`Medtronic, Inc., Medtronic Vascular, Inc.,
`& Medtronic Corevalve, LLC
`v. Troy R. Norred, M.D.
`Case IPR2014-00395
`
`
`
`
`
`
`Figure 1
`
`The aortic valve is a tricuspid structure. Each cusp
`folds up toward the aorta during the contraction phase
`and then folds back against the others in the relaxation
`phase.
`[Figure 1] However, it is important
`to understand
`that the structure of the aortic valve is complex, with
`integral relationships beyond its three—leaflet valve
`structure.
`For instance, each leaflet sits directly
`opposite an out pouching of the proximal aorta. This
`dilated segment, called the sinus of valsalva,
`is part of
`an anatomic relationship that assists the repetitive
`opening and closing of the valve while minimizing the
`stress on any point within this valvular apparatus.
`Further,
`the proximal portion of the aortic valve is
`highly elastic, which allows it to dilate during the
`contraction phase of the left ventricle.
`Moreover,
`these valvular structures are integrally
`related to the coronary arteries, which supply blood to
`the heart. These arteries, as represented in Figure 2,
`are located within 2 of the three sinuses. Thus, each
`component plays a vital role in the function and
`durability of the valve.
`The first components of the aortic valve I would
`like to discuss are the leaflets.
`As stated,
`the number of leaflets within a normal
`aortic valve is three. Any congenital variation in the
`
`NORRED EXHIBIT 2287 - Page 2
`NORRED EXHIBIT 2287 - Page 2
`
`2
`
`
`
`.) number of leaflets causes significant problems with
`the
`function. When there are less than three valves,
`valve undergoes rapid stenosis and restriction. An
`individual with a unicusped valve rarely survives beyond
`the first year of life. Among individuals with congenital
`alterations in the valve number,
`the most frequently
`encountered is a bicuspid aortic valve.
`Individuals with
`this variation in valve number can survive into
`adulthood. However,
`this valve combination becomes more
`and more stenotic and regurgitant by the 4th and 5th
`decade, which usually results in the need for surgical
`replacement.
`(See figures 3 and 4). Rarely, an individual
`with a quadricusped valve will survive into adulthood.
`This alteration in design also results in marked
`
`stenosis.
`The anatomy of a normal aortic valve (three cusps,
`sinuses, aortic arteries) permits the dispersion of
`pressure over a larger surface area in the structure.
`
`30
`
`30
`
`20
`
`IO
`
`IO
`
`Figure 4.1
`
`This dispersion resists the exhaustion of any one
`. component of the valve. Moreover,
`the curvature of the
`
`3
`
`NORRED EXHIBIT 2287 - Page 3
`NORRED EXHIBIT 2287 - Page 3
`
`
`
`cusp structure allows the leaflet to reverse curvature,
`an ability needed in order to fold and allow the maximum
`opening diameter during contraction. Finally, a curved
`design allows a redundancy in the coaptation area of the
`leaflets.
`The area of coaptation is the valve edge that
`must meet and close in order to prevent regurgitation.
`Hence, both the number of leaflets and their overall
`shape is important
`in the function and durability of the
`valve.
`the valve leaflets have a
`As mentioned earlier,
`direct relationship to the sinuses of valsalva.
`The
`sinus diameter is almost twice that of the aorta.
`
` (B)
`
`Figure4.2
`
`This cavity plays an important role in the mechanism of
`valve closure.
`
`An oblique section through
`[referenced Mano Thubrikar]
`the leaflet— sinus assembly shows this remarkable
`relationship {see Figure 4). This section reveals that
`the sinus and leaflet form a circle when the valve is in
`a closed position.
`Furthermore, it is angulated to a
`degree as to allow pressure
`transduction along the
`entire surface of this unit. All this suggests that the
`shape of the leaflet— sinus assembly is important
`in
`determining how stresses are developed within the valve
`This relationship also allows the valve leaflets to close
`without straining the aortic valve. Finally,
`this
`relationship of the sinuses and valve allows for the
`efficient flow of blood in the coronary ostia.
`
`4
`
`NORRED EXHIBIT 2287 - Page 4
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`
`
`
`Another structure,
`the aortic root, has been
`The
`observed to expand during ventricular contraction.
`dilatation of this structure reduces tension, which in
`
`turn reduces resistance to flow, as predicted by
`Poisselles'
`law, which describes the relationship of
`resistance to vessel diameter,
`length of tube and fluid
`viscosity. This phenomenon also allows for complete
`opening of the aortic valve.
