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...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.展开更多
Camptothecin has a strong tumor killing ability for a variety of tumor cells with its special anti-cancer mechanism including the breast cancer.However,because of its infinite hydrophobic property,its clinical applica...Camptothecin has a strong tumor killing ability for a variety of tumor cells with its special anti-cancer mechanism including the breast cancer.However,because of its infinite hydrophobic property,its clinical application has been greatly limited.Early prevention of loco regional recurrence for the breast cancer is critical for patients who have undergone breast-conserving therapy.In the study,CPT was used for the inhibition of the recurrence after the operation.The hollow mesoporous silica nanoparticles were used as the carrier to improve the hydrophilic property and increase its bioavailability with the high loading capacity.The ability of the cellular uptake and antitumor activity was increased.Hydrogel was the ideal carrier for local therapy,so the CPT@HMSNs were loaded into the PLEL thermo sensitive hydrogel to be injected into the tumor sites after the tumor was resected.The recurrence was reduced in the group of CPT-HMSNs-PLEL and the side effect of CPT was decreased.They exhibit distinguished potential as drug carrier for local delivery.展开更多
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 ker...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.展开更多
Currently,generalized therapy for traumatic optic neuropathy(TON)is lacking.Various strategies have been developed to protect and regenerate retinal ganglion cells(RGCs)after TON.Intravitreal injection of supplements ...Currently,generalized therapy for traumatic optic neuropathy(TON)is lacking.Various strategies have been developed to protect and regenerate retinal ganglion cells(RGCs)after TON.Intravitreal injection of supplements has been approved as a promising approach,although serious concerns,such as low delivery efficacy and pain due to frequent injections,remain.In this study,we tested an injectable thermosensitive hydrogel drug delivery system engineered to deliver ciliary neurotrophic factor(CNTF)and triamcinolone acetonide(TA).The results of rheological studies showed that the prepared drug-loaded hydrogel possessed a suitable mechanical modulus of�300 Pa,consistent with that of vitreum.The hydrogel exhibited thermosensitive with sustained drug release performance.In vitro co-culture of the CNTF-loaded hydrogel system with primary RGCs also induced significant axon regeneration,with 38.5%increase in neurite length,indicating the regenerative response of the thermosensitive hydrogel drug delivery system.A Sprague-Dawley rat optic nerve crush model was constructed and applied to determine the neuroprotective and regenerative capacities of the system.The results demonstrated that a single intravitreal injection of the drugloaded hydrogel(PLGA-PEG-PLGAþTA or PLGA-PEG-PLGAþCNTF)significantly increased RGC survival at both 14 and 28 days.The RGC survival rate was 31.05±1.41%for the drug-loaded hydrogel system(the control group was 16.79±1.50%)at Day 28.These findings suggest that the injectable drug-loaded thermosensitive hydrogel delivery system is a promising therapeutic tool for treating optic nerve degeneration.展开更多
Treating severe burn wounds poses significant challenges,including considerable cell loss,excessive inflammation,and a high susceptibility to bacterial infections.Ideal burn dressings should exhibit excellent antibact...Treating severe burn wounds poses significant challenges,including considerable cell loss,excessive inflammation,and a high susceptibility to bacterial infections.Ideal burn dressings should exhibit excellent antibacterial properties,anti-inflammatory effects,and promote cell proliferation.Additionally,they need facilitate painless dressing changes and be user-friendly.Herein,we synthesized a thermosensitive hydrogel by crosslinking poly(N-isopropylacrylamide-co-allyloxybenzaldehyde)(PNA)and amino-terminated Pluronic F127(APF)through a Schiffbase reaction.It exhibited reversible gelsol transition and spread-ability.By incorporating piezoelectric gold nanoparticle-modified barium titanate(Au@BaTiO3)and cas-cade antioxidant MOF-818,a nanocomposite hydrogel dressing with diverse bioactive functionalities was developed.Results demonstrated that the nanocomposite hydrogel possessed gel-sol transition properties,maintained a stable gel state within a broad temperature range,and desirable self-healing property.Au@BaTiO3 exhibited good piezoelectric properties and ROS generation upon ultrasound stimulation,while MOF-818 displayed highly efficient cascade nanozyme activity.The combination of Au@BaTiO3 and MOF-818 promoted fibroblast proliferation and migration,reduced intracellular ROS levels,and induced anti-inflammatory polarization of macrophages under ultrasound stimulation.In vitro and in vivo antibacterial results disclosed that the nanocomposite hydrogel had excellent antibacterial activity under highintensity ultrasound stimulation.When applied to infected burn wounds,the nanocomposite hydrogel can rapidly sterilize the wound upon initial high-intensity ultrasound,and then reduce inflammation and promote M2 macrophage polarization by the following low-intensity ultrasound stimulation,and thus accelerating the healing by improving granulation tissue formation,angiogenesis,and collagen deposition.展开更多
A novel sprayable adhesive is established(ZnMet-PF127)by the combination of a thermosensitive hydrogel(Pluronic F127,PF127)and a coordination complex of zinc and metformin(ZnMet).Here we demonstrate that ZnMet-PF127 p...A novel sprayable adhesive is established(ZnMet-PF127)by the combination of a thermosensitive hydrogel(Pluronic F127,PF127)and a coordination complex of zinc and metformin(ZnMet).Here we demonstrate that ZnMet-PF127 potently promotes the healing of traumatic skin defect and burn skin injury by promoting cell proliferation,angiogenesis,collagen formation.Furthermore,we find that ZnMet could inhibit reactive oxygen species(ROS)production through activation of autophagy,thereby protecting cell from oxidative stress induced damage and promoting healing of skin wound.ZnMet complex exerts better effects on promoting skin wound healing than ZnCl2 or metformin alone.ZnMet complex also displays excellent antibacterial activity against Staphylococcus aureus or Escherichia coli,which could reduce the incidence of skin wound infections.Collectively,we demonstrate that sprayable PF127 could be used as a new drug delivery system for treatment of skin injury.The advantages of this sprayable system are obvious:(1)It is convenient to use;(2)The hydrogel can cover irregular skin defect sites evenly in a liquid state.In combination with this system,we establish a novel sprayable adhesive(ZnMet-PF127)and demonstrate that it is a potential clinical treatment for traumatic skin defect and burn skin injury.展开更多
