MA/7.5 w/v%LAP based on injection molding,compression modulus,swelling properties,rheological properties,and 3D printing properties of the hydrogel system.In-vitro cytocompatibility experiments showed that both CMC-MA and CMC-MA/LAP hydrogel had no inhibitory effect on cell proliferation and can promote cell growth when cultured on the surface of the hydrogel matrix.Moreover,the hydrogel containing LAP particles significantly facilitated cell adhesion(>60%)compared with the hydrogel without LAP(20%).Our findings demonstrate that the CMC-MA/LAP hydrogel has great potential for tissue repair in neural tissue engineering.

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.

Autophagy inhibition mediated via an injectable and NO-releasing hydrogelfor amplifying the antitumor efficacy of mild magnetic hyperthermia

While mild hyperthermia holds great potential in the treatment of solid tumors, the thermal stress-triggered selfrepairingautophagy significantly compromises its efficacy. To circumvent this obstacle, an injectable hydrogel(NO-Gel) composed of thermosensitive poly(ethylene glycol)-polypeptide copolymers modified with abundantNO donors on their side chains is developed. Meanwhile, ferrimagnetic Zn0.5Fe2.5O4 magnetic nanoparticles(MNPs) with high magnetic-heat conversion efficiency are synthesized and loaded into NO-Gel to obtainMNPs@NO-Gel. The MNPs@NO-Gel system exhibits a sol-gel transition upon heating, and has the ability toperform multiple magnetic hyperthermia therapy (MHT) after only one administration due to the even distributionand strong immobilization of MNPs in NO-Gel. NO can be continuously liberated from NO-Gel and thisprocess is markedly accelerated by MHT. Additionally, MNPs@NO-Gel maintains its integrity in vivo for over onemonth and the released MNPs are metabolized by the spleen. After a single administration of MNPs@NO-Gel atthe tumor site, three mild MHT treatments with similar effects are fulfilled, and the sufficient supply of NOeffectively inhibits MHT-induced autophagic flux via blocking the formation of autophagosomes and synchronouslydestroying lysosomes, thereby substantially boosting the efficacy of mild MHT. As a consequence, CT-26colon tumors are completely eliminated without causing severe side-effects.

Injectable“cocktail”hydrogel with dual-stimuli-responsive drug release,photothermal ablation,and drug-antibody synergistic effect

The combination of the first-line standard chemotherapeutic drug doxorubicin hydrochloride(DOX)and the molecular-targeted drug Herceptin(HCT)has emerged as a promising strategy for human epidermal growth receptor 2(HER-2)overexpressing breast cancer treatment.However,insufficient drug accumulation and severe cardiotoxicity are two major challenges that limit its clinical application.Herein,an in situ forming gold nanorods(AuNRs)-sodium alginate(ALG)hybrid hydrogel encapsulating DOX and HCT was engineered for tumor synergistic therapy involving injectable,dual-stimuli-responsive drug release,photothermal ablation,and drug-antibody synergistic therapy.The photothermal agent AuNRs,anticancer drug DOX,and anticancer antibody HCT were mixed in ALG solution,and after injection,the soluble ALG was quickly transformed into a hydrogel in the presence of Ca^(2+)in the body.Significantly,the hybrid hydrogel exhibits an extremely high photothermal conversion efficiency of 70%under 808 nm laser irradiation.The thermal effect can also provide photothermal stimulation to trigger the drug release from the gel matrix.In addition,the drug release rate and the releasing degree are also sensitive to the pH.In vitro studies demonstrated that the PEI-AuNR/DOX/HCT/ALG hydrogel has facilitated the therapeutic efficiency of each payload and demonstrated a strong synergistic killing effect on SK-BR-3 cells.In vivo imaging results showed that the local drug delivery system can effectively reduce the nonspecific distribution in normal tissues and increase drug concentration at tumor sites.The proposed hydrogel system shows significant clinical implications by easily introducing a sustainable photothermal therapy and a potential universal carrier for the local delivery of multiple drugs to overcome the challenges faced in HER-2 overexpressing cancer therapy.

