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Ann Thorac Surg 1996;62:772-777
© 1996 The Society of Thoracic Surgeons

Original Articles: Cardiovascular

Impact of Glutaraldehyde on Calcification of Pericardial Bioprosthetic Heart Valve Material

Martin Grabenwöger, MD, Jamil Sider, MD, Florian Fitzal, MD, Christian Zelenka, MD, Ursula Windberger, MD, Michael Grimm, MD, Anton Moritz, MD, Peter Böck, MD, Ernst Wolner, MD

Department of Cardio-Thoracic Surgery and Zentrum für Biomedizinische Forschung, University of Vienna, Vienna, Austria; and Institute of Histology and Embryology, Veterinary University of Vienna, Vienna, Austria

Accepted for publication April 30, 1996.


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background. This study was conducted to investigate the impact of the preservation method of bioprosthetic heart valve materials on calcification rates and biocompatibility of the biologic tissue.

Methods. In subcutaneous rat implants, conventionally preserved bioprosthetic heart valve material was compared with bovine pericardium that was treated with L-glutamic acid to reduce residual glutaraldehyde released from the fixed tissue. Both these methods were compared with bovine pericardium that was stabilized by a dye-mediated photooxidation reaction without glutaraldehyde. Biocompatibility of these biomaterials was tested in vitro using human endothelial cell cultures.

Results. Conventionally preserved bovine pericardium with a high amount of glutaraldehyde incorporated into the tissue resulted in severe calcification 63 days after subcutaneous implantation in rats (165.4 ± 20 mg Ca2+/g dry weight). Postfixation treatment with L-glutamic acid, which reduces free, unbound aldehyde groups, showed a significant decrease in calcification (89.6 ± 14 mg Ca2+/g dry weight). Glutaraldehyde-free preservation by dye-mediated photooxidation showed no calcification after 63 days of subcutaneous implantation (1.0 ± 0.4 mg Ca2+/g dry weight). Regular endothelial cell proliferation was observed on photooxidized and L-glutamic acid-treated tissue, whereas conventionally treated tissue caused endothelial cell death.

Conclusions. This study underlines the detrimental role of glutaraldehyde in the calcification process of bioprosthetic heart valve materials and emphasizes alternative preservation methods that reduce or avoid the use of glutaraldehyde.


   Introduction
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 Footnotes
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Calcification is the major drawback in the clinical use of bioprosthetic heart valves that are fabricated either from aldehyde-preserved porcine aortic valves or from bovine pericardium [1, 2]. Although the exact mechanism of this so-called dystrophic calcification is not yet identified, tissue preservation with glutaraldehyde is suspected to be essential for calcification of bioprosthetic material [3–5].

In the development of alternative tissue preservation procedures, particular attention is paid to various pre- and postfixation tissue treatments to offset the effects of glutaraldehyde [33,6–8]. A preservation method for collagenous biomaterials that avoids the use of glutaraldehyde completely is the dye-mediated photooxidation reaction. This treatment results in modification of specific amino acids in proteins, thus forming a protein mass that is insoluble under the most denaturing conditions and insoluble toward pepsin digestion [9].

The present study was conducted to evaluate biocompatibility and calcification rates of bioprosthetic heart valve materials prepared according to three different methods. In subcutaneous rat implants, conventionally preserved pericardium was compared with alternatively preserved pericardium that was treated with L-glutamic acid and pericardium that was stabilized through a dye-mediated photooxidation reaction. Biocompatibility of the bioprosthetic tissues was determined by measurement of the growth properties of seeded human umbilical vein endothelial cells on the biologic tissues.


   Material and Methods
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 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Tissue Preservation
GLUTARALDEHYDE TISSUE PRESERVATION.
Conventionally preserved pericardium consisted of freshly excised bovine pericardium that was dissected free from adhering fat tissue, cut into 1-cm2 pieces, and placed in phosphate-buffered saline solution (PBS/-Ca2+) containing glutaraldehyde 0.5% (pH 7.4) for 72 hours at 4°C. The fixed pericardium was stored in 0.25% glutaraldehyde (pH 7.4, 4°C).

