First Time in Human Study: Neuroseal Dural
Sealant Prevents Cerebrospinal Fluid Leakage Following Elective Cranial Surgery
Pal Barzo, Sandor Szabo2, Peter Orbay3 and Virginia Jamieson4*
1Department of Neurosurgery, University of Szeged, Albert Szent-Györgi Medical Center, Hungary
2 Department of Neurosurgery, Medical School University Debrecen, Hungary
3 National Institute of Neurosurgery, Hungary
4Kuros Biosurgery AG, Switzerland
Submission: January 24, 2020; Published: February 06, 2020
*Corresponding author: Virginia Jamieson, Kuros Biosurgery AG, Wagistrasse 25, 8952 Schlieren, SwitzerlandBrasilia, DF, Brazil
How to cite this article: Pal B, Sandor S, Peter O, Virginia J. First Time in Human Study: Neuroseal Dural Sealant Prevents Cerebrospinal Fluid Leakage
Following Elective Cranial Surgery. Open Access J Neurol Neurosurg. 2020; 12(5): 555850.DOI: 10.19080/OAJNN.2020.12.555850.
Cerebrospinal Fluid (CSF) leakage remains a significant cause of morbidity and mortality and can occur when no watertight Dural closure is achieved after neurosurgery. We carried out a retrospective clinical study to investigate the safety and effectiveness of a novel dural sealant, Neuroseal, to stop or prevent CSF leakage following elective cranial surgery. In a prospective, open, multi-center, single-arm study in 45 adult patients (n=38 completed) eligible patients received Neuroseal, a novel, colored synthetic dural sealant to augment dural closure following suturing of the dura. The performance of Neuroseal was considered effective if there was no intra operative CSF leakage evident visually or during a Valsalva maneuver up to 20 cm H2O held for 5-10 seconds from the dural repair after a maximum of two applications. The patients were followed up for any CSF leakage and secondary complication for 90 days following surgery. For the 40 patients in whom the device was properly applied, 100% intra operative sealing of the dura was achieved. No leakage was seen up to 90 days after surgery. All AEs that occurred during the study reflected the typical post-operative complications for the study population. Neuroseal was considered easy and quick to assemble as 98 % of preparations took less than 5 minutes. Ease of application was considered very good by 71 % and good by 29 % of the investigators. Neuroseal offers an easy-to-use and visible topical therapy which is safe and effective to provide a watertight dural closure as an adjunct to suturing [1,2].
Cerebrospinal Fluid (CSF) leakage remains a significant cause of morbidity and mortality and occurs when no watertight dural closure is achieved after neurosurgery [3-6]. The occurrence of CSF leakage after surgery can produce serious complications such as infections, severe headaches, meningitis and neurological complications. Furthermore, the financial consequences of CSF leakage may be significant: in a study of 412 procedures in one neurosurgical department CSF leakage accounted for 22% of the total cost of the neurosurgical procedures . Numerous materials and methods have been evaluated in the past decades to identify an optimal sealant to achieve watertight dural closure
with as yet no consensus on a standardization of dural closure methods and assessment of outcomes. Despite advances in neurosurgical techniques to repair dural defects, the incidence of post-operative CSF leaks remains high with rates of 12.8% and 34% for infratentorial and skull-based surgeries, respectively .
Neuroseal, previously known as I 020805 is a novel, synthetic colored polyethylene Glycol (PEG)-based hydrogel that is an easy to use sealant that provides watertight closure as an adjunct to dural suturing following intracranial neurosurgical procedures. Neuroseal has undergone extensive biocompatibility, and pre-clinical safety and effectiveness testing. A watertight dural closure, is achieved by forming a hydrogel layer in situ that
adheres to the dura, thus preventing CSF leakage and associated
complications. In vitro studies showed that Neuroseal did not
contribute to bacterial growth, as tested with bacillus atrophaeus,
staphylococcus epidermidis, pseudomonas aeruginosa or
micrococcus luteus bacteria. Two synthetic PEG based hydrogels
are marketed as dural sealants (DuraSeal™ by Integra, Adherus™
by Hyperbranch). While DuraSeal™ is an effective dural sealant for
supratentorial procedures [2,5] its swelling properties (130 240%
volume increase in vitro) may have limited its use elsewhere. Preclinical
data show Neuroseal has ideal characteristics to support
its investigation as a safe and effective adjunct to sutured dural
repair to provide a watertight dural closure in patients undergoing
elective cranial surgery [7-8].
