744

Periodontal Therapy: Prospects for

the Future*
Roy C. Page

Prior to the 1950s, Periodontitis was treated mostly by tooth exfoliation or ex-
traction, and that is still the predominant treatment for most of the world's populations
today. Debridement of the root surface by scaling and root planing came into relatively
common use in the first half of the present century and has become the central feature
held in common by all currently-used forms of periodontal therapy. Until the 1980s, the
most commonly-used treatment consisted of scaling and root planing, followed by re-
sective surgery aimed at achieving zero pocket depth. During the 1980s, data were
obtained demonstrating that the thoroughness of root debridement and subgingival in-
fection control, not the presence or absence or periodontal pockets, is the major deter-
minant of successful periodontal therapy, and non-surgical therapy became a commonly-
used treatment. Neither resective surgery nor non-surgical therapy results in significant
regeneration of periodontal attachment. With the realization that Periodontitis is an in-
fectious process, the use of antibiotics and other anti-infective agents came into common
use as adjuncts to other standard therapies. An understanding of the pathways by which
the soft and calcified tissues of the periodontium are destroyed has led to the likelihood
of widespread future use of the non-steroidal, anti-inflammatory family of drugs to
suppress alveolar bone destruction by blocking Prostaglandin production, and to the use
of chemically-modified tetracyclines that chelate divalent cations and thereby block tissue
destruction by the metalloproteinases. Recent data clearly show that regeneration of the
previously-destroyed periodontal attachment tissues is biologically possible, and regen-
eration has become the goal of therapy for the 1990s. Use of osteoconductive and os-
teoinductive graft materials can, under favorable conditions, induce roughly 60% to 70%
regeneration of bone lesion height or volume with concomitant improvement in the
clinical conditions. Regeneration by grafting may be further enhanced by use of barrier
membranes that exclude gingival fibroblasts and epithelium from the healing site. Still
further enhancement seems to be possible by local application of various growth factors,
although studies in this important area are now only in their infancy. The future of
periodontal therapy is exceedingly bright. It seems likely that we may be able to achieve
nearly complete regeneration of periodontal attachment at many, although not all, sites
through the use of root debridement and anti-infective and anti-inflammatory drugs and
agents that inhibit metalloproteinases to arrest progress of disease and resolve the in-
flammatory process, followed by the combined use of graft material, barrier membranes,
and growth factors to induce regeneration of periodontal attachment tissues. J Periodontol
1993; 64:744-753.
Key Words: Grafts/surgery; periodontal diseases/therapy; periodontal attachment; mem-
branes, barrier; forecasting.

