Jan Lindhe. Clinical Periodontology

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REGENERATIVE PERIODONTAL THERAPY • 665

failed to confirm the regenerative potential of DFDBA

grafting (Sonis et al. 1985, Caplanis et al. 1998).

The controversial results regarding the effect of

DFDBA on the regeneration of periodontal intraos-

seous defects along with great differences in the

osteoinductive potential (ranging from high to no

osteoinductive effect) of commercially available

DFDBA (Becker et al. 1994,1995, Shigeyama et al. 1995,

Schwartz et al. 1996, Garraway et al. 1998), and the (

although minute) risk for disease transmission have

raised concern about the clinical applicability of

DFDBA. In EU countries, the commercially available

DFDBA is not granted a CE mark permitting distribu

tion of the material within the community.

Xenogeneic grafts

The use of xenogeneic bone grafts (xenografts) in

regenerative periodontal surgery was examined sev-

eral years ago. Nielsen et al. (1981) treated 46 in-

trabony defects with Kielbone

(i.e. defatted and de-

proteinized ox bone) and another 46 defects with in-

traoral autogenous bone grafts. The results, which

were evaluated by periodontal probing and radiog-

raphically, showed no difference between the amount

of clinical gain of attachment and bone fill obtained in

the two categories of defect. A study in monkeys also

demonstrated that the two types of bone graft dis-

played similar histologic features and were frequently

seen in the connective tissue of the healed defects as

isolated bone particles surrounded by a cementum-

like substance (Nielsen et al. 1980).

Recently, new processing and purification methods

have been utilized which make it possible to remove

all organic components from a bovine bone source and

leave a non-organic bone matrix in an unchanged

inorganic form (e.g. Bio-Oss

, Geistlich AG, Wol-

husen, Switzerland; Endobone ", Merck Biomateri-

alen, Darmstadt, Germany; Laddec

, Ost Develop-

ment, Clermont-Ferrand, France; Bon-Apatite

, Bio-

Interfaces Inc., San Diego, US). However, differences

in the purification and manipulation methods of the

bovine bone exist, leading to commercially available

products with different chemical properties and pos-

sibly different biological behavior. These materials are

available in different particle sizes or as block grafts.

To date, no controlled human study has compared

the effect of such graft materials in periodontal defects

with flap surgery alone, but a recent clinical study

demonstrated that implantation of Bio-Oss

resulted

in pocket reduction, gain of attachment and bone fill

in periodontal defects to the same extent as that of

DFDBA (Richardson et al. 1999). Human histology

(

Camelo et al. 1998) and animal experiments (Cler-

geau et al. 1996) have also suggested a beneficial effect

of placing bovine bone-derived biomaterials in peri-

odontal bone defects.

The use of coral skeleton as a bone graft substitute

was proposed some decades ago (Holmes 1979,

Guillemin et al. 1987). Depending on the pre-treat-

ment procedure, the natural coral turns into non-re-

sorbable porous hydroxyapatite (e.g. Interpore 200,

Interpore International, Irvine, US) or to a resorbable

calcium carbonate (e.g. Biocoral, Inoteb, St Gonnery,

France) skeleton (Nasr et al. 1999). Implantation of

coralline porous hydroxyapatite in intrabony peri-

odontal defects in humans produced more probing

pocket depth reduction, clinical attachment gain and

defect fill than non-grafting (Kenney et al. 1985, Krejci

et al. 1987, Yukna 1994, Mora & Ouhayoun 1995,

Yukna & Yukna 1998), and similar results were found

when compared with grafting of FDBA (Barnett et al.

1989). When porous hydroxyapatite was compared

with DFDBA for the treatment of intraosseous defects,

similar results were also obtained (Bowen et al. 1989),

but another study reported clinical results in favor of

this material (Oreamuno et al. 1990). However, both

animal (West & Brustein 1985, Ettel et al. 1989) and

human studies (Carranza et al. 1987, Stahl & Froum

1987) have provided only vague histologic evidence

that grafting of natural coral may enhance the forma-

tion of true new attachment. In most cases, the graft

particles were embedded in connective tissue with

minimal bone formation.

Alloplastic materials

Alloplastic materials are synthetic, inorganic, biocom-

patible and/or bioactive bone graft substitutes which

are claimed to promote bone healing through osteo-

conduction. There are four kinds of alloplastic mate-

rials, which are frequently used in regenerative peri-

odontal surgery: hydroxyapatite (HA), beta tricalcium

phosphate (13-TCP), polymers, and bio-active glasses

(

bio-glasses).

Hydroxyapatite (HA)

The HA products used in periodontology are of two

forms: a particulate non-resorbable ceramic form (e.g.

Periograf

, Miter Inc., Warsaw, IN, US; Calcitite

, Cal-

citek Inc., San Diego, US) and a particulate, resorbable

non-ceramic form (e.g. OsteoGraf/LD

, CeraMed

Dental, Lakewood, CO, US). In controlled clinical

studies, grafting of intrabony periodontal lesions with

HA resulted in a PAL-gain of 1.1-3.3 mm and also in a

greater bone defect fill as compared with non-grafted

surgically debrided controls (Meffert et al. 1985,

Yukna et al. 1985, 1986, 1989, Galgut et al. 1992). In

these studies, improvement of clinical parameters (i.e.