Pre-operative eligibility: Patients were aged 18 years or
more and scheduled for an elective cranial procedure (involving
surgical wound classification Class I/Clean) entailing a dural
incision of at least 2cm in length or more for supratentorial
location or posterior fossa approach whatever is the origin e.g.
tumor, vascular indication. Non pregnant females of childbearing
potential were eligible if they used acceptable birth control or
abstinence until 90 days after surgery. Patients were not eligible if
they required a procedure involving trans labyrinthine, transoral
or any procedure that penetrated the air sinus or mastoid air cells,
had symptomatic hydrocephalus, pre-existing external ventricular
drainage or lumbar CSF drain, or had received radiotherapy in the
planned surgical region ending within 3 months before surgery, or
had systemic infection or evidence of surgical site infection, or a
history of clinically significant coagulopathy including hemophilia,
or were using an oral anticoagulant. Intra-operative eligibility
Same as pre-operative but with a dural margin of at least 3 mm
from the edges of the bony defect; on satisfactory completion of
the sutured dural repair leakage of CSF was assessed visually or
via Valsalva maneuver with a maximum of 20 cm H2O for 5 10
seconds. Patients were not eligible if they were unable to tolerate a
Valsalva maneuver, or had an intra operative CSF shunt, or needed
to use synthetic or non-autologous duraplasty material, or there
was a gap of more than 2 mm after primary closure of the dura.
This was a prospective, open label, single arm study
(Figure 1) with patients enrolled at one center in Germany
(Universitätsmedizin Neurochirurgische Kinik, Berlin; and three
centers in Hungary (Szegedi Tudományegyetem, Szent-Györgyi
Albert Klinikai Központ, Szeged; Országos Idegtudományi Intézet,
Budapest; Debreceni Egyetem Orvos és Egészségtudományi
Centrum, Debrecen) from 14 February 2011 to 02 November
2011. Study conduct complied with ethical standards and the
Declaration of Helsinki. Written informed consent was obtained
from each participant before undergoing any study assessments.
After dural suturing, eligible patients received Neuroseal and,
if necessary, autologous grafts to augment dural closure. Neuroseal
was delivered from a double syringe applicator to create a fine
layer over the dura, which quickly set to form a watertight seal.
Patients were followed-up for any subsequent CSF leakage and
secondary complications at several time points (Figure 1) or at
the point of any withdrawal, whichever occurred first.
Neuroseal (Figure 2) comprises three hydrogel components:
a PEG-based polymer in solution containing a colorant which
changes color during setting for better product visualization;
a lyophilized PEG polymer; and an activator solution. Before
application, the polymer solution is transferred into the
lyophilized PEG polymer vial under vacuum, which ensures
effective mixing. The resulting solution is transferred into one chamber of a double syringe spray applicator, and the activator
solution is aspirated into the second chamber. After mixing of
the 2 polymers Neuroseal needs to be applied within 45 minutes.
Prior to application the spray nozzle is attached to the applicator.
During application, the contents of the two chambers are mixed
within the spray nozzle. A cross linking reaction between the
two polymers produces a hydrolytically degradable conformal
coating which has good physical adherence to the dura mater and
resistance to CSF pressure. In this study, up to two applications
from one kit were considered appropriate to provide an effective
seal. After the dura was closed and Neuroseal had been applied,
a Valsalva maneuver was performed to demonstrate a watertight
seal had been achieved.
Patients were monitored daily for laboratory and vital signs
and incidence of CSF leakage for up to 8 days following surgery
or before discharge from hospital, whichever occurred first.
The incidence of CSF leakage, CSF leakage with breaking skin
(pseudo meningocele-related surgical intervention), and CSF
leakage confirmed by clinical evaluation was monitored for 90
days (±14 days) following surgery. Moreover, diagnostic testing
with MRI was performed on days 7 (±1 days) and 90 (±14 days).