For L-glutamic acid treatment, the pericardium was cut into pieces 1 cm2 in size and placed in pbs/-Ca2+ containing glutaraldehyde 0.5% (pH 7.4) for 72 hours at 4°C. Fixed pericardial patches were washed (3 x 10 minutes in 10 mL PBS/patch) and transferred to a saturated aqueous solution of L-glutamic acid (ph 3, room temperature) for 48 hours. storage was performed in paraben (chemosan, vienna, austria) (aqueous solution of 0.02% propyl-hydroxy-benzoate and 0.18% methyl-hydroxy-benzoate).

GLUTARALDEHYDE-FREE TISSUE PRESERVATION.
Dye-mediated photooxidized (Photofix, CarboMedics, Austin, TX) pericardial tissue patches 1 cm2 in size were obtained from CarboMedics Inc (Sulzer Medica, Austin, TX). Bioprosthetic tissue was stored in 50% ethanol solution.

Endothelial Cell Cultivation
Human umbilical vein endothelial cells were isolated and cultivated as described previously [10]. Endothelial cells were characterized by immunostaining for factor VIII (von Willebrand factor) and by typical cobblestone-like arrangement and shape. These cells were seeded on differently prepared pericardial tissue patches (see previous section) at an initial density of 6,000 ± 1,000 cells/cm2. On days 1, 3, 5, and 7 after seeding, the cells were detached by incubation with collagenase, stained with crystal violet, and counted in a hemocytometer.

Subcutaneous Implants in Rats
Pericardial patches were rinsed thoroughly (3 x 10 minutes in 10 mL PBS/patch) and inserted in subcutaneous pockets in the ventral abdominal region of 30 anesthetized male rats (Sprague-Dawley strain, 180 to 230 g in weight). Each animal received three patches, each of them preserved in a different manner (see Tissue Preservation section). On days 21 and 63 after implantation, 15 animals were sacrificed, respectively, and the retrieved specimens were prepared for further processing. For measurement of calcium content, explanted specimens were washed in distilled water, freeze-dried, and weighed. After hydrolysis in 6N HCl, atomic absorption spectroscopy for calcium was performed at 315.18 nm wavelength [11].

All animals were maintained on a standard diet of Lab Chow (Ralston-Purina, St. Louis, MO). All experiments were performed according to the "Austrian law of animal experimentation."

Morphologic Evaluation
For light microscopy, specimens were routinely fixed in 3% neutral formalin and embedded in paraffin. Serial sections were cut at 10 µm thickness and stained with hematoxylin and eosin, Weigert's elastica stain, and von Kossa's silver method for calcium deposits [12]. For scanning electron microscopy, specimens were fixed in 2.5% glutaraldehyde in PBS (4°C, pH 7.2) and dehydrated in a series of graded ethanols. After critical point drying with carbon dioxide, the specimens were sputtered with gold-palladium and examined with a Jeol JSM 5400 (Jeol, Tokyo, Japan) scanning electron microscope.

Statistical Analysis
Analysis of variance was performed. The level of significance was p less than 0.05.


   Results
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 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Endothelial Cell Proliferation
Proliferation kinetics of human umbilical vein endothelial cells cultivated on differently preserved pericardium are shown in Figure 1Go. Regular endothelial cell proliferation was observed on photooxidized tissue and on L-glutamic acid-treated pericardium. On conventionally preserved pericardium, by contrast, endothelial cells did not proliferate at all.



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  		Fig 1. . Proliferation kinetics of endothelial cells on photooxidized, L-glutamic acid-treated, and conventionally preserved bovine pericardium. Note the regular endothelial cell proliferation on photooxidized and L-glutamic acid-treated pericardium as compared with control cells cultivated on plastic dishes. (*p < 0.05.)

