Cell-Based BioMEMS
Miniaturization using microtechnology tools offers key advantages over conventional approaches to interrogate cells but also introduces new challenges. The advantages parallel those seen in the semiconductor revolution (faster, cheaper, parallelism, advantageous microscale phenomena); however the challenges arise primarily from the difficulty associated with biological constraints such as innocuous manipulation of cells and maintaining cellular phenotypes to mimic in vivo behavior. Towards this end, we have developed new strategies for controlling the phenotype of immobilized cells and characterized several new methods to rapidly array living cells. Specifically, our group has explored the use of electromagnetic fields (electrophoresis (DC) or dielectrophoresis (AC)), miniaturized optical tweezers, photochemistry, patterned surface chemistries, robotic spotting, and microfabricated wells- all to array living cells for parallel observation.
Figure 1: Hydrogel tissue with controlled microscale architecture. Left, low magnification of photopolymerized thin film. Middle, array of cells clustered within film in 3D using dielectrophoresis (green): surrounded by second cell type (red), all entrapped in hydrogel (not visible). Right, high magnification of cell clusters in 3D, green indicating viability.
We have extensively characterized the ‘biocompatibility’ of this suite of techniques and have now developed projects to utilize these tools to understand a variety of phenomena including: differentiation of embryonic stem cells in combinatorial microenvironments [Flaim, Nature Methods ; Flaim, Stem Cells & Development ], the role of 3D cell organization on tissue function [Albrecht, Nature Methods; Albrecht, Biophysical Journal ; Albrecht, Lab-Chip ; Underhill, Biomaterials], and the dynamics of cell-cell interaction using reconfigurable silicon MEMS [Hui, PNAS; Hui, JoVE ]. A major emphasis in our technology development has been the seamless integration with conventional biomedical platforms (inverted microscopes, aseptic technique, etc) with the goal of developing tools that can be easily disseminated to biomedical researchers, especially in the stem cell community. Currently, we are on developing an electrophoretic chip for measuring biological exposures that cause DNA damage (Bevin Engelward, BE), studying the role of extracellular matrix microenvironments on embryonic stem cell differentiation along the pancreatic lineage (Douglas Melton, Harvard), dissection of the cell cycle checkpoint using multiplexed time lapse microscopy (Jagesh Shah, Harvard), and a microfluidic model of sickle cell disease in collaboration with L. Mahadevan at Harvard [Higgins, PNAS ]. Our long-term goals are to disseminate these tools broadly to life science investigators to transform the study of living cells in much the same way microarrays have revolutionized genomics.
Miniaturization using microtechnology tools offers key advantages over conventional approaches to interrogate cells but also introduces new challenges. The advantages parallel those seen in the semiconductor revolution (faster, cheaper, parallelism, advantageous microscale phenomena); however the challenges arise primarily from the difficulty associated with biological constraints such as innocuous manipulation of cells and maintaining cellular phenotypes to mimic in vivo behavior. Towards this end, we have developed new strategies for controlling the phenotype of immobilized cells and characterized several new methods to rapidly array living cells. Specifically, our group has explored the use of electromagnetic fields (electrophoresis (DC) or dielectrophoresis (AC)), miniaturized optical tweezers, photochemistry, patterned surface chemistries, robotic spotting, and microfabricated wells- all to array living cells for parallel observation.
Figure 1: Hydrogel tissue with controlled microscale architecture. Left, low magnification of photopolymerized thin film. Middle, array of cells clustered within film in 3D using dielectrophoresis (green): surrounded by second cell type (red), all entrapped in hydrogel (not visible). Right, high magnification of cell clusters in 3D, green indicating viability.
We have extensively characterized the ‘biocompatibility’ of this suite of techniques and have now developed projects to utilize these tools to understand a variety of phenomena including: differentiation of embryonic stem cells in combinatorial microenvironments [Flaim, Nature Methods ; Flaim, Stem Cells & Development ], the role of 3D cell organization on tissue function [Albrecht, Nature Methods; Albrecht, Biophysical Journal ; Albrecht, Lab-Chip ; Underhill, Biomaterials], and the dynamics of cell-cell interaction using reconfigurable silicon MEMS [Hui, PNAS; Hui, JoVE ]. A major emphasis in our technology development has been the seamless integration with conventional biomedical platforms (inverted microscopes, aseptic technique, etc) with the goal of developing tools that can be easily disseminated to biomedical researchers, especially in the stem cell community. Currently, we are on developing an electrophoretic chip for measuring biological exposures that cause DNA damage (Bevin Engelward, BE), studying the role of extracellular matrix microenvironments on embryonic stem cell differentiation along the pancreatic lineage (Douglas Melton, Harvard), dissection of the cell cycle checkpoint using multiplexed time lapse microscopy (Jagesh Shah, Harvard), and a microfluidic model of sickle cell disease in collaboration with L. Mahadevan at Harvard [Higgins, PNAS ]. Our long-term goals are to disseminate these tools broadly to life science investigators to transform the study of living cells in much the same way microarrays have revolutionized genomics.