NORRED EXHIBIT 2241 - Page 1
`Medtronic, Inc., Medtronic Vascular, Inc.,
`& Medtronic Corevalve, LLC
`v. Troy R. Norred, M.D.
`Case IPR2014-00395
`
`

`
`(
`
`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. This cavity plays an
`important role in the mechanism of valve closure (referenced Mano Thubrikar). An
`oblique section through the leaflet—sinus assembly shows this remarkable relationship.
`(Figure4). 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. This suggests that the shape of the
`leaflet—sinus assembly is importantfljlietermining how stresses are developed within the
`valve.
`It is also this relationship that allows the valves to close without pulling upon the
`aortic valve as has been suggested. Finally, this relationship of the sinuses and valve
`allow for the efficient flow of blood ’
`,
`,e,coro,nary,,,ostia.
`
`The aortic root has been.
`ribed to expandxcluring ventricular contraction. The
`
`dilatation of this structure by the Po1sselles”"la’wirediides tension, which in turn reduces
`resistance to flow. It is this phenomenon that also allows for complete opening of the
`aortic valve.
`Interestingly when the cusps open
`is inaiiita: M
`
`that is at least the same as before contraction. Mc51~;s;osv;>."1+,"s itiiiisi as even
`larger than the original orifice. (Medical Engineering & PhysicsM1'9(8)i 696—710,1997).
`In more detail, this behavior allows the valve to have reduced circumferential stress and a
`reduced Reynolds shear stress number. This is the number used to evaluate the amount
`,..S,.t,.1i€:SS..in..a..
`System.
`In a similar manner, the inner lining of the cusp of
`the valve, the lamina ventriculafisfixtends into the ventricular myocardium. There is a
`confluence of fibers at the base called the fibrous coronet, which is a distinct separation
`between the elastic fibers above, and the myocardium below. However, this structure is
`not static. In contrast it is a very dynamic structure, which bends and molds to the forces
`that are exerted from the ventricular myocardium (Cardiovascular Research,
`22,7,1988)(Journal of Biomechanics33 (6): 653-658, 2000June). In a similar fashion as
`the aortic root this structure allow the valvular apparatus to open with the least amount of
`strain.
`
`if
`
`if
`
`The coronary arteries arise within or above the sinus of valsalva. The blood flow
`ofthe heart occurs mostly when the ventricle relaxes. At this
`‘csf“t‘hei'a¢s'1?t‘i¢
`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 the most laminar
`flow characteristics. This in turn promotes the greatest amount of flow with the least
`amount of resistance. In disease states where these relationships are lo st, it has been
`proposed that this could lead to increase stress at the coronary ostia. (The Aortic Valve
`CRC press).
`These integral relationship not only pertain to the gross anatomy of the valvular
`apparatus, but also the microanatomy shows the integral nature of these structures. The
`amount of elastin is in a higher concentration as shown by staining methods (American
`Journal of Pathology 445 (7): 1931). This allows a greater amount of dilatation of the
`structures in this area. Further, scanning electron micrographs have shown the unique
`arrangement of collagen in the valves, which permit the unique reversal of curvature,
`which is vital in the fimction of the valve (figure 6)(Anatomic Embryology 172(61):
`1985). The fibers are unusually small and arranged in sheets with unique distances
`between each strand. In theoryifithis would give a greater amount oftensile strength while
`
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`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 better understood in a dynamic state given it is not a
`static structure. To fully understand this structure it is integral to understand 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
`'t minimizes shear stress, resistance to flow and tensile forces.
`The opening anficlosing ofthe 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.
`ffio"st“'c”"dffiprlehenslive“study~
`I £51.
`encompassed a model developed by Bellhouse
`In this model, the flow of fluid
`through the aortic valve was studied by injecting dye within the flow of fluid.
