Engineering in vivo gradients of sphingosine-1-phosphate receptor ligands for localized microvascular remodeling and inflammatory cell positioning

Biomaterial-mediated controlled release of soluble signaling molecules is a tissue engineering approach to spatially control processes of inflammation, microvascular remodeling and host cell recruitment, and to generate biochemical gradients in vivo. Lipid mediators, such as sphingosine 1-phosphate (SIP), are recognized for their essential roles in spatial guidance, signaling and highly regulated endogenous gradients. SIP and pharmacological analogs such as FTY720 are therapeutically attractive targets for their critical roles in the trafficking of cells between blood and tissue spaces, both physiologically and pathophysiologically. However, the interaction of locally delivered sphingolipids with the complex metabolic networks controlling the flux of lipid species in inflamed tissue has yet to be elucidated. In this study, complementary in vitro and in vivo approaches are investigated to identify relationships between polymer composition, drug release kinetics, SIP metabolic activity, signaling gradients and spatial positioning of circulating cells around poly(lactic-co-glycolic acid) biomaterials. Results demonstrate that biomaterial-based gradients of SIP are short-lived in the tissue due to degradation by SW lyase, an enzyme that irreversibly degrades intracellular SIP. On the other hand, in vivo gradients of the more stable compound, FTY720, enhance microvascular remodeling by selectively recruiting an anti-inflammatory subset of monocytes (SlP(3)(high)) to the biomaterial. Results highlight the need to better understand the endogenous balance of lipid import/export machinery and lipid kinase/phosphatase activity in order to design biomaterial products that spatially control the innate immune environment to maximize regenerative potential. (C) 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.