In this paper we discuss the research that have been carried out till date for developing retinal implant for two major disease, age-related macular degradation (ARMD) and retinal pigmentosa (RP) and Diabetic Macular Enedema. Paper talks about the motivation for building these devices, detailed fabrication steps, evaluation and results. Retinal prosthesis and implants have tremendous potential for improving a patient’s living condi-tions and simplifying medical procedure to treat certain type of disease. At the same time development of such devices is extremely complex and takes a considerable amount of time, years to be exact to develop. The devices discussed here use Microelectromechanical System or MEMS technology to address the complexity and all the devices have an actuation mechanism embedded in a micropump for controlled release of the drug. Various test results, both animal and human trials have also been reported in the paper for each device.

1. Microelectromechanical Systems (MEMS) Based Micropumps With
Application In Retinal Implants: A Review Of Its Historic Development
And Recent Advancement.
K. Sai Siva
Department of Mechanical Engineering, The University of Illinois at Chicago
Abstract: In this paper we discuss the research that have been carried out till date for developing retinal implant
for two major disease, age-related macular degradation (ARMD) and retinal pigmentosa (RP) and Diabetic
Macular Enedema. Paper talks about the motivation for building these devices, detailed fabrication steps,
evaluation and results. Retinal prosthesis and implants have tremendous potential for improving a patient’s living
conditions and simplifying medical procedure to treat certain type of disease. At the same time development of
such devices is extremely complex and takes a considerable amount of time, years to be exact to develop. The
devices discussed here use Microelectromechanical System or MEMS technology to address the complexity and
all the devices have an actuation mechanism embedded in a micropump for controlled release of the drug. Various
test results, both animal and human trials have also been reported in the paper for each device.
Keywords: micropump, retinal prosthesis
Introduction:
Microelectromechanical Systems or MEMS are
devices, in a wide sense, which are manufactured
using IC fabrication techniques, has a micromachine
which is controlled by microelectronics. MEMS
manufacturing processes such as surface
micromachining, bulk micromachining, molding,
etc. are mainly adopted from IC fabrication industry.
[1] MEMS industries and technologies are fairly
mature when their technological impact and
significance are considered. Its foundation had been
laid by Richard Feynman in his speech in 1960 titled,
“There is Plenty of Room at the Bottom”,and his talk
on Infinitesimal Machinery. [2] [3] Which was
strengthened by a paper published in 1982 by Kurt E.
Petersen. [4] However recent funding and market
demand has pushed this technology to a new heights
resulting in state of the art devices and consumer
products. Their small form factor and high reliability
combined with compatibility proven by in-vivo
experiments makes MEMS devices ideal for
healthcare devices. This review paper discusses this
very aspect of mems with prime focus on
micropumps used in medical devices (retinal
implants) used for drug delivery.
While some drugs can be ingested as soon as it is
administered, other drugs needs specific time,
interval and dosage for administration. One of the
popular drug that is very important to consider when
talking about drug delivery via micropumps is
insulin, the dosage of which varies according to age
of the subject and the type of diabetes s/he has. [5]
Other fairly new, but highly important application of
interest for drug delivery is liquid chemical
neurotransmitter delivery through micropumps in
retinal prosthesis.
This requires microfluidic dispenser that is small
enough to be implantable inside the subject, near the
intended area. Also the dispenser should be efficient
enough when it comes to delivering drug quantities
well within specified limits, reliably and most
important it should be bio-compatible.
A Piezoelectric Micropump Based on
Micromachining of Silicon. [6]
According to a publication [7] this was the
beginning of the ear of micropumps for drug
delivery. This paper proposed the possibility of
realizing a micropump based on micromachining of
silicon and thin-film techniques.
The design included a two-valve and a three-valve
pump, both having a glass/silicon/glass sandwich
structure. For the review purpose we will analyze
two valve system only. The cross section of which
are shown in the figure-1.

2. The application of electric voltage over the
piezoelectric disc causes the double layer to bend
downwards. The volume of the pump chamber and
the liquid is forced through valve 2 to the outlet,
while valve 1 checks the return flow to the inlet.
