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Periodontology 2000, Vol.

17, 1998, 151-1 75 Copyright 0 Munksgaard 1998

Printed in Denmark All rights reserved
ISSN 0906-6713

Guided bone regeneration at

oral implant sites

Guided bone regeneration is an accepted method the bone volume: osteoinduction by the use of ap-
successfully employed in dental practices to increase propriate growth factors (148, 149, 181); osteocond-
the volume of the host bone at sites chosen for im- uction, where a grafting material serves as a scaffold
plant placement. Originally, the biological principle for new bone growth (30, 149); distraction osteogen-
leading to the method of guided tissue regeneration esis, by which a fracture is surgically induced and
was discovered by Nyman and Karring (103, 104, 131, the two fragments are then slowly pulled apart (91,
133) in the early 1980s as a result of the desire to 92); and finally, guided tissue regeneration, which
regenerate lost periodontal tissues. As a conse- allows spaces maintained by barrier membranes to
quence, novel possibilities to regenerate periodontal be filled with new bone (50, 54, 56, 81, 109, 110, 135).
tissues with new root cementum, periodontal liga- Since biochemical induction of bone formation
ment and alveolar bone became available (70, 71, is still in an experimental phase, and since distrac-
130, 134). tion osteogenesis cannot be applied in the healing
Soon, guided tissue regeneration found appli- of local bone defects in the jaw bones, guided
cations in other areas, including the regeneration of bone regeneration and the use of bone grafting
bone tissue (129). As a result of animal experiments materials are the only methods commonly applied
(52, 54, 56, 167) and clinical applications in humans in clinical practice. Among the techniques de-
(14, 34, 114, 116, 132, 184), guided tissue regenera- scribed, guided bone regeneration has shown the
tion has become a clinically accepted method for best and most predictable results when employed
augmenting bone in situations with an inadequate to fill peri-implant bone deficits with new bone
volume for the placement of endosseous dental im- (13, 27, 34, 53, 75, 132).
plants. The formation of new bone in conjunction Although bone regeneration using membrane bar-
with the placement of dental implants is also a clin- riers is often successfully achieved in clinical prac-
ically well documented and successful procedure tice, many problems remain and need to be resolved
(13, 51, 53, 100, 112, 116). to increase predictability. The problems most fre-
There is general agreement that guided bone re- quently encountered with guided bone regeneration
generation is difficult to perform and demanding re- include partial or total collapse of the barrier mem-
garding the skills and experience of the therapist. brane, exposure of membranes due to soft tissue
Whereas enlargement of jaw bone in conjunction dehiscences resulting in local infection and incom-
with implant placement is the most frequent indi- plete bone regeneration within the space provided
cation, it has also been used to increase the bone by the membrane. In order to overcome these diffi-
volume in order to achieve better aesthetics (47). culties, often resulting in unsatisfactory clinical re-
This chapter discusses the scientific and clinical sults, various attempts have been made to improve
aspects of guided bone regeneration based on avail- the devices and the surgical techniques.
able data. It soon became evident that improved knowledge
about the biological mechanisms and the temporal
dynamics of new bone formation under the con-
Biological basis of guided bone ditions of guided regeneration is critical. Scientists
regeneration and clinicians considered this knowledge a prerequi-
site to better understand the healing steps leading to
In principle, four methods have been described to regenerated and fully mature bone in order to be
increase the rate of bone formation and to augment able to beneficially influence healing for further de-

Hamnzerle & Karring

Guided bone regeneration at oral implant sites

velopments in the field and for increased predict- on the size of the defect has previously been eluci-
ability of the clinical outcomes. dated in an experimental rodent model. In cortical
So far, the type of bone being formed by applying bone, circular defects of less than 200 pm had the
the principle of guided tissue regeneration has only potential to heal with concentric formation of lamel-
been investigated in a few animals (79, 110, 154) and lar bone (97, 155). In larger defects of 200 to 500 pm,
some human studies (81). Two of these animal bone healing was characterized by formation of a
studies were dealing with surgically prepared bone trabecular network of woven bone bridging the de-
defects (79, 154). One study focused on tissue heal- fect. Subsequently, the spaces between the trabecu-
ing in bone defects in the mandible of dogs (154). lae were filled with lamellar bone. However, in de-
The other experiment investigated the temporal and fects of 500 pm and larger, bridging by direct forma-
spatial dynamics of bone regeneration in calvarial tion of bone did not occur. Following 3 weeks of
defects in rabbits (79). The third experiment ex- healing, such defects exhibited a central area char-
plored the possibility of augmenting the naturally acterized by the presence of connective tissue.
present bone volume in the mandible of rats (110). The intermediate connective tissue described in
In all these experiments, a similar basic pattern of the two above-mentioned experiments (81, 154) pro-
bone formation was observed. Initially, trabeculae of vided the appropriate mechanical properties necess-
woven bone proliferated into the defect. In two ary to allow for unimpeded ingrowth of blood capil-
studies, the space provided by the membrane was laries during angiogenesis (Fig. la), which always
filled with a newly formed connective tissue matrix precedes bone formation (162). However, with in-
prior to the formation of mineralized bone (79, 81, creasing defect size the biomechanically stable zone
154).The investigators concluded that the size of the becomes successively limited to the marginal area of
defects did not allow for direct formation of mineral- the defect, whereas the central region is exposed to
ized bone, since new bone is only formed at loca- biomechanical forces presumably preventing bone
tions where biomechanical stability is guaranteed, formation. This view is supported by experimental
that is, where pressure and tensile forces are ex- and clinical observations that showed that, in large
cluded (177). Otherwise, an intermediate tissue with bone defects, bone formation is limited to the defect
appropriate mechanical properties will arise before margins (11, 50, 60, 80, 123).
ossification. In the experiment with the augmentation of the
The mechanism of bone healing being dependent mandibular ramus in rats, in contrast, the new bone
proliferated into the defect space without a nonmin-
eralized connective tissue matrix occupying the en-
Fig. 1. a. Newly formed bone trabeculae (purple) closely tire area for regeneration (110).
follow the pathway given by the proliferating vessels Similar observations regarding bone formation
(brown).b. The new bone (black) consists of irregularly have been reported in canine mandibular and ro-
shaped, delicate trabeculae lined with osteoid seams (0s) dent calvarial bone defects (79, 154). The new bone
and a layer of cuboidal osteoblasts (arrows). Collagen
fibers (arrow heads) are progressively embedded into the formation generally originated from the bony bor-
mineralizing osteoid. c. A newly formed trabeculae of ders of the defect. This new bone appeared as a scaf-
woven bone is embedded in a highly vascularized connec- fold of delicate trabeculae comprised of woven bone,
tive tissue. The bright red osteoid seam is covered by a from which several extensions were directed towards
layer of osteoblasts (arrows).Osteocytes are encircled by the center of the defects (Fig. lb, c). The surfaces of
the mineralizing bone (arrowheads). d. Fluorochrome
labeling demonstrates the sequential steps of the re- the trabeculae were commonly covered by osteoid
generation of mineralized bone. Bone stained in bright seams lined by a dense layer of cuboidal osteoblasts.
yellow (tetracycline label) is of woven nature (wb).Lamel- The trabeculae were embedded in a well-organized
lar bone deposition (arrows) is labeled in red (alizarine and vascularized granulation tissue. At various loca-
label) and green (calceine label). e. Osteoclasts (Oc) are tions integration of collagen fiber bundles into the
resorbing the primarily formed woven bone (Wb). Osteo-
blasts (Ob) in their immediate vicinity deposit layers of new bone matrix could be detected. In the course of
mature lamellar bone on the remnants of the original tra- bone apposition, surrounding connective tissue
becular scaffold. f. Remnants of the dark-stained,primary fibers became embedded into the osteoid and finally
trabecular scaffold are covered by new bone lamellae. integrated into the new bone. Within the network of
g. By continuous apposition of lamellar bone, a primary the trabecular scaffold, numerous blood capillaries
osteon (PO) with a central blood vessel is formed. h. As part
of normal bone turnover osteoclasts were resorbing parts
were consistently found connected with the vessels
of the cortical bone followed by osteoblastic bone appo- of the opened bone marrow cavity of the adjacent
sition leading to the formation of secondary osteons (so). bony defect borders. In addition, a considerable

