Guided bone regeneration using bone grafts and collagenmembranesHorn-Lay Wang, DDS, MSD'/William J. Carroll, DDS,

When nonabsorbable membranes are used tor guided bone regeneration (GBR), second surgeries arerequired tor membrane retrieval. In addition, these types of membranes show a high incidence of fiapsloughing and membrane exposure that often lead to infection and unfavorable resuits. Absorbable barrierssuoh as oollagen membranes were developed to overcome tiiese drawbacks. This article presents theprincipies and the olinicai procedure of using barrier membranes composed of absorbable ccliagen inGBR aimed at the repair and regeneration ct ridge dehiscence defects around implants. The unique prop-erties ot coilagen membranes that mai<e them idealiy suited to GBR procedures are reviewed. In addition,the indications and contraindications for using ccliagen membranes lor GBR procedures are examined.Finaliy, cases are presented to demonstrate details ct surgical principles and techniques. (QuintessenceInt 2001:32:504-515)

Key words: barrier materials, bone-replacement grafts, coilagen membranes, guided bone regeneration,guided tissue regeneration, implants

Prostheses fabricafed on implants have increasedstability and retention compared to traditional

removable partial dentures and are more conservativeof tootb structure tban fixed appliances. In addition,numerous studies bave documented long-term successrates for implants.''^ It is no wonder that in tbe last 10years tbe use of implants in tbe United States basincreased dramatically. Alveolar bone loss created bydisuse atropby, disease, trauma, residual bone defects,or sinus pneumatization can limit the amount of boneavailable botb in beight and width. This restricts theability to place impiants in the appropriate positions.Furthermore, it creates difficulties for clinicians whorestore implant prostheses as well as causes improperocclusai loads on impiants, which could result in boneloss or implant failure in some cases. Placing implantsinto less-than-adequate bone, but with optimal pros-thetic position, may also lead to disappointment whenbony dehiscences and fenestrations are discovered atthe time of second-stage surgery. Unfortunately, even

'Associate Protessor and Direclor of Gradúale Periodontics, DeparimenI oíPeriodortics/Prevention/Geriatrics, School of Dentistry, University cfMichigan. Ann Arbor, Michigan.

'Adjuncl Assistant Prafessor, Departmenl of Periodontics/Prevention/Geriatrics, School of Denlislry, University ot Michigan, Ann Arbor; andPrivate Praefice in Periodcntics, Toledo, Ohio.

Reprint requests: Dr Horr-Lay Wang, Associate Professor and Director ofGraduate Periodontics, Department ot Ferio donf i cs/P reven lie n/Geriafrics,University of Michigan School of Dentistry, 1011 North Universily Avenue,Ann Arbor, Michigan 48109-1078. E-mail: horrilay@umich.edu

under the best of circumstances where implants osseo-integrate well into correct prosthetic position, peri-implarttitis can subsequently develop and damageimplant-sup porting bone.

A reasonable solution to the prostbetic dilemmacreated by lack of available bone would be to augmentridge deficiencies prior to or during implant place-ment. Such an approach could enhance the prognosisof implant prosthesis cases. Guided bone regeneration(GBR) is a surgical technique used to regenerate alve-olar bone defects prior to, in conjunction with, or sub-sequent to tbe placement of implants. The principlesof GBR were derived from knowledge generated bytbe development of guided tissue regenerafion (GTR)tecbnology, wbich had as its goal the regenerafion ofperiodontal tissues damaged by disease.

PRINCIPLES OF GBR

Guided bone regeneration sbares in common witb GTRthe use of barrier membranes to achieve regeneration.To achieve better clinical outcomes, tbe GBR barriershould possess the foliowing properties. ''

• Cell exclusion: Certain cells must be excluded fromthe area targeted for bone regenerafion. In GBR,tbe barrier membrane is used to prevent gingivalfibrobiasts and/or epithelial cells from gainingaccess to the wound site and forming fibrous con-nective fissue.

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• Tenting: The membrane is carefully fitted and appliedin such a manner that a space is created beneath themembrane, completely isolating the defect to beregenerated from the overlying soft tissue. To accom-plish this lenting function and to completely isolatethe defect, it is important that the membrane betrimmed so that it extends 2 to 3 mm beyond tbemargins of the defect in all directions. Care shouidalso be taken to round tbe comers of tbe membraneto prevent inadvertent flap perforation.

• Scaffolding: Tbis tented space initially becomesoccupied by a fibrin clot, wbich serves as a scaffoldfor the ingrowth of progenitor cells. In GBR, theceils will come from adjacent bone or bone marrow.

