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Vol 8, No 6, November/December 2000
339
Adcon-L (Gliatech, Inc, Cleveland,
Ohio) is a sterile absorbable gel
matrix composed of a gelatin in a
carbohydrate polymer. The material
is biodegradable, does not incite
any inflammatory reaction, and is
reported to disappear completely
within 21 days after implantation.
Animal studies have shown that
Adcon-L (or its prototypes) can
reduce the development of fibrotic
epidural scars in rat, rabbit, and
dog laminectomy models.
1,2
On
the basis of subsequent studies in
dog laminectomy and diskectomy
models, as well as a large prospec-
tive multicenter randomized trial
performed in Europe,
3
the US Food
and Drug Administration (FDA)
recently approved Adcon-L as a
device (rather than as a drug) for
marketing in the United States.
Since receiving approval in May
1998, Gliatech has been marketing
Adcon-L with the following FDA-

approved wording on its label:
“(1) Adcon-L significantly reduces
postsurgical scarring and adhe-
sions. (2) Adcon-L improves pa-
tient outcome and reduces activity-
related pain as compared to the
control group. (3) Adcon-L has no
significant adverse events attrib-
uted to its use.”
Epidural Fibrosis
With proper patient selection, more
than 90% of patients who undergo
surgical treatment for lumbar disk
herniations can be expected to have
an excellent or good result. Lack of
pain relief initially after surgery
may be attributed to improper
diagnostic interpretation, surgical
error, or improper patient selec-
tion. If there is initial improvement
and later recurrence of symptoms,
the reason may be postoperative
infection, recurrent disk herniation,
arachnoiditis, or epidural fibrosis
(Fig. 1).
The exact cause of epidural fi-
brosis following lumbar laminecto-
my remains unknown. Key and
Ford
4

first studied this issue in 1948
when they reported epidural scar
formation after laminectomy and
diskectomy. They theorized that
the postoperative adhesions were
derived from the surgically dam-
aged anulus fibrosus. Nachemson
5
also supported this early theory
and felt that leakage from the dis-
rupted intervertebral disk was a
causative factor in epidural fibrosis.
However, LaRocca and Macnab
6
felt
that this “laminectomy membrane”
was actually a layer of fibrotic tis-
sue that covered the laminectomy
site as a result of migration of
fibroblasts from the raw surface of
the erector spinae musculature.
Postoperative epidural fibrosis
can surround nerve fibers, leading
to increasing neural tension and
adhesion to the nerve root. It has
also been theorized that epidural
scar increases the vulnerability of
nerve roots to compression or ten-
sion, which can occur with recurrent
disk herniation or stenosis.

Most clinical studies assess post-
operative scar formation with quali-
tative methods, such as graded his-
Dr. Fischgrund is Attending Spine Surgeon,
William Beaumont Hospital, Royal Oak,
Mich.
Reprint requests: Dr. Fischgrund, Suite 100,
16800 West Twelve Mile Road, Southfield, MI
48076-2176.
Copyright 2000 by the American Academy of
Orthopaedic Surgeons.
Abstract
Adcon-L is a biodegradable gel matrix that was recently approved by the Food
and Drug Administration for use during single-level posterior lumbar laminec-
tomy or laminotomy procedures. Experimental and clinical studies have sug-
gested that the use of this product will decrease postoperative epidural scarring.
However, the relationship between epidural fibrosis and patient outcome
remains unclear. If the treating surgeon is of the opinion that there is a need to
reduce epidural scar, the use of this product appears worthwhile. However, fur-
ther studies are needed to evaluate clinical outcome and justify the use of this
product on a routine basis.
J Am Acad Orthop Surg 2000;8:339-343
Use of Adcon-L for Epidural Scar Prevention
Jeffrey S. Fischgrund, MD
Perspectives on Modern Orthopaedics
Use of Adcon-L for Epidural Scar Prevention
Journal of the American Academy of Orthopaedic Surgeons
340
tology and dissection. Abitbol et al
7