H_(2)O_(2)-Responsive Injectable Polymer Dots Hydrogel for Long-term Photodynamic Therapy of Tumors

Photodynamic therapy(PDT)has been emerged as a promising modality for cancer treatment.However,the development of drug delivery system enabling continuous release of photosensitizers(PSs)for long-term PDT treatment still remains challenges.Herein,a H_(2)O_(2)-responsive injectable hydrogel,covalently crosslinked by N^(1)-(4-boronobenzyl)-N^(3)-(4-boronophenyl)-N^(1),N^(1),N^(3),N^(3)-tetramethylpropane-1,3-diaminium(TSPBA)with PVA containing polythiophene quaternary ammonium salt(PT2)polymer dots(PDots)as a photosensitizer was fabricated.Under the stimulation of H_(2)O_(2),the obtained injectable hydrogel gradually degrades and releases PDots.In vitro experiments suggested that the released PDots could realize efficient tumor cells inhibition through its robust singlet oxygen generation capability upon 577 nm laser irradiation.In vivo studies demonstrated a sustained retention of PDots for at least 7 days following single-dose administration,facilitating efficient tumor inhibition with light treatments for 3 times without apparent biotoxicity.This work presents an innovative polymer dots-based composite local drug delivery system for long-term PDT in cancer treatment.

An injectable,self-healable,and reusable PEDOT:PSS/PVA hydrogel patch electrode for epidermal electronics

Injectability empowers conductive hydrogels to transcend traditional limitations,unlocking a realm of possibilities for innovative medical,wearable,and therapeutic applications that can significantly enhance patient care and quality of life.Here,we report an injectable,self-healable,and reusable hydrogel obtained by mixing the concentrated poly(3,4-ethylenedioxythiophene)doped with polystyrene sulfonate(PEDOT:PSS)suspension(~2 wt.%solid content),polyvinyl alcohol(PVA),and borax.Leveraging the presence of reversible borax/hydroxyl bonds and multiple hydrogen bonds,this PEDOT:PSS/PVA hydrogel exhibits notable shear-thinning behavior and self-healing capabilities,enabling it to be injected as a gel fiber from a syringe.As-prepared injectable hydrogel also demonstrates an ultra-low modulus(~2.5 MPa),reduced on-skin impedance(~45%of commercial electrodes),and high signal-to-noise ratio(SNR)(~15-22 dB)in recording of electrocardiography(ECG),electromyography(EMG),and electroencephalogram(EEG)signals.Furthermore,the injectable hydrogels can be remolded and reinjected as the reusable electrodes,maintaining nearly identical electrophysiological recording capabilities and brain-computer interface(BCI)performance compared to commercial wet electrodes.With their straightforward fabrication,excellent material properties and electronic performance,ease of cleaning,and remarkable reusability,our injectable PEDOT:PSS/PVA hydrogels hold promise for advancements in BCI based electronics and wearable bioelectronics.

Peroxidase-like nanozyme based microenvironment-responsive injectable hydrogel for bacteria-infected wound healing

Hydrogel stands out as one of the most attractive wound dressings due to its excellent moisturizing properties and capacity to absorb wound exudates.However,conventional hydrogel dressings often lack responsiveness to the microenvironment,merely acting as protective barriers for the wound.Consequently,they exhibit limited effectiveness in preventing infection and facilitating wound repair.To address these problems,we have developed a multifunctional injectable hydrogel,CF/MS@HG,based on peroxidase-like nanozymes,aiming at rapidly healing bacterial-infected wounds.The hydrogel is mainly composed of oxidized sodium alginate,aminated gelatin,and polylysine,encapsulating MIL-101(CuFe)NPs(CF)and manganese selenide nanoparticles(MnSe_(2) NPs,or MS NPs).After injection,the complex rapidly gelatinizes at the infected wound site through a Schiff base reaction.In vitro experiments have demonstrated the hydrogel’s strong adhesion and self-healing capabilities.Moreover,CF exhibiting peroxidase(POD)-like activity,catalyzes in situ hydrogen peroxide(H_(2)O_(2))to generate highly toxic hydroxyl radicals(·OH)within the wound microenvironment,inducing oxidative damage to bacteria.Meanwhile,MS decomposes into H2Se in the slightly acidic wound microenvironment,disrupting bacterial metabolism and inhibiting proliferation.The addition of polylysine further enhances the hydrogel’s antibacterial properties.In vivo experiments have shown that the hydrogel exhibits excellent biological safety and significantly promotes wound healing.This multifunctional smart hydrogel holds great promise for the treatment of bacterial-infected wounds.

