Jul 24 2019
MIT researchers have created an innovative sensor that can remarkably speed up the process of diagnosing sepsis, a major cause of death in the U.S. hospitals and kills almost 250,000 patients every year.
An MIT-invented microfluidics device could help doctors diagnose sepsis, a leading cause of death in U.S. hospitals, by automatically detecting elevated levels of a sepsis biomarker in about 25 minutes, using less than a finger prick of blood. (Image credit: Felice Frankel)
When the body’s immune system responds to infection, it sets off an inflammation chain reaction all through the body, leading to sepsis. Symptoms include shortness of breath, high fever, high heart rate, and other complications.
If this condition is left unchecked, it may result in septic shock, where organs shut down and blood pressure falls. To diagnose sepsis, physicians normally depend on numerous diagnostic tools, such as blood tests, vital signs, and other imaging and laboratory tests.
In the recent past, scientists have identified protein biomarkers in the blood that serve as early indicators of sepsis. Interleukin-6 (IL-6)—a type of protein created in response to inflammation—is shown to be a potential candidate.
In patients suffering from sepsis, the concentrations of IL-6 can increase hours before other symptoms start to show. However, even at these increased levels, standard assay devices cannot detect it rapidly because the protein levels in the blood are extremely low.
MIT researchers will present a paper at the Engineering in Medicine and Biology Conference. They will describe a novel microfluidics-based system that automatically spots clinically relevant levels of IL-6 to diagnose sepsis in approximately 25 minutes, by simply using just a small amount of blood.
In one specific microfluidic channel, microbeads doped with antibodies combine with a blood sample to collect the IL-6 biomarker. In another microfluidic channel, only beads comprising the biomarker fix to an electrode. When a voltage is run through the electrode, an electrical signal is produced for every biomarker-laced bead, which is subsequently transformed into the biomarker concentration level.
For an acute disease, such as sepsis, which progresses very rapidly and can be life-threatening, it’s helpful to have a system that rapidly measures these nonabundant biomarkers. You can also frequently monitor the disease as it progresses.
Dan Wu, Study First Author and PhD Student, Department of Mechanical Engineering, MIT
Joining Wu on the study is Joel Voldman, co-director of the Medical Electronic Device Realization Center, professor and associate head of the Department of Electrical Engineering and Computer Science, and a principal investigator in the Research Laboratory of Electronics and the Microsystems Technology Laboratories.
Integrated, Automated Design
Standard assays that identify protein biomarkers are costly, bulky machines deployed in laboratories that need around a milliliter of blood and generate results in hours. In the recent past, portable “point-of-care” systems have been created that utilize microliters of blood to obtain analogous results in just 30 minutes.
However, point-of-care systems can be extremely expensive as most of these products utilize costly optical components to identify the biomarkers. Besides, they can capture merely a small number of proteins, most of which are among the more profuse ones in blood. Any attempts to miniaturize components, reduce the cost, or elevate protein ranges have a negative impact on their sensitivity.
In their analysis, the investigators wanted to miniaturize the components of the magnetic-bead-based assay, which is frequently employed in laboratories, onto an automated microfluidic device that measures about several square centimeters. To accomplish this task, beads have to be manipulated in micron-sized channels and a device needs to be fabricated in the Microsystems Technology Laboratory that automates fluids’ movement.
The beads are laced with an antibody that attracts IL-6 proteins and also a catalyzing enzyme known as horseradish peroxidase. Both the blood sample and the beads are then injected into the device, traversing an “analyte-capture zone,” which is essentially a loop. Along this loop is a peristaltic pump, which is often used for regulating liquids, that has valves which are controlled automatically by an external circuit.
Closing and opening the valves in particular sequences allow the blood to circulate and cause the beads to combine together. After approximately 10 minutes, the IL-6 proteins adhere to the antibodies coated on the beads.
When the valves are automatically reconfigured at that time, the mixture becomes a smaller loop, known as the “detection zone,” where they remain trapped. The beads are collected by a small magnet for a short wash and then released around the loop. After around 10 minutes, several beads get stuck on an electrode laced with a distinct antibody that attracts IL-6 proteins. During that time, a solution enters into the loop and rinses the untethered beads, while the beads with IL-6 protein stay on the electrode.
A specific molecule carried by the solution reacts to the horseradish enzyme and produces a compound that easily responds to electricity. Upon applying a voltage to the solution, each remaining bead generates a tiny current. “Amperometry”—a standard chemistry approach—changes that current into a readable signal. The novel device counts these readable signals and measures the IL-6 concentration.
On their end, doctors just load in a blood sample using a pipette. Then, they press a button and 25 minutes later they know the IL-6 concentration.
Dan Wu, Study First Author and PhD Student, Department of Mechanical Engineering, MIT
The device utilizes only 5 μl of blood, which is roughly a quarter the volume of blood drawn by pricking a finger and a fraction of the 100 μl needed to detect protein biomarkers in laboratory-based assays. The device is capable of capturing IL-6 concentrations down to 16 picograms per milliliter, which is less than the concentrations that indicate sepsis. This means, the device is sufficiently sensitive to offer clinically pertinent detection.
A General Platform
The existing design has eight individual microfluidics channels to simultaneously determine many different blood samples or biomarkers. Different antibodies can be utilized in the same channel to detect many biomarkers concurrently, or different enzymes and antibodies can be utilized in individual channels to identify different biomarkers.
The scientists are planning to develop a panel of major sepsis biomarkers, including procalcitonin, C-reactive protein, interleukin-8, and interleukin-6, for the device to capture. However, the device can measure any number of different biomarkers for any type of disease, Wu added. Remarkably, the U.S. Food and Drug Administration has approved over 200 protein biomarkers for many conditions and diseases.
This is a very general platform. If you want to increase the device’s physical footprint, you can scale up and design more channels to detect as many biomarkers as you want.
Dan Wu, Study First Author and PhD Student, Department of Mechanical Engineering, MIT
Analog Devices, Maxim Integrated, and the Novartis Institutes of Biomedical Research funded the study.