Generational Biodegradable and Regenerative Polyphosphazene Polymers and their Blends with Poly (lactic-co-glycolic acid)

Abstract

New fields such as regenerative engineering have driven the design of advanced biomaterials with a wide range of properties. Regenerative engineering is a multidisciplinary approach that integrates the fields of advanced materials science and engineering, stem cell science, physics, developmental biology, and clinical translation for the regeneration of complex tissues. The complexity and demands of this innovative approach have motivated the synthesis of new polymeric materials that can be customized to meet application-specific needs. Polyphosphazene polymers represent this fundamental change and are gaining renewed interest as biomaterials due to their outstanding synthetic flexibility, neutral bioactivity (buffering degradation products), and tunable properties across the range. Polyphosphazenes are a unique class of polymers composed of an inorganic backbone with alternating phosphorus and nitrogen atoms. Each phosphorus atom bears two substituents, with a wide variety of side groups available for property optimization. Polyphosphazenes have been investigated as potential biomaterials for regenerative engineering. Polyphosphazenes for use in regenerative applications have evolved as a class to include different generations of degradable polymers. The first generation of polyphosphazenes for tissue regeneration entailed the use of hydrolytically active side groups such as imidazole, lactate, glycolate, glucosyl, or glyceryl groups. These side groups were selected based on their ability to sensitize the polymer backbone to hydrolysis, which allowed them to break down into non-toxic small molecules that could be metabolized or excreted. The second generation of degradable polyphosphazenes developed consisted of polymers with amino acid ester side groups. When blended with poly (lactic acid-co-glycolic acid) (PLGA), the feasibility of neutralizing acidic degradation products of PLGA was demonstrated. The blends formed were mostly partially miscible. The desire to improve miscibility led to the design of the third generation of degradable polyphosphazenes by incorporating dipeptide side groups which impart significant hydrogen bonding capability to the polymer for the formation of completely miscible polyphosphazene-PLGA blends. Blend system of the dipeptide-based polyphosphazene and PLGA exhibit a unique degradation behavior that allows the formation of interconnected porous structures upon degradation. These inherent pore-forming properties have distinguished degradable polyphosphazenes as a potentially important class of biomaterials for further study. The design considerations and strategies for the different generations of degradable polyphosphazenes and future directions are discussed.

Keywords: biocompatibility; biodegradable polyphosphazene; biomaterials; poly (lactic-co-glycolic acid); regenerative engineering.

Fig. 1.

The different generations of degradable polyphosphazenes obtained from poly (organo) phosphazene.

Fig. 2.

Mechanism of nucleophilic macromolecular substitution depicting single-substituent and mixed-substituent polyphosphazenes.

Fig. 3.

Small molecule model reactions demonstrating the feasibility of selected nucleophilic organic substituents. (a) Glycylglycine ethyl ester reacting with HCCTP (b) Phenylphenol reacting with HCCTP.

Fig. 4.

Degradation mechanism of amino acid ester-substituted polyphosphazenes. The degradation products are ammonia and phosphate which constitute a natural buffer.

Fig. 5.

Chemical structures showing the high hydrogen bonding sites for glycylglycine ethyl ester substituent. a) Intra-molecular hydrogen bonding within the peptide molecules b) Inter-molecular hydrogen bonding between the peptide of polyphosphazene and carbonyl oxygen of PLGA.

Fig. 6.

Characterizations of miscibility for the blends of poly[(glycineethylglycinato)50(phenylphenoxy)50phosphazene](PNGEGPhPh) and PLGA. a) DSC curves for the blends and individual polymers and the blends exhibit single glass transition temperatures indicating miscibility b) FTIR spectra for the individual polymers and their blends. The peaks at 1677 cm-1 for the blend matrices correspond to the intermolecular hydrogen bonding between the peptide of the polyphosphazene and carbonyl oxygen of the PLGA [30]. Copyright 2010. Reproduced with permission from Elsevier Science Ltd.

Fig. 7.

Histological representation of the H&E stained sections of PLGA and the blend matrices, indicating the inflammatory response during the post-implantation period. PLGA recorded higher inflammatory responses after 2 and 4 weeks due to the acidic degradation products, whereas the blend matrices showed minimal inflammatory responses as a result of the near-neutral pH of their degradation products [30]. Copyright 2010. Reproduced with permission from Elsevier Ltd.

Fig. 8.

Peptide ester substituted polyphosphazene-PLGA blend a) SEM image of nanofibers composed of miscible blend indicating no phase separation b) Fluorescence image of a live/dead assay of primary osteoblast seeded on the miscible blend after 48 hours. Green color signifies that the cells are living and no evidence of red color which symbolizes dead cells c) Surface morphology of the blend showing the in situ pore forming ability after 12 weeks of implantation d) SEM image of the cross-section of the polyphosphazene spheres indicating smaller pores on them after 10 weeks of implantation. The porosity on the polymer spheres will provide extra surface area and room for more cell-polymer interactions [30, 33]. Copyrights 2010. Adopted with permissions from Elsevier Ltd and John Wiley and Sons Inc.