- The Annals of Thoracic Surgery

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, and Shlomo Gabbay, MD
Section of CardiothoracicSurgery,UMDNJ-NewJersey MedicalSchool, Departmentsof Surgeryand PreventiveMedicineand
CommunityHealth,Newark,NewJersey
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 im-
plants throughout the 14-week period (mean tissue Ca’+
content = 1.3 ~ 0.7 @rng at 14 weeks.) Glutaraldehydetreated cusps underwent protracted calcification (Ca’+
content = 190.6 * 89.5 @m& 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 glutaraldehydetreated tissue showed signs of nonviability by 6 hours,
with 100Yo 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.
T
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
he 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 307. 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.
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.
01996 by The Society of ThoracicSurgeons
Publishedby ElsevierScience Inc
(Ann Thorac Surg 1996;62:1724-30)
0003-4975/96/$15.00
PII S0003-4975(96)00948-4
ABOLHODAET AL 1725
BIOPROSTHETIC
VALVEDETOXIFICATION
Ann Thorac Surg
1996;62:1724-30
30C
E
$
c
8
,:g
~+
Y6m
OS
al
z
40
~-
190.6*89
N-4 I
I
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).
25C
141.5*44.2
N-7
I
200
150
t-
100
50
0
3
6
14
Weeks
I
n No-React
Cusp ~ Glutaraldehyde Cusp
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.
(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
10Yoneutral buffered formalin for light microscopic examination. The remainder of each sample underwent
mineral analysis.
Material and Methods
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~o nitric and
perchloric acids (GFS Chemicals, Columbus, OH). National Institutes of Standards and Technology bovine
liver (SRM 1577a; Gaithersbur~ 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).
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 O, 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-O 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
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 pm
1726
ABOIS+O~A
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BIOPROSTHETICVALVEDETOXIFICATION
Ann Thorac Surg
1996;62:1724-30
Fig 2. Light photornicrographs of glutaraldehyde-treated cusp explantsat 6 weeks. (A) Disruption of the collagen fibrils and inflammatory rea&”on (hematoxylin and eosin), (B) A glutaraldehyde-treated CUSPsfained with von Kossa stain; calcium deposits are seen as black spots. (0
Higher magnijcation of an aoti”c cusp explant showing severe inflammatory cell infiltration. (D) Higher magnification of B hematoxylin and
eo~in. (Ma~ifications:”A, X1OO;B, X1OO;C, x200; D, x200J
thick were stained by hematoxylin and eosin and von
Kossa stain.
Cytocompatibility Studies
CELL CULTURE. The cell line used was L-929 mouse fibro-
tion (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.
blast 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 pg/mL), amphotericin B
(2.5 #g/mL), fetal bovine serum (10%), and nonessential
amino acids (l%) (BRL, Grand Island, NY). The culture
flask was incubated in 37°C humidified incubator with
57’. C02 concentration in air. After 72 hours, the confluent
cells were subculture 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.
DYEEXCLUSIONMETHOD. Six, 24, and 48 hours after tissue
incubation, 0.5 mL of 0.06Y0 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 (e@hrosin 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 (X1OO) 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.)
CYTOCOMPATIBILITY TEST. Glutaraldehydeand NRpretreated 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 solu-
Tissue calcium content were compared for differences
between GTA- and NR-pretreated tissues using twotailed independent Student’s f test. Percent cell viability
—.
Statistical Methods
Ann Thorac Surg
1996;62:1724-30
ABOLHODAET AL 1727
BIOPROSTHETIC
VALVEDETOXIFICATION
Fig 3. Light photomicrographs of No-React-treated cusp explants at 6 weeks. (A) Collagen matrixof the cusp is preserved; no inflammatory
reaction is seen (hematoxylin and eosin). (B) Same cusp stained with von Kossa stain; no calckm deposits are seen. (C) Higher magni$cation
of No-React–treated cusp exulant with well-vresewed architecture (hematoxvlin and eosin). (D) Von Kossa stain of the CUSPin slide C. (Ma~~i+”cations:~ xIW; B,’ xlh; C, x2W; D, ‘x200.)
