W1A.001

MEMS ENABLED TECHNOLOGIES FOR OCULAR MONITORING AND THERAPY
Ellis Meng1, Eugene Yoon1, and Christian Gutierrez2
1
University of Southern California, Los Angeles, USA and2
Verily Life Sciences, South San Francisco, USA
technologies that have been developed for the eye by
examining the needs of several ocular conditions.

ABSTRACTThe healthy human eye is an exquisite collection ofdifferent cell types that collectively form an intricate optoelectro-mechanical system that shapes the final input to thevisual processing areas of the brain to achieve vision. A
number of different diseases affecting the eye are amenable
to engineering solutions enabled by MEMS technologies.
The purpose of this paper is to examine different
opportunities for MEMS technologies to impact ocular
health and review examples of past and current research inthis field. Commercial progress is also discussed.

KEYWORDS
Ocular microdevices, contact lens devices, glaucoma
drainage devices, intraocular pressure, accommodative
intraocular lens, retinal prostheses, retinal electrode arrays,in vivo force sensors

Figure 1: (left) Illustration of cross section of human eye
detailing the configuration of major structures involved invision. (right) Close-up view of the retina showing thelayered arrangement of different neuronal cell types. Light
bypasses the outer layers in contact with the vitreous
humor and is converted into electrical pulses by the rods
and cones in the photoreceptor layer. Image Source:
OpenStax College, Vision. October 17, 2013,
http://cnx.org/content/m44761/latest/Figure_36_05_02.pn
g, OpenStax CNX under CC BY 3.0.

INTRODUCTION
In order to understand the device-related opportunities
in the eye, it is first necessary to briefly review how visible
light enters and is processed by the eye before it istransmitted by the optic nerve to different downstream
processing centers in the brain (Fig. 1). Then, progress in
MEMS-enabled technologies for the eye are reviewed
including surgical tools, research devices, and monitoringor therapeutic devices categorized by the major oculardisease conditions they target.
Visible light is first refracted by the cornea, passes
through the pupil, and is refracted once more by the lens
into a small inverted image that is focused on the backretina. The lens is part of a mechanical system within theeye; the ciliary muscle acts on the lens via zonular fibers.
Contraction and relaxation of the muscle causes increases
in convexity or flattening which in turn allow the eye tofocus on objects that are near or far, respectively.
Light exiting the lens then bypasses the outer layers of
the 100-300 µm thick retina through several cell types andis projected onto the photoreceptor layer consisting of rod
and cone cells (~130 million) which transduce the lightstimulus into electrical pulses. Unlike other parts of thesensory system, a great deal of signal processing occurs in
the retina outside of the brain. The electrical pulses are
passed from photoreceptors to a cascade of different
neuronal cell types (horizontal, bipolar, amacrine, andganglion cells) that each contribute to visual processing.
Action potentials are then transmitted by ~1.2 million
ganglion cells through the optic nerve and on to the visualcortex and other parts of the brain.
The malfunction of or damage to any of these ocularcomponents can result in vision impairment. As vision isa critical part of our sensory system, much attention has
been devoted by researchers and industry to treat different
ocular conditions. The following introduces MEMS

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GLAUCOMA
Glaucoma is an incurable disease that affects millions
worldwide. Vision loss occurs via damage to the optic
nerve. Elevated intraocular pressure (IOP) is strongly
implicated in the pathogenesis of glaucoma. Intraocularpressure is affected by the balance between production andoutflow of aqueous humor. Glaucoma can be managed by
implantation of drainage devices which lower IOP byimproving the outflow of aqueous humor.
MEMS devices for the management of glaucoma
include sensors to monitor IOP and glaucoma drainage
devices that lower IOP by improving the outflow of
aqueous humor [1]. Pressure sensors that are integrated
into contact lenses or implanted have been proposed [2].
The Sensimed Triggerfish® is a contact lens sensor thatuses a strain gauge to continuously monitor changes in IOP
patterns by capturing circumferential changes in thecorneoscleral area. The sensor transmits information
wirelessly to an antenna adhered around the eye and stores
data via Bluetooth to a portable recorder worn by thepatient for later analysis. This system obtained US
regulatory approval in 2016.
The contact lens format is also being explored for
glucose sensing in tears in a joint effort between Verily andNovartis [3]. This was inspired by earlier researchdemonstrating L-lactate sensing in a MEMS contact lensdevice where platinum electrodes were evaporated ontopoly(ethylene terephthalate) substrates, functionalized