 
Scanning electron microscopy revealed well-spread endothelial cells on photooxidized and L-glutamic acid-treated patches. Close contact of endothelial cells to the underlying pericardium was indicated by numerous cytoplasmic protrusions extending into the fibrillar collagenous matrix (Fig 2AGo). On day 7 after seeding, an endothelial cell monolayer with characteristic cobblestone morphology could be observed (Fig 2CGo). On conventionally preserved pericardium, only a few endothelial cells could be observed 1 day after seeding. Endothelial cells were buckled and showed loose contact with the underlying tissue. On day 7, only dead and shrunken cells could be seen (Fig 2BGo).



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  		Fig 2. . Scanning electron microscopy of human umbilical vein endothelial cells cultivated on differently prepared bovine pericardium. (A) Well-spread endothelial cells on L-glutamic acid-treated pericardium 3 days after seeding (x1,500). (B) Dead and shrunken cells on conventionally fixed pericardium after 7 days of cultivation (x2,000). (C) Confluent endothelial cell monolayer cultivated on photooxidized pericardium (x350). (All magnifications are before 10% reduction.)

 
Calcification
Atomic absorption spectroscopy revealed no calcification of dye-mediated photooxidized pericardium. The calcium content of L-glutamic acid-treated pericardium was significantly lower than that of conventionally preserved pericardium during the entire experiment (p < 0.05). Detailed results are given in Figure 3Go.



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  		Fig 3. . Calcium content of photooxidized, L-glutamic acid-treated, and conventionally preserved bovine pericardium on days 21 and 63 after subcutaneous implantation in rats. At 21 days after implantation, differences between photooxidized and L-glutamic acid-treated pericardium were not significant, whereas all other groups showed significant differences. (*p < 0.05.)

 
Light microscopic examination of photooxidized pericardium showed a regular texture of collagen fibers after 21 as well as 63 days of implantation. Calcium deposits could not be identified using morphologic methods. Collagen bundles remained well oriented and tightly gathered, closely resembling native pericardium. Macrophages and multinucleated giant cells invaded only superficial layers of the biomaterial. Phagocytosis of collagen fibrils was not observed (Figs 4E, 4FGoGo). The host response against conventionally fixed and L-glutamic acid-treated pericardium was more accentuated than that for photooxidized pericardium. Numerous macrophages invaded the collagenous fibers toward the central areas of conventionally fixed pericardium and loosened the texture of the biomaterial (Fig 4AGo). Initial calcium deposits were seen in central areas of L-glutamic acid-treated pericardium after 21 days of implantation. These deposits were increased in size after 63 days (Figs 4C, 4DGoGo). Morphologic analysis of conventionally preserved pericardium revealed numerous foci of calcium deposits already at 21 days after implantation. After 63 days, large areas of the biomaterial were disintegrated and replaced by solid mineral deposits (Fig 4BGo).



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  		Fig 4. . Histologic examination of conventionally prepared bovine pericardium (A, B), L-glutamic acid-treated pericardium (C, D), and photooxidized pericardium (E, F) after 63 days of subcutaneous implantation in rats (x30). Bioprosthetic material is indicated (black brackets); macrophages are outlined (encircled regions). Calcium deposits were stained with von Kossa's silver method (B, D).

 

   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
This study shows that calcification of bioprosthetic heart valve material can be avoided completely in subcutaneous rat implants when stabilization of the bioprosthetic tissue is performed using a glutaraldehyde-free dye-mediated photooxidation reaction. Removal of residual glutaraldehyde by postfixation treatment with L-glutamic acid significantly reduces calcification of the tissue. Severe calcification and poor biocompatibility are seen in conventionally preserved bioprosthetic heart valve materials.

