Principal Investigator Roger Kamm
Drug development to protect humans from infectious pathogens broadly involved two stages before the drugs is actually introduced to a human subject. These are in vitro tests on petri dishes which offer the advantage of high-throughput but are very unrealistic representations of in vivo dynamics. On the other end of the spectrum are animal models. Although these animal models capture the dynamics in human systems quite well, they are extremely complex making it prohibitively difficult to isolate the effect of a single factor which is key to targeted drug development. They are also very expensive.
Our approach involves engineering realistic microenvironments in vitro to bridge the in vitro - in vivo gap. We use microfluidic systems to precisely control the physical and biochemical cues that the host and pathogen cells experience to mimic the in vivo microenvironment. The way our systems are designed makes it very conducive to imaging host-pathogen interactions. Fundamental questions like whether a pathogen invades the epithelial barrier through paracellular or transcellular pathways could be answered using our system. Further we have an automated impedance based method of monitoring of the integrity of the epithelial barrier which makes the system scalable to a high-throughput drug screening tool.
The group deals specifically with infectious diseases of the human airway such as Influenza A. Traditionally Madin Darby Canine Kidney (MDCK) cells that express influenza receptors are grown on petri dishes and used to grow populations of the virus. The Influenza virus does indeed replicate on MDCK monolayers. But the extrapolation of these results to influenza invading human airway cells is questionable. Instead, we grow airway epithelial cells, both primary Normal Human Bronchial Epithelial (NHBE) and immortalized Calu-3 cells on a bimimetic substrate with the right stiffness at an air-liquid interface with dynamic mechanical properties such as stretch and in vivo like substrate stiffness to closely mimic in vivo like infection dynamics and host-pathogen cross talk.