The performance of Neuroseal was considered effective if there
was no intra operative CSF leakage during a Valsalva maneuver
(up to 20 cm H2O held for 5 10 seconds) from the dural repair
after a maximum of two applications. Neuroseal could be applied
a second time if leakage was observed as a result of the Valsalva
maneuver following the first application. Following the second
application a further Valsalva maneuver was to be performed. The
device failed if CSF leakage was seen intra operatively during the
Valsalva maneuver (up to 20 cm H2O for 5-10 seconds) after up to
two applications of Neuroseal.
Patients were monitored for Adverse Events (AEs) and Serious
Adverse Events (SAEs) from the time of informed consent until
the end of the study. Vital signs, physical examinations including
neurological status and laboratory assessment and wound healing
impairment, were performed in accordance with the study
schedule of assessments. In particular patients were monitored
for signs of post-operative surgical infection and unexpected
neurological signs for 90 days (±14 days) following surgery.
During the hospital period patients were monitored daily for up
to 7 days (±1 day) or up to discharge from hospital whichever
occurred first and specific follow up visits were performed on day
42 (±14 days) and at the end of the study day 90 days (±14 days)
The device was evaluated with respect to: preparation time
(i.e., mixing of polymers, and transfer into double syringe); ease
of application (i.e., including setting time, material run-down,
spray properties, clogging, and spray nozzle exchange); gel
properties (i.e., color, texture, adhesiveness, and layer thickness)
and any possible failures in relation to these; and suitability of
instructions for use and packaging concept, including unsterile/
All statistical analyses were performed using SAS v9.2 or
higher. The Safety Analysis Set was used for all efficacy analyses.
The primary endpoint was the frequency and incidence (%) of
performance failure (95% Confidence Interval [CI]). The Clopper
Pearson Exact method was used to assess the incidence, and the
secondary performance endpoints relating to CSF leakage. A
sample size of 40 was planned on the assumption that the true
incidence of intra operative CSF leakage (assuming no occurrence
of intra operative CSF leakage) would be no more than 8.8%3.
A total of 51 patient were screened, and 45 were enrolled.
All 45 patients were white Caucasian and comprised 28 males
and 17 females. The mean age was 48.5 years (Table 1). Patients
undergoing surgery suffered a variety of lesions some which were
benign such as anerysms and ateriovenous malformations and
others malignant such as gliomas or astrocytomas. The majority
of lesions were supratentorial lesions with 20% infratentorial
or skull based. Forty-one patients received Neuroseal. Thirtynine
patients received a single application from a single kit, one
partient received two applications from a single kit and one
patient received two applications from two separate kits, as the
first application of the device was removed because it had been
applied too thickly. Thirty-eight patients (84%) completed the
study (Figure 3).
In 40 out of the 41 patients the device was properly applied,
and this achieved 100% sealing of the dura intra operatively, and
no leakage was seen up to 90 days after surgery (Table 2). In 1
patient, out of the 41 treated, spontaneous CSF leakage occurred
following the incorrect application of the device. The material was
not applied correctly to the dural suture line, leaving part of the
suture line uncovered. Neuroseal was applied for a second time
but spontaneous leakage continued because the investigator was
unable to cover the remaining dural suture line with the residual
1 mL (4 mL out of the 5 mL of product had been used during the
first application). This was considered a use error and not a device
failure, as confirmed by the investigator.
Neuroseal was considered a safe adjunct to sutured dural
repair during cranial surgery because all the AEs that occurred
during the study reflected the typical post-operative complications
for this population.
Symptoms of malaise (nausea, vomiting, headache and
fever) were the most common post-surgery AEs, but none were
considered to be related to the use of Neuroseal. Overall, 228
treatment-emergent adverse events (TEAEs), i.e., events that
started or increased in severity on or after the date of surgery,
were reported by 40 (97.6%) patients, of which, most were mild
(92.7%), non-serious, were considered unrelated to the study
device and did not lead to subject withdrawal. Two patients
experienced adverse events that were considered possibly related
to the device 1 case of mild wound secretion that was treated with
routine wound care and 1 case of wound infection which was
considered serious as it extended the hospital stay for the patient.
Both resolved completely. The most common TEAEs, i.e., those
that were reported by 5.0% or more of patients are summarized
in Table 3.
