Preparation And Characterization Of Soft-tissue-mimic Hydrogel Scaffolds

Hydrogels based on natural or synthetic polymers,due to their high water content,biocompatibility,injectability and biodegradability,have been an important material in biomedical applications like drug delivery and tissue regeneration.In this dissertation,we employed natural polysaccharides and PEG as base materials to develop four hydrogel systems.Microspheres and nanoparticles were utilized as drug carriers and to improve hydrogel mechanical properties.Heparin and peptide were included to form crosslinkings and bind small-molecule drugs or cells.Enzymes,magnetic or thermal-sensitive particles were employed to generate responsive hydrogels with particular properties,which were anticipated to be applied to disease treatment,drug delivery and tissue regeneration.In this dissertation,we employed natural or synthetic polymers and peptides for hydrogel production,and combined micro-or nano-particles as drug carriers in polymer networks.Four different hydrogel systems were generated and their mechanical properties,biodegradability,drug delivery properties were characterized.Chitosan and its derivatives,as well as chondroitin sulfate,one of the composition materials in natural soft tissue,were utilized to develop a soft-tissue-mimic hydrogel scaffold.Gelation was based on Schiff base reaction between amino groups and aldehyde groups from carboxymethyl chitosan and functionalized chondroitin sulfate.Chitosan microspheres were prepared by emulsification crosslinking method as drug carriers,with BSA encapsulated as a model drug.Chitosan microspheres could also be covalently crosslinked to the polymer network,helping immobilize drug molecules in gel.Characterization on size and morphology of microspheres showed that the particles had average diameter of around 40 um with good size distribution,and exhibited spherical shape.Compression experiment,swelling,degradation and drug release study proved that incorporation of microspheres improved mechanical property and stability of the composite gel and effectively slowed down the release rate.To further control drug delivery and improve physical and chemical properties of hydrogel scaffolds,we introduced Fe3O4 nanoparticles into chitosan microspheres to form a drug vehicle which can respond to external magnetic stimuli.Sodium chloride was employed in gel fabrication to generate cations/anions and slow down the reaction rate between chitosan and cellulose.This gel was derived from electrostatic interaction and found to have uniform structure together with self-healing property.Rheology study demonstrated that the gel has good self-healing ability and reversible thermal-sensitive gelation,which made scaffolds with particular shape easily manipulated.We composited magnetic microspheres with hydrogels to generate hybrid hydrogels and lyophilized porous scaffolds with magnetic responsiveness.These scaffolds showed desirable stability under physiological condition,which made this material potential for targeted treartment and tissue regeneration.Although hydrogels embedded with microspheres based on natural polysaccharides exhibited homogeneous structure,controlled drug release and biodegradability,high hydrophilicity of these gels will sometimes limit the entrapment of hydrophobic pharmaceuticals or small-molecule drugs like growth factors.Meanwhile,hydrogels derived from natural polymers usually showed softer structure and lower modulus.Hence,we chose easily-modified synthetic polymer PEG to develop hydrogels,and amphiphilic liposomes with unique structure were utilized as nano drug carriers.Rapamycin,a hydrophobic molecule,was encapsulated in liposomes at decent efficiency and FGF-2 was loaded in gel networks.To immobilize and stabilize FGF in gels with high water content,low-molecularweight heparin was incorporated in PEG hydrogels after grafted with maleimide groups.Rheology and dug release study proved that this hydrogel had ideal mechanical property and joint delivery of different drug molecules could be achieved.Cell study indicate this gel was highly biocompatible and was potential material as cardiovascular scaffold or other softtissue-mimic scaffold for clinical application.Applications of implanted biomaterials usually require hydrogels to be biodegradable.For specific use like drug delivery in cancer treatment,sensitivity to external stimuli of hydrogels will help render targeted release and increase therapeutic efficacy.Therefore,we fabricated a hybrid hydrogel by preparing thermal-sensitive liposomes and synthesizing MMP-cleavable peptide.This hydrogel was expected to have both temperature sensitivity and enzymatic degradability.DLS during heating process and DSC results determined the melting temperature of liposomes was 41 oC,indicating that liposome structure would respond to outer mild thermal stimuli and enabled drug release.MMP-1 was used to degrade hydrogel and this enzyme was found more active in cancer site microenvironment than normal.In situ degradation test and DOX release test proved that this liposome-hydrogel showed quick response to enzymes and mild heating in the environment.This gel could be interesting drug vehicle for anticancer therapy.