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A Randomized, Double-Masked Clinical Trial of Optisol-GS vs Chen Medium for Human Corneal Storage
Joel Naor, MD, MSc;
Allan R. Slomovic, MA, MD, FRCS(C);
Mary Chipman, MA;
David S. Rootman, MD, FRCS(C)
Arch Ophthalmol. 2002;120:1280-1285.
ABSTRACT
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Objective To determine whether the clinical outcome of corneal transplantation
performed with tissue stored in Chen Medium (CM; Chen Laboratories, Phoenix,
Md) is superior to that of Optisol-GS (Chiron Ophthalmics, Irvine, Calif).
Design Randomized, double-masked trial.
Participants and Setting Ninety patients undergoing corneal transplantation at a tertiary center.
Intervention Donor cornea pairs were stored, one in CM and the other in Optisol-GS,
transplanted, and followed up for 3 months.
Main Outcome Measures Endothelial cell loss (ECL) at 3 months. Secondary outcomes were thickness
and epithelialization at days 1, 7, 30, and 90, as well as primary and secondary
graft failure.
Results Mean percentages of ECL 3 months after surgery were similar for corneas
stored in Optisol-GS and corneas stored in CM. The 95% confidence interval
(CI) for the difference was -3.4% to 13.2%. Covariate-adjusted 95% CI
was -6.1% to 9.1%. Pachymetry values were similar in the 2 treatment
groups. Eighty-eight percent of the corneas stored in each medium achieved
epithelialization of 75% to 100% of the surface area within 1 week after transplantation.
No primary donor failures occurred in either group. One graft that was preserved
in CM failed during the study period.
Conclusion The clinical outcomes of corneal transplantation with tissue that was
preserved in CM were similar to those of grafts preserved in Optisol-GS.
INTRODUCTION
INTERMEDIATE-TERM CORNEAL storage allows storage of the tissue at 4°C
for as long as 2 weeks. It offers flexibility in scheduling the keratoplasty,
a longer period to observe and test the tissue, and it involves no complex
technical procedures. Consequently, it is the most widespread preservation
method in the world.
Chen Medium (CM; Chen Laboratories, Phoenix, Md) was recently introduced
as an intermediate-term corneal storage medium and received permission for
marketing by the US Food and Drug Administration. It is isotonic (approximately
305 mOsm) and contains the metabolic substrate  -hydroxybutyrate, streptomycin
sulfate, gentamicin sulfate, and N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid buffers to stabilize the
pH at approximately 7.4 on phenol red indicator, and approximately 7% dextran
in Tc199 medium modified by reducing sodium chloride to 85mM and omitting
sodium bicarbonate.1 Chen medium enables the
cornea to maintain a high level of metabolic activity and to generate adenosine
triphosphate with concurrent suppression of acid formation and accumulation
and uses a built-in bicarbonate-generating system for pH stability and for
prevention of exogenous sodium bicarbonate–elicited adverse effects.2
Whenever a new therapeutic modality becomes available, it is important
to compare its safety and efficacy to the existing alternatives. The end user
can then make an informed choice based primarily on the medical considerations.
To that end, to determine whether there is an advantage to using CM, we conducted
a randomized, double-masked clinical trial comparing it with Optisol-GS (Chiron
Ophthalmics, Irvine, Calif), the most commonly used medium.3-4
MATERIALS AND METHODS
The study was conducted at a tertiary eye-care service; namely, the
Cornea and External Disease Service at the Department of Ophthalmology, Toronto
Western Hospital, University Heath Network, Toronto, Ontario. Two surgeons
participated in the study (A.R.S. and D.S.R.). The protocol was approved by
the Human Subjects Review Committee of the University of Toronto and the University
Health Network Research Ethics Board. Informed consent was obtained from all
study participants. Patients were enrolled from September 1999 through June
2000, when the target sample size was attained.
The study population consisted of patients undergoing corneal transplantation
either alone or in conjunction with the following procedures: cataract extraction
with or without intraocular lens insertion, intraocular lens exchange, and
intraocular lens insertion. We excluded patients with the following conditions,
which carry a poor prognosis for graft clarity, and would consequently make
the main outcome assessment difficult: severe chemical burns, radiation burns,
ocular pemphigoid, Stevens-Johnson syndrome, and neuroparalysis. Patients
who could not make themselves available for preadmission tests and the informed
consent process 1 week prior to surgery, or who would be unavailable for follow-up
were also excluded. Patients were approached consecutively.
