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Ann Thorac Surg 1996;62:1724-1730
© 1996 The Society of Thoracic Surgeons

Original Articles: Cardiovascular

No-React Detoxification Process: A Superior Anticalcification Method for Bioprostheses

Amir Abolhoda, MD, Sumei Yu, MS, J. Rodrigo Oyarzun, MD, Keith R. Allen, MD, John R. McCormick, MD, Shenggao Han, MD, Francis W. Kemp, MS, John D. Bogden, PhD, Qi Lu, MD, Shlomo Gabbay, MD

Section of Cardiothoracic Surgery, UMDNJ-New Jersey Medical School, Departments of Surgery and Preventive Medicine and Community Health, Newark, New Jersey


   Abstract
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Introduction
 Material and Methods
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Background. Glutaraldehyde pretreatment of bioprosthetic heart valves is the major pathogenic factor in their calcific degeneration. This comparative study investigates the merit of the No-React aldehyde detoxification process as an alternative modifier of xenograft tissues.

Methods. Glutaraldehyde- and No-React-pretreated porcine aortic valve cusps were implanted subcutaneously in 6-week-old rats (n = 20). At 3, 6, and 14 weeks, randomly selected animals were sacrificed and the explants underwent mineral and morphologic analyses. Glutaraldehyde- and No-React-treated bovine pericardium and porcine aortic valve cusp were incubated in fibroblast cell culture plates. Cell viability was observed under reversed microscope at 6, 24, 48, and 96 hours. Erythrosin B dye exclusion test was used to validate percent cell death.

Results. Pretreatment with No-React significantly inhibited calcification of aortic cusp subcutaneous implants throughout the 14-week period (mean tissue Ca2+ content = 1.3 ± 0.7 µg/mg at 14 weeks.) Glutaraldehyde-treated cusps underwent protracted calcification (Ca2+ content = 190.6 ± 89.5 µg/mg; p < 0.01). Morphologic findings correlated with mineral analyses. One-hundred percent of fibroblast cells survived in the presence of No-React-treated tissue, with a growth pattern indistinguishable from control cell culture (ie, in the presence of no tissue). The cells incubated with glutaraldehyde-treated tissue showed signs of nonviability by 6 hours, with 100% cell death by 48 hours. Dye exclusion tests validated these findings.

Conclusions. The No-React detoxification process completely abolishes the cytotoxicity of the xenograft tissue and inhibits calcific degeneration.


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See also page 1730.

The search for a durable bioprosthetic heart valve has been a focus of intense investigation for the past two decades. Biological valve prostheses display superior hemodynamics and low thrombogenicity [1]. The relative simplicity of insertion and reported reduced incidence of thromboembolism are among the other advantages of the biological valve prosthesis over mechanical valves [1]. However, the major factor limiting clinical use of the commercially available glutaraldehyde (GTA)-pretreated bioprosthetic valves is their late structural deterioration, most commonly as a result of calcific mineralization and degeneration. Reoperation, and its associated morbidity and mortality, is the eventual outcome in approximately 20% to 30% of the bioprosthetic valve recipients by the tenth postoperative year [1, 2]. Moreover, several retrospective clinical reports have described accelerated tissue valve calcification and earlier functional failure in young adults and children, condemning biological valve implantation in these groups of patients [3–5]. Glutaraldehyde is currently the standard reagent for preservation and biochemical fixation of fresh bioprosthetics of either bovine pericardium or porcine aortic valve cusp origin. Multiple studies have implicated the aldehyde-induced collagen cross-linkages and devitalization of the intrinsic connective tissue cells of the bioprosthetic valves in initiating tissue mineralization [2, 6–8]. The cytotoxicity of GTA has been detected in animal tissues as long as 6 months after implantation [9]. Furthermore, alarmingly, GTA has been traced in human porcine valve explants up to 14 years after implantation [10].