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Intrascleral and suprachoroidal interfaces are positioned in
the eye wall in layers outside of the retina.
The MEMS component in many of these efforts is themultielectrode retinal interface [14, 15]. Different flexible
substrate materials including silicone rubber, Parylene C,polyimide, and liquid crystal polymer have been explored.
Likewise, different electrode materials have been reported
including platinum and sputtered iridium oxide films(SIROF).
Epiretinal prostheses typically include a rectangularmultielectrode array attached to a multiwire cable.
Electrode sites are ideally located within 100 µm ofganglion cells for effective electrical stimulation. The
Argus® II uses a simple retinal tack to secure the electrodearray in place. One challenge posed by this arrangement is
the interfacial contact pressure imposed upon the delicate
retina. A MEMS pressure sensor array (Fig. 2) was
developed to study the magnitude of mechanical loading on
the retina imposed by the contact of the array with theretina during surgical placement and tacking [16]. These
Parylene C pressure sensing arrays were thermally shaped
to match the curvature of the retina, a technique developed
earlier for Parylene C epiretinal microelectrode arrays [17].

with appropriate chemical additives, and coated withmedical grade polyurethane. The amperometric sensor wascapable of stable in situ monitoring of L-lactate in tear fluidat temperatures comparable to those at the surface of theeye [4].
Implantable IOP sensors are being pursued by anumber of academic research groups [2]. Most utilize
capacitive sensing methods which necessitates a wirelessmethod for obtaining pressure data. A passive mechanicalsensor was developed based on the Bourdon tube andallowed optical readout of pressure [5, 6].
To properly regulate IOP, MEMS glaucoma drainage
shunts have been devised with micro check valves [7, 8] ormagnetoelastic resonators micromachined from Metglas
2826MB (Fe40Ni38Mo4B18) for wireless actuation [9].
Drainage shunts that resist biofouling and minimize
unwanted protein adhesion by using microfluidics
composed of unique polyethylene glycol materials havealso been described [10].

RETINITIS PIGMENTOSA
Diseases affecting the photoreceptor layer of the retina
prevent the adjacent and otherwise intact layers fromconducting visible light information to the brain. For
example, retinitis pigmentosa is marked by degeneration of
the photoreceptors and is incurable. The progressive lossof photoreceptors first results in compromised peripheral
vision and eventually blindness.
Although thephotoreceptors in the outer retina are lost, the cells in the
inner retinal layers are partially spared. Electricalstimulation of the inner retina has been shown to provide
some level of useful light perception [11].
Dozens of research groups worldwide have thus
pursued development of retinal prostheses including major
efforts in the US, Germany, France, Japan, Korea,
Australia, Taiwan, Israel, and China [12]. The approaches
differ and can be categorized by the implant location within
the eye and the mechanism by which electrical stimulation
is applied to the ganglion cells of the inner retina. The
Argus® II retinal prosthesis developed by Second Sight
Medical Products includes an epiretinal microelectrodearray designed to lay on top of the inner retina with theelectrodes exposed to the ganglion cell layer. Visual
information is acquired by an external camera mounted oneyeglass frames and that information is converted into an
appropriate pattern of stimulus pulses by a processing unit.
The Argus® II received US regulatory approval in 2013.
In addition to epiretinal placement, other ocularinterface strategies to restore vision include subretinal,
intrascleral, and suprachoroidal placement. Subretinal
prostheses use electrode arrays or photodiodes inserted into
the eye wall adjacent to the retina. Unlike microelectrodes
which are used to send electrical impulses to tissue,
photodiode arrays convert light stimulus into electricalcurrent which is then converted into electrical stimulus.
The advantage of the photodiodes is the elimination of theexternal camera and processor. The highest recoveredvisual acuity reported to date was obtained in a patient
using the Alpha-IMS subretinal photodiode prosthesis
developed by the University of Tübingen [13]. This device
received regulatory approval in Europe in 2013.

