Detailed_Design_Report (final)

BMEN90017
Biomedical Engineering Design Report
Department of
Biomedical Engineering
Detailed Design Report
Current Propagation of Electrical Pulses From An Electrode in Nerve Tissue
Keith Tan November 2014

BMEN90017 Detailed Design
Report
November 2014
Detailed Design Report
Current Propagation of Electrical Pulses From An Electrode in Nerve Tissue
Keith Tan
University of Melbourne
Department of Biomedical Engineering
Prepared for The University of Melbourne
BMEN90017 Biomedical Engineering Design Report

BMEN90017 Detailed Design Report ii
Table of Contents
Figures and Tables............................................................................................... iii
Executive Summary .............................................................................................. 1
1 Technical Design Task ..................................................................................... 2
1.1 Introduction........................................................................................... 2
1.2 Methods................................................................................................ 3
1.3 Results ................................................................................................. 6
1.4 Discussions ............................................................................................ 9
2 TGA and FDA Approvals................................................................................ 11
2.1 Standards ............................................................................................. 11
2.2 Overview of TGA Approval...................................................................... 11
2.3 Overview of FDA Approval ...................................................................... 11
2.4 Steps to Market ..................................................................................... 13
2.5 Classifications ....................................................................................... 14
2.6 Preclinical and Clinical Trials ................................................................... 14
2.7 Risk Assessment .................................................................................... 15
3 Intellectual Property ...................................................................................... 17
4 Costing and Economic Analysis ........................................................................ 20
4.1 Overall Price of Hyperbate....................................................................... 20
4.2 Economic Savings and Hyperbate Viability ................................................. 23
5 Conclusions and Recommendations.................................................................... 26
References.......................................................................................................... 27

BMEN90017 Detailed Design Report iii
Figures and Tables
Figures
Figure 1. 3D model representation of Hyperbate electrode cuff around a nerve tissue -
(a) front view, (b) top view, and (c) side view. ........................................................... 4
Figure 2. Mesh of entire model. ............................................................................... 5
Figure 3. Electric potential of tissue component and current density distribution from
electrodes to nerve tissue when all active electrodes were activated. ................................ 7
Figure 4. Electric potential of tissue component and current density distribution from
electrodes to nerve tissue when two electrodes positioned side by side are activated............ 8
Figure 5. Fascicular distribution used in model. .......................................................... 9
Figure 6. Waterfall diagram of product realisation process. (Brawn, 2014) ...................... 13
Figure 7. Flowchart leading to the total cost of Hyperbate. Due to some missing cost
information such as the cost to manufacture platinum and/or parylene, initial costing is
based on total cost of cochlear implant as most materials used are similar. Moving down
the flowchart, the cost increases by a certain percentage as listed. Manufacturing and
training increases were estimated based on complication of device design. Patent costs and
cost associated with premarket approval are also incorporated into the manufacturing and
training cost increase. Hospital related increases are based on the average risk adjusted
Medicare payments compiled in (Birkmeyer et al., 2012). As no surgical cost was shown
for implantation of a neural cuff, costs are based on the closest surgery type listed, CABG. 22
Figure 8. QALY chart comparing the quality of life among patients who had received
Hyperbate implantation, patients with Hyperbate complications and patients who did not
receive Hyperbate treatment. ’A’ is the area between the blue and yellow graph, showing
the amount of QALY that is gained as a result of Hyperbate treatment. Similarly, area
’B’ is the area between the orange and yellow graph and shows QALY that is gained as
well. ’C’ is the area between orange and yellow; grey and yellow, showing the initial loss
of QALY due to complications associated with Hyperbate treatment, with and without
continued usage of device respectively. ..................................................................... 24
Tables
Table 1. Material conductivity used in model ............................................................. 3
Table 2. Life-cycle approach to the regulation of a medical device ................................. 12
Table 3. Steps to obtain FDA approval .................................................................... 13
Table 4. Risk assessment of device .......................................................................... 16
Table 5. Previous patents for hypertension control devices ........................................... 19
Table 6. ICER of Hyperbate and health programs. The cost of health program is based on
the ’know your health program’ and is adjusted to give a cost per day (del, 2013). Values
were determined based on the assumption that the increased lifespan due to Hyperbate
and health program treatment was 5 and 2 years respectively. The increased QALY due
to these treatments were also estimated to be 0.3 for Hyperbate and 0.1 for health program. 25