described a new experimental model
in dogs that allowed objective biome-
chanical quantification of the effect
of postoperative scar. The ultimate
load of postoperative adhesions on
nerve roots and the dura was mea-
sured. Their findings suggested a
beneficial effect of hyaluronic acid
in decreasing the biomechanical
strength of extradural adhesions
after laminotomy for nerve root
exploration or disk excision com-
pared with the use of fat graft or no
interpositional membrane.
One of the major questions re-
garding the formation of epidural
fibrosis is its causal relationship to
clinical symptoms. The literature
contains numerous anecdotal reports
of patients with postoperative epi-
dural fibrosis and radicular pain
8,9
;
however, the cause-and-effect rela-
tionship remains to be delineated.
Conversely, recent reports concern-
ing computed tomography (CT) and
magnetic resonance (MR) imaging
studies on patients who have under-
gone laminectomy or diskectomy

have shown a high prevalence of epi-
dural fibrosis even in patients with
clinically excellent outcomes.
10,11
Both high-resolution CT and MR
imaging have been used for postop-
erative evaluation. Cervellini et al
12
examined 20 asymptomatic postop-
erative patients and 20 patients with
recurrent sciatic pain after disk sur-
gery. No patients had bone steno-
sis, recurrent stenosis, or any other
identifiable cause of failed symptom
relief. Their observations revealed
no difference in the amount or loca-
tion of fibrosis demonstrated by CT
between symptomatic and asymp-
tomatic patients. It was concluded
that the degree and type of fibrosis
were not related to recurrence of
symptoms.
Tullberg et al
13
reported a pro-
spective study of 36 patients with
radicular leg pain and lumbar her-
niation who underwent single-level
diskectomy. They found that 64%
of the patients had evidence of

postoperative epidural fibrosis
(documented by gadolinium–
diethylenetriamine-penta-acetic
acid MR imaging). There was no
correlation between the postopera-
tive MR findings and the clinical
outcome.
Annertz et al
14
reported on 16
patients evaluated with MR imag-
ing after lumbar diskectomy. Two
matched groups of 8 patients each—
one group being symptomatic and
the other asymptomatic—were
compared. No relationship was
found between epidural fibrosis and
sciatica in the two groups. Addi-
tionally, the 8 symptomatic patients
underwent reexploration and neu-
rolysis of the adhesion; 6 (75%) had
no statistically significant benefit
from the second surgical procedure.
The authors of this study concluded
that epidural fibrosis alone was not
the cause of the symptoms, as surgi-
cal release of these adhesions did
not result in patient relief.
The prevention of epidural fi-
brosis has been a field of intensive

research by clinical investigators.
Animal studies have included the
placement of a gelatin foam sponge,
Silastic sheeting, fat grafts, polylac-
tic acid membrane, and hyaluronic
acid in the laminectomy defect.
15-17
Most of these studies have shown a
remarkable decrease in the amount
of postoperative scarring; however,
the clinical efficacy of these agents
remains unproved.
In contrast to the numerous ani-
mal studies performed, there are
few prospective human trials that
demonstrate the greater efficacy of
one interposition membrane over
another. Jacobs et al
18
performed a
clinical trial that compared gelatin
foam sponge and free fat graft and
found that those patients with a fat
graft had a better clinical outcome.
Their patients represented a mixed
sample; 28% had previous opera-
Figure 1 T1-weighted magnetic resonance images obtained before (A) and after (B)
administration of gadolinium demonstrate scar formation around the left S1 nerve after
L5-S1 lumbar diskectomy.
A B

Jeffrey S. Fischgrund, MD
Vol 8, No 6, November/December 2000
341
tions, 34% underwent procedures
involving multiple levels, and 58%
underwent simple disk-herniation
surgery.
A prospective randomized study
by MacKay et al
10
included 156 pa-
tients who were treated surgically
for lumbar disk herniations and
randomly assigned to one of three
groups. All patients underwent an
uncomplicated one-level lumbar
laminectomy for disk herniation. In
two groups, either fat or gelatin
foam sponge was placed in the
laminectomy defect; in the third
group, no interposition membrane
was used. The patients were as-
sessed at 1 year. Overall, the extent
of epidural scar formation was
rated excellent or good in 83% of
the patients. The authors concluded
that the clinical outcome after disk
surgery did not correlate with the
use or type of interposition mem-
brane placed to prevent epidural

