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Eur J Cardiothorac Surg 2000;17:440-448
© 2000 Elsevier Science NL

Polyurethane: material for the next generation of heart valve prostheses?

^a University Department of Cardiac Surgery, Glasgow Royal Infirmary NHS Trust, 10 Alexandra Parade, Glasgow G31 2ER, UK
^b University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, UK
^c Department of Veterinary Anatomy, University of Glasgow, Glasgow, UK

Corresponding author. Tel.: +44-141-211-4730; fax: +44-141-552-0987
e-mail: d.j.wheatley{at}clinmed.gla.ac.uk

	Abstract

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. Conference... References

 
Objectives: The prospects for a durable, athrombogenic, synthetic, flexible leaflet heart valve are enhanced by the recent availability of novel, biostable polyurethanes. As a forerunner to evaluation of such biostable valves, a prototype trileaflet polyurethane valve (utilising conventional material of known in vitro behaviour) was compared with mechanical and bioprosthetic valves for assessment of in vivo function, durability, thromboembolic potential and calcification. Methods: Polyurethane (PU), ATS bileaflet mechanical, and Carpentier–Edwards porcine (CE) valves were implanted in the mitral position of growing sheep. Counting of high-intensity transient signals (HITS) in the carotid arteries, echocardiographic assessment of valve function, and examination of blood smears for platelet aggregates were undertaken during the 6-month anticoagulant-free survival period. Valve structure and hydrodynamic performance were assessed following elective sacrifice. Results: Twenty-eight animals survived surgery (ten ATS; ten CE; eight PU). At 6 months the mechanical valve group (n=9) showed highest numbers of HITS (mean 40/h, P=0.01 cf. porcine valves), and platelet aggregates (mean 62.22/standard field), but no thromboembolism, and no structural or functional change. The bioprosthetic group (n=6) showed low HITS (1/h) and fewer aggregates (41.67, P=1.00, not significant), calcification and severe pannus overgrowth with progressive stenosis. The PU valves (n=8) showed a small degree of fibrin attachment to leaflet surfaces, no pannus overgrowth, little change in haemodynamic performance, low levels of HITS (5/h) and platelet aggregates (17.50, P<0.01 cf. mechanical valves, P=0.23 cf. porcine valves), and no evidence of thromboembolism.Conclusions: In the absence of valve-related death and morbidity, and retention of good haemodynamic function, the PU valve was superior to the bioprosthesis; lower HITS and aggregate counts in the PU valve imply lower thrombogenicity compared with the mechanical valve. A biostable polyurethane valve could offer clinical advantage with the promise of improved durability (cf. bioprostheses) and low thrombogenicity (cf. mechanical valves).

Key Words: Polyurethane • Prosthetic heart valve • In vivo • Thrombogenicity

	1. Introduction

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. Conference... References

 
Over 5000 prosthetic heart valves are implanted annually in the UK [1]. In spite of more than 30 years of research into valve development, none of the prostheses currently available is ideally suited for any clinical situation. While the mechanical valve is relatively durable, it demands continuous anticoagulation therapy for the patient with the associated risks of thromboembolic complication or anticoagulant-related bleeding episodes. This is a particular problem where medical services are not always readily available for patient follow-up, and when patient compliance with anticoagulant regimes is poor. Bioprosthetic valves have a limited lifetime due to calcification (particularly in the young), pannus overgrowth and tissue failure, although recipients do not usually require long-term anticoagulation [2,3].

