Sickle cell disease (SCD), known in the homozygous form as sickle cell anemia, affects 1 in 50 African Americans with debilitating, chronic, crisis episodes and reduced life expectancy. SCD is an inherited blood disorder caused by a single point mutation in the beta-globin gene. Sickle hemoglobin (HbS) has the unique property of polymerizing when deoxygenated, triggering red blood cell (RBC) sickling and dehydration, leading to vaso-occlusion and impaired blood flow in capillaries and small vessels. The biochemistry of HbS polymerization in vitro is well understood. However, inside RBC, the mechanism of underlying changes in cell mechanics and adhesion properties resulting from HbS polymerization is poorly understood due to a lack of appropriate measurement methods and realistic models. Three research teams with complementary expertise in bio-photonics (lead by Peter So, MIT), in biomechanics and microfluidics (lead by Ming Dao, MIT), and in SCD treatment (lead by Gregory Kato, UPMC) will join force to develop technologies that can quantify RBC biomechanics during RBC sickling. While there are many factors contributing to vaso-occlusion, RBC biomechanics is known to play a key role. The development of a predictive vaso-occlusion model will deepen our understanding of SCD etiology on a system level allowing the development of more effective drugs and treatments. Toward these goals, our team will develop reflection mode quantitative phase microscopy and a 3-D dissipative particle dynamics (DPD) multi-scale model. These technologies together will allow us to quantify RBC rheological properties with unprecedented accuracy during sickling transition inside microfluidic devices with precisely controlled oxygenation level. We will further develop complementary phase microscopy based spectroscopic methods to quantify HbS oxygenation and polymerization states. Simultaneous measurement of changes in RBC shape and rheology with changes in HbS biochemical states should allow us to better understand how intracellular molecular level variations drive RBC biomechanics, a key factor in vaso-occlusion and SCD crisis. The power of this approach will be evaluated in pilot studies to elucidate the therapeutic mechanisms of hydroxyurea, the only FDA approved drug specifically for SCD, and Aes -103, a new drug under development. These studies will develop proof of principle that this platform could be utilized in screening new anti-sickling drugs. The UPMC sickle cell disease registry will provide a rich clinical database to annotate the patient specimens that will be analyzed by advanced RBC biomechanics assays. This will allow preliminary exploratory statistical correlation of clinical characteristics to the potential biomarkers derived from the biomechanics assays.

Public Health Relevance

Sickle cell disease (SCD) is an inherited blood disorder affecting 90,000 to 100,000 people in the United States alone. The sickle hemoglobin (HbS) causes the affected red blood cells to stiffen and twist, leading to occlusion of small blood vessels. Among other problems such as impaired vision and chest pains, patients with SCD are also at serious risk for strokes. Joining the strengths of three interdisciplinary research teams, with expertise in bio-photonics, biomechanics, and SCD treatment, this proposal advocates the development of novel imaging technologies and biomechanical models to quantify structural changes of red blood cell that is known to be an important parameter in understanding vaso-occlusion in SCD patients. The findings will help to improve diagnostics and to understand the mechanisms of leading drugs for SCD treatment.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Enabling Bioanalytical and Imaging Technologies Study Section (EBIT)
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Hanspal, Manjit
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Massachusetts Institute of Technology
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Biomed Engr/Col Engr/Engr Sta
United States
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