`Interestingly, when the
`cusps open, a circular dimension is maintained that is at
`least the same diameter as before contraction(Medical
`
`Engineering & Physics 19(8): 696—710,1997). This
`behavior reduces circumferential stress on the valve and
`generates a reduced Reynolds shear stress number
`(the
`number used to evaluate the amount of stress in a
`confined fluid system).
`In a similar manner,
`the inner
`lining of the cusp of the valve,
`the lamina
`ventricularis, extends into the ventricular myocardium
`when the valve is in an open position.
`A confluence of
`fibers at the base, called the fibrous coronet,
`is a
`distinct structure separating the elastic fibers above
`and the myocardium below. However,
`this structure is not
`static.
`It is a very dynamic structure, which bends and
`molds to the forces exerted from the ventricular
`myocardium (Cardiovascular Research, 22,7,1988)(Journal
`of Biomechanics33 (6): 653—658, 2000 June).
`In a fashion
`similar to the aortic root,
`this structure allows the
`valvular apparatus to open with the least amount of
`strain.
`The coronary arteries arise within or above the
`sinuses of valsalva.
`The blood flow to the heart occurs
`during ventricular diastole. At this time,
`the cusps of
`the aortic valve are closed, and as mentioned,
`the
`diastolic forces of the blood against the valve are
`dispersed along the valve and adjacent sinus.
`The
`opening, or ostia, of the coronary arteries, when located
`near the apex and middle of the sinuses, allows for least
`turbulent, most
`laminar flow characteristics.
`
`NORRED EXHIBIT 2287 - Page 5
`NORRED EXHIBIT 2287 - Page 5
`
`
`
`Slnuluhular iunctf - :1
`
`
`
`Left coronary
`sinus
`
`Right coronary
`Sim-IS
`
`Non—coronary
`sinus
`
`figure 1—6. Coronary Artery Orifice-Varlafions. Diagram showing the location or the coro-
`nary onfioes in a sari-as of 23 normal heart grew-Hens. The iumlnal aspect of the aorta is
`W. The markers represem tenths ol the horizontal and vehical measurements in the
`si'ruses. (Adapled from ref. 3)
`
`Figure 5
`
`(This optimal location will be important to keep in mind
`when designing a replacement valve because this
`relationship promotes the greatest amount of flow with
`the least amount of resistance.)
`In disease states where
`these relationships are lost, it has been proposed that
`this loss could increase stress at the coronary ostia.
`
`[The Aortic Valve CRC press].
`These integral relationships are not only seen in
`. the gross anatomy of the valvular apparatus. The
`microanatomy shows the integral nature of these
`structures as well.
`The amount of elastin shown by
`staining methods is in a higher concentration here than
`anywhere else in the body( American Journal of Pathology
`445 (7): 1931). This concentration allows a greater
`
`
`
`6
`NORRED EXHIBIT 2287 - Page 6
`NORRED EXHIBIT 2287 - Page 6
`
`
`
`Further, scanning electron micrographs have shown the
`unique arrangement of collagen in the valves, which
`permits the unique reversal of curvature and is vital in
`the function of the valve.
`(See Figure 6).
`(Anatomic
`Embryology 172(61): 1985).
`The fibers are unusually
`small and arranged in sheets with unique distances
`between each strand.
`In theory,
`this would give a
`greater amount of tensile strength while allowing
`continued flexibility. As always, nature has selected
`the most efficient machinery, and we have only to
`
`discover the reasons why.
`
`II. Aortic Valve Dynamics and Physics
`The aortic valve is not a static structure. Full
`understanding of this structure requires understanding
`the dynamics and physics of the opening and closing of
`the valve:
`the motion of the various parts,
`the design of
`the valve in vitro and the hydrodynamics of the valve.
`The valve's ultimate function is to allow fluid
`transfer from the ventricle to the systemic circulation.
`In order to do this efficiently, it minimizes shear
`stress, resistance to flow and tensile forces. The
`opening and closing of the aortic valve depends upon
`differential pressures,
`flow velocity characteristics
`and, as mentioned earlier,
`the unique anatomic
`relationship between the valves and the sinuses of
`valsalva.
`
`The most comprehensive model of this process has
`been developed by Bellhouse et al.
`In this model,
`the
`flow of fluid through the aortic valve was studied by
`injecting dye into the flow of fluid.
`Some of the
`pertinent observations incorporated in this model were as
`follows: 1) The valve opens rapidly, and as the leaflets
`move into the sinuses, vortices form between the leaflet
`and the sinus walls; 2) The flow enters the sinus at the
`sinus ridge, curls back along the sinus wall and leaflet
`and flows then back into the main stream;
`3} During the
`end of systole,
`the vorticeal motion forces the valves
`back toward a closed position. These observations are
`important because they show that absolute pressure
`
`NORRED EXHIBIT 2287 - Page 7
`NORRED EXHIBIT 2287 - Page 7
`
`7
`
`
`
`differences created between the aorta and ventricle are
`
`not
`
`the source of initial closure of the aortic valve.
