Alternating release of different bioactive molecules from a complexation polymer system

Regeneration of bone is driven by the action of numerous biomolecules. However, most osteobiologic devices mainly depend on delivery of a single molecule. The present studies were directed at investigating a polymeric system that enables localized, alternating delivery of two or more biomolecules. The osteotropic biomolecules studied were simvastatin hydroxyacid (Sim) and parathyroid hormone (1-34) (PTH(1-34)), and the antimicrobial peptide cecropin B (CB) was also incorporated. Loaded microspheres were made using the complexation polymer system of cellulose acetate phthalate and Pluronic F-127 (blend ratio, 7:3). By alternating layers of the different types of microspheres, 10-layer devices were made to release CB and Sim, CB and PTH, or Sim and PTH. In vitro experiments showed five discrete peaks for each molecule over a release period of approximately two weeks. MC3T3-E1 osteoblastic cells alternately exposed to the osteotropic biomolecules showed enhanced proliferation and early osteoblastic activity. Alternating delivery of 10 nM Sim and either 500 pg/ml or 5 ng/ml PTH showed additive effects compared to the CB/Sim or CB/PTH devices. These implantable formulations may be useful for alternating delivery of different biomolecules to stimulate concurrent biological effects in focal tissue regeneration applications. (c) 2008 Elsevier Ltd. All rights reserved.