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Ann Thorac Surg 2010;90:1301-1306. doi:10.1016/j.athoracsur.2010.05.024
© 2010 The Society of Thoracic Surgeons
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Original Articles: Pediatric Cardiac

Clinical Performance of Decellularized Cryopreserved Valved Allografts Compared With Standard Allografts in the Right Ventricular Outflow Tract

Phillip T. Burch, MDa,*, Aditya K. Kaza, MDa, Linda M. Lambert, MSN, FNPa, Richard Holubkov, PhDb, Robert E. Shaddy, MDc, John A. Hawkins, MDa

a Division of Cardiothoracic Surgery, Primary Children's Medical Center and the University of Utah, Salt Lake City, Utah
b Division of Pediatric Critical Care Medicine, Primary Children's Medical Center and the University of Utah, Salt Lake City, Utah
c Division of Pediatric Cardiology at Children's Hospital of Philadelphia, Philadelphia, Pennsylvania

Accepted for publication May 10, 2010.

* Address correspondence to Dr Burch, Division Cardiothoracic Surgery, Primary Children's Medical Center, 100 N Mario Capecchi Dr, Salt Lake City, UT 84113 (Email: phillip.burch{at}hsc.utah.edu).

Presented at the Forty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 25–27, 2010.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 References
 
Background: Although decellularized cryopreserved valved allografts (DCAs) have reduced immunogenicity, proof of clinical superiority over standard cryopreserved allografts (SCAs) is lacking. To assess functional results and durability, we studied a group of patients with DCAs implanted between 2000 and 2005 and compared them with a similar group with SCAs.

Methods: From July 2000 until January 2005, 47 patients underwent insertion of a DCA between the right ventricle and pulmonary arteries. The DCA patients were compared with 47 age-matched and diagnosis-matched controls receiving SCAs. All patients received pulmonary allografts and were matched for valve position (orthotopic versus heterotopic). We analyzed each group for survival, reoperation, reintervention (surgical or catheter-based), stenosis, and regurgitation.

Results: There were no differences between groups with respect to weight, age, valve size, or survival. Actuarial freedom from reintervention at 8 years was 79% for DCAs as compared with 63% for SCAs (p = 0.31, log-rank). Echocardiogram in the DCA group (median 66 months) showed a slightly lower median peak gradient of 16 mm Hg (range, 0 to 82 mm Hg) as compared with 22 mm Hg (range, 0 to 63) in the SCA group (median 61 months, p = 0.051, Wilcoxon). However, when conduits 18 mm or less in diameter were compared, DCA patients had a median peak gradient of 10 mm Hg (range, 0 to 43) compared with 25 mm Hg in SCAs (range, 0 to 55 mm Hg, p = 0.03). There were no differences in the degree of allograft insufficiency in either group.

Conclusions: Decellularized cryopreserved valved allografts have a nonsignificant trend toward lower peak valve gradient and reintervention in comparison with SCAs. Small valve sizes (18 mm or less) show a slight but significant improvement in peak gradient, but no advantage in valve insufficiency. These findings and a significantly higher cost (>$3,000) make further direct comparisons necessary before widespread use of DCAs can be justified.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 Discussion
 References
 
Standard cryopreserved pulmonary allografts (SCAs) are commonly used for right ventricular outflow tract reconstruction during a variety of congenital cardiac defect repairs. Allografts are the preferred conduit for right ventricular outflow tract reconstruction and pulmonary valve replacement at many centers due excellent handling properties, ease of insertion, and an excellent hemodynamic profile after implantation. Despite numerous advantages, SCAs have variable durability especially in very young children and frequently require repeat operations to replace failing conduits [1–5]. Studies in humans have demonstrated both cellular and humoral immune responses to human leukocyte antigens present on the implanted allografts [6, 7]. It has been theorized that allograft failure is at least partially the result of the host immune response to antigens present in the allograft. Infants and children tend to have the greatest immunologic reaction to cryopreserved allograft material [8], with a shorter period of freedom from reintervention after valved allograft implantation than is seen in adult patients [1]. Decellularized cryopreserved valved allografts (DCAs) were developed to ameliorate the recipient immune response to the implanted conduit. In addition, DCAs were designed to provide an acellular matrix that could be infiltrated by autologous cells. In theory, a DCA repopulated by recipient cells would be capable of repair and remodeling similar to native tissue endowing it with increased durability.