Glutaraldehyde was introduced by Carpentier and colleagues [13] as a compound to modify heterograft collagen chemically and make it immunologically acceptable in the human host. Augmentation of mechanical resistance and reduction of the thrombogenicity of collagen are additional advantages of this preservation agent. However, in the calcification process of bioprosthetic heart valves, glutaraldehyde pretreatment is presumed to be a critical determinant [4, 5]. This was confirmed by Nimni and associates [14], who assumed that the reaction of glutaraldehyde with collagen and other matrix components results in functional groups that are causatively related to the calcification process. Glutaraldehyde in dilute aqueous solution is prone to form oligomers and polymers by reacting with water through a hemiacetal-type polymerization process. It has been assumed that glutaraldehyde polymers and free carbonyl residues provide sites for initial calcium complex formation [15].

The results of the present study underline the role of glutaraldehyde in the calcification process. High amounts of glutaraldehyde incorporated in the tissue resulted in severe calcification during subcutaneous implantation in rats. Postfixation treatment with L-glutamic acid, which reduces the concentration of free aldehyde groups, significantly reduced calcium deposition. L-Glutamic acid reacts with aldehydes on the surface of collagen fibrils, forming acetals and esters [16]. Glutaraldehyde-free preservation of collagen, realized in the dye-mediated photooxidation reaction, prevented calcium deposition in subcutaneous rat implants. The photooxidation reaction results in a stabilized, cross-linked pericardial tissue that is stable toward chemical, enzymatic, and in vivo degradation while maintaining the physical properties of natural tissue [9]. The resistance toward biologic degradation was confirmed by our morphologic observations on subcutaneous rat implants, which revealed no phagocytosis of the collagen fibrils of the photooxidized tissue. Nevertheless, further studies have to be done to evaluate the mechanical stability of alternatively fixed pericardium.

Apart from the apparent role of glutaraldehyde in the calcification process, the cytotoxic nature of this preservation agent was addressed in several studies [3, 17, 18]. It could be shown that free aldehyde groups released from bioprosthetic heart valve material inhibited endothelial cell growth in vitro. This is substantiated by morphologic investigations on explanted bioprostheses, which showed endothelial cell ingrowth only in the basal areas of the bioprosthetic heart valves [19, 20]. It can be speculated that the absence of an intact endothelial cell layer on the valve surface promotes degenerative alterations due to plasma insudation, lipid insudation, and invasion of macrophages. Our in vitro study showed regular endothelial cell proliferation on dye-mediated photooxidized and L-glutamic acid-treated pericardial tissue. In contrast, endothelial cells could not survive on conventionally preserved pericardium because of the cytotoxic nature of glutaraldehyde.

The use of autologous pericardium for bioprosthetic heart valves represents another promising approach in the development of bioprosthetic tissue with low glutaraldehyde content. Only brief immersion in glutaraldehyde (5 to 15 minutes) is necessary to make the pericardium stiff enough to be used for valve construction [21]. Excellent results already have been reported with autologous pericardium used for mitral valvuloplasty [22]. However, the long-term performance of an autologous tissue valve treated with brief immersion in glutaraldehyde (Autogenics valve; Autogenics, Santa Barbara, CA) still has to be evaluated.

The results of this study highlight the need for an improved preservation procedure. Glutaraldehyde-free tissue stabilization or removal of glutaraldehyde incorporated in the tissue will attenuate calcification. High biocompatibility of bioprosthetic tissue, as indicated in vitro by regular endothelial cell proliferation, should have a beneficial effect on spontaneous endothelialization in vivo. Both of these measures should result in improved long-term durability of bioprosthetic heart valves.


   Acknowledgments
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
This work was supported by the "Ludwig Boltzmann Institut für Herzchirurgische Forschung."


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Address reprint requests to Dr Grabenwöger, Department of Cardio-Thoracic Surgery, University of Vienna, Währinger Gürtel 18-20, 1090 Wien, Austria.