PPD reduction and PAL gain) was more evident in the

grafted sites than in the sites treated only with de-

bridement, especially for initially deep defects. How-

ever, animal studies (Barney et al. 1986, Minabe et al.

1988, Wilson & Low 1992), and human histologic data

(Froum et al. 1982, Moskow & Lubarr 1983, Ganeles et

al. 1986, Sapkos 1986) showed that bone formation

was limited and that a true new attachment was not

formed consistently after grafting of intrabony peri-

odontal defects with HA. The majority of the HA

particles were embedded in connective tissue and new

bone was only observed occasionally around particles

666 • CHAPTER

in close proximity to host bone. A junctional epithe-

lium was lining the major part of the roots.

Beta-tricalcium phosphate ((3-TCP)

b-TCP (Ca

(PO

)

) (e.g. Synthograft

, Johnson and

Johnson, New Brunswick, NJ, US) has been used in a

series of case reports for the treatment of periodontal

osseous lesions (Nery & Lynch 1978, Strub et al. 1979,

Snyder et al. 1984, Baldock et al. 1985). After variable

time intervals, a significant gain of bone was observed

by means of re-entry or radiographs. However, there

no controlled study comparing the result of 13-TCP

grafting with that of open flap debridement, and his-

tologic data from animal (Levin et al. 1974, Barney et

al. 1986) and human studies (Dragoo & Kaldahl 1983,

Baldock et al. 1985, Bowers et al. 1986, Stahl & Froum

1986, Froum & Stahl 1987, Saffar et al. 1990) showed

that 13-TCP is rapidly resorbed or encapsulated by

connective tissue, with minimal bone formation and

no periodontal regeneration.

Polymers

There are two polymer materials that have been used

as bone graft substitutes in the treatment of periodon

tal defects: a non-resorbable, calcium hydroxide coat-

ed co-polymer of poly-methyl-methacrylate (PMMA)

and poly-hydroxylethyl-methacrylate (PHEMA)

which

is often referred to as HTR (hard tissue replace

ment) (

e.g. HTR

, Bioplant Inc., New York, NY, US),

and a

resorbable polylactic acid (PLA) polymer

(Driloc ®,

Osmed Corp., Costa Mesa, CA, US).

In controlled clinical studies, implantation of HTR

polymer grafts in intrabony defects resulted in a defect

fill of approximately 2 mm, representing about 60% of

the initial defect depth, but the improved clinical re-

sponse with grafting was not significantly better than

that following solely flap operation (Yukna 1990,

Shahmiri et al. 1992). Human histologic data from an

experimental study (Plotzke et al. 1993), and from two

case reports (Stahl et al. 1990b, Froum 1996) also re-

vealed that grafting of osseous periodontal defects

with HTR does not promote periodontal regeneration.

The HTR particles were most frequently encapsulated

by connective tissue with only scarce evidence of bone

formation. Healing resulted in a long junctional epi-

thelium along the root surface, and true new attach-

ment formation was not observed.

When PLA particles were implanted into intrabony

defects in humans and compared with DFDBA or

surgically debrided controls, it was found that the

healing results were less favorable than after flap

operation alone, both in terms of clinical parameters

(

PPD and PAL gain), and in terms of bone fill (Mead-

ows et al. 1993).

Bioactive glasses (Bio-glasses)

Bio-glasses are composed of SiO

, Na

O, P

and are

resorbable or not resorbable depending on the relative

proportion of these components. When bio-glasses are

exposed to tissue fluids, a double layer of silica gel and

calcium phosphate is formed on their surface.

Through this layer the material promotes absorption

and concentration of proteins used by osteoblasts to

form extracellular bone matrix which theoretically

may promote bone formation (Hench et al. 1972).

Commercially available bio-glasses in particulate

form, and theoretically resorbable, have been pro-

posed for periodontal treatment (e.g. PerioGlass'j, US

Biomaterials Corp., Alachua, FL, US; BioGran

, Or-

thovita, Malvern, PA, US).

A human case report demonstrated that implanta

tion of bio-glass in periodontal osseous defects re-

sulted in a gain of clinical attachment of 2.0-5.3 mm

and a radiographic bone fill of 3.5 mm, and in a

controlled study, the treatment with bio-glass in in-

trabony defects also resulted in greater clinical im-

provements than surgical debridement alone (Froum

et al. 1998). However, other controlled studies (Zamet

et al. 1997) and split-mouth studies on grafting of

intrabony defects with bio-glass (Ong et al. 1998)

failed to demonstrate statistically significant better

clinical results than surgery alone or DFDBA grafting

(

Lovelace et al. 1998). Although experimental studies

in monkeys have suggested that bio-glass grafting of

periodontal intrabony defects (Karatzas et al. 1999)

may favor new cementum formation and inhibit epi-

thelial down-growth, there is no histological evidence

in humans that bio-glass may promote true periodon

tal regeneration. In a histologic evaluation of bio-glass

implanted in intrabony defects in humans it was ob-

served that although clinically satisfactory results

were produced, healing had most frequently occurred

with a junctional epithelium along the previously dis

eased part of the root, and new cementum with insert

ing collagen fibers was found in only one out of five

treated teeth. Bone formation was limited in all speci

mens (Nevins et al. 2000).

