TOB
`15612
`+1
`,_
`
`t
`
`UNlVERSITE DE LAUSANNE
`
`FACULTE DE BIOLOGIE ET DE MEDECINE
`
`SERVICE DE CHIRURGIE CARDIO-VASCULAIRE
`
`Chef de service: Professeur Ludwig K. von Segesser
`
`CHIRURGIE VALVULAIRE
`PAR VOlE ENDOVASCULAIRE
`
`THESE
`
`Presentee it la faculte de biologie et de medecine de
`
`L' Universite de Lausanne pour l'obtention
`
`Du grade de
`
`DOCTEUR EN MEDECINE
`
`par
`
`Zhou Junqing
`
`Medecin diplome de l'Universite de Zhejiang, Chine
`
`Lausanne
`
`2003
`
`Edwards Exhibit 1032, pg. 1
`
`
`15612
`+1
`,_
`
`t
`
`UNlVERSITE DE LAUSANNE
`
`FACULTE DE BIOLOGIE ET DE MEDECINE
`
`SERVICE DE CHIRURGIE CARDIO-VASCULAIRE
`
`Chef de service: Professeur Ludwig K. von Segesser
`
`CHIRURGIE VALVULAIRE
`PAR VOlE ENDOVASCULAIRE
`
`THESE
`
`Presentee it la faculte de biologie et de medecine de
`
`L' Universite de Lausanne pour l'obtention
`
`Du grade de
`
`DOCTEUR EN MEDECINE
`
`par
`
`Zhou Junqing
`
`Medecin diplome de l'Universite de Zhejiang, Chine
`
`Lausanne
`
`2003
`
`Edwards Exhibit 1032, pg. 1
`
`
`
`UNIVERSITE DE LAUSANNE
`
`FACULTE DE BIOLOGIE ET DE MEDECINE
`
`SERVICE DE CHIRURGIE CARDIO-VASCULAIRE
`
`Chef de service: Professeur Ludwig K. von Segesser
`
`CHIRURGIE VALVULAIRE
`PAR VOlE ENDOVASCULAIRE
`
`THESE
`
`Presentee a la faculte de biologie et de medecine de
`
`L'Universite de Lausanne pour l'obtention
`
`Du grade de
`
`DOCTEUR EN MEDECINE
`
`par
`
`Zhou Junqing
`
`Medecin dip16me de l'Universite de Zhejiang, Chine
`
`Lausanne
`
`2003
`
`BCU - Lausanne
`
`*1094410178'"'
`
`Edwards Exhibit 1032, pg. 2
`
`
`
`JJI
`I U (";;\n I I D g~IVERSITE
`\!!J III '= lAUSANNE
`
`Faculte de biologie et de medecine
`
`Licence, Diplome, Doctorat decerne
`
`Attention: ces donnees servent de support a I'impression du titre.
`No d'immatriculation (figurant sur la carte d'etudiant) : 01-426-766
`Mme 0
`M.~
`Nom:
`ZHOU
`Prenoms :
`Junqing
`Lieu de naissance (ville, pays): Zhejiang, Chine
`Date de naissance:
`08.12. 1966
`Nationalite : Chinoise
`Pour les Suisses, commune d'origine et canton:
`Adresse valable pour I'envoi du grade: Cardiothoracic Department
`The No 1 People 's Hospital of Shaoxing
`61 East Street Shaoxing
`Zhejiang CHINE
`
`POUr Ie grade de docteur, completer les rubriques suivantes :
`
`Premier grade obtenu : Medecin diplomi de Chine
`
`Date d'acceptation de la these par Ie Conseil de Faculte : 17 septembre 2003
`
`Titre de la these: Chirurgie valvulaire par voie endovasculaire
`
`Nom et prenom du directeur de these:
`
`Prof Ludwig K. von Segesser
`
`Instltut ou subdivision de la Faculte: Service de chirurgie cardio-vasculaire
`o Diplome.de medecin de l'Universite
`o Diplome UNIL de medecin specialiste
`o Diplome de specialiste en pharmacologie et en toxicologie
`I3J Doctorat en medecine
`Lieu et date :
`'
`
`Lausanne, Ie 30 janvier 2004/sda
`
`A renvoyer au Rectorat de IUniversite de Lausanne, BRA Dorigny, 10
`
`Sign~trr~
`~~
`Prof atrice
`
`Edwards Exhibit 1032, pg. 3
`
`
`
`Contents
`
`Contents ... .... .... .. ................ ....... ... ......... ............. ... ..................... 1
`
`Introduction .. .. .... .. .. ........ ...... ........... ....... ... ... .. ........ ................... .. 3
`
`1. History review ......................................................................... 5
`
`1.1 Valve surgery .... .. .. .... .. ................................................ 5
`
`1. 1. 1 Before the era of heart surgery ................ .... 5
`
`1.1.2 The era of close heart surgery ..................... 6
`
`1.1.3 The era of open heart surgery .... ................. 7
`
`1. 1.4 The era of prosthetic cardiac valves.. .......... 8
`
`1.2 Endovascular stent graft ........................ .......... .... .. . 1 4
`
`1.3 Endovascular valved stent .. ................................ ... 1 6
`
`2. In vitro evaluation of valved stents ............................ .. .... ... 1 8
`
`2.1 Device construction ........ .. .. .. .................................. 1 8
`
`2.2 Device leakage test.. ........ .. ...... ............ ...... .... .. .... .. 2 1
`
`2.3 Mock loop simulation test.. .... ...... .... ...................... . 2 3
`
