Mark C Preul is the NewsomeFamily Endowed Chair ofNeurosurgery Research at BarrowNeurological Institute of St. Joseph'sHospital and Medical in Phoenix,AZ. Dr Preul has extensiveexperience in project managementand development programmes formedical technology (pre-clinical andclinical). He served his surgeryinternship at Dartmouth-HitchcockMedical Center and his neurosurgeryresidency at the MontrealNeurological Institute-McGillUniversity, where he was awardedthe Penfield-McNaughton Prize inNeurosurgery. Prior to this DrPreul was educated at The OhioState University, Oxford, TheUniversity of Toledo College ofMedicine and at Johns Hopkins University.

a report by

Ma r k C P r e u l 1 , P a t r i c k K C ampb e l l 2 , S t e v e n L B e n n e t t 2 , and

T im R Mu en c h 3

1. Barrow Neurological Institute, St. Josephís Hospital and Medical Center; 2. Confluent Surgical, Inc.;

3. NAMSA

A Unique Dua l - func t ion Dev i ce – A Dura l Sea lant wi th Adhes ion-prevent ion Proper t i e s

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I n t r o d u c t i o n

Neurosurgical procedures in the spine often requiredural closure. Intentional incisions of the dura materand arachnoid are usually relatively easily sutured,while incidental tears are often more difficult toclose. If the dural incision or tear is not properlyrepaired, and watertight closure is not achieved,cerebrospinal fluid (CSF) can escape from thesubarachnoid space into the extradural compartment,presenting a risk for significant morbidity. Failure ofstandard techniques to achieve watertight closuremay be due, in part, to the fact that the suturepinholes and gaps between the sutures create high-pressure defects allowing for CSF seepage. Theintegrity of intra-operative closures are often testedwith Valsalva’s manoeuvre, which if successful, ispredictive of post-operative success. Typically, if aCSF leakage is controlled intra-operatively andtested under pressure with a Valsalva’s manoeuvre,the dural repair is considered to remain watertightafter surgery.

Separate from the challenging complication of post-operative CSF leakage, the formation of post-operative peridural scar tissue is part of a naturalhealing process following spinal operations. Ofapproximately 800,000 patients undergoing lumbarsurgeries per year worldwide, 5–40% experiencerecurrent back pain and limitation in activities.Approximately 15% of patients will requirereoperation within five years following initialsurgery. At reoperation, dense scar tissue isfrequently encountered at the surgical site, renderingthe dissection of intraspinal elements morechallenging and time-consuming for the surgeon,and putting surrounding tissue at higher risk ofiatrogenic injury.

Various different surgical techniques and treatmentshave been evaluated to minimise peridural fibrosis,many with inconsistent results. A dual-functiondevice that both reduces post-operative CSF leaksand prevents peridural fibrosis would present a newtreatment paradigm to neurological and orthopaedicspinal surgeons.

Ma t e r i a l s

DuraSeal™ is a synthetic hydrogel developed toreduce (CSF) leaks and post-operative periduralfibrosis following cranial and spinal surgery. Thehydrogel system consists of two aqueous-basedprecursor solutions. The first solution contains amodified polyethylene glycol (PEG) precursor, andthe second contains a low molecular weight amineprecursor. When mixed, these two solutionscrosslink within seconds to form a strong tissue-adhering, absorbable hydrogel. The formed hydrogelremains impervious to fibroblasts and adherent todura for four to eight weeks. During this period thehydrogel separates the dura from the extraduraltissues, allowing them to heal independently, thuspreventing scar formation. The hydrogel then breaksdown into water-soluble PEG molecules throughhydrolytic degradation and is cleared primarilythrough the kidneys. Federal Food, Drug andCosmetic Act (FD&C) blue No.1 dye is added toone of the precursor solutions to aid visualisation ofproduct application. The colorant diffuses out fromthe hydrogel within hours following application andis excreted by the kidneys from the body.

DuraSeal Sealant was evaluated for neurotoxicitywhen placed in direct contact with neural tissues.Micro forceps were used to implant pieces ofDuraSeal into brain parenchyma in test animals, andto create sham injuries in controls. Followingimplantation, animals were regularly examined forclinical signs of disease or abnormality. At days 4 and42 after implantation, four animals per treatmentgroup were euthanised. The brain and proximalportion of the cervical spinal cord were dissected andremoved. No neurological deficits were noted andno adverse reactions were observed for any of the testsites at explant.

In order to allow precise DuraSeal application, a newplug-resistant applicator is now available. The air-assisted MicroMyst™ Applicator allows for precisesealant application in confined or minimally invasivesurgery (MIS) procedures, where the greater controlof sealant volume and thickness is needed. The

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malleable shaft and flexible polymer tip simplifyaccess in many procedures.