`Some of
`the pertinent observations found within 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 then back into the main stream; 3) During the end of systole the
`vorticeal motion created during contraction foryces the valves back toward a closed
`
`
`position. These observations, é important to shot
`iqpjpqghat absolute pressure differences
`created between the aorta and ventricle a‘:~’e”nolt'the source of initial closure of the aortic
`
`valves. In fact, it would be detrimental to valve stress if these forces dictated closure of
`the aortic valve.
`For example, if two objects are a greater distance apart and a set
`amount of force is applied to each, the greater distance 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.
`In conclusion,
`the cusps and the relationship of closure for prosthetic valves must incorporate passive
`closure during systole that would logically lengthen the lifespan of any such device.
`To expand these concepts, we must explore the theory of laminar flow as it relates
`to aortic valve function.
`Laminar flow is predicted by Reynolds number, which
`incorporates the laws as described by Outsell and Bernoulli. In general, the lower the
`j *wR£yI’ifSld§Wrimnber he more likely that flow will be laminar. The equation that describes
`‘
`the Reynolds nu I er 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 system is also predicted by the rate of acceleration or deceleration that is
`described by the Strouhal number. In explanation, in a system where viscosity, velocity
`and radius vary slightly, the rate of acceleration or deceleration predicts laminar versus
`non laminar flow. When looked at in perspective, it is easy to see the relevance. Only a
`small pressure difference is required to open the native aortic valve. Maintaining a small
`
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`pressure difference minimizes acceleration to flow. Thus, laminar flow is more likely.
`The deceleration phase is naturally a gradual process; however, as stated above it is the
`relationship between the sinuses and the cusps, which 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 is 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
`
`
`
`III.
`
`Adult Aortic Stenosis
`
`Aortic stenosis is a condition where there is a 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 produces
`pressure overload on the left ventricle. Clinically, this produces dramatic
`symptoms, and 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. In the early 20”‘ century the
`most common etiology 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 filsion 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, then the valve has increased deterioration
`and calcification. Unfortunately, post infectious aortic stenosis can result in rapid
`progression to severe aortic stenosis. Of the total cases of aortic stenosis in the 1940’s,
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`reportedly 52% were the result of rheumatic fever. Currently, less than 9% of the cases
`of aortic stenosis are post inflammatory.
`
`’
`
`A
`
`
`
`(A)
`
`(B)
`
`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.
`Inherently, it loses the anatomic relationship between the sinuses and the valve cusp.
`Further, the opening and closing characteristics of the valve are altered which in turn
`alters the acceleration and deceleration to 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.
`Currently, the most common cause of aortic stenosis is degenerative aortic
`stenosis. By the 7”‘ decade, the normal aortic valve can undergo degenerative changes.
`The characteristics, which define these changes, are increased calcium deposition along
`the body of the cusps. Predominantly the calcification is located at the bases of the cusp
`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
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`stenosis reaches as high as 12% in octogenarians. This population accounts for 51% of
`the current cases of aortic stenosis. The factors, which promote aortic stenosis in
`
`
`
`a normal valve are the same as those, which contribute to athersclerosis in arteries (nejm
`1996). Thus, degenerative aortic stenosis has become the most prevalent etiology.
`Clinically, symptomatic aortic stenosis has not only disabling symptoms, but also
`a high mortality. Currently aortic stenosis is graded upon the calculated aortic valve area
`(figure7). As represented in the table severe aortic stenosis occurs when the valve area
`is less than 1.0cm2(AVA index of <0.6crn2/m2). The most frequent symptom is angina
`pectoris occurring in up to 70%. 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 is a
`condition that can produce severe life limiting symptoms and ultimately is fatal.
`
`IV.
`
`Aortic regurgitation
`
`30
`
`30
`
`20
`
`'0
`
`IO
`
`Aortic Regurgitation is a condition where there is backflow of blood from
`the aorta to the left ventricle. This regurgitation results in a decreased effective
`cardiac output. In turn, longstanding aortic regurgitation results in an increased
`amount of volume work on the left ventricle. In time, the left ventricle begins to
`dilate. Contrary to aortic stenosis, this condition can be well tolerated for many
`years. However, once the left ventricle begins to dilate and lose its contractility, it
`
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`The most common etiology of aortic regurgitation has been rheumatic
`fever. However, just as 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 root dilatation in certain patients. Moreover, a dilatation of
`the aortic root can in essence 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 leak.