In haemodynamic terms, the trileaflet central flow design of the natural aortic valve and the majority of pericardial and porcine aortic valves currently available is favoured [4]. Synthetic elastomeric materials allow the possibility of engineering a material to provide the best qualities of both mechanical valves and bioprostheses in a new flexible synthetic leaflet valve prosthesis. Historically, several synthetic polymers have been tested as leaflet materials [5–8]. Silicone and polyolefin rubbers had inadequate durability [9,10]. A polytetrafluoroethylene valve was seriously compromised by thrombosis and calcification [8,11]. Much research has focused on polyurethanes: the segmented nature of these materials permits alteration of the polymer chemistry to achieve both flexibility and mechanical strength within the same material. They are bio- and blood-compatible, with applications in a wide range of medical devices [12,13]. Several research groups have investigated a variety of polyurethanes for application in heart valves [8,9] and have reported problems with calcification and thrombosis. Long-term in vitro durability of polyurethane valves has been achieved [14] and, in our own experience, polyurethane valves manufactured from a commercially available textile polyurethane were capable of achieving more than 800 million cycles in laboratory fatigue testing (equivalent to more than 20 years of ‘normal’ function) [15]. Calcification localised only to tears and wear-induced defects in the material, during in vitro fatigue testing [16,17]. Our previous research highlighted the need to modify the valve leaflet [18] and frame design (unpublished data) to minimise stenosis of the valve by reducing the pressure gradient across the valve, especially critical in smaller sizes. A prototype polyurethane valve has resulted with leaflet geometries as previously defined [19,20]. The frame was machined from polyetheretherketone (PEEK), coated with a thin layer of leaflet polyurethane. Leaflets of a commercially available polyetherurethane suitable for animal implantation (Estane 58315, BF Goodrich, Westerlo-Oevel, Belgium) were dip-coated onto the frame as previously described [19,20]. This valve design has achieved durabilities in excess of 400 million cycles during in vitro fatigue testing.

The present study compares this prototype polyurethane valve with well-established mechanical and bioprosthetic valves in a sheep implant model, in terms of in vivo function, durability, thromboembolic potential and calcification risk.

	2. Methods

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. Conference... References

 
2.1. Valve implantation
Polyurethane valves (24 mm) were implanted in growing Texel sheep. ATS bileaflet mechanical valves (24 mm) and Carpentier–Edwards supra-annular porcine aortic valves (25 mm) were implanted for comparison. All valves were placed in the mitral position. The procedures were carried out in conformance with the Home Office code of practice and standards, and with the appropriate Home Office project and personal licences granted under the Animals (Scientific Procedure) Act 1986.

Anaesthesia was induced with alfaxalone/alfadolone (0.333 ml kg^-1) following intravenous diazepam premedication (0.2 mg kg^-1) and maintained with 3% inhaled isoflurane. A single bolus of atracurium (0.5 mg kg^-1) was given intravenously.

A left thoracotomy was performed through the bed of the resected fifth rib. The animal was heparinised (300 units kg^-1). The descending aorta was cannulated for arterial return and venous blood drained from the right ventricle via the main pulmonary artery. Normothermic cardiopulmonary bypass was set up and the heart was electrically fibrillated. The left atrial appendage was opened and the anterior leaflet of the mitral valve was resected leaving a 1–2 mm cuff of leaflet base. The posterior leaflet was partially resected with preservation of secondary chordae. The valve was sutured into the mitral position using 12 interrupted 2/0 Ethibond pledgeted sutures, placed with the pledgets on the ventricular side and tied on the atrial side of the mitral annulus. No anticoagulation was used postoperatively.

Investigative studies were carried out at 6 weeks, 3 months and 6 months after surgery. The sheep were killed humanely by intravenous overdose of barbiturate. They were exsanguinated and full post-mortem examinations performed. The hearts were removed and the valves excised for further examination. Samples of myocardium from the free wall of the left ventricle, caudal lobe of the lung, spleen, kidney, cerebral cortex and right lobe of the liver were collected into 10% neutral buffered formalin for histological examination.

2.2. Follow-up investigations
Carotid Doppler studies for detection of high-intensity transient signals (HITS), echocardiographic assessment of valve function and examination of blood smears for platelet aggregation were performed at follow-up. Valve structure and hydrodynamic performance were assessed following elective sacrifice at 6 months.