Polysaccharide based supramolecular injectable hydrogels for in situ treatment of bladder cancer

Implantable system maximizes drug concentration and continuously releases drugs near the tumor,which is an effective tool to solve the difficult retention of chemotherapy drugs in bladder cancer.In this work,a novel polysaccharide supramolecular injectable hydrogel(CCA hydrogels for short)is rapidly constructed by simply mixing cationic chitosan,anionic sulfobutyl etherβ-cyclodextrin(SBE-β-CD)and a trace amount of silver ions.The injected hydrogel reconstituted and regained its shape in less than 1 h,and it can still maintain the elasticity suitable for the human body.By packaging the drug directly,the gel achieves a high concentration of doxorubicin,an anticancer drug.Using MB49-luc cells as the model of bladder tumor for anti-tumor in vivo,the CCA-DOX gel has obvious inhibitory effect on bladder tumor,and its inhibitory effect is much greater than that of free DOX.Therefore,this self-healing injectable hydrogel has great potential for in situ treatment of bladder cancer.

Injectable Electrospun Fiber-Hydrogel Composite Delivery System for Prolonged and Nociceptive-Selective Analgesia

Nociceptive-selective analgesia is often preferred over traditional methods,providing effective pain relief with minimum systemic side effects.The quaternary lidocaine derivative QX-314,is a promising local anesthetic for achieving selective analgesia.However,due to its inability to penetrate the cell membrane,its efficacy is limited to intracellular administration.In this study,we aimed to develop an injectable electrospun fiber-hydrogel composite comprising QX-314-loaded poly(ε-caprolactone)electrospun fiber and capsaicin(Cap)-loaded F127 hydrogel(Fiber-QX314/Gel-Cap composite)for long-term and nociceptive-selective analgesia.The sequential and sustained release mechanism of Cap and QX-314 helped remarkably extend the sensory blockade duration up to 44.0 h,and prevent motor blockade.Specifically,our findings indicated that QX-314 can traverse the cell membrane through the transient receptor potential vanilloid 1 channel activated by Cap,thus targeting the intracellular Na+channel receptor to achieve selective analgesia.Moreover,the composite effectively allevi-ated incision pain by suppressing c-Fos expression in the dorsal root ganglion and reducing the activation of glial cells in the dorsal horn of the spinal cord.Consequently,the Fiber-QX314/Gel-Cap composite,designed for exceptional biosafety and sustained selective analgesia,holds great promise as a non-opioid analgesic.

Injectable body temperature responsive hydrogel for encephalitis treatment via sustained release of nano-anti-inflammatory agents

Skull defects are common in the clinical practice of neurosurgery,and they are easily complicated by encephalitis,which seriously threatens the life and health safety of patients.The treatment of encephalitis is not only to save the patient but also to benefit the society.Based on the advantages of injectable hydrogels such as minimally invasive surgery,self-adaptation to irregularly shaped defects,and easy loading and delivery of nanomedicines,an injectable hydrogel that can be crosslinked in situ at the ambient temperature of the brain for the treatment of encephalitis caused by cranial defects is developed.The hydrogel is uniformly loaded with nanodrugs formed by cationic liposomes and small molecule drugs dexmedetomidine hydrochloride(DEX-HCl),which can directly act on the meninges to achieve sustained release delivery of anti-inflammatory nanodrug preparations and achieve the goal of long-term anti-inflammation at cranial defects.This is the first time that DEX-HCl has been applied within this therapeutic system,which is innovative.Furthermore,this study is expected to alleviate the long-term suffering of patients,improve the clinical medication strategies for anti-inflammatory treatment,promote the development of new materials for cranial defect repair,and expedite the translation of research outcomes into clinical practice.

Decellularised extracellular matrix-based injectable hydrogels for tissue engineering applications

Decellularised extracellular matrix(dECM)is a biomaterial derived from natural tissues that has attracted considerable attention from tissue engineering researchers due to its exceptional biocompatibility and malleability attributes.These advantageous properties often facilitate natural cell infiltration and tissue reconstruction for regenerative medicine.Due to their excellent fluidity,the injectable hydrogels can be administered in a liquid state and subsequently formed into a gel state in vivo,stabilising the target area and serving in a variety of ways,such as support,repair,and drug release functions.Thus,dECM-based injectable hydrogels have broad prospects for application in complex organ structures and various tissue injury models.This review focuses on exploring research advances in dECM-based injectable hydrogels,primarily focusing on the applications and prospects of dECM hydrogels in tissue engineering.Initially,the recent developments of the dECM-based injectable hydrogels are explained,summarising the different preparation methods with the evaluation of injectable hydrogel properties.Furthermore,some specific examples of the applicability of dECM-based injectable hydrogels are presented.Finally,we summarise the article with interesting prospects and challenges of dECM-based injectable hydrogels,providing insights into the development of these composites in tissue engineering and regenerative medicine.