Preparation And Biological Application Of Temperature-sensitive Hydrogel

In recent years,stimuli-responsive hydrogels have received widespread attention as biomaterials.Stimuli-responsive hydrogels could be injected into body in a minimally invasive manner.Through external stimulus conditions,in situ coagulation or gelation could be achieved into tissues or organs.It is also possible to control the drug release and specifically target the site of administration by changing the polymer structure,obtaining on-demand drug administration,which exactly matches the physiological needs.At present,temperature-sensitive hydrogels are widely studied as stimulus-responsive hydrogels in drug delivery systems.Temperature-sensitive hydrogels present a sol state at low temperatures,which is beneficial for encapsulating drugs and targeting sites of action.After injection into the body,the polymer solution turn into hydrogel,which help to control drug release.With the development of modern biomedicine,there is an urgent need to develop temperature-sensitive hydrogels with characteristics such as biocompatibility,injectability,and biodegradability.Two temperature-sensitive hydrogels were successfully prepared in this paper,and their potential applications in biomedical field were also discussed.The main research contents and results are as follows:?1?Poly?lactide-co-glycolide?-b-polyethyleneglycol-b-poly?lactide-co-glycolide??PLGA-PEG-PLGA?temperature-sensitive hydrogel was synthesized by ring-opening polymerization of glycolide?GA?and D,L-lactide?D,L-LA?.The proton nuclear magnetic resonance?¹H NMR?and fourier infrared spectroscopy?FT-IR?test methods were adopted to analyze the structure of the polymer.The molecular weight and molecular weight distribution of the polymer were determined by gel permeation chromatography?GPC?.The gelation properties of the PLGA-PEG-PLGA temperature-sensitive hydrogel were studied by the phase transition process.The mechanical properties of the PLGA-PEG-PLGA temperature-sensitive hydrogel were analyzed by dynamic mechanics.Finally,the biodegradability and biocompatibility of PLGA-PEG-PLGA temperature-sensitive hydrogel were studied.The results showed the PLGA-PEG-PLGA temperature-sensitive hydrogel with biodegradability and biocompatibility was successfully prepared.The hydrogel has temperature-sensitive gelling property and good mechanical property at 37°C.It can maintain the stable shape of the hydrogel after injection into the body.?2?The application of PLGA-PEG-PLGA temperature-sensitive hydrogels in treatment of hepatocellular carcinoma.In order to evaluate the application of PLGA-PEG-PLGA temperature-sensitive hydrogels in biomedicine,the PLGA-PEG-PLGA hydrogel was used to encapsulate Regorafenib?REGO?and Rapamycin?RAPA?in the treatment of hepatocellular carcinoma.The anti-tumor effects of PLGA-PEG-PLGA hydrogel on liver cancer were evaluated by testing the tumor size,blood biochemistry and pathology of liver cancer.The results showed that Gel+REGO,Gel+RAPA and Gel+REGO+RAPA have a good inhibitory effect on tumors,but Gel+REGO+RAPA has a better inhibitory effect on tumor and no metastasis has been found in other liver lobes.Due to the sustained drug release of PLGA-PEG-PLGA hydrogel,the mouse's heart,liver,spleen,lung,and kidney were not obviously damaged.?3?Polyethylene glycol monomethyl ether-polyalanine-poly?aspartic acid-N-hydroxysuccinimide?(m PEG₄₅-PAla₃₀-P?Asp₉-NHS₇?bioadhesive hydrogel.Blockcopolymerpolyethyleneglycolmonomethyl ether-polyalanine-poly?aspartate benzyl ester?(m PEG₄₅-PAla₃₀-PBLA₉)was synthesized by ring-opening polymerization of NCA monomers using m PEG-NH₂as a macromolecular initiator.And then the polyethylene glycol monomethyl ether-polyalanine-poly?aspartic acid?(m PEG₄₅-PAla₃₀-PAsp₉)was prepared by debenzylationprotectionofm PEG₄₅-PAla₃₀-PBLA₉.Finally,m PEG₄₅-PAla₃₀-P?Asp₉-NHS₇?was obtained by EDC/NHS reaction of m PEG₄₅-PAla₃₀-PAsp₉.The structure of the polymer was analyzed by ¹H NMR and FT-IR.Thegel-formingandmechanicalpropertiesof m PEG₄₅-PAla₃₀-P?Asp₉-NHS₇?were studied by the test tube inversion method and dynamic mechanical analysis.The microstructure of m PEG₄₅-PAla₃₀-P?Asp₉-NHS₇?hydrogel was observed by SEM and the secondary structure of polymer was analyzed by circular dichroism.In order to evaluate the biodegradability and biocompatibility of m PEG₄₅-PAla₃₀-P?Asp₉-NHS₇?,in vivo degradation and cytotoxicity experiments were performed.Finally,the adhesion properties of m PEG₄₅-PAla₃₀-P?Asp₉-NHS₇?hydrogel to skin,heart,liver,spleen,lung,and kidney were tested.The results showed that m PEG₄₅-PAla₃₀-P?Asp₉-NHS₇?hydrogel with biodegradability and biocompatibility was successfully prepared.By analyzing the gelling mechanism it was found that m PEG₄₅-PAla₃₀-P?Asp₉-NHS₇?hydrogel has a?-sheet structure,which endows it with better gelling performance and mechanical properties.In addition,m PEG₄₅-PAla₃₀-P?Asp₉-NHS₇?hydrogel has good adhesion properties to skin,heart,liver,spleen,lung,and kidney,indicating the potential applications in tissue repair.