BMEN90017 Detailed Design Report iv

BMEN90017 Detailed Design Report 1
Executive Summary
Hypertension is one of the leading cost of mortality and costs the working industry
an approximate $861 million dollars annually. Of the individuals who has hyper-tension,
30% - 40% have resistant hypertension and require non-pharmacological
interventions. Hence, an implantable device which controls blood pressure is
developed.
The proposed device has several modules that interact with each other, and
follows cochlear implant design where possible. The goal is to provide a system
that uses a feedback loop with the body’s baroreflex to control blood pressure.
This is achieved by the components that make up the device.
The power circuitry includes internal and external coils and batteries to provide
power to the internal circuitry. The internal battery is rechargable and therefore
the external components will only need to be worn during charging; otherwise
the device is fully functional without external components.
Internally, there is a processor that interacts with a blood pressure sensor and
electrode array to simultaneously measure and regulate blood pressure. The
sensor is a silicone cuff around the common carotid artery that measures blood
pressure using a capacitance. A platinum electrode array interfaces with the
vagus and glossopharyngeal nerve and stimulation activates when blood pressure
is over a certain threshold. Patient exercise is also considered and the device will
not stimulate when exercise is detected by the system. The device will enter an
inactive mode once stimulation has occurred for two days, avoiding unnecessary
stimulation and conserving power, and wait to activate again at a later time by
periodically assessing blood pressure.
Physiological parameters (blood pressure, heart rate) are taken before implan-tation.
During implantation, the sensor is calibrated by comparing it against
another measure of blood pressure. The electrode array is selectively stimulated
to determine the electrode configuration to maximise baroreflex response while
minimising other parasympathetic effects; to determine the stimulation current;
and to verify that the sensor is implanted and calibrated correctly. All these
parameters are used to provide a customised stimulation strategy for the patient.

1 Technical Design Task
1.1 Introduction
In recent years, neural prosthesis has garnered the interest of many as they are
able to restore sensory and motor function through neural stimulation. Addition-ally,
studies which manipulates artificial stimulation of the nerve and/or neural
pathway have been underway to treat neuronal diseases such as epilepsy, Parkin-son’s,
and resistant hypertension (Chapin and Moxon, 2000). These stimulation
are achieved through electrode placement within or around a region of interest,
termed invasive and transcutaneous stimulation respectively (Badia et al., 2011;
Sluka and Walsh, 2003). The effectiveness of these stimulation on evoking an
action potential is dependent on the electric field generated, which in turn is
dependent on electrode design, tissue properties, the distance of the electrode
to excitable tissue and the distribution of cathodes and anodes (McIntyre et al.,
2004; Tehovnik, 1996; Butson and McIntyre, 2005). In terms of electrode design,
the larger the surface area of the electrode, the lower the magnitude of current
density, which is defined as the current divided by the area of a sphere (Tehovnik,
1996; McIntyre and Grill, 2001). This relationship is also used to determine the
intensity of current with varying distances of electrode from target tissue. For a
constant current, the further apart the electrode, the smaller the current density
(Tehovnik, 1996). Hence more current is needed to evoke activation of axons.
Tissue properties of interest such as size greatly affects current magnitude. As
reported by (Grinberg et al., 2008), the thicker the perineum, the higher the re-sistance,
and thus the conductivity of current in this tissue is reduced. Similarly,
fascicle thickness, which is related to perineum thickness also lowers conductivity
of current with increased thickness. As there are different fascicles with vary-ing
thickness bundled together in a nerve tissue, the separation distance among
these fascicles also affect the excitability of axons (Grinberg et al., 2008). For
example, when two fascicles with varying sizes are bundled close together, the
activation threshold for a target fascicle either decreases or increases. This is
due to the property that current flows along the path of least resistance. If the
target fascicle is thick in size and has a smaller sized neighbour fascicle, then
activation threshold is said to decrease as the current path has changed and now
flows along the neighbouring fascicle. The reverse also holds true. Therefore,
this results in activation of the wrong bundle of axons, resulting in a different
functional response (Grinberg et al., 2008; Gustafson et al., 2009). It is for this