`However, there are unique entities, which promote aortic regurgitation.
`For example, Marfan’s syndrome is a disease in which there is defective collagen
`deposition. This 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.
`In a certain portion of
`patients, aortic dilatation with concomitant aortic regurgitation is the only
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`manifestation of their hypertension. Thus, there are distinct differences, which
`can cause aortic regurgitation in the presence of a structurally normal aortic valve.
`Severe aortic regurgitation has a poor prognosis. From the work by
`Goldschlager et al it was 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, among those patients who undergo surgical replacement for aortic
`regurgitation, they report an increase level of functioning that they didn’t realize
`they had lost.
`In fact, although more well tolerate, aortic valve regurgitation is a
`serious disease, which is limiting to a patient’s lifestyle as well as life.
`V. Surgical Therapy
`
`For patients suffering from aortic regurgitation or aortic stenosis, the best
`therapy to date is surgical. There is no questioning the benefit of surgical vs. medical
`management for these conditions. The 5-year survival for 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. Unfortunately, aortic
`valve replacement carries certain surgical morbidity and mortality.
`Aortic valve replacement may be among the mo st invasive surgeries. Logically,
`the surgery requires 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 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 as 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 this
`is a central point of attachment for the chest cavity, it must withstand considerable force.
`The sternum currently is wired back into place with a series or interrupted suture wire
`from the cranial end to the dorsal end. The difficulty is in wound dehiscence and
`infection. The patients who are at risk include the diabetics, the immunosuppressed and
`the elderly. Wound dehiscence or 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.
`Among the immediate risk there are significant decreases in cerebral function.
`The bypass pump allows the surgeon to operate in a controlled fashion to achieve good
`results. It is being more and more realized that this in and of itself promotes dysfunction.
`There is an immediate risk of major stroke that is reported to be 1 to 3%. However,
`among those patients without recognizable strokes, there are still reported neurological
`deficits and deficits in cognitive function. When this cognitive dysfunction is measure in
`terms of IQ points it can be dramatic. In one series, up to 60% of patient undergoing
`bypass surgery had an immediate drop in their IQ scores by 20 points. This can be
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`dramatically recognized by family and friends who are likely to report a distinct drop in
`mental alertness. Thus even in a techniqucly successfiil surgery there can be a substantial
`drop in cognitive fiJI'ICl2i0I'l.
`The long—term risk includes infectious endocarditis, thromboembolism and valve
`dysfunction.
`
`"3
`O
`
`The objective ofthis study is to demonstrate the feasibility ofa percutaneously
`
`placed aortic valve.
`
`II.
`
`Hypotheses:
`
`I. We speculate that a cross-linked nitinol expandable stent can be annealed
`to a biological valve (see appendix).
`2. We speculate that the flow characteristics produced by this uniquely
`designed device will perform in a similar fashion to that of other
`bioprosthetic valves.
`3. We speculate that the strain relationships will be proportionate to the
`native valve structure
`
`4. We speculate that the flexible base will allow more even dispersion of
`flexion strain.
`
`5. We speculate that the interface of the stcnt aorta will he suliicient to
`maintain the valve in the proper position for function in-vivo.
`6. We speculate that the stent/valve can be inserted percutaneously.
`7. We speculate that the ascending aorta can accornniodate a stented valve
`structure without rupture or significant dissection.
`8. We speculate that the ascending aorta and coronary arteries can be
`visualized with existing techniques.
`9. We speculate that with detailed visualization the stent!valve will be place
`as to avoid obstructing the native valve fimction.
`10. We speculate that the stentfvalve combination will not significantly
`obstruct coronaiy flow.
`l 1. We speculate that a biotome can be directed across the interatrial septum
`into the left ventricle.