While there is evidence that DCAs do not elicit a significant immune response [9, 10] and host cells have been demonstrated infiltrating decellularized allografts [11, 12], there is no definitive data demonstrating clinical superiority over SCAs [13–17]. Previous studies have been limited by small numbers of patients and short duration of follow-up; thus, there is little information regarding the long-term clinical function of these conduits. In order to determine long-term clinical performance and durability of DCAs compared with SCAs, we studied a group of patients who had DCAs implanted and compared them with a similar group of SCA with both groups having undergone surgery between 2000 and 2005.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Discussion
 References
 
Patients
The Institutional Review Board at Primary Children's Medical Center and the University of Utah approved this retrospective review. Waiver of parental consent was obtained as part of Institutional Review Board approval. The Cardiothoracic Surgery database at Primary Children's Medical Center was reviewed, collecting data from July 2000 until January 2005. Forty-seven patients were identified who had undergone insertion of a DCA (CryoValveSG; CryoLife, Inc, Kennesaw, GA) between the right ventricle and pulmonary arteries. Forty-seven controls who had received SCAs for right ventricular outflow tract reconstruction during this same time period were selected for comparison. These forty-seven controls were first diagnosis-matched and then secondarily age-matched to develop a control group immunologically similar to and having a similar distribution of conduit sizes as the DCA group. Additional demographic data collected by review of medical records included number of prior surgeries and operative times, including cross-clamp times. Each group was further assessed for survival, reoperation, reintervention (surgical and [or] catheter based), and echocardiographic performance with respect to allograft stenosis and regurgitation.

Allografts
All allografts in this study were pulmonary allografts obtained from CryoLife, Inc. (Kennesaw, GA). Standard cryopreserved allograft material was harvested and cryopreserved according to previously published methods [18, 19]. Decellularized cryopreserved allograft material is prepared by harvesting techniques similar to those used for standard allograft material, but undergoes a decellularization process that first involves cell lysis in hypotonic sterile water solution. Next, the allograft tissue is equilibrated in buffer and is treated by enzymatic digestion of nucleic acids with a combined solution of ribonuclease and deoxyribonuclease. The allograft tissue is washed in isotonic neutral buffer to further reduce cellular staining when evaluated with hematoxylin and eosin staining of cryosectioned tissue [20]. The processed decellularized valves are then cryopreserved according to a controlled rate freezing protocol [21]. The resulting decellularized cryopreserved allografts have been shown to have approximately a 99% reduction in staining of endothelial and interstitial cellular elements, as well as marked reduction in staining for class I and class II histocompatability antigens [12]. No attempts were made, in this study, to match patients and conduits based on blood groups. Also, no immunosuppressive regimen was used in this study.

Study Methods
Patients within both groups underwent echocardiographic follow-up consisting of standard surface two-dimensional and Doppler echocardiography. Allograft stenosis was evaluated with standard Doppler techniques. The peak velocity across the valved conduits was obtained with pulsed or continuous-wave Doppler evaluation, and the gradient was determined with the modified Bernoulli equation. Pulmonary valve regurgitation was graded echocardiographically according to a method described previously by our institution. This method has been validated and compared with traditionally used angiographic measures [22]. The most recent echocardiogram was used for comparison of regurgitation and stenosis between groups.

Statistical Analysis
Freedom from reintervention curves were generated using the Kaplan-Meier method [23]. Differences in freedom from event (death, reintervention, or explantation) rates were assessed between patient groups using the log-rank test. Events were also compared between patient subgroups as binary outcomes using the Pearson {chi}2 test; in the case of small cell counts the Fisher's exact test was used. All p values are two-sided. Mean values of continuous factors were compared between subgroups using the two-sample t test. Normally distributed values are reported as mean ± standard deviation. Median and ranges for values are included where appropriate.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Discussion
 References
 
Demographics
The DCA patients and SCA patients did not significantly differ with regard to age, weight, number of prior cardiac surgeries, conduit size, conduit position (orthotopic versus heterotopic), cross-clamp time, cardiopulmonary bypass time, or duration of follow-up after conduit implantation (Table 1).