`2.3.1 Objective: .............. .... .... ................................. 2 3
`
`2.3.2 Materials and methods: .. .......... .................... .. 2 3
`
`2.3.3 Results ........................................................... 2 7
`
`2.3.4 Conclusion: ........ .. ............................. ..... ......... 2 8
`
`3. In vivo evaluation of valved stents ...... .. .............................. 2 9
`
`3.1 Inferior vena cava ...................... .. ........................... 2 9
`
`Edwards Exhibit 1032, pg. 4
`
`
`
`3. 1. 1 Background: ........... ... .... ................................. 2 9
`
`3. 1.2 Materials:.. ... .... .... .. ......... .............................. .. 3 0
`
`3.1.3 Methods: ... ........ .............................................. 3 1
`
`3.1.4 Results: .......................................................... 3 3
`
`3. 1.5 Discussion .... .... ................................ ...... ........ 3 5
`
`3.1.6 Conclusion: ..... ... ....... .................. ..... ... .. .......... 3 8
`
`3.2 The pulmonary valve position ... .............................. 3 9
`
`3.2.1 Background.. ........................................ .......... 3 9
`
`3.2.2 Materials ......................................................... 4 0
`
`3.2.3 Methods .......................................................... 4 1
`
`3.2.4 Results ........................................................... 4 5
`
`3.2.5 Discussion. .......... ........ ............................ ... ... . 4 9
`
`3.2.6 Conclusions .. ...... ...... .... ............................. ..... 5 3
`
`Conclusions ......................................................... ............. ...... 5 4
`
`References .......... ............................ .. ......................... ............ 5 5
`
`Acknowledgements ........... ... ................... .. ... .......................... 6 4
`
`Resume ... ....................................... .. ... .................. .. ... ............ 6 5
`
`Appendices .............................. ... .. .......................... ................ 6 9
`
`2
`
`Edwards Exhibit 1032, pg. 5
`
`
`
`Introduction
`
`A valved stent
`
`is a combination of a biological valve and
`
`self-expandable endovascular stents -
`
`the former functions as a prosthetic
`
`valve, the latter allows fixation in an artery without suturing. Due to the
`
`specific design of this valve, it is possible to perfom valve replacement with
`
`endovascular catheter technique avoiding cardiac bypass and sternotomy.
`
`This
`
`technique
`
`IS called either "endovascular
`
`transcatheter valve
`
`deployment" or "trans luminal valve replacement". It is a promlsmg
`
`treatment attractive to both the cardiac surgeons and patients.
`
`Exciting results have been reported by pioneers over the last 40 years.
`
`In 1965, Davies H. deployed a catheter-mounted unicuspid valve above the
`
`aortic valve for the relief of aortic insufficiency (32). In 197 I, Moulpoulos S.
`
`et al designed a catheter-mounted aortic valve that consists of an umbrella
`
`shaped membrane with a controlling unit that unfolds the valve (33)
`
`Andersen H.R. from 1989 to 1992 developed a new stent valve for
`
`transcatheter implantation in subcoronary and supracoronary porcine aorta.
`
`In his experiments, the stent valve consisted of a porcine aortic valve fixed
`
`on a steel wire stent skeleton (34.35). In 1992, Pavcnik and colleagues placed
`
`via percutaneous transcatheter a self-expanding caged-ball valve in the
`
`aortic valve position in mongrel dogs (36). In 1996, Moazami N. et al
`
`3
`
`Edwards Exhibit 1032, pg. 6
`
`
`
`constructed a trileaflet stent valve with bovine pericardium sewn on the
`
`stent(37). In 2000, Bonhoeffer P. and Boudjemline Y. sutured a biological
`
`valve into a platinum stent and successfully performed a percutaneous
`
`pulmonary valve implantation in 5 sheep (38). In the same year, Sochman J. et
`
`al designed a catheter-based aortic valve consisting of a stent cage and a
`
`prosthetic flexible tilting valve disc (39). In 2002, Lutter G. et al deployed a
`
`valved stent with barbs in a porcine aorta (40).