Hammerle & Karring

number of proliferating blood capillaries ac- steps of guided bone regeneration describe bone
companied and even preceded the bone trabeculae healing in the molar area in the mandible (81). Hol-
growing towards the mid-part of the defect (79, 154, low titanium test cylinders measuring 3.5 mm in
162).As the mineralized bone grew, blood vessels ly- outer diameter, 2.5 mm in inner diameter and a
ing in its immediate vicinity became incorporated height of 4 mm were placed into standardized holes
into the new bone matrix. in the retromolar area of healthy volunteers. The cyl-
The remainder of the defect area, which was not inders were placed in such a way that 1.5 to 2 mm
filled with bone yet, contained loose connective of the test devices was submerged below the level of
tissue comprised of scarce collagen fibers without a the surrounding bone, and 2 to 2.5 mm surpassed
preferential orientation. Sparsely distributed cells, the bone surface. The bone-facing ends of the de-
predominantly fibroblasts and macrophages as well vices were left open. The soft tissue facing ends were
as a moderate number of wide blood capillaries were closed by means of expanded polytetrafluoroethy-
seen. lene membranes (Gore-Tex Periodontal Material@,
In contrast to the findings in the other studies, Flagstaff, AZ) before the soft tissue flaps were su-
bone islands arose within this fibrovascular tissue in tured for primary healing. After observation times
the calvarial defect model as identified by means of ranging from 2 to 36 weeks, the cylinders along with
radiographs and serial sections (79). Their texture the regenerated tissue were harvested and analyzed.
was consistent with that of woven bone, that is, ir- The tissue generated at 2 and 7 weeks exhibited a
regular bundles of collagen fibers and extremely nu- cylindrical shape, whereas the specimens harvested
merous, large osteocytes, and they were without at 12 weeks and at later time points, yielded the form
contact with the marginal bone. The proliferation of of an hourglass. Specimens of 12 weeks and less
new bone in this pattern has not been described pre- healing time almost entirely contained soft tissue.
viously, unless a sutural growth area was given ac- Specimens with generation times of 4 months and
cess to the defect area (11, 60). The investigators more contained both soft tissue and increasing
concluded that osseous defect closure arising both amounts of mineralized bone.
from the margins of the bone defect and as islands Up to a period of 6 months of healing, new bone
may be a faster healing process than marginal bone was primarily filling the previously prepared defect
formation alone. within the host bone. Therefore, by reaching the
Common to all these experiments was the finding level of the surrounding host bone, true regeneration
that the bone volume increased with time and that of bone had occurred. Interestingly, bone formation
the primary intramembranous trabecular scaffold did not come to a halt at this point but proceeded
underwent intense remodeling: numerous osteo- above the borders of the skeleton, thereby altering
clasts arose and began to eliminate the primitive the genetically determined form of the mandible.
woven bone, whereas a new generation of osteo- This formation of new bone beyond the skeletal bor-
blasts deposited mature lamellar bone layers on the ders by applying the method of guided tissue re-
woven bone remnants (Fig. Id, e). As a consequence generation was first demonstrated on the calvaria of
of the continuous remodeling of the primary bony rabbits (161). Subsequently, these findings were con-
network, most of the trabeculae contained only a firmed in other experimental animals such as rab-
small, intensely stained core of woven bone sur- bits, rats, and dogs (83, 99, 109, 110, 118, 122, 160).
rounded by thick bone layers of regular lamellar tex- The first guided bone neogenesis in humans was
ture and thus comprised the secondary spongiosa demonstrated by applying the novel model system
(Fig. If). The continuous growth of the bone tra- used in the present study. Furthermore, neoforma-
beculae resulted in the narrowing of the intertra- tion of bone beyond the skeletal borders can also be
becular connective tissue and in the formation of achieved by the combined use of bone substitutes
primary osteons containing vascular channels (Fig. and membranes (78, 159).
lg). The presence of osteoid seams with overlying
osteoblasts indicated continuation of the osteogenic
process. At the defect borders facing the membranes
cortical bone was formed by continuous lamellar Treatment of localized defects of
bone deposition. Finally, secondary osteons were the alveolar ridge
formed replacing the previously formed cortical
bone (Fig. lh). To date, guided bone regeneration can most success-
The only available human data on the sequential fully be used to regenerate localized alveolar defects