The DuraSeal Sealant was recently approved forcranial dural sealing in the US, and has CE Markapproval (European clearance) as a cranial, spinal,thoracic and vascular sealant. The MicroMystApplicator has both US and CE Mark approvals.

Du r a S e a l E v a l u a t i o n s

E v a l u a t i o n o f D u r a S e a l S e a l i n g

S t r e n g t h

Burst pressure testing was performed to determinethe pressure-holding strength of DuraSeal whenapplied to collagenous materials (ASTM 2392-04).Collagen casing (#320, Nippi, Inc., Tokyo, Japan)with six uniform needle holes (CV-301 needle on a6-0 Surgilene suture, Tyco Healthcare) was clampedinto a pressure vessel. DuraSeal was applied to theneedle-punched collagen surface (1–2mm sealantthickness). One minute following DuraSealapplication, the vessel was pressurised, and thepressure at which DuraSeal leaked water through theneedle holes was determined.

A total of 30 samples were evaluated. The averageDuraSeal thickness tested was 1.6 + 0.3mm, whichresulted in an average burst pressure of 317 + 56mmHg (+ SD). All failures were cohesive, in that thefailures occurred through the gel, rather than at thegel-collagen interface. This data supports observationsof excellent tissue adherence with this material.

S e a l i n g S t r e n g t h i n t h e C a n i n e M o d e l

A study was performed to evaluate both the safetyand effectiveness of the DuraSeal Sealant in a caninecranial durotomy model. In 26 adult dogs a 2cmincision of cranial dura and arachnoid was createdand loosely repaired. Hydrogel was applied over the2mm dural gap in 13 dogs, while 13 control dogsreceived no hydrogel application. Terminalprocedures were performed at 1, 4, 7 and 56 days. Atthat time, animals were anaesthetised, bone flapswere raised and the dural closure was leak-testedwith Valsalva’s manoeuvre up to 55 cmH2O.

All dogs remained neurologically intact throughoutthe study. After bone flap was removal, the duralpressure integrity was tested. At every time point,dura in control animals leaked CSF at pressures muchlower than the dura in DuraSeal-treated animals (p<0.05). Although not a specific aim of this study,marked peridural adhesions to the bone flap wereencountered in most of the control dogs at the 7-and56-day time points. These adhesions were the

putative cause for dural tearing during bone flapelevation in one control animal. No dural adhesionswere observed in the hydrogel-treated group.

Pathologist evaluation of tissues found that theDuraSeal-treated animals exhibited normalprogression of dural healing, no dural adhesions andno underlying effects on the brain. While duralhealing progressed normally, the control animalsdisplayed marked peridural adhesions.

E v a l u a t i o n o f A d h e s i o n P r e v e n t i o n

Laminectomy Model

A study was performed in a canine lumbarlaminectomy model to evaluate the ability ofDuraSeal to prevent post-laminectomy epidural scar formation.

Laminectomies were performed at two levels (L3 andL5) and were separated by an un-operated level in 12canines. The two surgical sites were randomised toeither treatment or control in each animal. The siterandomised to treatment had DuraSeal applied to thelaminectomy site, followed by a sterile saline rinse.Control sites received no additional treatment. Allanimals were terminated at 12–14 weeks post-operatively. At that time, six animals were selectedfor gross pathological examination and surgical re-exploration by a blinded neurosurgeon, and theremaining six animals for histopathologicalexamination by a blinded pathologist.

The general health of the animals remainedexcellent throughout the study. During gross re-exploration of the surgical sites in six animals, theblinded neurosurgeon measured the extent andseverity of peridural scar attachment to the dura.Five of the control sites (87%) had peridural scarobserved on the dura, compared with three of thetreated sites (50%). One of the treated sites had asmall 4mm2 scar. If a threshold of peridural scarformation of 10mm2 is selected, then only 33% ofthe treated sites had scar, while the incidence of thecontrol sites remains unchanged.

The blinded pathologist evaluated healing, gelcompatibility, and peridural adhesion formation ateach surgical site for the six animals not surgicallyre-explored. Adhesion formation was scored aseither ‘Partial’ adhesions, or ‘Complete’ adhesions.Compared to non-treated vertebral sites, DuraSealdecreased the severity and incidences of periosteal-dural adhesions, i.e. complete adhesions wereobserved in four of six non-treated sites, whereaspartial adhesions were observed in two of sixtreated sites.

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SEALANT SYSTEM

DuraSeal

act™

For more information:www.durasealinfo.com orwww.confluentsurgical.com

During critical spine procedures, a watertight dural

seal is essential to prevent post-op CSF complications.

The DuraSeal Xact™ Sealant System

enhances the delivery of the DuraSeal hydrogel

technology that has revolutionized the way a surgeon

achieves a precise, TRUE watertight dural seal.

The DuraSeal Xact Sealant System is exactly what

you need to seal the spinal dura.

