Spinal cord injury therapy through active learning

Therapy employing epidural electrostimulation holds great potential for improving therapy for patients with spinal cord injury (SCI) (Harkema et al., 2011). Further promising results from combined therapies using electrostimulation have also been recently obtained (e.g., van den Brand et al., 2012). The devices being developed to deliver the stimulation are highly flexible, capable of delivering any individual stimulus among a combinatorially large set of stimuli (Gad et al., 2013). While this extreme flexibility is very useful for ensuring that the device can deliver an appropriate stimulus, the challenge of choosing good stimuli is quite substantial, even for expert human experimenters. To develop a fully implantable, autonomous device which can provide useful therapy, it is necessary to design an algorithmic method for choosing the stimulus parameters. Such a method can be used in a clinical setting, by caregivers who are not experts in the neurostimulator's use, and to allow the system to adapt autonomously between visits to the clinic. To create such an algorithm, this dissertation pursues the general class of active learning algorithms that includes Gaussian Process Upper Confidence Bound (GP-UCB, Srinivas et al., 2010), developing the Gaussian Process Batch Upper Confidence Bound (GP-BUCB, Desautels et al., 2012) and Gaussian Process Adaptive Upper Confidence Bound (GP-AUCB) algorithms. This dissertation develops new theoretical bounds for the performance of these and similar algorithms, empirically assesses these algorithms against a number of competitors in simulation, and applies a variant of the GP-BUCB algorithm in closed-loop to control SCI therapy via epidural electrostimulation in four live rats. The algorithm was tasked with maximizing the amplitude of evoked potentials in the rats' left tibialis anterior muscle. These experiments show that the algorithm is capable of directing these experiments sensibly, finding effective stimuli in all four animals. Further, in direct competition with an expert human experimenter, the algorithm produced superior performance in terms of average reward and comparable or superior performance in terms of maximum reward. These results indicate that variants of GP-BUCB may be suitable for autonomously directing SCI therapy.

MEMS for Diabetic Retinopathy

As the worldwide prevalence of diabetes mellitus continues to increase, diabetic retinopathy remains the leading cause of visual impairment and blindness in many developed countries. Between 32 to 40 percent of about 246 million people with diabetes develop diabetic retinopathy. Approximately 4.1 million American adults 40 years and older are affected by diabetic retinopathy. This glucose-induced microvascular disease progressively damages the tiny blood vessels that nourish the retina, the light-sensitive tissue at the back of the eye, leading to retinal ischemia (i.e., inadequate blood flow), retinal hypoxia (i.e., oxygen deprivation), and retinal nerve cell degeneration or death. It is a most serious sight-threatening complication of diabetes, resulting in significant irreversible vision loss, and even total blindness.

Unfortunately, although current treatments of diabetic retinopathy (i.e., laser therapy, vitrectomy surgery and anti-VEGF therapy) can reduce vision loss, they only slow down but cannot stop the degradation of the retina. Patients require repeated treatment to protect their sight. The current treatments also have significant drawbacks. Laser therapy is focused on preserving the macula, the area of the retina that is responsible for sharp, clear, central vision, by sacrificing the peripheral retina since there is only limited oxygen supply. Therefore, laser therapy results in a constricted peripheral visual field, reduced color vision, delayed dark adaptation, and weakened night vision. Vitrectomy surgery increases the risk of neovascular glaucoma, another devastating ocular disease, characterized by the proliferation of fibrovascular tissue in the anterior chamber angle. Anti-VEGF agents have potential adverse effects, and currently there is insufficient evidence to recommend their routine use.

In this work, for the first time, a paradigm shift in the treatment of diabetic retinopathy is proposed: providing localized, supplemental oxygen to the ischemic tissue via an implantable MEMS device. The retinal architecture (e.g., thickness, cell densities, layered structure, etc.) of the rabbit eye exposed to ischemic hypoxic injuries was well preserved after targeted oxygen delivery to the hypoxic tissue, showing that the use of an external source of oxygen could improve the retinal oxygenation and prevent the progression of the ischemic cascade.