Guided bone regeneration at oral implant sites

Fig. 2. a. Insufficient bone volume to place an implant

under standard conditions in the right premolar region of
the mandibular arch in a 22-year-old caries-free patient.
b. 'Ityosupporting screws of the Memfix system have been
placed in order to augment the local bone volume lat-
erally. c. The cortical bone has been perforated at multiple
locations to allow for bleeding from the bone marrow
spaces. d. An expanded polytetrafluoroethylene mem-
brane has been carefully adapted to the bony borders of
the defect being draped over the two supporting screws.
Stabilization of the membrane has been achieved by pla-
cing three Memfix fixation screws (Institut Straumann,
Waldenburg, Switzerland).

with new bone tissue (Fig. 2-4). Although various either covered with expanded polytetrafluoroethy-
attempts have been described aiming at augmenting lene membranes, covered with membranes and
the bone over extended areas of the jaw, no valid grafted with porous hydroxyapatite or with a tissue
technique or clinical procedure has been presented growth matrix of porous polytetrafluoroethylene,
so far. grafted with these same materials but not covered
with membranes, or finally, neither grafted nor cov-
ered with membranes. Morphological and histologi-
Guided bone regeneration prior to implant cal analysis revealed that, in sites treated with mem-
branes, with or without the addition of grafts, the
In situations with a bone defect at a site, where the entire space between the membrane and the jaw
primary stability of an implant cannot be achieved bone was filled with bone. In the absence of mem-
or when implant placement is not possible in ideal branes, bone formation was lacking.
location for subsequent prosthetic therapy, guided Later, in a similarly designed study, columns of
bone regeneration prior to implantation represents cortical bone were used to support membranes in-
the method of choice. tended for bone regeneration of previously prepared
Experimental research on ridge augmentation alveolar ridge defects in dogs (174). Again, the mem-
using guided bone regeneration was presented in the branes under this particular experimental situation
early 1990s (167). In a dog model, large defects of proved efficacious in regenerating bone within the
the alveolar ridge were surgically prepared both in space created, whereas the controls without mem-
the mandible and in the maxilla. The defects were branes failed to heal with bone.

Hammerle & Karring

Fig. 3. a. At membrane removal

surgery 9 months later, excellent
bone formation is observed. b. A
hollow-cylinder implant can be
placed in perfect location under
standard conditions.

Fig. 4. a. After completion of prosthetic treatment, the b. Radiographic examination of the treatment result.
mandibular arch is free of edentulous spaces, thus in- Close adaptation of the marginal bone to the implant
creasing chewing comfort and aesthetics for the patient. neck. Note that the perforations in the cortical bone are
The same clinical procedures were performed in the area still visible radiographically.
of the second premolar at the mandibular left side.

The conclusions drawn from these and other ex- prepared in the mandibular ramus of rats (55). The
periments were that the method of guided bone re- sites of surgery were allowed to heal during a period
generation can indeed be successfully employed in of 12 weeks. Upon surgical inspection it was found
the regeneration of alveolar ridge defects (154, 167, that although, some bone regeneration had taken
174). place at the defect borders, primarily soft connective
In the majority of the experimental studies on tissue had filled the defect. This soft tissue was care-
guided bone regeneration the effect of this method fully removed and expanded polytetrafluoroethylene
was tested in situations in which the ridge defects membranes were adapted buccally and lingually to
had been freshly prepared. One might, however, as- the bone surrounding the defects. Histological
sume that the reaction of the bone when freshly in- analysis after 6 weeks demonstrated complete heal-
jured is different than the situation when a state of ing of the previous defects with regenerated bone,
tissue equilibrium had been reached in the defect whereas the control defects without membranes
area. In an animal study, transosseous defects were failed to consistently heal with bone. Hence, iso-

Guided bone regeneration at oral implant sites

Fig. 5. a. The minimal width of the

ridge (arrows) in this patient with a
completely edentulous maxilla pre-
cludes standard implant therapy.
b. A titanium-reinforcedexpanded
polytetrafluoroethylene membrane
has been adapted to the surround-
ing bone in such a way that a space
is created between the membrane
and the knife-like ridge. The mem-
brane is secured in place by use of
titanium pins.

