Manipulation of micro/mesoscale tissues (0.1 millimeters to 1 millimeter in size) plays an important role in clinical procedures and biomedical research. This technology is vital for intra-cytoplasmic sperm injection for in vitro fertilization, drug response assays in cancer research, and fabrication of bioengineered tissues in regenerative medicine. However, even with the existing tools and protocols, one of the main factors that affects the success of these procedures is still the skill of the operator. There is an unmet need for a sensing technique that provides quantitative and reliable information, rather than experiences or intuition alone, to help operators make a correct decision. This project aims to meet this need by providing a method of real-time micro/mesoscale manipulation based on 3D imaging and micro-scale force sensing. This will be accomplished by building a manipulator system comprised of microfabricated cantilever force sensors and arrayed microscopes to provide suitable real-time visual feedback to the operator. As all the data gathered by this system is digital, the system can be remotely viewed and controlled via the internet, which makes the system an excellent platform for STEM education. The team will work with a local high school to develop and test educational biological experiments for K-12 students. This will enhance their learning by providing application-based research methods otherwise not available to students.
Elastography is an emerging imaging modality to quantify the elasticity of tissues. When a mechanical force is applied to a tissue, the induced internal strain distribution indicates the map of elasticity. Soft regions show larger deformation compared to the hard regions, and vice versa. This elasticity map provides crucial information needed for medical diagnosis or guidance of surgical tools. The use of elastography is currently based on ultrasound imaging to observe macroscale organs in the size range of a few centimeters. The central hypothesis to be investigated is that the benefit of elastography can be scaled down to tissues that are about 100 times smaller than those studied in conventional ultrasound elastography. The goal of the project is to establish the method of real-time micro/mesoscale elastography that targets biosamples between 0.1 millimeters and 1 millimeter in size. A real-time micro/mesoscale tissue manipulation system will be developed to provide quantitative 3D force-deformation analysis to enable operators to reliably manipulate tissues and make informed diagnostic choices. The two key enabling technologies are microscale cantilever-based manipulation and 3D real-time tomography. As the force-sensing cantilever applies a force to the sample, multi-angle images are simultaneously acquired from the 16-arrayed microscopes to reconstruct high-resolution 3D images. Maps of 3D deformation will be generated to find the strains induced within the sample and the cantilever. Knowing the mechanical stiffness of the cantilever, the stress induced in the sample will be found. Since the proposed method is based on optical deformation analysis, it will provide force sensing capabilities without using electrical force sensors. Not only the microfabricated cantilevers but also conventional tools including glass tubes and needles will be used with the added function of force sensing, once their stiffness is calibrated. The efficacy of the system will be validated through manipulation of 3D microtissues and sperm injection experiments using zebrafish eggs. The ability to visualize and manipulate micro/mesoscale objects plays an important role in many emerging biomedical applications. However, mechanical tools that focus on samples in such size scales are still in their infancy. The proposed research is among the first steps in this direction.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