• Stabilization: Tbe membrane must also protect tbeclot from being disturbed by movement of the over-lying flap during beahng. It is tberefore often, butnot always, fLxed into position witb sutures, minibone screws, or bone tacks. Sometimes, tbe edges ofthe membrane are simply tucked beneath tbe mar-gins of tbe naps at tbe time of closure, tbereby pro-viding stabilization.

• Framework: Where necessary, as in non-spacemaintaining defects such as dehiscences or fenestra-tions, the membrane must be suppotied to preventcollapse. Bone-replacement grafts consisting ofautografts, allografts. xenografts. alloplasts, or com-binations of tbese materials are often used for tbispurpose. They sen'e as a sort of internal frameworkto provide a measure of support to tbe graft, Stiffermembranes sucb as titanium-reinforced membraneshave also been used for this purpose.

DrSADVANTAGES OFNONABSORBABLE MEMBRANES

Much research has been done with nonabsorbablemembranes such as expanded polytetrafluoroethylene(e-PTFE) membranes.'" Membrane exposure caused byvariable amounts of flap sloughing during healing hasbeen a frequent poststirgical complication associatedwith the tise of nonabsorbable membranes.' Exposurerates as high as 31Ao resulting in GBR failure havebeen reported.* Membrane expostire permits a commu-nication between tbe oral environment and newlyforming tissues, increasing the potential for infectionand decreasing the likelihood of regeneration. Simionet aP reported significantly less bone regenerationaround implants placed into immediate implant siteswhen membranes became exposed compared to non-exposed membrane sites (41.6% versus 96.6o.o), Inaddition, nonabsorbable membranes must be retrievedby employing a second surgical procedure that can attimes be a tedious undertaking and can aiso disturb

bealing. From a clinical point of view, one may predictthat an absorbable barrier could enhance healing bysimplifying the surgical regimen aimed at regeneration.

USE OF COLLAGEN MEMBRANES IN GBR

Unique properties of collagen membranes

Collagen membranes sbare in common witb allabsorbable membranes tbe fact tbat they do notrequire a second surgery for retrieval. Tbis saves timeand cost and is also greatly appreciated by patients. Inaddition, collagen membranes possess unique proper-ties tbat make tbem ideal for GBR and GTR proce-dures. Collagen is tbe principal component of connec-tive tissue and provides structural support for tissuestbrougbout the body,

• Memostasis: Collagen is a bemostatic agent and pos-sesses tbe ability to stimulate platelet attacbmentand to enbance fibrin linkage, wbich may facilitateinitial ciot formation, and to promote clot stabiliza-tion and maturation, leading to enbanced bealingand improved regeneration.'"

• Chemotaxis: Collagen bas been shown to be cbemo-tactic for fibroblasts in vitro." This property couldenhance cell migration in vivo. Should primary cov-erage not be attained upon closure or membraneexposure occur during bealing, this property mayencourage wound closure and prevent graft failure.

• Ease of manipulation: Collagen can easily bemanipulated and adapted. This property is especiallyuseful in GTR where membranes must be adapted toroot surfaces.

• Well tolerated: Coüagen bas also been demonstratedto be a weak immunogen'^ and is therefore well tol-erated by patients. A study by Johns et al' demon-strated that membranes made of bovine collagen donot elicit an antibody response when used in GTR.This is not a surprising finding given the extensivedistribufion of collagen tbrougbout the body.

• Bioabsorbable: Because collagen is bioabsorbable,during enzymatic degradation it will incorporatewith tbe nap to support new connective tissueattachment.'' This may result in augmenting tissue/flap thickness to further protect underlying bone for-mation and prevent future bone loss.

• Slow absorption: Membranes must remain in placeuntil ceils capable of regeneration are established atthe wound site. Collagen membranes cross linkedwitb formaldehyde have been shown by Blumen-thai"' to last 6 to 8 weeks before being absorbed,whereas non-cross linked membranes lose theirstructural integrity in 7 days.