Periodontal disease has plagued mankind since his first ap-
pearance on the earth. Bone lesions typical of Periodontitis
are present in fossils from the paleolithic culture of Nean-
derthal man. Periodontal diseases were described in ancient
Chinese writings, and a form of suppurating Periodontitis
'Research Center in Oral Biology, Health Sciences Center, University of
Washington, Seattle,WA.
appears to have been one of the most common diseases of
the Egyptians more than 4,000 years ago.1 During these
millennia, the only form of treatment was spontaneous tooth
exfoliation or extraction. This form of treatment predomi-
nated throughout the world until the middle of the present
century, and still persists today for most of the world's
populations.
The first efforts to preserve periodontally-diseased teeth
Volume 64
Number 8
by treatment appears to have been the use of root debride-
ment. Roughly 1,000 years ago, Albucasis wrote:
Sometime on the surface of the teeth, both inside and
outside, as well as under the gums, are deposited
rough scales, of ugly appearance, and black, green
or yellow in colour; thus corruption is communicated
to the gums, and so the teeth are in the process of
time denuded. It is necessary for thee to lay the pa-
tient's head upon thy lap and to scrape the teeth and
molars, on which are observed these incrustations, or
something similar to sand, and this until nothing more
remains of such substances.1
Thus, even though there existed some understanding of the
potential benefits of removal of calcified deposits from the
crowns and roots for the next several centuries such treat-
ment appears to have been rarely performed and affected
teeth continued to be exfoliated or extracted. By the 1860s
and 1870s a treatment combining some sort of surgical in-
tervention with removal of tooth deposits had been devel-
oped by Dr. J.M. Riggs.2 This treatment became so popular
that for a time Periodontitis became known as Riggs' dis-
ease. Nevertheless, this treatment disappeared from use after
a few years. By the turn of the 20th Century, the idea that
calculus was a mechanical irritant had become firmly
embedded in dental dogma, and calculus removal by scaling
and root planing was commonly practiced.
RESECTIVE THERAPY
The modern era of periodontal therapy in the United States
began roughly 40 years ago with the publication in 1949
of a paper by Schluger describing the basic principles of
surgical pocket elimination and osseous surgery.3 From the
1950s through the 1970s, highly sophisticated surgical tech-
niques were developed and surgical pocket elimination be-
came the treatment of choice for Periodontitis. To perform
resective therapy, mucoperiosteal flaps were elevated, the
root surfaces thoroughly debrided, and the marginal bone
resected to reestablish normal contours. The goal was to
establish a healthy periodontium but at a level more apical
than normal (Fig. 1). The sine qua non of successful peri-
odontal therapy became the achievement and maintenance
of zero pocket depth; by the 1970s resective periodontal
therapy had reached its zenith. Throughout this period, root
debridement remained a central component of therapy.
ANTIMICROBIAL THERAPY
By the 1960s and 1970s the infectious nature of Periodon-
titis had become apparent and this new knowledge led to
new approaches to therapy. For the first time, we realized
that root deposits were important in the etiology of peri-
odontal disease, not because of mechanical irritation but
rather because of their microbial content. These observa-
tions led to intensified efforts to achieve impeccable oral
hygiene and to the gradual introduction of antimicrobial
therapy, specifically the systemic use of antibiotics as an
PAGE 745
Figure 1. The results of treatment of a deep periodontalpocket containing
pathogenic microbial plaque by thorough debridement of the root and
crown surfaces, followed by resective therapy aimed at elimination of the
pocket and establishment of a normal attachment at a more apical level.
adjunct to other standard forms of therapy. Currently the
use of antibiotics is being greatly extended through devel-
opment of slow-release devices placed directly in the peri-
odontal pocket which maintain extremely high drug con-
centration for 1 to 2 weeks at the local site.4 6 Thus, while
mechanical debridement with or without various surgical
manipulations had been our only therapy for centuries, the
use of antimicrobial drugs now provided a chemotherapy
aimed directly at elimination of the pathogenic bacteria
present in the periodontal pocket and tissues. Additionally,
there is a rapidly growing body of evidence indicating that
antibiotics and combinations of antibiotics, especially
amoxicillin or doxycycline and metronidazole may be ef-
fective in controlling the progression of periodontal destruc-
tion in cases that do not respond to other standard forms of
therapy.7"11
NON-SURGICAL THERAPY
By the late 1970s and early 1980s, some clinicians and
investigators began to suspect that pocket elimination was
not essential to the success of periodontal therapy; that con-
trol of subgingival infection was sufficient.12,13 This ap-
proach became known as non-surgical therapy (Fig. 2). The
idea that an appropriate goal for periodontal therapy was
not zero pocket depth but rather conversion of infected dis-
eased periodontal pockets to healthy pockets maintained
free of pathogenic bacteria was enormously controversial.
As a consequence, large numbers of longitudinal studies
were initiated comparing the outcome of various therapeutic
modalities such as surgical pocket elimination versus scal-
ing and root planing with or without chemotherapy.1419
These studies demonstrated clearly that the quality of the
subgingival debridement and infection control, not the pres-
ence or absence of the periodontal pocket, was the major
determinant of successful periodontal therapy. Such therapy
may result in resolution of the inflammatory response, ces-
sation of the progress of periodontal destruction, a small
gain in periodontal attachment, significant reduction in