It is very challenging to visualize implantable medical devices made of biodegradable polymers in deep tissues.Herein,we designed a novel macromolecular contrast agent with ultrahigh radiopacity(iodinate content>50...It is very challenging to visualize implantable medical devices made of biodegradable polymers in deep tissues.Herein,we designed a novel macromolecular contrast agent with ultrahigh radiopacity(iodinate content>50%)via polymerizing an iodinated trimethylene carbonate monomer into the two ends of poly(ethylene glycol)(PEG).A set of thermosensitive and biodegradable polyester-PEG-polyester triblock copolymers with varied polyester compositions synthesized by us,which were soluble in water at room temperature and could spontaneously form hydrogels at body temperature,were selected as the demonstration materials.The addition of macromolecular contrast agent did not obviously compromise the injectability and thermogelation properties of polymeric hydrogels,but conferred them with excellent X-ray opacity,enabling visualization of the hydrogels at clinically relevant depths through X-ray fluoroscopy or Micro-CT.In a mouse model,the 3D morphology of the radiopaque hydrogels after injection into different target sites was visible using Micro-CT imaging,and their injection volume could be accurately obtained.Furthermore,the subcutaneous degradation process of a radiopaque hydrogel could be non-invasively monitored in a real-time and quantitative manner.In particular,the corrected degradation curve based on Micro-CT imaging well matched with the degradation profile of virgin polymer hydrogel determined by the gravimetric method.These findings indicate that the macromolecular contrast agent has good universality for the construction of various radiopaque polymer hydrogels,and can nondestructively trace and quantify their degradation in vivo.Meanwhile,the present methodology developed by us affords a platform technology for deep tissue imaging of polymeric materials.展开更多
Long-terrn injectable microspheres have some inherent disadvantages such as migration of microspheres from the originalsite an.d the burst effect. In order to avoid these problems, microsphere-loaded thermosensitive, ...Long-terrn injectable microspheres have some inherent disadvantages such as migration of microspheres from the originalsite an.d the burst effect. In order to avoid these problems, microsphere-loaded thermosensitive, hydrogel system was designed and expected to achieve a zero-order release Of biomolecular drugs in relativehigh initial drug loadings. Lysozyme, an antibacterial protein usually used to reduce prosthetic valve endocarditis,was selected as the model drug. Poly （DL-lactide-co-glycolide） （PLGA） microspheres, prepared by solvent evaporation method, were employee to encapsulate lysozyme and dispersed into thermosensitive pre-gel solution containing methylcellulose （MC）, polyethylene glycol （PEG）, sodium citrate （SC）, and sodium alginate （SA）. The mixture could act asadrug reservoir by.performing sol-gel transition rapidly if the temperature was raised from roomtemperature to 37℃. The in vitro release results showed that the burst effect was avoided due to strengthening ofdiffusion resistance in the gel. The formulation was able.to deliver lysozy.me for over.30 daysin a nearly zero-order release profile with a rate of 32.8μg.d^-1 which exhibits its remarkable potential for effective aoolication in long-term drug delivery.展开更多
Low-melting-point alloys have the advantages of good biocompatibility, plasticity, and near-bone mechanical strength, making them suitable as bone defect-filling materials for direct injection into defective bone site...Low-melting-point alloys have the advantages of good biocompatibility, plasticity, and near-bone mechanical strength, making them suitable as bone defect-filling materials for direct injection into defective bone sites. However, using low-melting-point alloys for orthopedic implants poses the challenge of causing thermal damage to the surrounding bone tissue during injection. In this study, a thermosensitive hydrogel is prepared and synergistically injected into the bone defect site with BiInSn. BiInSn solidifies and releases heat during injection, while the thermosensitive hydrogel absorbs heat and transforms into a gel state,encapsulating BiInSn. Therefore, the surrounding bone tissue is effectively protected from thermal damage. When BiInSn and the thermosensitive hydrogel were injected synergistically, in vitro thermal experiments revealed that the maximum temperature of the surrounding bone tissue reached 42℃. This temperature is below the 47℃ threshold, which causes permanent damage to bone tissues. In vivo experiments demonstrated that rats in the BiInSn-thermosensitive hydrogel group exhibited better recovery at the bone defect sites. These results suggest that the synergistic injection of Bi-based alloy and thermosensitive hydrogel is beneficial in reducing thermal damage to bone tissue, guiding bone tissue growth, and effectively facilitating the repair of bone defects.展开更多
Arterial vasospasm after microsurgery can cause severe obstruction of blood flow manifested as low tissue temperature,leading to tissue necrosis.The timely discovery and synchronized treatment become pivotal.In this s...Arterial vasospasm after microsurgery can cause severe obstruction of blood flow manifested as low tissue temperature,leading to tissue necrosis.The timely discovery and synchronized treatment become pivotal.In this study,a reversible,intelligent,responsive thermosensitive hydrogel system is constructed employing both the gel–sol transition and the sol–gel transition.The“reversible thermosensitive(RTS)”hydrogel loaded with verapamil hydrochloride is designed to dynamically and continuously regulate the extravascular microenvi-ronment by inhibiting extracellular calcium influx.After accurate implantation and following in situ gelation,the RTS hydrogel reverses to the sol state causing massive drug release to inhibit vasospasm when the tissue tem-perature drops to the predetermined transition temperature.Subsequent restoration of the blood supply allevi-ates further tissue injury.Before the temperature drops,the RTS hydrogel maintains the gel state as a sustained-release reservoir to prevent vasospasm.The inhibition of calcium influx and vasospasm in vitro and in vivo is demonstrated using vascular smooth muscle cells,mice mesenteric arterial rings,and vascular ultrasonic Doppler detection.Subsequent animal experiments demonstrate that RTS hydrogel can promote tissue survival and alleviate tissue injury responding to temperature change.Therefore,this RTS hydrogel holds therapeutic po-tential for diseases requiring timely detection of temperature change.展开更多
