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.

Control mechanisms in the human binocular oculomotor system

A study of human eye movements was made in order to elucidate the nature of the control mechanism in the binocular oculomotor system.

We first examined spontaneous eye movements during monocular and binocular fixation in order to determine the corrective roles of flicks and drifts. It was found that both types of motion correct fixational errors, although flicks are somewhat more active in this respect. Vergence error is a stimulus for correction by drifts but not by flicks, while binocular vertical discrepancy of the visual axes does not trigger corrective movements.

Second, we investigated the non-linearities of the oculomotor system by examining the eye movement responses to point targets moving in two dimensions in a subjectively unpredictable manner. Such motions consisted of hand-limited Gaussian random motion and also of the sum of several non-integrally related sinusoids. We found that there is no direct relationship between the phase and the gain of the oculomotor system. Delay of eye movements relative to target motion is determined by the necessity of generating a minimum afferent (input) signal at the retina in order to trigger corrective eye movements. The amplitude of the response is a function of the biological constraints of the efferent (output) portion of the system: for target motions of narrow bandwidth, the system responds preferentially to the highest frequency; for large bandwidth motions, the system distributes the available energy equally over all frequencies. Third, the power spectra of spontaneous eye movements were compared with the spectra of tracking eye movements for Gaussian random target motions of varying bandwidths. It was found that there is essentially no difference among the various curves. The oculomotor system tracks a target, not by increasing the mean rate of impulses along the motoneurons of the extra-ocular muscles, but rather by coordinating those spontaneous impulses which propagate along the motoneurons during stationary fixation. Thus, the system operates at full output at all times.

Fourth, we examined the relative magnitude and phase of motions of the left and the right visual axes during monocular and binocular viewing. We found that the two visual axes move vertically in perfect synchronization at all frequencies for any viewing condition. This is not true for horizontal motions: the amount of vergence noise is highest for stationary fixation and diminishes for tracking tasks as the bandwidth of the target motion increases. Furthermore, movements of the occluded eye are larger than those of the seeing eye in monocular viewing. This effect is more pronounced for horizontal motions, for stationary fixation, and for lower frequencies.

Finally, we have related our findings to previously known facts about the pertinent nerve pathways in order to postulate a model for the neurological binocular control of the visual axes.