`
`12. We speculate that once inserted into the lefl ventricle that the native valve
`can be excised in a controlled manner.
`
`13. We speculate that an animal would survive the placement ofa
`percutarteous valve.
`I4. We speculate that the stented aortic valve in vivo will have a gradient of
`less than lflmmhg.
`
`111.
`
`Equipment and supplies
`
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`1. Lab associated equipment for the modification if needed of the existing
`valve. .
`
`
`
`‘°.°°.\‘.°‘.V‘:'>‘."’!\’
`
`Nitinol wire
`
`Nitinol soldering device
`Template equipment
`Aqueous solutions for the flow system
`Preservation material
`
`Dissection tools
`
`Pig Hearts
`. Operating Room
`10. Valve Flow Model with software
`
`11. Statistical Software
`
`12. Intracardiac echocardiography (Probes and Base)
`1 3 . Catheters
`
`IV.
`
`14. Biotomes and microengineering tools
`Associates
`
`1. Flow Modeling
`i. Troy Norred MD
`ii. Steven Lombardo PhD
`
`iii. Frank Fu PhD
`
`2. Valve Development
`i. Troy Norred
`ii. Fu Fung Hsieh
`iii. Harold Huff
`
`3.
`
`In Vitro Modeling
`i. Troy Norred MD
`ii. Steve Lombardo PhD
`
`iii. Fu Fung Hsieh PhD
`4. Procedure
`
`i. Troy Norred MD
`ii. Timothy Catchings MD
`iii. Darla Hess MD
`
`iv. Wayne McDaniels PhD
`v. Michael Sturek PhD
`
`5. Editing and Data analysis
`i. Troy Norred MD
`ii. Greg Flaker MD
`iii. Fu Fung Hsieh PhD
`iv. Steven Lombardo Phd
`
`v. Timothy Catchings MD
`vi. Darla Hess MD
`
`vii. Frank Fu PhD
`
`viii. Wayne McDaniels PhD
`ix. Michael Sturek PhD
`
`Data Acquisition
`1. Hemodynamics
`
`
`
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`i.
`
`ii.
`
`Pressure gradients
`Cardiac Output
`Peripheral resistance
`2. Dissection of the specimens
`i.
`Histological Data
`Morphologic data
`3. Visualization Data
`
`iii.
`
`ii.
`
`VI.
`
`In—Vitro Modeling system
`4.
`5. Histological sections
`Budget
`1. Flow Model System
`i. Laser Doppler Anometer
`ii. Vivitec Flow Model
`iii. Sofiware analysis System
`iv. Post—Doc Salary for 6 weeks
`v. Secretarial Time
`hr/wk)
`vi. Sodium Iodide, glycerol, l%water by volume ($75.00)
`2. Valve Modification
`
`($1500.00)
`($13,500)
`($650.00)
`($3750.00)
`($12.00/hr X25
`
`i. Pig Hearts
`1. Slaughter House Material
`2. Technician Processing Time
`ii. Preservation Material
`
`1. Liquid Nitrogen
`2. Formalin
`3. Clean up time
`4. Freezer Space Rental
`5. Lab Space Rental
`iii. Nitinol Wiring
`1. Soldering Kit
`2. Nitinol wiring
`3. Engineering Consultant Fee
`iv. Technician and Physical Plant time
`v. Secretarial Expense
`1.
`10 hours/week
`
`vi.
`
`($10.00/heart)
`($150.00)
`($17.00/hr)
`
`($25.00/canister)
`($5.00/6oz)
`(17.00/hr)
`($10.00/day
`(13.00/hr)
`
`($1950.)
`($950.00/fl)
`($2500.00)
`($25.00/hr)
`
`3. Experiment with Pigs
`($75.00/pig)
`i. Pigs
`($110.00/day
`ii. Fluoroscopic Time
`($17.00/hr)
`iii. Technician time
`($500.00)
`iv. Lab expense
`v. Catheters (variable if donated, but approx. $200.00)
`vi. Data Sofiware (included in Fluoroscopic room)
`vii. Statistician Expense
`($250.00)
`viii. Secretarial Time (20hrs)
`4. Total cost of for 6 week project
`
`$36,610.00
`
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`gal
`
`VII.