`
`In fact, it would be detrimental to valve stress if these
`
`forces dictated closure of the aortic valve. For example,
`
`if two objects are separated and a set amount of force is
`applied to each,
`increasing the distance between them
`would produce greater velocity and the momentum at impact
`would be greater. Therefore, if the leaflets are closed
`or near closure as contraction is coming to an end,
`then
`
`the force used for coaptation would be less.
`
`Less force
`
`per cycle equates to greater longevity of the valve.
`
`This phenomenon would affect the design for
`prosthetic valves.
`The cusps and the relationship of
`closure for prosthetic valves must incorporate passive
`closure during systole in order to lengthen the life span
`
`of any such device.
`
`To understand how to do this, we must explore The
`
`theory of laminar flow as it relates to aortic valve
`
`function. Laminar flow is predicted by the Reynolds
`number, which incorporates the laws as described by
`Outsell and Bernoulli.
`In general,
`the lower the
`Reynolds number,
`the more likely that flow will be
`laminar.
`The equation that describes the Reynolds
`number in the aorta is as follows:
`
`Ua/v = Reynolds number
`
`That is U, which equals the velocity of blood and a,
`which represents the radius of the aortic valve,
`is
`inversely related to the viscosity of blood.
`As the
`velocity increases or the viscosity decreases,
`the
`tendency towards turbulent flow also increases.
`Moreover,
`the behavior of the fluid in a system is
`predicted by the Strouhal number.
`In a system where
`viscosity, velocity and radius vary minimally,
`the rate
`of acceleration or deceleration of the fluid predicts
`
`laminar versus non laminar flow. When looked at in this
`
`perspective, it is easy to see the relevance of this
`information to valve function. Only a small pressure
`difference is required to open the native aortic valve.
`
`8
`
`NORRED EXHIBIT 2287 - Page 8
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`
`
`
`Maintaining a small pressure difference minimizes
`acceleration to flow. Thus,
`laminar flow is more likely.
`
`The deceleration phase is naturally a gradual process;
`however, as stated earlier, it is the relationship
`between the sinuses and the cusps that allows this
`deceleration to occur without an abrupt pressure drop.
`When laminar flow is produced,
`the resistance to flow,
`wall stress, shear stress and circumferential stress are
`reduced. This reduction decreases cardiac work and
`
`increases the longevity of the valvular apparatus.
`Ultimately, a design to replace a diseased aortic valve
`must incorporate many if not all of these relationships.
`
`III. Aortic Stenosis
`
`Aortic stenosis is the condition of restriction to
`the ejection of blood from the left ventricle to the
`systemic circulation at the aortic valve level.
`If the
`aortic valve cusps do not open, or there is failure of
`the valvular apparatus,
`then a pressure gradient
`develops.
`In order to overcome this pressure
`difference,
`the left ventricle begins to hypertrophy.
`Over a period of time,
`this process produces pressure
`overload on the left ventricle, which produces dramatic
`clinical symptoms.
`In the most severe form, it is fatal
`unless treated. The incidence of aortic stenosis varies
`considerably.
`In epidemiological studies,
`the incidence
`is between 2 to 4% of the general population.
`
`the most common etiology
`In the early 20th century,
`of aortic stenosis was rheumatic fever. This
`streptococcal infection produces inflammatory changes in
`the aortic valve.
`Interestingly,
`these
`changes affect
`the coaptation surface to a greater degree than the other
`structures of the aortic valve. Affecting the coaptation
`points results in fusion of cusps. This fusion results
`in a restriction to the opening of the cusps.
`A pressure
`difference develops as well as non—laminar flow. Once
`this cycle develops, valve deterioration and
`calcification increases. Unfortunately, post infectious
`aortic stenosis can result in rapid progression to severe
`.aortic stenosis. Of the total cases of aortic stenosis
`
`NORRED EXHIBIT 2287 - Page 9
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`
`9
`
`
`
`in the 1940's, reportedly 52% were the result of
`rheumatic fever. Currently,
`less than 9% of the cases of
`
`aortic stenosis are post inflammatory.
`
`In
`
`an
`
`n a
`
`6804.36
`
`
`
`
`.
`
`so
`no
`a)
`m.
`
`10
`o
`
`The second most common cause of aortic stenosis is a
`bicuspid aortic valve. This has remained relatively
`constant throughout the decades.
`It accounts for 33 to
`40% of the total cases of aortic stenosis.