Stem cell therapy is a promising approach to treat myocardial infarction. However, direct delivery of stem cells into hearts experiences poor cell engraftment and differentiation, due to ischemic conditions （low nutr...Stem cell therapy is a promising approach to treat myocardial infarction. However, direct delivery of stem cells into hearts experiences poor cell engraftment and differentiation, due to ischemic conditions （low nutrient and oxygen） in the infarct hearts. Development of suitable cell carriers capable of supporting cell survival and differentiation under these harsh conditions is critical for improving the efficacy of current stem cell therapy. In this work, we created a family of novel cell carriers based on thermosensitive hydrogels and insulin-like growth factor 1 （IGF-1）, and investigated if these cell carriers can improve cell sur- vival and differentiation under ischemic conditions. The thermosensitive hydrogels were synthesized from N-isopropylacryla- mide, acrylic acid, acrylic acid N-bydroxysuccinicimide ester, and 2-hydroxyethyl methacrylate-oligo（hydroxybutyrate）. The hydrogel solutions can be readily injected through 26G needles, and can quickly solidify at 37 ~C to form highly flexible hy- drogels. IGF-I was immobilized into the hydrogels in order to support long-term cell survival and differentiation. Different amount of IGF- 1 was immobilized by using hydrogels with different content of N-hydroxysuccinicimide ester groups. Cardio- sphere derived cells were encapsulated in the hydrogels and cultured under ischemic conditions. The results demonstrated that a significant improvement of cell survival and differentiation was achieved after IGF-1 immobilization. These IGF-1 immobi- lized hydrogels have the potential to improve cell survival and differentiation in infarct hearts.展开更多
Parkinson’s disease(PD)is a prevalent neurodegenerative disorder accompanied by movement disorders and neuroinflammatory injury.Anti-inflammatory intervention to regulate oxidative stress in the brain is beneficial f...Parkinson’s disease(PD)is a prevalent neurodegenerative disorder accompanied by movement disorders and neuroinflammatory injury.Anti-inflammatory intervention to regulate oxidative stress in the brain is beneficial for managing PD.However,traditional natural antioxidants have failed to meet the clinical treatment demands due to insufficient activity and sustainability.Herein,Cu-doping zeolite imidazolate framework-8(ZIF-8)nanozyme is designed to simulate Cu/Zn superoxide dismutase(SOD)by biomimetic mineralization.The nanozyme composite is then integrated into thermosensitive hydrogel(poly(lactic-co-glycolic acid)-poly(ethylene glycol)-poly(lactic-co-glycolic acid)(PLGA-PEG-PLGA))to form an effective antioxidant system(Cu-ZIF@Hydrogel).The thermosensitive hydrogel incorporating nanozymes demonstrate distinct viscoelastic properties aimed at enhancing local nanozyme adhesion,prolonging nanozyme retention time,and modulating antioxidant activity,thus significantly improving the bioavailability of nanozymes.At the cellular and animal levels of PD,we find that Cu-ZIF@Hydrogel bypass the blood-brain barrier and efficiently accumulate in the nerve cells.Moreover,the Cu-ZIF@Hydrogel significantly alleviate the PD’s behavioral and pathological symptoms by reducing the neuroinflammatory levels in the lesion site.Therefore,the hydrogel-incorporating nanozyme system holds great potential as a simple and reliable avenue for managing PD.展开更多
Chitosan/glycerophosphate thermosensitive hydrogel crosslinked physically was a potential drug delivery carrier;however, long gelation time limits its application. Here, chitosan-amino acid (AA) thermosensitive hydrog...Chitosan/glycerophosphate thermosensitive hydrogel crosslinked physically was a potential drug delivery carrier;however, long gelation time limits its application. Here, chitosan-amino acid (AA) thermosensitive hydrogels were prepared from chitosan (CS), αβ-glycerophosphate (GP), and L-lysine (Lys) or L-glutamic acid (Glu). The prepared CS-Lys/GP and CS-Glu/GP hydrogel showed good thermosensitivity and could form gels in a short time. The optimal parameters of CS-Lys/GP hydrogel were that the concentration of CS-Lys was 2.5%, the ratio of CS/Lys was 3.5/1.0, the ratio of CS-Lys/GP was 4.5/1.0. The optimal parameters of CS-Glu/GP hydrogel were that the concentration of CS-Glu was 3.0%, the ratio of CS/Glu was 2.0/1.0, and the ratio of CS-Glu/GP was 4.0/1.5. Chitosan-amino acid (CS-AA) thermosensitive hydrogel had a three-dimensional network structure. The addition of model drug tinidazole (TNZ) had no obvious effect on the structure of hydrogel. The results of infrared spectroscopy showed that there were hydrogen bonds between amino acids and chitosan. In vitro release results showed that CS-Lys/GP and CS-Glu/GP thermosensitive hydrogels had sustained release effects. Thus, the chitosan-amino acid thermosensitive hydrogels hold great potential as a sustained release drug delivery system.展开更多
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....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.展开更多
Tissue engineering technologies offer new treatment strategies for the repair of peripheral nerve injury, hut cell loss between seeding and adhesion to the scaffold remains inevitable. A thermosensitive collagen hydro...Tissue engineering technologies offer new treatment strategies for the repair of peripheral nerve injury, hut cell loss between seeding and adhesion to the scaffold remains inevitable. A thermosensitive collagen hydrogel was used as an extracellular matrix in this study and combined with bone marrow mesenchymal stem cells to construct tissue-engineered peripheral nerve composites in vitro. Dynamic culture was performed at an oscillating frequency of 0.5 Hz and 35° swing angle above and below the horizontal plane. The results demonstrated that bone marrow mesenchymal stem cells formed membrane-like structures around the poly-L-lactic acid scaffolds and exhibited regular alignment on the composite surface. Collagen was used to fill in the pores, and seeded cells adhered onto the poly-L-lactic acid fibers. The DNA content of the bone marrow mesenchymal stem cells was higher in the composites constructed with a thermosensitive collagen hydrogel compared with that in collagen I scaffold controls. The cellular DNA content was also higher in the thermosensitive collagen hydrogel composites constructed with the thermosensitive collagen hydrogel in dynamic culture than that in static culture. These results indicate that tissue-engineered composites formed with thermosensitive collagen hydrogel in dynamic culture can maintain larger numbers of seeded cells by avoiding cell loss during the initial adhe-sion stage. Moreover, seeded cells were distributed throughout the material.展开更多
In clinic,the combination of intravenous pembrolizumab(PD-1 monoclonal antibody)with oral Lenvatinib(LEN)exhibited an enhanced synergistic benefit for cancer therapy.However,the clinical outcomes were always limited b...In clinic,the combination of intravenous pembrolizumab(PD-1 monoclonal antibody)with oral Lenvatinib(LEN)exhibited an enhanced synergistic benefit for cancer therapy.However,the clinical outcomes were always limited by the problems of inconsistent pharmacokinetic profiles of two drugs,lower drug accumulation in tumor and obvious side effects during the combination therapy.Here,in situ-forming thermosensitive hydrogels based on PLGA-PEG-PLGA triblock copolymers were prepared for local administration of anti-PD1 and LEN(P&L@Gel)to improve therapeutic efficacy and safety.After peritumoral or surgical resection site injection,the significant increased concentrations of both drugs in tumor were observed with the local sustained release of P&L@Gel.In comparison with the group of intraperitoneal anti-PD1 plus oral LEN(P-ip&L-po),significantly higher tumor inhibition efficiency on CT26 tumor models could be obtained in P&L@Gel group,even at the dose of one-eighth of the former,same tumorinhibition effects could be achieved.The enhanced antitumor efficacy of P&L@Gel group was probably associated with the 2.2 folds of increased level of CD8+T cells and the polarization of tumor associated macrophage from M2 to M1 along with the increased drug accumulation.Moreover,compared with the obvious side effects of P-ip&L-po group,no significant changes of PLT,ALT and UA in blood,as well as IL-1αand IL-1βin mice paws were observed between P&L@Gel group and untreated group.These results suggested that local administration of anti-PD1 and LEN with thermosensitive hydrogel could offer a potential strategy for tumors or tumor postoperative adjuvant treatment.展开更多
