Harshu Musunuri. Image courtesy of Pioneer
Sepsis is one of the leading causes of death in hospitals, and incidences are on the rise, according to the National Institute of General Medical Sciences (NIGMS). Two independent cohort studies published in JAMA found that sepsis contributed to 1 in every 2 to 3 deaths.1
Harshu Musunuri wants to help prevent such deaths. Majoring in Chemical Engineering at Stanford, the 18-year-old student is developing a synthetic (polymer) material that could act as both a diagnostic and a therapeutic agent for the bacterial toxins involved in the infections associated with sepsis. She has just won the first Pioneer tournament, a global competition that helps winning innovators advance their projects through funding and mentorship.
“I believe infectious disease in general deserves more attention, especially with the rise of antimicrobial resistance, which is why I chose to focus my work on sepsis,” Musunuri told MD+DI. “My interest in this topic actually began after reading an Atlantic article about the current industry gold standard for detecting toxins derived from gram-negative bacterial species. It’s called the LAL assay, and it uses horseshoe crab blood! This piqued my curiosity, and I realized that this test was so important because it was a way to prevent the incidence of septic shock.”
Musunuri said that current treatments for sepsis—which include the administration of vasopressors, IV fluids, and broad-spectrum antibiotics to bring down inflammation as doctors attempt to identify the source and type of infection—can have mixed results. “However, while the source is still unknown, reducing free endotoxin levels in the blood can reduce mortality and risk of organ failure and stabilize the presence of other inflammatory markers, which is where these polymers would come in,” she said. “Abnormally high endotoxin levels upon admission may also indicate to a physician that the patient has a gram-negative bacterial infection, allowing them to quickly administer more targeted antibiotics, and avoid unnecessary antimicrobials.”
Given her previous research in material sciences for energy applications, Musunuri decided to investigate a synthetic approach. In addition, “most existing technologies use biomolecular approaches to endotoxin capture and neutralization, which can be expensive and ineffective under certain conditions,” she explained. “Reading literature on the binding mechanism of polymers and its similarity with the non-covalent nature of biological antibodies gave me the idea to develop a synthetic material that could act as both a diagnostic and a therapeutic agent for bacterial toxins.”
She explained that “the polymers are synthesized so that they fluoresce in response to binding with endotoxins. By establishing a correlation between fluorescence intensity and endotoxin concentration, we’re able to effectively quantify blood endotoxin concentrations. This allows us to draw conclusions about severity of illness and predict risk of hospital/ICU mortality and risk of gram-negative infection (as shown by the MEDIC clinical trial). As for the potential treatment mechanism, these polymers are also designed to engage in competitive inhibition of a molecular complex that sets off the septic cascade.”
Musunuri is currently conducting tests “to determine whether treatment is possible via intravenous administration of the polymers or if column-based filtration (like kidney dialysis) would be more appropriate. The goal is to have the polymers immobilized onto small cartridges that would be exposed to patient blood samples (that are spun down to isolate the plasma) and be measured using a fluorescence spectrometer (for diagnosis).”
She envisions that such a solution could be used at emergency centers and intensive care units, “since this is where most sepsis patients end up. Identifying whether a gram-negative infection is the source of a patient’s symptoms within a matter of minutes rather than waiting many hours for blood culture results can be incredibly informative for the physician, in addition to being able to treat high endotoxin levels using these polymers,” she said.
Musunuri has “characterized the affinity, morphology, and composition of these materials using a variety of analytical chemistry tools to confirm that they function at a level comparable to that of a biological antibody,” she said. “I’m currently in the process of conducting a couple key in vitro assays to determine the neutralization capacity of the polymers. Afterwards, I’m hoping to design and carry out in vivo assays to evaluate how these polymers function within the body, with the support of my lab in the Stanford ChEM-H department.”
There may be some challenges in incorporating this test into the ICU workflow, “considering the change in behavior this would require from physicians,” she said. Another would be “the optimization of polymer synthesis at scale to achieve consistent fluorescence intensities at biologically relevant concentrations of endotoxins.”
In the meantime, Musunuri is focused on optimizing and standardizing the technology “to the point where it is ready for implementation,” she said. “I’m hoping to work with a medtech company with more experience with the FDA submission process to then license it and bring it to market.”
1. "Hospital Deaths in Patients With Sepsis From 2 Independent Cohorts," Vincent Liu, et al, JAMA. 2014.