`This
`condition affects most parameters of aortic function
`because the optimal anatomic relationship between the
`sinuses, arteries and the valve cusp is lost. Further,
`the opening and closing characteristics of the valve are
`altered, which in turn alters the acceleration and
`deceleration of flow.
`As a result, non-laminar flow
`characteristics are developed.
`Because of the altered
`anatomy, a bicuspid aortic valve cannot easily reverse
`curvature.
`Due to this limitation,
`the bicuspid aortic
`valve has increased stress at the base.
`It is at this
`point where morphologic changes first appear. However,
`this valve is usually survived into adulthood.
`
`NORRED EXHIBIT 2287 - Page 10
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`
`10
`
`
`
`the most common cause of aortic stenosis
`Currently,
`is degenerative aortic stenosis.
`By the 7th decade,
`the
`normal aortic valve can undergo degenerative changes.
`The characteristic that defines these changes is
`increased calcium deposition along the body of the cusps.
`
`
`
`Predominantly the calcification is located at the
`bases of the cusp (see asterix in picture) and on the
`aortic side. When enough calcium is deposited as to
`restrict flow,
`then there will be a variable amount of
`fusion along the coaptation surface.
`The incidence of
`aortic stenosis reaches as high as 12% in octogenarians.
`This population accounts for 51% of the current cases of
`aortic stenosis.
`The factors that promote aortic
`stenosis in a normal valve are the same as those that
`contribute to atherosclerosis in arteries [nejm 1996].
`Thus, degenerative aortic stenosis has become the most
`prevalent etiology.
`
`Clinically, symptomatic aortic stenosis not only has
`disabling symptoms, but also a high mortality. Aortic
`stenosis is currently graded according to the calculated
`aortic valve area (see Figure7). As represented in the
`table, severe aortic stenosis occurs when the valve area
`is less than 1.0cm2 (AVA index of <O.6cm2/m2). The most
`
`M
`
`NORRED EXHIBIT 2287 - Page 11
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`
`
`
`frequent symptom is angina pectoris, occurring in up to
`70% of these cases. This is followed by syncope or
`presyncope. Once aortic stenosis becomes symptomatic,
`the 2—year mortality can be as high as 50% [Braunwal
`1973].
`The 10—year survival is a dismal 10%.
`In
`conclusion, aortic stenosis can produce severe life-
`limiting symptoms and ultimately is fatal.
`
`the
`Whatever the etiology of aortic stenosis,
`proposed percutaneous valve offers a unique and
`beneficial approach to replacement.
`
`IV. Aortic Regurgitation
`
`Aortic regurgitation is the condition of leaked
`backflow of blood from the aorta into the left ventricle.
`This regurgitation results in a decreased effective
`cardiac output.
`In turn,
`longstanding aortic
`regurgitation results in an increased volume of work for
`the left ventricle.
`In time,
`the left ventricle begins to
`dilate. Unlike aortic stenosis,
`this condition can be
`well tolerated for many years. However, once the left
`ventricle begins to dilate and lose its contractility, it
`becomes rapidly symptomatic.
`
`just as
`
`Etiologically, aortic regurgitation and stenosis are
`very similar. The most common etiology of aortic
`regurgitation has been rheumatic fever. However,
`in stenosis,
`this incidence has decreased as the
`incidence of rheumatic fever has decreased. Logically
`whenever there is stenosis,
`there can be increase
`circumferential stress placed upon the proximal aortic
`root. It is this stress that promotes aortic root
`dilatation in certain patients. Moreover,
`a dilatation
`of the aortic root can separate the cusps of the aortic
`valve and create regurgitation.
`Thus, senile aortic
`stenosis, bicuspid aortic valves and distinctly rheumatic
`aortic valves have a propensity to regurgitate.
`However,
`there are other unique entities, which promote
`aortic regurgitation.
`For example, Marfan's syndrome is
`
`NORRED EXHIBIT 2287 - Page 12
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`
`12
`
`
`
`defined by defective collagen deposition. This
`deficiency manifests as dilatation of the aortic root at
`
`a very young age, and tragically can result in the
`dissection of the aorta. More commonly,
`the aorta can
`become dilated in response to systemic hypertension.
`a certain portion of patients, aortic dilatation with
`concomitant aortic regurgitation is the only
`there are
`manifestation of their hypertension. Thus,
`distinctly different causes for aortic regurgitation in
`the presence of a structurally normal aortic valve.
`Severe aortic regurgitation has a poor prognosis.
`Work by Goldschlager et al found that the survival of
`aortic regurgitation is about 50% at 8years (Am. J. Med.
`(54): 1973). With maximum medical
`therapy, it still has
`a poor prognosis.
