Polyphosphazenes for Advanced Biomaterial Applications

Open Access
Krogman, Nicholas Ryan
Graduate Program:
Doctor of Philosophy
Document Type:
Date of Defense:
May 06, 2008
Committee Members:
  • Harry R Allcock, Committee Chair
  • Mary Elizabeth Williams, Committee Member
  • Karl Todd Mueller, Committee Member
  • James Patrick Runt, Committee Member
  • polymers
  • biomedical materials
  • polyphosphazenes
  • polymer hydrolysis
The work described in this thesis focuses on the design and synthesis of novel polyphosphazenes for advanced biomedical applications, including tissue engineering and controlled drug delivery. In addition, polyphosphazene/poly(lactide-co-glycolide) (PLGA) blends were fabricated and the physical properties of these blends were characterized for tissue engineering applications. Chapter 1 outlines the basic fundamental principles of polymer chemistry with a detailed introduction to polyphosphazenes and their uses as biomedical materials. Chapter 2 discusses the synthesis of five novel polyphosphazenes with glycyl-glycine ethyl ester dipeptide side groups in multiple side group ratios, poly[(glycyl-ethyl glycinato)x(ethyl glycinato)yphosphazene]. The dipeptide side groups possessed two hydrogen bonding protons for interactions with other polymer systems. Polymer blends of these polyphosphazenes with poly(lactide-co-glycolide) (PLGA) were fabricated and the miscibility was studied. Characterization of the polymer blends utilized differential scanning calorimetry and scanning electron microscopy techniques. Poly[(glycyl-ethyl glycinato)1.5(ethyl glycinato)0.5phosphazene] formed completely miscible blends with PLGA, irrespective of the composition of the PLGA. Chapter 3 describes the synthesis of new dipeptide ethyl esters that were synthesized via the mixed anhydride solution phase peptide route. These dipeptide ethyl esters were utilized for covalent linkage to the polyphosphazene backbone. The design of these side groups required the amino acid to be covalently linked to the polyphosphazene backbone to generate steric hindrance at the á-carbon to decrease the hydrolysis rate of iv the polyphosphazene. The second amino acid needed limited steric hindrance to the amino proton, and the C-terminus had to be ester protected. Therefore, glycine ethyl ester was used. Thus, the amino acids alanine, valine, and phenylalanine were coupled with glycine ethyl ester during the peptide synthesis. The primary amino function of these dipeptides was covalently linked to poly(dichlorophosphazene) with the co-substituents glycine ethyl ester or alanine ethyl ester. The molecular structure was characterized by use of multinuclear NMR techniques and the physical characteristics were studied by DSC and GPC techniques. The hydrolysis mechanism of these polymers in various buffered aqueous media of pH=4.0, pH=7.0, and pH=10.0 was analyzed. It was determined that the phenylalanine ethyl ester substituted polyphosphazenes provided the most protection to the backbone and all the polymers were more stable in pH 10.0 medium. Chapter 4 describes dipeptide ethyl ester substituted polyphosphazenes blended with two different polyesters, PLGA and polycaprolactone (PCL). Fabrication of the blends was conducted by a solution casting process and by electrospinning. The miscibility of the polymer blends was examined by DSC and SEM techniques. These studies showed that polyphosphazenes substituted with alanyl-glycine ethyl ester or valinyl-glycine ethyl esters are miscible with PLGA when solution-cast. However, electrospinning of the blended solutions produced nanofiberous mats that were completely immiscible. There was no miscibility when these polyphosphazenes were blended with PCL, regardless of the processing technique that was utilized. v Chapter 5 evaluates the use of tris(hydroxymethyl)amino methane (THAM), a biological buffer, covalently linked to the polyphosphazene backbone. The primary amino function of THAM was utilized for covalent linkage to the backbone, together with the co-substituents glycine ethyl ester or alanine ethyl ester. These polyphosphazenes formed very miscible blends with PLGA. Hydrolysis studies showed that the polyphosphazene did not significantly degrade within six weeks. Cells studies showed good biocompatibility of the blend surfaces after 14 days. Chapter 6 describes the synthesis of polyphosphazene block copolymers with poly(L-lactide), poly(trimethylene carbonate), and polycaprolactone. The organic blocks were designed to possess amino end functions that were utilized for covalent linkage to the growing polyphosphazene chain. Anionic ring opening polymerization conditions were utilized for the synthesis of the organic blocks, followed by deprotection of the amine terminus. The polyphosphazene chain was synthesized via the living cationic polymerization route. The molecular structures of the block copolymers were examined by 1H and 31P NMR techniques and molecular weights were analyzed by gel permeation chromatography. Chapter 7 discusses the synthesis of phosphazenes substituted with the purines, guanine and adenine, and the pyrimidine cytosine. These side groups have a primary amino function that in principle should replace all the chlorine atoms within the phosphazene system. Hexachlorocyclotriphosphazene syntheses proved that full chlorine replacement could not be achieved. At the polymer level, the purine and pyrimidine side groups were used in a co-substitution synthesis pattern together with glycine ethyl ester, vi alanine ethyl ester, or ethylene glycol methyl ether. These polymers were found to provide good thermal stability and hydrolytic sensitivity. Chapter 8 contains a discussion of the utility of serine and threonine amino acids as substituents on polyphosphazene chains. Two different types of covalent linkage are exploited to influence the chemical and physical properties of the polymers. When the free amino terminus of serine or threonine ethyl ester was utilized, poly(L-lactide) was grafted from the free alcohol terminus linked to the á-carbon. This linkage also imparts hydrolytic sensitivity to the polymer skeleton. When the amino terminus was protected, the alcohol function was utilized for chlorine replacement with poly(dichlorophosphazene). The P-O-C linkage is more chemically stable than P-N-C units based on comparisons of polyphosphazenes substituted with amino acid ester side groups. Subsequent deprotection chemistry was utilized to fabricate polymers with free N- and C-termini from the amino acid side group. Polyphosphazenes that possessed the free N- and C-termini are soluble in water, regardless of the pH, and crosslinked hydrogels were obtained in the presence of calcium ions.