The problem of optical scattering was long thought to fundamentally limit the depth at which light could be focused through turbid media such as fog or biological tissue. However, recent work in the field of wavefront shaping has demonstrated that by properly shaping the input light field, light can be noninvasively focused to desired locations deep inside scattering media. This has led to the development of several new techniques which have the potential to enhance the capabilities of existing optical tools in biomedicine. Unfortunately, extending these methods to living tissue has a number of challenges related to the requirements for noninvasive guidestar operation, speed, and focusing fidelity. Of existing wavefront shaping methods, time-reversed ultrasonically encoded (TRUE) focusing is well suited for applications in living tissue since it uses ultrasound as a guidestar which enables noninvasive operation and provides compatibility with optical phase conjugation for high-speed operation. In this paper, we will discuss the results of our recent work to apply TRUE focusing for optogenetic modulation, which enables enhanced optogenetic stimulation deep in tissue with a 4-fold spatial resolution improvement in 800-micron thick acute brain slices compared to conventional focusing, and summarize future directions to further extend the impact of wavefront shaping technologies in biomedicine.
Optical scattering of biological tissue limits the working depth of conventional biomedical optics, which relies on the detection of ballistic photons. Recent developed optical phase conjugation (OPC) technique breaks through this depth limit by harnessing the scattered photons and shaping an optical wavefront that can “undo” the optical scattering. The OPC system measures the complex light field exiting the tissue and reconstructs a phase conjugated copy of the measured wavefront, which propagates in the reversed direction to the source of the light. To focus light inside a scattering medium, an embedded light source or “guidestar” is often required. Therefore, developing guidestar mechanisms plays an important role in advancing the OPC technique for deep tissue optical focusing and imaging. In addition to having strong optical modulation efficiency and compact size, a favorable guidestar for biomedical applications should also have good biocompatibility, fast response time, and be noninvasive or require only minimally invasive procedure. While a number of guidestar mechanisms have been developed and showed promising for various biomedical applications, they all have their own limitations. We have been developing new guidestars and tailoring them to meet the need for biomedical imaging and therapies. We are going to present our recent progress in novel guidestar development, compare them with established guidestar mechanisms, and discuss their potential in biomedical applications.
The optical opacity of biological tissue has long been a challenge in biomedical optics due to the strong scattering nature of tissue in the optical regime. While most conventional optical techniques attempt to gate out multiply scattered light and use only unscattered light, new approaches in the field of wavefront shaping exploit the time reversible symmetry of optical scattering in order to focus light inside or through scattering media. While these approaches have been demonstrated effectively on static samples, it has proven difficult to apply them to dynamic biological samples since even small changes in the relative positions of the scatterers within will cause the time symmetry that wavefront shaping relies upon to decorrelate. In this paper we investigate the decorrelation curves of acute rat brain slices for thicknesses in the range 1-3 mm (1/e decorrelation time on the order of seconds) using multi-speckle diffusing wave spectroscopy (MSDWS) and compare the results with theoretical predictions. The results of this study demonstrate that the 1/L^2 relationship between decorrelation time and thickness predicted by diffusing wave spectroscopy provides a good rule of thumb for estimating how the decorrelation of a sample will change with increasing thickness. Understanding this relationship will provide insight to guide the future development of biophotonic wavefront shaping tools by giving an estimate of how fast wavefront shaping systems need to operate to overcome the dynamic nature of biological samples.
We proposed a low cost optical cavity based biosensor with a differential detection for point-of-care diagnosis. Two lasers at different wavelengths are used for the differential detection. This method enhances the sensitivity through higher responsivity and noise cancelation. To reduce noise further, especially due to the unstable low cost laser diode output, we employed a referencing method in which a reference pixel value in each CMOS image frame is subtracted from all other pixels. To validate the designed structure and demonstrate the sensitivity of it, we perform refractive index measurements of fluids with our design. In this presentation, we will discuss our design, simulation results, and measurement results.
We propose an optical cavity based biosensor with chained differential detection. A three laser diode sensing mechanism provides multiplexing capability and is used to enhance the responsivity and improve fabrication tolerance using a chained differential detection approach. The differential calculation enhances the sensitivity through (1) increased responsivity compared to the actual optical power changes of the individual laser diodes and (2) noise reduction by canceling out some uncontrollable variations along the path of light since all wavelengths of light used for the differential calculation propagate through the same path. However, the responsivity dies off quickly due to even small variations from the designed cavity width. To correct for this and to improve fabrication tolerance, we introduce another wavelength and employ a chaining approach. In this presentation, we will present simulation results of an optical cavity based biosensor with chained differential detection and progresses toward experimental demonstrations.