When the voltage is switched off, the membrane will
adopt its original shape and fluid will be drawn
through valve 1 while at the same time valve 2 will
check the return flow from the outlet.
Fig-1: Cross sectional view of a) two valve pump and b)
three valve pump
The yield of this two-valve pump is strongly
dependent of the outlet pressure and, in the case of
excess pressure at the inlet, both valves will open and
allow liquid to pass continuously.
When the pump membrane is activated
downwards the pressure in the pump chamber is
increased. Provided this pressure exceeds the sum of
the outlet pressure and the pre-tension if valve 2, the
latter valve will open. Due to the pressure difference
across the gap underneath the sealing ring, the fluid
will flow through this gap, thereby reducing this
difference. After a short period the chamber pressure
will equal the sum of the pre-tension of valve 2 and
the outlet pressure, and the valve will close, shown
in figure. The opposite is obtained when the voltage
is switched off. The pump membrane moves
upwards, causing a pressure decrease in the pump
chamber. Valve 1 opens, and the fluid flows into the
pump chamber until the chamber pressure equals the
inlet pressure minus the pre-tension of valve 1,
shown in figure-1.
The total pumped volume is calculated by:
∆𝑽 = ∆𝑽 𝒑𝒊𝒆𝒛𝒐 − (𝒑 𝒐𝒖𝒕 − 𝒑𝒊𝒏 + 𝒑 𝒗𝒂𝒍𝒗𝒆𝟏 + 𝒑 𝒗𝒂𝒍𝒗𝒆𝟐) × (∆𝒗 𝒎𝒆𝒎𝒃
+ ∆𝒗 𝒗𝒂𝒍𝒗𝒆𝟏 + ∆𝒗 𝒗𝒂𝒍𝒗𝒆𝟐)
The outlet pressure can have a large influence on the
total pumped volume. If 𝒑 𝒐𝒖𝒕 − 𝒑𝒊𝒏 is negative and
exceeds 𝒑 𝒗𝒂𝒍𝒗𝒆𝟏and 𝒑 𝒗𝒂𝒍𝒗𝒆𝟐 both valve will open.
Permitting a continuous flow. The holes and
channels in the silicon wafer are etched by a solution
of ethylene diamine, pyrocatechol and pyrazine in
water (EDP). Silicon oxide was used as a masking
material, so that flat diaphragms can be etched giving
well defined edges. The etching process being
anisotropic, the diaphragms are actually facetted, but
for the simulation they regarded it as circular. The
bonding between the glass and the silicon is obtained
by anodic bonding. The thermal expansion of both
the types of glass used is the same for heating of 20
to 300 °C, because of which a bonding temperature
of 300°C was used to avoid thermal stresses. Cyano-
acrylate adhesive was used in order to attach the
piezo disc to the glass. In order to fill the micropump
it was submerged in water in a bell jar and air is
admitted to fill the micropump.
The yield was measure with the aid of a glass
capillary tube, and the outlet pressure by using a
water reservoir. This enabled to accurately measure
exceptionally small yields of the order of µl/min.
Neurotransmitter-Based Retinal Prosthesis Using
an Inkjet Print-head. [8]
Most of the retinal prosthesis used were typically
based on an electric interface to stimulate
depolarized nerve cells by generating field
potentials, which is usually non-specific and can lead
to cell damage. This paper discuss a proven surrogate
MEMS device in the form of a print head of a
desktop printer, used to eject a pattern of
neurotransmitters(bradykinin) onto living rat
pheochromocytoma (PC12) cells, which can be used
in retinal prosthesis and implants. The patterned
stimulation was measured using fluorescent calcium
imaging.
Fig-2: Device schematics
The objective here is to deliver a neurotransmitter
solution in very precise quantities and are well-
defined locations, mimicking a synapse. Authors
state that chemical stimulation may have definite

3. advantages in stimulating complex sensory organs
such as retina by selective stimulation of “on” and
“off” signal pathways.
The print-head used here is piezoelectric actuator
which is suitable option since it doesn’t employ heat
for bubble formation which may decompose the
chemicals, also piezoelectric print-head can deliver
small quantities consistently to precise locations.
The authors used Epson 740 Stylus color printer
for dispensing neurotransmitter onto the PC12 cells.