`Even among asymptomatic patients,
`there is a decrease in the max V02 as measured with a
`
`In
`
`standard cardiopulmonary exercise test. Moreover, many
`patients who undergo surgical replacement
`of the native
`valve for aortic regurgitation report an increase level
`of functioning that they didn't realize they had lost.
`In fact, although well— tolerated, aortic valve
`
`regurgitation is a serious disease, which limits a
`patient's lifestyle as well as life span.
`
`V. Surgical Therapy
`
`For patients suffering from aortic regurgitation or
`aortic stenosis,
`the best therapy to date is surgical
`valve replacement. There is no questioning the benefit
`of surgical vs. medical management for these conditions.
`The 5—year survival for medical
`treatment of symptomatic
`aortic stenosis is 20% vs.
`80% with a standard valve
`
`The natural history of the valve has been
`replacement.
`well characterized by the work of Braunwald et al in
`1973.
`
`U
`NORRED EXHIBIT 2287 - Page 13
`NORRED EXHIBIT 2287 - Page 13
`
`
`
`I AVR
`.
`I Treated medically E!
`
`P<n.oon¢o1
`
`Unfortunately, aortic valve replacement carries certain
`surgical morbidity and mortality. Aortic valve
`replacement may be among the most invasive surgeries. It
`requires access to the native valve, which necessitates a
`
`the heart must be stopped and placed
`sternotomy. Also,
`on a bypass pump. Further,
`the ascending aorta is cross—
`clamped at a position proximal
`to the great vessels.
`The
`native valve is then excised, and depending upon the
`condition of the aortic root, it may be excised also.
`
`Then the mechanical or biomechanical valve (metallic vs
`
`Although this is a
`tissue) valve is sutured into place.
`life—saving procedure for those patients suffering from
`these disorders,
`the surgery is not without significant
`risk of mortality and morbidity.
`The risks of the surgery can be classified into
`
`immediate and long—term risks.
`
`The immediate risks of
`
`the surgery involve the mechanics of the valve
`
`replacement procedure.
`
`In accessing the heart,
`
`the
`
`sternum is split in two by a reciprocating saw. Given
`
`that the sternum is a central point of attachment for the
`
`chest cavity, considerable effort must be applied to
`
`maintain the correct anatomic durability.
`
`The sternum
`
`currently is wired back into place with a series of
`interrupted suture wire from the cranial end to the
`dorsal end.
`Known difficulties encountered with this
`
`procedure are wound dehiscence and infection.
`
`The
`
`patients most at risk include diabetics,
`the
`immunosuppressed and the elderly. Wound dehiscence or
`
`NORRED EXHIBIT 2287 - Page 14
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`
`14
`
`
`
`".
`
`infection can be mild and readily amendable to simple
`wound care techniques. Or,
`these can be so severe as to
`
`lead to death or significant morbidity.
`
`The incidence is
`
`in 200 in low risk groups, and
`reported to be as low as l
`as high as 10 in 100 in high—risk groups.
`
`Thrombosis {4%)
`
`Endocarditis
`
`Paravalvular heal: {8%)
`
`(10%)
`
`Another immediate risk is a significant decrease in
`
`cerebral function.
`
`It is becoming more and more
`
`apparent that use of a bypass pump promotes cerebral
`
`dysfuntion. Under the best of circumstances,
`
`there is an
`
`immediate risk of major stroke reported to be 1
`
`to 3%.
`
`However, among those patients without recognizable
`
`strokes,
`
`there are still reported deficits in cognitive
`
`function. When this cognitive dysfunction is measured in
`
`terms of IQ points, it can be dramatic.
`
`In one series,
`
`up to 60% of patients undergoing bypass surgery had an
`
`immediate drop in their IQ scores by 20 points.
`
`Family
`
`and friends often recognize a distinct drop in mental
`
`alertness.
`Thus, even in a technically successful
`surgery,
`there can be a substantial drop in cognitive
`function.
`
`The long—term risks are also serious and include
`
`infectious endocarditis,
`
`thromboembolism and valve
`
`dysfunction.
`[expand and then discuss balloon
`. valvuloplasty]
`
`NORRED EXHIBIT 2287 - Page 15
`NORRED EXHIBIT 2287 - Page 15
`
`U
`
`
`
`VI. The Study Objectives and Stages
`The objective of this study is to demonstrate the
`feasibility of a percutaneously placed aortic valve as
`reflected in the testing of these 14 hypotheses. We
`speculate that the following assertions can be
`demonstrated to be the case:
`
`1. A cross—linked nitinol expandable stent can be
`
`appendix).
