Doctor of Philosophy

dissertationOptical methods are well-established in the fields of neuroscience, medical imaging, and diagnostics, etc. Optogenetics, for example, enables molecular specificity in optical neural stimulation and recording and has been named the "Method of the Year 2010" by Nature Methods. A novel microdevice was designed, fabricated, developed, and tested to facilitate three-dimensional (3D) deep-tissue light penetration with the capacity to accommodate spatiotemporal modulation of one or more wavelengths to advance a broad range of applications for optical neural interfaces. A 3D optrode array consisting of optically transparent "needles" can penetrate >1 mm directly into tissue, thereby creating multiple independent paths for light propagation that avoid attenuation due to tissue absorption and scattering, providing a high level of selectivity and comprehensive access to tissue not available in current interfaces. Arrays were developed based upon silicon and glass. The silicon optrode array is based upon the well-established Utah electrode array architectures and is suitable for near-infrared (NIR) applications; glass optrodes are appropriate waveguides for both visible and NIR wavelengths. Arrays were bulk-micromachined with high-aspect ratio, a process that has not been reported to be applied to glass previously. In addition to device fabrication, extensive laboratory testing was performed with various optical sources to determine loss mechanisms and emitted beam profiles in tissue across the relevant wavelength ranges, with particular focus on performance metrics for optogenetic and infrared neural stimulation applications. Optrode arrays were determined to be amenable to integration with typical neural stimulation and imaging light delivery mechanisms such as optical fibers and microscopes. Glass optrodes were able to transmit light at ~90% efficiency through depths many times greater than the tissue attenuation length, with negligible light in-coupling loss. Si optrodes were determined to be only ~40% efficient with losses mostly from high index contrast, tip backreflection, and taper radiation. The in-coupling technique and optrode geometry may be modified to produce illumination volumes appropriate for various experimental paradigms. While the focus of this work is on optical neural stimulation, optrode array devices have application in basic neuroscience research, highly selective photodynamic therapy, and deep tissue imaging for diagnostics and therapy

NOVEL FIBER OPTIC TIP DESIGNS AND DEVICES FOR LASER SURGERY

Fiber optic delivery of laser energy has been used for years in various types of surgical procedures in the human body. Optical energy provides several benefits over electrical or mechanical surgery, including the ability to selectively target specific tissue types while preserving others. Specialty fiber optic tips have also been introduced to further customize delivery of laser energy to the tissue. Recent evolution in lasers and miniaturization has opened up opportunities for many novel surgical techniques. Currently, ophthalmic surgeons use relatively invasive mechanical tools to dissect retinal deposits which occur in proliferative diabetic retinopathy. By using the tight focusing properties of microspheres combined with the short optical penetration depth of the Erbium:YAG laser and mid-IR fiber delivery, a precise laser scalpel can be constructed as an alternative, less invasive and more precise approach to this surgery. Chains of microspheres may allow for a self limiting ablation depth of approximately 10 µm based on the defocusing of paraxial rays. The microsphere laser scalpel may also be integrated with other surgical instruments to reduce the total number of handpieces for the surgeon. In current clinical laser lithotripsy procedures, poor input coupling of the Holmium:YAG laser energy frequently damages and requires discarding of the optical fiber. However, recent stone ablation studies with the Thulium fiber laser have provided comparable results to the Ho:YAG laser. The improved spatial beam profile of the Thulium fiber laser can also be efficiently coupled into a fiber approximately one third the diameter and reduces the risk of damaging the fiber input. For this reason, the trunk optical fiber minus the distal fiber tip can be preserved between procedures. The distal fiber tip, which degrades during stone ablation, could be made detachable and disposable. A novel, low-profile, twist-locking, detachable distal fiber tip interface was designed, assembled, and tested for use in Thulium fiber laser lithotripsy. A 1.00-mm-outer- diameter detachable fiber tip interface was designed, constructed, and tested ex vivo on urinary stones in the laboratory. Similar stone ablation rates between the previously studied tapered distal fiber tip and the detachable fiber tip were measured. For urologists desiring faster TFL lithotripsy procedures, the incorporation of detachable distal fiber tips allows for rapid replacement of damaged fiber tips without concern about the laser to trunk fiber connection. This method for preserving the trunk fiber could be a motivation for integrating a dedicated laser fiber into the ureteroscope, with detachable distal tips, thus freeing the working channel for the use of other surgical instruments. During laser lithotripsy, distal fiber tip degradation increases as the fiber core diameter decreases. However, smaller fiber diameters ( = 200 µm ) are more desirable because of increased saline irrigation rates in the single working channel of the ureteroscope and less impact on ureteroscope deflection. A hollow fiber cap is proposed to reduced fiber tip degradation in small diameter fibers, without compromising stone ablation rates. The disadvantage of the hollow fiber tip observed in the study is the increase in stone retropulsion. However, integrating the hollow fiber tip with a clinically used stone basket may allow for a robust stone ablation instrument that also minimizes retropulsion. These surgical approaches involving novel specialty fiber optic tip designs are discussed in this thesis

