`
`PERCUTANEOUS AORTIC VALVE REPLACEMENT
`
`to develop a
`This proposal for a project
`percutaneous aortic valve replacement is divided into
`seven sections. The section on anatomy describes the
`native aortic valve and its function. The following
`section on the valve‘s dynamics and physics discusses the
`implications of the anatomy for the valve’s successful
`function. The sections on aortic stenosis and
`
`regurgitation describes valve dysfunction and the section
`on surgical therapy discusses current surgical
`replacement therapy and its problems. The final two
`sections outline the study objectives and stages. The
`
`purpose of the study is to develop a percutaneous
`placement technique and prosthetic valve that would mimic
`the function of the native valve and avoid problems
`
`associated with current methods for surgical replacement.
`
`
`
`I. Aortic Valve Anatomy
`The aortic valve directs the flow of blood from the
`
`left ventricle into the systemic circulation through the
`aortic artery.
`It accomplishes this function by opening
`during the contraction of the left ventricle and closing
`when the left ventricle relaxes.
`
`three leaflete
`In a normally functioning valve,
`shaped cusps open widely to allow the unimpeded
`transference of blood, and then close tightly, not
`allowing any blood back into the left ventricle.
`Significant restriction to blood flow is called stenosis,
`and blood leakage back into the left ventricle is called
`regurgitation.
`
`
`
`
`
`NORRED EXHIBIT 2051 - Page 1
`Medtronic, Inc., Medtronic Vascular, Inc.,
`& Medtronic Corevalve, LLC
`
`v. Troy R. Norred, MD.
`Case |PR2014-00110
`
`

`

`
`
`
`
`
`
`Figure l
`
`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 threewleaflet 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
`“durabilit
`
`
`The first components of the aortic valve I would
`like to discuss are the leaflets.
`
`
`
`the number of leaflets within a normal
`As stated,
`aortic valve is three. Any congenital variation in the
`
`NORRED EXHIBIT 2051 - Page 2
`
`

`

`
`
`number of leaflets causes significant problems with
`function. When there are less than three valves,
`the
`
`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
`
`this valve combination becomes more
`adulthood. However,
`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.
`
`
`
`l;
`
`V
`
`-
`
`3O
`
`30
`
`IO
`
`_mFi99re allow...“w
`
`
`
`This dispersion resists the exhaustion of any one
`component of the valve. Moreover,
`the curvature of the
`
`NORRED EXHIBIT 2051 - 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
`.wmust meet audioloselinlordermtoupreventwregurgitationiwwwmWWMWW i,
`Hence, both the number of leaflets and their overall
`
`shape is important
`valve.
`
`in the function and durability of the
`
`As mentioned earlier,
`the valve leaflets have a
`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
`
`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.
`
`
`
`NORRED EXHIBIT 2051 - Page 4
`
`

`

`
`
`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
`WwiiiiiresistanceWtoivesselmdiameterfwlengthmefwtubewandwfluid—--------------------------------------------------------—
`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
`number used to evaluate the amount of stress in a
`
`(the
`
`In a similar manner,
`confined fluid system).
`lining of the cusp of the valve,
`the lamina
`ventricularis, extends into the ventricular myocardium
`
`the inner
`
`A confluence of
`when the valve is in an open position.
`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
`
`the valve are
`diastolic forces of the blood against
`dispersed along the valve and adjacent sinus.
`The
`opening, or ostia, of the coronary arteries, when located
`allows for least
`
`turbulent, mostlaminar flow characteristics.
`
`
`
`NORRED EXHIBIT 2051 - Page 5
`
`

