Polyphosphazenes biomedical materials

Some of the most useful polyphosphazenes are fluoroalkoxy derivatives and amorphous copolymers (11.27) that are practicable as flame-retardant, hydrocarbon solvent- and oil-resistant elastomers, which have found aerospace and automotive applications. Polymers such as the amorphous comb polymer poly[bis(methoxyethoxyethoxy)phosphazene] (11.28) weakly coordinate Li " ions and are of substantial interest as components of polymeric electrolytes in battery technology. Polyphosphazenes are also of interest as biomedical materials and bioinert, bioactive, membrane-forming and bioerodable materials and hydrogels have been prepared. 

The use of synthetic polymers in medicine and biotechnology is a subject of wide interest. Polymers are used in replacement blood vessels, heart valves, blood pumps, dialysis membranes, intraocular lenses, tissue regeneration platforms, surgical sutures, and in a variety of targeted, controlled drug delivery devices. Poly(organosiloxanes) have been used for many years as inert prostheses and heart valves. Biomedical materials based on polyphosphazenes are being considered for nearly all the uses mentioned above. 

Copolymers consisting of polyphosphazene norbornene derivatives, (III), were prepared by Allcock [4] and used as electrically conductive materials, biomedical materials, and as compatibihzing agents. 

Laurencin, C.T., Koh, H.J., Neenan, T.X., AUcock, H.R., Langer, R., 1987. Controlled release using a new bioerodible polyphosphazene matrix system. Journal of Biomedical Materials Research 21 (10), 1231-1246. 

Polyphosphazenes are also of interest as biomedical materials and bioinert, bioactive, membrane-forming, and bioerodable materials (1). 

Figure 4.13 Osteoblast proliferation on 2D and 3D polyphosphazene (PPHOS = PNEGmPh) matrices. Gells were found to proliferate on 3D matrices over the 21-day culture time whereas a decline in cell number was found for 2D films after 7 days. TOPS tissue-culture polystyrene. Reproduced with permission from C.T. Laurencin, S.F. El-Amin, S.E. Ibim, D.A. Willoughby, M. Attawia, H.R. Allcock and A.A. Ambrosio,of Biomedical Materials Research, 1996, 30,133. 1996, John Wiley Sons, Inc. [12]...

The synthetic flexibility of poly(organo)phosphazenes, combined, when required, with a tunable degradability, can be used to prepare speciality materials with precisely designed functions. With intelligent design and structural modifications, it is envisaged that many advanced biomedical materials of the future could be derived from polyphosphazenes. As the many reports summarised in this book confirm, progress in this direction is indeed already well underway ... 

Peach, M.S., James, R., et al., 2012b. Polyphosphazene functionalized polyester fiber matrices for tendon tissue engineering in vitro evaluation with human mesenchymal stem cells. Biomedical Materials (Bristol, England) 7 (4), 045016. Available at http //www.ncbi.nlm. nih.gov/pubmed/22736077 (accessed 10.10.14.). 

Polyphosphazenes are some of the most diverse inorganic type polymers known. The presence of phosphorus and nitrogen atoms in the backbone and the unusual method of synthesis, with which an almost infinite variety of side groups and combinations of (fifferent side groups can be linked to the backbone, confer to the polymers a variety of interesting properties (1-3). Therefore, the applications of polyphophazenes can be very broad, and includes flame retardent materials, high performance elastomers, optical and electronic materials, biomedical materials etc.(3-8). The application potentials of some elastomers included aerospace, marine, oil exploration and industrial fields. However, despite to the hundreds of the polyphosphazenes synthesized, they are still expensive to produce and very few of them have been commercialized (6). 

Aside from the commercial fluoroelastomer mentioned above, many applications for polyphosphazenes have been proposed. In particular, recent smdies have looked at modified polyphosphazenes as potential biomedical materials [20,21]. Phosphazenes with hydrophilic side chains in water exhibit a lower critical solution temperature (LCST) (Section 3.3) and their hydrogels have been considered for controlled drug release and other biomedical applications [22-24]. However, no large-scale use has yet emerged. 

