PROJECT SUMMARY
The immune response to a peripheral infection is a fundamental feature of the human immune system,
providing robust protection from a myriad of infectious agents. The response necessarily invokes the innate
immune system, but many features of this orchestrated response are poorly understood, limiting our ability to
augment the response to new and ever evolving threats. In particular, the innate response engages the bone
marrow to modify the magnitude and dynamics of the response. There are important differences between the
mouse (primary model to study the innate immune response) and human innate immune responses, in
particular scale and dynamics, and new technologies in 3D cell and tissue culture provide exciting
opportunities in the field known as “organ-on-a-chip”. The primary goal of this project is to design, build, and
validate an integrated human “ImmuneChip” platform that mimics key dynamic features of the production and
trafficking of polymorphonuclear leukocytes (PMN, i.e., neutrophils) between the bone marrow, systemic
circulation, and peripheral site of bacterial infection. Developing this technology is important because of the
alarming expansion of antibiotic resistance bacteria which will demand creative and alternative approaches to
combat. The specific aims are to: 1) design, build, and test a microfluidic ImmuneChip that simulates the
homeostatic interaction between bone marrow, systemic circulation, and a sterile skin model; 2) establish a
homeostatic circuit in the ImmuneChip in which HSPC expansion, PMN trafficking, and antimicrobial defenses
respond to soluble mediators of bacterial infection; and 3) demonstrate an appropriate response to contain a
methicillin-resistant (and sensitive) S. aureus peripheral infection within the ImmuneChip, and produce a test-
bed for novel biological strategies to combat infection. The in vitro model will be able to uniquely simulate the
dynamics of peripheral infection-bone marrow communication including transport barriers, residence time in
the circulation, and dilution due to the large difference in the size of the compartments. Accomplishing our
primary goal will create a technology that advances a new class of model systems to understand the human
response to peripheral infection.