Biological systems are the ultimate in engineered design, from small molecule catalytic reactions to complex multicell organisms. Expanding on the wealth of recent discoveries toward understanding the governing principles of biology will bring even greater control and informed approaches to using biological processes to address societal challenges. iCET research themes involve cellular engineering technologies for applications including, but not limited to, human health, synthetic biology, materials, energy, and the environment.
1. Micro and Nanosystems for Cell Manipulation and Analysis
The lack of real time non-destructive analysis techniques to monitor cell processes is a barrier for advancing the field of cellular engineering. Novel tools and techniques are needed that provide nanoscale cell interfaces for controlling efficient intracellular delivery, sampling, and analysis. Such tools would impact fundamental understanding of biological processes, feedback control, and data analysis for specific natural and synthetic pathways. With these precise capabilities, platforms for application to synthetic biology, disease modeling, and drug discovery and toxicology testing using iPSCs will emerge. One approach is using microfluidics, which provide the control and scale to enable biological and clinical studies that may not be practical to carry out with current technologies. By integrating optimized cell culture and functional testing on a microfluidic platform, patient-specific disease analysis, drug testing and personalized drug toxicity screening will be possible. Examples of projects include:
• Novel sampling techniques for non-destructive analysis of cells
• Bio-MEMS for mechanobiological analysis and control of cell phenotype
• Microfluidic platforms for multiplexed cell culture and analysis
• Cell culture platform with integrated sensors for electrophysiological measurements
• Fabricated functional biosensor devices that enable diagnostic or therapeutic applications
2. Understanding Governing Principles through Systems Analysis
As the technologies are developed to provide temporal and single-cell analysis data, computational methods to extract conclusions and time-resolved mechanisms are needed. Data-driven systems analyses are now being developed for understanding regulatory networks for phenotype control and cell-cell interactions. Much of the data acquired through research of cellular engineering processes can be analyzed at a systems level to identify key cell input parameters, enable development of reprogramming and differentiation feedback systems, and guide the optimization of cellular manipulation. Examples of projects include:
• Analysis of multi-cell signal transduction networks during cell reprogramming
• Predictive models of cell phenotype based on temporal biochemical, mechanical, and functional analysis
3. Cell Reprogramming, Differentiation, and Trans-differentiation
The state of the art in cell reprogramming has progressed significantly since the initial Yamanaka discovery of activating four genes in a cell to induce pluripotency. The generation of reprogrammed cells is now routine in many laboratories, although with low efficiency. Subsequent cell differentiation is highly complex and poorly understood because it is influenced by chemical, mechanical, and genetic factors. The resulting cell populations are highly heterogeneous, with differing cell types and maturity levels within each culture, which makes studies based on these populations inconclusive. While numerous lab-on-a-chip platforms are being developed for modeling diseases or mimicking organs, many challenges remain—especially with respect to ensuring complete functional maturity of the differentiated cells used in these platforms. Incomplete functional maturity limits the understanding of disease mechanisms and stimuli responses that are the goal of these studies. Addressing this problem requires approaches such as recapitulation of in vivo cellular microenvironment and integration of cell functionality measurements. Simultaneous assessment of complex molecular and functional phenotype over time would impart comprehensive knowledge of cell engineering systems. Examples of projects include:
• Engineered molecular scaffolds for improving differentiation of stem cells into desired cell types
• Intra- and inter-cellular biosensors (e.g., FRET, molecular beacons, optogenetics) to monitor specific cellular processes in real time
• Single-cell gene expression profiling to understand inherent cell heterogeneity
• Simultaneous measurements of molecular and functional phenotype
• Integrated feedback controlled platforms for optimal process discovery and development
4. Manufacturing and Automation
Manipulating cells can be a time consuming process requiring precise environmental conditions, real-time feedback, and modular engineered platforms leading to an integrated system. The system features can be created efficiently utilizing advanced manufacturing and automation principles to first design and then digitally optimize modular components. Advances in computer aided design, multiphysics simulations, and additive manufacturing techniques, such as stereo-lithography and photopolymer printing, promise unprecedented prototyping capabilities. Examples of projects include:
• Methods for multi-material printing for integrated sensors and actuators
• 3D printing of miniaturized valves for microfluidic system control
• New chemistries for biocompatible printable materials
• Novel designs for platform integration, from cell sorting and manipulation to multiplexed multimodal sensor readings.
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