To collect the Doppler ultrasound data, the animal was sedated with an intravenous bolus dose of 0.4 mg kg^-1 diazepam. Additional boluses of 0.2 mg kg^-1 were administered every 20 min when required. Thirty minutes of the Doppler spectra and audio signal were then recorded from the thoracic outlet of the carotid artery at the base of the neck, using an EME TC 4040 multichannel transcranial Doppler ultrasound machine (Eden Medizinische Elektronik, Uberlingen, Germany) equipped with a dual-depth probe. HITS were counted according to standard criteria [21]. HITS data for all valves were collected at 3 months and 6 months of follow-up.

Blood smears were made from femoral arterial samples collected into EDTA/formalin at 6 weeks, 3 months and 6 months follow-up, and stained with May–Grunwald–Giemsa stain. Platelet aggregate counts were averaged over nine standard fields under light microscopy at x100 magnification.

Haemodynamic function of the valves was assessed by transthoracic echocardiography, performed after sedation of the animal with a single dose of 0.2 ml kg^-1 of intramuscular ketamine. Pressure gradient and flow velocity across the prosthesis was measured at 6 weeks, 3 months and 6 months.

Mean pressure gradients across the explant valves were measured in vitro using a pulse duplicator, described previously [19]. The valves were tested in the mitral position at five pulsatile flow rates, ranging from 3.6 to 9.6 l min^-1, at a mean aortic pressure of 95 mmHg.

Organ sections were stained with haematoxylin–eosin. In addition, kidney sections were stained with Sirius Red to demonstrate collagen and splenic sections by the Perl's method for iron. Thin sections of explant polyurethane valve leaflets were prepared from wax-embedded portions of leaflet. The sections were stained for calcium using Alizarin Red S or von Kossa: von Kossa-stained sections were counter-stained with haematoxylin–eosin, Gomori or Von Gieson stains for examination of fibrous material attached to the explanted leaflets. Following sputter-coating with gold, segments of leaflet surface were mounted for scanning electron microscopy and examined at 15 kV accelerating voltage.

2.3. Statistical analysis
Results are expressed as mean (SD) unless otherwise stated. Statistical analyses were performed using Minitab for Windows, release 12 (Minitab Inc.), assuming a significance level of 5%. HITS data were incremented by 1, to remove zero values, followed by logarithmic transformation, to approximate normality among groups. The transformed data were then analysed using a general linear model (ANOVA), incorporating the three follow-up times as a repeated-measures variable, with Bonferroni-corrected multiple post hoc comparisons (using a Minitab macro supplied by Glasgow University Department of Statistics). Logarithmic transformation was applied to aggregate data prior to similar data analysis. Velocity data from echocardiographic studies were compared by similar methods without data transformation. Pressure gradient data could not be transformed to approximate normality and equal variance, and hence were analysed using Kruskal–Wallis one-way analysis of variance.

	3. Results

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. Conference... References

 
Details of the numbers of sheep implanted for each valve type and post-operative survivors are displayed in Table 1. Of ten post-operative survivors in the mechanical valve group, one death occurred at 6.6 weeks but no definitive pathology was discovered at post-mortem examination. A total of nine sheep survived to 6 months with a mechanical valve implant. Two out of ten post-operative survivors in the porcine valve group died, at 2 weeks and 15.14 weeks, from valve-related causes: both valves were heavily stenosed, associated with pannus overgrowth of the leaflets. A total of six sheep survived to 6 months with a porcine valve implant. No animals in the polyurethane valve group (eight post-operative survivors) died from valve-related causes. All eight post-operative survivors with a polyurethane valve implant survived to 6 months. The mechanical valves were unchanged in appearance at explant with no significant pannus overgrowth of the valve leaflets (Fig. 1). All the porcine valve explants were affected by extensive pannus overgrowth with minor focal calcification (Fig. 2). One polyurethane valve had two leaflets restrained by a chordal loop. All polyurethane valve leaflets showed a degree of fibrin attachment with no significant pannus overgrowth and calcification that was exclusively associated with fibrin material attached to the leaflets (Fig. 3).