lation of the defect and the adjacent bone from the vertical bone height was measured, reaching up to a
neighboring soft tissues seems to suffice for success- maximum of 7 mm.
ful bone regeneration with guided bone regeneration In an attempt to augment bone 2.7 mm above the
(Fig. 5, 6). present crest at titanium implants in dogs, re-
In a controlled clinical study in seven patients inforced expanded polytetrafluoroethylene mem-
with similar contralateral fenestration defects, one branes showed 1.8 mm of gain, standard expanded
side was treated with guided bone regeneration, polytetrafluoroethylene membranes revealed 1.9
whereas the other one served as control (51). The mm and the bone height increased by 0.5 mm in the
results demonstrated that guided bone regeneration controls without membranes (99). No graft materials
treated dehiscences were consistently filled with new had been incorporated. In both membrane groups,
bone. In the sites where the defect had only been about 1 mm of nonmineralized tissue was present
covered by the mucoperiosteal flap, denuded im- between the mineralized bone and the membrane at
plant surfaces devoid of bone coverage were ob- its highest point, corroborating the results of Simion
served at re-entry surgery. et al. (172). In accordance with these data are the
On the one hand, lateral ridge augmentation has results obtained with a perforated dome-shaped ti-
been shown to be a method with predictable success tanium space maintainer (150). Although vertical
(15, 35-37, 51, 128, 132). On the other hand, the re- ridge augmentation with bone did occur, the pres-
sults regarding vertical augmentation of the alveolar ence of nonmineralized connective tissue under-
ridge are controversial. neath the top of the dome was frequent.
Implants protruding 4 to 7 mm from the bone It appears that, depending on the clinical treat-
crest were covered with titanium-reinforced ex- ment protocol, varying amounts of bone height may
panded polytetrafluoroethylene membranes in a re- be gained. The factors critical for success or failure
cent study in five patients (172). Biopsies taken 9 have not been worked out. In addition, no data are
months following membrane placement revealed available indicating whether there is a biologically
mineralized bone to have formed up to a level 3 to limited maximum of bone gain, and if so, by what
4 mm above the previous alveolar crest. Beyond this parameters this maximum is influenced.
level, soft connective tissue was found. Other investi- On the one hand, according to the law of Frost
gators have reported more vertical gain of bone (61), bone is resorbed if it is not functionally stimu-
(178). Six patients were treated with a similar lated. On the other hand, if loading surpasses a criti-
method. In contrast to the above study, these thera- cal level, damage to the implant-supporting bone
pists grafted the area underneath the titanium-re- my occur. In a recent dog study it was revealed that
inforced membranes with autogenic bone grafts col- occlusal loading of newly regenerated bone may lead
lected in a suction filter. Twelve months following to partial loss of this bone (18). Of the 3-month gain
membrane placement, an average gain of 5 mm of in bone height of 4.6 mm, the experimental sites

Hammerle & Karring

Fig. 6. Excellent bone regeneration is Fig. 7. a. Histological section of a 3-month specimen comprising nonminerd-
observed 9 months later. A n implant ized connective tissue yielding the shape of an hourglass. Note the covering
with a diameter of 4.1 mm has been expanded polytetrafluoroethylene membrane. The polished cylinder walls
placed into the regenerated bone. prevented cellular attachment, thus allowing the tissue to be pulled away
from the walls. b. Histological section of a %month specimen. The height of
the mineralized tissue has reached 80% of the cylinder space. Note the un-
changed shape resembling an hourglass in comparison with the %month

showed 1.8 mm of regenerated bone height still in- between this study and the experiment discussed
tact at 6 months, whereas the control sites exhibited above (18) may be based on the difference in healing
4.3 mm of 4.8 mm initially still intact. Other investi- time allowed to the regenerated bone before loading.
gators have reported a loss in total bone volume fol- In the former study, this time amounted to 9
lowing membrane removal but an increase in area months, whereas loading was initiated after 3
density of mineralized bone at titanium implants in months in the latter.
rabbit tibia over an observation period of 6 months Evidence emerging from clinical studies also sug-
(147). The loss in volume observed in this study may gests that the regenerated bone is capable of with-
well be compensated by the documented increase in standing the occlusal loading forces exerted by func-
area density of mineralized bone, thus providing the tional forces and is hence stable over time. A clinical
peri-implant bone with a higher capacity to bear follow-up study of 626 titanium implants that had
loading forces. either been placed into regenerated bone or adjacent
In contrast, implants placed entirely into regener- to which bone had been regenerated at their place-
ated bone in another dog model were either restored ment revealed an overall cumulative success rate of
and subjected to loading forces or not restored (39). 93.8% (62). The observation periods ranged from 6
All implants were osseointegrated to a similar de- to 51 months. A prospective study involving 12 im-
gree, and no apparent differences were reported with plants over the observation period of 5 years demon-
respect to bone-remodeling activities. Control sites strated stable peri-implant marginal bone levels with
that were augmented, but where no implants had an average 0.3 mm of cumulative bone loss (38). This
been placed, demonstrated bone atrophy under- bone loss is within the range of bone loss measured
neath the membranes. The investigators concluded for implants placed into pristine bone (187). These
that placement of an implant represents a stimulus preliminary data indicate that bone generated by
sufficient to maintain regenerated bone and that the guided bone regeneration reacts to implant place-
regenerated bone was able to withstand the loading ment and to functional loading like natural jaw
forces in this model system. The contrasting findings bone.