`annealed to a biological valve (see
`2. The flow characteristics produced by this
`
`uniquely
`designed device will perform in a similar fashion to
`that of other bioprosthetic valves.
`3. The strain relationships will be proportionate to
`the native valve structure.
`
`4. The flexible base will allow more even dispersion
`
`of
`
`flexion strain.
`
`5. The interface of the stent aorta will be
`
`sufficient to maintain the valve in the
`
`proper
`
`position for function in—vivo.
`6. The stent/valve can be inserted percutaneously.
`7. The ascending aorta can accommodate a stented
`valve
`
`structure without rupture or significant dissection.
`8. The ascending aorta and coronary arteries can be
`visualized with existing techniques.
`9. With detailed visualization ,the stent/valve will
`
`be placed as to avoid obstructing the native valve
`function.
`
`10. The stent/valve combination will not
`
`significantly
`
`obstruct coronary flow.
`11. A biotome can be directed across the interatrial
`
`septum into the left ventricle.
`12. Once a properly designed catheter is inserted
`into the left ventricle ,
`the native
`valve can be
`
`excised in a controlled manner.
`
`13. An animal would survive the placement of a
`
`percutaneous valve,
`14. The stented aortic valve in vivo will have a
`
`NORRED EXHIBIT 2287 - Page 16
`NORRED EXHIBIT 2287 - Page 16
`
`16
`
`
`
`gradient of less than lOmmhg.
`Our belief is that a properly designed valve can be
`
`placed nonsurgically without the assistance of a bypass
`pump and mimic the function of a native valve. The tasks
`of the study will be divided into 4 related stages:
`flow
`
`modeling, valve modification, catheter design and in—vivo
`
`experiments. These stages are discussed in detail in the
`
`following protocol
`
`VII. Equipment and supplies
`1. Lab associated equipment for the modification if
`
`needed of the existing valve.
`2 Nitinol wire
`
`3 Nitinol soldering device
`
`4. Template equipment
`
`5 Aqueous solutions for the flow system
`6 Preservation material
`
`7. Dissection tools
`
`8. Pig Hearts
`
`9. Operating Room
`10. Valve Flow Model with software
`
`11. Statistical Software
`
`12. Intracardiac echocardiography (Probes and Base)
`13. Catheters
`
`l4. Biotomes and microengineering tools
`
`VIII. Associates
`
`1. Flow Modeling
`
`Troy Norred MD
`Steven Lombardo PhD
`
`Frank Fu PhD
`
`2. Valve Development
`
`Troy Norred
`
`Fu Fung Hsieh
`Harold Huff
`
`3-
`
`In Vitro Modeling
`
`Troy Norred MD
`Steve Lombardo PhD
`
`NORRED EXHIBIT 2287 - Page 17
`NORRED EXHIBIT 2287 - Page 17
`
`1?
`
`
`
`.
`
`Fu Fung Hsieh PhD
`4. Procedure
`
`Troy Norred MD
`
`Timothy Catchings MD
`Darla Hess MD
`
`Wayne McDaniels PhD
`Michael Sturek PhD
`
`5. Editing and Data analysis
`Troy Norred MD
`
`Greg Flaker MD
`Fu Fung Hsieh PhD
`Steven Lombardo Phd
`
`Timothy Catchings MD
`Darla Hess MD
`
`Frank Fu PhD
`
`Wayne McDaniels PhD
`Michael Sturek PhD
`
`IX.Data Acquisition
`
`l. Hemodynamics
`2.
`
`Pressure gradients
`
`3.
`
`4.
`
`5.
`
`Cardiac Output
`
`Peripheral resistance
`Dissection of the specimens
`
`6. Histological Data
`
`7. Morphologic data
`8. Visualization Data
`
`9.
`In—Vitro Modeling system
`10. Histological sections
`
`X Budget
`
`1. Flow Model System
`
`Laser Doppler Anometer
`Vivitec Flow Model
`
`Software analysis System
`Post—Doc Salary for 6 weeks
`Secretarial Time
`
`($1500.00)
`
`($13,500)
`
`($650.00)
`
`($3750.00)
`
`($12.00/hr X25
`
`hr/wk)
`Sodium Iodide, glycerol, 1%water by volume
`($75.00)
`
`.