fibrosis.
Adcon-L
Adcon-L is supplied in gel form in
5-g tubes. The package insert lists
the indications for its use as single-
level posterior lumbar laminectomy
or laminotomy procedures in which
nerve roots are exposed.
The use of Adcon-L was evaluated
in a recent publication by Ross et al,
19
who described the association be-
tween epidural scar and recurrent
radicular pain after lumbar diskec-
tomy. This study (which was sup-
ported by Gliatech) reported on 197
patients who underwent first-time
single-level unilateral diskectomy
for lumbar disk herniation. At 6
months after surgery, all patients
recorded their pain on a visual ana-
log pain scale. Additionally, all pa-
tients underwent MR imaging 6
months postoperatively. The studies
were evaluated by a neuroradiolo-
gist who was blinded to the clinical
findings. The amount of scar for-
mation was graded from 0 to 4, with
a score of 0 indicating no scar for-
mation or only traces thereof and a

score of 4 indicating that more than
75% of one quadrant was filled with
scar. Overall, the authors concluded
that the amount of scarring was a
significant (P = 0.009) predictor of
recurrent radicular pain. Those
patients with extensive scar forma-
tion (scar score of 4) were 3.2 times
more likely to experience recurrent
radicular pain than patients with a
scar score of less than 4.
Several components of pain were
measured in that study, including
pain when most severe, pain on
average, and pain at the end of the
day. Only the “pain on average”
and the “pain when most severe”
measures were analyzed. Only the
latter measurement correlated sig-
nificantly with scar formation.
This study still leaves unanswered
several questions about the role of
epidural fibrosis in postoperative
radicular pain. Only 14 (17%) of the
84 patients who had extensive scar
(grade 4) had recurrent radicular
pain (most severe). The other 83%
of the patients with extensive scar
reported no radicular pain. There-
fore, there must be factors other than

scar formation that also influence
patient outcome.
As part of the FDA approval for
marketing of Adcon-L in the United
States, the manufacturer, Gliatech,
was required to complete the US
clinical study and submit the results
for inclusion in product labeling. In
June 2000, the FDA reviewed these
clinical results and issued a report
that raised many concerns regard-
ing the data from the US study. In
this ongoing study, the researchers
attempted to validate the postopera-
tive MR imaging studies by reading
and scoring 115 of the 324 MR stud-
ies a second time. According to a re-
cent story in The Wall Street Journal
(August 31, 2000; Marketplace sec-
tion:B11), scrutiny by the FDA
investigators reportedly revealed
that 32 of the 115 readings were
allegedly different from the original
readings, with 29 second scorings
resulting in a more favorable out-
come for Adcon-L. In addition, it
appeared that 6 of the second scor-
ings had erasures or write-overs,
which resulted in a more favorable
outcome for Adcon-L. The issues

raised by this FDA audit call into
question the accuracy of the entire
study.
In an animal study, Einhaus et al
1
examined seven adult mongrel dogs
on which multiple-level unilateral
hemilaminotomy and annular fen-
estration were performed. In each
animal, Adcon-L was applied to
two randomly assigned sites around
the diskectomy, the nerve roots, and
the hemilaminotomy. Identical
surgery was performed on a third
site in each animal, but no interposi-
tion membrane was placed. The rel-
ative amount of anterior scarring
around the diskectomy site and pos-
terior scarring at the hemilaminot-
omy site was assessed histologically,
as was the extent of healing of the
annular defect. The authors found
that Adcon-L significantly (P<0.05)
reduced epidural fibrosis in this
model and did not inhibit healing of
the anulus fibrosus.
The large European clinical study
by de Tribolet et al
3
deserves care-

ful scrutiny. In that prospective,
multicenter, randomized, double-
blind trial at nine neurosurgical
centers in three countries, the data
on 269 patients who underwent
primary lumbar surgery for re-
moval of a unilateral single-level
herniated disk were evaluated.
Patients were randomly assigned
to receive either Adcon-L or no
interposition membrane (control
group). Both preoperative and 6-
month postoperative MR studies of
all patients were obtained. In the
treatment group, 3 to 5 g of Adcon-L
gel was applied to all accessible
surfaces of the nerve root between
the thecal sac and the posterior lon-
Use of Adcon-L for Epidural Scar Prevention
Journal of the American Academy of Orthopaedic Surgeons
342
gitudinal ligament, between the
dorsal surface of the thecal sac and
the overlying muscle and fascia up
to the lower surface of the lamina,
and around the nerve root as it en-
tered the foramina.
The 6-month postoperative MR
imaging study was used to quanti-
tate the extent of epidural scar. The