Donor corneas for the study were processed by the Eye Bank of Canada
(Ontario Division, Toronto) in the usual manner and according to the standards
are set by the Eye Bank Association of America.5 After
obtaining consent from the donor's family, corneal tissue was retrieved by
whole-globe enucleation. Donor blood was collected and tested for human immunodeficiency
virus, hepatitis B, and hepatitis C. Whole globes arrived at the eye bank
laboratory and underwent a screening slitlamp examination. Corneoscleral rims
were excised, and based on the results of the randomization, they were transferred
to either CM or Optisol-GS. Specular microscopy of the central endothelium
was performed for each cornea, and endothelial cell counts were recorded (Video
Enhancement Digitization System, Bioptics, Arlington, Mass). Endothelial cell
counts were the mean of 3 measurements of at least 50 endothelial cells per
analysis. Corneas with endothelial cell densities less than 2000 cells/mm2 were considered not suitable for use. Tissue was released to the surgeon
at the day of surgery after a second screening slitlamp examination.
During surgery, the Hanna trephine system and viscoelastics were used
in combination with either interrupted and running 10-0 nylon, or a double-running
suture (10-0 and 11-0 nylon). Anterior vitrectomy was performed in eyes with
displacement of vitreous into the anterior chamber. Subconjunctival gentamicin
sulfate, cefazolin sodium, and methylprednisolone were administered at the
end of each procedure. Patients received a tobramycin-dexamethasone eye drop
4 times daily for the first few weeks followed by topical corticosteroids
as needed thereafter.
Randomization was performed at the eye bank and recorded in a log. The
instrument for randomization was a table of random digits. Single corneas
were the unit of randomization. Each cornea was randomly assigned to one of
the 2 storage media, one of the 2 surgeons who participated in the study,
and one of the patients scheduled to be operated on by the assigned surgeon.
A pair of corneas from a single donor was preserved with one in CM and the
other in Optisol-GS, hence matching for donor characteristics.
Recipients were masked to the type of storage media used for the tissue
that they had received. The labels on the vials containing the corneas, which
were distributed to the surgeons, did not specify the type of solution used.
During tissue manipulation, the color of the storage solution was visible
to the surgeons. Optisol-GS is a lighter hue of red than CM; however, to distinguish
between the two, one would need to place them one beside the other. It was
expected that the lack of a frame of reference would impose masking. A masked
observer analyzed the endothelial images.
Patients underwent clinical assessments on days 1, 7, 30, and 90. In
addition to a slitlamp examination, an ultrasonic pachymetry of the central
cornea (Ophthasonic A-scan/Pachymeter; Teknar Inc, St Louis, Mo) and an assessment
of the extent of epithelial defect with fluorescein staining (0%-25%, 26%-50%,
51%-75%, and 76%-100%) were performed. During the last visit (at day 90) specular
microscopy of the central cornea was performed. Endothelial cell counts were
carried out in a manner similar to the one described for the donor tissue
at the Eye Bank.
The sample size was determined by evaluating data from a pilot study
at the same settings and conducted by the same investigators. Thirteen pairs
of patients received corneal buttons preserved in either CM or Optisol-GS.
Two months after transplantation, the pooled mean endothelial cell loss was
16.4% (SD, 11.6%). For the present study it was decided that a clinically
relevant reduction in mean endothelial cell loss would be 10% or more (eg,
15% to 5% loss). A sample size of 34 pairs of donor eyes (68 recipients) was
calculated for a type I error P value of .05, a type
II error P value of .20, a 2-sided alternative hypothesis,
and a paired test. Ninety patients were enrolled to allow for loss to follow-up.
The primary efficacy outcome was endothelial cell loss (ECL) 3 months
following surgery. It was defined as the percentage difference between the
baseline cellular density (measured at the eye bank in vitro) and the cellular
density 3 months following surgery (measured at the ophthalmology clinic in
vivo). Secondary efficacy outcomes were corneal thickness, measured at 1,
7, 30, and 90 days following surgery; the extent of epithelialization of the
graft (measured at similar time points); as well as primary and secondary
graft failures. Primary graft failure was defined as an irreversible opacification
of the graft occurring within 2 weeks after transplantation.
Demographics and baseline characteristics were summarized and tested
for treatment group comparability using the t test
or the  2 test. The treatment effect on the primary outcome
(ECL) was calculated using a paired t test. Subsequently,
to increase the precision of the estimate of the treatment effect on ECL,
multiple linear regression methods were used. A set of explanatory variables
(recipient characteristics and operative and postoperative factors) was evaluated
and included in an initial model if they had a significant association with
ECL or a larger than 10% influence on the estimate of the medium effect compared
with the paired t test. Variables were then eliminated
in a backwards fashion based on the probability of their association with
the outcome and the effect of their elimination on the standard error of the
estimate of the storage medium effect. The final model yielded the smallest
SE for the estimated medium's effect. For average corneal thickness, it was
decided a priori that a statistical comparison be made only for the interval
where, based on clinical judgment, a significant disparity exists. Comparisons
were completed using the repeated-measures analysis of variance. We used the
SAS 7.0 (SAS Institute, Cary, NC) GLM (generalized linear models) and MIXED
procedures. A P value of .05 or less was considered
statistically significant. Other secondary outcomes, namely, the distribution
of epithelial defects by size at different time points, as well as primary
and secondary graft failure rates, were described without employing formal
statistical tests.
