TAILORABLE AND DEPLOYABLE TRANS-CORNEAL DRAINAGE DEVICE FABRICATED WITH NANOPOROUS LIQUID CRYSTAL ELASTOMER by ROSS VOLPE B.S. SUNY Environmental Science and Forestry, 2014 A thesis submitted to the Faculty of the Graduate School of the University of Colorado in partial fulfillment Of the requirements of the degree of Masters of Science Bioengineering 2016
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TAILORABLE AND DEPLOYABLE TRANS-CORNEAL DRAINAGE DEVICE
FABRICATED WITH NANOPOROUS LIQUID CRYSTAL ELASTOMER
by
ROSS VOLPE
B.S. SUNY Environmental Science and Forestry, 2014
Trans-corneal drainage is on the forefront of glaucoma device industry interest. It
offers a predictable outflow of AH while avoiding bleb formation and complications
associated with invasive surgery such as scarring and inflammation. Implanting a trans-
corneal drainage device requires minimal surgical skill and is therefore well suited for
treatment of glaucoma in developing countries. There are several additional considerations
when designing a trans-corneal drainage device compared to traditional ab interno devices,
which are not exposed directly to the environment. First of all, the trans-corneal device must
provide a microbial barrier. Secondly, the device must rely solely on its intrinsic drainage
properties to manage IOP – there is no downstream pressure barrier. Lastly, the trans-corneal
device must be secured in place without the use of barbs or sutures as many ab interno
devices are. Fabrication of a trans-corneal drainage device as proposed in this investigation
meets all three of these requirements, as well as offering additional advantages for users and
surgeons.
The first aim of this study was creating tailorable nanofibers via electrospinning. It is
widely reported in literature that electrospinning solution is the most sensitive parameter in
changing the diameters of nanofibers produced(43-46). It was found that by raising the
concentration of PVA (Mowiol 8-88) in the electrospinning solution from 10% to 25%, fibers
from 54 nm to 712 nm could be fabricated, respectively.
Fundamental information about the nature of electrospinning was also gained in this
process. By using two types of PVA, Mowiol 8-88 and Mowiol 10-98, relationships between
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average molecular weight and fiber morphology were observed, as well as relationships
between degree of hydrolysis and solubility of PVA in water. While using 8% w/w
concentrations of both Mowiol 8-88 and Mowiol 10-98, drastically different fiber
morphologies were observed. While solutions of Mowiol 10-98 produced fibers with a
unique, branching and cylindrical morphology, solutions of Mowiol 8-88 produced fibers
with a flattened, ribbon like morphology. As indicated by Tao, J, this was directly related to
the entanglement concentration of the type of PVA used. Mowiol 10-98 would yield an
entangled solution at lower concentrations due to the increased hydrophilic interactions.
These would create stable nanofibers upon electrospinning while the same concentration of
Mowiol 8-88 would produce flattened fibers. This is an important observation because only
unique, cylindrical fibers will be suitable to achieve a drainage device with tailorable,
controllable and predictable outflow.
The relationship between degree of hydrolysis of the PVA and its ability to dissolve
in water was counter intuitive, but allowed fibers of higher diameters to be fabricated when
taken advantage of. The manufacturing of PVA is achieved by hydrolyzing
poly(vinylacetate), a polymer which is not water soluble (Figure 33). Contrary to common
sense, increasing the degree of hydrolysis does not always increase the water solubility. At
Figure 33 – Hydrolysis of poly(vinylacetate) into
poly(vinylalcohol) (1)
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very high (99%) levels of hydrolysis, solid PVA forms very stable crystal structures which
are require heating above 100 oC in water to dissolve. At a lower level of hydrolysis (85%),
the remaining acetate groups act as steric hindrance to tight crystal structure formation and
allow for much easier dissolution of PVA in water at temperature below 100 oC. The
majority of this study was performed with lower hydrolysis Mowiol 8-88 due to its ability to
dissolve at high concentration and thus create a wide range of fiber diameters.
The difference in fiber diameters between the two types of PVA at an electrospinning
solution concentration of 10% can be explained by the difference in surface tension between
the solutions (47). The highly hydrolyzed PVA is more hydrophilic and thus has an increased
surface tension compared to a less hydrophilic polymer solution. This increase in surface
tension alters the Rayleigh instability relationships during splaying of the polymer jet in the
electric field. This alteration causes earlier gelation of the fiber jet as it travels to the
collector, thus increasing the size of fibers collected.