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  		Table 1 Patient Characteristics
 
Echocardiographic Performance
The most recent follow-up transthoracic echocardiogram was reviewed to obtain peak instantaneous gradient across the valve and grade of conduit regurgitation. Patients had a similar length of follow-up with the most recent echocardiogram being performed a median of 66 months (range, 23 to 98) postimplant in the DCA group, and a median of 61 months (range, 26 to 120) postimplant in the SCA group. The median peak instantaneous gradient for all patients who received a DCA was 16 mm Hg (range, 0 to 82) while patients who received SCAs had a median peak instantaneous gradient of 22 mm Hg (range, 0 to 63). Although the gradient was higher in SCA patients than in DCA patients, it did not reach statistical significance (p = 0.051). However, the median peak gradient for DCA patients with conduits of 18 mm or less (n = 12) was 10 mm Hg (range, 0 to 43) while SCA patients with conduits of 18 mm or less (n = 13) had a median peak gradient of 25 mm Hg (range, 0 to 55, p = 0.03). The median grade of conduit insufficiency was 1+ (range, 0 to 3) for DCAs and 1+ (range, 0 to 2.5) for SCAs at the most recent follow-up (p = not significant). When the conduits were assessed based on the prior subgroupings for conduits of 18 mm or less there was still no significant difference in regurgitation between SCAs and DCAs.

Conduit Reintervention
A total of 21 patients required explantation of their conduit with 9 explants occurring in DCA patients while 12 explants were performed in SCA patients. Actuarial freedom from conduit explantation at 8 years was 79% for DCAs compared with 66% for SCAs (p = 0.44 [Fig 1 ]). Surgical explant data and catheter-based interventions were combined to obtain the overall rate of reintervention. Twenty-two patients underwent reintervention with 9 reinterventions in DCA patients and 13 performed in SCA patients. Actuarial freedom from reintervention at eight years was 79% for DCA patients compared with 63% for SCA patients (p = 0.31 [Fig 2 ]).


Figure 1
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  		Fig 1. Actuarial freedom from valve explant after implantation of both standard and decellularized cryopreserved allografts in 47 patients.

 

Figure 2
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  		Fig 2. Actuarial freedom from reintervention (explant or catheter-based intervention) after implantation of both standard and decellularized cryopreserved allografts in 47 patients.

 
Separating the groups into orthotopic versus heterotopic (or conduit position) yielded a total of 24 orthotopic and 23 heterotopic position patients in the SCA group and 25 orthotopic and 22 heterotopic position patients in the DCA group. Actuarial freedom from reintervention was 84% for SCA in the orthotopic position at 72 months as compared with 76% for the DCAs (p = 0.56, log-rank). However, there was a trend toward superiority for DCAs when comparing conduits in the heterotopic position with an actuarial freedom from reintervention of 50% for SCAs at 72 months as compared with 83.3% for DCAs (p = 0.11).

Survival
There were 2 deaths in the DCA group (4%) and 1 death in the SCA group (2%). None of the deaths were attributed to conduit failure or other cardiac issues.


   Comment
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 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Discussion
 References
 
There is ample evidence demonstrating that standard homografts elicit a marked recipient immune response [5, 8, 10]. Within our own institution we have demonstrated a significant increase in panel reactive antibodies within months of implantation of homograft material [7, 24]. It has been theorized that specific cellular and humoral responses by the recipient contribute to early graft deterioration and tissue calcification with subsequent clinical failure. The evidence supporting an immunologic cause for graft failure is largely circumstantial. In our study no additional efforts were made to blunt the immune response of either DCA or SCA recipients. The DCAs showed trends toward improved durability over SCAs with regard to explantation and reintervention but these trends did not reach statistical significance. Late peak echocardiographic gradient in small conduits was the only parameter in this study in which DCAs were significantly better than SCAs. Despite the fact that SCAs elicit a more profound immunologic response than DCAs, DCAs were superior to SCAs with regard to only one parameter in one subset of patients. Furthermore, this did not result in any changes in the longevity of the conduits.