Evaluation of alloplastic materials

There are no controlled clinical studies demonstrating

that grafting with tricalcium phosphate or polymers

results in significant clinical improvements beyond

that of flap surgery, whereas several reports have

indicated that grafting with hydroxyapatite or bio-ac-

tive glasses may produce more gain of attachment

than open flap debridement (Galgut et al. 1992, Zamet

et al. 1997, Froum et al. 1998) or a gain similar to that

obtained following grafting with DFDBA (Lovelace et

al. 1998). Histologic evidence that the use of alloplastic

or synthetic graft materials may lead to periodontal

regeneration in humans is lacking, and animal experi

ments have failed to demonstrate regeneration of a

functional periodontium following implantation of

hydroxyapatite, tricalcium phosphate or polymers in

periodontal lesions (Barney et al. 1986, Shahmiri et al.

1992). It was reported, however, that treatment with

bio-active glasses in experimental animals produced

significantly more bone fill and new attachment com

pared with that in non-grafted controls (Fetner et al.

1994, Karatzas et al. 1999) or in sites grafted with

REGENERATIVE PERIODONTAL THERAPY •

667

hydroxyapatite or tricalcium phosphate (Wilson &

Low 1992). Although some bone formation has been

reported following the use of alloplastic materials,

there is no evidence that these materials may stimulate

the formation of new cementum with inserting colla-

gen fibers. At the 1996 American Academy of Perio-

dontology World Workshop, it was concluded that

synthetic graft materials function primarily as defect

fillers. If regeneration is the desired treatment out-

come, other materials are recommended.

Biologic concept of using bone grafts or alloplastic

materials

The biologic rationale behind the use of bone grafts or

alloplastic materials in periodontal regenerative sur-

gery is the assumption that these materials may either

(1) contain bone forming cells (osteogenesis), (2) serve

as a scaffold for bone formation (osteoconduction), or

that (3) the matrix of the grafting material contains

bone inductive substances (osteoinduction). It is be-

lieved that the use of such materials may stimulate not

only the regrowth of alveolar bone but also the forma-

tion of new attachment. However, such complete re-

generation of the periodontal attachment apparatus

following such grafting procedures would imply that

cells derived from bone would possess the ability to

form new cementum with inserting collagen fibers on

a previously periodontitis-affected root surface. This

assumption is in conflict with current knowledge

about the biology of periodontal wound healing, that

repopulation of the detached root surface with cells

from the periodontal ligament is the prerequisite for

new attachment formation. This means that all thera

peutic procedures involving the placement of bone

grafts or bone substitute implants are based on a

biologic concept which cannot explain how such treat

ment should result in regeneration of the periodon-

tium.

Root surface biomodification

Much research has been directed to altering the peri-

odontitis-involved root surface in a manner that will

promote the formation of a new connective tissue

attachment. Removal of bacterial deposits, calculus

and endotoxins in the cementum is generally consid-

ered essential for the formation of a new connective

attachment (Garrett 1977). However, it was suggested

by Stahl et al. (1972) that demineralization of the root

surface, exposing the collagen of the dentin, would

facilitate the deposition of cementum by inducing

mesenchymal cells in the adjacent tissue to differenti

ate into cementoblasts. The biologic concept is that

exposure of collagen fibers of the dentin matrix may

facilitate adhesion of the blood clot to the root surface

and thereby favor migration of the fibroblasts.

Several studies using various animal models dem-

onstrated an improved healing response histologi-

cally following citric acid and tetracycline root surface

demineralization (Register & Burdick 1976, Crigger et

al. 1978, Polson & Proye 1982, Claffey et al. 1987).

However, in a study in dogs where naturally occur-

ring furcations were treated with citric acid, several

specimens demonstrated ankylosis and root resorp-

tion (Bogle et al. 1981). This finding corroborates that

of Magnusson et al. (1985a) in monkeys where citric

acid conditioning was evaluated in combination with

coronally displaced tissue flaps after 6 months. These

investigators found root resorption on 28 out of 40

surfaces examined and 21 of these also presented

ankylosis.

New connective tissue attachment following citric

acid demineralization of root surfaces has been dem-

onstrated histologically in humans (Cole et al. 1980,

Frank et al. 1983, Stahl et al. 1983, Stahl & Froum

1991a). Cole et al. (1980) showed histologic evidence

of a new connective tissue attachment and bone for-

mation coronal to reference notches placed in the api

cal extent of calculus, identified on the root surface at

the time of surgery. However, despite histologic evi-

dence of regeneration following root surface biomodi-

fication with citric acid, results of controlled clinical

trials failed to show any improvements in clinical

conditions compared to non-acid treated controls

(

Moore et al. 1987, Fuentes et al. 1993).

In recent years, biomodification of the root surface

with enamel matrix proteins (Emdogain

) during sur-

gery and following demineralization with EDTA has

been introduced to encourage periodontal regenera-

tion. The biologic concept is that the application of

enamel matrix (amelogenins) proteins may promote

periodontal regeneration because it mimics events

that took place during the development of the peri-

odontal tissues (Hammarstrom 1997, Gestrelius et al.

2000). This view is based on the finding that the cells

of the Hertwigs epithelial root sheath deposit enamel

matrix proteins on the root surface prior to cementum

formation and that such proteins are the initiating

factor for the formation of cementum. The commer-

cially available product, Emdogain ", a purified acid

extract of porcine origin contains enamel matrix de-

rivatives (EMD), supposed to be able to promote peri-

odontal regeneration. In case series reports, 4-4.5 mm

gain of clinical attachment, and about 70% bone fill in

intrabony defects were reported following treatment

with EMD (Heden et al. 1999, Heden 2000).