View larger version (119K): [in this window] [in a new window]   Fig. 1. Outflow surface of mechanical valve viewed in situ immediately prior to explant.

View larger version (79K): [in this window] [in a new window]   Fig. 2. Porcine valve viewed in situ immediately prior to explant. (a) Inflow surface; (b) outflow surface; (c) radiograph of explant porcine valve.

View larger version (87K): [in this window] [in a new window]   Fig. 3. Explant polyurethane valve viewed in situ immediately prior to explant. (a) Inflow surface; (b) outflow surface; (c) radiograph of explant polyurethane valve.

Echocardiographic data are presented in Table 4. At 6 weeks and 3 months, there were no significant differences in blood velocity across the three valve types. At 6 months, the mechanical valve and polyurethane valve groups were not significantly different and both groups produced significantly lower velocities than the porcine valve group (P<0.01 for both valve types). Neither the mechanical nor the polyurethane valve groups indicated any increase in velocity with time. The porcine valve group produced increasing velocities between 6 weeks and 3 months (P=0.06), with differences becoming significant comparing 6 weeks with 6 months (P<0.01). Significant increases in valvular pressure gradients were also associated with the porcine valve group at 3 months and 6 months follow-up. No other significant differences in pressure gradients were present among valve types.

View larger version (14K): [in this window] [in a new window]   Fig. 4. Mean pressure gradient versus RMS flow (mean value±SEM plotted for nine mechanical valve explants, all eight polyurethane valve explants and five polyurethane valve explants at five pulsatile flow rates, and six porcine valve explants at four pulsatile flow rates).

	4. Discussion

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. Conference... References

 
There has long been an interest in developing a prosthetic heart valve that combines the durability of a mechanical valve with the flow profile and blood compatibility of a bioprosthesis, while overcoming the disadvantages of each of these types of valve. Polyurethanes have been a popular choice of material, given their relatively good blood- and bio-compatibility. However, there have been problems associated with long-term implant, with material degradation causing premature failure of devices. Thus, the development of heart valves made of such materials has been slower than anticipated. Recent developments in polymer science have resulted in the synthesis of a number of reportedly biostable polyurethanes. The availability of such materials has confirmed the usefulness of polyurethanes in their ability to be chemically engineered to fit a specific purpose and has rekindled interest in the use of these materials in prosthetic heart valves. As a prelude to developing research incorporating biostable polyurethanes into new valve designs, this study utilised a well-characterised, non-biostable polyurethane to investigate the ability of an altered polyurethane valve design to perform satisfactorily in a short-term implant environment. Major concerns in respect of valve design are the haemodynamic performance and the propensity of the design and/or material to induce a thombotic blood response, either on the valve itself or in the circulation.

The haemodynamic function of the valves was assessed by echocardiography and by in vitro hydrodynamic measurements on the valves. The thrombotic response was assessed by counting platelet microaggregates and HITS.

The exact nature of HITS is controversial. Current opinion is that such HITS result from circulating gaseous microbubbles, although there have been suggestions that a contribution to HITS formation comes from circulating microthrombi. HITS frequency is higher in recipients of mechanical valve prostheses, which require systemic anticoagulation, in contrast to bioprosthetic valves, which are relatively non-thrombogenic [22,23]. HITS have also been detected, with this technique, in patients with clinically evident embolic sources, e.g. atrial fibrillation or carotid stenosis without the presence of a prosthetic valve, although in these cases the nature and aetiology of the HITS may be different [24]. In our study, HITS were also much more frequent in the mechanical valve group than in either the porcine or the polyurethane valve groups, and correlated significantly with platelet aggregate counts at 3 and 6 months. As expected, the mechanical valves produced the greatest numbers of aggregates reflecting their higher thrombogenicity. As stenosis progressed, the porcine valves produced larger numbers of aggregates suggesting an increasing tendency to thrombogenicity, although they did not produce an increased frequency of HITS with time. Regardless of whether HITS are directly related to thrombogenesis, the correlation between HITS and platelet aggregation suggests that these phenomena are related, so that valve factors that tend to increase thrombogenicity also act to increase HITS. Therefore, the low HITS and aggregate numbers associated with the polyurethane valve group suggest that the polyurethane valve, like the bioprosthesis, is relatively non-thrombogenic. Moreover, the aggregate numbers suggest that aggregate counts are the more sensitive means of assessing thrombogenic potential and that a stenosed bioprosthesis develops an increased thrombogenic potential. The sheep model tends to be less thrombogenic than human recipients of valves, hence the success of mechanical valve implants without the use of long-term anti-coagulation. However, the pattern of HITS production is generally similar to that found in our clinical experience and suggests a similar pattern of behaviour. The current study makes use of mechanical and bioprosthetic valve controls over the polyurethane valve implants, and hence the data produced are comparative and might reasonably be expected to reflect a similar pattern of behaviour in the human recipient.

