Preparation And Properties Of Amino Acid Ester Based Polyphosphazene Biomaterials

The rapid development of tissue engineering and drug delivery expands a large demand for novel biomaterials.Biodegradable polyphosphazenes have flexible molecular designability,excellent biocompatibility,and their degradation products are non-toxic or low toxic phosphate,ammonium and amino acid esters,all of which can be readily excreted by human body.Recently,the development of polyphosphazene materials greatly inceases the choice of novel biomaterials.However,there are still many problems and challenges remaining in the preparation and application of polyphosphazene materials.First,the linear type polyphosphazene based injectable hydrogels are lack of mechanical strength and anti-water-dissolvability,which make it difficult to be used in tissue engineering and drug delivery field,and the traditional improvement method employes reinforcements with biological safety risks,which will cause new problems.Second,the cyclomatrix type polyphosphazene materials also have biological safety worries due to toxic aromatic organic monomers used,which will be released during the materials degradation,so the biologically safe amino acid esters are applied to replace the aromatic monomers.Third,there is no report about the synthesis of non-aromatic monomer substituted cyclomatrix polyphosphazene nanoparticles,and the main hurdle remains unknown.Forth,the hydrolyzation study on the cyclomatrix polyphosphazene nanoparticles is rare,providing few theoretical basis for these materials in practical applications.Fifth,cyclomatrix polyphosphazenes can be hardly made into other morphologies except nanoparticles,due to their inherent highly crosslinked molecular structure,which limited their applications in complex situations.Aiming at these problems,we studied both linear type polyphosphazenes and cyclomatrix type polyphosphazenes,improved the mechanical strength and anti-water-dissolvability of linear polyphosphazene injectable hydrogel,prepared amino acid ester substituted cyclomatrix polyphosphazene nanoparticles and studied their stimuli-responsive hydrolyzation property,fabricated cyclomatrix polyphosphazene nanofibers by electrospinning.The details are as follows:1.We fabricated monoacrylic-terminated PEG and glycine ethyl ester co-substituted polypshophazene,and mixed them with?-cyclodextrin to form host-guest inclusion physical hydrogels,then employed UV light to further cure the physical hydrogel and formed chemical hydrogels with certain mechanical strength.The tunability of cellular adhesion was discussed.2.We studied the oligomer properties of cyclomatrix polyphosphazene prepared from cystine methyl ester and hexachlorocyclotriphosphazene,termed PPZ-CysM.We proposed the application of“water-triggered self-assemble polycondensation”method for the preparation of cyclomatrix polyphosphazene nanoparticles.The transition mechanism of oligomers to nanoparticles is detailly studied by TEM and DLS,and the influence of mixed solvent solubility parameter(?_m)to the preparation of uniform PPZ-CysM is confirmed,the diameter of nanoparticles was tuned by controlling the concentration of oligomers.3.Through the reaction between HCCP and non-aromatic monomers(cystine methyl ester,lysine methyl ester,arginine methyl ester and diaminodecane),four corresponding cyclomatrix polyphosphazene oligomers and nanoparticles were prepared.The behavior of oligomers can be adjusted by controlling the?_m,and the upper/lower critical solubility parameter(UCSP/LCSP),nanoparticle size and yield of oligomers can be adjusted by tuning the substitution rate and hydrophilicity of organic monomers.4.The hydrolyzation rate and mechanism of PPZ-CysM nanoparticles at 37?were studied.The reductive-sensitive degradability of PPZ-CysM nanoparticles was evaluated by Dithiothreitol(DTT)and Glutathione(GSH),and their final hydrolyzation products were confirmed by NMR and GPC.The drug release profile of PPZ-CysM nanoparticles was studied under mimic intracellular condition(20 mM GSH,pH 5.5),and the pH-triggered drug release rate was promoted by introducing more hydrophilic lysine methyl ester.5.Two electrospinning methods were used and compared for the preparation of PPZ-CysM electrofibers with oligomers.The electrofibers prepared from the mixed solution of PPZ-CysM and polyvinylpyrrolidone presented discontinuous fibers.Then the study focused on the direct electrospinning of PPZ-CysM oligomer solution,after the optimization of solvents,concentration,removing impurity and further drying solvents,uniform electrofibers with diameter of 800 nm were prepared.