Reaching the Ultimate Limits of Biology
Sensing and manipulating biology at its ultimate “quantum” limits, using single cells and single molecules, is poised to revolutionize medical diagnostics, transform our capabilities to develop drugs and cell therapies, and accelerate engineering of biological solutions to food and energy sustainability. Micro and nanotechnologies designed to operate at micrometer length scales are uniquely suited to sense and manipulate single cells and single molecules. Concerning diagnostics, these approaches promise to lay the foundation for continuously monitoring health through minute quantities of biomarkers undiscernible by present-day technologies – a revolution that will lead to detecting and re-defining the concept of disease to be unique to each individual. In parallel, the ability to automate cellular and molecular evolution can accelerate the development of new therapies and biosensors. These advances will lay a foundation for sensing and treating disease at its earliest stages, increasing health span, and reducing healthcare costs.
The Di Carlo Lab leverages microfluidics, microfabrication, and nanotechnologies to develop interfaces with cells and molecules for applications in disease diagnosis, therapeutic discovery, tissue regeneration, and directed evolution. Instead of scaling down macroscale concepts, we take advantage of unique physics at small scales to process and analyze cells and manufacture smart biomaterials structured at sizes smaller than a human hair. We aim to engineer solutions that utilize commonly available laboratory equipment and consumer electronic devices so that they can be readily adopted by researchers, doctors, and patients. These tools not only excel at the manipulation and analysis of single cells and molecules, but also are cost-effective and easily accessible – thus democratizing advanced biotechnology capabilities to solve medical problems.
We explore fundamental aspects of inertial flow to better understand the nonlinear mechanisms at play, with the aim of leveraging these unique physics at the microscale level for biological analysis, cellular engineering, and advanced materials. Current projects use inertial microfluidics for high-throughput particle and cell sorting, cell isolation and analysis, and manipulating the shape of fluid itself to create micro-structured materials.
Polymer particles or biomaterials with precise morphology and chemistries are finding unique uses in a variety of applications, including tissue engineering, drug delivery, barcoding, and diagnostic imaging. We are developing microfluidic platforms which enable high-throughput precision synthesis of unique designer materials. Using these platforms we create particles to interface with single cells, as well as assemblies of particles to form higher-order scaffolds that can interface seamlessly with tissues, thus mitigating the foreign body response.
Cells modulate and respond to physical forces during physiological function. The mechanical properties of cells or the forces they apply can reveal their internal cell state and organization, as well as serve as a manifestation of disease. We have developed high-throughput tools to assay mechanical phenotypes of cells to rapidly classify cells based on their resistance to applied loads in a label-free manner. We have also developed automated tools to assay forces that cells exert on their environment, and are using these tools to uncover new compounds that modulate force generation critical to a number of diseases. Finally, we have shown that mechanical forces applied to cells using magnetic particles can elicit cellular changes to modulate disease processes. These “mechanoceuticals” can act independently and more locally compared to traditional pharmaceuticals.
The ultimate limits of diagnostics in biology are the “quantum” units that convey information: single nucleic acids, proteins, and cells. Microfluidics has emerged as a powerful tool to compartmentalize single cells and molecules into sub-nanoliter droplets as individual bioreactors to enable sensitive detection and analysis down to this quantum limit. However, the current systems for quantum diagnostics have not been widely adopted, partly due to the requirement of specialized instruments and microfluidic chips to generate uniform droplets and perform adequate manipulations. We are developing platforms to fractionate volumes in simplified, instrument-free ways in order to democratize single-molecule and single-cell technologies.