`
`However, all of these experiments demonstrate one or more problems.
`
`For example, the availability of various sizes of valved stents, the degree of
`
`patency and competency of the valve, the fixation of the valved stent in the
`
`artery, the paraprosthetic leakage and the uncertainty with valve function
`
`longevity. Furthermore, large sized valves are still difficult to deploy due to
`
`the large profiles and the large sized introducers required in comparison with
`
`the limited size of the peripheral access vessels. The avoiding of coronary
`
`orifice occlusion
`
`is still a difficulty with transluminal aortic valve
`
`replacement.
`
`Hence, we attempted to develop a new valved stent to overcome these
`
`shortcomings and to explore the feasibility of deployment in the inferior
`
`vena cava (near right atrium), pulmonary valve and aortic valve position by
`
`transluminal technique without cardiac bypass.
`
`4
`
`Edwards Exhibit 1032, pg. 7
`
`
`
`1. History review
`
`1.1 Valve surgery
`
`1.1.1 Before the era of heart surgery
`
`By the late 19th century: Much was known about cardiac anatomy,
`
`physiology, and pathology, but operating on the heart was still a taboo
`
`among surgeons.
`
`15th and 16th century: Leonardo Da Vinci and Andreas Vesalius
`
`secretly dissected and drew the human heart. Leonardo Da Vinci described
`
`the anatomy of the mitral valve as resembling a "bishop mitre" and gave the
`
`'Mitral Valve' its name.
`
`1628: Experiments of William Harvey established the concept of
`
`blood circulation and marked the beginning of modem cardiology (I).
`
`1902: Sir Lauder Brunton (2) suggested the possibility ofperfo~ming a
`
`transventricular valvulotomy
`
`to
`
`treat mitral stenosis. He chose
`
`the
`
`ventricular approach on the grounds that the thicker wall of the left ventricle
`
`would be less prone to bleeding than the thinner left atrium.
`
`5
`
`Edwards Exhibit 1032, pg. 8
`
`
`
`1.1.2 The era of closed heart surgery
`
`1912: Theodore Tuftier (3) successfully dilated a stenotic aortic valve of
`
`a 26 year-old patient by pushing the invaginated aortic wall through the
`
`valve with finger.
`
`1923: Eliott Cutler and Samuel Levine
`
`(4) performed the first
`
`transventricular mitral valvulotomy at the Peter Bent Brigham Hospital on a
`
`12 year-old girl using a special knife called a valvulotome.
`
`1923-1928: Cutler (5) and Souttar (6) reported 10 cases of mitral stenosis
`
`surgery - only 2 patients survived these operations.
`
`1948: Dwight Harken (7) and Charles Bailey (8) had arrived at the same
`
`surgical procedure from different backgrounds - one from Boston and
`
`World War II experiences and the other from Philadelphia and laboratory
`
`experiments. They performed their first transatrial commissurotomies to
`
`treat mitral valve stenosis only 6 days apart, Bailey on 10 June 1948 and
`
`Harken on 16 June. A breakthrough in valve surgery was made by both.
`
`6
`
`Edwards Exhibit 1032, pg. 9
`
`
`
`1.1.3 The era of open heart surgery
`
`1953: John Gibbon
`
`(9) performed the first successful open-heart
`
`operation on a human patient using a heart-lung machine, initiating the era
`
`of open-heart surgery. The road to this triumph was fraught with setbacks,
`
`delays, and technical difficulties, yet Gibbon, with his perseverance, was
`
`able to pursue his dream to its end. He describes his first success as an
`
`"event that I hardly dreamed of in 1931," the year he was first inspired by
`
`the idea of extracorporeal circulation.
`
`1954-1955: C.Walton Lillehei (10) began open-heart surgery to repair
`
`VSD and F4 with extracorporeal circulation (the cross circulation
`
`technique). He became one of the most important pioneers in this domain.
`
`1956: Lillehei (II) On May 23, 1956, successfully performed an open
`
`mitral commissurotomy and aortic valvuloplasty in a 52-year-old man with
`
`mitral stenosis and combined aortic stenosis and incompetence. This was
`
`done with the use of a blood pump and the first bubble oxygenator.
`
`7
`
`Edwards Exhibit 1032, pg. 10
`
`
`
`1.1.4 The era of prosthetic cardiac valves
`
`1.1.4.1 Ball valves
`
`1951: Charles Hufnagel developed the first ball valve, a methacrylate
`
`ball contained in a methacrylate tube (12). The ball sat snugly at the proximal
`
`end of the tube during diastole, and three bulbous pouches opened around
`
`the ball with its systolic position at the distal portion of the tube allowing
`
`blood to flow in one direction. In October 1952, the prosthesis was first
`
`clinically used in a patient with aortic insufficiency and was positioned into
`
`the descending thoracic aorta.