Figure 2: Illustration of Parylene-based pressure sensing
array with discrete integrated sensors. The array was
designed to operate in the wet ocular environment andmimic the shape and placement of an epiretinal electrodearray. A tack hole allows the device to be secured to theretina.
Epiretinal arrays sized for research animals are also
being pursued that will allow further understanding ofelectrical stimulation-based restoration of vision. Figure 3
shows a Parylene C epiretinal array having Pt stimulationelectrodes of varying sizes with an integrated ribbon cable.
The device has been thermally shaped to match the ocular
anatomy of rats such that the electrode array is positionedon the retina and the ribbon cable bends around the eye
wall. This arrangement allows the array to be sutured
securely onto the sclera. The ribbon cable routes thecontact pad array to head-mounted electronics. Opticalcoherence tomography and fundus images confirmed
placement of the array within 100 µm of the retina inexperiments performed with unpackaged arrays.

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the eye, and were followed for 90 days [20]. Further
clinical studies are required before regulatory approval forsuch technology can be obtained.
Other MEMS approaches have been explored forocular drug delivery beyond electrolysis pumps. MEMS
transducers were developed for sonophoretic [21, 22] andiontophoretic [23] delivery. Delivery of defined doses ofantiantiogenic drug targeting diabetic retinopathy wasdemonstrated using a magnetically activated drug reservoir[24, 25].

PRESBYOPIA
Presbyopia, a natural part of the aging process, ischaracterized by stiffening of the lens causing the eye to be
fixed at a long-distance focus. In a healthy eye, thecompliant lens is reshaped naturally as the zonular fibers
respond to the activity of the ciliary muscle. As the muscle
contracts, the lens increases in convexity which allows
proper focus of light on the retina for close objects. As themuscle relaxes, the lens flattens allowing for focus of far
objects. The process of changing optic power to enablefocus is called accommodation.
Static corrective lenses in the form of glasses orcontact lenses can provide vision correction but cannot
restore accommodation.
Novartis and Verily havepartnered to achieve an autofocus contact lens to treat
presbyopia which has yet to enter clinical trials.
It is also possible for the lens to be surgically replacedwith intraocular lenses (IOLs). IOLs consist of a lens andhaptics. First, the natural lens is removed, leaving an
empty lens capsule. The IOL is positioned directly within
the lens capsule and secured in place with the haptics torestore focusing power. Unlike conventional IOLs, thehaptics in an accommodative IOL are flexible and interact
with the ciliary muscle. Specifically, the microhinges
enable the lens to vault forward and backward within theeye following the normal accommodation mechanism.
A recent example of an accommodative IOL uses a
shape memory alloy ring actuator in combination with
Parylene spring and shoes [26]. Alternatively, the lens
shape can be directly manipulated by using an inflatableliquid-filled balloon with a self-sealing valve in place of thelens [27]. Commercially available accommodative IOLs
include the Crystalens (approved in 2003) and Trulign
Toric (approved in 2013) by Bausch + Lomb. Many other
IOLs are being developed.

Figure 3: Prototype epiretinal array device sized for rat.
a) Side view of device showing the thermally formed arrayand cable at the tip. The contact pad array is visible on theright. b) Top down view of device. Wires are placed on
the cable periphery to minimize damage during surgicalhandling. c) Magnified view of the electrode array prior tothermal shaping. Electrode diameters are 210, 110, 80,
and 60 µm in the top row and 160 µm in the bottom.

AGE-RELATED
DEGENERATIONMACULAR EDEMAAND

MACULAR
DIABETIC

Age-related macular degeneration (AMD) affects themacula located near the center of the retina and thus affects
the quality of central vision. The disease is incurable anda common form of vision loss among the elderly. The wet
form of AMD is associated with abnormal blood vessel
growth. Diabetic macular edema (DME) follows fromdiabetic retinopathy and also results in loss of vision in thecentral field.
The impairment is caused by fluid
accumulation in the macula due to leaky blood vessels.
Both conditions are treatable and a number of different
interventions are available.
Pharmaceutical intervention typically entails drug
injections via needles into the back of the eye. Drug is thus
delivered to the vitreous humor, a jelly-like fluid filling theeye, and in close proximity to the retina. These drugs act
to control the growth of blood vessels and slow theirleaking. However, the need for frequent and repeatedintraocular dosing to manage the progression of disease canlead to undesirable complications and further suffers frompoor patient adherence.
An alternative to frequent intravitreal injections is theuse of implantable drug delivery systems. Intraocular
pumps have been developed using MEMS electrolysis
pumps [18, 19]. In addition to replacing intravitreal
injections, such pumps could also be used to deliver
therapeutics to the front of the eye to manage, for example,
glaucoma. In 2014, Replenish, Inc. reported the first-inman safety study of their 60 µL payload MicroPump. A
small group of 11 DME patients received the micropump,were administered microdoses into the vitreous cavity of