(discontinuous data) were evaluated by # analysis using
the Fisher exact test. Statistical significance was declared
at p less than 0.05.
only an attenuated inflammatory cellular response, but
also marked paucity of calcific deposits, again in concert
with mineral results (Figs 2, 3).
Results
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 1. Glutaraldehydetreated cusps showed progressive unremitting calcification over the time span of the experiment with mean
tissue calcium content increasing from 72.0 ~ 40.5 #g/mg
at 3 weeks to 190.6 ~ 89.5 pg/mg at 14 weeks. No-Reacttreated cusp mineralization remained negligible even
after 14 weeks of subcutaneous implantation (p < 0.01
versus GTA control).
Morphologic Analyses
Glutaraldehyde-treated aortic cusp explants revealed
minimal inflammatory infiltration in spite of intense von
Kossa calcium stainin~ a finding consistent with calcium
content data. No-React-treated cusp demonstrated not
Fig 4. Reverse light photomicrographs of cell culture plates incutissue
bated with pericardial tissue at time 0. (A) No-React-treated
(Ts)atthebottomof thefigure;livematurefibroblastsat the top of
the figure, (B) Glutaraldehyde-treated Ts at the bottom; live fibroblasts at the top.
1728
ABOLHODAETAL
BIOPROSTHETIC
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Ann Thorac Surg
1996;62:1724-30
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 bep’n to acquire red stain (black round figares) 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.
Cytocompatibility Tests
Comment
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 100Yoloss 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 100Yo 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 4-6).
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 explanation 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
Dye Exclusion Test
Table 1 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 7
is a graphic demonstration of the cell count comparing the
GTA versus the NN 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).
—
1729
ABOLHODAETAL
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VALVEDETOXIFICATION
Ann Thorac Surg
1996;62:1724-30
24 hours
48 hours
DhIo-React ~Glutaraldehyde ~Control
Fig 7. Dye exclusion test: comparison of dead cell count between the
No-React– and glutaraldehyde-treated tissues.
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.
References
Table 1. Dye ExclusionTest (E~fhrosin B)a
Tissue Type
GTA-pericardium (n = 10)
NR-pericardium (n = 10)
GTA-cusp (n = 10)
NR-cusp (n = 10)
Control (no tissue)
24-Hour
Incubation
48-Hour
Incubation
83.1 t 16.2
2.8 ~ 1.0
89.0 t 5.0
2.0 * Iol
2.5 * 1.2
a Percentage of total cells stained with erythrosin B in presence of GTAbp <
versus NR-treated bovine pericardium or aortic valve cusp.
0.0001(GTA versus NR).
NR = No-React.
GTA = glutaraldehyde;
1. Schoen FJ, KujovichJL, LevyRJ, Sutton MSJ. Bioprosthetic
valvefailure.CardiovascClin 1987;18:289-17.
2. Schoen FJ, TsaoJW, LevyRJ. Calcificationof bovine pericardium used in cardiac valve bioprostheses: implications for
the mechanism of bioprosthetic tissue mineralization. Am J
Pathol 1986;123:134-9.
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.
4. Jamieson WRE, Rosado LJ, Munro AI, et al. CarpentierEdwards standard porcine bioprostheses: primary tissue
failure (structural valve deterioration) by age groups. Ann
Thorac Surg 1988;46:155-62.
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 Thomc Surg
1994;58:378-85.