746 FUTURE PERIODONTAL THERAPY
Figure 2. Results of treatment of a deep periodontal pocket containing
pathogenic microbial plaque by thorough scaling and root planing (non-
surgical therapy) to arrest the progress of tissue destruction and establish
a long junctional epithelium with residual pocket depth.
probing depth (believed to be due to reduction in edema),
and formation of a long junctional epithelium (Fig. 2).
MODIFICATION OF HOST RESPONSES
During the 1970s and 1980s we obtained an enormous amount
of new information about the pathways by which the al-
veolar bone, periodontal ligament, and gingival tissues are
destroyed in periodontal disease.20 This new knowledge
served as the basis for a third entirely new approach to
periodontal therapy; i.e., drugs that modify host response.
Tissue macrophages, activated by pocket bacteria and their
products, produce large quantities of arachidonic metabo-
lities known as the Prostaglandins and these, especially PGE2,
mediate pathologic alveolar bone résorption (Fig. 3). The
non-steroidal, anti-inflammatory family of drugs can sup-
press or block Prostaglandin production, and could be ex-
pected to block or suppress alveolar bone destruction. Clin-
ical trials have demonstrated that this is indeed the
case.21-22 As shown in Figure 4,22 administration of the anti-
inflammatory drug naproxen as an adjunct to scaling and
root planing not only blocked alveolar bone loss, but also
resulted in significant bone gain relative to placebo. There
is yet another example of therapy of this type. Activated
macrophages and other cells in the pocket wall also produce
a large family of enzymes known as the metalloproteinases,
and these are the principal agents of destruction of the peri-
odontal ligament and gingival tissue (Fig. 5). These en-
zymes are dependent upon divalent cations for their activ-
ity. Golub and his colleagues have demonstrated that
antibiotics of the tetracycline class are not only detrimental
to bacteria, but also they chelate divalent cations and thereby
suppress or block metalloproteinase activity.23 Golub and
coworkers synthesized chemically-modified tetracyclines
(CMTs) that did not have antibacterial activity but retained
their capacity to inhibit metalloproteinases. CMTs are ef-
fective in reducing collagenase and other metalloproteinases
in experimental animal model systems and in humans with
J Periodontol
August 1993 (Supplement)
Activated Macrophages
Arachidonic Acid
I
Cyclooxygenase
Nonsteroidal
Anti-Inflammatory
Drugs
Prostaglandins
Alveolar Bone Destruction
Figure 3. Diagrammatic representation of the production of arachidonic
acid metabolites, including Prostaglandin PGE?
0.4
-0.2
placebo naproxen
Figure 4. Mean change in alveolar bone height measured using stan-
dardized digital radiography. There was significantly less bone loss during
the treatment period in the naproxen-treated patients compared with the
placebo patients (P 0.001, U test). Note the mean change in bone
=
height indicates a small amount of bone gain in naproxen-treated patients
(from Jeffcoat et al., 1991,22 with permission).
Periodontitis, and in suppressing destruction of collagenous
tissue (Fig. 6).
Thus, as we entered the decade of the 1990s, periodontal
therapy had 3 central components each approaching the
disease from a different direction: 1) scaling and root plan-
ing with or without opening mucoperiosteal flaps aimed at
debridement of the surfaces of the tooth roots; 2) antibiotics
and other antimicrobials aimed directly at destruction of the
bacteria present in the periodontal pockets and in the peri-
odontal tissues; and 3) use of drugs aimed at modification
of host-response mechanisms to suppress or inhibit prosta-
glandin-mediated alveolar bone résorption and metallopro-
Volume 64
Number 8 PAGE 747

MACROPHAGES, FIBROBLASTS, PMNs, KERATINOCYTES

LATENT METALLOPROTEIN ASE

PLASMIN (?)

ACTIVE ENZYME

TISSUE DESTRUCTION
DES
TIMPs O2-MACR0GL0BULIN

INACTIVE ENZYME

Figure 5. Diagrammatic representation of the production of latent metal-

loproteinases by various cells present in inflamed periodontal tissues,
potential enzyme activation by plasmin, degradation of extracellular ma-
trix components, and enzyme inactivation by tissue inhibitors of metalo-
proteinases (TIMPs) and a-macroglobulin.

Macrophages and
Other Cells Figure 7. Diagrammatic representation of treatment of a diseased peri-
odontal site by (A) resective techniques or (B) non-surgical procedures
compared to (C) the desired outcome of treatment by regenerative pro-
cedures.