The commercially available print-head ejects drops
at a rate of 50 kHz but it was limited to 25 Hz for the
experiment, which had robust drop ejection
technology in which electrical pulses causes the ink
reservoir wall to deflect inward, projecting ink
through the nozzle.
Firstly the PC12 cells were cultured on glass
coverslips. The coverslips were initially cleaned and
treated for providing adhesive layer for the cells.
Experiments were done under 24 hours of seeding,
as the cell adhesion begins to deteriorate after this
time limit. The cell density was noted to be 1 ×
104
𝑐𝑒𝑙𝑙𝑠/𝑐𝑚2
or 50 cells in a visible region
approximately.
Fig-3: Experimental setup, print-head lowered on the
petridish and activity observed from below
Now, the ink jet nozzle were separated by a
distance of about 200 microns, and the nozzle
opening diameter being 20 microns. Drop volume
are in 6 picoliter range, corresponding to drop
diameter of 20 microns. Print-head was arranged in a
three row of 48 nozzle so that it helps in aligning the
nozzle directly over the cells, as shown in the figure-
4. The inkjet cartridges were replaced with syringes
containing fluorescent dye (for alignment) and
neurotransmitter (stimulation). The entire system
was positioned above the inverted microscope as
shown in the figure. Firstly the precise location of the
nozzle was determined using the dye and then the
horizontal position of the nozzle and the microscope
was fixed. Once this is done the glass coverslip
containing PC12 cells was slipped in-between.
Fig-4: SEM image of arrangement of ink-jet print-head
Measurement of bradykinin stimulation was
accomplished by observing changes in intracellular
Ca2+ levels, using fluo-4. The loading solution was
made from fluo-4 reconstituted in DMSO at 1mM,
mixed in Ringer’s solution to a final fluo-4
concentration of 1µM. The coverslips upon which
cells had been seeded were rinsed in Ringer’s
solution, and immersed in loading solution for 20-30
minutes. They were rinsed again and allowed to sit
for additional 30-40 minutes in Ringer’s solution at
room temperature. The stimulating solution was
made of bradykinin at 100µg/ml. Changes in
Florescent levels were observed with an inverted
Fluorescent microscope.
The final proof was demonstrated by a time lapse
fluorescence micrographs of cell stimulation when
the inkjet print-head was activated with a specific
pattern, in this case the letter “A”. Preliminary results
show time dependence of the intensity of the cells.
Experiment is focused in three cells after
stimulations, the first cell excited was directly below
the nozzle, other two being further away from the
nozzle resulting into 1-2 second delay in their
respective excitation. An interesting find was that the
neurotransmitter propagation is pressure dependent
with a spread of about 100 microns per second when
observed with ejection of fluorescent dye from the
nozzle. It was confirmed that the stimulation was
indeed due to bradykinin. The concentration used for
stimulation was 100µM, five order greater than
actually required of 1 1µM, owing to the fact that the
dish was filled with Ringer’s solution with tens of
millimeters, diluting the solution seven times.

4. Fig-5: Before and after images, showing stimulation.
Capture directly below the nozzle.
The power required to run this type of device was
found out to be in the orders of picowatts (10-12
watts). Since available photodiodes generate about
10-9 watts in ambient light, the photodiode can
charge hundreds of such devices, which is very less
compared to electrical stimulation. Though the
materials used in this actual device may not be
compatible, work towards bio-compatible
polyimides and silicon rubbers are underway.
Optically Powered Microactuator for a
Microfluidic Dispenser. [9]
The concept for this microactuator is inspired by
the need of a system that can deliver liquid chemical
neurotransmitter, in contrast with stimulating the
neurons by electrical current, in a retinal prosthesis
for patients suffering from photoreceptor diseases
such as age-related macular degradation (ARMD)
and retinal pigmentosa (RP). The patients affected by
the above mentioned diseases has degenerated retinal
photoreceptor cells which absorb light entering the
eye and produce chemicals that triggers the vision
process. The authors of the research want to
stimulate the neurons in a biomimetic manner, the
usual way in which our vision works.