Donor information was kept at the eye bank as part of its regular record
system, in the form of a Microsoft Access (Microsoft Inc, Redmond, Wash) electronic
database. Recipient characteristics and the results of the follow-up examinations
were collected in a case report form and were later entered into a Microsoft
Access electronic database that was created for this purpose. For the purpose
of analysis, the donor and recipient databases were merged and imported to
SAS. No prospectively defined stopping rules were used.
RESULTS
A total 45 pairs of donor corneas were assigned individually and randomly
to CM (45 corneas) or Optisol-GS (45 corneas) and subsequently distributed
to 90 eyes of 90 patients. The baseline characteristics of the pairs of donor
corneas are presented in Table 1.
Corneas from a single donor were not necessarily transplanted on the same
day; nevertheless, the difference in storage time between the 2 treatment
groups was not statistically significant. The baseline characteristics of
the 90 recipients were statistically balanced (Table 2).
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Table 2. Recipient Characteristics and Surgical Procedures by Treatment
Group*
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Eighty-seven patients (96.7%) completed the 90-day examination (44 [97.8%]
in CM and 43 [95.6%] in Optisol-GS) (Figure
1). The corneas of 7 patients failed to achieve sufficient clarity
to allow specular microscopy at 90 days (3 [6.7%] in CM and 4 [8.9%] in Optisol-GS).
Endothelial cell counts were available for 35 pairs of corneas (77.8%) at
90 days.
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Figure 1. Flow of patients throughout the
trial. Asterisks indicate corneas that were not clear enough to allow specular
microscopy; dagger, corneas that were a secondary graft failure; and double
dagger, cornea pairs with one unclear mate were excluded.
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The average percentage of ECL (observed 90 days after transplantation)
for the 2 treatment groups combined was 21.5% (SD, 19.3%) (Table 3). This corresponded to a reduction in cell density of 567
cells per mm2 (SD, 505 cells per mm2). The average percentage
of ECL in the Optisol-GS group was 4.9% more than in the CM group (24.0% [SD,
20.5%] and 19.1% [SD, 18.0%], respectively). This difference was not statistically
significant (P = .25; 95% confidence interval [CI],
-3.4% to 13.2%).
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Table 3. Endothelial Cell Counts and Loss 90 Days After PKP*
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Constructing a multivariable model increased the precision of the estimate
of the treatment effect on ECL. The model that yielded the smallest SE for
the estimated medium's effect on ECL included variables to adjust for donor
characteristics, the presence of glaucoma prior to surgery, and the occurrence
of a rejection episode. We achieved with this model an estimate of 1.52 with
an SE of 3.87 (t = 0.39, P =
.70; F1,37 = 2.04, P = .02; the F test
applied to the entire model). Hence, the adjusted average percentage of ECL
difference between the Optisol-GS group and the CM group was reduced to 1.5%.
When compared with the paired t test, the calculated
reduction in the variance of the estimate was 16%, and its 95% CI had tightened
to between -6.1% and 9.1%.
Figure 2 graphically displays
corneal thickness values, by medium, 1, 7, 30, and 90 days after the operation.
Corneal thickness is at its highest immediately following the operation and
decreases over time to reach a plateau. The corresponding numerical data is
presented in Table 4. At days
1, 7, and 30, Optisol-GS–stored corneas were, on average, thinner than
corneas stored in CM (30 µm, 5 µm, and 1 µm, respectively),
while at day 90, the CM-stored corneas were thinner, on average, by 14 µm
than the corneas stored in Optisol-GS. For both storage media, corneal thickness
values at days 30 and 90 were in the vicinity of the 512 µm (SD, 35
µm) reported for normal corneas.6 Consequently,
the repeated-measures analyses of variance were performed only for the first
30 postoperative days. The results for the model, which include variables
for time and treatment, are presented in Table 5. The estimate for the time effect was significant, showing
a 45-µm decrease in thickness (SE, 0.5 µm) for every unit of time
(in days). The estimate of the treatment effect was not significant; thus,
there was no difference in thickness between the corneas that were stored
in CM and in Optisol-GS during the first 30 postoperative days. Other models
were fitted with time in several categories (to relax the assumption of a
linear association between thickness and time) and with interaction terms
for treatment with time (to allow for different treatment effects at different
points in time). The estimate for the effect of the storage medium remained
nonsignificant and there was no evidence of interaction.