Since the introduction of the No-React (NR) biochemical modification method by Biocor, Belo Horizonte, Brazil, our laboratory has engaged in delineating the merits of this aldehyde detoxification process in preventing xenograft dystrophic calcification. Previous studies in our laboratory have demonstrated comparable in vitro tensile strength of the NR-processed heart valve bioprostheses [11, 12]. Moreover, we have described antiinflammatory and anticalcification properties of the NR on bovine pericardial subcutaneous implants [13]. We have observed severe foreign body reaction in the form of giant cell infiltration in GTA-pretreated pericardial implants, a response completely abrogated by NR pretreatment. These findings were suggestive of a correlation between the inflammatory destruction of the tissue implant and the pericardial calcification. The present study illustrates our longitudinal observations on the trend of mineralization of subcutaneously implanted porcine aortic valve cusps pretreated with GTA versus NR. Furthermore, it examines the dichotomous results of extensive cytocompatibility testing of GTA-treated versus NR-treated xenografts, and investigates the potential correlation between xenograft tissue cytocompatibility and calcific mineralization.


   Material and Methods
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 Material and Methods
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In Vivo Calcification Studies
SUBCUTANEOUS IMPLANTATION.
Twenty Sprague-Dawley rats (SD strain; Taconic Laboratories, German Town, NY), 6 weeks old (80 to 100 g), were used. On day 0, all animals received GTA- and NR-pretreated porcine aortic valve cusp implants in separate subcutaneous pouches in the anterior abdominal wall. All procedures were performed under sterile conditions after intraperitoneal pentobarbital injections. The wounds were closed with 5-0 Vicryl (Ethicon, Somerville, NJ) suture material. The rats were fed Lab Rodent Diet (Purina Meals Inc, St. Louis, MO) and received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for The Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by National Institutes of Health (NIH publication 86-23, revised 1985). At 3, 6, and 14 weeks after implantation, randomly selected animals were sacrificed with a lethal intraperitoneal dose of thiopental (300 mg/kg) and the tissue specimens were retrieved. A small portion of each specimen was immediately fixed in 10% neutral buffered formalin for light microscopic examination. The remainder of each sample underwent mineral analysis.

MINERAL ANALYSES.
Aortic cusp explants were washed with sterile saline solution and dried to constant weight in a 90°C desiccator oven. Tissue concentrations of calcium was determined by previously described techniques [14] using flame atomic absorption spectrophotometry (Perkin-Elmer model 603; Perkin-Elmer, Norwalk, CT) after digestion with a 3:1 mixture of 70% nitric and perchloric acids (GFS Chemicals, Columbus, OH). National Institutes of Standards and Technology bovine liver (SRM 1577a; Gaithersburg, MD) was used as a quality control sample for all analyses. Concentrations were expressed as micrograms per milligram of dry tissue weight (mean ± standard deviation).

MORPHOLOGIC ANALYSES.
Sample fragments removed for histologic evaluation were fixed immediately in 10% neutral buffered formalin, dehydrated in graded concentrations of ethanol, cleared in xylene, and embedded in paraffin according to standard methods. Sections 5 µm thick were stained by hematoxylin and eosin and von Kossa stain.

Cytocompatibility Studies
CELL CULTURE.
The cell line used was L-929 mouse fibroblast cell line obtained from the American Type Culture Collection (Rockville, MD). The cryovial of cells was immersed in oscillating 37°C water bath within 1 to 1.5 minutes. The cell suspension was then sterilely transferred to a 75-cm2 culture flask containing preequilibrated and prewarmed Dulbecco's modified Eagle medium (pH = 7.30), supplemented with penicillin (100 IU/mL), streptomycin (100 µg/mL), amphotericin B (2.5 µg/mL), fetal bovine serum (10%), and nonessential amino acids (1%) (BRL, Grand Island, NY). The culture flask was incubated in 37°C humidified incubator with 5% CO2 concentration in air. After 72 hours, the confluent cells were subcultured at approximately 40,000 cells/cm2 in 12-well dishes (Falcon, Becton Dickenson, NJ) and allowed to grow to a monolayer of cells before introduction of tissue samples.

CYTOCOMPATIBILITY TEST.
Glutaraldehyde- and NR-pretreated tissue segments were cut into 3 x 3-mm strips under sterile conditions. The strips were washed in three serial changes of sterile phosphate-buffered saline solution (pH = 7.3) and individually introduced into the cell culture wells. The wells were then supplemented with fresh medium. At 6, 24, 48, or 96 hours after incubation, the cells were examined under a reversed light microscope. One cell culture dish containing no tissue was assigned as a control in each set of experiments.

