a report by

D r J o e y H e i n z e

University of Oklahoma, Department of Periodontology

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

The use of guided tissue regeneration techniques totreat periodontal defects is now commonplace. Theprotocol employs barrier membranes to regenerateperiodontal ligament, cementum and bone byexcluding the faster growing soft tissue cells from thedefect space. Clinical studies have widelydemonstrated superiority of this treatment modalityover traditional open flap debridement techniques.1–2

A variety of membranes are available in themarketplace, starting from non-resorbablepolytetraflouroethylene (PTFE) membranes toresorbable collagen and polylactide (PLA)polyglycolic acid (PGA)-based membranes, all ofwhich exhibit satisfactory clinical outcomes.3–5

Tatakis et al.6 have referred to a set of designrequirements that need to be met for a periodontalmembrane to be effective. In short, these arebiocompatibility, cell exclusion, space maintenance,tissue integration, ease of use and biological activity.The failure of a device in one or more of thesecriteria may be the reason for unsatisfactoryperformance in the regeneration of periodontaldefects. Most of the membranes currently availablehave incorporated these criteria into their design tovarying degrees.

Nevertheless, none of the first-generationmembranes exhibits a truly optimal design, satisfyingall the criteria. Two of the design criteria mentionedhave been particularly hard to meet so far. They arespace maintenance and biological activity.

A membrane that features optimal space maintenancehas to be stiff, so that it will not collapse over thedefect it spans. This is particularly true if no graftmaterials are used in the defect to support themembrane mechanically from underneath. If amembrane collapses into the defect space, thepotentially regenerated volume is reduced and willnot allow optimal clinical outcome. The membraneshould be stiff enough to withstand the pressuresexerted by the overlying flaps and to withstandexternal forces like mastication, until the blood clotbuilding underneath the membrane has maturedenough to support it.

This stiffness, on the other hand, would not allowgood clinical manageability or ease of use, as a stiffmembrane cannot be contoured easily to a three-dimensional-defect – it would have sharp cornersthat may perforate the gingival tissues and membraneimmobilisation could be difficult due to its spring-back effect. Therefore, there has been a trade-offbetween these criteria to present date.

The second criteria that has not been satisfied by themembranes of the first generation is that ofbiological activity. Some pre-clinical research isunderway in which membranes in combinationwith growth factors are evaluated,7–9 withencouraging results. The growth factors are addedto accelerate the regeneration of periodontium andlead to faster healing. Undoubtedly, the futurebelongs to these devices. However, it is yet unclearwhether such devices will become available to theend user in the near future, simply because of thehigh cost of growth factors and the fact that these

A Space-mainta in ing Resorbab le Membrane forGu ided T i s sue Regenerat ion

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1. Nyman et al. “New attachment following surgical treatment of human periodontal disease”, J. Clin. Periodontol. (1982).2. Gottlow J et al. “New attachment formation in the human periodontium by guided tissue regeneration”, Case reports, J.

Clin. Periodontol. (1986).3. Cortellini P et al. “Periodontal regeneration of human infrabony defects with bioresorbable membranes. A controlled clinical

trial”, J. Periodontol. (1996).4. Eickholz P et al. “Periodontal surgery of vertical bony defects with or without synthetical bioabsorbable barriers”, 12 months’

results, J. Periodontol. (1998).5. Needleman I G et al. “Guided tissue regeneration for periodontal infra-bony defects” (Cochrane Review), The Cochrane

Library (2001).6. Tatakis et al. “Gingival recession treatment: guided tissue regeneration with bioabsorbable membrane versus connective tissue

graft”, J. Periodontol. 71: (2000).

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require a lengthy regulatory process before they canbe marketed for a specific clinical application. Thisis the impetus for devices that exhibit biologicalactivity without the use of growth factors.

Inion Inc., a medical device company specialising inthe development and manufacture of resorbableimplants, has concentrated its periodontal membranedevelopment on closing these design gaps. In thefollowing section, the new Inion GTR™Biodegradable Membrane System and how itaddresses all design aspects will be discussed.