CONCLUSION
Many opportunities exist to treat chronic curable
conditions that lead to vision loss. The anatomy and sizeof the eye are well matched to the strengths and features
afforded by MEMS technology.
Although several
conditions are now addressed by recently approved
medical devices incorporating MEMS technology, theperformance achieved still lags behind that of a healthy
ocular system. In addition to medical devices formonitoring and therapy, research devices also play animportant role in informing new or improved interventions.

ACKNOWLEDGEMENTS
This work was supported in part by the NSF under381

[14] J. Jeong, S. H. Bae, J.M. Seo, H. Chung, S. J. Kim,
"Long-term evaluation of a liquid crystal polymer(LCP)-based retinal prosthesis," J. of neural eng., vol.
13, p. 025004, 2016.
[15] F. Yang, M.Y. Chang, C.H. Yang, C.C. Teng, L.S.
Fan, "Flexible, high-density microphotodiode arraywith integrated sputtered iridium oxide electrodes forretinal stimulation," J. of Micro/Nanolitho., MEMS,
and MOEMS, vol. 15, pp. 015002-015002, 2016.
[16] C. Gutierrez, "Development of flexible polymer-based
MEMS technologies for integrated mechanicalsensing in neuroprosthetic systems," University ofSouthern California, 2011.
[17] D. C. Rodger, A. J. Fong, L. Wen, H. Ameri, A. K.
Ahuja, C. Gutierrez, et al., "Flexible parylene-based
multielectrode array technology for high-density
neural stimulation and recording," Sensors andActuators B-Chemical, vol. 132, pp. 449-460, 2008.
[18] P. Y. Li, J. Shih, R. Lo, S. Saati, R. Agrawal, M. S.
Humayun, et al., "An electrochemical intraocular drugdelivery device," Sensors and Actuators A-Physical,
vol. 143, pp. 41-48, 2008.
[19] S. Saati, R. Lo, P. Y. Li, E. Meng, R. Varma, M.
Humayun, "Mini Drug Pump for Ophthalmic Use,"
Current Eye Research, vol. 35, pp. 192-201, 2010.
[20] M. Humayun, A. Santos, J. C. Altamirano, R. Ribeiro,
R. Gonzalez, A. de la Rosa, et al., "Implantable
MicroPump for Drug Delivery in Patients with
Diabetic Macular Edema," Trans. Vision Science &Tech., vol. 3, p. 5, 2001.
[21] S. Nayak, M. Jadhav, V. Bhaskar, "Recent Advancesin Ocular Drug Delivery Systems," Research J.
Pharmacy and Tech., vol. 9, p. 995, 2016.
[22] M. Nabili, A. Shenoy, S. Chawla, S. Mahesh, J. Liu,
C. Geist, et al., "Ultrasound-enhanced ocular deliveryof dexamethasone sodium phosphate: an in vivo
study," J. of Therapeutic Ultrasound, vol. 2, pp.6,
2014.
[23] Y. Zhang, Y. Chen, X. Yu, Y. Qi, Y. Chen, Y. Liu, etal., "A flexible device for ocular iontophoretic drugdelivery," Biomicrofluidics, vol. 10, p. 011911, 2016.
[24] F. N. Pirmoradi, J. K. Jackson, H. M. Burt, M. Chiao,"On-demand controlled release of docetaxel from abattery-less MEMS drug delivery device," Lab Chip,
vol. 11, pp. 2744-52, 2011.
[25] F. N. Pirmoradi, K. Ou, J. K. Jackson, K. Letchford, J.
Cui, K. T. Wolf, et al., "Controlled delivery ofantiangiogenic drug to human eye tissue using a
MEMS device," 2013 IEEE (MEMS), pp. 1-4.
[26] T. D. O. Moura, T. Tsukamoto, D. W. de Lima
Monteiro, S. Tanaka, "Hybrid MEMS-SMA structure
for intraocular lenses," Sensors and Actuators A:
Physical, vol. 243, pp. 15-24, 2016.
[27] C. M. T. DeBoer, J. K. Lee, B. P. Wheelan, C. Cable,
W. Shi, Y. C. Tai, et al., "Biomimetic Accommodating
Intraocular Lens Using a Valved Deformable Liquid
Balloon," IEEE Trans. on Biomed. Eng., vol. 63, pp.
1129-1135, 2016.