Guided bone reeeneration at oral imrtlant sites

Guided bone regeneration in conjunction 0.1 mm at re-entry. However, in the 20 cases with
with implant placement premature removal of the membranes, a mean re-
sidual bone deficit of 2.4 mm of an initial mean de-
Following tooth loss, the bone of the alveolar process fect depth of 6.4 mm was present at re-entry. The
has been shown to be subjected to a continuous re- mean amount of marginal bone loss mesially and
sorptive process that is most pronounced in the distally of the implants, which amounted to 0.72 mm
early phases after tooth removal (4, 6, 41). In order over the 7.5 months of observation time, compared
to reduce the problems resulting from this loss of favorably to values for implants placed into pristine
bone, dental implants have been placed into fresh bone (1, 146, 187).This study illustrated that guided
extraction sockets (14, 116, 132).When implants are bone regeneration is very successful for implants
placed into extraction sockets, a partial incongru- that are immediately placed into extraction sockets
ency between the outer surface of the implant and in the absence of soft tissue complications during
the bony walls of the socket often results in a bone the healing period.
deficit in the peri-implant area. Instead of reducing Exposures and infections are common findings as-
the height of the alveolar ridge in order to obtain a sociated with bone regeneration at immediate im-
sufficient width for implantation (1791, barrier mem- plants (8, 17, 157, 170, 184). Conflicting results have
branes have been demonstrated to be successfully been reported regarding the amount of bone re-
applied in order to allow the peri-implant area to be generation in the presence of exposures. Although
filled with new bone in both animal experiments (13, some investigators still obtained very good defect fill
20, 184) and clinical studies (14, 19, 27, 53, 63, 75, with new bone in the presence of membrane ex-
100, 101, 112). posures (531, it is generally agreed that membrane
The one-stage method of combining implant exposures lead to compromised results (17, 89, 170,
placement with guided bone regeneration has been 184, 190, 192) and that proper flap design, a careful
applied much more frequently in clinical practice surgical technique and a strict maintenance pro-
than the two-stage method using guided bone re- gram minimize postoperative complications (14).
generation prior to implantation. The benefits of the One matter of initial discussion dealt with the
simultaneous approach are 1) reduced number of question of whether an implant that is placed at the
surgical interventions, 2) shortened treatment time, time of regenerative surgery will actually be osseo-
3) ideal placement of the implant into the alveolar integrated by the newly formed bone. Subsequent
housing of the lost tooth and 4) reduction of treat- studies have consistently documented that this pro-
ment costs. cedure will lead to osseointegration of the exposed
titanium implant surfaces (13, 21, 56, 66, 101, 172,
Guided bone regeneration at submerged implants. 186).
A recent multicenter study evaluated the results of Depending on the structure of the peri-implant
guided bone regeneration with expanded polyte- defect and the presence or absence of bony walls
trafluoroethylene membranes for the treatment of to support the membrane, different results regarding
bone defects at implants placed into extraction bone fill have been reported. In a recent study (16),
sockets (17). Forty-nine implants were placed into sites with a bony wall showed a mean residual lack
extraction sockets immediately following removal of of bone of 0.3 mm at re-entry surgery, whereas sites
the teeth. The reasons for extraction mainly encom- with dehiscence defects measured 0.6 mm on aver-
passed advanced periodontal disease, root fractures age. In situations with extensive bone defects follow-
and failed endodontic therapy. Flap incisions prior ing tooth extractions, the two-stage surgical ap-
to extraction were performed with the aim of proach is generally preferred.
allowing for primary coverage of the membrane and Extraction sockets show an excellent tendency for
the two-stage implant. Primary stability was spontaneous healing with bone (3). One might as-
achieved by preparing implant beds reaching into sume that, in the presence of ideal peri-implant de-
pristine bone beyond the socket. Premature removal fect structure, the implant will be properly osseo-
of membranes due to exposures, inflammation of integrated without the need for guided bone re-
the surrounding tissues or infections of the area was generation. In a previous study in humans
necessary in 41% of the sites. The 1-year survival rate comparing bone fill in artificially prepared defects
of the implants was 93.9%. In the absence of compli- between the test group using an expanded polyte-
cations, the mean bony defect fill was very good, trafluoroethylene membrane and a control group
changing from 4.9 mm at the deepest site initially to treated without membrane, better results were ob-

Hammerle & Karring

tained in the membrane group (138).These findings mucosal implants (see the section on the benefit of
are in agreement with results from other human and resorbable membranes in this chapter).
animal studies in which the control groups consist-
ently failed to provide as good results as those ob- Guided bone regeneration at transmucosal im-
tained in the test groups (51, 56). In contrast, other plants. In the studies discussed above, surgery was
investigators reported that undisturbed bone forma- performed to submerge both the implant and the
tion in fresh extraction sockets was quite good, so membrane under the soft tissue flap, thus aiming at
that only few threads remained uncovered at the healing by primary intention.
time of abutment connection of submerged immedi- The technique of guided bone regeneration has
ate implants (151). recently been used in conjunction with the place-
Tissue healing and bone regeneration of extrac- ment of transmucosal implants into fresh extraction
tion sockets are profoundly influenced by the inser- sockets (27, 45, 112, 180). Case reports using this
tion of implants. The outcome of such a healing pro- method were first presented in 1993 (45). The critical
cess cannot be foreseen. Hence, conducting clinical difference from the above-mentioned procedures is
studies with negative controls is precluded for ethi- that the implant was deliberately left in a transmu-
cal reasons. cosal position during the entire phase of bone re-
A disadvantage of combining guided bone re- generation. In a prospective study involving 16 con-
generation with implant placement is the fact that, secutively treated patients with 25 implants over an
in case of a compromised treatment outcome re- observation period of 2.5 years, the details of this
garding bone formation, only the more apical part method were described (112). As opposed to the
of the implant will be properly osseointegrated. In above-described methods for immediate implan-
such situations, long-term prognosis is impaired tation in conjunction with guided bone regenera-
(58), and the rate of soft tissue complications is in- tion, this technique does not aim at primary closure
creased (117). When the two-stage technique is ap- of the flap completely covering both membrane and
plied, then the implant is placed in a second surgical implant. In contrast, the flap is adapted around the
procedure, at membrane removal, and such a prob- neck of the implant, thus indeed covering the mem-
lem can adequately be dealt with at this moment. brane but leaving the implant in transmucosal posi-
No data are available concerning the long-term tion.
performance of implants placed under these clinical The results of a study on 10 patients with surgical
conditions. Most of the data available represent new re-entries 6 months following guided bone regenera-
developments with respect to the combination of tion therapy demonstrated successful bone gener-
implant placement and the guided bone regenera- ation into defects around transmucosal implants
tion procedure without the proper validation necess- (75). The mean fill of the defects with bone
ary for general recommendation in patient treat- amounted to 94%, which is in the upper range of the
ment. During the development period, the surgical defect fill reported in earlier investigations. Pre-
technique, the patient selection and the guidance of viously, mean bone fill was reported to amount to
the patient, as well as the proper membrane and, if 75% (511, 90% (1001, 94% (19) and 82% (53).
applicable, the optimal grafting material are being Comparison between the clinical results of im-
tested and appropriately refined. Following this de- mediate transmucosal implants and implants placed
velopment period, the successful treatment ap- under standard conditions at 1 year following incor-
proaches should enter an evaluation period, in poration of fixed prostheses revealed favorable con-
which the implants, placed under these specific pro- ditions for the 20 patients in each of the two groups
tocols, can be evaluated on a long-term basis. Re- (27). Low plaque and mucositis scores, similar
sulting from this evaluation period, long-term sta- amounts of recession, probing pocket depth and
bility of successfully applied treatment outcomes clinical attachment levels were registered.
can be determined. It has previously been claimed that primary
Unfortunately, the application of nonresorbable wound closure following guided bone regeneration
membranes necessitates a rather extensive second surgery was a prerequisite for the formation of min-
surgical intervention for their removal. By using re- eralized bone (34, 184).This statement was based on
sorbable membrane barriers this second surgery the finding that bone formation was less favorable
may be limited to the minimum necessary for abut- when dehiscences occurred, compared with situ-
ment connection and prosthetic and aesthetic treat- ations in which the soft tissues remained intact dur-
ment, or not be required at all in the case of trans- ing the entire regenerative period (17, 34, 89, 170,

