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.

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.

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.

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.

Collagen fibril-like injectable hydrogels from self-assembled nanoparticles for promoting wound healing

Soft hydrogels are excellent candidate materials for repairing various tissue defects,yet the mechanical strength,anti-swelling properties,and biocompatibility of many soft hydrogels need to be improved.Herein,inspired by the nanostructure of collagen fibrils,we developed a strategy toward achieving a soft but tough,anti-swelling nanofibrillar hydrogel by combining the self-assembly and chemical crosslinking of nanoparticles.Specifically,the collagen fibril-like injectable hydrogel was subtly designed and fabricated by self-assembling methylacrylyl hydroxypropyl chitosan(HM)with laponite(LAP)to form nanoparticles,followed by the inter-nanoparticle bonding through photo-crosslinking.The assembly mechanism of nanoparticles was elucidated by both experimental and simulation techniques.Due to the unique structure of the crosslinked nanoparticles,the nanocomposite hydrogels exhibited low stiffness(G’<2 kPa),high compressive strength(709 kPa),and anti-swelling(swelling ratio of 1.07 in PBS)properties.Additionally,by harnessing the photo-crosslinking ability of the nanoparticles,the nanocomposite hydrogels were processed as microgels,which can be three-dimensionally(3D)printed into complex shapes.Furthermore,we demonstrated that these nanocomposite hydrogels are highly biocompatible,biodegradability,and can effectively promote fibroblast migration and accelerate blood vessel formation during wound healing.This work presents a promising approach to develop biomimetic,nanofibrillar soft hydrogels for regenerative medicine applications.

Promoting lacunar bone regeneration with an injectable hydrogel adaptive to the microenvironment

Injectable hydrogel is suitable for the repair of lacunar bone deficiency.This study fabricated an injectable,self-adaptive silk fibroin/mesoporous bioglass/sodium alginate(SMS)composite hydrogel system.With controllable and adjustable physical and chemical properties,the SMS hydrogel could be easily optimized adaptively to different clinical applications.The SMS hydrogel effectively showed great injectability and shapeability,allowing defect filling with no gap.Moreover,the SMS hydrogel displayed self-adaptability in mechanical reinforcement and degradation,responsive to the concentration of Ca2+and inflammatory-like pH value in the microenvi-ronment of bone deficiency,respectively.In vitro biological studies indicated that SMS hydrogel could promote osteogenic differentiation of bone marrow mesenchymal stem cells by activation of the MAPK signaling pathway.The SMS hydrogel also could improve migration and tube formation of human umbilical vein endothelial cells.Investigations of the crosstalk between osteoblasts and macrophages confirmed that SMS hydrogel could regulate macrophage polarization from M1 to M2,which could create a specific favorable environment to induce new bone formation and angiogenesis.Meanwhile,SMS hydrogel was proved to be antibacterial,especially for gram-negative bacteria.Furthermore,in vivo study indicated that SMS could be easily applied for maxillary sinus elevation,inducing sufficient new bone formation.Thus,it is convincing that SMS hydrogel could be potent in a simple,minimally invasive and efficient treatment for the repair of lacunar bone deficiency.

Arginine-solubilized lipoic acid-induced β-sheets of silkfibroin-strengthened hydrogel for postoperative rehabilitation ofbreast cancer

Breast cancer is the most common cancer among women worldwide, and adjuvant radiotherapy (RT) followingtumor removal is one of the most commonly used treatments for breast cancer. However, the high risk of tumorrecurrence and inevitable radiation skin injury after RT remain fatal problems, seriously challenging the patient’spostoperative rehabilitation. Herein, a multifunctional poly (lipoic acid)-based hydrogel is constructed throughone-step heating the mixture of α-lipoic acid (LA)/arginine (Arg)/silk fibroin (SF), without introducing any nonnaturalmolecules. The multiple synergistic interactions among LA, Arg, and SF not only enhance the solubilizationof LA in aqueous systems but also stabilize poly(lipoic acid) through strong salt bridge hydrogen bondsand ionic hydrogen bonds. Intriguingly, the LA-based surfactant induced β-sheet transformation of SF can furthermodulate the bulk strength of the hydrogel. Regulating the content of LA in hydrogels not only allows efficientcontrol of hydrogel bioactivity but also enables the evolution of hydrogels from injectable forms to adhesivepatches. Based on the different biological activities and forms of hydrogels, they can be implanted internally orapplied externally on the mice’s skin, achieving simultaneous prevention of tumor recurrence post-surgery andassistance in treating radiation-induced skin damage after radiotherapy.

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.