`
`1955: In England, Judson Chesterman (13) performed the first reported
`
`mitral valve replacement. A caged ball valve designed by Clifford
`
`Lamboume of the Northern Hospital was placed into a 34-year-old man,
`
`who survived for only 14 hours.
`
`1961: Starr and Edwards ( 14) reported the first four successful valve
`
`prostheses implanted in humans. Starr, a young cardiac surgeon at the
`
`University of Oregon, and Edwards, a mechanical engineer, designed the
`
`Starr-Edwards valve which consisted of an outer methacrylate cage, a
`
`Teflon-covered suturing ring, and a Silicone rubber ball (Fig I). The
`
`Starr-Edward Ball-Valve Prosthesis functioned well, and became one of the
`
`most successful and widely used prosthetic valves that continue today in
`
`clinical use.
`
`8
`
`Edwards Exhibit 1032, pg. 11
`
`
`
`Fig 1. Starr-Edwards Valve
`
`1.1.4.2 Disc Valves
`
`The physiological disadvantages of ball-valve prostheses were soon
`
`recognized. There was an inevitable low-grade but tolerable hemolysis from
`
`the serial impact of the ball on the cage. Also, the effective cross-sectional
`
`area of the valve orifice was not ideal because the poppet occupied a
`
`significant percentage of the orifice area. These considerations led to the
`
`development of disc prostheses.
`
`The Bjork- Shiley tilting-disc prosthesis was first reported in 1969 (15).
`
`This excellent initial prosthesis was developed by Viking Bjork at the
`
`Karolinska Institute in Stockholm, Sweden, working in conjunction with the
`
`Shiley Corporation in California. Several other disc · prostheses were
`
`developed and used briefly (for example: 1963, Lillehei-Cmz-Kaster Tilting
`
`Disc Valve; 1966,Wada-Cutter Tilting Disc Heart Valve etc.), but the Bjork
`
`valve quickly became the disc valve of choice and was widely used for
`
`many years.
`
`9
`
`Edwards Exhibit 1032, pg. 12
`
`
`
`Fig 2. Bjork-Shiley tilting disc valve
`
`In 1977, The St. Jude pyrolytic carbon disc heart valve become the first
`
`bileaflet valve to achieve major success. 20 years later, it remains one of the
`
`most popular and durable prostheses (16). In 1976, Xinon C. (Chris) Posis, an
`
`industrial engineer, and Demetre Nicoloff, MD, a cardiovascular surgeon at
`
`the University of Minnesota, designed a floating hinge valve with the pivots
`
`near the periphery of the retaining annul as and with a central opening. It was
`
`named the St Jude valve, after being suggested by Mr Vil1afana who formed
`
`a company to support the research. The St Jude valve (Fig 3) was first used
`
`by Nicoloff on October 3, 1977 ( 17).
`
`Similarly effective disc prostheses
`
`III current use
`
`include
`
`the
`
`Medtronic-Hall (1977), Omniscience (1978), Carbomedics (1986), ATS
`
`(1992), and others. There seems to be little physiological difference.
`
`Fig3. SUude bileaflet disc valve
`
`1 0
`
`Edwards Exhibit 1032, pg. 13
`
`
`
`1.1.4.3 Biological valves (tissue valves)
`
`The insolvable problem of thromboembolism with metallic prostheses
`
`quickly led to the investigation of tissue prostheses. Initially, different
`
`tissues in the human body were used, especially pericardium and fascia lata.
`
`Senning in Zurich, Switzerland, has extensive experience with aortic valves
`
`constructed with fascia lata(J8). It was quickly found that thromboembolism
`
`was much less common than with valvular prostheses.
`
`In 1967, Donald Ross (19) in London, England, reported the ingenious
`
`concept of replacing the aortic valve with the patient's pulmonary valve
`
`(autologous tissue valve), and replacing the absent pulmonary valve with a
`
`homograft pulmonary valve. With the low pressures in the pulmonary artery,
`
`the durability of the homograft valve is better than in the aortic position.
`
`With the great advantage of freedom from anticoagulation drugs and good
`
`durability for at least 10 to 15 years, the operation has become increasingly
`
`popular throughout the United States and European countries in recent years,
`
`and is now often considered the prime choice when valve replacement is
`
`required in children. The availability of cryopreserved grafts for insertion in
`
`the pulmonary position has helped significantly. The "Ross switch" is now
`
`being increasingly used in young adults.
