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Final Project for Nanotechnology and Nanosensor course authorized by

Technion Israel Institute of Technology

Course Instructor Prof. Hossam Haick

Submitted on 15th of June 2015

Title

A conceptual framework in the design and development of embedded

nanoelectronic device with thin film Carbon Nanotube transistors, Quantum Dots

and Graphene as an artificial retinal substrate to restore vision for patients with

retinal degeneration

Submitted by

(Mohammad Hossein Saberi)

Project team members

1) Mohammad Hossein Saberi , M.Sc. in chemical engineering, Catalysis and

Nanostructured Materials Research Laboratory, School of chemical engineering,

University of Tehran, Tehran, Iran.

2) Rogelio Federico Nochebuena , Holds a BSEE from National Institute

Polytechnic, a MSEE from Brigham Young University and a MBA from

Pepperdine University. Research engineer at Carl Zeiss, Perkin Elmer, Xerox

PARC and Agilent Technologies.

3) Dr.Saravanan Subramaniam, Post Doctoral Fellow, Department of Neurosurgery,

University Hospital Tubingen, and Centre for Integrative Neuroscience

(Neuroprosthetics), Tubingen, Germany.

( Members contributed equally to this project)

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Table of Contents

1) Abstract

2) Introduction

3) Literature review

a) Current strategies for restoring vision

b) The cortical approach

c) The optic nerve approach

d) The retinal approach

e) Nanotechnology for restoration of vision

f) Characterization results of Kimura et al. work

4) Discussion and project description

a) Over all framework

b) Power supply via Inductive coupling

c) Processing of nanotubes prior placement on the inkjet cartridge

d) Nanotube characterization

e) Rendering Illumination profile

f) Animal Testing

5) Conclusions and recommendations

6) References

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Abstract

Visual blindness affects millions of people worldwide, with varied pathogenesis and

many prevalent and potentially devastating causes of vision loss cannot be effectively

treated. In the recent years, the possibility of restoring vision to blind individuals has

been a topic of intense scientific research as well as of science fiction. Recent advances in

microelectronics have led to the development of visual prosthetic devices that are

designed to stimulate viable neuronal tissue in the hope of regaining some level of

functionality. Human clinical trials with visual prosthetic devices are underway, but it is

still in its infancy, and many technical challenges remain unsolved due to the thickness

and size of the device impeding sclera buckling and rhegmatogenous retinal detachment,

hence it s necessary to have an alternate biocompatible device which is thin, transparent

and does not cause post implant complications. Hence, there is a compelling reason to

pursue the development of carbon nanotube thin film transistors as a viable therapeutic

option to restore vision in patients with visual blindness. Here we introduce a conceptual

idea that could potentially be very inexpensive and sensitive, the use of plastic electronics

(ink-jet technology to produce active and passive electronic devices on flexible and

transparent substrates such an electronic chip designed to convert photons from the visual

environment in to electrical signal travelling via the optic pathway terminating in the

primary and association visual cortex in the brain to restore the perception of vision.

There are several ongoing investigations addressing this issue in different parts of the

world, using microelectronic technology, which has potential adverse effects due to its

thickness and size, hence we have developed a conceptual design using thin film

transistors using carbon nanotubes, to reduce the chip size and increase the sensitivity

which could accord for reduced cost. This nanoelectronic chip is designed to be

implanted in the retina with its projections sink and encapsulates the surrounding retinal

axons which converge as a bundle to form the optic nerve traversing along its pathway to

the primary visual cortex for visual processing in the association visual cortical areas in

the brain to restore the perception of vision.

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Introduction

Visual blindness is one of a major global public health problem. The World Health

Organization (WHO) assessed that 1% of the total global encumbrance of disease

measured as Disability-Adjusted Life Years (DALY) was assignable to vision loss [1].

Corresponding to the World Health Report, about 42.7 million people were assessed to be

blind and 272.4 million people have low vision [2]. Degenerative retinal diseases such as

atrophic macular degeneration and retinitis pigmentosa can lead to severe vision loss.

While vision loss is disastrous at any age, retinitis pigmentosa often affects working-age

adults. Retinitis pigmentosa is an outer retinal degeneration that involves the retinal

pigment epithelium and the photoreceptors. Eyes with retinitis pigmentosa react to

electrical stimulation because in many patients, the inner retina and ganglion cell layer

still have some function. The existing treatment possibilities are limited and vitamins

help slow disease progression. Visual cycle modulators are in clinical trials, and initial

practice proposes they slow disease progression and may ameliorate vision in patients

with mild to moderate disease. For blind patients with light perception, or even no light

perception vision, many scientific investigators and companies around the world are

working on retinal implants in order to restore visual function, chip implants have to

detect light, convert the light energy to electrical energy, and then stimulate the retina.