Metalloproteinases tion now becomes: Is it possible to achieve this goal in a

practical and predictable manner?

CMTs Chelate Grafting with Bone and Bone Substitutes

Cations and inhibit Attempts have been made for many years to restore peri-
odontal tissues through grafting procedures, but until re-
cently with mixed evidence of success. Nevertheless, over
roughly the past 10 years, outcomes have changed in part
because of new knowledge about the disease process and
Periodontal Tissue wound healing, and in part because of the availability of
Destruction new materials.24 Grafting materials can be classified as var-

6.
Figure Diagrammatic representation of the inhibition of metallopro-
teinase degradation of extracellular matrix components by chemically-
modified tetracydines (CMTs) that act by chelating divalent cations.
teinase-mediated tissue destraction. Using existing thera-
pies, we have been remarkably successful in arresting the
progress of periodontal destruction in most patients with or
without osseous resection and with or without pocket
elimination.
REGENERATIVE THERAPIES
As we now enter the decade of the 1990s we have redefined
our goals for periodontal therapy. We are no longer content
with a reduced, but healthy periodontium with or without
healthy periodontal pockets (Fig. 7A and 7B). We now
have the goal of not only arresting the progress of peri-
odontal tissue destruction, but in addition, of regeneration
of previously-destroyed tissues and restoration of a com-
pletely normal periodontal status (Fig. 7C). The key ques-
ious bone preparations including autografts, allografts, and
xenografts, and bone substitutes such as hydroxyapatite ce-
ramics. Grafts are also classified as osteoconductive when
they merely serve as a scaffolding upon and within which
new bone can grow, and osteoinductive when they release
factors that induce differentiation of osteoblasts and new
bone formation.25 Non-demineralized freeze-dried bone al-
lografts and porous hydroxyapatite are two commonly used
osteoconductive materials, while decalcified freeze-dried bone
allografts are an example of osteoinductive material. The
grafting procedure is perfomed by elevating mucoperiosteal
flaps, debridement of the root surface, removal of the gran-
ulation tissue, and placement of the graft material within
the intrabony defect, followed by suturing (Fig. 8).
Numerous experimental clinical trials in humans have
been performed using these and other grafting materials. In
these trials, generally teeth with vertical bone defects have
been treated by elevation of flaps, thorough root debride-
ment, and placement of the graft material. In many studies,
treated sites have been re-entered after 6 months for post-
 J Periodontol
748 FUTURE PERIODONTAL THERAPY August 1993 (Supplement)
Table 1. Osteogen i Effects in 50 Non-Submerged Defects in 6
Patients

Collagen
+ DFDBA +
Measurement Collagen Osteogenin DFDBA* Osteogenin
New attachment 0.08 0.05 1.72 2.33
New cementum 0.11 0.08 1.73 2.35
New bone 0.08 0.20 2.48 2.70
Alveolar
crest height 0.09 0.32 2.47 2.63
Figure Diagrammatic representation of a diseased periodontal site
8.
treated by elevation of a mucoperiosteal flap, thorough debridement, and From Bowers et al., 1991,42 with permission.
*DFDBA Decalcified freeze-dried bone allograft.
=

placement of a graft material, resulting in regeneration offunctional peri-

odontal attachment.

Table 2. Intrabony Defects Treated With Porous Hydroxyapatite or

treatment measurements. The use of non-decalcified freeze- Decalcified Freeze-Dried Bone

dried bone allografts in the treatment of intrabony peri- PHA*(SE) DFDBf(SE)
odontal lesions has been studied in detail.26 30 In one study,
_Center
Mean Attachment Gain A 2.67 (0.22) 2.08 (0.10)
60% to 64% of grafted defects healed with 50% or greater 3.10(0.22) 2.12(0.16)
3.25 (0.33) 2.33 (0.31)
bone fill, with corresponding reduction in clinical probing Defect Fill A
3.24 (0.24) 2.48 (0.22)
depth and attachment gain.31 In a subsequent larger study,
1,521 sites were treated. In this study, 329 sites were grafted From Oreamuno et al., 1990,52 with permission.
*PHA Porous hydroxyapatite.
with non-demineralized freeze-dried bone and 176 sites were
=

fDFDB Decalcified freeze-dried bone.