Micromachined Optical and Acoustic Waveguide Systems for Advance Sensing and Imaging Applications

Evolving from the IC fabrication processes, micromachining technologies allow mass production of 2D or 3D microstructures, which are otherwise difficult to achieve with traditional machining techniques. In this research, novel micromachining processes have been developed to enable new micro optical and acoustic waveguide systems for advanced optical sensing and acoustic imaging applications. The investigated applications include non-invasive cancer detection inside human body, in-field soil characterization, and time-delayed and multiplexed ultrasound and photoacoustic tomography. Micromachining technology enables miniaturized optical waveguide system for efficient light transmission. The small size and light-guiding capabilities are particularly useful for optical sensing at places deep inside the human body or underground. Two micromachined optical waveguide systems were fabricated and tested. The first one was used to conduct oblique incidence diffuse reflectance spectroscopy (OIDRS) for the determination of tumor margins on human pancreas specimens. The second one was used to conduct visible-near-infrared diffuse reflectance spectroscopy (VNIR-DRS) for extracting the compositional information of soil samples. Micromachining technology also makes it possible to utilize single-crystalline silicon as a structural material for acoustic wave propagation. It enables the development of high-performance integrated acoustic circuits and allows direct acoustic signal processing and control. The acoustic properties and propagation inside silicon waveguides were characterized, and the acoustic signal processing using micromachined acoustic waveguide system was investigated. Based on the results, two acoustic waveguide systems were designed and constructed. The first system utilized micromachined acoustic delay lines to passively delay acoustic signal thereby reducing the required transceivers and processing electronics; while the second system employed micromachined acoustic multiplexer to actively control the transmission of acoustic signals. Both techniques are expected to provide new solutions to reduce the complexity and cost of the acoustic receiver systems in ultrasound and photoacoustic imaging

A 3D glass optrode array for optical neural stimulation

pre-printThis paper presents optical characterization of a first-generation SiO2 optrode array as a set of penetrating waveguides for both optogenetic and infrared (IR) neural stimulation. Fused silica and quartz discs of 3-mm thickness and 50-mm diameter were micromachined to yield 10×10 arrays of up to 2-mm long optrodes at a 400-mm pitch; array size, length and spacing may be varied along with the width and tip angle. Light delivery and loss mechanisms through these glass optrodes were characterized. Light in-coupling techniques include using optical fibers and collimated beams. Losses involve Fresnel reflection, coupling, scattering and total internal reflection in the tips. Transmission efficiency was constant in the visible and near-IR range, with the highest value measured as 71% using a 50-mm multi-mode in-coupling fiber butt-coupled to the backplane of the device. Transmittance and output beam profiles of optrodes with different geometries was investigated. Length and tip angle do not affect the amount of output power, but optrode width and tip angle influence the beam size and divergence independently. Finally, array insertion in tissue was performed to demonstrate its robustness for optical access in deep tissue

Optical super-resolution and periodical focusing effects by dielectric microspheres

Optical microscopy is one of the oldest and most important imaging techniques; however, its far-field resolution is diffraction-limited. In this dissertation, we proposed and developed a novel method of optical microscopy with super-resolution by using high- index dielectric microspheres immersed in liquid and placed on the surface of the structures under study. We used barium titanate glass microspheres with diameters of D~2-220 µm and refractive indices n~1.9-2.1 to discern minimal feature sizes ~?/4 (down to ~?/7) of various photonic and plasmonic nanostructures, where ? is the illumination wavelength. We studied the magnification, field of view, and resolving power, in detail, as a function of sphere sizes. We studied optical coupling, transport, focusing, and polarization properties of linear arrays of dielectric spheres. We showed that in arrays of spheres with refractive index n=v3, a special type of rays with transverse magnetic (TM) polarization incident on the spheres under the Brewster’s angle form periodically focused modes with radial polarization and 2D period, where D is the diameter of the spheres. We showed that the formation of periodically focused modes in arrays of dielectric spheres gives a physical explanation for beam focusing and extraordinarily small attenuation of light in such chains. We showed that the light propagation in such arrays is strongly polarization- dependent, indicating that such arrays can be used as filters of beams with radial polarization. The effect of forming progressively smaller focused beams was experimentally observed in chains of sapphire spheres in agreement with the theory. We expanded the concept of periodically focused modes to design a practical device for ultra-precise contact-mode laser tissue-surgery, with self-limiting ablation depth for potential application in retina surgery. By integrating arrays of dielectric spheres with infrared hollow waveguides and fibers, we fabricated prototypes of the designs and tested them with an Er:YAG laser. Furthermore, we proposed another design based on conical arrays of dielectric spheres to increase the coupling efficiency of the probe