`
`2. Valve Modification
`
`Pig Hearts
`
`($10.00/heart)
`
`18
`NORRED EXHIBIT 2287 - Page 18
`NORRED EXHIBIT 2287 - Page 18
`
`
`
`Slaughter House Material
`Technician Processing Time
`Preservation Material
`
`($150.00)
`($17.00/hr)
`
`Liquid Nitrogen
`Formalin
`
`($25.00/canister)
`($5.00/6oz)
`
`Clean up time
`Freezer Space Rental
`Lab Space Rental
`Nitinol Wiring
`Soldering Kit
`Nitinol wiring
`Engineering Consultant Fee
`Technician and Physical Plant
`
`Secretarial Expense
`
`Experiment with Pigs
`Pigs
`Fluoroscopic Time
`Technician time
`
`Lab expense
`ACUVIEW SYSTEM
`
`(17.00/hr)
`($10.00/day
`(13.00/hr)
`
`($1950.)
`($950.00/ft)
`($2500.00)
`time
`($25.00/hr)
`
`10 hours/week
`
`($75.00/pig)
`($110.00/day
`($17.00/hr)
`
`($500.00)
`($30,000)
`
`Catheters (variable if donated, but approx.
`
`$200.00)
`
`Data Software (included in Fluoroscopic room)
`Statistician Expense
`($250.00)
`Secretarial Time
`(20hrs)
`
`Total cost of for 6 week project
`
`$66,610.00
`
`Aorta Valve Modeling
`
`I9
`NORRED EXHIBIT 2287 - Page 19
`NORRED EXHIBIT 2287 - Page 19
`
`
`
`DATA
`
`APmax = 300mmHg = 30cmHg
`
`Q = Sliters/min = 5000cm3/min
`
`D =
`
`3cm,
`
`R =1.5cm
`
`.
`
`(rupture stress}
`0r >= lZOOmmI-Ig
`n (blood) = l cP = 0.01P
`
`A = nDZ
`
`n9/4 = 7.1cm2
`
`4
`
`C= 2nr = 9.4cm
`
`20
`NORRED EXHIBIT 2287 - Page 20
`NORRED EXHIBIT 2287 - Page 20
`
`
`
`Treat
`
`the aorta as a rigid capillary and the blood as a
`
`homogeneous liquid with viscosity of
`
`1cP.
`
`Some important quantities:
`
`1w = RAP
`
`shear stress at wall
`
`2L
`
`L = length
`
`6 2
`
`Q
`
`HRZ
`
`7 = 4 Q
`
`HR2
`
`Mean velocity
`
`Shear rate at wall
`
`w =
`
`1.50m x 30cm Hg
`2
`(low)
`
`=22.5cm
`
`
`Re = DVP
`_
`
`= 3cm * 12cm/sec *
`L1 0.0lg/cm/sec
`= 3600
`= Rem 1200
`
`lgm/cm3
`
`for blood, n=3cP
`
`
`y = 5000Cm3/min = 1min
`=l2cm
`
`n (l.5)2*cm2
`
`60sec
`
`sec
`
`
`7 = 4(5000cm3/min)
`l min/605 = 30/sec
`
`n
`
`(1.5)3 * cm3
`
`The maximum stress upon the cusps when the Vlave is
`closed is
`
`Fmax = AP*A = 30.0cmHg *7.lcm2
`
`22
`
`200cmHg/cm
`
`To keep the rupture stress below 1200mmHg, we require a
`
`certain amount of stent/aorta interface area.
`
`Fmax = or * A(stent)
`
`If we specify that or
`
`22
`
`300mmHg,
`
`then we need
`
`200.0cmHg * cm2
`
`= 300mmHg * A(stent)
`
`NORRED EXHIBIT 2287 - Page 21
`NORRED EXHIBIT 2287 - Page 21
`
`21
`
`
`
`.
`
`A(stent) = 7.1cm2
`
`Convert P = 300mmHg
`
`To
`
`MP2
`
`300mmHg * 1.0 x10(5)
`
`P2 * 1MP2
`
`= 0.04MP2
`
`760mmHg
`
`10(6JP2
`
`From Pilhey
`
`TA
`
`407.2, p55
`
`1994
`
`P1
`
`Uniform load simply
`
`supported
`
`r =2
`
`Pl 2g4}
`Eh(4)
`
`=
`
`
`1 016
`* W0
`l—r
`
`h
`
`+
`
`0.376 (g9):3)
`
`h
`
`=. mgr) :
`
`
`Eh(2) [1.238
`2Q)L]rRQ}
`
`W_o
`h
`
`+ 0.244(wO1g2fl
`
`h
`
`J
`
`Wo = 7.5 x lO(-6)m
`
`5(rq) = 8.4MP2
`
`When the valve is closed.r
`
`the
`
`maximum force is given by Fmax
`
`=AP *A.
`
`How is this force
`
`transmitted.
`
`This stress must be opposed by
`
`a stress arising from
`
`aorta/stent interaction.