scar formation was given a score
from 0 to 4 based on the percentage
of fibrosis within a quadrant. Post-
operative outcome was assessed
with an activity-related pain ques-
tionnaire, the straight-leg-raising
examination, and a clinical assess-
ment of pain. A single radicular fac-
tor score for each patient was then
determined on the basis of the
scores for 5 of 12 specific daily activi-
ties evaluated on the activity-related
pain questionnaire.
Analysis of the postoperative MR
results demonstrated a significant
(P = 0.002) reduction in epidural
scar formation in patients treated
with Adcon-L (Table 1), similar to
the results in previous animal stud-
ies.
1
These results were supported
by the clinical findings in a small
group of patients who underwent
reoperation at some point between
the first postoperative week and as
long as more than 1 year later. Nine
of the 11 patients had no nerve root
adhesion or only minimal adhesion
around the nerve root, and 8 had no

anterior adhesions or only minimal
adhesions. Residual Adcon-L gel
was not observed in any patient
who underwent reoperation more
than 22 days after the initial surgery.
Considerably more important
than the MR findings is the postop-
erative patient outcome, which
unfortunately is difficult to assess
from this single trial. Significantly
(P = 0.013) fewer Adcon-L–treated
patients reported increased pain
when performing activities of daily
living compared with the control
group. However, careful review of
the data indicates that there was no
significant difference in the radicu-
lar pain response from the baseline.
That is, the amount of leg pain the
patient was having postoperatively
was clinically improved in both
patient groups, and no intergroup
difference was noted at 6 months
postoperatively.
Interestingly, Adcon-L–treated
patients experienced less back
pain. It is hard to explain this fact
physiologically, because the major
advantage of Adcon-L is reduction
of epidural fibrosis around the

nerve root, which has not been
proved to affect low back pain.
Furthermore, Adcon-L–treated
patients also had improved scores
on straight-leg-raising examination
on the operative as well as the non-
operative side. The authors found
this improvement particularly
important, because they believe
this clinical test is the standard
used by many surgeons for assess-
ment of postoperative outcome.
The European clinical study did
not report any complications
directly attributable to the use of
Adcon-L. There was no effect on
wound healing, and the incidence
of postoperative infection was not
increased compared with the con-
trol group. However, there are the-
oretical concerns regarding its use
after incidental durotomy. Because
this product decreases the inci-
dence of postoperative epidural
scar by decreasing the inflammatory
response, there may also be persis-
tence of dural leaks. Small dural
lacerations can occur during rou-
tine surgery and may go unnoticed
by the operating physician. During

the course of normal postoperative
healing, these leaks rarely become
clinically significant, as the inflam-
matory reaction that occurs after a
surgical procedure is often suffi-
cient to seal the leak. Therefore,
the surgeon should use this prod-
uct very cautiously if an incidental
dural laceration is suspected.
Summary
On the basis of the available infor-
mation, it is difficult to advocate the
routine use of Adcon-L after lum-
bar laminectomy. Unfortunately,
the manufacturer of Adcon-L has
sponsored all experimental and
clinical studies presented and pub-
lished thus far, and recent FDA
concerns have called into question
the reliability of the data. These
studies indicate that the use of this
product will decrease the amount
of postoperative fibrosis in the lam-
inectomy defect. Because of this
decrease in fibrosis, there is a theo-
retical advantage to using this
product in patients who require
revision surgery (patients in whom
Adcon-L was placed at the initial
surgery). However, it has not yet

been conclusively shown that this
reduction in epidural scarring
translates into improved patient
outcome.
If the treating surgeon is of the
opinion that there is a need for a
product to reduce epidural scar, use
of this product may be worthwhile.
Table 1
Distribution of Scar Based on MR Imaging in Study by de Tribolet et al
3
No. of Evaluable Patients (%)
Extent of Scar Adcon-L–Treated (n = 127) Control (n = 139)
Minimal or no scar 17 (13) 5 (4)
Moderate 62 (49) 65 (47)
Extensive 48 (38) 69 (50)
Vol 8, No 6, November/December 2000
343
However, it should be noted that
the current charge to hospitals for
one tube of Adcon-L is $495. If it is
estimated that 200,000 laminec-
tomies are performed in the United
States every year, routine use of
Adcon-L would add a rather large
expenditure to the national health-
care bill. Further studies are needed
to evaluate clinical outcomes and
establish the cost-effectiveness of
this procedure.