Guided bone reaeneration at oral imalant sites

184, 192). As a consequence of these results, it was cessive forces in very unfavorable biomechanical
concluded that a flap dehiscence following primary situations were applied and lead to these findings.
wound closure represents a complication usually Evidence in favor of bacterial causes of late peri-im-
leading to a compromised healing outcome. How- plant tissue breakdown is most overwhelming (115).
ever, on the one hand, implants placed in a transmu- Since the causes and pathogenesis of peri-implant
cosal position do not impair the successful outcome and periodontal lesions are similar, it is reasonable
of the bone regeneration process per se (27, 45, 75, to anticipate that the treatment should be the same.
112). On the other hand, in accordance with the re- Antimicrobial and regenerative therapies are estab-
sults of studies evaluating guided bone regeneration lished for the treatment of periodontal disease (69,
at submerged implants, defect fill with new bone in 108, 1451, and antimicrobial treatment can be used
the presence of flap dehiscence, inflammation and in the treatment of early peri-implantitis (59, 126).
infection was not as successful as when a flap dehis- In two early studies on guided bone regeneration
cence did not occur (75). Hence, infection control in the treatment of peri-implant bone loss, ligature-
appears to be the key factor for an optimal treatment induced tissue breakdown was initiated around ti-
outcome rather than the mere situation of sub- tanium implants in beagle dogs (72). After 5 months,
merged or transmucosal implant position. the ligatures were removed and regenerative therapy
Attempts to fill defects around freshly placed sub- conducted. Membranes of expanded polytetrafluo-
merged implants with bone have consistently been roethylene were applied to isolate the defects from
documented to lead to osseointegration of the ex- the flap tissue and half of the implants were left in a
posed titanium implant surfaces (13, 21, 56, 66, 101, transmucosal and half in a submerged healing situ-
186). Osseointegration has not been documented ation. Plaque control using antiseptics was per-
following bone regeneration around transmucosal formed for 1 week. At the transmucosal implant sites
implants. However, regeneration of the periodontal mechanical brushing was initiated after 1 week. Soft
apparatus is predictably achieved around teeth in tissue complications were frequent and the mem-
spite of the fact that teeth are located transmucosally branes were removed 4 weeks following placement.
(102, 145). Numerous articles have been published Histological analysis revealed a complete failure of
documenting the intimate contact between the pre- the attempt to regenerate the peri-implant bone (72,
viously exposed root surface and the newly formed 165).
cementum with inserting collagen fibers. Based on From these and other studies it may be concluded
these results from periodontal regeneration studies, that, in accordance with the situation in peri-
it is reasonable to assume that previously exposed odontics, regenerative therapies are not suitable for
implant surfaces can become osseointegrated during the treatment of infectious diseases such as peri-
bone regeneration in cases of transmucosal implant odontitis or peri-implantitis. They can successfully
position. be applied, however, in the treatment of the sequelae
The method of achieving regeneration around of such disease processes: to regenerate the de-
transmucosal implants can be particularly beneficial stroyed periodontal or peri-implant tissues. It is,
when the combination of implantation and re- therefore, of paramount importance to realize that
sorbable membranes may eliminate the need for a the infectious disease process has to be adequately
second surgical procedure. However, further studies treated, prior to regenerative surgery.
testing resorbable membranes are necessary before Successful re-osseointegration of bacterially con-
definite recommendations can be made. taminated implant surfaces by the use of guided
tissue regeneration was reported in a recent animal
study (98). In this experiment the peri-implant bone
Guided bone regeneration in the treatment of tissue had been removed surgically. Subsequently,
peri-implant defects
the implant surface was allowed to be colonized by
Research suggests that peri-implant tissue destruc- pathogenic bacteria during 12 weeks of undisturbed
tion may be caused by bacterial infection and that ligature induced plaque accumulation. Guided tissue
the concomitant inflammation seen is similar to that regeneration therapy was then performed. Histologi-
in periodontal disease (113, 119, 127, 163, 164). Peri- cal analysis of the specimens retrieved after 2
implant tissue breakdown and actual loss of some months showed that new bone formation occurred
implants as a consequence of occlusal overload have in the space underneath the membrane and fulfilled
recently been reported in an animal experiment (93, the histological criteria for osseointegration (2).
94). It is important to note, however, that truly ex- More recent experimental data, however, have