=

grafted with the same material, but also containing auto-

genous bone. Bone fill exceeding 50% was obtained in 67%
of defects grafted with non-demineralized freeze-dried bone,
and in 78% of sites grafted with this material plus auto-
genous bone.31 The success rate can be enhanced by in-
cluding tetracycline in the grafting material.32-33
Success rates can be enhanced further by using decalci-
fied freeze-dried bone.27 30-34 37 Décalcification is thought
to expose and permit release of bone morphogenic proteins.
Such proteins have been isolated from bone matrix and
characterized, and recently their genes have been cloned
and expressed.38-39 Libin et al.40 were the first to use de-
calcified freeze-dried bone allografts in periodontal defects.
Using such material, 2- to 4.2-fold more bone is observed
at grafted relative to non-grafted sites treated by open-flap
debridement.31 Histologically, grafted sites consistently
manifest new bone, cementum, and periodontal ligament,
whereas non-grafted sites in the same patients heal with a
long junctional epithelium.41
Bowers et al.42 performed a clinical trial in which they
treated 86 intrabony pockets by grafting with demineralized
freeze-dried bone or bovine tendon-derived matrix, with
and without the bone morphogenic protein osteogenin. As
shown in Table l,42 the collagen matrix with or without
osteogenin was ineffective in inducing new bone, cemen-
tum, or attachment. Demineralized freeze-dried bone was
effective and the effectiveness enhanced by addition of
osteogenin.
Grafts using bone substitutes have also been studied in
humans.29-37-43"49 Kenney et al.43 grafted 1 angular inter-
proximal defect in each of 25 patients with hydroxyapatite
and used a second defect treated conventionally as control.
Grafted sites had a mean defect fill 4.8-fold greater than
control sites. Connective tissue infiltrated into the grafts
and onto the graft surface followed by bone formation.44
Pepelassi etgrafted 26 Class II and 14 Class III fur-
al.50
cations in 15 patients using a composite consisting of tri-
calcium phosphate, plaster of Paris, and doxycycline. After
6 months, grafted sites were 4-fold more likely to have
defect fill of 50% or more than conventionally-treated sites.
Yukna51 used a graft material consisting of polymethyl
methacrylate, a porous polymer, coated with calcium hy-
droxide. Sites were treated by open debridement with or
without grafting. After 6 months, 60.8% defect fill was
observed at grafted sites as compared to 32.2% fill at con-
trol sites.
Other studies have been performed comparing freeze-
dried bone allographs with porous hydroxyapatite grafting
material.29-37 In one such study, 12 paired defects in 12
patients at each of two clinical centers were treated with
porous hydroxyapatite or decalcified freeze-dried bone and
the results assessed after 12 months.52 As shown in Table
2,52 mean attachment gain as well as defect fill were ob-
served at sites of both types, although porous hydroxyapa-
tite gave significantly better results at both centers than
demineralized freeze-dried bone.
Guided Tissue Regeneration
Our ability to regenerate previously-destroyed periodontal
tissues was advanced enormously when Nyman and
coworkers53 55 demonstrated that exclusion of gingival
epithelium and fibroblasts from the periodontal wound site
by placement of a barrier over the wound allowed cells,
presumably from the periodontal ligament and/or adjacent
alveolar bone, to populate the wound and these cells gave
Volume 64
Number 8 PAGE 749