This system includes a light modulated
microfluidic dispenser for the transmission of liquid
chemical, which is powered by the incoming
irradiation (bright light conditions). The solid state
solar cell is integrated with the actuator which further
decreases the entire size of the device. The solid state
solar cell that is fabricated in the device has a low
efficiency of 16% but it makes it with the feasibility
of fabrication and compatibility with the device and
its requirements. Also the solar cell integration with
the microactuator is accomplished by creating a p-n
doped area in the surrounding solid structure that
provides support to the piezoelectric microactuator
and encloses the dispenser chamber in the center.
Fig-6: Microdispenser array concept
The whole prosthetic device consists of an array of
dispenser units that will transduce visual stimuli into
a 2D- chemical signal that stimulate the surviving
retinal neurons, mimicking physiological stimulation
achieved in synaptic transmission.
The application constraint for the device is 0.5mm
in depth and lateral dimensions are limited to
1cm×1cm. The two array sizes available are 5×5 and
10×10, so the corresponding microdispenser sizes
are 2mm×2mm and 1mm×1mm respectively.
Preliminary calculations indicate that an irradiation
of 3W/m2 power density is required, which is light
reaching the retinal under bright light conditions
naturally. Other important calculation is the liquid
rate that the device must dispense, which is 0.1-1
pl/s. Or simply stated the broad objective of the
device is to tailor the microactuator performance for
dispensing the liquid in the dispenser chamber
through each of the outlet ports at an average rate of
about 1 pl/s when the power density of the input light
irradiance is 3 W/m2. Electric field plots showed a
maximum of 0.42V was generated at this irradiance.
The construction includes a unimorph
piezoelectric microactuator with circular composite
structure comprising of an active piezoelectric (PZT)
layer and a passive silicon diaphragm (PZT layer
being used in two thicknesses 61µm and 65µm). The
following schematic diagram showing the basic
construction and working of the dispenser.

5. Fig-7: Dispenser structure
Fig-8: Dispenser working
The piezoelectric layer is controlled by electrodes
comprising of Ag-Cr and Pt-Ti on top and bottom,
respectively, of PZT as shown in the figure.
Fig-9: 2D cross section showing composite structure
Some of the important snslysis of this ecperiment
includes Finite Element Analysis (FEA) and time
respose of the actuator. FEA results shows excellent
compliance with the analytical analysis, within an
error of 0.5% for pressure and voltage loading cases,
and within an error of 3.5% for the combined loading
case 6 thereby validating the analytical model used
in the design optimization. Time response for the
actuator is another very important factor. Authors
have defined response time as ‘the time period in
which the microactuator moves from its initial
unelected state to its maximum deflected state,’ and
also varies as a complex function of solar-cell
characteristic and the PZT characteristic. The plot
shows the response time vs voltage.
Fig-10: response time vs Voltage
The authors have assumed certain quantities
which were necessary for the development of the
device because of lack of data, such as thin film
properties, solar cell behavior and analytical
modeling of illumination conditions. Still this
device has opened new doors for further prototype
development.
Implantable Micropump for drug delivery in
patients with Diabetic Macular Endema. [10]
Though this paper includes drug delivery in case of
Diabetic Macular Enedema still it has an interesting
actuation mechanism that can be used for AMD.
According to the authors Intravitreal injections
(IVT) drugs such as anti-vascular endothelial
growth factor (VEGF), VEGF trap-eye, and
triamcinolone can now maintain or improve vision
in patients who before did not have treatment.
Patients are now followed and treated in a monthly
basis. This, however, created a burden foe
physician, health system, and patients. Such as poor
compliance, patients who miss the medical
appointments might run the risk of irreversible
vision loss. In addition, the need of multiple
injections over the years increase the incidence of
adverse events (AEs), such as endopthalmitis and
retinal detachments. There are several novel
therapeutic strategies have been pursued in order to
decrease side effects from repeated monthly IVTs,
by using drugs with longer treatment intervals,
sustained drug delivery system, and implantable
drug delivery systems.
The group claims that they have developed
prototypes of Posterior MicroPump Drug Delivery
System (PMP) that demonstrated the delivery of
micro-doses in benchtop tests and long term safety
when implanted in an animal model. Current
engineering benchtop device can continue to
function reliably for more than 100 programmable

6. injections of intraocular drugs including
ranibizumab. At a monthly regime, this could
possibly represent more than 8 years of monthly
IVTs.