Advanced hepatocellular carcinoma(HCC)is one of the most prevalent malignancies,and the clinical treatment outcomes are not satisfactory.Due to the complexity,heterogeneity,and immunosuppressive microenvironment of HC...Advanced hepatocellular carcinoma(HCC)is one of the most prevalent malignancies,and the clinical treatment outcomes are not satisfactory.Due to the complexity,heterogeneity,and immunosuppressive microenvironment of HCC,monotherapies have limited effects.Therefore,combined therapy may effectively enhance antitumor treatment by remodeling the tumor immune microenvironment.This study reports an injectable thermosensitive microsphere-hydrogel composite system for local co-delivery of the targeted drug sorafenib(SOR)and immunomodulatory cytokines for the combined therapy of HCC.The delivery system exhibited superior properties such as dual-drug delivery,sustained and slow release,local injectability,thermosensitivity,and low side effects.Moreover,it successfully remodeled the immune microenvironment of HCC by increasing the infiltration of CD8^(+)T cells and natural killer cells while decreasing the infiltration of immunosuppressive Treg cells,thereby achieving a potent synergistic effect with SOR.This safe composite delivery system can remodel the tumor microenvironment and enhance anti-tumor treatment,providing a valuable option for the treatment of HCC.展开更多
Thermosensitive hydrogel can integrate vapor molecular capture,in-situ liquefaction,and thermal-induced water release for freshwater capture.This study aimed to examine the dynamic behavior of poly(N-isopropylacrylami...Thermosensitive hydrogel can integrate vapor molecular capture,in-situ liquefaction,and thermal-induced water release for freshwater capture.This study aimed to examine the dynamic behavior of poly(N-isopropylacrylamide)(PNIPAM)single chain and cross-linking thermosensitive hydrogel through molecular dynamics simulation.Specifically,the impact of lower critical solution temperature(LCST)on the conformation of polymer chain and the interaction between water and polymer chain were also investigated.The polymer chain conformation underwent a transition from coil to globule when the temperature exceeded the LCST,indicating the temperature responsiveness of PNIPAM.Additionally,thermosensitive hydrogel samples with different cross-linking degrees(DOC)were studied,and relevant parameters such as the number of free water,the diffusion coefficient of water,and the pore size distribution were counted to evaluate the temperature responsiveness and water release characteristics of thermosensitive hydrogel.展开更多
Atherosclerosis remains a major cause of morbidity and mortality worldwide.Intraplaque neovascularization critically promotes atherosclerotic progression and instability.Vascular endothelial growth factor A(VEGFA)stim...Atherosclerosis remains a major cause of morbidity and mortality worldwide.Intraplaque neovascularization critically promotes atherosclerotic progression and instability.Vascular endothelial growth factor A(VEGFA)stimulates aberrant microvessel growth in plaques by inducing endothelial cell proliferation and migration.Pigment epithelium-derived factor(PEDF)potently inhibits VEGFA-dependent neovascularization.This study introduces a thermosensitive hydrogel(PFSgel)developed from poloxamer 407(F127)and sodium alginate(SA)to deliver PEDF locally to atherosclerotic lesions.The PFSgel demonstrated a suitable liquid-solid transition at body temperature(37°C),then forming a stable 3D network structure after SA gelling with the Ca2+in the physiological environment which contributed to the character of controlled release.Rheological analysis confirmed its phase transition temperature of 28.7°C and notable self-healing properties,making it ideal for dynamic vascular environments.In vitro experiments showed that PFSgel could suppress VEGFA-induced endothelial cells’proliferation and migration through modulation of CD31 and MMP-2/MMP-9 signaling.Notably,in vivo degradation test validated the controlled release pattern of PFSgel.In Apoedeficient atherosclerotic mice,ultrasound-guided PFSgel injection onto the abdominal aorta enabled gradual in situ release of encapsulated PEDF.This effectively reduced plaque burden,neovascularization,and luminal stenosis,even with exogenous VEGFA administration.Histological analyses confirmed reduced lipid deposition,plaque area,and neovascularization within plaques.Overall,this novel in situforming PEDF delivery platform enables targeted suppression of pathological neovascularization via CD31 and MMP-2/MMP-9 pathways,representing a promising approach to stabilize high-risk plaques by intervening against VEGFA-dependent neovascularization.展开更多
基金financially supported by the National Natural Science Foundation of China(Grants 52172276)fund from Anhui Provincial Institute of Translational Medicine(2021zhyx-B15)。
文摘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.
基金supported by the National Natural Science Foundation of China(Nos.31700869,31700868,31771096)the National Science Fund for Distinguished Young Scholars(No.NSFC31525009)+1 种基金the Fundamental Research Funds for the Central Universities/the Postdoctoral Research Foundation of Sichuan University(Nos.2017SCU12032,2017SCU12040)Sichuan Innovative Research Team Program for Young Scientists(No.2016TD0004)
文摘Camptothecin has a strong tumor killing ability for a variety of tumor cells with its special anti-cancer mechanism including the breast cancer.However,because of its infinite hydrophobic property,its clinical application has been greatly limited.Early prevention of loco regional recurrence for the breast cancer is critical for patients who have undergone breast-conserving therapy.In the study,CPT was used for the inhibition of the recurrence after the operation.The hollow mesoporous silica nanoparticles were used as the carrier to improve the hydrophilic property and increase its bioavailability with the high loading capacity.The ability of the cellular uptake and antitumor activity was increased.Hydrogel was the ideal carrier for local therapy,so the CPT@HMSNs were loaded into the PLEL thermo sensitive hydrogel to be injected into the tumor sites after the tumor was resected.The recurrence was reduced in the group of CPT-HMSNs-PLEL and the side effect of CPT was decreased.They exhibit distinguished potential as drug carrier for local delivery.