`
`In 1962, Aortic homograft valves were initially used by Donald Ross (20)
`
`1 1
`
`Edwards Exhibit 1032, pg. 14
`
`
`
`(
`
`in London, England, and also by Barratt-Boyes in Auckland, New Zealand,
`
`in 196i21
`
`). In 1987, Mark 0 Brien (22) reported from Brisbane, Australia,
`
`long-term experiences with cryopreservation. Their remarkable data suggest
`
`that a few cells remain viable even after 10 years of preservation.
`
`Cryopreservation is now generally accepted as the best method for long
`
`periods of preservation. However, the limited availability of homograft
`
`valves in many areas of the world has restricted their widespread use.
`
`Once the low frequency of thromboembolism with tissue valves was
`
`recognized, heterograft valves were investigated because of the limited
`
`availability of homograft valves. Experiences
`
`in
`
`the 1960s with
`
`formaldehyde preserved valves were initially encouraging, but the valves
`
`failed in 2 to 3 years. Fortunately, a few years later it was discovered that
`
`glutaraldehyde was an excellent tissue preservative. This led Carpentier (23)
`
`in Paris to explore the use of porcine aortic valves preserved with
`
`glutaraldehyde. In contrast to all other experiences with different forms of
`
`heterograft preservation,
`
`the durability of glutaraldehyde preserved
`
`prostheses was dramatically better - more
`
`than 90%
`
`functioned
`
`satisfactorily 5 years after implantation, and 75% to 85% after 10 years.
`
`Bovine (calf) pericardial valves, initially used by Ionescu and others (24), are
`
`becoming widely used' as well.
`
`1 2
`
`Edwards Exhibit 1032, pg. 15
`
`
`
`Fig.4 The porcine valve and the pericardial valve.
`
`1.1.4.4 Mitral valve reconstruction (valvuloplasty)
`
`All prosthetic valve have a number of problems: thromboembolism and
`
`the need for anticoagulation, the lifelong risk of endocarditis, and durability.
`
`Metallic prostheses now have excellent durability but require lifelong
`
`anticoagulation. Tissue valves often do not require anticoagulation but have
`
`limited durability, especially after the first 10 years of implantation. Both
`
`types of valves are equally vulnerable to endocarditis.
`
`In the late 1960s and throughout the 1970s, the Carpentier team (25) in
`
`France and the Duran team (26) in Spain explored different forms of mitral
`
`valve reconstruction. Carpentier, one of the pioneers in this field, first
`
`demonstrated that thin mitral leaflet tissue could be excised and successfully
`
`sutured without dehiscence of the suture line when the heart began beating
`
`again. This was primarily accomplished with an annuloplasty, supported by
`
`a prosthetic ring, which removed tension from the suture line in the leaflets.
`
`Over the subsequent years of clinical research (27), the impressive
`
`durability has gradually led to widespread adoption of mitral valve
`
`1 3
`
`Edwards Exhibit 1032, pg. 16
`
`
`
`reconstruction. The operation is especially attractive for young women of
`
`childbearing age. With excellent long-term durability, the operation is now
`
`performed at an early stage of significant mitral insufficiency, preferably
`
`before significant enlargement ofthe left atrium has developed and while the
`
`patient is still in sinus rhythm. Patients who remain in sinus rhythm after the
`
`operation remain strikingly free from thromboembolism and also have an
`
`extremely low frequency of endocarditis (27) .
`
`Fig. 5 The Carpentier-Edwards 'Physio'-annuloplasty ring
`
`1.2 Endovascular stent graft
`
`In 1969, Charles Dotter (28) first suggested the concept of the
`
`endovascular graft. He placed coilspring stent grafts into canine peripheral
`
`arteries, and at two years follow up, the grafts were found to be stenotic but
`
`patent.
`
`In 1983 (29) Dotter developed the first transluminal expandable nitinol
`
`1 4
`
`Edwards Exhibit 1032, pg. 17
`
`
`
`stent graft, whilst Cragg was placing new endoprostheses in dog abdominal
`
`aortas via catheters. Short-term follow-up revealed minimal
`
`luminal
`
`narrowing and excellent vessel patency. He then used this device to treat
`
`abdominal aortic aneurysm (AAA) in dog models.
`
`In 1986 Balko(30) et al. created artificial abdominal aortic aneurysms in
`
`dogs by enlarging aortotomies with Dacron patches. They inserted a
`
`polyurethane covered nitinol frame through a femoral artery cut-down into
`
`the canine aortas.