The use of multiple fiber collector geometries allowed manipulation of the fiber array
patterns from randomly oriented to fully aligned. This is advantageous because when used in
device fabrication, these two array patterns will yield very different drainage properties. As
discussed earlier, the Hagan-Poiseuille equation dictates fluid flow through a single pipe. It
states that drainage rate is proportional to the length of this tube. Considering with just one
nanochannel in a 1mm long drainage device, path length fluid will travel if the nanochannel
was formed with unaligned fibers will be much greater than 1mm. However, if an aligned
fiber array is used to fabricate the drainage device, the path length of fluid flow through the
device will be very close to, if not exactly, 1mm. In this study, unaligned fiber arrays were
studied due to their ease of handling compared to unaligned fiber which generally are formed
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between two electrodes (hanging in air) rather than directly on a collector. Future studies
may investigate a manufacturing technique that allows for aligned fibers to be incorporated
into the device.
The use of varying concentrations of PVA solution yielded tailorable and predictable
nanofiber morphologies and topologies. This is the basis of obtaining a viable trans-corneal
drainage device as the size and morphology of the fibers impacts not only the drainage rate,
but the physical barrier to microbes on the surface of the eye. As the average size of corneal
bound microbes is about 1 micron, any concentration of low hydrolysis PVA would be able
to create a physical barrier to microbes if used to fabricate a sacrificial template for a GDD.
Synthesis of LCE was a simple one pot click reaction which required minimal
chemical synthesis skill. Following Yakacki et al, the TAMAP reaction produced and
elastomer which would set within 15-20 minutes of adding catalyst. This was helpful because
the reaction mixture was able to be poured into a mold around PVA nanofibers when it still
had a relatively low viscosity. Therefore the reaction mixture was able to fully penetrate the
nanofiber web before setting.
The change of diameter of the cylinder shown in Figure 27 gives an example of the
shape memory properties of this material. The chemistry used to synthesize these cylinders
can be easily tailored to achieve a thinner initial diameter by decreasing the crosslink density
during the first stage of the reaction. This, however, is at the expense of expansive strength of
the polymer. Outside the scope of this study, but still of significant importance to the final
product, would an investigation of the fixity and relaxation strength of the shape memory
behavior of a cylindrical LCE.
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In this investigation, only the first stage of the reaction was used. This was effective
to observe whether the fiber mesh was being fully infiltrated by LCE monomers. In a second
stage reaction, a cylindrical sample would be stretched lengthwise and cured with a UV light.
Upon heating the sample up to body temperature, the device would expand both lengthwise
and axially (see Figure 11). The strength at which the device locks in place is crucial for
effective placement of the device as IOP swings of around 15 mmHG upon inversion of the
head (48).
Visual confirmation of pores via several modes of imaging showed that once samples
were treated to 48 hours of 60 oC water, or alternatively 30 minutes of sonication and 24
hours of 60 oC water, fibers were able to be dissolved out of the bulk LCE. In addition to
LCE, MMA/DEGDMA was a useful bulk polymer to fabricate test samples. This polymer is
glassy at room temperature, where LCE is quite rubbery. The hardness of MMA/DEGDMA
made it possible to create rigid cylinders which could be reliably superglued into testing
fixtures. Its amorphous nature differs from the LCE polydomain substructure and makes the
MMA/DEGDMA optically clear while the LCE is opaque. This allowed the fluorescent
images to be taken with MMA/DEGDMA (Figure 25) while the cross section SEM images
clearly showed nanopores in the LCE sample (Figure 24). The mechanical and optical
differences not only proved convenient, but the use of two different materials shows the
robustness of the manufacturing process.
The fluorescent image seen on the right side of Figure 25 is a powerful visual which
clearly shows fluid infiltrating the nanochannels. This indicates that fluid would pass through
a drainage device manufactured in the same manner. This image differs from the left side of
Figure 25 because the microscope used to take these images creates 15 micron deep Z-stacks
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starting from the bottom of the sample. When imaging a 1mm thick sample, the camera only
captures the bottom most fibers in the sample. The 80 micron thick sample shows many more
fibers within the 15 micron deep window that was available to image. These images show
that fluid may be easily infiltrated into the nanochannels created after dissolution of
nanofibers embedded in a shape memory polymer.
To prove without a doubt that fluid may pass through a nanoporous drainage device
fabricated with an electrospun sacrificial template, water column perfusion tests were
performed with several indicators and a variety of test fixtures.