In a multicenter clinical study involving 33 subjects

with 34 paired intrabony defects, application of EMD

resulted in larger amounts of PAL-gain (2.2 mm) and

statistically significantly more bone gain (2.6 mm)

than open flap debridement after 36 months, evalu-

ated clinically and radiographically (Heijl et al. 1997).

Similar results were reported in another split-mouth

clinical trial (23 patients) published more recently (

Froum et al. 2001). In that study a PPD reduction of

4.9 mm, a PAL gain of 4.3, and a bone gain of 3.8 mm

(evaluated by re-entry surgery) were observed after

EMD application in 53 intrabony defects. These values

were statistically significantly larger than those ob-

668 • CHAPTER 28

Fig. 28-20. Photomicrograph (a) of a degree III furcation defect in a dog following root surface biomodification with

enamel matrix proteins and subsequently covered with a resorbable membrane. The defect has healed completely

with bone (NB), a periodontal ligament (p) and new cementum (NC). The arrows indicate the apical extension of

the lesion. (b) The cementum (NAC) formed on the root surface in the apical portion of the defect was acellular

with inserting extrinsic collagen fibers (ECF) while (c) that (NCC) formed in the coronal portion had a cellular (cc)

character.

tained by flap surgery (2.2 mm, 2.7 mm and 1.5 mm,

respectively, in 31 defects).

In a more recent prospective multicenter random-

ized controlled clinical trial, the clinical outcomes of

papilla preservation flap surgery (simplified papilla

preservation flap, SPPF) with or without the applica-

tion of enamel matrix proteins, were compared (Ton-

etti et al. 2002). A total of 83 test and 83 control patients

with similar baseline periodontal conditions and de-

fect characteristics were treated with either SPPF and

Emdogain" or with SPPF alone. The test defects exhib

ited significantly more CAL gain than the controls (3.1

± 1.5 mm and 2.5 ± 1.5 mm, respectively). In addition,

this study demonstrated that the treatment outcomes

of the test group were significantly affected by the

smoking status of the patient and the number of walls

of the intrabony defect. Smokers gained less attach-

ment than non-smokers. Defects with very dense cor-

tical or very porous and bleeding walls gained less

CAL than normal corticalized defects, and intrabony

defects with three walls had a higher predictability in

CAL gains than those with one-wall.

Similar results were also reported in other control-

led studies (Pontoriero et al. 1999, Silvestri et al. 2000).

When application of EMD was compared with GTR

treatment, it was found that similar clinical improve-

ments were obtained. In a randomized controlled

clinical study, Pontoriero et al. (1999) compared EMD

application with GTR with resorbable (two kinds:

Guidor and Resolut) and non-resorbable (e-PTFE)

membranes in intrabony defects (10 patients per

group). After 12 months, there were no significant

differences among the groups, and EMD application

resulted in a PPD reduction of 4.4 mm and a PAL gain

of 2.9 mm, while the corresponding values from the

membrane-treated sites (all GTR groups combined)

were 4.5 mm and 3.1 mm, respectively (Pontorierio et

al. 1999). Silvestri et al. (2000) reported a PPD reduc

tion of 4.8 mm and a PAL gain of 4.5 mm after EMD

application in intrabony defects versus 5.9 mm and 4.8

mm, respectively, after GTR with non-resorbable

membranes (randomized controlled study, 10 patients

per group). Similar results were reported by Sculean

et al. (1999a,b).

Histologic evidence of new cementum formation

with inserting collagen fibers on a previously perio-

dontitis-affected root surface and the formation of

new alveolar bone in human specimens have been

demonstrated following EMD treatment (Mellonig

1999, Sculean et al. 1999b). However, while in the

study of Mellonig (1999) healing had occurred with

acellular cementum on the root surface, the newly

formed cementum in the study of Sculean et al. (1999b)

displayed a predominantly cellular character. The

ability of EMD to produce regeneration has been con

firmed in controlled animal experiments (Fig. 28-20),

following the treatment of intrabony, furcation and

dehiscence defects (Hammarstrom et al. 1997, Araujo

& Lindhe 1998, Sculean et al. 2000).

Further research is needed to elucidate the function

of EMD and the predictability of this regenerative

periodontal procedure.

Growth regulatory factors for periodontal

regeneration

Growth factor is a general term to denote a class of

polypeptide hormones that stimulate a wide variety

of cellular events such as proliferation, chemotaxis,

REGENERATIVE PERIODONTAL THERAPY •

669

differentiation and production of extracellular matrix

proteins (Terranova & Wikesjo 1987). Proliferation

and migration of periodontal ligament cells and syn-

thesis of extracellular matrix as well as differentiation

of cementoblasts and osteoblasts is a prerequisite for

obtaining periodontal regeneration. Therefore, it is

conceivable that growth factors may represent a po-

tential aid in attempts to regenerate the periodontium.