`
`Protocol
`
`1. Flow Modeling
`The initial experiments will be performed to assess the valvular function in a
`flow model. As listed in equipment and supplies, the systems used include a
`simulated flow model and devices used to measure the pressure and resistance.
`(See adjacent picture). The models are static and therefore limit the assessment.
`However, important stress and strain relationships can be obtained. The valve
`will be initially placed by hand in the model system. The basic measurements
`will be derived, and from these measurements we will publish our first data on the
`experimental valve. The timeline for these experiments are thought to be 4 to 6
`weeks. The initial bulk of our time will be in the preparation for these
`experiments. During this time several mock runs will be used to modify the
`devices as necessary to obtain the most accurate hemodynamic information.
`Once we have accurate information concerning laminar flow characteristics,
`Reynolds number and strain relationships, we will proceed to practice for in-vivo
`experiments.
`The flow system has been developed to have set points of measurements
`embedded at certain distances from the valve. In a 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.
`In the flow models, there can be taken high-speed photography to demonstrated
`the function of early closure in relationship with sinuses. (Annals of Biomedical
`Engineering. Vol. 26). Thus, the flow model measurements coupled with
`functional data will be reported.
`The final phase of these experiments 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 that variations in different geometric configurations alter
`the fimction. Thus, with detailed in—vitro experiments we will save valuable time
`and resources in pre—experimental troubleshooting.
`2. Valve modification
`
`The valve/stent combination has reached a point in design and
`development where modification must be backed by experimental direction. The
`initial design has several areas that may need modification. The most obvious is
`the stent arrangement. For maximum compression, it has been proposed that an
`interlaced series of nitinol wire would be favorable. This may hold to be true,
`however, reinforcement at the base may be necessary for more stability. Further,
`carefiil consideration of the sinuses may necessitate a more direct modeling
`system. It is possible that for each individual aortic root the normal variance may
`preclude a one size fits all approach. For example, the placement of the coronary
`ostium varies significantly among individuals. It seems logical that a system,
`which avoids directly obstructing the coronaries, would be preferable. Differing
`designs can be employed to exactly set the relationship of an opening in the
`stented structure. The angle between the coronaries, the depth of the sinuses, the
`
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`\3
`
`1
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`size of the cusps directly opposite the ostia and the degree in which the stented
`segments contour the ostia may be needed for the most effective percutaneously
`replaced valve.
`With the placement of the valve, it is crucial to allow enough distance
`between the native valve and the coronaries. It has been shown that differing
`techniques of harvesting biological valves can have a dramatic impact on the
`function. When a valve is harvested and placed in formalin, it undergoes an
`amount of swelling from cellular death and necrosis. This can increase the
`thickness of the valve. Increasing the thickness of the valve can be detrimental to
`the placement by inhibiting the flow of blood into the coronary ostia. Moreover,
`with more cellular death the longevity and function of the valve may be
`negatively impacted. Our initial valve development will necessitate differing
`techniques of preservation. We will try simple formalin preserved valves as well
`as cryopreserved valves. Differing buffering solutions may also be evaluated if
`found necessary. Thus there are several considerations in the modification of this
`valvular model.
`
`I have made several prototypes and find considerable variability in the
`interface of the stent and valve. Whether this variability will be important in the
`overall function of the valve is unknown at this time. Our initial experience
`reveals the meticulous nature of the annealing process. If a single suture is
`disrupted the entire valvular apparatus can tear. Diligent work and documentation
`to the most effective way to anneal the two components of the valve is necessary.
`Fortunately, much of this work has begun and many lessons have been learned,
`but more time and resources will need to be devoted to this line of modification.
`
`An estimate of one 40-hour week dedicated to this endeavor is realistic.
`
`A potential problem with a nonsurgically placed valve is perivalvular leak.