In patients who progress to heart transplant, DCAs are clearly a better choice as they result in minimal activation of the recipient's immune system, thus preventing sensitization that would limit donor compatibility. Patients with congenital heart disease requiring right ventricular outflow tract reconstruction currently represent approximately 15% of patients who ultimately progress to transplantation [25]; however, there is limited data with regard to the percentage of patients requiring right ventricle to pulmonary artery conduits who go on to develop heart failure requiring transplantation. With improvements in operative technique and long-term management strategies it is likely that a limited number of these patients progress to transplant and would benefit from decellularized grafts with regard to immune system activation. Predicting those patients likely to progress to transplant is very complicated but would be helpful in determining those patients most likely to benefit from decellularized grafts. Until better algorithms exist to predict progression to heart failure, implanting decellularized allografts in any patient with decreased ventricular function, or very complicated anatomic defects who may be at higher risk, would limit the development of anti-human leukocyte antigen antibodies that may prohibit transplant in the future.

Three prior studies have evaluated the long-term performance of DCAs in the right ventricular outflow tract in comparison to SCAs [14, 16, 17]. Bechtel and colleagues [14] evaluated a cohort of adult patients who had undergone the Ross procedure. They demonstrated no difference with regard to conduit regurgitation or reintervention, but surprisingly SCAs were superior to DCAs with regard to conduit stenosis. Konuma and colleagues [16] studied a pediatric population who had primarily undergone a Ross or Rastelli procedure. At long-term follow-up, there was no difference between DCAs and SCAs with regard to regurgitation, stenosis, or reintervention. However, when patients were assessed for clinically significant pulmonary insufficiency (ie, ≥3+) DCAs were superior. When patients were subdivided into groups less than 2 years and greater than 2 years at repair, DCAs had significantly higher late peak gradients than SCAs in the older group. In a recent large scale, multicenter study by Brown and colleagues [17], valve durability and freedom from explant was no different between DCAs and SCAs, similar to our findings. However, they did find that gradients for DCA valves were significantly lower for the orthotopic position Ross procedure patients, but this difference was only 3 mm Hg and is of questionable clinical significance. In contrast to our study, Brown and colleagues found the DCA valves to have lower insufficiency grades overall for both the orthotopic and heterotopic positions. Our study has a more heterogeneous patient cohort in terms of diagnosis and patient age than any of the other three studies. In contrast to the findings of Bechtel and colleagues and Konuma and colleagues, DCAs had slightly lower late peak gradients than did SCAs in our study and this became statistically significant when conduits 18 mm or less in diameter were examined. If immune mediated damage to the conduit is the cause of conduit stenosis then this would be the expected finding, but again our results are at odds with the findings of these prior studies. Of note, the mean diameter of the conduits used in the Konuma and colleagues study was 18 mm. We did not demonstrate an advantage for either conduit type in reference to pulmonary insufficiency. An increased incidence of regurgitation might be expected in the current study and in the results of Konuma and colleagues given that a significant percentage of the patients in each study had the conduit placed in a heterotopic position. However, this does not account for the performance advantage of DCAs observed in the other two studies. Given that our study does not confirm this finding it may be more readily explained by variations in anatomy and positioning of the conduits. Importantly, the finding of nonsignificant differences in performance with regard to explantation and reintervention is consistent between all of the studies.

As the search for the ideal conduit for right ventricular outflow tract reconstruction proceeds; even incremental improvements in performance and durability can have a substantial impact. Nonetheless, in the current era of healthcare, cost is an important consideration when making choices regarding all therapies. Before a more costly therapy can be recommended as the standard of care, it must demonstrate clear superiority over existing therapies. In our study, DCAs trend toward lower peak gradients at long-term follow-up when compared with SCAs but similar studies demonstrate an advantage for SCAs with regard to stenosis. Despite these contradictory findings the clinical significance of a 6 to 15 mm Hg gradient is debatable. Furthermore, it could be argued that the durability of a conduit is the most important indicator of clinical function and there was no statistical difference between DCAs and SCAs with regard to reintervention in this study or in prior studies of long-term function. Although the combined results of these papers demonstrate no clearly significant advantage for DCAs, based on the findings of this study one may be justified in using a DCA for small patients (ie, requiring ≤18 mm conduit), for replacement of conduits in the heterotopic position, or in particularly complex heart disease when later transplantation may be necessary.

The availability of homografts is limited in general and small-sized homografts are in especially short supply. The DCAs on average cost $3,000 more than SCAs (CryoValveSG). In addition, the shelf life of decellularized grafts is approximately one-tenth that of traditional cryopreserved allografts (CryoValveSG). The potential for DCAs to expire prior to use, particularly in small and moderate volume centers, is increased thus wasting an already limited resource. Given these findings, further direct comparison between DCAs and SCAs proving a distinct clinical advantage is warranted before widespread use of DCAs can be justified.