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TABLE 1

Name

Collagen barriers presently available

Manufacturer Source

Commercially available in the iJnited StatesBio Mend Sulzer CalcitekBIO Mend-Extend Sulzer CalcitekBioGuide Geistlich

Bovirte tendonBovine tendonPorcine dermis

Commercially available outside the Uhiled StalesPeriogenParoguide

Biostite

Collagen Inc.Coletica

Col etica

Tissue Guide Koken

Biobar Col ber Research8 Development Ltd

Bovirte üermisCalf skin

Calf skin

Bovine dermis+ tendcnBovine tendon

Main components

tO0% type 1 collagentOO% type 1 collagenTypes 1 and III collagen

Types 1 and III collagen96% type 1 collagen and4% chondroitin-4-sulfate88% hydroxyapatite.9.5% type 1 coiiagen, and2.5% chondroitin-4-sulfateAteloc oll agen (primary)+ tendon collagen100% type 1 collagen

Several absorbable collagen membrartcs arepresently in product development or are commerciallyavailable for use in the United States. Table 1 liststbese products, together witb tbeir sources and maincomponents.

Indications

Numerous studies bave documented the success ofGBR procedures employing nonabsorbable mem-branes in restoring borizontal and vertical alveolarridge defects, in treating debiscence and fenestrationdefects associated with implants, and in obtainingbone fill associated witb immediate and failingimplants.'^-'' Potentiai indications for the use of colla-gen membranes in GBR include:

• Local alveolar ridge deficiencies (horizontal or lim-ited vertical)

• Osseous fill around immediate implants• Dehiscenccs and fenestrations associated with

implants• Bone defects associated with failing implants• Residual bone lesions• Aid repair of sinus membrane perforations

Except for the first indication, these uses of collagenmembranes have not yet been approved by the USFood and Drug Administration.

In a multicenter study reported by Nevins et al,'^tbe success of implants placed in conjunction with

GBR procedures was evaluated. GBR proceduresemploying e-PTFE membranes and various types ofbone graft material were used. Implants were placedsimultaneously witb GBR procedures wben implantswere placed into extraction sockets or when implantpiacement resulted in dehiscence or fenestrationdefects. Implants were placed subsequent to GBR pro-cedures in a staged manner when ridge augmentationwas undertaken. Implants were followed for up to 74months, and a 97.5% success rate was reported.

There is a paucity of clinical studies in the literatttreregarding tbe use of collagen membranes for GBRprocedures. Recently, Parodi et al'^ reported on theuse of collagen membranes to augment aiveolar ridgedeficiencies. Following treatment, 75% of defectstreated witb collagen membranes demonstrated suffi-cient width for implant placement. In another recentstudy, by Zitzmann et al, " collagen membranes usedin conjunction with an anorganic bone xenograft totreat defects associated with implants outperformed e-PTFE membranes and resulted in 92% defect fill.Sevor and Meffert ' demonstrated more osseous fill atimmediate implant shes treated with collagen mem-branes than at sites treated without membranes. Basedon the work of Colangelo et al, = who observed honeformation in surgically created defects in rabhitmandibles tbat were allowed to heal covered by colla-gen membranes and fibrous fill wben they were notcovered with membranes, the authors have used colla-gen membranes to treat various residual bone lesionsincluding periodonta! cysts and periapica! granulomas.

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They have also used collagen membranes to heal tearsin sinus membranes that occurred during sinus liftsurgery and were not amenable to suturing.

Contrairjdications

From their cfinical experience, the authors believe thatthe following conditions are contraindications for thisty pe of ciinical procedure. Any medical problem thatwould prevent a patient from undergoing routine perio-dontal/implant surgery is also a contraindication forcollagen membrane-GBR procedures. There should beno active infection present at the site to be treated.Poor oral hygiene is considered an absolute contra-indication for regenerative stirgery. Smoking is consid-ered hy the authors to he a relative contraindication.They believe that smokers wbo are able to cut eon-sumpdon in half 1 week prior to and for 1 week follow-ing surgery obtain results similar to nonsmokers.Further investigation will be needed to clarify this sup-position. Ability to maintain space is a key for GBRsuccess. If the space cannot be created/maintained withother adjunctive techniques (ie, fixation pins) or bone-replacement grafts, then the surgery should not he per-formed. Good soft tissue quality is an essential elementfor achieving primary wound coverage. If the soft tissueconditions are not adequate (eg, active inflammation),then the procedure should he delayed or avoided.

Surgical principies

Ttie surgical principles employed by the authors inclinical practice are described below.

• Initial incision: An attempt is always made to locatethe initial incision away from the defect site so thatclosure is not directly over the defect site. Verticalreleasing incisions are used when indicated.

• Reflection: A full-thickness mucoperiosteal flap isreflected 2 to 3 mm heyond the margins of the defect.Traction is then placed on the flap, and an incision ismade through the periostetun. The reflection is thencontinued by blunt dissection, creating a split-thick-ness flap that can be repositioned free of tension overthe area to he treated to obtain primary closure.