`
`22
`NORRED EXHIBIT 2287 - Page 22
`NORRED EXHIBIT 2287 - Page 22
`
`
`
`Since we know the aorta can withstand 30cmHg hydrostatic
`. pressure (which is less than 120.0cmHg rupture strength),
`we will use o(r) = 30.0 cmHg and thus
`
`Astent = 7.1cm(2)
`
`For stents of 1mm width,
`
`lOmmhigh and an angle of
`
`60degrees
`
`2
`
`12
`
`4
`
`l4
`
`6
`
`16
`
`8
`
`10
`
`18
`
`20
`
`20 x 0.1 cm x 1cm = 2cm(2)
`
`NEED 4 APPROXIMATE!) STENTS TO WITH STAND 300mmHg
`
`. Friction must hold the stent in place
`
`CoF = Ft
`
`Fn
`
`=>T
`
`Ft = Fmax
`
`= AP *A = 30cmHg
`
`* 7.1cm(2)
`
`=
`
`200cmHg/cm(2)
`
`The norma force exerted by the stent
`
`( which is opposed
`
`by the arterial wall)
`
`is
`
`.
`
`Fn = Ft
`—
`
`= o(r)
`* A(stent}
`Cof Cof
`
`NORRED EXHIBIT 2287 - Page 23
`NORRED EXHIBIT 2287 - Page 23
`
`23
`
`
`
`For the stent not to move,
`
`the normal force must exceed
`
`Ft/Cof
`
`Fn
`
`> Ft/Fcof > 0(r) *A(stent)
`Cof
`0.20
`
`=
`
`200cmHg cm(2)
`
`If Cof > 0.20,
`
`Fn : 1000cmchm(2)
`
` on = Fn = lOOOcmchm(2)
`
`
`
`Astent
`7.1cm(2)
`
`=
`
`140cmHg
`
`Thus this approximates the rupture stress of lZOcmHg
`
`(l200mmHg)
`
`As you can see the amount of stent/aorta interface
`
`required for pressure far exceeding that physiologically
`
`required are easily achieved with a minimal amount of
`stents. This force naturally will only be required until
`the stent undergoes endothelialization.
`
`Protocol
`
`Flow Modeling
`
`The initial experiments will be performed to assess
`
`the valvular function in a flow model, which will be used
`
`to measure pressure and resistance (see adjacent
`
`picture).
`
`NORRED EXHIBIT 2287 - Page 24
`NORRED EXHIBIT 2287 - Page 24
`
`24
`
`
`
`
`
`The model is static and therefore will limit the
`
`assessment. However,
`
`important
`
`information about stress
`
`and strain relationships can be obtained.
`
`Basic
`
`measurements will be derived, and from these, we will
`publish our first data on the experimental valve.
`The timeline for these experiments is expected to be
`to 6 weeks.
`The preparation for these experiments will
`4
`take up the majority of our project time. During this
`
`period, several mock runs will be used to modify the
`
`devices in order to obtain the most accurate hemodynamic
`information. Once we have accurate information concerning
`laminar flow characteristics, Reynolds number and strain
`relationships, we will begin to practice for in—vivo
`
`experiments.
`
`Two types of flow systems have been developed, each
`with set points of measurements embedded at certain
`distances from the valve.
`One uses ultrasound sensors
`
`and the other laser sensors.
`
`In the pulsed laser system,
`
`the lasers are set at perpendicular angles to measure
`
`differential velocities.
`
`Further,
`
`these velocities can
`
`measure shear stresses along the systolic flow and
`
`regurgitant flow.
`
`The flow systems allow high—speed photographs
`
`to be
`
`NORRED EXHIBIT 2287 - Page 25
`NORRED EXHIBIT 2287 - Page 25
`
`25
`
`
`
`taken to demonstrate the function of early closure in
`relationship to the sinuses (Annals of Biomedical
`
`Engineering. Vol. 26). We will be able to combine the
`
`flow model measurements and photographs to assess the
`affects of design variations. This final phase of the
`flow modeling experiment will help prepare for a more
`
`successful attempt at in—vivo placement of the
`
`experimental valve.
`
`With current software available from Memry
`
`Corporation, we will have the data necessary to begin
`
`modification of the valve system before our in—vivo
`
`attempts. This software can help deduce strain
`
`relationships in a computer model. Differing values can
`
`be used to assess the effects upon the flow model system.
`
`These detailed in—vitro experiments will save valuable
`
`time and resources by troubleshooting prior to actual in—
`
`vivo experimentation.
`
`Valve modification
`
`The valve/stent combination has reached a point in
`design and development where successful modification
`
`depends on experimentation.
`
`First, differing techniques of harvesting biological
`
`valves can have a dramatic impact on their function.
`
`When a valve is harvested and pl