   Discussion
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 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
References
 
DR JOSEPH FORBESS (Dallas, TX): I'd like to ask that if these patients' PRAs (panel-reactive antibodies) are low, is that worth the $3,000, if it's a young child, and what are your thoughts on the sensitization issues?

DR BURCH: I think that decellularized grafts are a promising technology. Unfortunately, we don't know what the denominator is. Most studies show that of those patients with congenital heart disease that progress to require transplantation, patients requiring right ventricular outflow tract reconstruction account for approximately 15% to 20% of the total. But as I said, unfortunately we don't know what that denominator is. Certainly there are those patients with tetralogy of Fallot with good function and relatively straightforward anatomy who won't progress to transplant, and in those patients it's probably not worth the cost. I think being selective with the implementation of this technology in those patients with complex anatomy and decreased function, at least in the short term, might be a more valid use of this technology.

DR JOHN MAYER (Boston, MA): I just want to clarify one thing; your matching population, were they contemporaneous?

DR BURCH: Yes, sir.

DR WOJCIECH MROWCZYNSKI (Geneva, Switzerland): The decellularization process changes the properties of the extracellular matrix, so not necessarily making it good for repopulation of the native cells. You did several explantations, I guess. Did you find some cells that were coming from outside?

DR BURCH: In our study we did not do any histologic exam of explanted conduits. Previous laboratory studies with this decellularization process have demonstrated some host cells repopulating the extracellular matrix.

DR GERHARD ZIEMER (Tübingen, Germany): Well, actually I can agree with almost everything you said; however, I missed some information. As for me, it is rather disappointing that the regurgitation is not less but the same as in the normal homograft. I would like to see a few explanted leaflets' pathohistology. Is there a difference to the changes seen in the wall or there is no difference?

One of the major problems with both the standard cryopreserved homografts and the decellularized one is that the process of cryopreservation is the same. Dr Schenke-Layland from UCLA showed optimized preservation of the extracellular matrix employing the so-called vitrification where you do not have the crystallization in cryopreservation (Ann Thorac Surg 2007;83:1641–50). And this may make really a difference and not the decellularization, because the extracellular matrix is damaged in the same way just by the way of conventional cryopreservation. Therefore I do not expect them to live longer. So far, however, nobody knows whether vitrification will lead to longer homograft durability.

DR BURCH: Again, we didn't look histologically at explanted conduits. I agree that they are subjected to the same freezing process. And also, I think after implantation, that both decellularized and standard conduits are subject to some nonspecific inflammation or nonspecific phagocyte-mediated immune response. And that may be responsible for why we don't see that much of a difference. Ultimately a short period of immunosuppression may allow for better realization of better function in these decellularized conduits.

DR ZIEMER: You may be aware of the dismal outcome of decellularized xenografts as was published from Vienna in 2002 where 3 out of 4 children died because the decellularized xenograft just ruptured. Do you have any idea why this does not happen in decellularized homografts?

DR BURCH: It's my understanding that in the study you're referring to the xenografts were composite grafts, not an intact conduit. They were the noncoronary cusp from three separate animals sewn together to create a composite conduit and perhaps that was the issue.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 References
 