The proposed MEMS device transports oxygen from an oxygen-rich space to the oxygen-deficient vitreous, the gel-like fluid that fills the inside of the eye, and then to the ischemic retina. This oxygen transport process is purely passive and completely driven by the gradient of oxygen partial pressure (pO₂). Two types of devices were designed. For the first type, the oxygen-rich space is underneath the conjunctiva, a membrane covering the sclera (white part of the eye), beneath the eyelids and highly permeable to oxygen in the atmosphere when the eye is open. Therefore, sub-conjunctival pO₂ is very high during the daytime. For the second type, the oxygen-rich space is inside the device since pure oxygen is needle-injected into the device on a regular basis.

To prevent too fast or too slow permeation of oxygen through the device that is made of parylene and silicone (two widely used biocompatible polymers in medical devices), the material properties of the hybrid parylene/silicone were investigated, including mechanical behaviors, permeation rates, and adhesive forces. Then the thicknesses of parylene and silicone became important design parameters that were fine-tuned to reach the optimal oxygen permeation rate.

The passive MEMS oxygen transporter devices were designed, built, and tested in both bench-top artificial eye models and in-vitro porcine cadaver eyes. The 3D unsteady saccade-induced laminar flow of water inside the eye model was modeled by computational fluid dynamics to study the convective transport of oxygen inside the eye induced by saccade (rapid eye movement). The saccade-enhanced transport effect was also demonstrated experimentally. Acute in-vivo animal experiments were performed in rabbits and dogs to verify the surgical procedure and the device functionality. Various hypotheses were confirmed both experimentally and computationally, suggesting that both the two types of devices are very promising to cure diabetic retinopathy. The chronic implantation of devices in ischemic dog eyes is still underway.

The proposed MEMS oxygen transporter devices can be also applied to treat other ocular and systemic diseases accompanied by retinal ischemia, such as central retinal artery occlusion, carotid artery disease, and some form of glaucoma.

Microelectrode Implants for Spinal Cord Stimulation in Rats

Paralysis is a debilitating condition afflicting millions of people across the globe, and is particularly deleterious to quality of life when motor function of the legs is severely impaired or completely absent. Fortunately, spinal cord stimulation has shown great potential for improving motor function after spinal cord injury and other pathological conditions. Many animal studies have shown stimulation of the neural networks in the spinal cord can improve motor ability so dramatically that the animals can even stand and step after a complete spinal cord transaction.

This thesis presents work to successfully provide a chronically implantable device for rats that greatly enhances the ability to control the site of spinal cord stimulation. This is achieved through the use of a parylene-C based microelectrode array, which enables a density of stimulation sites unattainable with conventional wire electrodes. While many microelectrode devices have been proposed in the past, the spinal cord is a particularly challenging environment due to the bending and movement it undergoes in a live animal. The developed microelectrode array is the first to have been implanted in vivo while retaining functionality for over a month. In doing so, different neural pathways can be selectively activated to facilitate standing and stepping in spinalized rats using various electrode combinations, and important differences in responses are observed.

An engineering challenge for the usability of any high density electrode array is connecting the numerous electrodes to a stimulation source. This thesis develops several technologies to address this challenge, beginning with a fully passive implant that uses one wire per electrode to connect to an external stimulation source. The number of wires passing through the body and the skin proved to be a hazard for the health of the animal, so a multiplexed implant was devised in which active electronics reduce the number of wires. Finally, a fully wireless implant was developed. As these implants are tested in vivo, encapsulation is of critical importance to retain functionality in a chronic experiment, especially for the active implants, and it was achieved without the use of costly ceramic or metallic hermetic packaging. Active implants were built that retained functionality 8 weeks after implantation, and achieved stepping in spinalized rats after just 8-10 days, which is far sooner than wire-based electrical stimulation has achieved in prior work.