We have used a microfluidic mass sensor to measure the density of single living cells. By weighing each cell in two fluids of different densities (see Figure 1), our technique measures the single-cell mass, volume, and density of approximately 500 cells per hour with a density precision of 0.001 g mL⁻¹. We observe that the intrinsic cell-to-cell variation in density is nearly 100-fold smaller than the mass or volume variation.  As a result, we can measure changes in cell density indicative of cellular processes that would be otherwise undetectable by mass or volume measurements. Here, we demonstrate this with four examples: identifying erythrocytes infected with Plasmodium falciparum malaria in a culture, distinguishing transfused blood cells from a patient’s own blood (as in Figure 2), identifying irreversibly sickled cells in a sickle cell patient, and identifying leukemia cells in the early stages of responding to a drug treatment. These demonstrations suggest that the ability to measure single-cell density will provide valuable insights into cell state for a wide range of biological processes.

1. W. H. Grover, A. K. Bryana, M. Diez-Silvac, S. Suresh, J. M. Higgins, and S. R. Manalis, “Measuring single-cell density,” Proc. National Academy of Sciences, vol. 108, no. 27, pp. 10992-10996, 2011.

Collaborators

• A. Amon, MIT
• M. Kirschner, Harvard
• K. Ligon, DFCI
• P. Mallick, USC
• D. Sabatini, MIT
• M. Toner, MGH

Postdoctoral Associates

• W. Grover, BE
• S. Knudsen, BE
• S. Byun, BE
• S. Olcum, BE

Graduate Students

• N. Cermak, CSB
• N. Chou, BE
• F. Delgado, BE
• A. Gulati, BE
• V. Hecht, BE
• R. Kimmerling, BE
• J. Shaw, BE
• S. Son, ME
• Y.C. Weng, CSB

Research Staff

• Kris Payer, Process Engineer

Support Staff

• Mariann Murray

Publications

W.H. Grover, A.K Bryan, M. Diez-Silva, S. Suresh, J.M. Higgins, S.R. Manalis. Measuring single-cell density. PNAS (2011); 108 10992-6.

J. Lee, R. Chunara, W. Shen, K. Payer, K. Babcock, T. Burg, S.R. Manalis. Suspended microchannel resonators with piezoresistive sensors. Lab on a Chip 2011; 11 645-651.

J. Lee, W. Shen, K. Payer, T. Burg, S.R. Manalis. Toward attogram mass measurements in solution with suspended nanochannel resonators. Nano Letters 2010; 10 2537-2542.

M. Godin, F.F. Delgado, S. Son, W.H. Grover, A.K. Bryan, A. Tzur, P. Jorgensen, K. Payer, A.D. Grossman, M.W. Kirschner and S.R. Manalis. Using buoyant mass to measure the growth of single cells. Nature Methods 2010; 7 387-391.

J.E. Sader, T.P. Burg, S.R. Manalis. Energy dissipation in microfluidic beam resonators. Journal of Fluid Mechanics 2010; 650 215-250

M.G. von Muhlen, N.D. Brault, S.M. Knudsen, S. Jiang, S.R. Manalis. Label-Free Biomarker Sensing in Undiluted Serum with Suspended Microchannel Resonators, Analytical Chemistry 2010; 82 1905-1910.

A. K. Bryan, A. Goranov, A. Amon, S. R. Manalis. Measurement of mass, density, and volume of yeast through the cell cycle. PNAS 2010; 107 (3) 999-1004.

P. Dextras, T.P. Burg, S.R. Manalis. Integrated Measurement of the Mass and Surface Charge of Discrete Microparticles Using a Suspended Microchannel Resonator. Analytical Chemistry. 2009; 81(11), 4517-4523.

T.P. Burg, J.E. Sader, S.R. Manalis. Non-Monotonic Energy Dissipation in Microfluidic Resonators. Physical Review Letters. 2009; 102 (22), 228103.

S.M. Knudsen, M.G. von Muhlen, D.B. Schauer, S.R. Manalis. Determination of Bacterial Antibiotic Resistance Based on Osmotic Shock Response. Analytical Chemistry 2009; 81(16), 7087-7090.

S. Son, W.H. Grover, T.P. Burg, S.R. Manalis. Suspended microchannel resonators for ultra-low volume universal detection. Analytical Chemistry. 2008; 80 4757-4760.

W.H. Grover, M. von Muhlen, S.R. Manalis. Teflon films for chemically-inert microfluidic valves and pumps. Lab on a Chip. 2008; 8 913-918.

T.M. Squires, R.J. Messinger, S.R. Manalis. Making it stick: convection, reaction, and diffusion in surface based biosensors. Nature Biotechnology. 2008; 26 417-426.

R. Chunara, M. Godin, S. M. Knudsen, S.R. Manalis. Mass-based readout for agglutination assays. Applied Physics Letters. 2007; 91 193902.

M. Godin, A.K. Bryan, T. Burg, and S.R. Manalis, Measuring the mass, density and size of particles and cells using a suspended microchannel resonator. Applied Physics Letters. 2007; 91 123121.

T.P. Burg M.Godin, W. Shen, G. Carlson, J.S. Foster, K. Babcock, and S.R. Manalis. Weighing of Biomolecules, Single Cells, and Single Nanoparticles in Fluid. Nature 2007; 446 1066-1069.

J. Hou, M. Godin, K. Payer, R. Chakrabarti, S.R. Manalis. Integrated Microelectronic Device for Label-free Nucleic Acid Amplification and Detection. Lab on a Chip 2007;  7 347-354.