CAREER: Innate and Adaptive Immunity in Response to Tissue Engineered Devices

Georgia Tech Research Corporation, Atlanta GA

Investigators

Abstract

0239152 Babensee Tissue engineering has the potential to revolutionize reconstructive surgery through the provision of engineered tissues and organs where no suitable alternative exists or to reduce morbidity associated with current procedures. Tissue engineered constructs must evade the host defense system to avoid rejection by the immune system and/or the consequences of inflammation. Otherwise, the cells of the construct will die, lose function, and/or be replaced by nonfunctional fibrotic or granulation tissue. Dendritic cells (DCs) function in innate immunity to recognize foreign pathogens and "danger signals" alert the effector arm of the immune/inflammatory system to initiate an adaptive immune response. DCs, provide a bridge between innate immune response to external signals such as foreign pathogens and the mounting of an adaptive immune response to presented foreign antigens. Similarly, it is expected that DCs play a central role in the inflammatory/immune response to tissue engineered devices. It is critical therefore, with the immunological complications of potential with tissue engineered cell/polymer constructs, to understand the molecular basis for controlling the phenotype of this cell. In this way, biomaterials may be designed on a molecular scale for this purpose. This CAREER proposal is focused on: 1) Understanding the role of biomaterial contact as a maturation stimulus for DCs, 2) Defining the "biomaterial associated molecular patterns" (through the protein layer that they direct) that regulate DC maturation, 3) Identifying the DC receptors that recognize these chemical motifs and hence the mechanism of their maturation, 4) Integrating biological and engineering principles of cell and tissue engineering within educational programs with a hands-on approach. The overall hypothesis of the research is that biomaterials induce the maturation of DCs, acting as a "danger signal", such that the DCs become efficient antigen presenting cells and T cell stimulators. Further hypothesized is that biomaterial-associated DCs mature under the control of receptors similar to those used to respond to microbial pathogens. The overall goal of the project is that through an understanding of the effects of biomaterial chemistry on DC maturation and the mechanisms by which biomaterials are DC maturation stimuli, biomaterials may be designed on a molecular level to control DC phenotype. Specifically, biomaterials will be designed to not support DC maturation where immune responses are undesirable as for tissue engineered devices while designed to support DC maturation where immune responses are desired as for non-viral delivery vehicles for DNA vaccines. The objective is to delineate the biomedical engineering principles that underlie the inflammatory and immune responses towards tissue engineering constructs to enable biomaterial and biomedical device design with improved clinical outcome. The overall engineering aspect of this project is the elucidation of design rules for robust tissue engineered devices that withstand host defense systems. In parallel with the research, the PI will develop and implement a novel cell and tissue engineering laboratory course for undergraduate biomedical engineering (BME) students in which the students will learn the key concepts of this field through active learning laboratory experiences. Presenting this course in a laboratory format will stress the research nature of this field as students perform experiments using non-textbook methods form the current literature. The experiments will introduce students to aspects that are under active investigation in the research community. Furthermore, diffusion of this knowledge to younger students will attract the biomedical engineers of the future. Middle school and high school students will be engaged in hands-on learning about tissue engineering and its impact on society in a new short course. Through collaboration with the Atlanta Girls' School, as an initial test bed for this course, the infrastructure is present in their Winterim program, for the development and presentation of this short course to a key target audience, young girls.