The effects of various growth factors were studied in

vitro, and a significant regeneration potential of

growth factors was also demonstrated in animal mod

els. Lynch et al. (1989, 1991) examined the effect of

placing a combination of platelet derived growth fac-

tors (PDGF) and insulin-like growth factors (IGF) in

naturally occurring periodontal defects in dogs. The

control sites treated without growth factors healed

with a long junctional epithelium and no new cemen-

tum or bone formation, while regeneration of a peri-

odontal attachment apparatus occurred at the sites

treated with growth factors. Similar results were re-

ported by other investigators following application of a

combination of PDGF and IGF in experimentally-in-

duced periodontal lesions in monkeys (Rutherford et

al. 1992, Giannobile et al. 1994, 1996). One study ex

amined the effect of PDGF and IGF in periodontal

intrabony defects and degree II furcations in humans

(

Howell et al. 1997). At re-entry after 9 months, signifi

cantly increased bone fill was only observed at the

furcation sites treated with growth factors. It can be

concluded that growth factors seem to have a positive

effect on periodontal regeneration, but several impor-

tant questions need to be resolved before this type of

regenerative treatment can be used in humans (Graves

& Cochran 1994).

Bone morphogenetic proteins (BMPs) are osteoin-

ductive factors that may have the potential to stimu-

late mesenchymal cells to differentiate into bone-

forming cells (Wozney et al. 1988). Sigurdsson et al.

(

1995) evaluated bone and cementum formation fol-

lowing regenerative periodontal surgery using re-

combinant human BMP in surgically-created supra-

alveolar defects in dogs. Following application of

BMP the flaps were advanced to submerge the teeth

and sutured. Histologic analysis showed significantly

more cementum formation and regrowth of alveolar

bone on BMP treated sites as compared to the controls.

Ripamonti et al. (1994) also reported about the efficacy

of bovine BMPs to induce periodontal regeneration in

degree II furcations in baboons. On one side BMP was

implanted with a collagenous matrix, while at the

control sites only the collagen matrix was used. Con-

siderable regeneration of cementum, periodontal liga-

ment and bone was observed in the BMP treated

furcations as compared to the control furcations

treated without BMP. Further experimentation is

needed to evaluate a possible role of BMP in periodon

tal regeneration.

GUIDED TISSUE REGENERATION

(GTR)

The experimental studies (Karring et al. 1980, Nyman

et al. 1980, Buser et al. 1990a,b, Warrer et al. 1993)

described previously have documented that the pro-

genitor cells for the formation of a new connective

tissue attachment are residing in the periodontal liga

ment. Consequently, it should be expected that a new

connective tissue attachment would be predictably

achieved if such cells populate the root surface during

healing. This view was confirmed in a study in mon-

keys in which both gingival connective tissue and

gingival epithelium were prevented from contacting

the root surface during healing by the use of a barrier

membrane (Gottlow et al. 1984). After reduction of the

supporting tissues around selected experimental

teeth, the root surfaces were exposed to plaque accu-

mulation for 6 months. Soft tissue flaps were then

raised and the exposed root surfaces were curetted.

The crowns of the teeth were resected and the roots

were submerged. However, prior to complete closure

of the wound, a membrane was placed over the curet

ted root surfaces on one side of the jaws in order (1) to

prevent gingival connective tissue contacting the root

surface during healing, and (2) to provide a space for

ingrowth of periodontal ligament tissue. No mem-

branes were placed over the contralateral roots. The

histologic analysis after 3 months of healing demon-

strated that the roots covered with membranes exhib

ited considerably more new attachment than the non

covered roots (Fig. 28-21). In four of the nine test roots,

new cementum covered the entire length of the root.

In all control specimens the surface coronal to the

newly formed cementum presented multinucleated

cells and resorption cavities. In one control specimen

virtually half the root was resorbed. Coronal regrowth

of alveolar bone had occurred to a varying extent in

test and control roots, and no relationship was found

between the amount of new cementum formation and

the degree of bone regrowth. The results of this study

strongly suggested that the exclusion of epithelial and

gingival connective tissue cells from the healing area

by the use of a physical barrier may allow (guide)

periodontal ligament cells to repopulate the detached

root surface. This observation provided the basis for

the clinical application of the treatment principle

termed "guided tissue regeneration" (GTR).

Clinical application of GTR

Clinical application of guided tissue regeneration

(

GTR) in periodontal therapy involves the placement

a physical barrier to ensure that the previous peri-

odontitis-affected root surface becomes repopulated

with cells from the periodontal ligament (Fig. 28-22).

Treatment of the first human tooth with GTR was

reported by Nyman et al. in 1982. Due to extensive

670 • CHAPTER 28

Fig. 28-21. (a) Microphotograph of membrane (M) covered root. Newly formed cementum is visible on the entire

length of the buccal root surface coronal to the notch (N) and also on part of the coronal cut surface (arrow). (b, c)

Higher magnifications of the areas at the upper and lower triangles in (a), showing that collagen fibers are inserted

into the newly formed cementum. AR: artifact.

Fig. 28-22. Drawing illustrating the placement of the

physical barrier which prevents the epithelium and gin

gival connective tissue from contacting the root surface

during healing. At the same time the membrane allows

cells from the periodontal ligament (arrow) to repopu-

late the previously periodontitis-involved root surface.

periodontal destruction, the tooth was scheduled for

extraction. This offered the possibility of obtaining

histologic documentation of the result of the treat

ment.

Following elevation of full thickness flaps, scal

ing of

the root surface and removal of all granulation

tissue, an

11 mm deep periodontal lesion was ascertained. Prior

to flap closure, a membrane was adjusted to cover parts

of the detached root surfaces, the osse

ous defect and

parts of the surrounding bone. His-

tologic analysis after 3 months of healing revealed that

new cementum with inserting collagen fibers had

formed on the previously exposed root surface (Fig.