Distinctive groups approach this in distinct ways [3, 4] thin film transistor based carbon

nanotube retinal chip implants offer hope for patients with visual loss.

Goal of the Project

a) The primary goal is to design and develop a novel embedded nanoelectronic

device using thin film carbon nanotube transistors and graphene for patients with

visual blindness following retinal degeneration.

b) The secondary goal is to test the biocompatibility and functionality of the device

invivo in a sheep model prior to testing in stages of human trials.

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Literature review

Current strategies for restoring vision

Most visual neuroprosthesis are designed upon the foundation, that focal electrical

stimulation of intact visual structures excites the sensation of distinct points of light

( phosphenes ) [5, 6]. It has been assumed that geometric visual percepts can be initiated

by producing applicable multi-site patterns of electrical stimulation. The sense of shapes

and images would be sensed in a method similar to screening an electronic scoreboard in

a stadium ( scoreboard approach ). It is widely recognized that complete maturation of

the visual system and previous visual experience are needed before a patient to be able to

properly and pertinently elucidate these visual patterns. Hence it remains indistinct if this

approach would be suitable to a patient who was blind since birth or early infancy.

The cortical approach

Basic involvement in visual prosthesis improvement was directed at stimulating the

visual cortex directly. In the late 60 s, Brindley and Lewin conducted seminal work by

chronically implanting 80 surface electrodes to overlie the visual cortex of a seriously

blind volunteer [7]. The conveyance of electrical current to the visual cortex elicited the

sensation of distinct albeit crude forms of bright light (phosphenes). More significantly it

was ascertained that the position of these phosphenes coincided roughly to the notable

cortical topographic representation of visual space. The successive finding was of

substantial importance and recommended that anticipated patterns of light may well

potentially be formed using focal electrical stimulation. A more current attempt has

succeeded to integrate a digital video camera system that entraps and transfers encoded

visual images to the cortical stimulating array [8]. The camera, staged onto a pair of

glasses, directs an image to a compact computer, which, in turn, decodes the signal into

suitable patterns of electrical stimulation, a number of blind volunteers have been

implanted with this device and one patient (who had been totally blind for over twenty

years) could apparently differentiate the contour of a person and recognize the orientation

of specific letters [9]. This work has established down a consequential foundation for

constructing a feasible visual prosthesis, in spite of the fact that the cortical approach

faces a number of technical confrontations, the invasiveness of surgical implantation and

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the risk of focal seizures induced by direct cortical stimulation present serious problems

for a patient s safety.

The optic nerve approach

A Belgian group has lately developed a quadruplet spiral cuff electrode intended to

stimulate the optic nerve preferably than the visual cortex. The intracranial electrode was

linked to a neurostimulating circuit that is fixed to the cranium underneath down the skin

and transmits through wireless communication with an outward appearance processor and

camera. This device was chronically implanted in a 59-year-old blind volunteer. In this

patient, electrical stimulation elicited the perception of frequently colored, phosphenes in

all the visual field [10]. After four months of practice and psychophysical testing, it was

declared that the patient could identify and differentiate directions of lines as well as

some shapes and letters [10] contempt only a limited number of stimulating electrodes

being used.

The retinal approach

In addition to the methods mentioned above this appraoch is engaged in implanting a

stimulating device at the level of the retina. In two common causes of blindness, retinitis

pigmentosa16 and age-related macular degeneration [11], there is a comparatively

selective degeneration of the photoreceptor layer of the outer retina. On the other hand,

ganglion cells within the inner retinal layers survive in large numbers and react to

electrical simulation even in progressive stages of the diseases [12, 13]. The proposition of

this retinal approach is to stimulate these cells in entity to restore lost photoreceptor

function. This procedure has the benefit of directing input more proximally alongside the

afferent visual pathway, thereby aiding from primitive physiological pre-processing and

encoding. Moreover ganglion cells are firmly packed and organized in a topographical

fashion throughout the retina. In assumption, a visual image may perhaps be generated in

a process similar to the cortical approach by directing multi-site patterns of electrical

stimulation to the ganglion cells.