same reason that placement of anodes and cathodes are important for artificial
stimulation of selected nerves (Butson and McIntyre, 2005).
In a separate report, an electrode cuff designed for the treatment of resistant
hypertension was documented. However its efficacy was not tested. As such, this
project aims to determine this. In particular, the current spread from the elec-trodes
to target tissue based on nerve tissue conductivity, and selective activation
of cathodes and anodes will be investigated. The effect of overlapping currents
and the resulting magnitude of extracellular potential will also be looked into. If
the effect did occur, appropriate changes will be made to the design to minimise
neural damage caused by over-stimulation.
1.2 Methods
A 3D reconstruction of Hyperbate electrode cuff was reconstructed in COMSOL
(Comsol Multiphysics 4.4) and shown in Figure 1. The model consists of 12
fascicles randomly distributed within a nerve with varying radius in the range
of 100 - 400m. The perineurium was set to range from 70 - 370m, thus hav-ing
a constant perineurium thickness of 30m. The nerve was modeled as an
epineurium. The conductivity of these materials were defined as shown in Ta-ble
1 below. These values are based on the ones described by (Grinberg et al.,
2008; Xiong et al., 2014). The electrodes were modeled as rectangular blocks
with a height of 2mm, width of 1.125mm, and a length of 1.2mm, spaced apart
by 2.79mm and spread along the entire length of the cuff. Each proceeding elec-trode
were also rotated by 40 to ensure that the electrodes spiral around the
nerve like an S-shape. Once done, the model was meshed and is shown in Fig-ure
2. Different components were meshed separately depending on geometry and
region to optimise computation efficiency. For example, the parylene component
was meshed with a courser dimensions of tetrahedral compared to the fascicles
and perineurium. This is also because the parylene component does not play
an important part in the analysis of the study. Conversely, the electrodes, fasci-cles,
perineurium were meshed to a finer extend as the results revolves aroud the
current distribution along these components.
Material Conductivity (S/m)
Perineurium 2.1e3
Fascicle 5.7e1
Epineurium 8.2e2
Parylene 1e30
Table 1. Material conductivity used in model

Figure 1. 3D model representation of Hyperbate electrode cuff around a nerve tissue - (a) front
view, (b) top view, and (c) side view.

Figure 2. Mesh of entire model.
The Physics that was used in the COMSOL simulation was Electric Current
and is used to determine the current density spread from source to target. The
equations used within this physics module are based on Maxwell’s equations as
well as Ohm’s law and are expressed as:
J = E + Je (1)
r J = r (rV Je) = 0 (2)
r (rV Je) = Qj (3)
where J is the current density, is the conductivity, E is the electric field, Je
is the externally generated current density, and Qj is the collection of current
sources (Comsol, 2013; Griffiths and College, 1999). In this model, there are no
externally generated current densities, hence Je can be removed from equations
(1-3). Equation (2) is the continuity law and can be rearranged to determine
the various current sources as specified in equation (3), which is similar to the
one used in (Butson and McIntyre, 2005). It is important to note that the above
equations are only accurate for modeling electric currents in steady-state. A 1V
voltage source was specified for all 8 active electrodes while the return was set
to ground. The parylene component was set as an electrical insulator. The time
step for the analysis was from 1-10ms with a step increase of 0.125ms. To simplify
the analysis, relative permittivity of all components were left at the default value
of 1. Besides that, as only the current spread from the electrode to nerve is
studied, the propagation nature of currents along axons were ignored. Instead, it
was assumed that the electrodes are aligned with the nodes of ranvier, and that a
voltage threshold along the fascicles was used to determine the selective activation

of axons. Any surface potential above 0.6V is considered to be activated in this
case.
1.3 Results
Figures 3 and 4 shows the electrical potential distribution from the surface of
the electrodes to surfaces of target tissue. The streamlines represent the flow of
current densities from active to ground electrodes through the fascicles. In Figure
3, when all electrodes are activated, the majority of the fascicles are activated
except the region where it is close to the ground electrode. In Figure 4, when
only 2 active electrodes and the ground is activated, it is shown that currents
densities were able to spread to the middle fascicle centered at (0,0,0), though
the electrical potential this translates to is only 0.4V. Furthermore, when only
side electrodes are activated, the 3 bottom most fascicles when looking from the
xy-axis was not successfully activated. No overlapping currents were observed
when 2 electrodes placed side by side are activated. It was also observed that
the surface potential is at its strongest (0.8-0.1V) directly under the electrode,
and gradually decreases to a range of 0.5-0.7V, when measured 1 fascicle away
from the fascicle that is directly under the electrode. If the middle fascicle is the
target, at least two electrodes, placed 90-120 apart needs to be activated.

Figure 3. Electric potential of tissue component and current density distribution from electrodes
to nerve tissue when all active electrodes were activated.

Figure 4. Electric potential of tissue component and current density distribution from electrodes
to nerve tissue when two electrodes positioned side by side are activated.

Figure 5. Fascicular distribution used in model.
1.4 Discussions
Based on the results obtained, the idea to position the electrodes as depicted is
justified. This is because different electrodes at different positions are responsible
for activating different axons as shown in Figure 4. Additionally, due to the fact
that selective stimulation is required and that manual determination of which
electrodes to activate is done to produced desired functional response, having
electrodes which are spaced far enough to prevent overlapping of currents and
is capable of stimulating any desired fascicle within the nerve is advantages.
Although, another electrode will be introduced and placed right beside the return
electrode such that stimulation of fascicles that are close to the return electrode
is possible. Current hopping, where inter-fascicular distance needs to be within
the physiological range of 9547m in order for it to occur, described in (Grinberg
et al., 2008) was not observed in this analysis. This is mostly due to the fact
that the fascicles are spaced further apart compared to realistic nerve geometries.
The only fascicles that are within this range are shown in Figure 5. Even then,
as they are positioned further apart from the electrode at the cuff surface, the
voltages and current density was not strong enough to spread into the middle
region, hence current hopping did not occur.