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Figure 2. The mean values at each time point
are presented.The error bars represent SDs.
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Table 4. Mean Corneal Thickness by Media
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Table 5. Effects of Time and Medium on Corneal Thickness
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Table 6 presents the distribution
of epithelial defects by size that was observed at the first and seventh postoperative
days. On the first postoperative day, 27 patients (77%) and 28 patients (80%)
in the CM and Optisol-GS groups, respectively, had epithelial defects extending
throughout more than 25% of their graft surface. On the seventh postoperative
day, the numbers decreased to 4 patients (11%) in each group. At postoperative
days 30 and 90, none of the patients had an epithelial defect larger than
25% of the graft area surface.
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Table 6. Distribution of Epithelial Defects at Postoperative Days 1
and 7*
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There were no primary graft failure events. Secondary failure of one
graft that was preserved in CM was attributed to a touch of the intraocular
lens with the posterior corneal surface.
COMMENT
The primary outcome of this study was ECL following transplantation.
At 90 days after surgery, the cornea had usually cleared, and specular microscopy
was possible. During most of this time, patients received topical antibiotics
and steroids to prevent infection and an inflammatory reaction. Ninety days
is close enough to surgery to assume that the endothelial cell counts predominantly
reflect the effects of storage as opposed to recipient-related factors.
On average, Optisol-GS–stored corneas lost 4.9% more endothelial
cells than CM-stored corneas 90 days after transplantation. This difference
was not statistically significant (P = .25; 95% CI,-3.4-13.2).
It includes the 10% judged clinically relevant, which was factored into the
sample size calculation. A multivariable model that adjusted for covariates
enhanced precision and the 95% CI had tightened to between -6.1% and
9.1%, which does not include 10%. This increases the confidence that the 2
media are similar with respect to the primary end point of the study. It concurs
with the results of a study comparing the first 15 patients who received corneas
preserved in CM with 17 patients who received corneas preserved in Optisol-GS.7 The latter group's average ECL 2 months after transplantation
was a nonsignificant 3% higher than the ECL of the former (95% CI was not
reported).
The mean (SD) percentage of ECL that we observed 90 days after surgery
for Optisol-GS–stored corneas (24.0% [20.5%]) was higher than values
reported in the past by Lass et al,8 Lindstrom
et al,4 and Bourne et al7 (3.6%
[15.7%], 5.0% [18.4%], and 11% [9%], respectively). However, the largest diagnostic
group in the first 2 studies was pseudophakic bullous keratopathy (PBK). It
constituted 42% in the first study and 53% in the second. In the third study,
Fuchs dystrophy constituted 52% of the reported diagnoses. In contrast, the
largest diagnostic group in the present study was regrafted, accounting for
22.2%. In a univariable analysis, preoperative diagnosis was significantly
associated with ECL (P<.01); specifically, regrafting
was associated with 8.8% and 13.3% higher rates of ECL 90 days after transplantation
as compared with PBK and Fuchs dystrophy, respectively. Hence, the discrepancy
in ECL rates during the early postoperative period between the above studies
and the present one could be related to differences in determinants of ECL
between the 2 study populations; namely, the preoperative diagnosis leading
to the corneal transplantation. Another contributing factor to the observed
variability in ECL rates after corneal transplantation could be different
eye bank practices; specifically, in situ corneal excision vs whole globe
removal (in the present study, the latter method was used exclusively).
Corneal thickness, a secondary outcome in this study, is known to be
associated with the function and number of corneal endothelial cells. Therefore,
it serves as a surrogate measure for the health and number of endothelial
cells during the early postoperative period when endothelial cell density
cannot be measured. Dextran, a constituent of both Optisol-GS and CM, an osmotically
active agent, enters the cornea during storage.9-10 This
results in swelling of the cornea once it is exposed to the aqueous humor
(an isotonic solution), with subsequent thinning as the endothelium resumes
its function. Indeed, for both storage media, corneal thickness was highest
immediately following transplantation, and it gradually decreased throughout
the follow-up.
