Physical Crosslinking And Click Chemistry Crosslinking And Properties Of Thermosensitive PLA-based Amphiphilic Co-network Gels

Environmental stimulation responsive hydrogel means that the shape,penetration rate,and recognition performance of the hydrogel will change accordingly.with the stimulation of the external environment such as pH,temperature,light,and so on.Hydrogels have good biocompatibility,and do not cause much inflammation,coagulation or tissue damage when applied to the human body or other biological tissues.Therefore,hydrogels have been widely used in the fields of biological tissue engineering and biomedicine,such as the embedding of active enzymes,artificial muscles,drug sustained release,and drug carriers and so on.Temperature is an important physiological parameter that reflects human health and is easy to control.Therefore,temperature-sensitive hydrogels have been widely studied.Polylactic acid(PLA)is an important degradable polymer material.Its synthetic raw materials are derived from renewable crops,which can be degraded into H2O and CO2 after use.It does not pollute the environment.The intermediate product lactic acid is a normal sugar metabolite in the body.PLA is non-toxic,non-irritating,and has good biocompatibility.The stereo complex of PLA has better physical properties,such as high melting point,high mechanical strength and more stable thermal properties,so PLA is widely used in the medical field.Poly(ethylene glycol)(PEG)is a hydrophilic,non-immunogenic and non-cytotoxic polymer,which has been found to have a wide range of applications in sustained-release treatment and tissue regeneration biomaterial design.The application of PEG hydrogels is limited due to the rapid drug release(under the action of hydrophilic drugs)or the low drug loading rate(in the case of hydrophobic drugs).Therefore,drug delivery based on PEG is restricted.In recent years,extensive research has been conducted on poly(methyl methacrylate)oligoethylene glycol methyl ether with temperature sensitivity,water solubility and biocompatibility,and by adjusting the feeding ratio of 2-(2-methoxyethoxy)ethyl methacrylate(MEO2MA)and ethylene glycol methyl ether methacrylate(OEGMA)copolymer is used to adjust the low critical solution temperature(LCST)of the polymer.The low critical solution temperature(LCST)values of PMEO2MA and POEGMA are 26℃ and 90℃,respectively.P(MEO2MA-co-OEGMA)has been extensively studied in drug delivery systems due to its temperature response,excellent hydrophilicity,biocompatibility and non-toxicity.Based on the above conditions,this paper first synthesizes the hydrophobic macromonomer HEMA-PLLA/PDLA,and stereocomplexes it by physical cross-linking.The thermosensitive and hydrophilic monomers MEO2MA and OEGMA are added to successfully synthesize the amphiphilic common network gels.In addition,this paper also modified the macromonomer HEMA-PLLA with MEO2MA and OEGMA to synthesize temperature-sensitive graft copolymer P(MEO2-MA-co-OEGMA)-g-PLLA,then the grafted copolymer was alkynylated and azide.finally,the amphiphilic network gel with temperature sensitivity was synthesized by"click" chemistry.Specific work is as follows:1.Under the action of 2-hydroxyethyl methacrylate initiator,L-lactide was subjected to ring-opening polymerization(ROP).and DBU was used as a catalyst to react at room temperature to form macromer HEMA-PLLA/PDLA.Then the macromonomers are mixed 1:1 by physical cross-linking for stereocomplexation,and then hydrophilic and temperature-sensitive monomers MEO2MA and OEGMA are added,which are formed by radical polymerization under the action of AIBN to form amphiphilic conetwork gel with temperature sensitivity.The structures of macromonomers and gels were confirmed by 1H NMR,FT-IR and powder X-ray diffractometer,which proved that the polymer was successfully synthesized.In addition,the swelling of the gel in both the organic and aqueous phases was studied,and the swelling behavior of the gel in the aqueous phase at different temperatures was different,which indicates that the gel has amphiphilicity and temperature sensitivity.The measurement results of DMA and DSC and thermal analysis system show that MEO2MA and OEGMA greatly improve PLA mechanical strength and thermal melting point.The cross-sectional area of the gel was judged by a desktop scanning electron microscope to be a three-dimensional network structure.In addition,the potential of gel as a drug carrier was also studied,and the hydrophobic drug doxorubicin was used as the drug model for this study.Doxorubicin was encapsulated in the gel by physical embedding method,and the drug loading of the gel was measured by changing the temperature and pH.The experiments proved that the parental co-network gel has a higher drug loading.Furthermore,it was found that the human body temperature was 37℃,and the gel could control the slow release of doxorubicin in the body.Moreover,the drug-loaded gel can quickly act on target cells.which can achieve high-efficiency effects,so the gel has great application value in the field of drug delivery.2.By using the macromer HEMA-PLLA synthesized in the first part as an initiator,MEO2MA and OEGMA were added,and the graft copolymer P(MEO2MA-co-OEGMA)-g-PLLA was synthesized by radical polymerization under the action of AIBN.The graft copolymer is brominated and azide to form P(MEO2MA-co-OEGM-A)-g-PLLA-N3,and alkynylates to alkyne-P(MEO2MA-co-OEGMA)-g-PLLA.Finally,the polymer with azide group and alkynyl group at the end is subjected to a"click chemistry,reaction and crosslinked to form a gel having a three-dimensional network structure inside.Using FT-IR to determine the graft copolymer,azide polymers,alkynyl polymers and gels were successfully synthesized.The LCST of the gel is determined by measuring the low critical temperature(LOST)of the graft copolymer.Click the formed gel to determine the mechanical strength of the gel by measuring its storage modulus(G’)and loss modulus(G")with a rheometer.The thermal properties of the gel are determined by measuring the thermal analysis system.The amphiphilicity and temperature sensitivity of the gel are determined by the swelling of the aqueous or organic phase at different temperatures.The three-dimensional network structure of the gel is observed on a desktop scanning electron microscope.Significant shrinkage of the pore size occurs.In addition,the in vitro drug release of the gel was also studied.The hydrophobic drug doxorubicin was encapsulated in the gel,and the gel was placed in a water phase at 37℃ to study the in vitro drug release of the gel.The above studies show that both physical gels and click chemical gels are temperature sensitive and amphiphilic,and both have good mechanical strength and thermal properties.All these make hydrogels have good applications in drug delivery,tissue engineering and sensors.