It is important to note that the results in this paper can only be used as an
estimation of how and where to position the electrodes. It cannot be used to
determine the amount of current or voltage to introduce to the system in order
to determine the degree of activation of fascicles in the nerve. In order to deter-mine
this, and to provide a more accurate representation of the current spread
within the tissue environment, the cable model developed by (Grinberg et al.,
2008; Butson and McIntyre, 2005; McNeal, 1976) needs to be incorporated. This
uses the Hodgkin-Huxley model, which takes into account parameters such as
membrane capacitance, voltage, and current as well as concentrations of ions
that contribute to action potentials to determine the activity of axons (McNeal,
1976). With this, realistic representation of current propagation along axons can
be determined. Additionally, stimulation parameters such as pulse width, dura-tion
and magnitude of stimulation can all be computed to determine the correct
settings to evoke action potential without causing any harm.
Even though the cuff designed for Hyperbate uses current controlled stimulation,
it was switched to voltage controlled as specifying current injection boundaries in
COMSOL resulted in the simulation going in an infinite loop, leading to failure
of obtaining a convergence value. Regardless, this does not cause a significant
change in current spread as equations (1-3) can be rearranged to solve for different
parameters, depending on which is specified. 1V was used in the simulation to
give prominent illustrations of the current spread. In reality, the actual range
of current to be introduced into system is around 1A, which translates into a
voltage value that is significantly less than 1V (Khodaparast et al., 2014; Hays
et al., 2014; Clark et al., 1999). This needs to be changed to produce accurate
results. This, and the inclusion of the cable model can be done as future work to
improve the model.

2 TGA and FDA Approvals
Certain regulatory requirements must be met before medical devices can enter
the market. The Therapeutic Goods Administration (TGA) in Australia and
the Food and Drug Administration (FDA) in the U.S. are responsible for these
requirements. It is desired for Hyperbate to be approved in both countries, as
this expands the market into which the device can enter.
Both regulatory bodies will be discussed separately in this report, but there are
many overlaps in the approval process and will be mentioned together. Figure
6 shows the waterfall product realisation process, utilized in general for develop-ment
of medical device. After a prototype has been manufactured, a pilot clinical
study should be conducted, followed by manufacturing transfer and clinical trials
to verify that design requirements are satisfied. Related regulatory files are then
submitted. When the device is approved by the TGA and FDA and is validated
to meet users’ needs, the product can enter the market and large scale production
can occur.
2.1 Standards
The device needs to meet the following relevant standards, applicable for both
the TGA and FDA:
• ISO 14971 Application of risk management to medical devices
• ISO 13485 Quality management systems: Requirements for regulatory pur-poses
• ISO 60601 Medical electrical equipment
2.2 Overview of TGA Approval
There is existing TGA approval for the cochlear implant, meaning the device as
well as the surgical procedure is easier to obtain approval for Valencia (2013).
These are summarised in Table 2 below.
2.3 Overview of FDA Approval
The FDA’s regulatory requirements for medical device approval are based on
the classification of the medical device. These are based off the FDC (food,

Stage Required regulatory action
Concept Consider the Essential Principles in Australian Regulatory
Guidelines for Medical Devices (ARGMD, Version 1.1, pp.
39) (Therapeutic Goods Administration, 2011).
Prototype Incorporate the Essential Principles into the design
Preclinical Seek approval from or notify the TGA of intention to com-mence
clinical trial
Clinical Follow clinical trial guidelines, Prepare clinical evaluation
of clinical data
Manufacturing Apply conformity assessment,procedures and then obtain
appropriate conformity assessment evidence
Marketing Adhere to the Therapeutic Goods Advertising Code
(TGAC)
Supply Apply to include the device in the Australian Register of
Therapeutic Goods (ARTG) (TGA, 2013); Monitor safety
and performance of the device during its lifetime; Maintain
conformity assessment evidence; Report any problems with
the,device to the TGA and to the users of the device, Recall
and/or correct devices that have defects, design flaws, or
unacceptable clinical risks or levels of performance
Obsolescence Notify the TGA so the device can be removed from the
ARTG
Table 2. Life-cycle approach to the regulation of a medical device

Figure 6. Waterfall diagram of product realisation process. (Brawn, 2014)
drug and cosmetics) Act; medical devices contained within chapter V of the Act.
Classification is the responsibility of the device developer.
Steps Description
Step 1 Classify your device
Step 2 Choose the correct premarket submission
Step 3 Prepare the appropriate information for your premarket,submission
to the FDA
Step 4 Send your premarket submission to the FDA and interact with FDA
staff during Review
Step 5 Complete the establishment registration and device listing
Table 3. Steps to obtain FDA approval
2.4 Steps to Market
Most of the steps mentioned in the above tables can be found in the respective
TGA or FDA websites. However, aspects that require consideration from the
device developers are focused on in this report. Therefore, for market approval,
the focus is on classification, pre-clinical and clinical trials and risk management.