`

` Slnulubular junction
`
`Lon coronary
`sinus
`
`Right coronary
`sinus
`
`Non—coronary
`sinus
`
`
`
`
`
`Figure 1-6. Coronary Artery Orifice—Variations. Diagram shaving the location 01 the coro-
`nary orifices ln :1 sodas ol 23 normal heart specimens. The luminal aspect of the aorta is
`dBplayod‘Tho markers represent lambs ot the horizontal and vertical moasurements In the
`Muses (Adapwd tram ref. 3.)
`
`Figure 5
`
`to keep in mind
`location will be important
`(This optimal
`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
`amount of dilatation of the structures in this area.
`
`
`
`
`
`Figure 6
`
`NORRED EXHIBIT 2051 - 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
`
`(Anatomic
`(See Figure 6).
`the function of the valve.
`The fibers are unusually
`Embryology 172(61): 1985).
`
`
`At*********************smali'and arranged““““ """"
`“““““intsheetsvwitn“uniguevdistances“““““““““““““““““““““““““‘
`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
`........................a.,:ig1__-.the s inus wal ls; 2) The flow __._e__Ii;te.rs .. Lhesmgéatthe
`sinus ridge, curls back along the sinus wall and leaflet
`and flows then back into the main stream; 3) During the
`
`
`
`the vorticeal motion forces the valves
`end of systole,
`back toward a closed position.
`These observations are
`important because they show that absolute pressure
`
`NORRED EXHIBIT 2051 - Page 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
`
`then
`or near closure as contraction is coming to an end,
`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
`
`
`
`Laminar flow is predicted by the Reynolds
`function.
`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:
`
`H
`
`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.
`
`the behavior of the fluid in a system is
`Moreover,
`predicted by the Strouhal number.
`In a system where
`
`viscosity, velocity and radius vary minimally,
`the rate
`”o”'acce era"ion"or'oec€T§f§€fi§T?fiffhafTfiia"predflfifi?wwwwwmmw
`
`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.
`
`NORRED EXHIBIT 2051 - Page 8
`
`

`

`
`
`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.
`difference,
`
`In order to overcome this pressure
`the left ventricle begins to hypertrophy.
`
`this process produces pressure
`Over a period of time,
`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
`
`the incidence
`In epidemiological studies,
`considerably.
`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
`‘Wdifference deveIOps as well as nonfilaminar 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 stenosifi
`
`
`
`NORRED EXHIBIT 2051 - Page 9
`
`

`

`
`
`reportedly 52% were the result of
`in the 1940‘s,
`rheumatic fever. Currently,
`less than 9% of the cases of
`aortic stenosis are post
`inflammatory.
`
`
`
`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
`
`Because of the altered
`characteristics are developed.
`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.
`
`10
`
`NORRED EXHIBIT 2051 - Page 10
`
`

`

`
`
`Currently,
`the most common cause of aortic stenosis
`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
`
`The incidence of
`fusion along the coaptation surface.
`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].
`
`X
`
`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 l.Ocm2 (AVA index of <O.6cm2/m2). The most
`
`
`
`H
`
`NORRED EXHIBIT 2051 - Page 11
`
`

`

`
`
`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.
`
`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
`
`just as
`
`there can be increase
`whenever there is stenosis,
`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
`
`
`
`12
`
`NORRED EXHIBIT 2051 - Page 12
`
`

`

`
`
`
`
`In
`
`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
`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
`replacement.
`The natural history of the valve has been
`well characterized by the work of Braunwald et al
`in
`1973.
`
`’
`
`x
`
`
`
`U
`
`NORRED EXHIBIT 2051 - Page 13
`
`

`

`\5Eiiiiii--§iil\fwfl__f
`
`10 AVR
`
`P-:0.001
`
`0 Tremud mmiimlly
`
`Chi2 w 23.5
`
`
`
`
`
`‘
`
`*
`
`Unfortunately, aortic valve replacement carries certain
`surgical morbidity and mortality. Aortic valve
`replacement may be among the most
`invasive surgeries. It
`‘vjw .4»..an
`reenires access to the native valve, which necessitates a
`sternotomy. Also,
`the heart must be stopped and placed
`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
`tissue) valve is sutured into place.
`Although this is a
`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
`the
`replacement procedure.
`In accessing the heart,
`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
`
`
`
`the
`patients most at risk include diabetics,
`immunosuppressed and the elderly. Wound dehiscence or
`
`l4
`
`NORRED EXHIBIT 2051 - Page 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
`reported to be as low as l
`in 200 in low risk groups, and
`as high as 10 in 100 in high~risk groups.
`
`Thrombosis (4%)
`
`[Endocardilis
`
`Paravalvuiur leak (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
`
`there are still reported deficits in cognitive
`strokes,
`function. When this cognitive dysfunction is measured in
`terms of IQ points, it can be dramatic.
`In one series,
`
`X
`
`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
`
`[expand and then discuss balloon
`dysfunction.
`valvuloplasty]
`
`
`
`U
`
`NORRED EXHIBIT 2051 - Page 15
`
`

