Polyphosphazene Design, Synthesis, and Characterization for Potential Ligament and Tendon Scaffolds

Open Access
Nichol, Jessica Lee
Graduate Program:
Doctor of Philosophy
Document Type:
Date of Defense:
July 18, 2014
Committee Members:
  • Harry R Allcock, Dissertation Advisor
  • Benjamin James Lear, Committee Member
  • Philip C. Bevilacqua, Committee Member
  • Michael Anthony Hickner, Committee Member
  • polyphosphazene
  • biomedical
  • polymer
  • elastomer
The work described in this thesis describes the progress towards developing polyphosphazenes designed specifically for tissue engineering applications with an emphasis on ligament and tendon repair and replacement. Chapter 1 outlines the fundamentals of polymer chemistry in conjunction with the importance of polyphosphazene chemistry and its potential for biomedical applications. Chapter 6 illustrates additional possibilities and considerations for designing future polymers for tissue engineering scaffolds. Chapter 2 discusses the design, synthesis, and characterization of new polyphosphazenes to determine their potential as scaffolds for ligament and tendon tissue engineering. The carboxylic acid moiety of the amino acids L-alanine and L-phenylalanine were protected with alkyl esters with increasing chain length from 5 to 8 carbon atoms. This combined the hydrolytic sensitivity of the amino acid ester polyphosphazenes with the elastomeric characteristics induced by the long chain alkoxy polyphosphazenes. Test side group substitution reactions were performed on the cyclic small molecule model, hexachlorocyclotriphosphazene (NPCl2)3, to determine if steric hindrance would inhibit the degree of chlorine replacement by the amino acid ester units. Counterpart polymers were then synthesized by replacement of the chlorine atoms in poly(dichlorophosphazene) (NPCl2)n by the same amino acid esters. The glass transition temperatures of the polymers decreased with increasing alkyl ester chain length, ranging from 11.6 to -24.2 °C. Polymer hydrolysis was studied for solid samples in deionized water at physiological temperature for 12 weeks. The starting pH was 6.3 and the final pH ranged between 5.2 and 6.8. Polymer film mass decreased between ~8.7 and 26 percent during the 12 week period, while the molecular weights decreased ~57 to 99 percent. Chapter 3 describes the development of a possible polymer candidate that could potentially serve as a ligament or tendon tissue engineering scaffold by meeting the requirements of biodegradability, biocompatibility, and elasticity. In an attempt to meet these requirements novel citronellol-containing polyphosphazenes were synthesized, characterized, and crosslinked to generate elastomers. Citronellol was chosen as a side group due to its anti-inflammatory properties in addition to the presence of a double bond in its structure to permit polymer crosslinking. Alanine ethyl ester was chosen as a co-substituent to tune hydrolysis rates without severely affecting the glass transition temperatures of the final polymers. Hydrolysis of the uncrosslinked polymers in the form of films in deionized water at 37 °C showed between a ~8 to 16% mass loss and between a ~28 to 88% molecular weight decline over 12 weeks. Polymers were also crosslinked using UV radiation for increasing amounts of time. Preliminary mechanical testing of the homo-citronellol polymer indicated increasing modulus and decreasing tensile strength with increased crosslink density. Chapter 4 outlines a different approach to attaching the anti-inflammatory molecule citronellol to the polyphosphazene backbone. By contrast, in this work citronellol, was used as an ester unit to the carboxylic acid moiety of the amino acids glycine, alanine, valine, and phenylalanine that were in turn linked to the polymer through the amino functionality. This method allowed the hydrolysis rate to be tuned via the steric hindrance generated by the amino acid ester while still providing two crosslinkable sites per repeat unit from the citronellol units. A hydrolysis study of the uncrosslinked polymers at physiological temperature showed between a 19.9 – 28.8% mass loss and between a 80.4 – 98.9% molecular weight decline after 12 weeks. The double bond in the citronellol structure also allowed polymer crosslinking by UV radiation to further tune the properties. Additionally, the mechanical properties of the alanine and phenylalanine citronellol polymers were studied as a function of crosslinking. In chapter 5 the field of ethoxyphosphaze polymers is considered for their potential as biomedical materials. This was accomplished by determining the properties and hydrolytic characteristics of poly(diethoxyphosphazene) and related derivatives with both ethoxy and hydrophobic co-substitutent groups in a near 1:1 molar ratio. Co-substituents such as 2,2,2-trifluoroethoxy, phenoxy, or p-methylphenoxy units were examined. These hydrophobic co-substitutents serve as models for bioactive counterparts. The hydrolytic sensitivity of the ethoxyphosphazene units was so pronounced that even hydrophobic or bulky O-linked co-substitutents failed to counteract the hydrolysis behavior during a twelve-week hydrolysis study. This work illustrates a pathway for the development of a new class of useful bioerodible polymers.