  1. Hawkins JA, Bailey WW, Dillon T, Schwartz DC. Midterm results with cryopreserved allograft valved conduits from the right ventricle to the pulmonary arteries J Thorac Cardiovasc Surg 1992;104:910-916.[Abstract]
  2. Clarke DR, Campbell DN, Hayward AR, Bishop DA. Degeneration of aortic valve allografts in young recipients J Thorac Cardiovasc Surg 1993;105:934-942.[Abstract]
  3. Yacoub M, Rasmi NR, Sundt TM, et al. Fourteen-year experience with homovitalhomografts for aortic valve replacement J ThoracCardiovasc Surg 1995;110:186-194.[Abstract/Free Full Text]
  4. O'Brien MF, Harrocks S, Stafford EG, et al. The homograft aortic valve: a 29-year, 99.3% follow up of 1,022 valve replacements J Heart Valve Dis 2001;10:334-344[discussion 335].[Medline]
  5. Baskett RJ, Ross DB, Nanton MA, Murphy DA. Factors in the early failure of cryopreserved homograft pulmonary valves in children: preserved immunogenicity? J Thorac Cardiovasc Surg 1996;112:1170-1179.[Abstract/Free Full Text]
  6. Shaddy RE, Hawkins JA. Immunology and failure of valved allografts in children Ann Thorac Surg 2002;74:1271-1275.[Abstract/Free Full Text]
  7. Hawkins JA, Breinholt JP, Lambert LM, et al. Class I and class II anti-HLA antibodies after implantation of cryopreserved allograft material in pediatric patients J Thorac Cardiovasc Surg 2000;119:324-330.[Abstract/Free Full Text]
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  9. Hawkins JA, Hillman ND, Lambert LM, et al. Immunogenicity of decellularized cryopreserved allografts in pediatric cardiac surgery: comparison with standard cryopreserved allografts J Thorac Cardiovasc Surg 2003;126:247-532.[Abstract/Free Full Text]
  10. da Costa FD, Dohmen PM, Duarte D, et al. Immunological and echocardiographic evaluation of decellularized versus cryopreservedallografts during the Ross operation Eur J Cardiothorac Surg 2005;27:572-578.[Abstract/Free Full Text]
  11. Ketchedjian A, Jones AL, Krueger P, et al. Recellularization of decellularized allograft scaffolds in ovine great vessel reconstructions Ann Thorac Surg 2005;79:888-896.[Abstract/Free Full Text]
  12. Elkins RC, Dawson PE, Goldstein S, Walsh SP, Black KS. Decellularized human valve allografts Ann Thorac Surg 2001;71(5 Suppl):S428-S432.[Medline]
  13. Bechtel JF, Gellissen J, Erasmi AW, et al. Mid-term findings on echocardiography and computed tomography after RVOT-reconstruction: comparison of decellularized (SynerGraft) and conventional allografts Eur J Cardiothorac Surg 2005;27:410-415.[Abstract/Free Full Text]
  14. Bechtel JF, Stierle U, Sievers HH. Fifty-two months' mean follow up of decellularized SynerGraft-treated pulmonary valve allografts J Heart Valve Dis 2008;17:98-104.[Medline]
  15. Tavakkol Z, Gelehrter S, Goldberg CS, Bove EL, Devaney EJ, Ohye RG. Superior durability of SynerGraft pulmonary allografts compared with standard cryopreserved allografts Ann Thorac Surg 2005;80:1610-1614.[Abstract/Free Full Text]
  16. Konuma T, Devaney EJ, Bove EL, et al. Performance of CryoValve SG decellularized pulmonary allografts compared with standard cryopreserved allografts Ann Thorac Surg 2009;88:849-855.[Abstract/Free Full Text]
  17. Brown JW, Elkins RC, Clarke DR, et al. Performance of the Cryovalve SG human decellularized pulmonary valve in 342 patients relative to the conventional Cryovalve at a mean follow-up of four years J ThoracCardiovasc Surg 2010;139:339-348.[Abstract/Free Full Text]
  18. McNally RT, Heacox AE, Brockbank KG. Short-term follow-up of cryopreserved allograft valves and valved conduits from the CryoLife clinical registryIn: Yankah AC, Hetzer R, Miller DC, Ross DN, Somerville J, Yacoub MH, editors. Cardiac valve allografts 1962–1987. Darmstadt, Germany: Steinkopff Verlag; 1988. pp. 323-332.
  19. Heacox AE, McNally RT, Brockbank KG. Factors affecting the viability of cryopreserved allograft heart valvesIn: Yankah AC, Hetzer R, Miller DC, Ross DN, Somerville J, Yacoub MH, editors. Cardiac valve allografts 1962–1987. Darmstadt, Germany: Steinkopff Verlag; 1988. pp. 37-42.
  20. O'Brien MF, Goldstein S, Walsh S, Black KS, Elkins R, Clarke D. The SynerGraft valve: a new acellular (nonglutaraldehyde-fixed) tissue heart valve for autologous recellularization first experimental studies before clinical implantation Semin Thorac Cardiovasc Surg 1999;11(4 Suppl 1):194-200.[Medline]
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