Acoustofluidic manipulation of gels for diagnostic and therapeutic applications

Abstract

Acoustofluidic (i.e., the combination of acoustics and fluid dynamics) technology has revolutionized the field of microfluidics for biomedical applications. With the increased development of acoustic transducer efficiency and design, acoustic technology has enabled revolutionary biomedical applications ranging from ultrasound fetal monitoring to contactless, active actuation of material within fluidic environments. Within the past 20 years, the combination of acoustic actuation within microfluidic environments has led to the precise manipulation of material ranging from the nanoscale to organism sized object. Acoustic manipulation within these microfluidic environments are advantageous given its contactless nature, active-control, tunable-resolution, versatility regardless of electromagnetic properties of the fluidic environment or the material, and deep penetration depth of the applied acoustic forces. The application of acoustofluidic technology has enabled novel applications, including extracellular vesical sorting from whole blood for enhanced disease detection, biomechanical characterization of cellular properties, larger-scale cell-cell interaction studies, and larger scale manipulation of droplets and organisms. Although much has been achieved in the application of acoustofluidic technology, the field of acoustofluidics is still in its infancy and the unique advantages provided by acoustofluidic technology have yet to achieve its full potential in material manipulation within micro-environments for novel applications. Furthermore, the accessibility and development of acoustic transducer fabrication methods limits the range of applicability of this technology. The development of surface acoustic wave-based acoustofluidic technology has been a critical component in driving the acoustofluidic technology, due to its versatility in acoustic wave shape and frequency design, which enables controlled resolution and high programmability. Surface acoustic wave-based acoustofluidic devices are fabricated by patterning micro to nano-sized electrodes on a rigid piezoelectric crystal. Although this technology demonstrates some advantages over traditional bulk acoustic wave-based device, the fabrication of this technology requires multi-step, chemical photolithography, and cleanroom facilities to achieve the resolution required for these devices. To enhance the accessibility and development of this technology, we implemented an additive manufacturing technique, aerosol jet printing, to directly print electrodes of varying materials at relevant resolutions. Through this study, we demonstrated the direct print of viable surface acoustic wave-based transducers, expanding the fabrication techniques available and availability of acoustofluidic technology. Furthermore, this fabrication technique can enable the direct fabrication of surface acoustic wave-based technology on chemically-sensitive or flexible piezoelectric substrates. In order to then further expand the acoustofluidic material manipulation capabilities, we investigated the material manipulation of gels for diagnostic and therapeutic purposes. With regards to diagnostic applications, we investigated the acoustofluidic enhancement of surface enhanced Raman spectroscopy (SERS) detection by combining acoustofluidic concentrating with thermal responsive polymer aggregation. SERS detection is largely driven by enhancing the electromagnetic “hot spot” that enhances the Raman signal by controlling the distance between metallic nanostructures. Acoustofluidic nanomaterial manipulation is largely limited by the scaling forces, limiting particle manipulation to ~100 nm. By implementing thermal responsive polymer aggregation with the acoustic forces and the induced heating of the acoustofluidic technology, we demonstrated that we could surpass the acoustic particle manipulation limit and enhance SERS detection capabilities 15x. This technology can be implemented to further lower the limit of detection of drug and biological detection of analytes of interest. Finally, we investigated the applicability of acoustofluidic technology of enhancing biological function of cells by manipulating the biomimetic hydrogel matrix. In this study, we developed the platform, acoustic traveling wave induced shear torsion (A-TWIST), which takes advantage of designed focused traveling surface acoustic waves to induce a controlled 3D deformation distribution of a collagen hydrogel to apply a biologically relevant strain within the matrix. Via rheometry, we measured the applied shear stress of A-TWIST to the biomimetic matrix. We then investigated how different hydrogel properties, including density and crosslinking density, affect the applied shear force through the hydrogel matrix. Next, we characterized the micromaterial 3D and 2D deformation distribution of A-TWIST via confocal and fluorescent microscopy and fluorescent particle displacement analysis. Finally, we applied A-TWIST to strain endothelial cell colony forming cells (ECFCs) laden within the collagen matrix, and demonstrated an increase in vascularization. Overall, A-TWIST demonstrates a novel physical force-based platform that demonstrates enhanced biological function, which could expand to different biomechanical cell models to generate therapeutically relevant biological constructs. The development of novel acoustofluidic fabrication techniques and increased applicability of acoustofluidic technology for the manipulation of gels for diagnostic and therapeutic applications, as shown in this dissertation, pushes forward the field of biomedical research for enhanced diagnostic and therapeutic applications.