The strength of DuraSeal. The precision of Xact.

Please refer to DuraSeal Xact Instructions for Use for indications, contraindications,warnings and precautions.

Product not available in all geographies.

DuraSeal is a registered trademark and Xact is a trademark of Confluent Surgical, Inc.

INTRODUCING

Confluent_ad.qxp 24/10/06 4:32 pm Page 43

Discectomy Model

A separate study was performed in a canine caudaequina discectomy model to assess the acute andsubchronic dural sealing, along with adhesionprevention of the dural sealant when applied to thelumbar region following spinal decompressivesurgery. Wound healing, tissue response, scarformation and nerve root mobility were evaluatedusing gross dissection and histopathology. Animalswere observed daily for general health with emphasison neurological deficits and pain. In addition,neurological examinations were conducted on days3, 7, 10, and 14 post-treatment, and weeklythereafter up to eight weeks. A total of 18 caninesunderwent discectomies through the L7-S1intervertebral space. After dorsal midline incision, theinterarcuate ligament was excised, exposing thecauda equina. Fat around the cauda equina and nerveroots was aspirated, and a partial discectomy wasperformed. Following removal of a section of disc,the dorsal aspect of the cauda equina and nerve rootswere abraded. Following injury, animals wererandomised to either have the dural sealant applied tothe discectomy and abrasion sites, or to receive nofurther treatment (control). All animals wereterminated at eight weeks post-operatively. In 16animals (eight test and eight control), the sites weregrossly evaluated for nerve root mobility prior tohistopathology. In two animals (one test and onecontrol), the sites were removed en bloc andmicroscopically evaluated only.

Animals were healthy over the course of the study,no significant neurological deficits were noted andno adverse reactions were macroscopically observedfor any of the dural sealant treated or control sites. Allanimals had normal healing of the skin, fascia andparaspinal muscles. No wound healing tissueresponse difference was noted between the test andcontrol groups. Eight weeks following implantation,the animals were euthanised, the spines recovered,and fixed in 70% ethanol. Following fixation,transverse sections of spine were cut through thediscectomy site, and a blinded surgeon evaluatednerved root mobility microscopically using aqualitative scoring system. The median nerve rootmobility score for the DuraSeal-treated and controlsites was 1.0 and 2.5, respectively. This represents a60% improvement in median nerve root mobilityscore in the DuraSeal-treated animals.

Histological examination revealed more foamymacrophages in the DuraSeal sites than in thecontrols. The magnitude of this macrophageresponse was limited and expected due to thedegradable nature of the test article. There was nosign of neurotoxicity, neurological damage or mass

effect in any of the animals evaluated. Alsoobserved was a reduced amount of scar protrusioninto the dural sac in the DuraSeal-treated animals.There was a 30% reduction of ventral scarprotrusion, and a 21% reduction of dorsal scarprotrusion in the DuraSeal group, relative tocontrol. These results suggest that the sealant orspace,filling properties of DuraSeal may havehelped maintain the dural sac morphology.

This study demonstrated an improvement in nerveroot mobility, and preservation of the dural sacmorphology in DuraSeal-treated animals. It isbelieved that following application, DuraSeal persistsas an inert space-filler, which separates tissues whilethey heal independently. This separation ismaintained while the tissues heal, and then the gelabsorbs without creating significant inflammation,resulting in the preservation of the surgical planebetween the dura and surrounding tissues.

P o s t - o p e r a t i v e S e a l a n t S w e l l i n g

DuraSeal Dural Sealant, like many absorbablehemostatic agents, has the potential to absorb fluidand increase dimensionally following implantation.The basic spray applicator provided with theDuraSeal kit may not provide adequate control tolimit applied thickness, and hence, could potentiallyresult in a large amount and thickness of hydrogeldeposition and neural compression. Thus, theMicroMyst Applicator has been developed toprovide increased control of applied volume andthickness. The fine tip and the air-assisted spray assistsin achieving a controlled coating of tissues. With thisapplicator, it is recommended that maximum sealantthickness be limited to 1–2mm. This increasedcontrol allows for safe and effective sealantapplication, as demonstrated in the animal studiesdescribed herein.

Con c l u s i o n s

The DuraSeal Dural Sealant has been evaluated inseveral preclinical studies to demonstrate lack ofneurotoxicity, ability to seal against egress of CSF, andreduce the formation of peridural scarring. It appearsto promote healing of dural incisions while reducingthe formation of scar between the dura and adjacenttissues. It also possesses dual attributes of a sealant andan adhesion barrier and could be an important tool forspinal surgery. The MicroMyst spray applicator hasbeen specifically designed to allow the controlleddelivery of DuraSeal in spinal surgery. ■

A longer version of this article containing references andimages can be found in the Reference Section on the websitesupporting this briefing (www.touchbriefings.com).

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