(371d) Delivery of Antibiotics and BMP-2 from Biodegradable Polyurethane Scaffolds

An urgent need for better bone healing and regeneration therapies results from the recognized limitations of current bone grafting procedures. Growth factors such as BMP-2 have been shown to enhance fracture healing, although infections can compromise healing even in the presence of BMP-2. We are developing a therapy for healing infected fractures using injectable, biodegradable polyurethane (PUR) scaffolds. These materials support osteoblast migration and proliferation, and degrade to non-cytotoxic products. In this study, we have developed PUR scaffolds that release BMP-2 and tobramycin for localized delivery. These biomaterials present potential clinical opportunities for enhanced treatment of infected fractures.

PUR foams were synthesized by reactive liquid molding of hexamethylene diisocyanate trimer and a hardener comprising a polyester triol, PEG 600, water, catalyst, stabilizer, and pore opener using previously reported techniques. Lyophilized tobramycin (8 wt%) and BMP-2 (0.001 wt%) with heparin (0.03 wt%) were incorporated separately into foams. In vitro release of tobramycin and BMP-2 in PBS at 37 ºC was measured up to 30 days. BMP-2 release was measured by ELISA, and tobramycin by HPLC. The released substrates were evaluated for bioactivity: BMP-2 by alkaline phosphatase activity and Western blots, and tobramycin by Kirby-Bauer and time-kill assays with methicillin-susceptible S. aureus. The in vivo behavior of the scaffolds was evaluated by subcutaneous implantation and tibial plugs in rats.

22-27% of the BMP-2 released from the foams by 24 days, with a continuing upward trend, which suggests extended, ongoing release. 60-70% of the tobramycin eluted after 24 hrs, with 90% released by 5 days. Kirby-Bauer tests revealed that sufficient tobramycin diffused from the foams and was effective against the bacteria. Zones of inhibition (ZI) were larger than the minimum sensitivity levels of 15 mm: 8% tobramycin (34.3 ± 1.2 mm), and blank foams displayed no inhibition. Histological sections of the subcutaneous implants showed extensive scaffold biodegradation by day 21, with new tissue formation and a limited giant cell response confined to the material remnants. Cellular infiltration and new bone formation were also observed in the tibial plugs.

This biocompatible and biodegradable PUR scaffold shows promise as an effective therapy for bone fracture healing. Its injectable application and resilience promote thorough contact with the surrounding bone, and the material properties can be tuned for varied strength and elasticity. In vivo studies show extensive cellular infiltration and new bone formation with minimal inflammation. Furthermore, we can release growth factors and antibiotics from these scaffolds in a controlled manner. This scaffold therefore provides a surface supporting attachment of osteoprogenitor cells, as well as a delivery system from which bioactives can be released locally to enhance healing of infected fractures.