6. Schoen FJ, Collins JJ, Cohn LH. Long term failure rate and
morphologic correlations in porcine bioprosthetic heart
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7. Inamura E, Sawotani O, Koyanagi H, et al. Epoxy com-
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Bernacca GM, Dimitri WR, Fisher AC, Mackay TG, Wheatley
DJ. Chemical modification of bovine pericardium and its
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Speer DP, Chvapil M, Votz RG, Holmes MD. Enhancement
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Aboul-Enein HY, Hughes H, Tipton LS, Feuchuk D, Prabhakar G, Duran CMG. Glutaraldehyde, y-carboxyglutamic
acid, and calcium in explanted bioprosthetic heart valves. In:
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heart valve bioprostheses. Austin, TX: Silent Partners, 1994:
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Gabbay S, Chuback JA, Khavarian C, Donahoo J, Oyarzun
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DISCUSSION
DR YARONBAR-EL(Haifa,Israel): I congratulateDr Gabbay
and his group for this excellent research and presentation. After
a careful review of the preclinical data, we at the Rambam
Medical Center in Israel have joined a few European and South
American clinical centers to investigate the No-React bioprosthesis. We have been using the No-React bioprosthesis for the
past year and have implanted various kinds of grafts in 8
patients. We have implanted two stentless mitral valves, five
aortic stentless valves, one porcine internal mammary artery
graft, and one femoropopliteal bypass below-knee graft using a
bovine internal mammary artery graft. I would like to draw your
attention to 2 patients who were youngsters, aged 12 and 13
years, at the time of operation.
The first is a girl who was flown in emergently with active
bacterial endocarditis that destroyed her mitral and aortic
valves, causing severe mitral and aortic insufficiency. We replaced both her valves with No-React stentless valves. The
postoperative course was uneventful, and she was discharged in
an excellent condition. Her last echocardiographic examination,
performed less than a month ago, a year after the operation,
revealed normal function of the valves and no signs whatsoever
of calcification.
The second case is of a 13-year-old boy at the time of
operation who was referred to our hospital approximately 2
months after the first girl and in a very similar condition, with
severe aortic and mitral valve insufficiencydue to active bacterial endocarditis. We replaced both his valves with No-React
stentless valves, and he too underwent a smooth operative and
postoperative course. His echocardiographic study done recently, about 9 months after the operation, shows no signs of
calcification, and the valves are functioning normally.
This initial experience, however small, makes us optimistic
about the further use of these valves, especially in young
patients, where early calcification and valve deterioration is of
great concern.
DR MARIO P. VRANDECIC (Belo Horizonte, Brazil): I congratulate Professor Gabbay for the excellent work in this very
important field. I also wish to say a few words about our clinical
experience. Although the longest follow-up will near 2 years
only, the results from current multicenter trials will soon be
available like the one you just heard from Dr Bar-EL I must add
that all was not rosy in the beginnin~ as Professor Gabbay had
stated; in the first few implants we experienced also some early
explants. The analysis of these explants resulted in better
understanding of the problem; thus those initial ditlicultieswere
fully corrected.
What is presented today are clinical results of a solid antimineralization treatment already subjected to the critical test of
prelimina~ experience. From May 1994 to the present, 172
Biocor No-React heart valves were implanted in 158 patients,
and it is worth noting that there were 40 patients less than 20
years of age and we have combined all the four model valve
types. Thirty-two patients had these valves implanted at reoperation, and 5 had active endocarditis either in the native or in
the prosthetic valve.
The hospitalmortalitywas 5.7~0, and none of the hospital deaths
were related to the valve or the treatment itself. There were five
reoperations: three due to early endocarditis and two due to
paravalvular leak, again, not related to the valve itself. The
patient follow-up was completed recently, and no other complications were recorded during this close to 2 years’ follow-up.
Using postoperative echocardiography, as was shown earlier
by the Rambam Hospital experience, we have observed the
same cuspal mobility, leaflet function, and same thickness
throughout this study. Even in patients less than 1 year of age,
we have seen that the cusps stay soft and pliable. This process
that renders tissue valve to be nontoxic is the only process I am
aware of that has proved total cytocompatibility by each valve
before clinical use. The current early follow-up has shown that
the Biocor No-React tissue heart valve seems to be a very
promising antimineralization process. The current clinical results should be confirmed by midterm and long-term follow-up,
because this clinical experience included many patients younger
than 20 years. The excellent midterm results might be very
significant.
DR GABBAY: I thank the discussants for their comments and for
presenting early clinical data of the No-React valves. Obviously
only time will tell what is the final judgment of this process.