Jeffrey S. Fischgrund, MD
References
1. Einhaus SL, Robertson JT, Dohan FC
Jr, Wujek JR, Ahmad S: Reduction of
peridural fibrosis after lumbar lami-
notomy and discectomy in dogs by a
resorbable gel (ADCON-L). Spine
1997;22:1440-1447.
2. Robertson JT, Meric AL, Dohan FC Jr,
Schweitzer JB, Wujek JR, Ahmad S:
The reduction of postlaminectomy
peridural fibrosis in rabbits by a carbo-
hydrate polymer. J Neurosurg 1993;79:
89-95.
3. de Tribolet N, Porchet F, Lutz TW, et
al: Clinical assessment of a novel anti-
adhesion barrier gel: Prospective, ran-
domized, multicenter, clinical trial of
ADCON-L to inhibit postoperative
peridural fibrosis and related symp-
toms after lumbar discectomy. Am J
Orthop 1998;27:111-120.
4. Key JA, Ford LT: Experimental inter-
vertebral-disc lesions. J Bone Joint Surg
Am 1948;30:621-630.
5. Nachemson A: Intradiscal measure-
ments of pH in patients with lumbar
rhizopathies. Acta Orthop Scand 1969;
40:23-42.
6. LaRocca H, Macnab I: The laminecto-

my membrane: Studies in its evolu-
tion, characteristics, effects and pro-
phylaxis in dogs. J Bone Joint Surg Br
1974;56:545-550.
7. Abitbol JJ, Lincoln TL, Lind BI, Amiel
D, Akeson WH, Garfin SR: Preventing
postlaminectomy adhesion: A new
experimental model. Spine 1994;19:
1809-1814.
8. Martin-Ferrer S: Failure of autologous
fat grafts to prevent postoperative
epidural fibrosis in surgery of the
lumbar spine. Neurosurgery 1989;24:
718-721.
9. Burton CV, Kirkaldy-Willis WH,
Yong-Hing K, Heithoff KB: Causes of
failure of surgery on the lumbar spine.
Clin Orthop 1981;157:191-199.
10. MacKay MA, Fischgrund JS, Herko-
witz HN, Kurz LT, Hecht B, Schwartz
M: The effect of interposition mem-
brane on the outcome of lumbar lami-
nectomy and discectomy. Spine 1995;
20:1793-1796.
11. Jensen TT, Asmussen K, Berg-Hansen
EM, et al: First-time operation for lum-
bar disc herniation with or without
free fat transplantation: Prospective
triple-blind randomized study with
reference to clinical factors and

enhanced computed tomographic scan
1 year after operation. Spine 1996;21:
1072-1076.
12. Cervellini P, Curri D, Volpin L, Ber-
nardi L, Pinna V, Benedetti A: Com-
puted tomography of epidural fibrosis
after discectomy: A comparison be-
tween symptomatic and asymptomatic
patients. Neurosurgery 1988;23:710-713.
13. Tullberg T, Grane P, Isacson J: Gado-
linium-enhanced magnetic resonance
imaging of 36 patients one year after
lumbar disc resection. Spine 1994;19:
176-182.
14. Annertz M, Jönsson B, Strömqvist B,
Holtås S: No relationship between
epidural fibrosis and sciatica in the
lumbar postdiscectomy syndrome: A
study with contrast-enhanced magnet-
ic resonance imaging in symptomatic
and asymptomatic patients. Spine
1995;20:449-453.
15. Songer MN, Rauschning W, Carson
EW, Pandit SM: Analysis of peridural
scar formation and its prevention after
lumbar laminotomy and discectomy in
dogs. Spine 1995;20:571-580.
16. DiFazio FA, Nichols JB, Pope MH,
Frymoyer JW: The use of expanded
polytetrafluoroethylene as an interpo-

sitional membrane after lumbar
laminectomy. Spine 1995;20:986-991.
17. Cook SD, Prewett AB, Dalton JE,
Whitecloud TS III: Reduction in peri-
neural scar formation after laminecto-
my with polyactive membrane sheets.
Spine 1994;19:1815-1825.
18. Jacobs RR, McClain O, Neff J: Control
of postlaminectomy scar formation:
An experimental and clinical study.
Spine 1980;5:223-229.
19. Ross JS, Robertson JT, Frederickson
RCA, et al: Association between peri-
dural scar and recurrent radicular pain
after lumbar discectomy: Magnetic
resonance evaluation. Neurosurgery
1996;38:855-863.