DYE EXCLUSION METHOD.
Six, 24, and 48 hours after tissue incubation, 0.5 mL of 0.06% erythrocin B solution was added to each cell culture well, dwelled for 30 seconds, and then withdrawn. The dyed cells immediately adjacent to the tissue were counted under bright-field reversed microscopy. The rationale for this technique is that viable cells are impermeable to dye (erythrosin B; Sigma, St. Louis, MO). On the other hand, the dye leaks into those cells that have sustained critical damage to their plasma membrane. The ratio of stained cells to total cells counted (x100) estimates the percent cell death. (Note: it is important to bear in mind that this method can overestimate viability, as other forms of cellular injury progressing to cell death are undetected.)

Statistical Methods
Tissue calcium content were compared for differences between GTA- and NR-pretreated tissues using two-tailed independent Student's t test. Percent cell viability (discontinuous data) were evaluated by {chi}2 analysis using the Fisher exact test. Statistical significance was declared at p less than 0.05.


   Results
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 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
Subcutaneous Implants
One animal died in the immediate postoperative period of anesthesia overdose. The results of mineral analyses of the GTA- versus NR-pretreated porcine aortic valve cusps after 3, 6, and 14 weeks of subcutaneous implantation are summarized in Figure 1Go. Glutaraldehyde-treated cusps showed progressive unremitting calcification over the time span of the experiment with mean tissue calcium content increasing from 72.0 ± 40.5 µg/mg at 3 weeks to 190.6 ± 89.5 µg/mg at 14 weeks. No-React--treated cusp mineralization remained negligible even after 14 weeks of subcutaneous implantation (p < 0.01 versus GTA control).



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  		Fig 1. . Trend of calcification of subcutaneous porcine cusp implants over a 14-week period. The glutaraldehyde-treated cusps show a progressive calcification over time. The No-React--treated cusps undergo minimal calcification with no progression over time (p < 0.01).

 
Morphologic Analyses
Glutaraldehyde-treated aortic cusp explants revealed minimal inflammatory infiltration in spite of intense von Kossa calcium staining, a finding consistent with calcium content data. No-React--treated cusp demonstrated not only an attenuated inflammatory cellular response, but also marked paucity of calcific deposits, again in concert with mineral results (Figs 2, 3GoGo).



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  		Fig 2. . Light photomicrographs of glutaraldehyde-treated cusp explants at 6 weeks. (A) Disruption of the collagen fibrils and inflammatory reaction (hematoxylin and eosin). (B) A glutaraldehyde-treated cusp stained with von Kossa stain; calcium deposits are seen as black spots. (C) Higher magnification of an aortic cusp explant showing severe inflammatory cell infiltration. (D) Higher magnification of B hematoxylin and eosin. (Magnifications: A, x100; B, x100; C, x200; D, x200.)

 


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  		Fig 3. . Light photomicrographs of No-React--treated cusp explants at 6 weeks. (A) Collagen matrix of the cusp is preserved; no inflammatory reaction is seen (hematoxylin and eosin). (B) Same cusp stained with von Kossa stain; no calcium deposits are seen. (C) Higher magnification of No-React--treated cusp explant with well-preserved architecture (hematoxylin and eosin). (D) Von Kossa stain of the cusp in slide C. (Magnifications: A, x100; B, x100; C, x200; D, x200.)

 
Cytocompatibility Tests
Serial observations of the cell cultures incubated with GTA-treated cusps revealed progressive rounding up and detachment of cells from the well substrate, starting as early as 6 hours after incubation, with 100% loss of cell viability by 48 hours. Meanwhile, the medium pH dropped from 7.30 to 2.0. A similar pattern was noted in cell culture wells incubated with GTA-treated pericardium, with 100% cell death at 48 hours. On the other hand, the cells in the presence of NR-treated tissue, cusp or pericardium alike, showed normal growth pattern at all time points of observation, indistinguishable from control cell culture (Figs 4Go–Go).



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  		Fig 4. . Reverse light photomicrographs of cell culture plates incubated with pericardial tissue at time 0. (A) No-React--treated tissue (Ts) at the bottom of the figure; live mature fibroblasts at the top of the figure. (B) Glutaraldehyde-treated Ts at the bottom; live fibroblasts at the top.