基金supported by PLA General Hospital Program,No.LB20201A010024(to LW).
文摘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.
基金supported by Natural Science Foundation of Zhejiang Province(LY24C100002)Wenzhou Science and Technology Foundation(Y20210266)+3 种基金Engineering Research Center of Clinical Functional Materials and Diagnosis&Treatment Devices of Zhejiang Province(WIUCASK20004)Zhejiang Engineering Research Center for Tissue Repair Materials(WIUCASZZXF21002)Joint Medical Research Center of Xiangshan Hospital Affiliated to Wenzhou Medical University and Wenzhou Institute of Chinese Academy of Sciences(WIUCAS)(XSZX09)startup grant from WIUCAS(WIUCASQD2023022,WIUCASQD2022035).
文摘Currently,generalized therapy for traumatic optic neuropathy(TON)is lacking.Various strategies have been developed to protect and regenerate retinal ganglion cells(RGCs)after TON.Intravitreal injection of supplements has been approved as a promising approach,although serious concerns,such as low delivery efficacy and pain due to frequent injections,remain.In this study,we tested an injectable thermosensitive hydrogel drug delivery system engineered to deliver ciliary neurotrophic factor(CNTF)and triamcinolone acetonide(TA).The results of rheological studies showed that the prepared drug-loaded hydrogel possessed a suitable mechanical modulus of�300 Pa,consistent with that of vitreum.The hydrogel exhibited thermosensitive with sustained drug release performance.In vitro co-culture of the CNTF-loaded hydrogel system with primary RGCs also induced significant axon regeneration,with 38.5%increase in neurite length,indicating the regenerative response of the thermosensitive hydrogel drug delivery system.A Sprague-Dawley rat optic nerve crush model was constructed and applied to determine the neuroprotective and regenerative capacities of the system.The results demonstrated that a single intravitreal injection of the drugloaded hydrogel(PLGA-PEG-PLGAþTA or PLGA-PEG-PLGAþCNTF)significantly increased RGC survival at both 14 and 28 days.The RGC survival rate was 31.05±1.41%for the drug-loaded hydrogel system(the control group was 16.79±1.50%)at Day 28.These findings suggest that the injectable drug-loaded thermosensitive hydrogel delivery system is a promising therapeutic tool for treating optic nerve degeneration.
基金the National Key Re-search and Development Project of China(No.2023YFC2412600)National Natural Science Foundation of China(Nos.52003216,82272155, 52403168)+3 种基金the Youth Project of Shaanxi Provin-cial Department of Science and Technology(Nos.2024JC-YBQN-0368,2024JC-YBQN-04502024JC-YBQN-0202)the High-Level Talents Program of Xi’an University of Science and Technology(No.2050122015)the China Postdoctoral Science Foundation(Nos.2022M712506,2024T170717).
文摘Treating severe burn wounds poses significant challenges,including considerable cell loss,excessive inflammation,and a high susceptibility to bacterial infections.Ideal burn dressings should exhibit excellent antibacterial properties,anti-inflammatory effects,and promote cell proliferation.Additionally,they need facilitate painless dressing changes and be user-friendly.Herein,we synthesized a thermosensitive hydrogel by crosslinking poly(N-isopropylacrylamide-co-allyloxybenzaldehyde)(PNA)and amino-terminated Pluronic F127(APF)through a Schiffbase reaction.It exhibited reversible gelsol transition and spread-ability.By incorporating piezoelectric gold nanoparticle-modified barium titanate(Au@BaTiO3)and cas-cade antioxidant MOF-818,a nanocomposite hydrogel dressing with diverse bioactive functionalities was developed.Results demonstrated that the nanocomposite hydrogel possessed gel-sol transition properties,maintained a stable gel state within a broad temperature range,and desirable self-healing property.Au@BaTiO3 exhibited good piezoelectric properties and ROS generation upon ultrasound stimulation,while MOF-818 displayed highly efficient cascade nanozyme activity.The combination of Au@BaTiO3 and MOF-818 promoted fibroblast proliferation and migration,reduced intracellular ROS levels,and induced anti-inflammatory polarization of macrophages under ultrasound stimulation.In vitro and in vivo antibacterial results disclosed that the nanocomposite hydrogel had excellent antibacterial activity under highintensity ultrasound stimulation.When applied to infected burn wounds,the nanocomposite hydrogel can rapidly sterilize the wound upon initial high-intensity ultrasound,and then reduce inflammation and promote M2 macrophage polarization by the following low-intensity ultrasound stimulation,and thus accelerating the healing by improving granulation tissue formation,angiogenesis,and collagen deposition.
基金supported,in part,by the National Key Research and Development Program of China Grants(2019YFA0906001)National Natural Science Foundation of China Grants(82022047,81972100)Guangdong Provincial Science and Technology Innovation Council Grant(2017B030301018).
文摘A novel sprayable adhesive is established(ZnMet-PF127)by the combination of a thermosensitive hydrogel(Pluronic F127,PF127)and a coordination complex of zinc and metformin(ZnMet).Here we demonstrate that ZnMet-PF127 potently promotes the healing of traumatic skin defect and burn skin injury by promoting cell proliferation,angiogenesis,collagen formation.Furthermore,we find that ZnMet could inhibit reactive oxygen species(ROS)production through activation of autophagy,thereby protecting cell from oxidative stress induced damage and promoting healing of skin wound.ZnMet complex exerts better effects on promoting skin wound healing than ZnCl2 or metformin alone.ZnMet complex also displays excellent antibacterial activity against Staphylococcus aureus or Escherichia coli,which could reduce the incidence of skin wound infections.Collectively,we demonstrate that sprayable PF127 could be used as a new drug delivery system for treatment of skin injury.The advantages of this sprayable system are obvious:(1)It is convenient to use;(2)The hydrogel can cover irregular skin defect sites evenly in a liquid state.In combination with this system,we establish a novel sprayable adhesive(ZnMet-PF127)and demonstrate that it is a potential clinical treatment for traumatic skin defect and burn skin injury.