Previous studies8, 11-14 compared
postoperative corneal thickness independently at different time points during
the postoperative period, thereby ignoring the fact that the values at each
time point are from the same individuals.15 In
the present study, a more exhaustive method was used (repeated-measures analysis
of variance). Additionally, models were fitted allowing for a nonlinear rate
of thinning (treating time as a categorical variable) and for different treatment
effects at different time points (treatment x time interaction). Corneal
thickness throughout the first 30 postoperative days was similar for the 2
treatment groups. The only statistically significant finding was confirmation
of the observed corneal thinning during the postoperative period in the 2
treatment groups. Specifically, the pooled (for all the corneas in the study)
average rate of thinning during the first 30 postoperative days was 4.5 µm
(SE, 0.5 µm) per day (P<.01).
Reportedly, corneas stored in CM are thicker during storage than those
stored in Optisol-GS.1 This study does not
suggest that this affects postoperative corneal thickness as measured from
day 1 onward. Admittedly, corneal thickness was not measured during the operation.
Intraoperative corneal thickness may influence tissue manipulation, but whether
it affects ECL or graft survival remains to be determined. The time points
at which thickness measurements were made were imposed by the follow-up schedule
of patients who have undergone penetrating keratoplasty. More frequent measurements
may increase the likelihood of detecting a difference. Yet, the clinical significance
of such a small true difference is questionable, as it is unlikely to be perceived
by the patient.
Postoperative pachymetry values observed in our study for Optisol-GS
compare favorably with those found in the literature.4, 7-8 The
values reported by Chen et al13 for CM are
somewhat higher; however, the sample contained only 5 pairs of patients.
The donor's epithelium is gradually replaced by that of the recipient,
and corneas with damaged epithelium are still considered suitable for use.
The degree of corneal epithelialization the first day after surgery is to
a great extent the result of insults that occurred during tissue manipulation
from the time of death of the donor, through processing at the eye bank, and
finally, during surgery. These factors are hard to measure. In the present
study, at the first postoperative day, 23% and 20% patients in the CM and
Optisol-GS groups, respectively, had completed epithelialization of 75% to
100% of their cornea. By the seventh day, the number increased to 88% of the
patients in each group. By day 30, all the patients had reached this stage.
As argued for corneal thickness, more frequent measurements may increase the
likelihood of detecting a difference. Another issue is the categorical scale
that was used to measure the deepithelialized area. Photography and image
analysis could further increase precision in future studies. However, it is
debatable as to whether the clinical significance of such small differences
at the early postoperative period justifies the effort.
From a patient's perspective, graft failure may be the most relevant
outcome for a clinical study that compares 2 corneal storage media. Yet, the
rarity of these events makes their use as outcome measures impractical since
it would require large sample sizes and long follow-up periods. The incidence
of secondary graft failure during the first few months after surgery is further
reduced by the application of topical steroids to prevent rejection.
Generalization of the study results to the population of patients who
require corneal transplantation seems adequate. Corneal transplantation is
usually performed in tertiary centers similar to the one where the present
study took place. Eligible for the study were patients undergoing all types
of corneal transplantations, whether alone or supplemented by another surgical
procedure. Although exclusion criteria included a few ocular conditions that
carried a very poor prognosis for graft clarity, in reality, no such patients
were encountered during the 9-month study period, testifying to the rarity
of these conditions. As to internal validity, the balance of baseline characteristics
between the treatment groups confirms effective randomization with respect
to known risk factors, and suggests balance with respect to unknown risk factors.
Nearly all patients (96.7%) completed the 90-day examination, and primary
outcome measurements were possible for 78%. The only statistically significant
difference in baseline characteristics between the patients who completed
the follow-up and those who did not, was a mean storage time 12 hours longer
for the latter group. Average (SD) storage time for all the patients in the
study was 99 (22) hours. Bourne et al7 demonstrated
a significant correlation between ECL at 2 months and storage time; however,
in the present study, no such association was detected.
In summary, this study found CM and Optisol-GS to be similar with respect
to corneal endothelial survival 3 months after transplantation, as well as
corneal thickness and reepithelialization. Thus, there seemed to be no safety
or efficacy differences that are clinically relevant between the 2 storage
media. It is reasonable that eye banks, in collaboration with the corneal
surgeons, determine which storage medium to use based on considerations like
availability, cost, and ease of work.
AUTHOR INFORMATION
Submitted for publication January 4, 2002; final revision received May
15, 2002; accepted May 29, 2002.
The authors would like to thank The Toronto Eye Foundation (Toronto)
and the Ontario Division of the Eye Bank of Canada (Toronto).
Corresponding author: Joel Naor, MD, MSc, 3841 W 23rd Ave, Vancouver,
British Columbia, Canada V6S 1K8 (e-mail: joelnaor{at}hotmail.com).
From the Department of Ophthalmology, Toronto Western Hospital, University
Health Network, University of Toronto, Toronto, Ontario.
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