2.5 Classifications
TGA: According to Australian Regulatory Guidelines for Medical Devices (ARGMD,
Version 1.1) Rule 5.7(1) and (2), the device should be classified as Class AIMD
since it is an active implantable medical device. The electrode leads associated
with sensors and processors belongs to Class III.
FDA: Hyperbate is classified as Class III (high risk), as it is implanted and similar
devices like the cochlear implant are class III (Food and Administration, 2014).
Class III devices require premarket approval; class I do not require FDA approval,
and Class II only require FDA premarket notification and clearance. In addition,
general controls are required for all medical devices in the approval process (FDA,
2014a).
2.6 Preclinical and Clinical Trials
TGA: The TGA conducts all clinical trials via the Clinical Trial Notification
(CTN) or the Clinical Trial Exemption (CTX) scheme. Ethics is regulated by
the National Health and Medical Research Council (NHMRC), Australian Health
Ethics Committee (AHEC) and a Human Research Ethics Committee (HREC).
The Clinical Trial Notification scheme is applicable for Hyperbate as the com-bination
of existing components as a new function requires clinical trials (TGA,
2014; Frauman, 2013).
FDA: Results from non-clinical and clinical trials, termed data requirements, are
submitted with the Pre-Market Approval. The data requirements are stated to
require in depth technical sections as deemed necessary by the device developer
(FDA, 2014b).
In general, the requirements from the TGA and FDA are quite self-directed, and
with adequate tests and documentation should allow the device to be approved.
The advantage of Hyperbate is that most components have gone through at least
some pre-clinical or clinical trials already. The pre-clinical trials that are to
be conducted in terms of toxicology, immunogenicity, carcinogenicity and other
material testing should be straightforward, as the materials used have all been
shown to be biocompatible for at least the device’s lifespan of 5 years (see Device
Development Report for details). Main additional testing would be hermeticity
testing, as some of the connections and enclosures are novel, as well as the use of
the Zylon leads (Lobodzinski and Laks, 2009). The main tests to be conducted
are animal trials, and consequently, human trials, on the functional aspect of the
device. The main functional or psychophysical measure is whether the barore-ceptor
reflex and its resetting phenomenon match that of simulated results. Side
effects of stimulation on the entire physiology of the animal require examination,

as well as any long term effects such as damage to the nerve or alteration of
the baroreceptor response. Following the results from animal trials, ethics for
human trials should be obtainable. Ethical considerations mainly encompass the
Informed Consent documentation given to clinical trial subjects. The major is-sue
is with the amount of detail to include in the report, with too little being
dangerous or uninformative and too much being cumbersome or confusing for
participants. In this case as with any other Informed Consent, consultation with
relevant medical and legal professionals is highly recommended (Frauman, 2013).
2.7 Risk Assessment
A brief risk assessment has been performed for the device, which includes an
attempt at reducing the risk, in accordance with ISO 14791 (ISO 14791). This
documentation is essential for regulatory approval.

Hazard Identifi-cation
Risk Level Mitigation Strat-egy
Residual Risk
Surgery Low to high Consult surgeon Low to high
Breakdown of
Likelihood is
blood pressure
medium, conse-quences
sensor
are major
to catastrophic -
high risk
Implement feed-back
system that
detects if the sen-sor
is failing; test
for sensor lifespan
during animal
testing
Moderate (Feed-back
system most
likely necessary)
Flat battery Likely, with moder-ate
to catastrophic
risk to patient -
high risk
Feedback system
might fail if inter-nal
battery fails,
therefore check
blood pressure
manually
Low (Routine
non-invasive blood
pressure checks, or
feedback system
failure as indicator)
Leakage of en-closure
Rare, with moder-ate
to major conse-quences
- medium
to significant risk
Possibly alter de-sign
to include
additional circuits
that detect leak-age;
integrate with
feedback system
Low (requires
detection then
replacement)
Stimulation:
adverse physi-ological
effects
as seen in vagus
nerve stimula-tors
(Sackeim
et al., 2001;
Ben-Menachem,
2001)
Low in articles ref-erenced
(voice al-teration
or hoarse-ness),
with poten-tial
to be high
Stimulating cuff
is selective fitting
of patients during
implantation only
stimulates regions
associated with
baroreflex
Unlikely with
minor to moder-ate
consequences
(hopefully,severe
consequences are
eliminated with
fitting) - moder-ate
risk, requires
consultation with
medical profes-sional
Stimulation:
physical damage
as seen in neural
stimulation (Mc-
Creery et al.,
1992)
Moderate like-lihood,
major
consequences
(damage to,nerve)-
high risk
Lower stimulation
frequency should
allow for less
charge to be passed
through
Low
Table 4. Risk assessment of device

