Abstract
Sepsis is a deadly syndrome (also known as “blood poisoning”) which ends the life of more than 250,000 Americans every year. Sepsis is often misdiagnosed, delaying treatment. To address the limitations of current understanding of sepsis and improve survival of sepsis patients, we are developing new assays to study the biology of infections and to detect sepsis early. Our work merges the engineering of novel microfluidic devices with the study of neutrophils, the most numerous white blood cells and earliest responders to infections, and a new hypothesis regarding the roles of neutrophils in sepsis. We designed and validated several microfluidic technologies that enable us to measure the motility phenotype of neutrophils with higher precision than ever before. We developed microfluidic devices that work directly with one droplet of blood and validated these in dozens of patients in critical condition and receiving intensive care. We identified a unique neutrophil phenotype that could serve as an accurate marker for sepsis. We found that human neutrophils can regulate their numbers at sites of acute inflammation, independently from the presence of other immune cells. We also have evidence for a new, previously underappreciated mechanism that makes capillary plexuses vulnerable to neutrophils, with relevance to organ failure during septic shock. Further studies of neutrophil phenotype in patients will enhance our understanding of the roles that neutrophils play before and during sepsis and will facilitate the design of new strategies for the diagnosis, monitoring, and prevention of sepsis.