   References
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Milano A, Bortolotti U, Talenti E, et al. Calcific degeneration as the main cause of porcine bioprosthetic valve dysfunction. Am J Cardiol 1984;53:1066 70.[Medline]
  2. Schoen FJ, Levy RJ. Bioprosthetic heart valve failure: pathology and pathogenesis. Cardiol Clin 1984;2:717–39.[Medline]
  3. Grimm M, Eybl E, Grabenwöger M, Böck P, Müller MM, Wolner E. Glutaraldehyde affects biocompatibility of bioprosthetic heart valves. Surgery 1992;111:74–8.[Medline]
  4. Golomb G, Schoen FJ, Smith MS, Linden J, Dixon M, Levy RJ. The role of glutaraldehyde-induced cross-links in calcification of bovine pericardium used in cardiac valve bioprostheses. Am J Pathol 1987;127:122–30.
  5. Levy RJ, Schoen FJ, Shermann F, Nichols J, Hawley M, Lund SA. Calcification of subcutaneously implanted type I collagen sponges. Am J Pathol 1986;122:71–82.[Abstract]
  6. Golomb G, Ezra V. Prevention of bioprosthetic heart valve tissue calcification by charge modification: effects of protamine binding by formaldehyde. J Biomed Mater Res 1991;25:85–98.[Medline]
  7. Rossi MA, Braile DM, Texeira MDR, Souza DRS, Peres LC. Lipid extraction attenuates the calcific degeneration of bovine pericardium used in cardiac valve bioprostheses. J Exp Pathol 1990;71:187–96.
  8. Webb CL, Flowers WE, Boyd J, Rosenthal EL, Schoen FJ, Levy RJ. Al--- binding studies and metallic cation effects on bioprosthetic heart valve calcification in the rat subdermal model. Trans Am Soc Artif Intern Organs 1990;36:56–9.
  9. Moore MA, Bohachevsky IK, Cheung DT, et al. Stabilization of pericardial tissue by dye-mediated photooxidation. J Biomed Mater Res 1994;28:611–8.[Medline]
  10. Jaffe EA, Nachmann RL, Becker CG, Minck CR. Culture of human endothelial cells derived from umbilical veins. J Clin Invest 1973;52:2745–56.
  11. Murthy GK, Rhea U, Teeler JT. Quantitative determination of calcium by atomic absorption. Environ Sci Technol 1971;5:436–42.
  12. Böck P, ed. Romeis-mikroskopische Technik. Vienna: Urban & Schwarzenberg, 1989:559–60.
  13. Carpentier A, Lemaigre G, Robert L, Carpentier S, Dubost C. Biological factors affecting long-term results in valvular heterografts. J Thorac Cardiovasc Surg 1969;58:467–83.[Medline]
  14. Nimni ME, Bernick S, Cheung DT, et al. Biochemical differences between dystrophic calcification of cross-linked collagen implants and mineralization during bone induction. Calcif Tissue Int 1988;42:313–20.[Medline]
  15. Phillips R, Thoma R, Lupkowski M. The role of surface chemistry in implant device calcification. Symposium Notebook: Surfaces in Biomaterials 1994:127–39.
  16. Sykes P, ed. A guideline to mechanism in organic chemistry. London: Longman Group Limited, 1982:52–8.
  17. Eybl E, Griesmacher A, Grimm M, Wolner E. Toxic effects of aldehydes released from fixed pericardium on bovine aortic endothelial cells. J Biomed Mater Res 1989;23:1355–8.[Medline]
  18. Speer DP, Chvapil M, Eskelson CD, Ulreich J. Biological effects of residual glutaraldehyde-tanned collagen materials. J Biomed Mater Res 1980;14:753–6.[Medline]
  19. Grabenwöger M, Grimm M, Eybl E, et al. New aspects of the degeneration of bioprosthetic heart valves after long-term implantation. J Thorac Cardiovasc Surg 1992;104:14–21.[Abstract]
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  22. Chauvaud S, Jebara V, Chachques JC, et al. Valve extension with glutaraldehyde-preserved autologous pericardium. J Thorac Cardiovasc Surg 1991;102:171–8.[Abstract]



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