Stereocomplexed Thermoresponsive Physical Hydrogels Based on Poly(Lactic Acid)/Poly (Ethylene Glycol)amphiphilic Block Compolymers

Author:Mao Hai Liang

Supervisor:pan peng ju


Degree Year:2018





Amphiphilic block copolymers are able to self-assemble into the core-shell micelles having the hydrophobic cores surrounded by hydrophilic shells in aqueous solution.When the micelles are destabilized and aggregated with the increase of intermicellar interactions,they can form hydrogel through physical crosslinking.The thermo-responsive phase transition and mechanical properity of physical hydrogels are closly related to the topology of copolymer,chemical composition,crystalline strucutres,hydrophilic/hydrophobic segmental ratio,and solvent.Poly(L-lactic acid)(PLLA)and poly(D-lactic acid)(PDLA),are a widely-used enantiomeric pair and able to form stereocomplex.Thus,we could tailor the thermo-induced phase transition,critical transition temperature,mechanical properity,and release behavior of poly(lactic acid)(PLA)/poly(ethylene glycol)(PEG)physical hydrogels by introducing PLLA/PDLA stereocomplexes and changing the density,mannaer of physical crosslinking.First,CBABC-type PLA/PEG pentablock copolymers composed of the central PEG block(A)and enantiomeric PLLA(B),PDLA(C)blocks were synthesized with different PLLA/PDLA ratio.Physical gelation,gel-to-sol transition,crystalline state,microstructure,rheological behavior,biodegradation,and drug release behavior of PLA/PEG pentablock copolymers and their gels are investigated;they were also compared with PLA-PEG-PLA triblock copolymers containing the isotactic PLLA or atactic poly(D,L-lactide)(PDLLA)endblocks and PLLA-PEG-PLLA/PDLA-PEG-PDLA enantiomeric mixtures.Such pentablock copolymers form physical hydrogels at high concentrations in aqueous solution,stemmed from the aggregation and physical bridging of copolymer micelles.These gels are thermoresponsive and turn into sols upon heating.PLA hydrophobic domains in pentablock copolymer gels change from the homocrystalline to stereocomplexed structure as the ratio of PLLA/PDLA block length approaches 1/1.The gel of symmetric pentablock copolymer exhibits wider gelation region,higher gel-sol transition temperature,higher crystallinity of hydrophobic domains,larger intermicellar distance,higher storage modulus,slower degradation and drug release rate compared to those of the asymmetric PLA/PEG pentablock copolymers or triblock copolymers.SAXS results indicate that the stereocomplexation of PLLA/PDLA blocks in pentablock copolymers facilitate the intermicellar aggregation and bridging.The stereocomplexation degree and intermicellar distance of pentablock copolymer gels increase with heating.PLA/PEG copolymers were synthesized by changing the copolymer topology,i.e.PEG-PDLA diblock copolymers and PLLA-PEG-PLLA triblock copolymers.A novel in situ formed gel system with potential biodegradability and biocompatibility is developed by mixing the diblock and triblock PLA/PEG copolymers with opposite configurations of PLA blocks.The stereocomplex formation can promote the formation of bridging networks in PLA/PEG hydrogels by tailoring the PEG block length in PLLA-PEG-PLLA.Driving by the stereocomplex formation,part of PLA-PEG-PLA chains act as the connecting bridges between star and flower-like micelles and the stereocomplexed crystallites in micelle cores act as physically cross-linked points.In situ gelation,gel-to-sol transition,crystalline structure,microstructures,and mechanical properties of PLA-PEG/PLA-PEG-PLA enantiomerically-mixed gels are significantly influenced by the mixing ratio,degree of polymerization for PEG block in triblock(DPPEG,tri)and diblock copolymers(DPPEG,di).It is found that in situ gelation of PLA-PEG/PLA-PEG-PLA enantiomeric mixture just happen at relatively smaller PLA-PEG/PLA-PEG-PLA mass ratio and larger DPPEG,tri.Then,we use the enantiomeric mixtures of PDLA/PEG diblock copolymer and PLLA/PEG triblock copolymer as a stereocomplexable system and report a novel thermogel that exhibits unique gel-sol-gel multiple transitions upon heating by changing hydrophibic/hydrophilic block ratio and concentration of copolymer solution.The thermally-induced phase transition of PEG-PDLA/PLLA-PEG-PLLA thermogel was governed by the copolymer composition and the stereocomplexation of PLLA/PDLA segments.Molecular motion of PEG segments enhances during the gel-sol transition but slows down in the following sol-gel transition.The gel-sol and sol-gel transitions occurred at low and high temperatures are driven by the increased mobility of PEG segments,micelles and the promoted PLLA/PDLA stereocomplexation,respectively.The PEG-PDLA/PLLA-PEG-PLLA gels can be used to capsulate and release the hydrophobic drug;the drug release rate enhances as the content of hydrophilic blocks increases.Finally,the effect of solvent environment on thermoresponsive sol-gel transition in PLA/PEG enantiomeric mixture was carried out by adding different concentrations of PEG homopolymer and NaCl ions.When PEG(Mn 2000)increases from 0 to 3 wt%,the critical sol-gel transition temperature(Ts-g)of PDLA-PEG-PDLA/PLLA-PEG-PLLA mixture(8 wt%)drops from 42 to 37 ℃.On the other hand,as the NaCl concentration increases up to 3 wt%,Ts-g of PDLA-PEG-PDLA/PLLA-PEG-PLLA mixture drops to 32 ℃.WAXD results indicate that stereocomplexation of PLLA/PDLA increases after adding PEG and NaCl,and this tendency become more significantely upon heating.SAXS results indicate that the fractal dimension of enantiomeric mixture increases and micelle clusters become more compact after adding PEG and NaCl.Meanwhile,the core-shell micelle structure still retains during sol-gel transition.The presence of free PEG homopolymers may decrease the solubility and mobility of PEG block in micelles.The addition of NaCl may increase the hydrophobicity of enantiomeric micelles.Thus,the addition of PEG and NaCl facilitates the stereocomplexation of PLLA/PDLA and intermicellar aggregation,which accelerates the sol-gel transition of enantiomeric mixtures upon heating.