28-

23). In a later study (Gottlow et al. 1986), 12 cases

treated with GTR were evaluated clinically, and in five

these cases histologic documentation was also pre-

sented. The results showed that considerable but

varying amounts of new connective tissue attachment

had formed on the treated teeth. Frequently, however,

REGENERATIVE PERIODONTAL THERAPY • 671

Fig. 28-23. Microphotograph of a

human tooth (a) 3 months follow-

ing GTR treatment using a Mil-

lipore filter (F). New cementum

with inserting collagen fibers

(

about 5 mm) has formed from the

notch (N) to the level of the arrow.

Bone formation underneath the fil

ter is lacking, probably due to the

inflammatory infiltrate seen in the

tissues adjacent to the filter. (b)

Higher magnification of the area

indicated by the arrowhead in (a)

showing newly formed cementum

with inserting collagen fibers. AR:

artifact.

bone formation was incomplete. The varying results

were ascribed to factors such as the amount of remain

ing periodontal ligament, the morphology of the

treated defect, technical difficulties regarding mem-

brane placement, gingival recession and bacterial con

tamination of the membrane and the wound during

healing.

In the last decades, GTR has been applied in a

number of clinical trials for the treatment of various

periodontal defects such as intrabony defects (for re-

view see Cortellini & Bowers 1995), furcation involve-

ments (for review see Machtei & Schallhorn 1995,

Karring & Cortellini 1999), and localized gingival re-

cession defects (Pini-Prato et al. 1996).

The clinical outcomes of GTR are most frequently

evaluated by changes in clinical attachment levels

(

CAL), bone levels (BL), probing pocket depths (PPD),

and the position of the gingival margin. In some of the

studies on degree II and III furcations, horizontal

changes in clinical attachment, bone level and pocket

depth were also measured. As previously pointed out,

evidence of true regeneration of periodontal attach-

ment can only be provided by histologic means. How-

ever, based on reports about the formation of a new

attachment apparatus in histologic specimens from

human biopsies harvested following GTR treatment (

Nyman et al. 1982, Gottlow et al. 1986, Becker et al.

1987, Stahl et al. 1990a, Cortellini et al. 1993a) and

based on the biologic concept of GTR (Karring et al.

1980, 1985, 1993, Nyman et al. 1980, Gottlow et al.

1984), it was suggested that clinical signs of probing

attachment gain and bone fill can be accepted as evi-

dence of periodontal regeneration in the evaluation of

GTR procedures (Lindhe & Echeverria 1994).

Procedural

guidelines

GTR is not a procedure for the treatment of periodon-

titis, but rather a technique for regenerating defects

which have developed as a result of periodontitis.

Therefore, appropriate periodontal treatment should

always be completed before GTR is initiated.

Surgery is initiated by sulcular or marginal inci-

sions at both the buccal and lingual aspect of the jaw,

followed by buccal and vertical releasing incisions.

The releasing incisions must be placed a minimum of

one tooth anterior and/or posterior to the tooth that

is being treated (Fig. 28-24). Care should be taken

during this procedure to preserve the interdental pa-

pillae. All pocket epithelium is excised so that a fresh

connective tissue is left on the full thickness flaps

following reflection. After elevation of the tissue flaps,

all granulation tissue is removed and thorough de-

bridement of the detached root surfaces is carried out

using curettes, burs, etc.

Various types of bioabsorbable and non-bioabsor-

bable barrier materials are available in a variety of

configurations designed for specific applications. The

configuration most suitable for covering the defect is

selected and additional tailoring of the material is

performed. The shaping of the material is carried out

in such a way that it is adapting closely to the tooth

and is completely covering the defect, extending at

least 3 mm on the bone beyond the defect margins

after placement (Fig. 28-25). This assures a good sta-

bility of the material and protects the underlying

blood clot during healing. At placement it is essential

to ensure good adaptation of the barrier material to

the alveolar bone surrounding the defect and to avoid

overlaps or folds of the material.

Although exceptions exist, the barrier materials

available are fixed to the tooth with a suture using a

672 • CHAPTER 28

Fig. 28-24. Following marginal incisions and vertical re-

leasing incisions on the buccal aspect of the jaw, buccal

and lingual full thickness flaps are elevated.

Fig. 28-25. The barrier material is placed in such a way

that it completely covers the defect and extends at least

mm on the bone beyond the defect margin.

Fig. 28-26. The elevated tissue flaps are coronally dis-

placed and sutured in such

a way

that the border of

the barrier material is at least 2 mm below the flap mar-

gin.

Fig. 28-27. In order to remove the barrier material an in

cision is made extending one tooth mesially and dis

tally

to the border of the barrier. After reflecting the

covering

tissue flaps, the barrier can be removed with-out

compromising the newly regenerated tissue.

REGENERATIVE PERIODONTAL THERAPY •

673

sling technique. For optimal performance, the barrier

should be placed with its margin 2-3 mm apically to

the flap margin. To maximize coverage of the barrier,

a horizontal releasing incision in the periosteum may

assist in the coronal displacement of the flap at the

suturing of the wound. However, care should be taken

not to compromise the blood supply to the flap. The

interproximal space near the barrier should be closed

first. In order to achieve good closure, a vertical mat-

tress suturing technique is advocated (Fig. 28-26).