S p a c e Ma i n t e n a n c e a n d E a s e o f U s e

The idea was to conceptualise a membrane that issoft only as long as it needs to be soft, during theinsertion phase. After insertion, when the membrane

contacts saliva, the membrane turns stiff withinminutes. This allows the surgeon to spare the use ofa bone grafting material, provided the defect is nottoo large. There would only be a blood clot in thedefect space and that is suggested to provide optimalregeneration conditions10 for periodontal ligament,cementum and bone.

This two-stage membrane characteristic is obtainedby the use of a plasticising agent, which temporarilysoftens the membrane matrix and leaches out slowlyafter the membrane is placed, thus rendering themembrane material stiff again. During the insertionphase the material is soft and a little stretchy orrubbery, but not as weak as collagen materials. Thisfacilitates the safe and precise trimming of themembrane, easy insertion and the formation of agood seal between the root of the affected toothand the membrane, hindering the intrusion of softtissue cells into the space. In the soft stage themembrane shows adequate contourability and theshape given is ‘conserved’ when the membranestiffens up. The stiffening can be accelerated byflushing with sterile water, thus accelerating therelease of the plasticiser. Moreover, the rubberymembrane material possesses enough tear strengthto be immobilised with sutures. It is easy to form aseal between the root of the affected tooth and themembrane by using a suture sling around the tooth.The pliability of the material helps to strictly apposethe membrane to the tooth when pulled tight withthe suture. The elimination of a residual gap willhelp exclude soft tissue cells from the defect andtherefore increase the success rate.

Another fast way to immobilise the membrane is touse the Inion GTR Biodegradable Tacks. Thesecan be inserted without membrane dislocationimmediately after pilot holes are drilled throughthe membrane into the bone. The tack kit isprovided with six tacks, a sterile drill and a single-use tack applicator, eliminating any preparatorywork for the physician.

In an in vitro test the membrane was exposed to awatery solution and its tensile strength behaviour wasmeasured after different exposure times. After oneminute of exposure in the solution, the membraneshows about double its initial strength, reaching itsultimate strength after approximately 30 minutesimmersion in water.

Figure 1: Inion GTR™ Biodegradable Membrane in

Soft Stage

Figure 2: SEM Photograph of the Inion GTR™

Membrane Surface Structure

7. Takeishi H et al. “Molded bone augmentation by a combination of barrier membrane and recombinant human bonemorphogenetic protein-2”, Oral Dis. (Sept. 2001).

8. Danesh-Meyer M J, “Tissue engineering in periodontics and implantology using rhBMP-2”, Ann. R. Australas. Coll.Dent. Surg. (15 Oct. 2000).

9. Sigurdson T J et al. “Periodontal regenerative potential of space-providing expanded polytetrafluoroethylene membranes andrecombinant human bone morphogenetic proteins”, J. Periodontol. (June 1995).

10. Wikesjö et al. “Significance of early healing events on periodontal repair: a review”, J. Periodontol. (Mar 1992).

A Space-mainta in ing Resorbab le Membrane for Guided T i s sue Regenerat ion

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T i s s u e I n t e g r a t i o n a n d C e l l O c c l u s i v i t y

One of the prime requirements for guided tissueregeneration barriers is occlusivity. It means that thebarrier membrane has to be impermeable forepithelial cells; otherwise, these faster growing cellswould populate the wound space and inhibit theregeneration of periodontium. This inhibition ofepithelial migration should be provided for the timespan the periodontal defect needs to heal (at least).This timespan was researched to be at least fourweeks6, but as healing depends greatly on a variety ofpatient related factors, this duration can besignificantly longer. The Inion GTR membraneprovides a barrier function of at least eight to 12weeks and thus allows sufficient time for regenerationwhile at the same time allowing re-entry of the siteshould this be necessary. After that time period, themembrane starts to disintegrate and resorb gradually.

