A sugar-based phase-transitioning delivery system for bone tissue engineering

Abstract

Bone tissue engineering approaches commonly involve the delivery of recombinant human bone morphogenetic proteins (rhBMPs). However, there are limitations associated with the currently used carriers, including the need for surgical implantation and the associated increase in infection risk. As an alternative to traditional porous collagen sponge, we have adopted a solution of the injectable sucrose acetate isobutyrate (SAIB) as a carrier for rhBMP-2. The ability to deliver rhBMP-2 and other agents by injection reduces the infection risk and lesion size whilst in surgery, with the potential to avoid open surgery altogether in some indications.The primary methodology used for this in vivo study was a C57BL6/J mouse ectopic bone formation model. Specimens were examined by x-ray, microCT, and histology at 3 weeks. SAIB was delivered non-invasively and produced up to 3-fold greater bone volume compared to collagen. To further refine and improve upon the formulation, SAIB containing rhBMP-2 was admixed with candidate compounds including ceramic microparticles, antiresorptives, and cell signalling inhibitors and further tested in vivo. The formulation combining SAIB/rhBMP-2, the bisphosphonate zoledronic acid (ZA), and hydroxyapatite (HA) microparticles yielded a 10-fold greater bone volume than SAIB/rhBMP-2 alone. To investigate the mechanism underlying the synergy between ZA and HA, we used in vitro binding assays and in vivo fluorescent biodistribution studies to demonstrate that ceramic particles could bind and sequester the bisphosphonate. These data show the utility of SAIB as a non-invasive rhBMP delivery system as well as describing an optimised formulation for bone tissue engineering. (Im and Tae, 2005). In another study, the risk of septic knee after retrograde intramedullary femoral nailing was four times greater in open fractures than closed fractures (Halvorson et al., 2012). In a trial comparing recombinant human bone morphogenetic protein-2 (rhBMP-2)/collagen sponge treatment with the standard of care treatment in open tibial fractures, the rhBMP-2 treated group showed a significant increase in infections (Aro et al., 2011). Thus the development of a system able to deliver rhBMPs percutaneously to an orthopaedic site could reduce lesion size and minimise infection risk. KeywordsAlthough various polymeric materials, such as degradable hydrogels, have been developed by many groups to serve as injectable scaffolds (Miyamoto and Takaoka, 1993;Han and Hubbell, 1996;Burdick and Anseth, 2002;Lutolf et al., 2003), progression towards clinical application has been limited. However, we have chosen a material called sucrose acetate isobutyrate (SAIB), a sugar-based ester that is currently used as a food additive (emulsifier E444), as well as in cosmetics and industrial processes. In the United States, SAIB is approved by the Food and Drug Administration as a food additive, and has an allowable daily intake of 20 mg/kg/ day (21 CFR 172.833; 64 Fed. Reg. 29949, 4 June 1999). It has been considered safe for u...

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