To reduce the risk of infection and to assure optimal

healing, the patient should be instructed to gently

brush the area postoperatively with a soft bristle

toothbrush and to rinse with chlorhexidine (0.2%) for

period of 4-6 weeks. In addition, systemic antibiotics

are frequently administered immediately prior to sur-

gery and during 1-2 weeks after surgery. When a

non-bioabsorbable barrier is used, it should be re-

moved after 4-6 weeks. However, if complications

develop it may be necessary to remove it earlier.

Removal of the material requires a minor surgical

procedure (Fig. 28-27). To obtain access to the barrier

material, a small incision is made extending one tooth

mesially and distally of the border of the barrier. The

soft tissue flap is gently reflected and the barrier ma-

terial dissected free from the flap using a sharp blade.

During this procedure it is essential not to compro-

mise the newly regenerated tissue. At removal of the

barrier material there will usually be some pocket

formation on the outer surface of the material. It is

important that this epithelium is removed so that fresh

connective tissue is in contact with the newly regen-

erated tissue after wound closure. It is essential that

the newly regenerated tissue is completely covered

after suturing. The patient is instructed to rinse with

chlorhexidine for 2-3 weeks during which period fre-

quent visits for professional tooth cleaning are recom

mended. After this period, brushing and interproxi-

mal cleaning can be resumed, chlorhexidine rinsing

discontinued, and the patient enrolled in a regular

periodontal maintenance program.

If the flap is excessively traumatized during sur-

gery either part or all of it may slough during healing.

Perforations may also occur, particularly in sites with

sharp bony ledges. A minor osteoplasty during place-

ment may help to allow the barrier to better follow the

contours of the ridge. Abscess formation may also

occur in the wound, probably due to severe bacterial

contamination of the barrier. Dependent on the sever

ity of such complications, early removal of the barrier

may be indicated.

Barrier materials for

regenerative surgery

the first GTR attempts, a bacterial filter produced

from cellulose acetate (Millipore

) was used as an

occlusive membrane (Nyman et al. 1982, Gottlow et

al. 1984, Magnusson et al. 1985h). Although this type

of membrane served its purpose, it was not ideal for

clinical application. Later studies have utilized mem-

branes of expanded polytetrafluoroethylene (e-PTFE)

especially designed for periodontal regeneration

(Gore

Tex Periodontal Material

). The basic molecule

of this

material consists of a carbon-carbon bond with

four

attached fluorine atoms to form a polymer. It is

inert

and does not result in any tissue reaction when

implanted in the body. This type of membrane persists

after healing and must be removed in a second opera

tion. Membranes of e-PTFE have been used success-

fully in animal experiments and in several clinical

studies. It was experienced from such studies that in

order for a barrier material to function optimally, it has

to meet certain essential design criteria:

To allow for good tissue acceptance it is important

that the material is biocompatible. The material

should not elicit an immune response, sensitization

or chronic inflammation which may interfere with

healing and present a hazard to the patient. Bio-

compatibility however, is a relative term since prac

tically no materials are completely inert.

The material should act as a barrier to exclude

undesirable cell types from entering the secluded

space adjacent to the root surface. It is also consid

ered an advantage that the material would allow

the passage of nutrients and gases.

Tissue integration is another important property of

a barrier material. Thus, tissue may grow into the

material without penetrating all the way through.

The goal of tissue integration is to prevent rapid

epithelial downgrowth on the outer surface of the

material or encapsulation of the material, and to

provide stability to the overlying flap. The impor-

tance of tissue integration was demonstrated in a

study in monkeys (Warrer et al. 1992) in which

bioabsorbable membranes of polylactic acid, a syn-

thetic polymer, were used for treatment of circum-

ferential periodontal defects. Due to the lack of

tissue integration, the membranes in this study

became surrounded by an epithelial layer and were

often encapsulated and exfoliated.

It is also essential that the barrier material is

capable

of creating and maintaining a space

adjacent to the

root surface. This will allow the

ingrowth of tissue

from the periodontal ligament.

Some materials may be so soft and flexible that

they collapse into the defect. Other materials are

too stiff and may

perforate the overlying tissue.

Finally, there are clinical needs in the design of a

barrier. It should be provided in configurations

which are easy to trim and to place.

Bioabsorbable materials

In recent years, natural or synthetic bioabsorbable

barrier materials for GTR have been introduced in

order to avoid a second surgery for membrane re-

moval. Barrier materials of collagen from different

species and from different anatomical sites have been

tested in animals and in humans (Blumenthal 1988,

1993, Pitaru et al. 1988, Tanner et al. 1988, Paul et al.

1992, Wang et al. 1994, Camelo et al. 1998, Mellonig

674 • CHAPTER

2000). Often the collagen used is a cross-linked variety

of porcine or bovine origin. When a collagen mem-

brane is implanted in the human body it is resorbed

by the enzymatic activity of macrophages and poly-

morphnuclear leucocytes (Tatakis et al. 1999). Success

ful treatment following the use of such barrier mate-

rials has been demonstrated, but the results of the

studies vary. Several complications such as early deg

radation, epithelial downgrowth along the material

and premature loss of the material were reported

following the use of collagen materials. The varying

results are probably due to differences in the proper-

ties of the material and the handling of the material at

the time of implantation. Although probably very

minimal, there is a risk that infectious agents from

animal products can be transmitted to humans, and

autoimmunization has also been mentioned as a risk.