`
`In 1991 Parodi(3 1) stitched a Dacron tube onto balloon expandable
`
`Palmaz stent and used this device to perform the first human stent graft
`
`implantation for treatment of AAA. Since then, many types of stent grafts
`
`have been developed, some balloon expandable, some self expanding, for
`
`example, Ancure Stent-Graft (EVT/Guidant, Menlo Park, CA), AneuRx
`
`Stent-Graft (Metronic, Sunnyvale, CA), Talent Stent-Graft (World Medical
`
`Inc.Sunrise, FLiMetronic, Sunnyvale, CA), Vanguard Stent-Graft (Boston
`
`Scientific Corp., Natick MA), Zenith Stent-Graft (Cook Inc., Bloomington,
`
`IN), Anaconda Stent-Graft (Sulzer Vascutech, Germany) etc. Each of these
`
`types has its advantages and disadvantages. The endovascular stent graft is
`
`now commonly used in the treatment of abdominal aortic aneurysm.
`
`J 5
`
`Edwards Exhibit 1032, pg. 18
`
`
`
`1.3 Endovascular valved stent
`
`Many exciting results have been reported by pioneers, though there are
`
`still some distances to the summit of success.
`
`In 1965, Davies H. reported a catheter-mounted unicuspid valve that
`
`was deployed above the aortic valve position for the relief of aortic
`
`insufficiency (32).
`
`In 1971 , Moulpoulos S. et al designed a catheter-mounted aortic valve
`
`consisting of an umbrella shaped membrane (33).
`
`From 1989 to 1992, Andersen H.R. developped a stent valve for
`
`transcatheter implantation in subcoronary and supracoronary aorta in pigs.
`
`The stent valve consisted of a porcine aortic valve fixed on steel wire stent
`
`skeleton (34)(35).
`
`In 1992, Pavcnik and colleagues placed a self-expanding caged-ball
`
`valve with a percutaneous transcatheter in the aortic valve position in
`
`mongrel dogs (36).
`
`In 1996, Moazami N et al constructed a trileaflet stent valve with
`
`bovine pericardium sewn on the stent (37).
`
`In 2000, Bonhoeffer P. and Boudjemline Y. sutured a biological valve
`
`into a platinum stent and successfully performed a percutaneous pulmonary
`
`valve implantation in 5" sheep (38). In the same year, Sochman J et al designed
`
`a catheter-based aortic valve consisting of a stent cage and a prosthetic
`
`1 6
`
`Edwards Exhibit 1032, pg. 19
`
`
`
`flexible tilting valve disc (39).
`
`In 2002, Lutter G. et al deployed a valved stent with barbs in the pig
`
`aorta (40) . Six of these valved stents were implanted in the descending aorta
`
`and 8 in the ascending aorta of anaesthetized pigs, 11 of which successfully
`
`implanted and demonstrated low transvalvular gradients (mean end-systolic
`
`gradient 5.4 ±3.3 mm Hg) and mild leakage. The coronary orifice, however,
`
`was problematic.
`
`So far, approximately 7 authors have reported implanting valved stents
`
`in animals. One author reported that a valved stent was clinically implanted
`
`in a failed right ventricle to pulmonary artery conduit. Some problems still
`
`exist such as the limited open area of valved stents, fixation in the aortic
`
`position, avoidance of coronary orifice occlusion, paraprosthetic leakage and
`
`long-term valve function . In summary, the valved stent is still far from
`
`perfect and further explorations are necessary. We are therefore trying to
`
`develop a new valved stent to overcome the existing shortcomings and to
`
`explore the feasibility of deployment in the inferior vena cava, pulmonary
`
`valve and aortic valve positions.
`
`I 7
`
`Edwards Exhibit 1032, pg. 20
`
`
`
`2. In vitro evaluation of valved stents
`
`2.1 Device construction
`
`The following steps describe the procedure followed in constructing
`
`valved stents.
`
`(1) A glutaraldehyde preserved bovine jugular xenograft with native
`
`valve (Venpro®) was cut I.5cm above the valve and I cm below the valve,.
`
`then the thick adventitia was trimmed to make the conduit much thinner.
`
`Two self-expandable Z nitinol stents were dismantled from an endovascular
`
`stent graft (Talent). The diameter of the stents were 30.25±0.15mm, the
`
`height were 15.42±0.34mm.
`
`(2) With 7/0 prolene, two self expandable Z stents with a distance of
`
`5-lOmm were sutured outside of the trimmed conduit, ensuring that the
`
`inside native valve leaflets not be sutured or damaged, otherwise the valve
`
`would leak severely (Fig.6).
`
`(3)Once the valved stent was prepared, its dimension was measured
`
`prior to its preservation in the glutaraldehyde solution. (Tab.l),
`
`I 8
`
`Edwards Exhibit 1032, pg. 21
`
`
`
`Fig. 6 The stent, xenograft and valved stent.
`
`Tab.1 The measured sizes of the valved stents
`
`Length
`
`Inner diameter
`
`Outer diameter
`
`No.