 


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  		Fig 6. . Erythrosin B dye exclusion test observed at 48 hours. (A) The fibroblasts form a confluent monolayer around the No-React--treated tissue (Ts). (B) Near 100% cell death with glutaraldehyde-treated Ts incubation.

 
Dye Exclusion Test
Table 1Go shows the percentage of total cells stained with erythrosin B at 24 and 48 hours after incubation with GTA- versus NR-treated pericardium and cusp. Figure 7Go is a graphic demonstration of the cell count comparing the GTA versus the NR; the difference is markedly significant (p < 0.0001). Clearly the fibroblasts around the NR tissue remain viable and do not appear to be different from the control cell cultures (no tissue placed in the cultures).


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  		Table 1. . Dye Exclusion Test (Erythrosin B)a
 


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  		Fig 7. . Dye exclusion test: comparison of dead cell count between the No-React-- and glutaraldehyde--treated tissues.

 

   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
The decision-making process affecting the choice of heart valve implants is influenced by a number of patient factors, such as age and presence of concomitant coronary artery disease and its incumbent morbid risk [5], and several implant attributes, such as hemodynamic performance, thrombogenicity, and long-term durability. In spite of the improved valve design and the recently reported favorable long-term results of pericardial valves [15], the significant incidence of late functional dysfunction requiring explantation is disturbing. Late calcific mineralization of the GTA-processed biological valves has been the main deterrent for implantation of these bioprosthetics in all but those patients with advanced age and short life expectancy. Modifying the valve selection process in favor of the biological implants demands introduction of a superior tissue preparative method, one that would maintain the tissue sterilizing and the stabilizing properties of the GTA while abolishing the late in vivo degenerative calcification.

No-React xenograft pretreatment involves (1) aldehyde cross-linkage to achieve high resistance to biodegradation, (2) an aldehyde detoxification process, and (3) surface modification with a surfactant. The results of the present study illustrate the superior biological properties of the NR biochemical modification process, the attributes that we believe are fundamental to formulation of an acceptable bioprosthetic tissue preparation method. These properties are as follows: (1) No-React pretreatment maintains intrinsic collagen architecture and structural integrity of both bovine pericardium and porcine aortic valve cusp in an in vivo environment. (2) No-React aldehyde detoxification process inhibits crystal enucleation on the xenograft tissue, in what we have observed as a near-complete abolishment of calcific mineralization of the implants to a degree indistinguishable from historical untreated tissue implants. (3) The remarkably inert nature of surfactant-protected NR-treated tissue supports coexistence and normal growth of connective tissue cells, illustrating optimal cytocompatibility. In other words, the NR biochemical modification process efficiently protects the components of the xenograft tissue that are subject to calcific deposition, namely collagen and connective tissue cells. We have also shown that conventional GTA is a clearly inferior tissue-preparative modality. Glutaraldehyde has toxic effects on both extracellular and cellular elements of bioprosthetic xenograft, inevitably leading to calcific degeneration.

Given these preclinical findings and the encouraging early results of the ongoing clinical investigations on the use of NR-treated biological implants [16, 17], we foresee the future era of the biological heart valve implantation to involve exclusive insertion of detoxified tissue valves with superior long-term durability in a wider spectrum of recipients.



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  		Fig 5. . Reverse light photomicrographs of cell culture plates at 6 and 24 hours after tissue incubation, with addition of erythrosin B to the medium. (A) Healthy dividing cells adjacent to No-React tissue (Ts) at 6 hours. (B) Cells begin to acquire red stain (black round figures) 6 hours after incubation with glutaraldehyde-treated Ts. (C) At 24 hours, 100% of the cells are viable in presence of No-React--treated tissue. (D) At 24 hours, progressive loss of viability of the cells incubated with glutaraldehyde-treated tissue is notable, as evident in the entire field.

 

   Footnotes
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Abstract
 Introduction
 Material and Methods
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 Comment
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Presented at the Thirty-second Annual Meeting of The Society of Thoracic Surgeons, Orlando, FL, Jan 29–31, 1996.

Address reprint requests to Dr Gabbay, UMDNJ-New Jersey Medical School, 185 South Orange Ave, Rm G-502, Newark, NJ 07103.