Biomedical Applications. In the area of biomedical polymers and materials, two types of appHcations have been envisioned and explored. The first is the use of polyphosphazenes as bioinert materials for implantation in the body either as housing for medical devices or as stmctural materials for heart valves, artificial blood vessels, and catheters. A number of fluoroalkoxy-, aryloxy-, and arylamino-substituted polyphosphazenes have been tested by actual implantation ia rats and found to generate Httle tissue response (18). 

Figure 12.30 Potential uses of polyphosphazenes (a) A thin film of a poly(aminophosphazene) sueh materials are of interest for biomedical applications, (b) Fibres of poly[bis(trifluoroethoxy)phosphazene] these fibres are water-repellant, resistant to hydrolysis or strong sunlight, and do not burn, (c) Cotton cloth treated with a poly(fluoroalkoxyphosphazene) showing the water repellaney eonferred by the phosphazene. (d) Polyphosphazene elastomers are now being manufaetured for use in fuel lines, gaskets, O-rings, shock absorbers, and carburettor eomponents they are impervious to oils and fuels, do not bum, and remain flexible at very low temperatures. Photographs by eourtesy of H. R. Allcock (Pennsylvania State University) and the Firestone Tire and Rubber Company.

The biomedical uses of polyphosphazenes mentioned earlier involve chemistry that could in principle be carried out on a classical petrochemical-based polymer. However, in their bioerosion reactions, polyphosphazenes display a uniqueness that sets them apart. This uniqueness stems from the presence of the inorganic backbone, which in the presence of appropriate side groups is capable of undergoing facile hydrolysis to phosphate and ammonia. Phosphate can be metabolized, and ammonia is excreted. If the side groups released in this process are also metabolizable or excretable, the polymer can be eroded under hydrolytic conditions without the danger of a toxic response. Thus, poljnners of this tjT are candidates for use as erodible biostructural materials or sutures, or as matrices for the controlled delivery of drugs. Four examples will be given to illustrate the opportunities that exist. 

Allcock, H. Polyphosphazenes as new biomedical and bioactive materials. Drugs Pharm. Sci. 45 163-193, 1990. 

Glucose-substituted polyphosphazenes such as (12.242b) also lead to water-soluble products with potential biomedical applications. The fact that aromatic azo groups can be successfully introduced into the polymer side chains as in (12.242a) suggests that such materials may prove to be the precursors of a new class of azo polymer dyestuffs (Section 12.8) [90,91]. 

H. R. Allcock, Polyphosphazenes as new biomedical and bioactive materials, in Biodegradable Polymers Ai Drug Delivery Systems, edited by M. Chasin, R. Langer (Marcel Dekker, New York, 1990) pp 163-194. 

Synthetic approaches to produce polymers with desirable biomedical characteristics for this class of materials have been extensively reviewed (Allcock, 1990 Crommen et al, 1993). Poly[(amino acid ester) phos-phazenes] are knovm to be susceptible toward hydrolytic degradation and hold promise as degradable materials. Recently, Laurencin etal (1987) used a poly(imidazole methylphenoxy) phosphazene to study the release characteristics ofBSA. Protein release was demonstrated using C-labeled BSA in a 20% imidazole-substituted polyphosphazene. Release from this matrix consisted of an initial burst of almost 25% of the protein, followed by release over several hundred hours in which a total of 55% of the protein was released. Polymer degradation for the 20% imidazole-substituted polyphosphazene was also studied and found to be quite slow, with 4% of the polymer degraded in 600 hr. 

Another field of biomedical applications in which polyphosphazenes can be used, is the field of drug delivery systems. One can distinguish two types of drug delivery systems. In a first type of systems, the drug to be released, is covalently attached to the polymer backbone. In a second concept, the polymer material is used as matrix system in which the drug is physically dispersed. 

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