基金Authors acknowledge funding from the National Natural Science Foundation of China(grant Nos.51773043,81772363 and 21975045)the National Key R&D Program of China(grant Nos.2020YFC1107102 and 2016YFC1100300).
文摘It is very challenging to visualize implantable medical devices made of biodegradable polymers in deep tissues.Herein,we designed a novel macromolecular contrast agent with ultrahigh radiopacity(iodinate content>50%)via polymerizing an iodinated trimethylene carbonate monomer into the two ends of poly(ethylene glycol)(PEG).A set of thermosensitive and biodegradable polyester-PEG-polyester triblock copolymers with varied polyester compositions synthesized by us,which were soluble in water at room temperature and could spontaneously form hydrogels at body temperature,were selected as the demonstration materials.The addition of macromolecular contrast agent did not obviously compromise the injectability and thermogelation properties of polymeric hydrogels,but conferred them with excellent X-ray opacity,enabling visualization of the hydrogels at clinically relevant depths through X-ray fluoroscopy or Micro-CT.In a mouse model,the 3D morphology of the radiopaque hydrogels after injection into different target sites was visible using Micro-CT imaging,and their injection volume could be accurately obtained.Furthermore,the subcutaneous degradation process of a radiopaque hydrogel could be non-invasively monitored in a real-time and quantitative manner.In particular,the corrected degradation curve based on Micro-CT imaging well matched with the degradation profile of virgin polymer hydrogel determined by the gravimetric method.These findings indicate that the macromolecular contrast agent has good universality for the construction of various radiopaque polymer hydrogels,and can nondestructively trace and quantify their degradation in vivo.Meanwhile,the present methodology developed by us affords a platform technology for deep tissue imaging of polymeric materials.
基金Supported by the National Natural Science Foundation of China （No.20576057） and Fundamental Research Foundation of Tsinghua University （JCqn2005033）.
文摘Long-terrn injectable microspheres have some inherent disadvantages such as migration of microspheres from the originalsite an.d the burst effect. In order to avoid these problems, microsphere-loaded thermosensitive, hydrogel system was designed and expected to achieve a zero-order release Of biomolecular drugs in relativehigh initial drug loadings. Lysozyme, an antibacterial protein usually used to reduce prosthetic valve endocarditis,was selected as the model drug. Poly （DL-lactide-co-glycolide） （PLGA） microspheres, prepared by solvent evaporation method, were employee to encapsulate lysozyme and dispersed into thermosensitive pre-gel solution containing methylcellulose （MC）, polyethylene glycol （PEG）, sodium citrate （SC）, and sodium alginate （SA）. The mixture could act asadrug reservoir by.performing sol-gel transition rapidly if the temperature was raised from roomtemperature to 37℃. The in vitro release results showed that the burst effect was avoided due to strengthening ofdiffusion resistance in the gel. The formulation was able.to deliver lysozy.me for over.30 daysin a nearly zero-order release profile with a rate of 32.8μg.d^-1 which exhibits its remarkable potential for effective aoolication in long-term drug delivery.
基金supported by the CAMS Innovation Fund for Medical Sciences (Grant No. 2021-I2 M-1–052)the Key Laboratory of Congenital Craniofacial Malformation of the Chinese Academy of Medical Sciences (Grant No. 2018PT31051)+2 种基金the Fund of CAMS Plastic Surgery Hospital (Grant Nos. YS202036, YS202003)the National Natural Science Foundation of China (Grant No. 31801046)the Foundation of Director of Technical Institute of Physics and Chemistry, Chinese Academy of Sciences。
文摘Low-melting-point alloys have the advantages of good biocompatibility, plasticity, and near-bone mechanical strength, making them suitable as bone defect-filling materials for direct injection into defective bone sites. However, using low-melting-point alloys for orthopedic implants poses the challenge of causing thermal damage to the surrounding bone tissue during injection. In this study, a thermosensitive hydrogel is prepared and synergistically injected into the bone defect site with BiInSn. BiInSn solidifies and releases heat during injection, while the thermosensitive hydrogel absorbs heat and transforms into a gel state,encapsulating BiInSn. Therefore, the surrounding bone tissue is effectively protected from thermal damage. When BiInSn and the thermosensitive hydrogel were injected synergistically, in vitro thermal experiments revealed that the maximum temperature of the surrounding bone tissue reached 42℃. This temperature is below the 47℃ threshold, which causes permanent damage to bone tissues. In vivo experiments demonstrated that rats in the BiInSn-thermosensitive hydrogel group exhibited better recovery at the bone defect sites. These results suggest that the synergistic injection of Bi-based alloy and thermosensitive hydrogel is beneficial in reducing thermal damage to bone tissue, guiding bone tissue growth, and effectively facilitating the repair of bone defects.
基金National Key Research and Development Program of China(2020YFA0908200)National Natural Science Foundation of China(81772099,81801928 and 52103173)+3 种基金China Postdoctoral Science Foundation(2021M692105)Shanghai Municipal Health Commission(20204Y0354)Shanghai Municipal Key Clinical Specialty(shslczdzk00901)Young Physicians Innovation Team Project of the Ninth People’s Hospital of Shanghai Jiao Tong University School of Medicine(QC201902).
文摘Arterial vasospasm after microsurgery can cause severe obstruction of blood flow manifested as low tissue temperature,leading to tissue necrosis.The timely discovery and synchronized treatment become pivotal.In this study,a reversible,intelligent,responsive thermosensitive hydrogel system is constructed employing both the gel–sol transition and the sol–gel transition.The“reversible thermosensitive(RTS)”hydrogel loaded with verapamil hydrochloride is designed to dynamically and continuously regulate the extravascular microenvi-ronment by inhibiting extracellular calcium influx.After accurate implantation and following in situ gelation,the RTS hydrogel reverses to the sol state causing massive drug release to inhibit vasospasm when the tissue tem-perature drops to the predetermined transition temperature.Subsequent restoration of the blood supply allevi-ates further tissue injury.Before the temperature drops,the RTS hydrogel maintains the gel state as a sustained-release reservoir to prevent vasospasm.The inhibition of calcium influx and vasospasm in vitro and in vivo is demonstrated using vascular smooth muscle cells,mice mesenteric arterial rings,and vascular ultrasonic Doppler detection.Subsequent animal experiments demonstrate that RTS hydrogel can promote tissue survival and alleviate tissue injury responding to temperature change.Therefore,this RTS hydrogel holds therapeutic po-tential for diseases requiring timely detection of temperature change.