Silica hollow core fibres for mid-infrared medical applications

In this thesis two types of silica hollow core microstructured fibres - the Negative Curvature Fibre and the Photonic Bandgap Fibre - are presented as a novel solution for the flexible delivery of Er:YAG laser radiation. The Negative Curvature Fibre and Photonic Bandgap Fibre had attenuations of 0.06 dB/m and 1.1 dB/m at 2.94 μm wavelength, respectively. This is an important wavelength regime for medical applications, specifically surgery, due to the existence of a strong absorption peak for water around 3 μm. The guidance of high energy pulses of the order of 195 mJ and 14.4 mJ respectively is demonstrated. These energies are sufficient to ablate soft and hard biological tissue. As verification, porcine bone was ablated in air and submerged in water to simulate practical application of a surgical device. The presented fibres are compared to alternative state-of-the-art solid and hollow core fibres, in respect of the fabrication, attenuation, pulse energy delivery capability, bend sensitivity and the output beam profile. The fabrication and characterisation of a novel sapphire endtip is also presented, which seals the hollow cores of the fibres from contamination and therefore increases the usability significantly. The endtip was shown to be mechanically robust, provide a hermetic seal and able to survive practical tissue ablation in air and water. These encapsulated fibres provide a new fully flexible delivery system for high energy Er:YAG laser radiation and hence will open up the possibility of new minimally invasive surgical procedures

Implantable Low-Noise Fiberless Optoelectrodes for Optogenetic Control of Distinct Neural Populations

The mammalian brain is often compared to an electrical circuit, and its dynamics and function are governed by communication across different types neurons. To treat neurological disorders like Alzheimer’s and Parkinson’s, which are characterized by inhibition or amplification of neural activity in a particular region or lack of communication between different regions of the brain, there is a need to understand troubleshoot neural networks at cellular or local circuit level. In this work, we introduce a novel implantable optoelectrode that can manipulate more than one neuron type at a single site, independently and simultaneously. By delivering multi-color light using a scalable optical waveguide mixer, we demonstrate manipulation of multiple neuron types at precise spatial locations in vivo for the first time. We report design, micro-fabrication and optoelectronic packaging of a fiber-less, multicolor optoelectrode. The compact optoelectrode design consists of a 7 μm x 30 μm dielectric optical waveguide mixer and eight electrical recording sites monolithically integrated on each shank of a 22 μm-thick four-shank silicon neural probe. The waveguide mixers are coupled to eight side-emitting injection laser diodes (ILDs) via gradient-index (GRIN) lenses assembled on the probe backend. GRIN-based optoelectrode enables efficient optical coupling with large alignment tolerance to provide wide optical power range (10 to 3000 mW/mm2 irradiance) at stimulation ports. It also keeps thermal dissipation and electromagnetic interference generated by light sources sufficiently far from the sensitive neural signals, allowing thermal and electrical noise management on a multilayer printed circuit board. We demonstrated device verification and validation in CA1 pyramidal layer of mice hippocampus in both anesthetized and awake animals. The packaged devices were used to manipulate variety of multi-opsin preparations in vivo expressing different combinations of Channelrhodopsin-2, Archaerhodopsin and ChrimsonR in pyramidal and parvalbumin interneuron cells. We show effective stimulation, inhibition and recording of neural spikes at precise spatial locations with less than 100 μV stimulation-locked transients on the recording channels, demonstrating novel use of this technology in the functional dissection of neural circuits.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/137171/1/kkomal_1.pd

