Biomaterial Strategies for Improved Bone Healing With Bone Morphogenetic Protein-2 Delivery

Musculoskeletal injuries account for two-thirds of all injuries that occur in the United States annually, and among these injuries, large bone defects are particularly challenging to repair. Although bone morphogenetic protein-2 (BMP-2) delivered on an absorbable collagen sponge (ACS) has shown clinical success in long bone healing, complications associated with the empirical use of supraphysiological doses of BMP-2, including heterotopic mineralization and inflammation, necessitate the development of a biomaterial carrier that localizes growth factors to the site of injury. In the development of bone tissue engineering strategies, another critical design parameter is the timing of delivery vehicle degradation, since bone regeneration may be impeded by the presence of residual biomaterials at the injury site. Furthermore, bioactive, naturally derived extracellular matrix (ECM) products with pro-healing and immunomodulatory properties are attractive therapeutics with rapid translatability that may function to attenuate heterotopic mineralization often observed with high dose BMP-2 treatment.

The goal of this work was to investigate hybrid biomaterial systems with controlled strategies for BMP-2 delivery to promote structural and functional restoration of segmental bone defects. Using a critically sized rat segmental bone defect model, we (i) evaluated the effects of alginate hydrogel oxidation on BMP-2 release and bone regeneration, (ii) elucidated the spatiotemporal effects of high dose BMP-2 on bone healing and gene expression, and (iii) investigated the ability of amniotic membrane to attenuate heterotopic mineralization in critically sized bone defects. Modification of the delivery vehicle to modulate growth factor availability may help minimize adverse side effects associated with high dose BMP-2 delivery, while harnessing the healing efficacy of BMP-2 for bone tissue engineering applications.

This thesis evaluated novel translatable strategies for promoting biomaterial degradation and growth factor localization, as well as attenuating heterotopic mineralization in a challenging segmental bone defect model. Of significance, our rat model recapitulated adverse effects associated with orthotopic high dose BMP-2 delivery, particularly heterotopic mineralization and systemic inflammatory effects. The spatiotemporal differences in gene expression as a function of BMP-2 dose may, in part, explain the heterotopic mineralization and tissue swelling seen clinically with high doses of BMP-2. By providing insight into the complex process of bone healing in the context of growth factor delivery, we may more effectively harness endogenous repair mechanisms for successful bone regeneration.

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Year

Entry

1999

Rowley JA, Madlambayan G, Mooney DJ. Alginate hydrogels as synthetic extracellular matrix materials. Biomaterials. January 1999;20(1):45-53.

2004

Simmons CA, Alsberg E, Hsiong S, Kim WJ, Mooney DJ. Dual growth factor delivery and controlled scaffold degradation enhance in vivo bone formation by transplanted bone marrow stromal cells. Bone. August 2004;35(2):562-569.

2011

Boerckel JD. Mechanical Regulation of Bone Regeneration and Vascular Growth in Vivo [PhD thesis]. Atlanta, GA: Georgia Institute of Technology; August 2011.

2011

Kolambkar YM, Dupont KM, Boerckel JD, Huebsch N, Mooney DJ, Hutmacher DW, Guldberg RE. An alginate-based hybrid system for growth factor delivery in the functional repair of large bone defects. Biomaterials. January 2011;32(1):65-74.

1892

Wolff J. Das Gesetz der Transformation der Knochen. Berlin: Hirschwald; 1892.