• Debridement: Granulation tissue is completelyremoved to help stop bleeding and to allow carefulinspection of the defect.

• Removal of epithelium: Where appropriate, as intreatment of defects associated witb existingimplants, epithelium should be removed from theinner surface of the flap using a sharp curette or dia-mond hur. The implant surface should then bedetoxified with appropriate agents (eg, 50 mg/mLtetracycline for 3 minutes).

• Fitting the membrane: Collagen membrane istrimmed and fitted so that it extends 2 to 3 mmheyond the margins of the defect in all directions.Usually, the collagen membrane is hydrated in ster-ile sahne or sterile water for 5 to 10 minutes beforeuse to improve handling (malleability); however, thisis not mandatory.

• Fitting the flap: The flap is checked, and trimmed ifnecessary, to ensure that primary tension-free clo-sure is possible.

• Cortical perforations: Cortical perforations are madewith a \2 round bur to create bleeding at the defectsite and to allow egress of progenitor cells.

• Bone-replacement graft placement: Graft material isplaced at the defect site to support the tented mem-hrane. Tenting screw(s) can also be used for thispurpose, either alone or in conjunction with graftmaterial (s).

• Membrane placement: The membrane is thenadapted at the defect site. If the membrane is stable,no attempt is made to fix it. However, if the mem-brane is not stable, then pins, hone screws, or tacksmay he needed to assist membrane stability.

• Closing: The surgical site is closed with Vicryl(Ethicon/Johnson & Johnson), e-PTFE, or silksutures with passive tension.

Postoperative care

The postoperative regimen recommended hy theauthors is as follows. Patients are routinely placed onan antibiotic (eg, amoxicillin) for a minimum of 10days to prevent postsurgical infection. Warm salt-waterrinses (versus chlorhexidine gluconate 0.12%mouthrinse) are recommended for the first 2 to 3weeks to encourage normal Oap healing without dis-turbing migrating cells. Chlorhexidine gluconate O.12''/o(eg, Peridex [Proctor and Gamble] or Periogard [Col-gate]) mouthrinse is subsequently used for 3 weeks tofacihtate plaque control. Sutures are removed at 10 to14 days. The surgical site is checked every 2 weeks for2 months.

CLINICAL CASES

Figures 1 to 3 illustrate the use of an ahsorbable colla-gen membrane to atigment (ï) a horizontal edentulousalveolar ridge defect, {2) extraction site defects associ-ated with immediate implant placement, and (3) ahorizontal ridge defect in conjunction with implantplacement.

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C A S E 1

Fig l a Horizontai augmentation cf an edentuious aiveoiarridge defect. Precperative view shows inadequate ridge widthand neighl

Fig 1b Surgical view shows ndge defecls.

Fig 1c Tenting screws (Leadfix absorbable pin. SulzerCalcitek) are used for barrier support and space creationboth norJzontaliy and vertically

Fig 1d Demineraii^ed freeze-dtied bone aliografl (DFDBA)in piace.

Fig Ie Coilagen membrane (BioMend) in piace. Fig H Suluring with 5-0 Vicryl suture (primary coverage wilhpassive fiap tension).

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Fig I g Reentry at 6 months shows new bone Iormation. Fig 1h Implants in place

Fig 1i Radiograph illustrates goodDone-to-implant contact.

ng l i implant stage 2 surgery (6 months later) tor prostheticabutment connection.

Fig 1 k Crowns are oemented.

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C A S E 2

Fig 2a Augmentation of extraction site defect associated Fig 2b Immediate impiants are piaced in extraction socket,wifh immediate implant placement. Preoperative view.

Fig 2c DFDBA in place. Fig 2d Coilagen membrane (BioMend) in piace.

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Rg 2e Closure with 5-0 Vicryl suture (primary coverage and Fig 2f Two weeks postoperative,passive flap tension).

F¡g 2g Reentry at 6 monttis stiows bone fill.

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CASE 3

Fig 3a Horizontal ridge augmentation in conjunction witiiimpiant piacement. Preoperalive view sfiows ridge defect.

Fig 3b Impiant placement witn buccal dehiscence.

Fig 3c DFDBA in pface. Fig 3d Collagen membrane (Biolvlencl) n place.

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Rg 3e Soft tissue healing at 2 months. Fig 3f Bone formation at time of second-stage surgery (6months posts Ljrgery].