Barrier materials of polylactic acid or copolymers

of polylactic acid and polyglycolic acid were evalu-

ated in animal and human studies and are commonly

used (Magnusson et al. 1988, Caffesse et al. 1994,

Caton et al. 1994, Gottlow et al. 1994, Laurell et al. 1994,

Hugoson et al. 1995, Poison et al. 1995a, Hiirzeler et

al. 1997, Sculean et al. 1999a). These materials are

biocompatible, but by definition they are not inert

since some tissue reaction may be expected during

degradation. The materials are degradated by hy-

drolysis and eliminated from the organism through

the Krebs cycle as carbon dioxide and water (Tatakis

et al. 1999).

The types of barrier materials tested in the studies

differ regarding configuration and design. It appears

that a number of bioabsorbable materials to a varying

extent meet the requirements of a good barrier listed

above. Indeed, there are several studies (Hugoson et

al. 1995, Cortellini et al. 1996b, Smith et al. 1998, Tonetti

et al. 1998, Cortellini & Tonetti 2000a) indicating that

similar satisfactory results can be obtained with bioab

sorbable barrier materials of polylactic and polygly-

colic acid as with non-bioabsorbable materials.

Intrabony defects

Early evidence that GTR treatment of deep intrabony

defects may produce clinical improvements in terms

of clinical attachment gain was presented in several

case reports (Nyman et al. 1982, Gottlow et al. 1986,

Becker et al. 1988, Schallhorn & McClain 1988, Cortel

lini et al. 1990). In recent years, a number of clinical

investigations have reported on a total of 1283 in-

trabony defects treated with GTR (Table 28-1). In these

studies, the issue of evaluating the predictability of the

clinical outcomes following application of GTR proce-

dures was addressed. The weighted mean of the re-

ported results indicates a mean gain in clinical attach

ment of 3.8 ± 1.7 mm, with a 95% confidence interval

ranging from 3.7 to 4.0 mm (Cortellini & Tonetti

2000a). The reported clinical attachment gains follow-

ing GTR treatment were significantly larger than the

ones obtained from conventional flap surgery. A re-

cent review (Lang 2000) on flap surgery reported a

weighted mean of 1.172 defects in 40 studies. CAL

gains were 1.8 ± 1.4 mm, with a 95% confidence inter

val ranging from 1.6 to 1.9 mm.

Different types of non-bioabsorbable (Fig. 28-28)

and bioabsorbable (Fig. 28-29) barrier materials were

used in the studies summarized in Table 28-1. A subset

analysis indicated that cases treated with non-bioab-

sorbable barrier materials (351 defects) showed a

mean gain in clinical attachment of 3.7± 1.7 mm which

did not differ from that obtained with bioabsorbable

barrier materials of 3.6 ± 1.5 mm (592 defects).

Analysis of the results reported in some of the

studies in Table 28-1 (i.e. 211 defects in 9 investiga-

tions; Proestakis et al. 1992, Cortellini et al. 1993b,

1995c, 1996b, Cortellini & Pini-Prato 1994, Laurell et

al. 1994, Mattson et al. 1995, Mellado et al. 1995, Tonetti

et al. 1996b) provides important information regard-

ing the predictability of GTR in intrabony defects.

Gains of 2-3 mm were observed in 29.2% of the defects,

gains of 4-5 mm in 35.4% of the defects, and gains of

6 mm or more in 24.9% of the defects. Only in 10.5%

of the treated defects was the gain less than 2 mm,

while no change or attachment loss was observed in

two cases.

In some of the investigations, changes in bone lev-

els were also reported (Becker et al. 1988, Handelsman

et al. 1991, Kersten et al. 1992, Cortellini et al. 1993b,c,

Selvig et al. 1993). Bone gains ranged between 1.1 and

4.3 mm and correlated with the reported gains in

clinical attachment. In a study by Tonetti et al. (1993b),

1 year after GTR the bone was found to be located 1.5

mm apically to the position of the attained clinical

attachment level.

Another important parameter related to the out-

come of regenerative procedures is the residual pocket

depth. hl the studies reported in Table 28-1, shallow

pockets were consistently found at 1 year. The

weighted mean of residual pocket depth was 3.4 ± 1.2

mm, with a 95% CI ranging from 2.3 to 3.5 mm.

The reported outcomes indicate that GTR proce-

dures predictably result in clinical improvements in

intrabony defects beyond that of flap surgery. This

was further confirmed in 11 controlled randomized

clinical trials in which guided tissue regeneration was

compared with conventional flap surgery (Table 28-2).

A total of 267 defects were treated with flap surgery

and 317 with GTR. In 9 of the 11 investigations, GTR

resulted in statistically significantly greater probing

attachment level gains when compared to flap sur-

gery. Similar results were also observed for residual

pocket depth. It should be emphasized that one of the

investigations reporting no significant differences be-

tween GTR and flap surgery was carried out in only 9

pairs of defects (18 defects) located on maxillary pre-

molars (Proestakis et al. 1992). In this study the in-

trabony component of the defects was shallow and 10

of the 18 defects had a furcation invol

ement. The

weighted mean of the results reported in the 11 studies

listed in Table 28-2 (Cortellini & Tonetti 2000a) indi-

cated that the gain in clinical attachment in sites