Towards the automatic control of laser ablation for surgical applications

The goal of this thesis is to propose and investigate a method of predicting depth of a laser dissection pulse in soft tissue without acquiring material properties of the tissue target or measuring the laser output. The method proposed is similar to what is used by laser surgical operators today, but uses regression learning to perform on-the fly predictions in place of a skilled laser surgeon. Power of the laser and the ablation depth were recorded for 57 samples and fed into the regression algorithm. Data exclusion was performed using Temperature before laser action as criteria. A linear and logarithmic model was explored using random points from the data post-exclusion, validation RMSE ranged from 135-200 micrometer. A linear and logarithmic model was explored using data points below a moving power threshold and validated with data points above said threshold, validation RMSE ranged from 108-170 micrometer. The t.test performed showed there was not a significant difference between the linear and the logarithmic models\u27 goodness of fit metrics, but it did show there was a significant difference between the model building methods (randomly selected data points, moving power threshold). The method of building a model using lower power levels to predict larger power levels had better goodness of fit metrics than the method of selecting data points at random. In the future, this method could be used to help approximate the laser settings for surgery on a procedural basis, and allow for surgeons to perform at a higher skill level with less training

Depth-Targeted Energy Delivery Deep Inside Scattering Media

Diffusion makes it difficult to predict and control wave transport through a medium. Overcoming wave diffusion to deliver energy into a target region deep inside a diffusive system is an important challenge for applications, but also represents an interesting fundamental question. It is known that coherently controlling the incident wavefront allows diffraction-limited focusing inside a diffusive system, but in many applications, the targets are significantly larger than a focus and the maximum deliverable energy remains unknown. Here we introduce the \u27deposition matrix\u27, which maps an input wavefront to the internal field distribution, and we theoretically predict the ultimate limit on energy enhancement at any depth. Additionally, we find that the maximum obtainable energy enhancement occurs at three-fourths the thickness of the diffusive system, regardless of its scattering strength. We experimentally verify our predictions by measuring the deposition matrix in two-dimensional diffusive waveguides. The experiment gives direct access to the internal field distribution from the third dimension, and we can excite the eigenstates to enhance or suppress the energy within an extended target region. Our analysis reveals that such enhancement or suppression results from both selective transmission-eigenchannel excitation and constructive or destructive interference among these channels

Doctor of Philosophy

dissertationPrecise optical neural stimulation is an essential element in the use of optogenetics to elicit predictable neural action potentials within the brain, but accessing specific neocortical layers, light scattering, columniation, and ease of tissue damage pose unique challenges to the device engineer. This dissertation presents the design, simulation, microfabrication, and characterization of the Utah Optrode Array (UOA) for precise neural tissue targeting through three main objectives: 1. Maskless wafer-level microfabrication of optical penetrating neural arrays out of soda- lime glass: Utah Optrode Array. 2. Utah Optrode Array customization using stereotactic brain atlases and 3D CAD modeling for optogenetic neocortical interrogation in small rodents and nonhuman primates. 3. Single optrode characterization of the UOA for neocortical illumination. Maskless microfabrication techniques were used to create 169 individual 9 × 9 arrays 3.85 mm × 3.85 mm with 1.1 mm long optrodes from a single two inch glass wafer. The 9 × 9 UOA was too large for precise targeting of the upper layers of the cortex in smaller animals such as mice, so an array customization method was developed using Solidworks and off-the-shelf brain atlases to create 8 × 6 arrays 3.45 mm × 2.45 mm with 400 μm long optrodes. Stereotactic atlases were imported into Solidworks, splined, and lofted together to create a single 3D CAD model of a specific region of interest in the brain. Chronic and acute brain trauma showed excellent results for the 8 × 6 arrays in C57BL/6 wild-type mice (Mus musculus) and macaque monkey (Macaca fascicularis). Simulation, characterization, and radiometric testing of a single optrode of the 9 × 9 array was necessary to prove the ability to transmit light directly to specific tissue. Zemax optical design software was used to predict the light transmission capabilities, and then these results were compared to actual bench-top results. Insertion loss was both predicted and measured to be 3.7 dB. Power budgeting showed 9% of the light was lost at the interfaces of the UOA's backplane and tip in air, and 48% was lost through back-scattering, leaving 43% transmitting through the optrode with no measurable taper loss. Scanning electron microscopy showed small amounts of devitrification of the glass, and atomic force microscopy showed average surface roughness to be 13.5 nm and a root mean square roughness of 20.6 nm. The output beam was profiled in fluorescein dye with a total divergence angle of 63◦ with a cross over distance to adjacent beams at 255 μm