Understanding diseases at the nanoscale
Researchers at the Nanomechanics Lab investigate the progression of red blood cell diseases with unique tools
Sickle cell disease is an inherited disease where red blood cells narrow and resemble a “C” shape. Under low-oxygen conditions, the sickled cells block small blood vessels, leading to excruciating pain and even other complications like stroke. In sickle cell disease and other diseases of red blood cells, securing a firm understanding of the problem itself is necessary to finding a solution that will help individuals with the disease. To this end, researchers at the Nanomechanics Laboratory strive to use the mechanical properties of nanomaterials to study the progression of and to understand the mechanisms of sickle cell disease and other life-threatening diseases.
Much of the current research at the Nanomechanics Laboratory has been geared towards diseases that involve red blood cells such as malaria and sickle cell anemia. The most lethal strain of malaria is caused by the parasite Plasmodium falciparum. The lab has been using microfluidics and different biomechanics tools such as optical tweezers and the Atomic Force Microscope (AFM) to understand the disease. Cells that become infected with malaria increase in rigidity as the disease progresses. These stiff cells clog microcirculation and hinder their own passage through inter-endothelial slits in spleen meshwork that screen and filter old cells. They go on to adhere to locations in the tissue, giving rise to many more infected cells. Since each ligament of the red cell cytoskeleton network is around 75 to 80 nanometers in size, it is best to study the inner workings of red cell diseases at the nanoscale.
According to Dao, current drugs for malaria have unwanted side effects, so it is especially important to understand the disease’s foundations. “Antimalarial drugs help to kill the malaria-infected cells, but they stiffen the uninfected cells, causing anemia... Gaining a more accurate understanding of the disease can improve these drugs,” says Ming Dao, the principal investigator and director of the Nanomechanics Laboratory.
Tools like optical tweezers use a focused laser beam to trap small particles. The laser beam can trap two particles on either side of a red-blood cell, and perform a single-cell uniaxial tension test. This test provides information about material properties of a cell like rigidity. With another imaging tool – diffraction phase microscopy (DPM), the phase-shift that the laser beam undertakes can be measured. This measurement corresponds to the distance the beam traveled inside the cell, and fluctuates at different membrane locations for each cell. In this way, a measurement of the cell’s rigidity and stiffness can be obtained.
The researchers at the Nanomechanics Lab have been studying the mechanisms of sickle cell disease by measuring the kinetics of mimicking the conditions of transient hypoxia — the low-oxygen conditions that cause sickling. The oxygen partial pressure in the microfluidic device can be controlled to study the process of sickling. For example, the oxygen levels can be reduced to observe the gradual sickling of the cells. However all cells are different, so some cells sickle faster and some slower, and when the oxygen levels are raised back to normal, the cells quickly un-sickle. Using microfluidic tools, Dao and the researchers at the Nanomechanics Lab are able to learn about the rates of sickling among red blood cells.
In addition to allowing researchers to investigate minute changes in cells, nanomaterials allow for innovation in drug delivery. In the recent Science paper “Ultralarge Elastic Deformation of Nanoscale Diamond,” Dao and his colleagues revealed that a nanoindenter can bend a diamond nanoneedle. This property of diamonds at the nanoscale makes them ideal for cellular drug delivery because drugs can be safely injected into cells without damage. “We don’t expect diamonds to bend this much, but diamonds at the nanoscale become very flexible but still strong,” says Dao.
Dao and his team at the Nanomechanics Lab are now investigating the applications of nanomaterials to medicine further. “Each person is different, so research in precision medicine can help personalize drugs and maximize the effectiveness of the drug on the patient,” says Dao. He is particularly excited by the new resolution and perspective that nanomechanics provides to research. “It is fascinating to study cell mechanics of diseases, because one can often visually see what is going on directly with all the latest nanomechanics tools,” Dao says. Studying cell mechanics at the nanoscale provides a detailed look into disease progression and helps researchers like Dao pinpoint treatment targets that attack the root of a disease.
Nov. 28, 2018: Factual corrections were made to reflect the science more precisely.