Experimental
Control

Figure 9. Diagrammatic representation of treatment of a diseased peri-

odontal site by guided tissue regeneration in which following elevation of
a mucoperiosteal flap and thorough debridement of the root surface, a
porous membrane is placed over the intrabony defect for the purpose of
exclusion of gingival epithelium and fibroblasts from the treated site.
rise to new cementum, periodontal ligament, and alveolar
bone. Extensive studies performed in experimental animals
and in humans have demonstrated that the procedure results
in periodontal regeneration in 2- and 3-walled intrabony
defects and in Class II furcations, especially on lower
molars.56"68 A variety of barrier materials have been used
including filters and membranes made of Teflon and other
substances, biodegradable polyglactic acid membranes, dura
mater, periosteum, synthetic skin, and collagen membranes
impregnated with antibiotics or other agents.61 ·62·65·66·69"74
The operative technique used has varied considerably from
one study to another. In general, the procedure is performed
as illustrated in Figure 9. Following elevation of mucogin-
gival flaps and debridement, the intrabony defect is covered
by a porous membrane which overlaps the bone 3 mm to
5 mm in all directions. In some cases the coronal border
of the membrane is placed coronal to the cemento-enamel
junction and the coronal border of the flap, while in other
cases it has been placed apical to the border of the flap and
the cemento-enamel junction. In some cases the filter has
been attached to the enamel surface of the crown, while in
others it was attached by a suture to either the tooth or the
flap. Systemically-administered antibiotics and chemical
plaque control agents may or may not be used; after several
weeks the membrane is removed.
The principle of guided tissue regeneration has been eval-
uated in numerous studies in animals using membranes of
various compositions in the treatment of both spontaneously
occurring and created intrabony lesions and Class II and
Class III furcations.56"69-70'75"77 Generally excellent results
have been reported, including complete fill of Class II fur-
cations in some cases.
Thirty-nine patients having a variety of vertical intrabony
defects and furcations were treated by guided tissue regen-
eration using filters and Gore-Tex periodontal material.th2
Thirty-seven intrabony defects were treated, 27 filled com-
pletely, 10 filled to greater than 50%, and none failed. Six
Class II furcations were treated, 3 filled completely, 2 filled
partly, and 1 failed. Fifteen Class III furcations were treated,
fW.L. Gore and Associates, Inc., Flagstaff, AZ.
REC PD AL
GTR vs flap curettage
Figure 10. Graph presenting the improvement in probing depth (PD) and
attachment level (AL) with no change in recession (REC) at experimental
sites treated with debridement and membranes, vs control sites treated
with debridement alone (from Metzler et al., 1991," with permission).
1.6-1 Experimental
Control
1.2
1
0.8
0.4
0-
RESP VOPA HOPA
GTR vs flap curettage
Figure 11. Graph from the same study described in Figure 10, illustrating
the improvement in vertical open probing attachment (VOPA) and hori-
zontal open probing attachment (HOPA ) at experimental and control sites
(from Metzler et al., 1991," with permission).
5 filledcompletely, 5 filled partially, and 5 failed. The
composition of the membrane was not an important deter-
minant of outcome, although Gore-Tex was found more
convenient because it was sterile, sufficiently stiff, break-
resistant, and had a collar.
In a small, controlled study, Caffesse et al.78 treated Class
II furcations by placement of Gore-Tex at 11 sites and per-
formed surgery only at 6. At 6 months there was 1.7-fold
greater pocket depth reduction and 2.7-fold attachment gain
at membrane-treated than at control sites. Metzler et al.64
treated maxillary Class II furcations in 17 patients with
advanced Periodontitis either with Gore-Tex membranes or
by flap debridement only. As shown in Figures 1064 and
11,64 after about 6 months the membrane-treated sites were
significantly better than control sites with regard to probing
depth, clinical attachment level, and vertical and horizontal
open probing attachment. Histologie studies have shown
the presence of new cementum, bone, and periodontal lig-
ament at most, although not all, experimental sites.79