In terms of haemodynamic function, as assessed by echocardiography, the polyurethane valves performed as well as the mechanical valve, with the porcine valve function becoming compromised with time. More sensitive laboratory-based hydrodynamic testing detected larger differences between the mechanical valve and the polyurethane valve, but the difference was not clinically significant at any follow-up time. The polyurethane valves were less stenotic after 6 months than the porcine valves. Three polyurethane valves were seriously affected by thrombus and fibrous attachment to the leaflets: one of these also had two leaflets restrained by a chordal loop around one of the stent posts. The fibrous material was also calcified, and these valves were considerably more stenotic than the remaining five polyurethane valves. The variability of the group mean pressure gradient data is greatly increased by the inclusion of the three stenosed polyurethane valves: the remaining five valves produced a more consistent performance (Fig. 4). The three most stenotic PU valves were implanted in the youngest sheep, between 16.86 and 18 weeks: mechanical and porcine valves had one sheep each implanted at 17.91 weeks, with all others implanted after 18.20 weeks and the remaining polyurethane valves were implanted in sheep between 24 and 25 weeks. No other factors were different among the valves. The differences in the three younger sheep implanted with polyurethane valves may have been partly related to the age at implant of the sheep or to physical factors associated with the individual implants. However, further implant experience with various ages of animals would be required to clarify this.

Overall, the polyurethane valve performed better than the porcine bioprosthesis. In terms of blood flow parameters, the mechanical valve performed best, but the risk of thromboembolic events remained and may have caused the premature death of one animal in this group. Only the porcine valve function was affected by pannus overgrowth, resulting in severe stenosis of the valve. There was only minor focal calcification detected (Fig. 2c), which was insufficient to affect leaflet function. There were no failures of the polyurethane valve leaflets and the slight increase in valve stenosis was due to the attachment of fibrous and thrombotic material to the leaflet surface and the subsequent calcification of this extrinsically attached material. In general, the fibrous, thrombosed network on the leaflet was a surface layer, clearly separate from the underlying leaflet polymer. A number of points on the leaflet surface indicated a concentration of this thrombus, with associated calcification, penetrating into the body of the polyurethane (Fig. 5). This is suggestive of a degradative process affecting the polyurethane surface structure, which is likely to accelerate as calcified host material penetrates the polymer. A few areas of the most severely fibrosed/thrombosed polyurethane valve leaflets appeared to be undergoing a degradative process, viewed by scanning electron microscopy (Fig. 6). Calcification of the leaflets was entirely associated with extrinsically calcified material attached to the leaflet with some early penetration from the surface (Fig. 5), which appeared to be associated with polymer degradation. No intrinsic polyurethane calcification was found associated with intact areas of polymer. It is likely that such ingressions would cause stress concentrations and/or material thinning, leading eventually to material failure. The problems of polyurethane biostability are well known [12] and such polymers are especially vulnerable when used in demanding flexing applications in which fatigue-induced damage seems to accelerate material biodegradation [25]. This problem has been the subject of much research interest, and a variety of approaches to its solution has been attempted. Many of these approaches have improved the biostability of polyurethanes and it is well recognised that a safe, durable and effective polymeric prosthetic valve is imminent [12].