3 Intellectual Property
Intellectual property (IP) is an important step in the commercialisation process of
a new product. Patents are a way of obtaining an exclusive competitive advantage
for a new invention. In order to obtain a patent for a product/device as a whole,
the invention must be novel. This requires that it has not been published by
someone else, has not been published by the inventor, has not been presented at
a conference and has not been disclosed to anyone outside the university. The IP
situation of the Hyperbate device with respect to the specified components and
the system as a whole will be discussed in this section.
The internal battery, model QL0130I-A from Quallion, is a Category 1 Product
according to the manufacturer, which means it is one of the Seller’s standard
commercial products. Therefore, the battery is free from any rightful claim for
infringement of any U.S. registered patents and trademarks from a third party,
once delivered to the buyer. The external battery, which will be used to charge
the internal battery, is the PowerOne Implant Plus. This component is not an
integrated component of the system, and therefore the Hyperbate device does
not depend on it. Regardless, IP will be discussed with the manufacturer of the
PowerOne Implant Plus. Future improvements on the Hyperbate device may
render battery recharging unnecessary, if the chosen internal battery lasts, for
instance, for 20 years.
The main circuit components of the external module are power circuitry and an
external processor. The power circuitry will convert the voltage and current of
the external batteries to a suitable voltage and current for recharging the internal
battery. The specific components in the external module which have been chosen
and documented in the Device Development Report are the TPS61251 boost
converter and the UC2577-ADJ step-up voltage regulator from Texas Instruments
(TI). It is very likely that more components will be sourced from TI. The policy
of TI is, TI does not warrant or represent that any license, either express or
implied, is granted under any patent right, copyright, mask work right, or other
intellectual property right relating to any combination, machine, or process in
which TI components or services are used.. Therefore, after the development of
the prototype or model of the Hyperbate, our team will contact Texas Instruments
and discuss if a license is needed for using their step-up voltage regulator and
boost converter for the purpose of our device.

A major component of the Hyperbate is the internal processor. The Altera Cy-clone
V FPGA was proposed to be used as the internal processor in the Device
Development Report. The Altera Cyclone V FPGA uses software called Quartus
II. The Altera online site does not state that Quartus II requires the user to obtain
a license to use it. Regarding the algorithms that will need to be programmed on
the Cyclone FPGA, Altera provides a system that helps the developer verify and
obtain IP for the algorithms (Altera Corporation, 2014). Moreover, the Cyclone
V Device Datasheet does not state that licensing is required for the Cyclone V
as hardware (Altera, 2014).
Another component category in the Hyperbate is leads. It has been proposed
to manufacture the conductive material from Zylon-AS and the enclosure from
Parylene C. Zylon-AS as a material has a trademark (Nielson, 2006). However
the process described in Lobodzinski and Laks, which uses Zylon and Parylene
C, does not have a patent (Lobodzinski and Laks, 2009). Therefore, the usage of
Zylon-AS merely requires consultation with the current company that produces
Zylon-AS, which is Toyobo Corporation.
Other components of the Hyperbate device cannot be patented. The concept of
the signal and power wireless transmission system has been published previously
in the literature (Kiani and Ghovanloo, 2010). Moreover, the concepts of the
electrodes and sensor have been published (Bingger et al., 2012; Loeb and Peck,
1996). Therefore, the aforementioned components cannot be patented.
In the case of deciding to patent the Hyperbate device after the IP evaluation,
the idea of controlling hypertension via neural stimulation will not be patented.
Moreover, the overall purpose of the device cannot be patented; several patents
for hypertension control (Table 5). However, more specifically, it is recommended
that the targeting of the Vagus and Glossopharyngeal nerves as a combination of
nerves, while also sensing blood pressure at the Common Carotid artery should
be patented. There are existing patents, which specifically state which nerves will
be stimulated, such as patent US 5707400 A, US 6393324 B2 and US 5700282 A
(Table 5). However, the nerves which the patents propose to stimulate are not
the Vagus and Glossopharyngeal nerves as a combination. The creators of the
Hyperbate recommend the patenting of the device, although the cost of producing
a model or a prototype must be taken into consideration. Producing a prototype
may be more costly than producing the commercial product itself.

