Biologic scaffold materials composed of extracellular matrix (ECM) have been derived from a wide variety of xenogeneic and allogeneic tissue and organ sources. These materials have been used in a similarly wide variety of pre-clinical and clinical tissue engineering and regenerative medicine approaches to tissue reconstruction. When prepared and utilized appropriately, ECM scaffolds have been shown to promote the formation of functional, site-specific host tissues. This is in direct contrast to the default mammalian host response to tissue injury, which involves inflammation and scarring. The exact mechanisms by which ECM scaffold materials are capable of modulating the default host response and promoting this type of "constructive" tissue remodeling are largely unknown. However, we have shown that those ECM scaffolds that are capable of promoting constructive remodeling are also associated with a distinct population of macrophages within the site of implantation. A number of changes in macrophage physiology have been observed to occur with advanced age. These changes have been associated with an inability to fight pathogens and to heal wounds. The exact mechanisms which underlie these changes are unclear, but have been suggested to include alterations in the local tissue microenvironment (i.e. ECM composition, and resident cell populations) which contribute to anergic macrophage behavior. The proposed work seeks to investigate the response of macrophages derived from young, adult, and aged mice following interactions with biologic scaffold materials composed of ECM derived from young, adult, and aged porcine donors (Aim 1). Further, the proposed work seeks to identify the ligands responsible for macrophage-ECM scaffold interactions and assess the relative presence of these ligands in ECM scaffold materials derived from young-adult and aged donors (Aim 2). These goals will be accomplished by experienced investigators through a set of in vitro studies which utilize state of the art high throughput methodologies. The completion of these studies will not only further the understanding of the mechanisms by which ECM scaffolds modulate the host response, but will also lead to a better understanding of the impact that the changes in macrophage physiology which occur with aging will have upon the potential to utilize regenerative medicine strategies in an aging population.
University of Pittsburgh McGowan Institute for Regenerative Medicine November 15, 2012 To Whom It May Concern: Suite 300 450 Technology Drive Pittsburgh, PA 15219-3130 412-624-5253 Fax: 412-624-5256 www.mirm.pitt.edu We submit a revision of our proposal entitled Macrophage Polarization and Aging in the Context of Regenerative Medicine for review and consideration for funding. The revised application contains responses to specific comments made by the Study Section and we have identified the modified portions of the text with a bold line in the margin. The subject matter of this proposal i directed to the Musculoskeletal Tissue Engineering Study Section (MTE) of the National Institute on Aging. The problems addressed and the approach proposed are best suited for review by that study section and this study section reviewed the original submission. We respectfully request assignment to MTE for the sake of continuity and the ability of the Study Section to evaluate the quality of our revisions. Thank you for your consideration. Sincerely, Bryan Brown, PhD Assistant Professor Department of Bioengineering McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA.