No ValveXchange products have yet been approved by or submitted for approval to any regulatory agency, including the US Food and Drug Administration. As ValveXchange moves toward these submittals and processes, however, physicians who are interested in keeping in touch with company developments and/or interested in potentially participating in clinical trials may register with ValveXchange. Please send us an e-mail and/or subscribe to our newsletter.

The ValveXchange technology has been endorsed by prominent physicians, some of which serve on our Medical Advisory Board and on the Board of Directors.

The Three Alternatives to Better Heart Valves:

The exchangeable valve technology grew from Dr. Vesely’s heart valve research program while at The Cleveland Clinic’s Department of Biomedical Engineering. After spending almost two decades developing an understanding of why and how tissue valves wear out and fail, it became clear that no major advances for making tissue valves last a lifetime are on the horizon. Historically, a lifetime prosthetic valve has been desirable because of the significant risks that redo surgery for a failed prosthesis pose for the patient.

There are three ways that one can implement a lifetime prosthetic valve strategy for the majority of patients in the world:

(i) A tissue valve that lasts 50 years - this will make it applicable not only to the western world where the age of implant is highly skewed to the old and middle-aged patients, but also for the developing world where rheumatic disease leads to valve dysfunction in the 20’s and 30’s.

(ii) A mechanical valve that does not require Coumadin – A good option, as mechanical valves today have almost no chance of catastrophic failure. Some patients, however, do not tolerate the noise these valves make.

(iii) An anticoagulant for mechanical valves that has no side effects – If the drug was truly without side effects, readily available and inexpensive, mechanical valves would see a comeback.

Option 1: A Bioprosthetic Valve With Significantly Improved Durability

Over the past 40 years, a huge amount of NIH funds have been expended at studying the mechanisms of bioprosthetic valve failure, and evaluating novel concepts for reducing calcification and mechanical damage. A key mechanism of bioprosthetic valve failure identified by Dr. Vesely is compressive buckling (see image right) that leads to material fatigue and leaflet tearing. For many years, it was believed that a better way of chemically treating and preserving the valve leaflet tissue would delay the onset of material damage and calcification. A second alternative is to fabricate living valves using the principles of Tissue Engineering. These two options are described below.

(a) Alternative Fixation Chemistry

Many scientists have studied the process of calcification and have proposed a wide range of anticalcification agents and approaches. Chemists have pretreated bioprosthetic valve tissues with detergents and surfactants [1,2] (see references below), ferric ions [3], aluminum ions [4], diphosphonates [5] amino-oleic acid (AOA) [3,6], ethanol [7] and alternate fixatives [8]. Valves have had cells removed [9,10] and new cells cultured on permanent and degradable matrices [11], but few of these have had any impact on improving valve durability [12]. Some have tried to address the mechanical damage mechanisms by making flexible stent posts [13], by varying the pressures [14,15], and geometric constraints at which these valves are fixed [16,17], and by eliminating the potentially constraining stent completely [18]. Improvements in overall valve durability have improved anecdotally, but the reality of this is difficult to demonstrate, as patient selection, surgical treatment and postoperative management have improved considerably over the years. Many institutions now routinely operate on octogenarians with excellent results.

Progress in implementing these alternative approaches has generally been slow. Because of competitive and regulatory pressures, new products are introduced into the market only if the risk of failure can be minimized. Many of the speculative anticalcification approaches, describe above, have therefore never been implemented in a commercial product. Most manufacturers have been wary of introducing new valves with different fixation chemistry to the US market because of uncertainty in their long-term durability. Over the years, valve manufacturers have introduced different stents, different anticalcification pretreatments, but all of these changes have been "safe" and evolutionary. In the only example of a "revolutionary" change, Sulzer Carbomedics introduced a completely new method of chemical stabilization, which unfortunately failed in clinical trials. The Carbomedics Photofix-α pericardial valve was crosslinked, not with conventional glutaraldehyde, but with a dye catalyzed photooxidization process [19]. This approach appeared to work very well in vitro and in animal trials, but failed during clinical trials due to unusual abrasions that were not detected during pre-clinical testing. Valve manufacturers have therefore become very wary of introducing a potentially less durable valve on the market, and innovation in alternative fixation techniques has been slow. Let us also not forget the huge problem that Silzone created in the St.Jude product line [20].

Given that the Edwards Perimount™ and the Medtronic Hancock II have near 20-year durability in the elderly, and fail primarily through material fatigue, it is unlikely that any huge improvement in tissue valve durability can be made any time soon. In these highly advanced valves, calcification has been reduced to such a low level that mechanical damage through flexural fatigue becomes the predominant mode of failure. At 15 years, bioprosthetic valves will have undergone 500 million cycles of loading, unloading and flexure. That is a lot to ask of essentially dead biological tissue. It is thus unlikely that such dead tissue can be made to last significantly beyond 15 to 20 years in the future.

(b) Tissue Engineered Valves:

Living tissues have the potential of resetting the clock on the valvular disease process, and thus possibly offer a single surgery, lifetime solution. Accordingly, many companies have had early investments in these technologies. In 1993, St. Jude invested $5 million in Advanced Tissue Sciences (ATS) of La Jolla, to develop a valve based on biodegradable scaffolds made of poly-lactic (PLA) or poly-glycolic acid. The concept was to grow cells on substrates that mimic valvular architecture, insert them into the patient and expect a new heart valve to re-grow as the PLA scaffold degenerates. In 1995, St. Jude realized that these approaches were not feasible in the short term and did not renew its contract with ATS. At the same time, LifeCell Inc. of The Woodlands, TX has worked on a much more promising approach of repopulating porcine aortic valves with human cells, thus creating a hybrid valve construct. In the late ‘90’s, Medtronic funded the company via an investment but apparently pulled out because of inconsistent fibrosis of the valve cusps in the sheep model. CryoLife Inc. has developed technology similar to that of LifeCell, and in October of 2000, CryoLife obtained CE Mark approval to sell the SynerGraft product in Europe to a limited group of patients that had few alternatives – the neonate with congenital valvular malformations.

Although the numbers are not widely reported, a number of patients in Vienna, Austria received these valves. Within a few weeks to months, many of these children began to suffer serious valvular complications. While some remained apparently unaffected, many valves became highly regurgitant, and a few children died. CryoLife rapidly withdrew the product from the market, and disclosed the negative clinical outcomes at the 2004 Florence Heart Valve meeting. In their 2003 paper, Simon et al. reported that one patient (age 7 years) died 7 days after implantation of the valve, one patient (age 9 years) died 6 weeks after surgery, and one patient (age 2.5 years) died one year after surgery. Death resulted from various cardiac complications related to inflammation, valve rupture and stenosis. One patient was reoperated upon 2 days after the primary surgery, in view of what happened to the others. All valves showed severe inflammation, both inside and out, fibrosis, encapsulation, perforation and deterioration of the leaflet tissues. Apparently there was some abnormal signaling generated by the acellular matrix that induced the invading cells to remodel, fibrose and contract what otherwise appears to be a perfect, mechanically sound valve matrix. The exact reasons for this remain unclear.

Although its first clinical usage was disastrous, proponents of this approach remain undeterred. Medtronic has a latent tissue-engineered valve development project and valvular tissue engineering thrives in many academic centers such as the labs of Drs. Hoerstrup, Sacks, Mayer, Tranquillo and others. However, progress has been extremely slow because of the difficulty in preventing non-specific fibrosis and in generating the required material strength of the engineered tissues. A review article on this was written a few years ago by Dr. Vesely. Based on the experience of ATS, and LifeCell, as well as Dr. Vesely's own 10-year laboratory experience in developing tissue-engineered valves, it is most likely that tissue-engineered valves are still several decades away from commercial success.
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Option 2: A Mechanical Valve That Does Not Require Coumadin

The On-X valve by MCRI has been touted as the “next generation” mechanical valve that requires less Coumadin. On the market in the US since 2001, the On-X valve has a number of evolutionary design features that aim to reduce turbulence, platelet activation and hence the need for anticoagulation. Some of these are highly polished carbon surface, better flow through hinges, and elongated housing for better flow.

Based on the relative success of its South African trial on a poorly anticoagulation population of indigents, MCRI has initiated a US clinical trial in which low risk aortic valve patients will be anticoagulated with only Plavix and aspirin; high risk aortic valve patients will be anticoagulated with Coumadin to INR levels of between 1.5 and 2.0, and mitral valve patients will be anticoagulated 2.0 to 2.5. The standard of care for conventional mechanical valve patients is an INR level of 2.0 to 3.0 for aortic valve replacement patients without risk and 2.5 to 3.5 for high risk aortic and mitral valve patients.

Clearly, any reduction of Coumadin and anticoagulation levels would benefit the patient. However, in the poorly anticoagulated South African clinical trial, the data is not better than for the standard of care in the developed world (see table below).

The question thus remains whether the survival of poorly anticoagulated patients with the On-X valve translates in any way to a reduced anticoagulation regimen in the western world. This is something that will need to be determined by the new trial that MCRI has initiated. According to ClinicalTrials.gov this trial will require 1200 patients and will take until 2015 to compile the data. Moreover, experts in the field have commented that while the South African data is interesting, good outcomes from a poorly anticoagulated population cannot be readily transferred to the Western world where physicians may be unwilling to reduce Coumadin below that of standard practice, for fear that their patients will have strokes and other complications and end up suing for malpractice.

Although a number of individuals are still working on a mechanical valve that does not need anticoagulation, success is unlikely. This is because mechanical valves cause platelet activation and thrombosis not because of materials that induce blood clotting, but because of the fact that they are hard, rigid structures. When the valve leaflets close, at the point of contact there is immediate rebound. This collision and rebound is a very violent event – so violent that cavitation was induced in some early heart valve designs. Even when cavitation does not occur, the shear stress induced in the vicinity of the closing and rebounding leaflets is extremely high. This activates platelets and leads to thrombosis and to thromboembolism downstream of the valve. The only likely way that platelet activation can be reduced is to eliminate the violent collision between the leaflets and the housing. That cannot be done with rigid materials.

Some have attempted to achieve this by designing “mechanical” valves from polymeric materials. Trileaflet valves made from polymers, such as polyurethanes, have the dual advantage of (i) having good hemodynamics and thus lower anticoagulation, and (ii) ease of manufacturability and hence a low cost to produce. Polymeric valves could be produced through dip casting, theoretically for a few dollars each. Polymeric valves thus remain an exciting commercial possibility.

The latest foray into polymeric valves was by AorTech from the U.K. with a new type of biostable polyurethane. Although in-vitro studies in the early part of this decade demonstrated good durability and stability in sheep for 9 months, the project ended abruptly a number of years ago. It would appear that, like all other polymeric valve projects for the past few decades, some pre-clinical data appeared to be negative. In the past, the main problem with polymer valves was that plasma proteins infiltrated the polymer leaflets through microcracks. These plasma proteins subsequently became the foci for calcification and other mineralization processes that occur passively in the presence of a biological environment. These polymeric leaflets eventually mineralized, hardened and fractured. Polymeric heart valves thus remain an ambitious project with no early solutions in sight.
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Option 3: An Anticoagulant For Mechanical Valves That Has No Side Effects

Alternative anticoagulant medication is an ongoing area of work at a number of pharmaceutical companies. Most recently, Ximelagatran and Dabigatran went through clinical testing as potential alternatives to Coumadin. Unfortunately, development of Ximelagatran was discontinued after it led to liver damage. Dabigatran in currently approved in Europe for some orthopedic surgery applications and is currently being tested for atrial fibrillation. Early evidence suggests that patients on Dabigatran do better than those on Coumadin, although there is a small but significant increase in the risk of heart attack, which may temper the enthusiasm for this drug.

From a theoretical point of view, however, is there such a thing as an anticoagulant with no side effects? While the absence of clotting on mechanical valves is certainly desirable, an impaired clotting mechanism will surely have some adverse effects on those patients who wish to remain active and engage in activities that risk injury and bleeding. Impaired clotting can thus be considered a “side effect” of a mechanical valve.
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Option 4: The Case for an Exchangeable Heart Valve:

Since none of the three proposed solutions for a “lifetime valve” show promise, we have proposed a fourth alternative – an exchangeable, serviceable tissue valve. If the durability of the tissue leaflets cannot be significantly increased, then why not make the valve serviceable to exchange the failed leaflets? If this could be done with minimal trauma to the patient, a serviceable, exchangeable tissue valve would truly be a “lifetime solution.”

The migration from mechanical valves to tissue valves appears to be unstoppable. While the improved durability of tissue valves has contributed to this, it is also being driven by patient preference. In recent years, it has become more common for younger patients to choose tissue valves over mechanical valves, even if they run the risk of outliving their implant and having to undergo surgery for a second implant at an advanced age. Indeed, Dr. Michael Banbury, a member of our Medical Advisory Board has commented that his “…45-year-old patients are already opting for bioprosthetic valves with the knowledge of future re-do’s, rather than having a mechanical valve and being on Coumadin”.

Reoperation for bioprosthetic valve failure is thus on the rise. This is counter to the decades long objectives of avoiding reoperation by titrating patients between mechanical and tissue valves. Until recently, patients received tissue valves to avoid the risks of reoperation. As the risks of reoperation come down, and the risks of being on Coumadin become weighed more severely, a shift towards tissue valves comes about. According to some published data, the freedom from reoperation for patients of all ages is 76% at 10 years, 61% at 15 years and only 59% at 20 years after the first surgery [21]. Experience has demonstrated that the durability of tissue valves reduces dramatically when implanted into younger patients. In middle-aged patients, freedom from reoperation at 10 years is only 65% [22] and in young adults (18 – 50 years of age), freedom from reoperation for bioprosthetic valve failure is 45% at 15 years [23]. Depending on the study details, reoperation for bioprosthetic valve failure is thus on the rise. Even though tissue valve longevity is on the rise, the trend towards placing tissue valves into younger people is met with the fact that tissue valves wear out much faster in younger patient, hence the need for more frequent reoperations. This was shown very clearly by Banbury and Blackstone for the Edwards valve (top image right) - the younger the patient, the faster the tissue valve fails. Indeed, in young females, there is a 50% probability that a tissue valve will fail in only 5 years if the patient is 20 years old. Admittedly, the bottom image at right was taken from a publication from 1985 by Blackstone and Kirklin, so these two curves are likely shifted to the right a bit when considering the new generation of tissue valves, like the Edwards Perimount. However, the “18-year” durability of the current-generation tissue valves that is often touted by valve companies thus applies only the extremely aged patient – in younger patients, 15-year durability, or less, should be considered as the mean survival time for any tissue valve product.

With patients preferring tissue valves and with reoperation now being considered an acceptable alternative to Coumadin and mechanical valves, we have strived to make reoperation faster, safer and less invasive. The best way to do this is by having an exchangeable heart valve. Although the first reoperation can be almost as safe as the initial surgery, it is highly dependent upon the experience of the physician. Technologies that minimize complications during valve replacement procedures and maximize the time between re-interventions are thus desirable. Although transcatheter valve delivery is an important new therapeutic approach, these devices induce serious procedural complications and morbidity and are reserved for only those patients that are too sick to undergo conventional open-heart surgery. Moreover, the engineering compromises required to deliver a valve via catheter lead to very poor longevity. Transcatheter valves are thus not appropriate for young patients who need a safe, long-lived valve solution.

To address the need for long-lived valves and atraumatic reoperation when bioprosthetic valves do fail, ValveXchange Inc. (VXi) has developed a rapidly exchangeable bioprosthetic valve. It is a two-component device, consisting of a permanent "docking station" that remains seated in the patient's heart, and a collapsible frame that supports the exchangeable leaflet set which plugs into the docking station. The old, worn-out leaflet set simply pulls out, and the new set snaps in place.
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Managing Fibrosis

Admittedly, ValveXchange Inc. is not the first to conceive of an exchangeable bioprosthetic valve. Perhaps the first exchangeable valve used clinically was the Medtronic/Tascon valve. That valve, however, was a failed approach and we have learned from their experience. The collective experience in the field suggests that two main issues likely prevented a successful exchange of the Tascon valve. These are (i) the fouling of the thread interface, and (ii) inability to apply sufficient torque to overcome “locked” threads. The Tascon patent suggests that there were at least three, robust, square profile threads that connected the permanent and exchangeable components (see image below). Even if made from stainless steel, minor surface corrosion over 10 years would have clearly locked them together. Had the two fouled pieces been outside the body, possibly sufficient torque could have been applied to the parts to free the fouled threads. With one piece in the patient, grasping the sewing cuff with hands would have been difficult and applying sufficient torque to free the leaflet set impossible. The table below summarizes the problems of the Tascon valve and the features of the VXi valve that overcome them.

It is unclear to what extent fibrosis prevented the exchange of the Tascon valve. Fibrosis in heart valves is relatively benign mechanically. While at the Cleveland Clinic, Dr. Vesely had the opportunity to examine well over a thousand explanted heart valves. This unique experience led to the notion that the leaflet set of a fully healed-in valve could actually be exchanged, provided that an appropriate mechanism was used.

From the Cleveland Clinic experience, fibrosis was clearly heavy in the area of the sewing cuff, but relatively mild along the tops of the stent posts, and typically thin and translucent, with minimal mechanical strength. Fibrosis has not been seen to penetrate into internal cavities - it appears to be a surface phenomenon only (see image below). Images A&B show the inflow and outflow aspects of an explanted porcine bioprosthesis.

Note that while the sewing cuff can be well healed-in, further up the stent posts the pannus is thin and translucent. Indeed, we have done materials tests on typical pannus obtained from explanted bioprostheses and found the highest failure strength to be about 30 grams/mm of pannus perimeter. The maximum extraction force integrated over the perimeter of a 29 mm diameter valve using the highest failure strength pannus is thus less than 2.8 Kg. The ValveXchange tools are capable of generating these and greater forces, and because of the design of the docking station holding tool, the forces are applied between the two heart valve assemblies, with no significant force applied to the heart itself. Also notable is evidence that even if the valve remains in the patient for over two decades, the fibrotic film remains thin. In what is perhaps a worst-case scenario, a 24-year explant (Image C) still had a relatively thin fibrotic cap. Also note that when the fibrotic film is removed from the valve and the Dacron cloth dissected away (Image D), the internal components are not fouled in any way.

The ability to manage fibrotic overgrowth was verified in our chronic sheep implant studies. It is well known that the young sheep is not only a hyper calcific animal model – hence its use to demonstrate pre-clinical safety – but it is also hyperfibrotic. The amount of fibrotic overgrowth that occurs in sheep at the 2 to 3 month time point is far greater than occurs in adult humans during a typical 15-year implant period. With this in mind, we used a 2 to 3 month implant period as the baseline for our leaflet exchange experiments.

In the images above, it can be seen that both the outflow (A) and inflow (B) aspects of the valve are very well healed. The sewing cuff, in particular, is completely covered with fibrotic overgrowth. The extracted leaflet set is shown in Images C&D. Note how the pannus that covered the base of the leaflet set has been clearly torn through (Image C). Also note that the underside of the extracted leaflet set (Image D) is free of overgrowth. This is because the underside of the pericardial leaflet was in contact with the docking station and hence not exposed to the blood environment. It is free from fibrotic overgrowth because it was internal to the valve. Accordingly, the corresponding mating surface of the docking station is also clean and free of fibrosis and can thus accept a fresh leaflet set that seats well without any leakage.

Through these preliminary animal studies, we have demonstrated the feasibility of an exchangeable bioprosthetic valve. We are now working on clinical implementations of the exchangeable valve concept, embodied in our Vitality™ and Vanguard™ valve models.
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Option 5: Revalving with Transcatheter Valves?

Is Valve-in-Valve a viable option for a lifetime tissue valve solution? The valve-in-valve option has received considerable interest in the field over the past few years. Perhaps the first use of the valve-in-valve approach was in the early days of transcatheter valve implantation, when inadvertently, a transcatheter valve was loaded on the catheter backwards and deployed in the native valve upside down. That potentially disastrous event was quickly solved by deploying another transcatheter valve inside the first one to rescue the patient. On the heels of that success, other valve-in-valve reports started to appear in publications. Thomas Walter from Leipzig appears to have the first publication that reports on animal experience. Later that year (2007) Grube from Siegburg, Germany published a paper reporting their results on patients. On the surface, the concept seems simple and appealing – rather than opening up the patient to surgically excise a failed bioprosthetic valve, a transcatheter valve is simply inserted inside the old one.

Like the implant for an initial transcatheter valve, the first wave of candidates will be those that are inoperable. Also, for patients whose life expectancy is predicted to be less than 5 years, a single “revalving” procedure may take them to end of life. The issue that needs to be considered when implanting a transcatheter valve inside a failed bioprosthesis is the expected longevity of the new transcatheter valve. As noted elsewhere in our web site, the serious concern with transcatheter valves is their limited longevity. When an elderly patient presents with a worn-out, failed bioprosthetic valve, the pros and cons that need to be weighed are the risks of re-operation today when the patient is still reasonably healthy, vs. 5 - 7 years later when the transcatheter valve wears out and fails. At that time, the patient will be older and then potentially inoperable, without any transcatheter valve option available.

Perhaps more important to offering a good prosthetic valve solution is the issue of transvalvular gradients. Interestingly, the transvalvular gradients reported for transcatheter valves are remarkably low. It should be kept in mind, however, that the modified Bernoulli equation relates pressure drop to the square of the exit velocity. For patients that are frail with poor ventricular function (i.e. the inoperable patient), the ejection velocity is likely to be low – hence a low measured transvalvular gradient. The gradients may very well be different for healthy patients or during exercise. When cardiac output goes up, so will the transvalvular pressure gradient. Certainly, the decades-long preoccupation with patient-prosthesis mismatch in the heart valve field suggests that reducing the effective orifice area for anyone but the sedentary patient, is not a good idea. Photos taken from the Walther paper nicely show the considerable reduction in effective orifice area that implantation of a transcatheter valve creates. In this image at right, the transcatheter valve was implanted into a non-stenotic bioprostheses. It is very likely that implantation of a transcatheter valve inside an old, stenotic bioprostheses will lead to incomplete expansion, and the use of even smaller diameter transcatheter valves. Indeed, in a recent study on the valve-in-valve concept, Tseng et al. reported that the patient-prosthesis mismatch for a valve-in-valve approach would be so severe that patients with 21 mm valves and smaller should not be considered.

Keep in mind, however, that if a valve-in-valve concept is warranted for reasons of patient frailty or preference, ValveXchange is developing the Vanguard™ - a transapically implantable valve with none of the durability compromises of conventional transcatheter valves.

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References:

1. Arbustini, E., et al., Modification by the Hancock T6 process of calcification of bioprosthetic cardiac valves implanted in sheep. Am J Cardiol, 1984. 53(9): p. 1388-96.
2. Hirsch, D., et al., Inhibition of calcification of glutaraldehyde pretreated porcine aortic valve cusps with sodium dodecyl sulfate: preincubation and controlled release studies. J Biomed Mater Res, 1993. 27(12): p. 1477-84.
3. Chen, W., et al., Synergistic inhibition of calcification of porcine aortic root with preincubation in FeCl3 and alpha-amino oleic acid in a rat subdermal model. J Biomed Mater Res, 1997. 38(1): p. 43-8.
4. Webb, C.L., et al., Inhibition of mineralization of glutaraldehyde-pretreated bovine pericardium by AlCl3. Mechanisms and comparisons with FeCl3, LaCl3, and Ga(NO3)3 in rat subdermal model studies. Am J Pathol, 1991. 138(4): p. 971-81.
5. Golomb, G., et al., Controlled-release drug delivery of diphosphonates to inhibit bioprosthetic heart valve calcification: Release rate modulation with silicone matrices via drug solubility. J Pharm Sci, 1987. 76(4): p. 271-276.
6. Gott, J.P., et al., Refinement of the alpha aminooleic acid bioprosthetic valve anticalcification technique. Ann Thorac Surg, 1997. 64(1): p. 50-8.
7. Vyavahare, N.R., et al., Prevention of calcification of glutaraldehyde-crosslinked porcine aortic cusps by ethanol preincubation: mechanistic studies of protein structure and water-biomaterial relationships. J Biomed Mater Res, 1998. 40(4): p. 577-85.
8. Girardot, J.M. and M.N. Girardot, Amide cross-linking: an alternative to glutaraldehyde fixation. J Heart Valve Dis, 1996. 5(5): p. 518-25.
9. Bader, A., et al., Tissue engineering of heart valves--human endothelial cell seeding of detergent acellularized porcine valves. Eur J Cardiothorac Surg, 1998. 14(3): p. 279-84.
10. Vesely, I., R. Noseworthy, and G. Wilson, Development of a hybrid xenograft/autograft aortic valve bioprosthesis. Canadian Journal of Cardiology, 1991. 7(Supp. A): p. 83A.
11. Shinoka, T., et al., Tissue engineering heart valves: Valve leaflet replacement study in a lamb model. Ann Thorac Surg, 1995. 60(6 Suppl): p. S513-6.
12. Vesely, I., The influence of design on bioprosthetic valve durability. Journal of Long-Term Effects of Medical Implants, 2001. In-press.
13. Christie, G.W. and B.G. Barratt-Boyes, On stress reduction in bioprosthetic heart valve leaflets by the use of a flexible stent. J Card Surg, 1991. 6(4): p. 476-81.
14. Vesely, I., Analysis of the Medtronic Intact bioprosthetic valve. Effects of "zero-pressure" fixation. Journal of Thoracic & Cardiovascular Surgery, 1991. 101(1): p. 90-9.
15. Duncan, A.C., D.R. Bouhgner, and I. Vesely, Dynamic glutaraldehyde fixation of a porcine aortic valve xenograft. I. Effect of fixation parameters on the final viscoelastic properties of the valve. Biomaterials, 1996. 17(19): p. 1849-1856.
16. Imamura, E., et al., Open-position fixation of bioprostheses for more physiological performance. Fluoroscopic observations of leaflet movements in vivo. Journal of Thoracic & Cardiovascular Surgery, 1984. 88(1): p. 114-21.
17. Butterfield, M., et al., Frame-mounted porcine valve bioprostheses: preparation during aortic- root dilation. Biomechanics and design considerations. J Thorac Cardiovasc Surg, 1993. 106(6): p. 1181-8.
18. David, T.E., C. Pollick, and J. Bos, Aortic valve replacement with stentless porcine aortic bioprosthesis. Journal of Thoracic & Cardiovascular Surgery, 1990. 99(1): p. 113-8.
19. Schoen, F.J., Pathologic findings in explanted clinical bioprosthetic valves fabricated from photooxidized bovine pericardium. J Heart Valve Dis, 1998. 7(2): p. 174-9.
20. Ionescu A., Payne N., Fraser A.G., Giddings J., Grunkemeier G.L., Butchart E.G., Incidence of embolism and paravalvar leak after St Jude Silzone valve implantation: experience from the Cardiff Embolic Risk Factor Study, Heart. 2003 Sep;89(9):1055-61.
21. Ruel, M., et al., Late incidence and determinants of reoperation in patients with prosthetic heart valves. Eur J Cardiothorac Surg, 2004. 25(3): p. 364-70.
22. Kulik, A., et al., Mechanical versus bioprosthetic valve replacement in middle-aged patients. Eur J Cardiothorac Surg, 2006.
23. Ruel, M., et al., Long-term outcomes of valve replacement with modern prostheses in young adults. Eur J Cardiothorac Surg, 2005. 27(3): p. 425-33.

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