Thermosensitive injectable hydrogel loaded with hypoxia-induced exosomes maintains chondrocyte phenotype through NDRG3-mediated hypoxic response

Current clinical treatments cannot effectively delay the progression of osteoarthritis(OA).Consequently,joint replacement surgery is required for late-stage OA when patients cannot tolerate pain and joint dysfunction.Therefore,the prevention of OA progression in the early and middle stages is an urgent clinical problem.In a previous study,we demonstrated that NDRG3-mediated hypoxic response might be closely related to the development and progression of OA.In this study,an injectable thermosensitive hydrogel was established by cross-linking Pluronic F-127 and hyaluronic acid(HA)for the sustained release of hypoxia-induced exosomes(HExos)derived from adipose-derived mesenchymal stem cells.We demonstrated that for OA at the early and middle stages,the HExos-loaded HP hydrogel could maintain the chondrocyte phenotype by enhancing chondrocyte autophagy,reducing chondrocyte apoptosis,and promoting chondrocyte activity and proliferation through the NDRG3-mediated hypoxic response.This novel composite hydrogel,which could activate the NDRG3-mediated hypoxic response,may provide new ideas and a theoretical basis for the treatment of early-and mid-stage OA.

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.

Advances of injectable hydrogel-based scaffolds for cartilage regeneration

Articular cartilage is an important load-bearing tissue distributed on the surface of diarthrodial joints.Due to its avascular,aneural and non-lymphatic features,cartilage has limited self-regenerative properties.To date,the utilization of biomaterials to aid in cartilage regeneration,especially through the use of injectable scaffolds,has attracted considerable attention.Various materials,therapeutics and fabrication approaches have emerged with a focus on manipulating the cartilage microenvironment to induce the formation of cartilaginous structures that have similar properties to the native tissues.In particular,the design and fabrication of injectable hydrogel-based scaffolds have advanced in recent years with the aim of enhancing its therapeutic efficacy and improving its ease of administration.This review summarizes recent progress in these efforts,including the structural improvement of scaffolds,network cross-linking techniques and strategies for controlled release,which present new opportunities for the development of injectable scaffolds for cartilage regeneration.

Therapeutic neovascularization promoted by injectable hydrogels

The aim of therapeutic neovascularization is to repair ischemic tissues via formation of new blood vessels by delivery of angiogenic growth factors,stem cells or expansion of pre-existing cells.For efficient neovascularization,controlled release of growth factors is particularly necessary since bolus injection of molecules generally lead to a poor outcome due to inadequate retention within the injured site.In this regard,injectable hydrogels,made of natural,synthetic or hybrid biomaterials,have become a promising solution for efficient delivery of angiogenic factors or stem and progenitor cells for in situ tissue repair,regeneration and neovascularization.This review article will broadly discuss the state-of-the-art in the development of injectable hydrogels from natural and synthetic precursors,and their applications in ischemic tissue repair and wound healing.We will cover a wide range of in vitro and in vivo studies in testing the functionalities of the engineered injectable hydrogels in promoting tissue repair and neovascularization.We will also discuss some of the injectable hydrogels that exhibit self-healing properties by promoting neovascularization without the presence of angiogenic factors.

Viscosity and degradation controlled injectable hydrogel for esophageal endoscopic submucosal dissection

Endoscopic submucosal dissection(ESD)is a common procedure to treat early and precancerous gastrointestinal lesions.Via submucosal injection,a liquid cushion is created to lift and separate the lesion and malignant part from the muscular layer where the formed indispensable space is convenient for endoscopic incision.Saline is a most common submucosal injection liquid,but the formed liquid pad lasts only a short time,and thus repeated injections increase the potential risk of adverse events.Hydrogels with high osmotic pressure and high viscosity are used as an alternate;however,with some drawbacks such as tissue damage,excessive injection resistance,and high cost.Here,we reported a nature derived hydrogel of gelatin-oxidized alginate(G-OALG).Based on the rheological analysis and compare to commercial endoscopic mucosal resection(EMR)solution(0.25%hyaluronic acid,HA),a designed G-OALG hydrogel of desired concentration and composition showed higher performances in controllable gelation and injectability,higher viscosity and more stable structures.The G-OALG gel also showed lower propulsion resistance than 0.25%HA in the injection force assessment under standard endoscopic instruments,which eased the surgical operation.In addition,the G-OALG hydrogel showed good in vivo degradability biocompatibility.By comparing the results acquired via ESD to normal saline,the G-OALG shows great histocompatibility and excellent endoscopic injectability,and enables create a longer-lasting submucosal cushion.All the features have been confirmed in the living both pig and rat models.The G-OALG could be a promising submucosal injection agent for esophageal ESD.