Patent Code Patent Title
US 5707400 A (reference) Treating refractory hypertension by nerve stimu-lation
US 6393324 B2 (reference) Method of blood pressure moderation
US 5700282 A (reference) Heart rhythm stabilization using a neurocyber-netic
prosthesis
Table 5. Previous patents for hypertension control devices

4 Costing and Economic Analysis
4.1 Overall Price of Hyperbate
The total cost of Hyperbate is approximately $52,000, and includes surgical,
post-operative care, and maintenance cost. This value is 30% more compared
to cochlear implants, priced at $40,000. The reason for the dramatic increase in
pricing is due to (i) non-standardise manufacturing techniques, (ii) high confor-mance
cost, (iii) low hospital and surgeon volume, (iv) high risk associated with
surgery, and (v) high maintenance cost.
As Hyperbate uses designs that are still new, there have yet to be a manufacturing
site/company that is able to produce the parts necessary to produce the device.
For the same reason, only a few devices are planned for production to determine
its efficacy by first conducting post market analysis. As such, capabilities needs to
be created within the company, and according to (Barney, 2012), this process is
very costly. The majority of the manufacturing cost goes to training of employees
such that they are capable of producing the desired product. Another portion
of this cost goes to conformance costs. These include the cost associated with
manufacturing a product with high quality, and increases exponentially with
increasing quality (Yasin et al., 1999). Since Hyperbate is an active implantable
medical device, not ensuring the quality might lead to adverse effects or even
death. The cost to repair these damages is very high and might cause the company
to lose its reputation, ultimately reducing the viability of the device (Yasin et al.,
1999). Thus, the non-standardise manufacturing nature of Hyperbate and high
conformance cost are some of the factors which causes the increase in price.
Hospital and surgical volume is defined as the number of procedures that the
hospital or surgeon undertakes. For example, within a month, a hospital might
accept patients that needs to undergo coronary artery bypass grafting (CABG).
The higher the number of patients, the higher the hospital volume. This also
translates to a higher volume of patients that the surgeon operates on, hence
higher surgeon volume. An increase in these volumes will lead to a reduce in hos-pital
cost due to lowered complications and excellent management of resources
(Ho and Aloia, 2008; Birkmeyer et al., 2012). Since there is only one other im-plantable
blood pressure control device (Rheos®) that is currently in the market
(Ng et al., 2011), the hospital and surgeon volume is low. Moreover, as surgeons
are required to manually determine which combination of electrode stimulation
from the electrode cuff produces the best functional response, the risk and ac-

companying complications associated with this is high. According to (Birkmeyer
et al., 2012), these complications can cost up to $10,000. Therefore, these cost
also contribute to the increased pricing of Hyperbate.
The high maintenance cost of Hyperbate also contributes to the increased pricing.
This is because the device is the first of its kind to be introduced into the market.
Post market analysis still needs to be done and thus the patient is required to
return for routine checkups to ensure negative side effects such as allergic reac-tions
to material(s) is minimised. If there are indeed adverse effects to health
due to Hyperbate, readmission and undergoing surgery is necessary. The fur-ther
increased complications of the surgery and prolonged stay in hospitals adds
onto the overall cost of the device (Ho and Aloia, 2008; Birkmeyer et al., 2012).
The overall costing due to the above mentioned factors are summarised in the
flowchart in Figure 7.

Figure 7. Flowchart leading to the total cost of Hyperbate. Due to some missing cost infor-mation
such as the cost to manufacture platinum and/or parylene, initial costing is based on
total cost of cochlear implant as most materials used are similar. Moving down the flowchart,
the cost increases by a certain percentage as listed. Manufacturing and training increases
were estimated based on complication of device design. Patent costs and cost associated with
premarket approval are also incorporated into the manufacturing and training cost increase.
Hospital related increases are based on the average risk adjusted Medicare payments compiled
in (Birkmeyer et al., 2012). As no surgical cost was shown for implantation of a neural cuff,
costs are based on the closest surgery type listed, CABG.