Hammerle & Karrina

questioned the possibility that implant surfaces once obviously not be demonstrated in any of these
exposed to plaque accumulation can be successfully studies, stability of the clinical result over a period
reosseointegrated (140). Following ligature-induced of 1.5 years was documented radiographically in one
peri-implant tissue breakdown, an antibiotic regi- study (77). Successful bone regeneration was ob-
men was initiated. Three weeks later, flaps were tained in spite of the fact that the implants remained
raised on the test sides, the granulation tissue within transmucosal during the entire treatment period.
the bone craters was curetted away and the implants Before guided bone regeneration treatment for
were carefully cleaned with a detergent. After place- late peri-implant failures can be recommended for
ment of expanded polytetrafluoroethylene mem- routine use in practice, some aspects of the clinical
branes and new cover screws, the flaps were sutured procedures still have to be established. These as-
for primary healing. On the control side no local pects include the appropriate antimicrobial therapy
treatment was performed. Histological analysis dem- in terms of the choice of medication, the dosage, the
onstrated no resolution of the defects and signs of duration of this treatment and the optimal manipu-
inflammation on the control side. On the test side lations of the implant surface, the ideal membrane
tissue healing had taken place, including bone re- material - resorbable or nonresorbable - the defects
generation into the previous defect area. On the one most amenable to treatment and the proper time
hand, a connective tissue capsule 200-300 pm thick frame of the regeneration period.
was consistently found in contact with the implant
surface previously exposed to plaque accumulation.
On the other hand, the regenerating bone had grown The use of bone grafts and
into contact with the newly placed pristine cover
screws. These results demonstrate that the healing
substitute materials
and regenerative capacity of the peri-implant tissues
Classification of bone graft materials
following experimental bacterial breakdown are not
impaired, but the applied treatment - debridement Bone grafts have long been used in reconstructive
and cleaning with a detergent - had not rendered surgery with the aim of increasing the bone volume
the implant surface biologically acceptable for bone in the previous defect area. Bone grafts and bone
to grow into contact with it. substitute materials may be classified into two main
In a recent study the effect of guided bone re- groups: autogenic and xenogenic materials. The
generation alone or in combination with various term autogenic graft refers to tissues that are trans-
bone substitutes was evaluated in the treatment of planted within one and the same organism. Auto-
peri-implant defects (87).Following ligature-induced genic bone is the most frequently used material in
tissue breakdown, the defects were debrided and the this group. Xenogenic grafts encompass all materials
exposed implant surfaces cleaned with an air-pow- of an origin other than the recipients organism and
der abrasive instrument. Histological data revealed may further be divided into materials from the same
varying amounts of bone regeneration depending on species but different individuals, materials from
the clinical procedure. The best results were ob- other species and products of nonorganic origin. De-
tained with the combination of guided bone re- mineralized freeze-dried bone represents an allograft
generation and bone substitutes. Furthermore, the material, that is, from the same species, but not the
investigators reported consistent contact between same individual, which has widely been used in
regenerated bone and the previously exposed im- bone augmentation procedures.
plant surfaces. In contrast to previous investigations
(1401, the treatment regimen for decontamination of
Biological behavior
the implant chosen in this study had rendered the
surface biologically acceptable for new bone to grow Introduction. A wide variety of graft materials have
into contact with it. been employed in experimental studies or in clinical
Human studies of the regeneration of tissues after practice. The range of materials used encompass
destruction due to peri-implantitis are limited to a autogenic cancellous or cortical human bone, xen-
few recent case reports documenting the use of ogenic bone transplants such as demineralized
guided bone regeneration in the treatment of early freeze-dried human bone and xenogenic bone sub-
and late implant failures (77).Although the re-estab- stitute materials such as natural and synthetic hy-
lishment of bone-to-implant contact on the surface droxyapatite, deproteinized bovine bone mineral
previously exposed to plaque accumulation could and calcium-phosphate compounds (73, 75, 78, 84,

Guided bone reEeneration at oral irndant sites

86, 105, 106, 136, 141-144, 159). The rationale for ized by a low metabolic index and hence form bone
using bone grafts in combination with guided bone at a slower rate than lower-ranking animals (48). In
regeneration encompasses factors such as support- addition, they have been documented to exhibit
ing the membrane in situations in which the defect lower reactivity to osteoinductive stimuli (153). Both
morphology will not adequately do so, to offer a factors may contribute to the confusion resulting
scaffold for ingrowth of capillaries and perivascular from contradictory results presented in different
tissue, in particular osteoprogenitor cells, and to studies. Whereas bone induction by demineralized
provide a carrier for factors enhancing bone forma- freeze-dried bone allograft has been shown in ro-
tion. Although mechanical support can also be dents, this has not been conclusively demonstrated
achieved by the use of stiffer membranes, pins, mini- in higher species such as dogs, monkeys or humans.
screws or metal reinforcements of membranes (15, Moreover, some of the contrast in the results from
34, 82, 991, the possible biological benefits of filler various studies possibly originates from the fact that
materials cannot be achieved in other ways. demineralized freeze-dried bone allograft prepara-
Bone substitutes should exhibit biocompatible tions from different bone banks and from different
material properties. They should not elicit allergic or batches from the same bank may respond quite dif-
immune reactions. They should be well tolerated ferently (166).Therefore, it has been postulated that
and integrated by the host tissues and ideally pro- assays should be developed to standardize the activ-
vide a scaffold for new bone to grow onto. It has ity of demineralized freeze-dried bone allograft.
been postulated that they should gradually be re- Another source of confusion may arise from the
placed by newly formed bone. Their three-dimen- fact that evidence that demineralized freeze-dried
sional structure should most closely resemble that of bone allograft promotes bone formation has gener-
natural bone with respect to macro- and micro- ally been provided at two different levels: the clinical
porosities. Finally, they should compartmentalize and the histological level. There is general agreement
larger defects into smaller fragments comparable to that the histological data are more reliable than clin-
that of natural human bone (31). ical measurements. Studies combining histological
Unfortunately, many of the products presently and clinical data have recently reported a disparity
available lack adequate scientific documentation to between the two methods of assessing the results of
recommend their general use in conjunction with regeneration (21). Hence, conclusions drawn from
guided bone regeneration procedures. It is therefore purely clinical evaluation of demineralized freeze-
difficult, to critically appraise many of the obtainable dried bone allograft should be interpreted with cau-
bone substitute materials. tion.
Finally, there are contradictory results regarding
Bone-inductive materials. The most intriguing the resorbability of demineralized freeze-dried bone
method of enhancing the local bone volume is by allograft in the host tissues (20, 23, 142).
inducing pluripotent mesenchymal cells to bone- In conclusion, although demineralized freeze-
forming cells. Theoretically, this can be accom- dried bone allograft holds some promise as an osteo-
plished by supplying growth factors or suitable pro- inductive material for use in guided bone regenera-
teins into the defect area. Demineralized freeze- tion procedures, it should be used with caution until
dried bone allograft is a substance that has been it can be provided in a well-standardized and con-
widely used with the purpose of achieving osteoind- trolled form from the bone banks, and until its effi-
uction. However, data from both animal experiments cacy in bone induction has been proven in nonhu-
and from human clinical studies are controversial man primates and in humans.
with respect to the bone-inducing effect of this ma-
terial. Although some earlier publications have pro- Transplantation of autogenic bone. It has long been
vided encouraging data (141, 148, 149, 181), more claimed that autogenic bone is the ideal material to
recent experiments have questioned the ability of increase the bone volume of the jaw bone (31). Be-
demineralized freeze-dried bone allograft to induce fore the advent of guided bone regeneration, intra-
new bone formation (5, 20-23, 142, 143).In this con- oral bone augmentation was commonly performed
text it appears that both the rank on the phylogen- by the use of autogenic bone transplants preferen-
etic ladder as well as the source and the preparation tially taken from the iliac crest. Such a procedure is
of the demineralized freeze-dried bone allograft pro- very demanding regarding operator skills and logis-
foundly influence the final outcome. Animals rank- tical support for the surgical intervention, is highly
ing high on the phylogenetic ladder are character- stressful for the patient and causes considerable