Effective exclusion of epithelial cells will occur if atight seal is formed between the membrane and bonyborders of the defect or the tooth root. Otherwise,epithelial cells can migrate through themembrane–bone gap into the wound space andcompromise the clinical result. In addition, themembrane outer surface must allow for soft tissueintegration so that retraction of soft tissue over themembrane (membrane exposure) can be avoided. The‘bioseal’ forming between the membrane and the fullthickness soft tissue flap also reduces the chances ofbacterial infection and wound failure. Equallyimportant, the inside of the membrane mustincorporate structural elements to allow the blood clotforming underneath the membrane to be stabilised.Only then can it mature uncompromised and developinto tissue regenerating the periodontium. The InionGTR membrane exhibits a surface structure thatallows epithelial cells as well as blood cells to adhere.Figure 2 shows an scanning electron microscope(SEM) photograph of the 3-D globular surfacestructure. It needs to be noted that the roughness isnot through and through but extends only on thesurface layer.

In vivo tests in a cranial rabbit model showed closeincorporation of epithelial cells into the membranesurface after four weeks. The incorporation with nosigns of exfoliation was determined by stainedhistological cross-sections (ref poster)

B i o c ompa t i b i l i t y

The Inion GTR membrane and tack materials werecarefully selected to combine strength, toughness anddegradation features. They are processed in such away that none of the material characteristics arenegatively influenced.

The proprietary compounds and resulting deviceswere independently tested according tointernationally recognised standards and werefound to possess excellent biocompatibility.Moreover, polymers made from identical buildingblocks were used safely already for decades inresorbable suture materials, sports medicine devicesand craniofacial implants.

In an in vivo degradation study, membranes wereimplanted in the mandibles of sheep andhistologically analysed after six and 12 months. Afterfollow-up, the membranes were resorbed to a greatdegree and the surrounding tissues showed no signsof irritation or sterile abscesses.

After serving as a barrier for periodontalregeneration, the membrane gradually resorbs and iscompletely cleared from the body in one to twoyears. This eliminates the need for a removal surgery.Degradation takes place by hydrolysis andmetabolisation in which the breakdown products arecarbon dioxide and water.

One of the further advantages of this material isthat it is fully synthetic and not of animal or humanorigin and therefore does not bear the risk ofdisease transmission.

B i o l o g i c a l A c t i v i t y

The plasticiser used to soften the membrane is abiocompatible substance called N-2methyl-pyrrolidone (NMP). When the membrane isimplanted, it leaches out of the membrane anddissipates into the surrounding tissues. Pre-clinicalstudies suggest that this substance, when used in smalldoses, stimulates bone growth.

The membrane was used to cover artificially createddefects in the skulls of rabbits, compared with acompetitive product and with empty control defects.After a four-week healing period, the defects coveredwith the Inion GTR membrane showed 79% defectfill versus 61% defect fill and 31% defect fill for thecompetitive membrane and the control, respectively. Results were verified by a cell line test with NMPpresent. This yielded a 2.5-fold increase in the ALP

Figure 3: Defect Covered with GTR (left) and Without (right)

activity of MC3T3-E1 cells (concentration-dependant). MC3T3-E1 cells resemble osteoblastsand therefore represent similar activity. Furthermore,the mineralisation of these cells was enhanced 1.5-fold over controls as determined by staining after fourweeks of incubation.

This phenomenon can be explained by thehypothesis that the NMP activates autogenousbone morhogenic proteins (BMPs), whichnaturally occur in the wound space. As NMP is a

hydrophilic solvent, the activation of it may beexplained through solubilisation of normally hardlysoluble BMPs. The NMP-activated proteins wouldthen lead to a faster maturation of preosteoblastsinto osteoblasts consequently accelerating bone andtissue formation. ■

These results were presented by Dr Franz Weber from theUniversity of Zürich at the Annual Conference of theInternational Association of Dental Research in March 2004,Honululu, USA. Further research on this topic is on-going.

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