Rg 3g Radiograph illustrates excelient txjne-to-implant con- Fig 3h Crown is cemented,tact

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DISCUSSION

The efficacy of collagen membranes used for GTR pro-cedures, such as the treatment of narrow two-walledinfrabony defects and Class II furcation defects, basbeen established.^'"" Preliminary studies using collagenmembranes to achieve root coverage-*^ have demon-strated results comparable to those obtained usingsubepitbelial connective tissue grafts.-' Nonabsorbablemembranes require second surgeries for retrieval andare associated with a high incidence of membraneexposure.'-^ Absorbable membranes eliminate the needfor second surgeries. Collagen membranes are bioab-sorbable and well tolerated by tissucs.'^'^ Tbey do notdemonstrate the high incidence of tissue sloughing andmembrane exposure tbat is seen with e-PTFE mem-branes. For these reasons, interest in the use of colla-gen membranes for GBR procedures is growing.

That GBR works is well documented in the litera-ture. - * GBR is a biologically simpler procedure tbanGTR. Tbe goal of GBR is to rebuild bone. The goal ofGTR is to regenerate bone, cementum, new attachment,and periodontal ligament contiguous with root struc-ture. It seems reasonable that if absorbable collagenmembranes work well for GTR procedures, tbey wouldprobably work better for GBR procedures. Tbe resultsof early studies support tbis supposition.'*-^" Contraryto tbe GTR procedures, additional bone grafting materi-als for space creation/maintenance tend to improveGBR outcomes. Tbis was supported by Hiirzeler et al. ^Tbose authors reported that collagen membranes com-bined witb bovine bydroxyapatite significantly enhancebone-to-implant contact when compared to collagenmembranes alone or non-membrane treated controlgroups; the results were comparable to those in tbe e-PTFE membrane plus bovine hydroxyapatite group inanother study. " Cases presented in this article demon-strate that the combinafion of bone-replacement graftsand collagen membranes can in fact work in a varietyof clinical situations requiring GBR procedures.

When choosing an ideal material for GBR, the fol-lowing requirements must be considered; wound stabi-lization, space creation and maintenance, protection ofthe underlying hlood clot, and the abifity to excludeunwanted tissues or cells (connective tissue and epithe-lium). Because collagen membranes fulfill all of thesecriteria, they have become one of the common materialsused in GBR procedures. So far, no study has definedthe actual time needed for GBR barriers.^ Generally,collagen membranes resorb in around 6 to 8 weeks. ^During GTR procedures, bone and/or periodontal liga-ment cell migration reach their plateau in 2 to 7 daysafter surgery, with a decrease in mitotic activity toalmost normal levels by tbe end of the third week. " Thiscould imply that ceils needed for regeneration arrive at

the wound sites in around 3 to 4 weeks. Hence, thelength that the collagen membrane retains its integritysbould be sufficient to allow selecfive cell repopulation.

Collagen membranes bave been reported to besuperior to nonabsorbable membranes witb regard tohealing. Also, a bigber incidence of dehiscence, mem-brane exposure, and/or premature membrane removalare noted wben nonabsorbable membranes areus^¿ 17,20,22 Similar to GTR procedures, membraneexposure has a negative impact on tbe amount of boneregenerated in GBR. Simion et al reported signifi-cantly less bone gain wben tbe membranes areexposed compared to nonexposed membrane-treatedsites (41.6% versus 96-6%).

Bone regeneration using collagen membranesseems promising. It should also be noted tbat tbeavailable data are from studies within the 1990s.Long-term studies are needed to confirm the successrate of implatits placed in regenerated bone.

Both GBR and GTR are applications of a broadertecbnology known as tissue engineering. Tissue engi-neering refers to tbe attetnpt to regenerate tissues out-side or inside tbe body. All tissue engineering proce-dures involve three components; cells, matrices, andsoluble regulating factors. These three components areknown as the tissue engineering triad. Collagen mem-branes not only work as tissue matrices, but also serveas insoluble regulators of cell function by providingbinding sites for various soluble growth factors (ie, bonemorpbogenetic proteins) and cell-attacbment proteins(ie, fibronectin}.^' Once attached, precursor cells areable to carry out ancborage-dependent functions suchas division, migration, growth, and differentiation.Tberefore, collagen membranes may play an importantrole in enhancing clinicians' abilities to promote tis-sue/bone regeneration. Furthermore, they may serve asa carrier to deliver growth factors or medications todefect sites. The role of absorbable collagen membranesin GBR will remain a fertile area for further explorafion.

ACKNOWLEDGMENTS

This study was partlatly supported by the University of Michigan,Periodontat Graduate Student Research Fund.

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