4.2 Economic Savings and Hyperbate Viability
The savings that Hyperbate can offer to individuals and the economy is measured
in terms of quality-adjusted life years (QALY) (Vergel and Sculpher, 2008). The
QALY is then used in an incremental cost-effectiveness ratio (ICER) to determine
the viability of the device. QALY is measured from a scale of 0 to 1, with 1 being
the patient experiencing the best health state possible (Vergel and Sculpher,
2008). Assuming that only 1000 devices were manufactured and all of them were
implanted, further assumptions based on the different pathways shown in the
flowchart of Figure 7 can be made:
• 95% of patients are considered well after surgery
• 3% of patients experience difficulties with the implant but choose to continue
with the treatment
• 2% of patients have difficulties with the implant and choose not to continue
with the treatment
• QALY 0.8 relates to individuals who are capable of working without expe-riencing
any impact on health
• The amount of work that an individual can contribute equals to $50 a day
Using the above criteria, and assuming that 95% of patients who did not ex-perience
any difficulties with the implant have a QALY of 0.8 one month after
surgery; 3% of patients have QALY value of 0.8 but increases to 0.8 after 12
months; and 2% have QALY values of 0.8, a QALY graph can be plotted and
is shown in Figure 8.

Figure 8. QALY chart comparing the quality of life among patients who had received Hy-perbate
implantation, patients with Hyperbate complications and patients who did not receive
Hyperbate treatment. ’A’ is the area between the blue and yellow graph, showing the amount of
QALY that is gained as a result of Hyperbate treatment. Similarly, area ’B’ is the area between
the orange and yellow graph and shows QALY that is gained as well. ’C’ is the area between
orange and yellow; grey and yellow, showing the initial loss of QALY due to complications
associated with Hyperbate treatment, with and without continued usage of device respectively.
Based on this graph, the amount of QALY gained, represented by areas ’A’ and
’B’ is significant. With improved quality of life, the amount of absenteeism will
be reduced, leading to reduced cost that accompanies absenteeism. Using the
above assumptions, the amount saved is $49,000 per day. Although the initial
cost of undertaking the treatment is high, the improved quality of health that
follows after (0.3 units of QALY gained) is substantial.
The ICER value for when Hyperbate is used compared to no treatments and
when health programs is used compared to no treatments were determined using
the equation described in (Gafni and Birch, 2006) and is expressed as:
ICER =
C
(LE1) E2
(4)
where C is the cost of treatment, L is the increased expected lifespan due to treat-ment,
and E1, E2 are the QALY after and before treatment respectively.Using
equation (1), the ICER values for both treaments are summarised in Table 6.
Based on these figures, the ICER value for Hyperbate treatment is lower com-pared
to health program treatment and according to (Gafni and Birch, 2006),
Hyperbate treatment is more cost effective. Therefore, Hyperbate treatment can
be said to be viable. Moreover it is able to save the economy and patients an

approximate $49,000 per day based on the assumptions used. The authors also
expect the price of Hyperbate to decrease exponentially until it matches the price
of cochlear implants with improved surgeon experience, better manufacturing
techniques and good resource management given adequate time.
Cost Increased Expected
Lifespan (L)
E1 E2 ICER
Hyperbate $52,000 5 0.8 0.5 $14,857 per QALY
Health Program $13,698 2 0.6 0.5 $19,568 per QALY
Table 6. ICER of Hyperbate and health programs. The cost of health program is based on
the ’know your health program’ and is adjusted to give a cost per day (del, 2013). Values
were determined based on the assumption that the increased lifespan due to Hyperbate and
health program treatment was 5 and 2 years respectively. The increased QALY due to these
treatments were also estimated to be 0.3 for Hyperbate and 0.1 for health program.

5 Conclusions and Recommendations
In conclusion, the position and alignment of the electrodes are deemed satisfac-tory
as they do not promote the overlapping of currents. An extra active electrode
will be placed next to the ground electrode to provide better selective stimulation
of fascicles that are directly below the ground electrode. Moreover, it is suggested
that 2 electrodes which are 90-120 apart be active if fascicles which are in the
middle of the nerve is to be targeted.
Although the initial price of Hyperbate is high, it is more cost effective compared
to health programs, based on ICER values specified in Table 6. Furhtermore,
the savings to individuals in terms of QALY gained (0.3 units) and to the econ-omy,
which is $49,000 a day per 1000 implanted Hyperbate devices, is capable
of reducing the economic impact that resistant hypertension causes. This initial
steep price is expected to decrease exponentially and asymptote at a price range
that is similar to cochlear implants due to improved management of resources by
hospitals associated with increased hospital and surgeon volume, and standadised
manufacturing techniques.
To shortened the time it takes to market Hyperbate, pre-clinical and clinical trials
are designed to be as accurate as possible. This is important as it determines
whether Hyperbate is the first of its kind or not, awarding the designers first
mover advantage. This in turn allows the company to capture the majority of the
market, gain customer loyalty and build up the company brand equity, ultimately
leading to a maximised return. As the pathway to market takes approximately
5-10 years, it was decided that a patent be applied for seeing as within the
time frame where Hyperbate is marketed, a patent would have been granted.
From there, the manufacturing process could be licensed to a different company,
reducing the cost of creating capabilities within the company and the overall price
of the device.

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