`If the edges of the valve begin to lift and form a low resistance channel, the valve
`may begin to develop torque upon itself, which may ultimately lead to valvular
`dysfunction and even failure. In addressing this hypothetical problem, it has been
`proposed to use a rim of perivalvular material to act as a counter valve, which
`seals itself hydrostatically and prevents or limits perivalvular leak. The in—vitro
`flow model will be invaluable in assessing this possibility. We will use the time
`at the end of the flow modeling to adjust for this possibility. Of the many
`possibilities that have been entertained, the two most direct methods of limiting
`this possibility are root mimicry and pericardial sleeves. In explanation, the root
`with the sinus morphology preserved will be attached to the proximal portion of
`the stented structure. Therefore, when the structure expands the lateral force of
`blood will create a large surface from which the intima can adhere. This same
`concept may be applied to the pericardium. It may be more useful because it is
`more malleable and more easily sutured into the stent structure. It is readily
`apparent that a detailed evaluation of the valve functions in each area will be
`needed before advancing to in—vivo experiments.
`The final consideration of valve modification involves the deployment of
`the stented valve. Several issues are potentially limiting in the expansion of a
`collapsed valve. The most immediate concerns involve the ability of the
`stent/valve connections to hold while expanding. Our initial experience has been
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`NORRED EXHIBIT 2241 - Page 13
`NORRED EXHIBIT 2241 - Page 13
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`favorable, but upon close evaluation of the valves we have discerned micro tears
`in the suture. These micro tears are obviously concerning in the development of
`mechanical failure. Potential solutions to this problem involve differing suture
`techniques and bioglue to seal the valve before it is collapsed. Histological
`examination will be required when the in—vitro model is tested. After all these
`points have been addressed we will proceed to in-vivo modeling.
`3. Catheter design
`The catheters required to place the experimental valve will be kept very
`simple initially. We will use the largest catheters available in the initial in—vitro
`attempts. The catheters from outdated stock are unfortunately too small.
`However, contact with Cordis has produced some promising leads as to the
`availability of larger catheters. Further, in the Dept. of Engineering, there are
`facilities available for the development of new catheters. If needed, Dr.
`Lombardo and Dr Fu have the ability to liaison this portion of the experiment.
`The in-vivo experiments will necessitate an entire system of native valve
`modification or extraction.
`I have designed different catheters that promote the
`percutaneous removal of the aortic valve. However, it is premature to divert
`much time to its development in the initial stages. As a matter of discussion, the
`most direct way of removing tissue is by biotome extraction. Upon this theme
`several different catheter types have been proposed, but the most useful will
`employ an anchoring device in to the thickened aortic valve.
`Initially, a catheter
`will be guided into the left ventricle via a transeptal approach. The catheter will
`be attached by a deployable screw into the native valve. This will allow the
`catheter to move with the valve movement. By moving with the valve
`translational variation with movement will be minimized. For example, if a man
`is on a ladder, which is swaying alongside a telephone pole, which is, also
`swaying then making repairs would be difiicult. Especially if the two movements
`were independent of each other. However, if the man were wrapped to the pole
`then the pole and the man are moving with the same motion. To the man, it
`would appear as if the pole were stationary. The same concept applies with
`extraction of a moving valve. With the device anchored, controlled sections of the
`native valve will be snipped out. It is unknown at this time whether complete
`removal of the aortic valve will be necessary. At a minimum, there will always
`be a rim of valve remaining on which the percutaneous valve will sit. With further
`understanding of the technique it has become apparent that simple aggressive
`debulking may accomplish the same task. Thus, both possibilities should be
`explored.
`The second set of catheters is a more ambitious project. These catheters
`involve the system of rotablation. In this design, a catheter with two lumens is
`used to guide a rotablator device onto the native valve. The tip of the catheter has
`a roof of material to serve as a template guide. This allows the rotablator device
`to come into contact with the native valve and chip away the native structure. A
`continuous high flow saline solution is directed into the return lumen of the
`catheter. This creates