750 FUTURE PERIODONTAL THERAPY
Figure 12. Diagrammatic representation of treatment of a diseased peri-
odontal site by guided tissue regeneration combined with placement of a
graft material resulting in regeneration of functional periodontal attach-
Experimental
Control
2A
H and several other factors secreted by macrophages. TGF-ß
o trophils, it also induces synthesis of fibronectin and types
RESP VOPA HOPA
Figure 13. Graph presenting improved vertical open probing attachment
(VOPA) and horizontal open probing attachment (HOPA) at experimental
sites treated with membranes and decalcified freeze-dried bone versus
control sites treated with membranes alone. Alveolar crest résorption (RESP)
was not different for the 2 treatments (from Anderegg et ai, 1991,81 with
permission).
Guided Tissue Regeneration with Grafts
Studies have been reported using guided tissue regeneration
and graft material in a procedure illustrated in Figure 12.
In general, more regeneration was observed at sites treated
with grafts and membrane than at those treated using mem-
branes only.67-68-80 Fifteen pairs of Class II and III furca-
tions were treated either with membranes alone or mem-
branes plus decalcified freeze-dried bone using Gore-Tex.81
As shown in Figure 13,81 after 6 months both types of sites
had improved greatly but the ones with grafted bone had
improved more.
Citric Acid and Coronally-Positioned Flaps
Several investigators have assessed the efficacy of citric
acid conditioning of tooth root surfaces and coronal place-
ment of periosteal flaps in enhancing regeneration of peri-
odontal attachment tissues.82'83 Partially decalcifying the
root surface with acid is thought to expose factors, possibly
similar to bone morphogenic protein, that can enhance heal-
ing. Stahl and Froum84 treated 6 suprabony pockets in 2
patients with citric acid demineralization and coronally-placed
flaps. They achieved new attachment and saw evidence of
new bone deposition.
J Periodontol
August 1993 (Supplement)
Growth Factors
Growth factors are biologic mediators which regulate con-
nective tissue cell migration, proliferation, and synthesis of
proteins and other components of the extracellular matrix.
Discussion of all such molecules is far beyond the scope
of this paper; the reader is referred to reviews by Wirthlin85
and by Lynch.86 The focus here is on those growth factors
that may have the most potential in periodontal regenera-
tion. Foremost among these are platelet-derived growth fac-
tor (PDGF), insulin-like growth factor-1 (IGF-1), trans-
forming growth factor beta (TGF-ß), and basic fibroblast
growth factor (bFGF). These molecules are released by
platelets, endothelium, fibroblasts, smooth muscle cells,
and macrophages in inflamed tissues and healing wounds.
PDGF is a chemoattractant for fibroblasts and neutrophils
and a potent mitogen for mesenchymal cells; acting syn-
ergistically with IGF-1, PDGF promotes general protein
synthesis and production of collagen, proteoglycans, and
other components of the extracellular matrix, and collag-
enase.85 87 Angiogenesis is stimulated by TGF-ß, bFGF,
induces biological responses very different from PDGF. In
addition to being a chemoattractant for fibroblasts and neu-
I, III, and V collagen, inhibits collagenase and Plasminogen
activator and stromelysin, induces production of tissue in-
hibitors of metalloproteinases (TIMPS), and stimulates Os-
teoblast activity.85 As might be expected, all of these mol-
ecules are likely to come into play in periodontal regeneration.
Immediately following injury, mRNA for growth factors
and their receptors can be detected in the tissues.88,89 Ex-
tensive data have been gathered using a standardized wound
in the skin of swine by Lynch.87 He tested EGF, TGF,
FGF, IGF, and PDGF in a methylcellulose gel applied im-
mediately after wounding. TGF-ß gave the most marked
response with a 148% increase in new connective tissue
volume and collagen content. The tissue also had acceler-
ated angiogenesis and maturity. IGF-1 alone had no sig-
nificant effect, while PDGF alone gave a 64% increase in
new connective tissue volume and a 68% increase in col-
lagen content. A combination of PDGF and IGF-1 gave a
132% increase in collagen and an increase in the thickness
of the new epidermis.
Lynch et al.90,91 also studied the role growth factors may
play in periodontal regeneration in beagle dogs with spon-
taneously-occurring Periodontitis. They used a methylcel-
lulose gel containing 3 µg each of PDGF and IGF-1 placed
around premolars in 13 dogs and used gel-only as a control.
Using radio-labeled material they demonstrated a half-life