`

`
`
`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 inwvivo.
`
`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
`
`16
`
`NORRED EXHIBIT 2051 - Page 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
`
`flow
`of the study will be divided into 4 related stages:
`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
`
`@QmL-dew
`
`Nitinol soldering device
`
`Template equipment
`
`Aqueous solutions for the flow system
`Preservation material
`
`Dissection tools
`
`Pig Hearts
`
`9. Operating Room
`10. Valve Flow Model with software
`
`ll. 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
`
`
`
`l7
`
`NORRED EXHIBIT 2051 - Page 17
`
`

`

`Fu Fung Hsieh PhD
`Procedure
`
`Troy Norred MD
`
`Timothy Catchings MD
`Darla Hess MD
`
`Wayne McDaniels PhD
`Michael Sturek PhD
`
`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 3 4 5 6
`
`7 8 9 l
`
`Pressure gradients
`
`Cardiac Output
`
`Peripheral resistance
`
`Dissection of the spec
`
`imens
`
`. Histological Data
`
`. Morphologic data
`. Visualization Data
`
`In—Vitro Modeling system
`
`O. Histological sections
`
`
`
`
`
`X Budget
`1. Flow Model System
`Laser Doppler Anometer
`Vivitec Flow Model
`
`Software analysis System
`
`($1500.00)
`
`($13,500)
`
`($650.00)
`
`Post~Doc Salary for 6 wee
`Secretarial Time
`
`ks
`
`($3750.00)
`($12.00/hr x25
`
`hr/wk)
`
`Sodium Iodide, glycerol,
`
`1%water by volume
`
`
`
`Valve Modification
`
`Pig Hearts
`
`($75.00)
`
`($10.00/heart)
`
`m
`
`NORRED EXHIBIT 2051 - Page 18
`
`

`

`
`
`Slaughter House Material
`
`($150.00)
`
`Technician Processing Time
`Preservation Material
`
`($17.00/hr)
`
`Liquid Nitrogen
`
`Formalin
`
`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
`
`(
`
`$25.00/canister)
`
`($5.00/6oz)
`
`(17.00/hr)
`
`($10.00/day
`
`(13.00/hr)
`
`($1950.)
`($950.00/ft)
`($2500.00)
`time
`($25.00/hr)
`
`v
`A.
`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
`Secretarial Time
`
`($250.00)
`(20hrs)
`
`Total cost of for 6 week project
`
`$66,610.00
`
`Aorta Valve Modeling
`
`
`
`I9
`
`NORRED EXHIBIT 2051 - Page 19
`
`

`

`20
`
`NORRED EXHIBIT 2051 - Page 20
`
`
`
`
`
`DATA
`
`APmax : 300mmHg = 30cmHg
`
`Q : Sliters/min = 5000cm3/min
`
`D x
`
`3cm,
`
`R z1.5cm
`
`Gr >2 lZOOmmHg
`
`(rupture stress)
`
`n (blood) 2 1 cP : 0.01P
`
`A = nD2
`
`n9/4 = 7.1cm2
`
`4 9
`
`.4cm
`
`
`
`
`
`
`
`
`
`