award numbers CBET-1343193 and EEC-0310723. The
authors would like to thank Dr. D. Zhu and the members of
the USC Biomedical Microsystems Laboratory for theirassistance.

REFERENCES[1] E. Meng, P.J. Chen, D. C. Rodger, Y.C. Tai, M.
Humayun, "Implantable Parylene MEMS for
Glaucoma Therapy," in IEEE Eng. in Med. and Bio,Oahu, Hawaii, 2005, pp. 116-119.
[2] D. E. Uttamchandani, Wireless MEMS Networks andApp., Woodhead Publishing Ltd. Oxford, 2016.
[3] N. M. Farandos, A. K. Yetisen, M. J. Monteiro, C. R.
Lowe, S. H. Yun, "Contact Lens Sensors in OcularDiagnostics," Adv. Healthcare Mat., vol. 4, pp. 792810, 2015.
[4] N. Thomas, I. Lähdesmäki, B. A. Parviz, "A contact
lens with an integrated lactate sensor," Sensors andActuators B: Chemical, vol. 162, pp. 128-134, 2012.
[5] P. J. Chen, D. C. Rodger, R. Agrawal, S. Saati, E.
Meng,
R.
Varma,
etal.,"Implantablemicromechanical parylene-based pressure sensors forunpowered intraocular pressure sensing," J.
Micromech. and Microeng., vol. 17, pp. 1931-1938,
2007.
[6] P. J. Chen, D. C. Rodger, M. S. Humayun, Y. C. Tai,
"Unpowered spiral-tube parylene pressure sensor for
intraocular pressure sensing," Sensors and Actuators
a-Phys., vol. 127, pp. 276-282, 2006.
[7] C.J. Park, D.S. Yang, J.J. Cha, J.H. Lee, "Polymericcheck valve with an elevated pedestal for precise
cracking pressure in a glaucoma drainage device,"
Biomed. Microdevices, vol. 18, p. 20, 2016.
[8] P. J. Chen, D. C. Rodger, E. M. Meng, M. S.
Humayun, Y. C. Tai, "Surface-micromachined
parylene dual valves for on-chip unpowered
microflow regulation," J. Microelectromech., vol. 16,
pp. 223-231, 2007.
[9] V. Pepakayala, J. Stein, Y. Gianchandani, "Resonant
magnetoelastic microstructures for wireless actuationof liquid flow on 3D surfaces and use in glaucoma
drainage implants," Microsys. & Nanoeng., vol. 1, p.
15032, 2015.
[10] R. S. Harake, Y. Ding, J. D. Brown, T. Pan, "Design,
Fabrication, and In Vitro Testing of an Anti-biofouling
Glaucoma Micro-shunt," Annals of Biomed. Eng., vol.
43, pp. 2394-2405, 2015.
[11] M. S. Humayun, E. de Juan, Jr., G. Dagnelie, R. J.
Greenberg, R. H. Propst, D. H. Phillips, "Visual
perception elicited by electrical stimulation of retina inblind humans," Arch Ophthalmol, vol. 114, pp. 40-6,
1996.
[12] D. L. Cheng, P. B. Greenberg, D. A. Borton,"Advances in Retinal Prosthetic Research: A
Systematic Review of Engineering and Clinical
Characteristics of Current Prosthetic Initiatives,"
Current Eye Research, pp. 1-14, 2017.
[13] K. Stingl, K. U. Bartz-Schmidt, D. Besch, C. K. Chee,
C. L. Cottriall, F. Gekeler, et al., "Subretinal Visual
Implant Alpha IMS – Clinical trial interim report,"
Vision Research, vol. 111, Part B, pp. 149-160, 2015.

CONTACT*E. Meng, tel: +1-213-7406952; ellis.meng@usc.edu

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