Thirteen SAEs were reported for 12 patients, of which one
event (SAE 1: wound infection) was considered possibly related to
the device. The other unrelated SAEs comprised aseptic meningitis,
left sided hemiparesis , disorientation, seizure, post procedural
hemorrhage, superficial wound infection (2 – one associated with
hemorrhage at site of surgery), cachexia progression of disease,
wound seroma. No deep wound infections were reported.
The most common clinically significant laboratory
abnormalities were reductions in hemoglobin and hematocrit and
increases in C reactive protein after surgery. All were considered
to be an expected consequence of surgery and unrelated to the
A total of 9 (22%) patients experienced unexpected
neurological symptoms/signs such as hemiparesis (two
patients), seizures (two patients), photophobia (one participant),
aphasia (one participant) aseptic meningitis (one participant)
disorientation, impaired short term memory loss (one
participant), confusion, motor dysphasia and temporal lobe
epilepsy (one participant) during the study period. None of these
were considered attributable to the use of Neuroseal, and most of
them of them recovered during study participation.
Device evaluation outcomes are summarized in Table 4. The
recorded preparation time was under 5 minutes in 97% of cases
and there were no preparation failures. Ease of application was
classified as very good for 71% of the preparations and good
for 29% of the preparation. The gel color, texture, adhesiveness
and layer thickness were considered appropriate by all users.
Application of the device as a fine spray produced a thin layer on
sutures 30 100 mm long. The volume of material supplied in one
kit (5 mL) was sufficient to apply an effective layer of Neuroseal
to the suture line as shown by a median volume used of 2.1 mL All
investigators considered the instructions for use and packaging
concept to be suitable.
The study population was a typical representation of patients
requiring elective craniotomy procedures following a protocol
that was typical for device evaluation at this stage of development.
An open label design was conducted to assess the performance
as the intraoperative endpoint which had a binary outcome, seal
or no seal under standard test conditions of Valsalva maneuver
up to CSF pressures of 20cms H2O). As with other marketed predicate devices such as Duraseal [2,5] and Adherus ,
Neuroseal demonstrated 100% sealing intra-operatively when
applied over the entire suture line with up to 2 spray applications.
Intra-operative sealing is well recognized as an important step
in preventing post-operative CSF leaks. In this study a follow
up period of 90 days was a secondary endpoint and considered
an appropriate timeframe in order to detect post-operative
CSF leakage and any adverse events that might be attributable
to the device. In this small sample of patients there were no
post-operative CSF leaks in the 40 patients receiving the device
correctly applied. Literature review of the use of predicate devices,
showed a post-operative leakage rate of 7.6% on Duraseal  and
8% (2/25) on Adherus , although the exact nature and site of
the surgery for these trials makes any meaningful comparison
Our study did not include a composite endpoint in the
protocol. In the next planned study a composite endpoint
comprising intraoperative, sealing, post-operative leakage within
90 days and lack of unplanned treatments attributed to the use of
the device will be included. As with any implantable device there
is a risk of infection. In this study one case of superficial wound
infection was reported as possibly related to the device. There
were no deep wound infections. Literature comparison with
other predicate devices is difficult given the different methods
of assessing attribution of an adverse event (e.g. investigator
alone or adjudication committee). True comparisons will require
prospective randomized controlled studies.
This study indicates that Neuroseal offers a safe and effective,
easy to use and easily visible topical therapy for obtaining a
watertight dural closure following cranial surgery that extends
into the post-operative period.
We acknowledge the help from the members of clinical site
team and other external supporting groups that contributed
to the success of this clinical study. We also acknowledge the
editorial and medical writing support of Kathryn White (Cathean
Ltd. Medical Writing Consultancy).
Virginia Jamieson was an employee of Kuros Biosurgery AG
and is currently a consultant to the company. All other authors
certify that they have no affiliations with or involvement in
any organization or entity with any financial interest (such as
honoraria; educational grants; participation in speakers’ bureaus;
membership, employment, consultancies, stock ownership, or
other equity interest; and expert testimony or patent-licensing
arrangements), or non-financial interest (such as personal or
professional relationships, affiliations, knowledge or beliefs) in
the subject matter or materials discussed in this manuscript.
All procedures performed in studies involving human
participants were in accordance with the ethical standards of
the institutional and/or national research committee and with
the 1964 Helsinki declaration and its later amendments or
comparable ethical standards. Informed consent was obtained
from all individual participants prior to inclusion in the study.