Nanotechnology for restoration of vision

There are some novel phototransistors. Konstantatos et al. propose a hybrid graphene-

PbS quantum dot [13]. According to their results, covering the graphene with a colloidal

PbS quantum dots thin film leads a responsivity and electron per photon gain of about 107

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AW-1 and 108, respectively. Actually, this ultrahigh gain originates from the high carrier

mobility of graphene sheet and the recirculation of charge carriers during the lifetime of

the carriers that remain trapped in the PbS quantum dots. A schematic of the graphene-

quantum dot hybrid phototransistor is shown in (Fig. 1).

Fig. 1. A schematic of the graphene-quantum dot hybrid phototransistor, in which a graphene flake is deposited

onto a Si/SiO2 structure and coated with PbS quantum dots [13]

In (Fig. 2) (a) the responsivity of this device as a function of the applied back-gate

voltage is plotted. They measured a responsivity as high as ~5 × 107 AW-1 when

VBG=VD, corresponding to a photoconductive gain of ~1 × 108 for an excitation

wavelength of 600 nm. By tuning the Fermi energy close to the Dirac point at VBG = 4 V,

the responsivity completely falls to zero. This feature demonstrates the potential of this

device as a back-gate-tunable ultrahigh-gain phototransistor. This tunability is of great

importance in photodetectors because it allows control of the state (on-off) of the detector

as well as adjustment of the required gain, depending on the light intensity to be detected.

The back-gate tunability of the graphene Fermi level is also could be exploited to develop

reset functionality in the detectors as an electronic shutter suited to video-frame-rate

imaging applications.

They measured the sensitivity of the detector by performing differential resistance and

responsivity measurements under variable optical intensity. (Fig. 2) (b) shows the

responsivity as a function of the incident optical power on the detector area. The

responsivity remains ~1 × 108 AW-1 for optical powers up to 50 fW, followed by a

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decrease with increasing light intensity. This photocurrent saturation comes from

increasing number of photo-generated electrons [13].

Fig. 2. Phototransistor device characteristics. (a) Responsivity as a function of back-gate voltage, (b) Responsivity

versus optical illumination power. The solid line is the best fit to the data [13].

In the term of mechanism, photon adsorption in PbS quantum dots creates electron-hole

pair separated at the graphene-quantum dot interface due to the band bending at the

interface and workfunction mismatch between graphene and quantum dots. The holes are

transferred to the graphene layer and drift by means of a voltage bias to the drain.

However, electrons remain trapped in the PbS quantum dots. As the electrons remain

trapped in the quantum dots, positive carriers in the graphene sheet are recirculated,

resulting in gain. Moreover, this device offers a gate-tunable sensitivity and speed which

is useful for pixelated imaging applications and spectral selectivity from the short-

wavelength infrared to the visible.

Characterization results of Kimura et al. work [14, 15]:

(Fig. 3) Displays, the irradiated illuminance vs output frequency. It is found that the

relationship between the irradiated illuminance and output frequency is proportional,

which is a suitable property.

Fig. 3. irradiated illuminance vs output frequency [14].

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(Fig. 4) Displays, the detection of the irradiation distribution. Here, a light beam is

irradiated on the retinal prosthesis. It is found that the circular area where the output

frequency is higher becomes larger as the circular area where the light beam is irradiated

becomes larger. It is concluded that the irradiation distribution can be detected [14].

Fig. 4. detection of the irradiation distribution [14].

In the Kimura et al. work, the artificial retina using poly-Si TFTs and wireless power

supply using inductive coupling are located in a light-shield chamber, and Vout in each

retina pixel is probed by a manual prober and voltage meter. White light from a metal

halide lamp is diaphragmmed by a pinhole slit, focused through a convex lens, reflected

by a triangular prism and irradiated through the glass substrate to the back surfaces of the

artificial retina on a rubber spacer. The real image of the pinhole slit is reproduced on the

back surface. (Fig. 5) Shows the detected result of irradiated light. It is confirmed that the

Lphoto distribution can be reproduced as the Vout distribution owing to the parameter

optimization of the wireless power supply system even if it is driven using the unstable

power source, although shape distortion is slightly observed, which is due to the

misalignment of the optical system or characteristic variation of TFTs [15].