View larger version (19K): [in this window] [in a new window]   Fig. 5. Thin section of polyurethane valve leaflet, stained for calcium, with von Kossa (x312).

View larger version (109K): [in this window] [in a new window]   Fig. 6. Scanning electron microscopy image of polyurethane valve leaflet, showing area of degradation surrounded by intact polymer.

	Acknowledgments

 
This research was funded by the British Heart Foundation.

	Footnotes

 
Presented at the 13th Annual Meeting of the European Association of Cardio-thoracic Surgery, Glasgow, Scotland, UK, September 5–8, 1999.

¹ Current MedLINK programme, in association with the University of Liverpool, Department of Clinical Engineering, the University of Leeds, Department of Mechanical Engineering, and AorTech International, with funding from the U.K. Department of Health and the Engineering and Physical Sciences Research Council.

	Appendix A. Conference discussion

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. Conference... References

 
Dr D. Cosgrove (Cleveland, OH, USA): Will you describe the electron microscopic surface of this material? Is it extremely smooth or do you expect in-growth?

Professor Wheatley: The new polyurethanes that we are testing have been strained to 100% and implanted in rat models for 6 months, and the appearance looks entirely homogeneous, absolutely amorphous. There is no evidence of any pitting or irregularity. Most of the other polyurethanes won't last 3 months, and they have craters and look like the surface of the moon in this test.

Dr R. Frater (Bronxville, NY, USA): We tested an earlier generation of polyurethane three-leaflet valves for a year in sheep, and at a year they all had intrinsic calcification, which was definitely not related to a surface phenomenon. It was within the substance of the polyurethane. I know polyurethane comes in many forms, and I am not sure whether the form of polyurethane you are using is necessarily different from the form we would have used some 10 years ago in terms of the potential for intrinsic calcification over time.

Professor Wheatley: I am not sure that I can answer that question. I really need my biochemical and polymer chemist colleagues to tell me that, but the structure of the soft segment is such that they don't believe that this will calcify. We have had this in a fairly demanding animal model for quite a good period, 6 months, but we have also had it in a calcifying model in the laboratory for equivalent periods of much longer than this, and there doesn't seem to be any intrinsic calcification at all. The answer is clearly a biochemical one and a chemical one, and I don't know that anybody really understands that.

Mr A. Ritchie (Cambridge, UK): A question or two. The new crop of stentless valves that is on the market now requires no warfarin therapy, as is the prospect with the polyurethane valves, so they are equivalent in that sort of a sense. The question which will remain over the stentless valves is their durability, which the polyurethane valve has to answer also. We have seen in three of your valves, perhaps as some may judge, early signs of failure. Where do you think they might lie in competing with stentless valves if that continues to show up?

Professor Wheatley: The changes in three of the valves were quite clearly related to a surface phenomenon. It was the expected finding we would have with a nonbiostable material. We want these valves to last at least as well as the current bioprostheses would in adults, because I think the future for this valve, at least initially, will be the parts of the world where rheumatic fever occurs in young patients, where the bioprosthesis is not an option as it behaves like the juvenile sheep, and where mechanical valves are not feasible. Stentless valve implantation techniques are such that the degree of skill needed for these makes them sometimes not the most obvious option. We can certainly fatigue these in the laboratory to do better than the current frame-mounted bioprostheses, but the answers are clearly going to come from a lot more further testing.

Dr Cosgrove: Could you tell us the mode of failure on the accelerated wear tester?

Professor Wheatley: Usually it is a fatigue-type fracture of the material, a crack which propagates slowly. Crack propagation is one of the concerns; we have to make sure there is good resistance to that. One of the arguments that was put up for the homografts many years ago is that they fail slowly, and we hope that such will be the same for these valves, not in the near future but perhaps that is the way these will eventually fail.

	References

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. Conference... References

 

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