of 3.0 hours for IGF-1 and 4.2 hours for PDGF. They
measured cementum length, bone area, and bone height at
2 and 4 weeks (Fig. 14). They demonstrated a significant
increase in new bone and cementum relative to control
specimens. Periodontal ligament was also formed and no
ankylosis was observed. Thus, growth factors may have
Volume 64
Number 8
6.0
5.5
5.0 M
I I
CONTROL
PDGF-B/IGF-I
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
LENGTH OF
NEW
AREA OP
NEW
HEIGHT OF LENGTH OF
NEW
AREA OF
NEW
CEMENTUM CEMENTI'M BONE
BONE
TWO WEEKS FIVE WEEKS
Figure 14. Histometric evaluation of increases in (A) new cementum length,
(B) new bone area, and (C) new bone height for diseased periodontal
sites in beagle dogs treated with a gel containing PDGF-ß and IGF-1, or
with carrier gel alone at 2 and 5 weeks after treatment. Control values
are shown as block bars, and experimental values as cross-hatched bars
(from Lynch et al, 1991, with permission).
great importance in stimulating periodontal regeneration in
humans, although such studies have yet to be performed.
CONCLUSIONS
Published studies described in this report document several
conclusions. Thorough debridement of the roots of peri-
odontally-diseased teeth by scaling and root planing or other
means is absolutely essential to the success of any therapy,
be it resective, non-surgical, or regenerative. Conservative
non-surgical therapy, with or without the use of antibiotics
and other chemotherapies, is effective in arresting the prog-
ress of Periodontitis in most, although not all cases. The
quality and thoroughness of the root debridement, not the
presence or absence of a periodontal pocket, is the major
determinant of successful therapy. Neither osseous surgery
nor non-surgical therapy results in significant regeneration
of periodontal attachment with formation of new bone, ce-
mentum, and periodontal ligament, except possibly in spe-
cial cases where flaps are coronally positioned. Regenera-
tion of periodontal attachment tissues previously destroyed
by disease is biologically possible in some, although not
all, cases. Regeneration is infrequent in lesions of some
types such as type III furcations especially on maxillary
molars, and for lesions of any type, complete regeneration
to the original state is rarely, if ever, seen in humans.
Clinical trials have demonstrated that the use of anti-
biotics and non-steroidal anti-flammatory drugs are effec-
tive adjuncts to other forms of therapy. Although not yet
subjected to extensive clinical trials, chemically-modified
tetracyclines that inhibit metalloproteinases show promise.
The use of both osteoconductive and osteoinductive graft
materials significantly enhances the process of periodontal
PAGE 751
6.0 tissue regeneration. Under favorable conditions, regenera-
-I 5.5 tion is generally in the range of 60% to 70% of the lesion
5.0 volume or height. The use of barrier membranes as prac-
4.5 ticed in guided tissue regeneration may enhance regenera-
4.0 tion of attachment significantly, and use of such membranes
3.5 in combination with osteoconductive or osteoinductive grafts,
3.0 although not yet thoroughly studied, may further enhance
2.5 regeneration. Studies of the efficacy of growth factors such
as PDGF, BFGF, IGF-1, and TGF-ß are in their infancy
2.0
1.5
although they show great promise. Published data demon-
strate that PDGF and IGF-1 act synergistically in enhancing
1.0
0.5
regeneration of cementum, bone, and periodontal ligament
in dogs. Whether this is the case in humans remains to be
0.0
HFIGHTOI seen. Intensive studies in this area, especially in the use of
NEW
recombinant bone morphogenic proteins, are needed and
BONE
may be expected to be fruitful.
The future of periodontal therapy is exceedingly bright.
The demonstration that osteoinductive and osteoconductive
grafts, use of barrier membranes, and application of growth
factors greatly enhance regeneration of bone, cementum,
and functional periodontal ligament is a genuine break-
through in periodontal therapy. The goal of periodontal
therapy in the future will be complete regeneration of peri-
odontal attachment. This goal will be achieved through use
of root debridement, anti-infective therapy, and drugs that
inhibit bone and soft-tissue destruction to arrest the progress
of the disease and resolve the inflammatory process, fol-
lowed by a combination of the use of graft materials, barrier
membranes, and growth factors to generate the periodontal
tissues.
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Send reprint requests to: Dr. Roy C. Page, Research Center in Oral
Biology SM-42, University of Washington, Seattle, WA 98195.