The first perfusion test involved supergluing a porous MMA/DEGDMA cylindrical
sample into the tip of a pipette. This was a delicate process that required glue around the
entire edge of the pipette tip while not allowing any glue to touch the flat top or bottom
surfaces of the sample as the leave the channels clear. Once the sample was secured and
sealed into the tip of the pipette and the pipette was filled with a colored dye, the tip of the
filter was dipped into a collection bath to wait for colored dye to perfuse the sample.
Encouraging results were obtained from these tests, with an indicator dye appearing to
perfuse through the nanochannels into a collection bath. While using a control sample
containing no pores, dye was not able to perfuse into the collection vial, proving a robust seal
around the cylinder.
The two other perfusion set ups also showed qualitative perfusion, with visual
confirmation being the indication of a positive result. In the future, a more elaborate
perfusion setup would be needed to quantify the flow rate at a given pressure. A
programmable syringe pump would be needed to obtain these results, such as Pump 11 Plus
by Harvard Apparatus.
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CHAPTER V
CONCLUSION
The purpose of this investigation was to create a manufacturing technique for a
tailorable trans-corneal glaucoma drainage device using a sacrificial nanofiber template
within a shape switchable liquid crystal elastomer. After fabrication of an electrospinning
power unit, several concentrations of poly(vinylalcohol) were used to create sacrificial
nanofiber templates on flat plate and wire collectors. SEM images of these arrays showed
various morphologies and topologies of the fibers, including randomly oriented and highly
aligned. The diameters of the fibers produced varied from around 50 nm to 750 nm, which
once dissolved out of a bulk polymer yielded nanochannels of the same diameter. It was
shown in imaging and perfusion tests that not only could these nanochannels be infiltrated
with a liquid, a fluid may pass through them in a controlled fashion.
There is one instance in the literature published by Bellan et al which uses sacrificial
electrospun nanofibers as a template for nanochannels in a bulk polymer (38). The current
study expands on this in several ways. While Bellan et al focus on creating these channels in
a poly(dimethylsiloxane), or PDMS, substrate, the current study uses a functional shape
memory elastomer. This implies greater potential for end usage of such a device including,
but not limited to, a trans-corneal glaucoma drainage device. Additionally, the study
performed by Bellan et al did not deeply explore the relationships between electrospun fiber
morphology and the various electrospinning parameters such as solution concentration.
These relationships play a key role in the tunable nature of such a device, especially
considering the Hagen-Pouseuille equation which dictates flow as a function of channel
diameter to the fourth power.
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There were limitations throughout this study that, if alleviated, would allow the
proper qualification of this transcorneal drainage device. Of particular importance is the
perfusion testing. These tests were designed to indicate a binary result – did the fluid pass
through or not. There was little means of measuring exact flow through test fixtures using the
low-tech solutions that were obtained for little to no cost. As a result, there was no way to
quantify the drainage rate of a trans-corneal filter containing convoluted and tortuous
nanochannels paths. As indicated previously, the Hagen-Pouseuille equation gives the
relationship between flow, pressure, and channel diameter. Another equation would better
suit this scenario if such quantifiable drainage information was available. The Darcy equation
relates flow and pressure inside a porous medium. The tortuous nature of the nanochannels
create a scenario that mimics a porous medium closer than a group of pipes. The Darcy
equation contains a K factor, which is derived from perfusion data. If an advanced perfusion
set-up (Pump 11 Plus, Harvard Apparatus) was available, a quantifiable relationship between
PVA solution concentration used in electrospinning and drainage rate of a trans-corneal
device could be derived.
Another limitation of the study was time. Aligned fiber arrays may prove necessary in
future studies if the drainage rates of filter devices using randomly oriented fiber arrays
proved too slow. Because of the different nature of aligned fibers (which collect between to
grounded units opposed to directly on a collector), separate manufacturing technique as well
as manufacturing fixtures must still be designed.
Lowering IOP in patients with glaucoma remains the cornerstone of limiting risk of
vision loss, and while there are many approaches to this, no current strategy is without
complications. This study proposed a unique solution to replace the gold standard both in
surgical and drainage device treatments of Glaucoma. A trans-corneal device which is
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replaceable, tunable and easily deployed into patients has the potential to greatly reduce the
number of those who lose their vision from the disease. It will especially make an impact in
areas of the world where ophthalmic surgeons and surgical arenas are not readily available.
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