Design of initial benchtop version of the
micropump is as follows. Manually and electrically
controlled mini drug pumps were designed,
fabricated, and tested using principles of
microelectromechanical systems (MEMS)
engineering. The manually and electrically
controlled systems share a common layout,
including a refillable drug reservoir and a
transscleral cannula. The reservoir is implanted
subconjunctivally, whereas the cannula is inserted
through an incision into either the anterior or
posterior segment, as shown in diagram.
Fig-11: conjunctiva (a), drug reservoir (b), sclera (c),
cannula (d), and cornea (e).
Dimensions for this mini drug pump were
selected such that the device is easily implanted and
stores enough drug to last several months without
needing a refill. Biocompatible materials (silicone
rubber, Parylene C, and platinum) were used to
construct the prototypes.
The manually controlled pump includes a check
valve (a one-way valve) to control drug delivery.
The pressure-sensitive check valve is located at the
tip of the cannula. It opens only when the internal
reservoir pressure exceeds the check valve cracking
pressure. The valve consists of an orifice sealed
against a valve seat. Beyond the cracking pressure,
the orifice lifts away from the valve seat, creating a
flow path. Once driving pressure is removed, the
orifice seals against the valve seat again to prevent
back flow into the device. The valve opening and
closing is linear from 470 to 2250 mm Hg, and then
it reaches a steady-state value. A new valve has
been designed for integration with the electrically
controlled pump and also includes a high-pressure
shut-off feature (i.e., a bandpass configuration) to
protect against transient pressure spikes.
Once the drug is depleted, the reservoir can be
refilled with the same or a different drug. Both
pump prototypes are refilled through the silicone
rubber reservoir wall; a refill site is not specified.
The ability to refill with a 30-gauge needle while
implanted is a novel characteristic of device that is
achieved by the resealing capability of silicone
rubber. Repeated ability to refill enables prolonged
use of the device for several years. Specifically,
silicone rubber membranes perforated up to 24
times in the same location were leak-tight even
when subjected to a pressure gradient (230 mm Hg).
Electrolysis was used as pumping mechanism
in the next generation of implanted devices.
Implanted batteries or wireless inductive power
transfer can be used to drive electrolysis.
Fig-12: Gas bubble evolution resulting from electrolysis
Benchtop testing showed 2.0 μL/min delivery
using 0.4 mW of power for electrolysis. Flow rate
was conveniently adjusted by varying the applied
current (from 5 μA to 1.25 mA). The flow rate
ranges obtained experimentally were 438 pL/min at
5 μA to 7 μL/min for 1.25 mA. Both data sets were
corrected to compensate for the evaporation of fluid
during testing. Flow rates below 2 μL/min are
recommended for ocular drug delivery. This is
consistent with the natural secretion rate of aqueous
humor from ciliary body in adults (2.4 ± 0.6
μL/min). A 1.0-mA driving current will dispense
250 nL in 2.36 seconds and, for 1.5-mA current, the
pulse time can be set as 1.75 seconds. Surgical
procedures were minimally invasive and well
tolerated. The devices were implanted in about 60
minutes. All implanted devices were biocompatible
and well tolerated during the 6-month follow-up
period. Surgical procedures were minimally
invasive and well tolerated. Transconjunctival
refilling was performed in less than 1 minute

7. without any complications. . No infection or
adverse events were observed, no devices extruded,
no occlusions of cannula were noted.
The use of MEMS technology allows integration
of highly functional electronic and fluidic systems
in biomedical platforms for biomedical applications.
The advantages of MEMS fabrication for producing
miniaturized and efficient drug delivery systems
have already been realized for delivery of insulin
and for delivery of bioactive compounds to neural
tissues. MEMS fabrication allows the device to be
miniaturized to facilitate surgical implantation and
uses materials with a proven biocompatible track
record. To the authours’ knowledge, this is the first
implantable ocular MEMS mini drug pump that is
refillable, enables long-term use, and possesses
broad drug compatibility.

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