“Ferrero-like”nanoparticles knotted injectable hydrogels to initially scavenge ROS and lastingly promote vascularization in infarcted hearts

Myocardial infarction(MI)exhibits a complicated and ever-accelerated pathological change involving excessive reactive oxygen species(ROS)and the up-regulation of pro-inflammatory cytokines in the initial stage,and a permanently inadequate blood supply.Herein,an injectable hydrogel fabricated by nanoparticles(NPs)knotted thiolated hyaluronic acid(HA-SH)was reported to reverse the hostile microenvironment and rebuild the heart functions after MI.Inspired by the composite shell-core structure of Ferrero chocolate sphere,a mimetic nanocarrier was designed to consist of the hydrophobic dimethyloxalylglycine(DMOG)NPs core and a thick polydopamine(PDA)shell formed by the self-polymerization of dopamine embedded with watersoluble drug epigallocatechin-3-gallate(EGCG)throughπ-πinteractions.The resulted"Ferrero-like"NPs exhibited a"three-inone"capacity,namely loading two distinct drugs,elimination of ROS,and serving a crosslinker to knot HA-SH."Ferrero-like"NPs and HA-SH could rapidly form a hydrogel that exhibited a stable mechanical property,high capability to capture ROS,and programmed release of EGCG and DMOG.Four weeks after deploying the"Ferrero-like"NPs knotted hydrogels into rat infarcted hearts,the ejection fraction(EF)increased by 23.7%,and the infarct size decreased by 21.1%,and the fibrotic area reduced by 24.4%.The outcomes of immunofluorescence staining and reverse transcription-polymerase chain reaction(RTPCR)demonstrated a down-regulation of inflammatory factors(tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),interferon-γ(IFN-γ)),up-regulation of vascular related growth factors(hypoxia inducible factor-1α(HIF-1α),vascular endothelial growth factor A(VEGFA),von Willebrand factor(vWF),angiopoietin-1(Ang-1))and cardiac-related m RNAs(gap junction protein(Cx43),Cadherin 2).All in all,in this report,a very simple approach to intertemporally address the intricate and ongoing pathological changes after MI by injecting"Ferrero-like"NPs knotted hydrogels is developed to reverse hostile microenvironment,with an ability to scavenge ROS,down-regulate pro-inflammation factors in the first stage,and promote angiogenesis in a long term,thereby contributing to a significant improvement of heart functions.

Injectable hydrogels for spinal cord injury repair

Spinal cord injury(SCI)often causes severe functional impairment of body,which leads to a huge burden to the patient and the whole society.Many strategies,especially biomaterials,have been employed for SCI repair.Among various biomaterials,injectable hydrogels have attracted much attention because of their ability to load functional components and be injected into the lesioned area without surgeries.In this review,we summarize the recent progress in injectable hydrogels for SCI repair.We firstly introduce the pathophysiology of SCI,which reveals the mechanism of clinical manifestations and determines the therapeutic schedule.Then,we describe the original sources of polymers and the crosslinking manners in forming hydrogels.After that,we focus on the in vivo therapeutic strategies and effects of injectable hydrogels.Finally,the recent challenges and future outlook of injectable hydrogel for SCI repair are concluded and discussed.We believe this review can be helpful and inspire the further development of injectable hydrogels for SCI repair.

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.

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.

Alkaline activation of endogenous latent TGFβ1 by an injectable hydrogel directs cell homing for in situ complex tissue regeneration

Utilization of the body’s regenerative potential for tissue repair is known as in situ tissue regeneration.However,the use of exogenous growth factors requires delicate control of the dose and delivery strategies and may be accompanied by safety,efficacy and cost concerns.In this study,we developed,for the first time,a biomaterial-based strategy to activate endogenous transforming growth factor beta 1(TGFβ1)under alkaline conditions for effective in situ tissue regeneration.We demonstrated that alkaline-activated TGFβ1 from blood serum,bone marrow fluids and soaking solutions of meniscus and tooth dentin was capable of increasing cell recruitment and early differentiation,implying its broad practicability.Furthermore,we engineered an injectable hydrogel(MS-Gel)consisting of gelatin microspheres for loading strong alkaline substances and a modified gelatin matrix for hydrogel click crosslinking.In vitro models showed that alkaline MS-Gel controllably and sustainably activated endogenous TGFβ1 from tooth dentin for robust bone marrow stem cell migration.More importantly,infusion of in vivo porcine prepared root canals with alkaline MS-Gel promoted significant pulp-dentin regeneration with neurovascular stroma and mineralized tissue by endogenous proliferative cells.Therefore,this work offers a new bench-to-beside translation strategy using biomaterial-activated endogenous biomolecules to achieve in situ tissue regeneration without the need for cell or protein delivery.

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.