基金supported by the National Science Foundation of the United States(1160122,1006734)
文摘Stem cell therapy is a promising approach to treat myocardial infarction. However, direct delivery of stem cells into hearts experiences poor cell engraftment and differentiation, due to ischemic conditions （low nutrient and oxygen） in the infarct hearts. Development of suitable cell carriers capable of supporting cell survival and differentiation under these harsh conditions is critical for improving the efficacy of current stem cell therapy. In this work, we created a family of novel cell carriers based on thermosensitive hydrogels and insulin-like growth factor 1 （IGF-1）, and investigated if these cell carriers can improve cell sur- vival and differentiation under ischemic conditions. The thermosensitive hydrogels were synthesized from N-isopropylacryla- mide, acrylic acid, acrylic acid N-bydroxysuccinicimide ester, and 2-hydroxyethyl methacrylate-oligo（hydroxybutyrate）. The hydrogel solutions can be readily injected through 26G needles, and can quickly solidify at 37 ~C to form highly flexible hy- drogels. IGF-I was immobilized into the hydrogels in order to support long-term cell survival and differentiation. Different amount of IGF- 1 was immobilized by using hydrogels with different content of N-hydroxysuccinicimide ester groups. Cardio- sphere derived cells were encapsulated in the hydrogels and cultured under ischemic conditions. The results demonstrated that a significant improvement of cell survival and differentiation was achieved after IGF-1 immobilization. These IGF-1 immobi- lized hydrogels have the potential to improve cell survival and differentiation in infarct hearts.
基金support by the CAS Interdisciplinary Innovation Team(No.JCTD-2020-08).
文摘Parkinson’s disease(PD)is a prevalent neurodegenerative disorder accompanied by movement disorders and neuroinflammatory injury.Anti-inflammatory intervention to regulate oxidative stress in the brain is beneficial for managing PD.However,traditional natural antioxidants have failed to meet the clinical treatment demands due to insufficient activity and sustainability.Herein,Cu-doping zeolite imidazolate framework-8(ZIF-8)nanozyme is designed to simulate Cu/Zn superoxide dismutase(SOD)by biomimetic mineralization.The nanozyme composite is then integrated into thermosensitive hydrogel(poly(lactic-co-glycolic acid)-poly(ethylene glycol)-poly(lactic-co-glycolic acid)(PLGA-PEG-PLGA))to form an effective antioxidant system(Cu-ZIF@Hydrogel).The thermosensitive hydrogel incorporating nanozymes demonstrate distinct viscoelastic properties aimed at enhancing local nanozyme adhesion,prolonging nanozyme retention time,and modulating antioxidant activity,thus significantly improving the bioavailability of nanozymes.At the cellular and animal levels of PD,we find that Cu-ZIF@Hydrogel bypass the blood-brain barrier and efficiently accumulate in the nerve cells.Moreover,the Cu-ZIF@Hydrogel significantly alleviate the PD’s behavioral and pathological symptoms by reducing the neuroinflammatory levels in the lesion site.Therefore,the hydrogel-incorporating nanozyme system holds great potential as a simple and reliable avenue for managing PD.
基金support from Natural Science Foundation of Henan Province(No.182300410213)National Natural Science Foundation of China(No.51103035).
文摘Chitosan/glycerophosphate thermosensitive hydrogel crosslinked physically was a potential drug delivery carrier;however, long gelation time limits its application. Here, chitosan-amino acid (AA) thermosensitive hydrogels were prepared from chitosan (CS), αβ-glycerophosphate (GP), and L-lysine (Lys) or L-glutamic acid (Glu). The prepared CS-Lys/GP and CS-Glu/GP hydrogel showed good thermosensitivity and could form gels in a short time. The optimal parameters of CS-Lys/GP hydrogel were that the concentration of CS-Lys was 2.5%, the ratio of CS/Lys was 3.5/1.0, the ratio of CS-Lys/GP was 4.5/1.0. The optimal parameters of CS-Glu/GP hydrogel were that the concentration of CS-Glu was 3.0%, the ratio of CS/Glu was 2.0/1.0, and the ratio of CS-Glu/GP was 4.0/1.5. Chitosan-amino acid (CS-AA) thermosensitive hydrogel had a three-dimensional network structure. The addition of model drug tinidazole (TNZ) had no obvious effect on the structure of hydrogel. The results of infrared spectroscopy showed that there were hydrogen bonds between amino acids and chitosan. In vitro release results showed that CS-Lys/GP and CS-Glu/GP thermosensitive hydrogels had sustained release effects. Thus, the chitosan-amino acid thermosensitive hydrogels hold great potential as a sustained release drug delivery system.
基金supported by the National Natural Science Foundation of China(Nos.81960404,81960401 and 82060308)Guizhou Province Science and Technology Project(Nos.[2019]1429 and[2019]2798)+2 种基金Guizhou Provincial People’s Hospital Doctoral Fund(No.GZSYBS[2019]01)Guizhou Provincial People’s Hospital Youth Fund(No.GZSYQN[2019]04)Guizhou Provincial Health Commission Science and Technology Fund(No.gzwkj2021-251).
文摘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.
基金supported by the National Natural Science Foundation of China,No.31071222Jilin Province Science and Technology Development Project in China,No.20080738the Frontier Interdiscipline Program of Norman Bethune Health Science Center of Jilin University in China,No.2013106023
文摘Tissue engineering technologies offer new treatment strategies for the repair of peripheral nerve injury, hut cell loss between seeding and adhesion to the scaffold remains inevitable. A thermosensitive collagen hydrogel was used as an extracellular matrix in this study and combined with bone marrow mesenchymal stem cells to construct tissue-engineered peripheral nerve composites in vitro. Dynamic culture was performed at an oscillating frequency of 0.5 Hz and 35° swing angle above and below the horizontal plane. The results demonstrated that bone marrow mesenchymal stem cells formed membrane-like structures around the poly-L-lactic acid scaffolds and exhibited regular alignment on the composite surface. Collagen was used to fill in the pores, and seeded cells adhered onto the poly-L-lactic acid fibers. The DNA content of the bone marrow mesenchymal stem cells was higher in the composites constructed with a thermosensitive collagen hydrogel compared with that in collagen I scaffold controls. The cellular DNA content was also higher in the thermosensitive collagen hydrogel composites constructed with the thermosensitive collagen hydrogel in dynamic culture than that in static culture. These results indicate that tissue-engineered composites formed with thermosensitive collagen hydrogel in dynamic culture can maintain larger numbers of seeded cells by avoiding cell loss during the initial adhe-sion stage. Moreover, seeded cells were distributed throughout the material.