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Fig. 5. result of irradiated light [15]

Discussion and project description

Over all framework

A mentioned earlier, the intended design of the artificial retina is based on Thin-

Film Transistors (TFTs) fabricated on transparent and flexible substrates, the deposition

of conductive and semiconductor layers is done using Ink Jet technology combined with

Carbon Nanotubes (CNT) which eliminate the need for expensive semiconductors. We

propose the use of layer of Parylene to encapsulate the device protecting the components

within it from the tissue fluids surrounding the device, since the device is designed to be

implanted in the retina of the patient with visual blindness. The array includes an active

matrix-like multiple pixels similar to what you see in the point on flat panel displays as

described by Kimura et al. The contact pads are located posterior and have a large area

(27.3 cm2) and a resolution of almost 150 ppi. There is a more recent technology as

described by Konstantatos et al [13], using PbS Quantum Nano Dots, having high

amplification levels that reduces the size of the device, and also increase its sensitivity,

therefore the blurred vision often associated with lower resolution will be eliminated,

hence we would modify the apparatus devised by Konstantatos et al [13] by changing the

Silicon substrate for a plastic electronics NMOS device that has Carbon Nanotubes to

carry either metallic interconnections or semiconductor activities, since graphene is a

monolayer sheet, it will not affect the visual characteristics and therefore we anticipate a

superior performance.

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.

Fig. 6. A schematic of the graphene-quantum dot hybrid phototransistor, in which a graphene flake is deposited onto a Si/SiO2 structure and coated with PbS quantum dots [13]

The retina pixel consists of a phototransistor, current mirror, and load resistance. To

optimize the phototransistor efficiency, the current mirror and load resistance are

designed to optimize the transistor performance. The photosensitivity of the reverse-

biased p/i/n poly-Si phototransistor is 150 pA at 1000 lx for white light and proper values

for all visible color lights. The mobility and the threshold voltage of the n-type and p-

type poly-Si TFT are fixed at 93 cm2 V-1s-1 , 3.6 V, 47 cm2 V -1s-1 and -2.9 V,

respectively. We anticipate that by using CNT in our design the mobility will increase

multiple times and also generate a higher photocurrent. The Fig 6.2 depicts the proposed

device including the thin-film phototransistor on a flexible substrate. When light hits the

device the following reactions takes place First, the phototransistors perceive the

irradiated light (Lphoto) and induce the photo-induced current (Iphoto). Next, the current

mirror is amplified several times Iphoto to the mirror current (Imirror). Finally, the load

resistance converts Imirror to the output voltage (Vout). Consequently, the retina pixels

irradiated with bright light output a higher Vout, whereas the retina pixels irradiated with

darker light output a lower Vout.

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Electronic photo devices and circuits are integrated on the artificial retina, which is

implanted on the inside surface of the retina on the posterior chamber of the eye ball.

Since the irradiated light comes from one side of the artificial retina and the stimulus

signal goes out of the other side, this transparent substrate is most preferable.

Fig 6.2, illustrates the concept model of the artificial retina fabricated on a transparent substrate implanted

epiretinally.

Control

P I N

Vcontrol Vapply Anode

75nm 25nm

Lphoto Fig 6.2 PIN Thin Film Photo Transistor

Flexible & Transparent Substrate

Current Mirror

Phototransistor

Load Resistors

Vout

Fig 6.1 Schematic of a cell used to generate the pixels to stimulate the rods and cones and restore vision

Vdd Iphoto Vdd Imirror

Biocompatible Encapsulation

L photo

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Power supply via Inductive coupling

Power supply to the device is delivered wirelessly via inductive coupling as shown in the

(Fig 6.4). This system includes a power transmitter, power receiver, Diode Bridge, and

Zener diodes. The power transmitter consists of an ac voltage source and induction coil.

The Vpp of the ac voltage source is 10 V, and the frequency is 34 kHz, which is a

resonance frequency of this system. The material of the induction coil is an enameled

copper wire, the diameter is 1.8 cm, and the winding number is 370 times. The power

receiver also consists of an induction coil, which is the same as the power transmitter and

located face to face. The diode bridge rectifies the AC voltage to the DC voltage, and the

Zener diodes regulate the voltage value [14].

Fig 6.4. Illustrating active epiretinal nanoelectronic Implant powered by inductive coupling via RF signal.

Following the design the system should be checked for its biocompatibility and any

adverse reactions in an animal model, the supply system in principle is very simple to

implant and the generated power should also be checked for its stability. Since the

intended artificial retina is fabricated on an insulator substrate, and has little parasitic

capacitance, and is subject to influence of noise. Therefore, it is necessary to confirm

whether the artificial retina can be correctly operated even using the unstable power

source. (4). To synthesize and ensemble the artificial retinas using thin film Carbon

Nanotubes on flexible and transparent substrates we propose the following process as

developed by Sajed et al [17].

