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Oxygen Transporter and Generator Devices to Treat Diabetic Retinopathy

Citation

Scianmarello, Nicholas E. (2019) Oxygen Transporter and Generator Devices to Treat Diabetic Retinopathy. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/JCS2-8E12. https://resolver.caltech.edu/CaltechTHESIS:05282019-074707723

Abstract

In recent years, Micro-Electrical Mechanical Systems (MEMS) have opened new areas of the human body to non-pharmacological treatment. Miniaturized implants have started to appear in volume or power constrained areas, such as the eye and the heart. In particular, the eye benefits from miniaturization, as it is very sensitive to pressure and volumetric changes, which can affect eyesight and blood flow.

Diabetic retinopathy is the worldwide leading cause of blindness among working age adults. As the numbers of diabetics increases, so does the number of retinopathies. By 2030, 191 million people are expected to be affected by the disease. As a patient’s retinopathy progresses, the chronic hyperglycemia from diabetes causes permanent changes to the vasculature; vessels become leaky and occluded, tissue becomes hypoxic due to this ischemia and begins to release vascular endothelial growth factor (VEGF) to promote angiogenesis.

Currently, treatments exist only for severe non-proliferative or proliferative DR, and rely on blocking VEGF (vascular endothelial growth factor) or panretinal laser photocoagulation to reduce retinal metabolic demand. VEGF antagonists are expensive; costing up to $164k per quality life adjusted year and must be administered by intravitreal injections monthly. Laser photocoagulation also requires retreatment and is known to reduce peripheral vision—up to 20% of the peripheral retina is ablated. Another treatment approach may be to supply oxygen. Oxygen is a strong vasoconstrictor and suppresses the hypoxic signaling that leads to release of VEGF. These two effects reduce the plasma volume leaked into tissue, which in turn reduces edema, and may help prevent ischemic related cell death. Literature supports this assertion. A study of nasally inspired oxygen in patients with macular edema showed a reduction of edema and improvement of visual acuity following 3 months of treatment. Another study on rabbits with an induced ischemia demonstrated that intravitreal oxygenation maintained the retina to a near healthy condition.

In this thesis, two devices, the oxytransporter and oxygenerator, that treat diabetic retinopathy are designed and tested. The former shuttles oxygen from areas of high concentration to the ischemic retina. The latter generates oxygen by electrolysis.

This thesis is grounded on a computational model of oxygen consumption in the retina. To estimate the oxygen consumption, the model accounts for the anatomical distribution of tissue and vasculature in the retina. Previous models in literature averaged over the effects in the inner retina. The model estimates that the devices must supply 0.25nmol/s of oxygen to the human macula with an oxygen tension dependent on the degree of ischemia.

A nanoporous filler material was developed and integrated into the oxytransporter to allow this device to operate in the high humidity environment of the eye. The material is capable of withstanding an environment with water vapor 1.4 times the bulk saturation pressure. Theory behind the material was tested and compared to simulation. Benchtop testing over a month demonstrated the stability of the device in conditions similar to the eye. This oxytransporter was implanted in rabbits and the diffusor, or output membrane, reached the favorable mark of 100mmHg in the vitreous humor from atmospheric oxygen alone. This is estimated to be sufficient to treat a mild to moderate ischemia in humans.

The oxygenerator is powered from a coil up to 3cm away, and can provide 0.25nmol/s continuously with an oxygen tension of up to 300mmHg for a human sized diffusor. A steady state test demonstrated the capability of maintaining the oxygen tension in the device by modulating the input power. The device is replenished through osmosis from the vitreous humor, and can absorb moisture at a rate comparable to the required oxygen consumption. One week implantation in vivo in rabbits demonstrated that the oxygen tension exceeded 200mmHg at the diffusor, which is estimated to be sufficient to treat severe ischemia. Future work should involve a study of the long term effects of oxygen in an ischemic animal model.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:diabetic retinopathy, vitreal oxygenation, oxygen, microfabrication
Degree Grantor:California Institute of Technology
Division:Engineering and Applied Science
Major Option:Electrical Engineering
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Tai, Yu-Chong
Thesis Committee:
  • Emami, Azita (chair)
  • Tai, Yu-Chong
  • Humayun, Mark
  • Gao, Wei
  • Wang, Lihong
Defense Date:8 May 2019
Non-Caltech Author Email:nscianmarello (AT) gmail.com
Funders:
Funding AgencyGrant Number
NIH7R01EY022059-02
Record Number:CaltechTHESIS:05282019-074707723
Persistent URL:https://resolver.caltech.edu/CaltechTHESIS:05282019-074707723
DOI:10.7907/JCS2-8E12
ORCID:
AuthorORCID
Scianmarello, Nicholas E.0000-0002-1207-4029
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:11548
Collection:CaltechTHESIS
Deposited By: Nicholas Scianmarello
Deposited On:29 May 2019 21:16
Last Modified:03 Jun 2020 20:50

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