基金supported by National Natural Science Foundation of China(Nos.81690264 and 81973259)the Open Project from Key Laboratory of Carcinogenesis and Translational Research,Ministry of Education/Beijing.
文摘In clinic,the combination of intravenous pembrolizumab(PD-1 monoclonal antibody)with oral Lenvatinib(LEN)exhibited an enhanced synergistic benefit for cancer therapy.However,the clinical outcomes were always limited by the problems of inconsistent pharmacokinetic profiles of two drugs,lower drug accumulation in tumor and obvious side effects during the combination therapy.Here,in situ-forming thermosensitive hydrogels based on PLGA-PEG-PLGA triblock copolymers were prepared for local administration of anti-PD1 and LEN(P&L@Gel)to improve therapeutic efficacy and safety.After peritumoral or surgical resection site injection,the significant increased concentrations of both drugs in tumor were observed with the local sustained release of P&L@Gel.In comparison with the group of intraperitoneal anti-PD1 plus oral LEN(P-ip&L-po),significantly higher tumor inhibition efficiency on CT26 tumor models could be obtained in P&L@Gel group,even at the dose of one-eighth of the former,same tumorinhibition effects could be achieved.The enhanced antitumor efficacy of P&L@Gel group was probably associated with the 2.2 folds of increased level of CD8+T cells and the polarization of tumor associated macrophage from M2 to M1 along with the increased drug accumulation.Moreover,compared with the obvious side effects of P-ip&L-po group,no significant changes of PLT,ALT and UA in blood,as well as IL-1αand IL-1βin mice paws were observed between P&L@Gel group and untreated group.These results suggested that local administration of anti-PD1 and LEN with thermosensitive hydrogel could offer a potential strategy for tumors or tumor postoperative adjuvant treatment.
基金supported by the National Natural Science Foundation of China(82172736 and 82272829)the State Key Laboratory of Oncogenes and Related Genes(ZZ-94-2306)the Special Project for Clinical Research in Health Industry of Shanghai Municipal Health Commission(20214Y0102)。
文摘Advanced hepatocellular carcinoma(HCC)is one of the most prevalent malignancies,and the clinical treatment outcomes are not satisfactory.Due to the complexity,heterogeneity,and immunosuppressive microenvironment of HCC,monotherapies have limited effects.Therefore,combined therapy may effectively enhance antitumor treatment by remodeling the tumor immune microenvironment.This study reports an injectable thermosensitive microsphere-hydrogel composite system for local co-delivery of the targeted drug sorafenib(SOR)and immunomodulatory cytokines for the combined therapy of HCC.The delivery system exhibited superior properties such as dual-drug delivery,sustained and slow release,local injectability,thermosensitivity,and low side effects.Moreover,it successfully remodeled the immune microenvironment of HCC by increasing the infiltration of CD8^(+)T cells and natural killer cells while decreasing the infiltration of immunosuppressive Treg cells,thereby achieving a potent synergistic effect with SOR.This safe composite delivery system can remodel the tumor microenvironment and enhance anti-tumor treatment,providing a valuable option for the treatment of HCC.
基金supported by National Natural Science Foundation of China(No.52206073)Fundamental Research Funds for the Central Universities(No.3132023119)Guangdong Basic and Applied Basic Research Foundation(Nos.2024A1515011379 and 2023A1515110613).
文摘Thermosensitive hydrogel can integrate vapor molecular capture,in-situ liquefaction,and thermal-induced water release for freshwater capture.This study aimed to examine the dynamic behavior of poly(N-isopropylacrylamide)(PNIPAM)single chain and cross-linking thermosensitive hydrogel through molecular dynamics simulation.Specifically,the impact of lower critical solution temperature(LCST)on the conformation of polymer chain and the interaction between water and polymer chain were also investigated.The polymer chain conformation underwent a transition from coil to globule when the temperature exceeded the LCST,indicating the temperature responsiveness of PNIPAM.Additionally,thermosensitive hydrogel samples with different cross-linking degrees(DOC)were studied,and relevant parameters such as the number of free water,the diffusion coefficient of water,and the pore size distribution were counted to evaluate the temperature responsiveness and water release characteristics of thermosensitive hydrogel.
基金National Natural Science Foundation of China (81972886 and 82172736)Shanghai Health and Family Planning Commission Fund (202240235)+1 种基金Natural Science Foundation of Shanghai (21ZR1451400)Shanghai Jiading District Health and Family Planning Commission Fund (2021-KY-10)。
文摘Atherosclerosis remains a major cause of morbidity and mortality worldwide.Intraplaque neovascularization critically promotes atherosclerotic progression and instability.Vascular endothelial growth factor A(VEGFA)stimulates aberrant microvessel growth in plaques by inducing endothelial cell proliferation and migration.Pigment epithelium-derived factor(PEDF)potently inhibits VEGFA-dependent neovascularization.This study introduces a thermosensitive hydrogel(PFSgel)developed from poloxamer 407(F127)and sodium alginate(SA)to deliver PEDF locally to atherosclerotic lesions.The PFSgel demonstrated a suitable liquid-solid transition at body temperature(37°C),then forming a stable 3D network structure after SA gelling with the Ca2+in the physiological environment which contributed to the character of controlled release.Rheological analysis confirmed its phase transition temperature of 28.7°C and notable self-healing properties,making it ideal for dynamic vascular environments.In vitro experiments showed that PFSgel could suppress VEGFA-induced endothelial cells’proliferation and migration through modulation of CD31 and MMP-2/MMP-9 signaling.Notably,in vivo degradation test validated the controlled release pattern of PFSgel.In Apoedeficient atherosclerotic mice,ultrasound-guided PFSgel injection onto the abdominal aorta enabled gradual in situ release of encapsulated PEDF.This effectively reduced plaque burden,neovascularization,and luminal stenosis,even with exogenous VEGFA administration.Histological analyses confirmed reduced lipid deposition,plaque area,and neovascularization within plaques.Overall,this novel in situforming PEDF delivery platform enables targeted suppression of pathological neovascularization via CD31 and MMP-2/MMP-9 pathways,representing a promising approach to stabilize high-risk plaques by intervening against VEGFA-dependent neovascularization.