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Processing of nanotubes prior placement on the inkjet cartridge

The fabrication process includes the following steps: (a) The Glass microscope slides will

be cleaned with acetone and ethanol and soft baked at 100 °C for 15 min; (b) SWCNT ink

will be printed using a Sonoplot GIX Microplotter II. Metallic SWCNT electrodes will be

printed from concentrated metallic SWCNT solution (1 mg in 10 ml aqueous solution,

Nanointegris) using a 30  μm tip. Transistor channel length of 200  μm and channel width

of 1300  μm will be printed. Metallic electrodes will be exposed in air for 24 hours and

then washed by soaking the substrate within a propriety acid wash for 24 hours. Followed

by curing at 250 °C and a next layer of metallic SWCNT will be printed over the previous

layer to increase SWCNT density of which the final sheet resistance could be obtained at

6 KΩ/square (c) Semiconducting SWCNT solution (1 mg in 100 ml aqueous solution,

Nanointegris) will be printed with a 30  μm tip to complete the transistor change. Clean

semiconducting SWCNT films will be obtained by soaking the printed substrate in a

propriety acid for 24 hours; (d) the ionic gel solution of PS-PMMA-PS (1.5%, weight)

and EMIM TFSI (8.5%, weight) in ethyl acetate will be prepared and supplied. Since the

ionic gel has a high viscosity, it will be printed using a 500  μm in diameter tip in order to

print a uniform and transparent layer of gel over the channel. The device will then be

cured at a temperature of 105 °C for 1 hour. After this process, all-SWCNT TFT

fabricated devices will then be subsequently tested [17].

Nanotube characterization

We intend to test the nanotubes using SEM (scanning electron microscope), DTA

(Differential Thermal Analysis), High-Energy Milling devices, Spark Plasma Sintering

and extrusion techniques soft chemistry (sol-gel) among others which will be decided

based on its feasibility with this intended protocol.

For electronic characterization, we intend to use four point probes, capacitance,

inductance, and frequency responses using impedance, network and spectrum analyzer.

Of course, the need for some specialized test rigs to check electrical connections is quite

obvious and it s included in the protocol.

Mechanical test include Young s Module, thermal conductivity, elongation, stiffness,

hardness. We make sure to use proper rigs to ensure that the testing is accurate. Optically

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speaking we can conduct test such as electro-luminescence, transmission, reflection,

fluorescence, refractive index, transparency and for chemical testing we intend to include

testing the pH level and spectroscopy.

Rendering Illumination profile

The Vout in each retina pixel will be probed by a manual prober and voltage meter. White light

from a metal halide lamp will be diaphragmmed by a pinhole slit, focused through a convex lens,

reflected by a triangular prism and irradiated through the glass substrate to the back surfaces of

the artificial retina on a rubber spacer. The real image of the pinhole slit will be reproduced on the

back surface [15, 16].

Animal Testing

Retinal degeneration will be induced in the sheep prior to implant and once the embedded

nanoelectronic retinal device is fabricated, the functionality and the biocompatibility will

be tested in a sheep, after induction of general anesthesia, local infiltration with lidocaine

will be delivered along the line of zygomatic arch and a small incision will be made on

the posterior rim of the orbit along the line of zygomatic arch and the subcutaneous tissue

will be retracted and fixed by clamps, bleeding will be arrested by a bipolar

electrocauterization and a small burr hole will be made with an electric burr on the

posterior rim of the orbit, then a trans sclera choroidal microincision will be made and the

fabricated transparent thin film carbon nanotube embedded nanoelectronic retinal device

will be implanted in the retinal surface as shown in the (Fig.7). The probe for power

transfer via RF signal will be packed subcutaneously with a pocket incision along the

mastoid process.

Fig.7. Illustrates the embedded nanoelectronic implant device invivo in the retinal surface of a sheep

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Conclusion and Recommendation

We propose that epiretinal implantation of this novel embedded nanoelectronic device

with enhanced capabilities augmented by Carbon Nanotubes and Quantum Dots,

combined with Graphene are able to generate electronic signals that our brain interprets

as natural stimulation to trigger neurons in the primary and association visual cortex, to

alleviate symptoms of perceptual visual blindness arising as a sequelae in patients with

retinitis pigmentosa and progressive macular degeneration. Prior to be used in humans we

recommend to test the biocompatibility of the devise and for any adverse complications

such as endophthalmitis, conjunctival erosion, and retinal hemorrhage arising from the

implant itself in vivo in a sheep model prior to stages of clinical trials in human subjects

with visual blindness as a sequelae of retinal degeneration.

References

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