`

`
`
`the aorta as a rigid capillary and the blood as a
`Treat
`homogeneous liquid with viscosity of
`lcP.
`
`Some important quantities:
`
`Iw = 392
`
`shear stress at wall
`
`2L
`
`L : length
`
`V =
`
`Q mm_
`UR2
`
`Y : 3&9
`HR2
`
`Mean velocity
`
`Shear rate at wall
`
`IN =
`
`léggmwgwgggm Hg
`2
`(1cm)
`
`=22.Scm
`
`Re = DVP
`2 gem * 12cm/sec * 1gm1qm3
`
`u 0.01g/cm/sec
`.
`= 3600
`w Ree 1200
`
`for blood, n=3cP
`
`
`
`V = QOOOcm3/min = 1min
`
`n
`(l.5)2*cm2
`
`=12cm
`
`60sec
`
`sec
`
`y = 4(5000cm3/min)
`
`l min/60$ : 30/sec
`
`fl
`
`(1.5)3 * cm3
`
`The maximum stress upon the cusps when the vlave is
`closed is
`
`Fmax 2 AP*A = 30.0cmHg *7.lcm2 m 200cmHg/Cm
`
`To keep the rupture stress below lZOOmmHg, we require a
`
`certain amount of stent/aorta interface area.
`
`Fmax = or * A(stent)
`
`2
`If we specify that or N 300mmHg,
`
`then we need
`
`200.0cmHg * cm2
`
`= 300mmHg * A(stent)
`
`
`
`M
`
`NORRED EXHIBIT 2051 -PageZ1
`
`

`

`
`
`A(stent) : 7.lcm2
`
`Convert P = 300mmHg
`
`To
`
`MP2
`
`300mmHg * 1‘0.§i9i§l-
`760mmHg
`
`lggg : 0.04MP2
`P2 *
`10(6)P2
`
`From Pilhey
`
`TA
`
`407.2, p55
`
`1994
`
`P1
`
`Uniform load simply
`
`supported
`
`AllélailJ/JLA
`
`r ::2
`
`
`
`m
`
`ipgig»
`1 — r
`
`
`* we
`
`h
`
`+
`
`0.376 (g9)(3)
`
`h
`
`ggig) F;L;§§
`2m)L1«Rm)
`
`fig
`h
`
`+ 0.244(WO2g2)l
`
`l1
`
`J
`
`Wo = 7.5 x lO(~6)m
`
`6(rq) = 8.4MP2
`
`
`
`When the valve is closed,
`
`the
`
`maximum force is given by Fmax
`
`3A? *A.
`
`How is this force
`
`aorta/stent interaction.
`
`transmitted.
`
`This stress must be opposed by
`
`a stress arising from
`
`
`
`22
`
`NORRED EXHIBIT 2051 - Page 22
`
`

`

`
`
`Since we know the aorta can withstand 30cmHg hydrostatic
`pressure (which is less than 120.0cmHg rupture strength),
`we will use 0(r) : 30.0 cmHg and thus
`Astent z 7.1cm(2)
`For stents of lmm width,
`60degrees
`
`lOmmhigh and an angle of
`
`2
`
`12
`
`4
`
`l4
`
`6
`
`16
`
`8
`
`18
`
`20
`
`10
`
`20 x 0.1 cm X 1cm = 2cm(2)
`
`NEED 4 APPROXIMATED STENTS TO WITH STAND 300mmHg
`
`RQ Friction must hold the stent in place
`
`COF = Ft
`
`Fn
`
`24>?
`
`= AP *A = 30cmHg
`Ft 3 Fmax
`200cmHg/cm(2)
`
`* 7.1cm(2)
`
`H
`
`The norma force exerted by the stent
`by the arterial wall)
`is
`
`( which is opposed
`
`*
`
`Fn = Ft
`
`
`: o(r)
`* A(stent)
`
`Cof Cof
`
`
`
`23
`
`NORRED EXHIBIT 2051 - Page 23
`
`

`

`
`
`For the stent not
`Ft/Cof
`
`to move,
`
`the normal force must exceed
`
`> Ft/Fcof > 6(r) :El§£§flfi>
`Fn
`_....................................................i MMbe
`r
`~ 0.20
`
`=
`
`WW ,1
`200cmHg cm(2) ____________________________________
`
`If Cof > 0.20,
`
`Fn : lOOOcmchm(2)
`
`on
`
`= Fn
`
`=
`Astent
`
`lOOOcmchm(2)
`7.1cm(2)
`
`i!
`
`l40cmHg
`
`Thus this approximates the rupture stress of lZOcmHg
`(lZOOmmHg)
`
`
`
`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).
`
`
`
`24
`
`NORRED EXHIBIT 2051 - Page 24
`
`

`

`
`
`
`
`
`
`The model is static and therefore will limit the
`
`information about stress
`important
`assessment. However,
`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
`
`In the pulsed laser system,
`and the other laser sensors.
`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
`
`t