(536h) Biodegradable Antibiotic Delivery Materials Developed From Renewable and Biocompatible Reagents

Polymers have a long history in biomedical applications because of their chemical versatility; the presence of specific chemical functional groups combined with optimal levels of cross-linking control the mechanical strength, biodegradability, and drug release. Thus, crosslinked polymers have received widespread attention for use in vascular and osseous tissue.^1,2

Crosslinked polymers are commonly used in medical procedures and implants, and the orthopaedic device field is constantly striving for improvements in devices. Though crosslinked materials are currently used as bone replacements, the ultimate goal in orthopaedic applications is the generation of new, healthy bone. One approach is through biodegradation by either the breakdown of polymer backbone through degradable linkages or breakdown of side-chain crosslinks in network polymers.^3,4 Another focus of crosslinked polymers in orthopaedic applications is drug delivery, such as antibiotic delivery, in prevention of bacterial infection. Slow local release of antibiotics incorporated into bone cements or implants has shown to have a reduction of bacterial activity at the implantation sites.⁵ However, problems exist if the biomaterial remains after all the antibiotics or deliverables are released into the media. A slow release biodegradable network is optimal for effective therapeutic release of deliverables into the body.

In this regard, esters are a common type of biodegradable linkage which will hydrolyze under physiological conditions. Previously, citric acid was reacted with glycerol in the presence of benzene and PTSA (p‑toluenesulfonic acid) to form a cross-linked ester copolymer.⁶ Although this polymer showed promise as a drug delivery system, the incorporation of benzene, a known carcinogen, and PTSA, a known toxin, create additional complications for biomedical and pharmaceutical applications.

Our approach utilizes the esterification of citric acid and glycerol using a condensation reaction mechanism to fabricate a drug delivery system. In designing this new biodegradable polymer, our product utilizes ester bonds only made from non-toxic, renewable components. The melt polymerization only produced water as a by-product of the condensation reaction. The thermoset polymer is fabricated at 90-150°C creating flexibility in processing for coatings on medical and orthopaedic devices. In addition, we found the amount of glycerol to control the physical properties, degree of cross-linking, and biodegradability. The rate of degradation, and release of drug, has been found to be inversely proportional to the amount of crosslinking between citric acid and glycerol.

Gentamicin was also integrated into the system to supply an antibacterial component to the final polymer. Gentamicin is an excellent antibiotic for this delivery mechanism because the condensation reaction of citric acid and glycerol occurs under heated conditions, and gentamicin has been reported to have minimal to no degradation under 121°C.⁷ We have found that gentamicin loaded polymers clear bacteria significantly better than non-loaded polymers for multiple days (p<0.05 up to 3 days, N=3).

In conclusion we have developed a biodegradable drug delivery system that is developed from biocompatible and renewable materials. The final polymer shows promise to incorporate deliverables, and therapeutically release these drugs for over 3 days. We will present data comparing different fabrication conditions as well as therapeutic activity of the polymers in the form of bacteria clearing results.

References:

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2.    Scholz M-S, Blanchfield JP, Bloom LD, et al. The use of composite materials in modern orthopaedic medicine and prosthetic devices: A review. Composites Science and Technology. 2011;71:1791-1803.

3.    Chung EJ, Kodali P, Laskin W, Koh JL, Ameer GA. Long-term in vivo response citric acid-based nanocomposits for orthopaedic tissue engineering. J. Mater Sci. Mater Med. 2011;22:2131-2138.

4.    Watkins AW, Anseth KS. Copolymerization of pohtocrosslinkable anydride monomers for use as a biodegradable bone cement. J. Biomater. Sci. Polymer Edn. 2003;14:267-278.

5.    Campoccia D, Montanaro L, Arciola CR. The significance of infection related to orthopedic devices and inssues of antibiotic resistance. Biomaterials. 2006;27:2331-2339.

6.    Parmanick D, Ray TT. Synthesis and biodegradation of copolyesters from citric acid and glycerol. Polymer Bulletin. 1988;19(4):365-370.

7.    Traub WH, Leonhard B. Heat stability of the antimicrobial acticity of sixty-two antib acterial agents. Journal of Antimicrobial Chemotherapy. 1995;35:149-154.