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`(mm)
`
`21.6
`
`23.7
`
`23 .1
`
`23.2
`
`23.2
`
`23.7
`
`23.4
`
`(mm)
`
`21.0
`
`21.5
`
`20.5
`
`22.1
`
`22.2
`
`22.5
`
`21.8
`
`(mm)
`
`26.4
`
`27.6
`
`26.0
`
`26.1
`
`26.1
`
`26.8
`
`25 .2
`
`Mean
`
`23 .1 ±0.7
`
`21.6±0.7
`
`26.3±0.7
`
`I 9
`
`Edwards Exhibit 1032, pg. 22
`
`
`
`Fig. 7 Static leakage test
`
`2 a
`
`Edwards Exhibit 1032, pg. 23
`
`
`
`2.2 Device leakage test
`
`2.2.1 Objective:
`
`To test for valve regurgitation under static water pressure.
`
`2.2.2 Materials:
`
`• A water reservoir
`
`• Calibrated glass tube,
`
`• One silicone tube with an inner diameter of20mm,
`
`• A three-way stopcock,
`
`• A measuring cylinder,
`
`• 7 Glutaraldehyde preserved valved stents.
`
`2.2.3 Method:
`
`The valved stented was tested for leakage by subjecting it under a
`
`pressure of 61 cm of water (or 45mmHg). This was achieved by connecting
`
`silicone tube to the water column (refer to fig 7). The valved stent was
`
`compressed and deployed the inside of the silicone tube by hand. Leakage
`
`from the valved stent was confirmed by measuring the rate of water leak
`
`below it. The silicone tube was used in order to recreate the compliance
`
`characteristic of the vessel.
`
`2 I
`
`Edwards Exhibit 1032, pg. 24
`
`
`
`2.2.4 Results:
`
`In vitro static performance testing ofthe 7 valved stents showed a mean
`
`leakage rate of 32.5±12.4 mUmin when subjected to a simulated afterload of
`
`45mmHg, (See Tab.2). The valved stent was fixed well in the silicone tube
`
`without migration.
`
`Tab. 2. The leakage test under 45mm Hg water column pressure
`
`Valved stent
`Leaking rate
`(mUmin)
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`Mean
`
`35.3
`
`47.6
`
`18.1
`
`28.9
`
`50.1
`
`23.8
`
`23 .6
`
`32.5±12.4
`
`2.2.5 Conclusion:
`
`The new valved stent has little regurgitation and no migration under a
`
`static pressure of 45mmHg,
`
`2 2
`
`Edwards Exhibit 1032, pg. 25
`
`
`
`2.3 Mock loop simulation test
`
`2.3.1 Objective:
`
`To test the valved stent in a simulated dynamic circulation in vitro.
`
`2.3.2 Materials and methods:
`
`2.3.2.1 Materials and setup of the Mock loop
`
`Mock loop was set up according to Fig 8 so as to form a closed
`
`circulation. The picture of this experiment was showed in Fig 9.
`
`Materials were described as following.
`
`• A pulsatile pump
`
`(Bi-ventricular Support
`
`system
`
`5000,
`
`Oberdorfstrassell-13, CH-6342, Baar ZG).
`
`• Several connecting tubes 0112
`
`• A silicone tube with an inner diameter of 18mm
`
`• Two SF Millar pressure transducer catheters (mpc-500, Houston,
`
`Texas, USA.)
`
`• Data recording system
`
`•
`
`Intravascular ultrasound (Clearview, Boston Scientific Corporation,
`
`Sunnyvale, California)
`
`2 3
`
`Edwards Exhibit 1032, pg. 26
`
`
`
`• 7 Valved stents
`• A 24 French stent introducing catheter with a piston inside
`
`(self-made).
`
`• A reservoir
`• Two gloves were regarded as
`
`the compliance chamber that
`
`simulated the elastic resistance of a blood vessel.
`
`~ ,,-:!
`
`-I
`data
`record
`
`tt
`II
`t,
`II
`
`It .'
`
`"
`
`reserV01r
`
`compliance
`chamber
`
`1. __________ _ _____ _
`
`pulsatile
`pump
`
`valved
`stent
`
`Fig 8. Schematic mock loop
`
`2 4
`
`Edwards Exhibit 1032, pg. 27
`
`
`
`-
`
`r--
`
`,
`
`Fig 9. Mock loop device and the dynamic test of the valve
`
`2 5
`
`Edwards Exhibit 1032, pg. 28
`
`
`
`2.3.2.2 Circulation of the mock loop
`
`The pump ran at a flow rate from 2 to 5 litres/min, with a systolic
`
`pressure between 87 and 144 mmHg.
`
`2.3.2.3 Deployment of the valve
`
`The valved stent was deployed into the silicone tube (diameter = 18mm)
`
`in the following fashion.
`
`• One plastic tube was first connected to the silicone tube by a "Y"
`
`connector.