   References
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 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

  1. Schoen FJ, Kujovich JL, Levy RJ, Sutton MSJ. Bioprosthetic valve failure. Cardiovasc Clin 1987;18:289–17.
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  3. Magilligan DC, Lewis JW, Stein P, Alan M. The porcine bioprosthetic heart valves: experience at 15 years. Ann Thorac Surg 1989;48:324–30.[Abstract]
  4. Jamieson WRE, Rosado LJ, Munro AI, et al. Carpentier-Edwards standard porcine bioprostheses: primary tissue failure (structural valve deterioration) by age groups. Ann Thorac Surg 1988;46:155–62.[Abstract]
  5. Jones EL, Weintraub WS, Craver JM, Guyton RA, Shen Y. Interaction of age and coronary disease after valve replacement: implications for valve selection. Ann Thorac Surg 1994;58:378–85.[Abstract]
  6. Schoen FJ, Collins JJ, Cohn LH. Long term failure rate and morphologic correlations in porcine bioprosthetic heart valve. Am J Cardiol 1983;51:957–64.[Medline]
  7. Inamura E, Sawotani O, Koyanagi H, et al. Epoxy compounds as new cross linking agent for porcine aortic leaflets. subcutaneous implant studies in rats. J Cardiovasc Surg 1989;4:50–7.
  8. Bernacca GM, Dimitri WR, Fisher AC, Mackay TG, Wheatley DJ. Chemical modification of bovine pericardium and its effects on calcification in the rat subdermal model. Biomaterials 1992;13:345–52.[Medline]
  9. Speer DP, Chvapil M, Volz RG, Holmes MD. Enhancement of healing in osteochondral defects by collagen sponge implants. Clin Orthop 1979;144:326–35.
  10. Aboul-Enein HY, Hughes H, Tipton LS, Feuchuk D, Prabhakar G, Duran CMG. Glutaraldehyde, {gamma}-carboxyglutamic acid, and calcium in explanted bioprosthetic heart valves. In: Gabbay S, Frater RW, eds. New horizons and the future of heart valve bioprostheses. Austin, TX: Silent Partners, 1994:191--201.
  11. Gabbay S, Chuback JA, Khavarian C, Donahoo J, Oyarzun JR, Scoma R. In vitro and animal evaluation with the Biocor No-ReactTM anticalcification treatment for bioprostheses (new concept in anticalcification treatment). In: Gabbay S, Frater RW, eds. New horizons and the future of heart valve bioprostheses. Austin, TX: Silent Partners, 1994:73--91.
  12. Oyarzun R, Abolhoda A, Yu S, et al. Effect of pretreatment on calcification of bioprosthetic valves. A comparative study of glutaraldehyde vs No-ReactTM. J Penn Assoc Thorac Surg 1996;4:13–7.
  13. Abolhoda A, Yu S, Oyarzun JR, McCormick JR, Bogden JD, Gabbay S. Calcification of bovine pericardium: glutaraldehyde versus No-React biomodification. Ann Thorac Surg 1996;62:169–74.[Abstract/Free Full Text]
  14. Bogden JD, Kemp FW, Han S, et al. Dietary calcium and lead interact to modify maternal blood pressure, erythropoiesis, and fetal and neonatal growth in rats during pregnancy and lactation. J Nutr 1995;25:990–1002.
  15. Cosgrove DM, Lytle BW, Taylor PC, et al. The Carpentier-Edwards pericardial aortic valve: ten year results. J Thorac Cardiovas Surg 1995;110:651–62.[Abstract/Free Full Text]
  16. Vrandecic M, Gontijo BF, Fantini FA, et al. The mitral and aortic porcine stentless heart valves-new concepts in design and tissue tanning: short- and mid-term clinical follow-up. In: Gabbay S, Frater RW, eds. New horizons and the future of heart valve bioprostheses. Austin, TX: Silent Partners, 1994:143--70.
  17. Vrandecic M, Gontijo BF, Fantini RA, Gabbay S, Vrandecic EA, Vrandecic E. Stentless heart valve concept: new anticalcification tissue tanning-preclinical trial. In: Piwnica A, Westaby S, eds. Stentless bioprostheses. Oxford: ISIS Medical Media, 1995:93--5.

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