Date of Completion

5-2-2018

Embargo Period

5-2-2019

Keywords

aging; macrophages; bone repair; calcium phosphate; simvastatin; drug delivery

Major Advisor

Liisa T. Kuhn

Associate Advisor

Marja M. Hurley

Associate Advisor

Sangamesh G. Kumbar

Associate Advisor

Lakshmi S. Nair

Field of Study

Biomedical Engineering

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Older adults suffer from weakened and delayed bone healing due to age-related alterations in bone cells and in the immune system. Given the interaction between the immune system and skeletal cells, therapies that address deficiencies in both the skeletal and the immune system are required to effectively treat bone injuries of older patients. The sequence of macrophage activation observed in healthy tissue repair involves a transition from a pro-inflammatory state followed by a pro-reparative state. In older patients, inflammation is slower to resolve and impedes healing. The goal of this dissertation was to design a novel drug delivery system for temporal guidance of the polarization of macrophages using bone grafting materials. A biomimetic calcium phosphate coating (bCaP) physically and temporally separated the pro-inflammatory stimulus interferon-gamma (IFN) from the pro-reparative stimulus simvastatin (SIMV). Effects on both human (THP-1) and aged mouse bone marrow macrophages were tested. Sequential M1-to-M2 activation was achieved with both cell types. Successful osteogenic differentiation of human osteoprogenitors derived from older patients was confirmed with the delayed delivery of SIMV from bCaP. These results suggest that this novel immunomodulatory drug delivery system holds potential for controlling macrophage activation to maximize older patient bone healing. In vitro studies prove our hypothesis and show successful macrophage phenotype modulation and improved in vitro osteogenesis in preparation for future in vivo studies.

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