`
`• The valved stent was loaded into the 24 F introducing catheter by
`
`hand cramping.
`
`• The introducing catheter now containing the valved stent was
`
`inserted into the silicone tube via the plastic tube. Once the
`
`introducer was in position, the valved stent was released by
`
`withdrawing the outside catheter while holding the inside piston in
`
`place. After deployment, the introducing system was withdrawn.
`
`The distal end of the plastic tube was connected to a hemostatic
`
`valve permitting the IVUS catheter to go in from here.
`
`2.3.2.4 Measurement
`
`The Millar catheter was used to measure the pressure on both sides of
`
`the valve for estimation of valve gradient.
`
`The Intravascular ultrasound (IVUS) catheter was inserted from the
`
`2 6
`
`Edwards Exhibit 1032, pg. 29
`
`
`
`hemostatic valve to the valved stent to measure valvular function.
`
`2.3.3 Results
`
`2.3.3.1 Peak systolic gradient across the valve
`
`The peak systolic gradient was 6.42 ± 2.75 mmHg at a mean flow rate
`
`of 4.32 ± 0.97 LlMin. In Fig 10, the gradient is the difference between the
`
`two curves.
`
`~ckloop test
`
`r,5 .-
`
`--
`
`- -
`
`--
`
`-
`
`--
`
`------ --
`
`I
`
`I
`
`160
`
`140
`
`120
`
`100
`
`80
`
`0>
`I
`E
`E
`
`~--
`
`.....
`~ -
`~ - - --_.-
`-. -----
`- ---
`---/ -
`60
`40 --.- - - - - - -----_. - --
`J
`20
`~ ~77
`.
`0
`-
`-
`:;;: "' ~ "' ;; "' "' "' N "' a; "' <0 "'
`~ "' ;:. "'
`;;; "' <; "'
`.... N "
`<0 "' "' ....
`;;;
`"'
`....
`""
`""
`'"
`"" " " "
`""
`I--+-- below valve - - - above valve I
`
`0
`
`~
`
`N
`
`N
`
`<Xl
`
`<0
`
`N
`<0
`
`<0
`
`~
`;:.
`....
`
`Fig. 10 The pressure curves recorded by the computer.
`
`2.3.3.2 The open and closed area of the valve.
`
`The open area of the valved stent is 204.8±1O.5mm2 and the closed area
`
`is 0 mm2 (see Fig 11). From the IVUS images, the two leaflets of the valve
`
`are seen to open and close completely. The valve was well fixed in the
`
`silicone tube without any migration.
`
`2 7
`
`Edwards Exhibit 1032, pg. 30
`
`
`
`Fig 11. IVUS views of the valve in open (left) and close (right) state.
`
`2.3.4 Conclusion:
`
`The competence of the valved stent (as judged by its opening and closure)
`
`tested favorably under our mock loop system as evident from the IVUS and
`
`Miller catheter findings.
`
`2 8
`
`Edwards Exhibit 1032, pg. 31
`
`
`
`3. In vivo evaluation of valved stents
`
`3.1 Inferior vena cava
`
`3.1.1 Background:
`
`Despite
`
`the
`
`successful
`
`introduction of
`
`the extracardiac
`
`total
`
`cavo-pulmonary connection (41)(42) in order to improve the surgical results in
`
`"functionally" univentricular hearts
`
`(43\
`
`the conversion of a fai ling
`
`conventional total cavo-pulmonary connection (modified Fontan procedure)
`
`can still be necessary, because of different anatomical as well as functional
`
`reasons, all of them leading to systemic venous hypertension (44)(45)(46).
`
`One of the main reasons for the failure is the elevated venous pressure
`
`in the right atrium and coronary sinus, with the subsequent development of
`
`supra-ventricular arrhythmias and myocardial failure. Gomez-Jorge J. (47) has
`
`percutaneously deployed a valved bovine jugular vein (which was mounted
`
`to a self-expanding nitinol stent) in the inferior vena cava of swine for the
`
`treatment of systemic venous valve insufficiency. Hence, we speculated that
`
`the insertion of a valve in the inferior vena cava, by creating a pressure
`
`gradient across the valve, could also reduce the right systemic venous
`
`hypertension and congestion due to the incompetent tricuspid valve or
`
`2 9
`
`Edwards Exhibit 1032, pg. 32
`
`
`
`failing total cavo-pulmonary connection, and therefore might become an
`
`alternative option in case of failing total cavo-pulmonary connection or
`
`regurgitation of the tricuspid valve.
`
`This experiment study has been designed to evaluate the feasibility of
`
`the off-bypass (transluminal) implantation of a self-expandable valved stent
`
`in inferior vena cava.
`
`3.1.2 Materials:
`
`Materials used were as follows:
`
`• 5 Bovine jugular xenograft containing native va
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