Hammerle & Karring ~~~ ~

post-operative pain, and the treatment is very costly. terials exhibiting large surface areas showed better
Ridge augmentation using bone grafts without mem- bone-graft contact than materials with a compara-
branes is subjected to extensive resorption of the tively small surface area (86, 105, 106).Deproteinized
graft (111, 175). Loss of graft volume in the magni- bone mineral in its unaltered form has presumably
tude of 50% have been reported during healing over ideal architecture for use as a bone graft material.
the period of 6 months. However, due to manipulations during the purifi-
One of the possible indications for guided bone cation process, different tissue integration properties
regeneration is the replacement of such procedures. of the natural bone mineral may result. Thus, bo-
A recent study (95) has demonstrated that the results vine-derived bone mineral exhibiting natural crystal-
of guided bone regeneration, when combined with linity (Bio-Oss, Geistlich, Wolhusen, Switzerland)
autogenic bone grafts, are superior to the traditional yielded increased bone-to-graft contact compared
method of transplanting bone without adequate with a product of the same origin but with larger
protection by barrier membranes. In this dog study crystal size (Endobon, Merck Biomaterials, Darm-
demineralized freeze-dried bone allograft and stadt, Germany) (96).
cortico-cancellous iliac autografts with and without The results regarding bone-to-graft contact and
barrier membranes of expanded polytetrafluoroe- hence the osteoconductive properties attributed to
thylene were compared. The best results were ob- the materials tested vary considerably between dif-
tained with the combination of the autogenic graft ferent studies, rendering interpretation and com-
and the membrane in terms of the graft volume in- parison difficult (76, 78, 85, 86, 96).
corporated as well as the direct bone-to-implant Bone-to-graft contact also depends, among other
contact. factors, on the density of bone in the vicinity of the
In a recent clinical article (371, the successful com- graft. In order to ameliorate interpretation of results,
bination of autogenic cortico-cancellous bone grafts this factor should be taken into consideration in the
and guided bone regeneration has been shown. A assessment of the osteoconductive properties of a
group of 40 patients consecutively treated with this bone substitute. Recently, an osteoconductivity
method demonstrated a very low frequency of soft index has been proposed, which was calculated by
tissue complications and successful ridge augmenta- using a model to detect phase association from the
tion in 66 sites. A mean gain in crest width of 3.5 direct bone-to-graft contact and the area density of
mm was measured allowing implant placement in bone in the vicinity of the graft (76). It was postu-
proper position in all 66 sites. lated that values above 1.0 indicate that the bone
These very good results may be used as a standard grows preferentially in contact with the graft,
against which new developments, aiming at reduc- whereas values of less than 1.0 indicate that the
ing efforts necessary to obtain successful treatment bone-to-graft contact is taking place at a level less
outcomes, can be tested. than what could be expected by randomly occurring
contact, and therefore, the bone is being hampered
Xenogenic bone substitutes. Xenogenic bone sub- from making graft contact. Thus an index that equals
stitutes of hydroxyapatite have recently been de- 1.0 indicates that bone-to-implant contact is occur-
veloped. Experimental studies have dealt with ma- ring at random. In that study, this parameter reached
terials manufactured synthetically (68, 86, 105, 144), values of 2.9 at the sites treated with membrane and
derived from corals or algae (73, 96, 105, 106, 144) or deproteinized bovine bone mineral and of 2.6 for the
originated from natural bone mineral (25, 46, 64, 76, sites treated with deproteinized bovine bone mineral
78, 96, 107, 156, 159, 176, 188). These materials are group, indicating high osteoconductivity of the graft
considered biocompatible and osteoconductive. (76).
Nevertheless, considerable differences in their be- Recent studies have evaluated a deproteinized bo-
havior based on material properties have been re- vine bone mineral as a filler in a guided bone re-
ported. generation procedure model on the rabbit skull (78,
Integration of natural bone mineral has been 159). In combination with a stiff bioresorbable mem-
shown to be superior to coral- or algae-derived hy- brane made of polylactic acid, this substitute im-
droxyapatite products (96). One of the reasons for proved the amount of initial soft tissue formation
these differences may be the three-dimensional and initially increased the rate of mineralized bone
structures, including the porosities of bone grafts, formation compared with blood-filled controls.
which have been documented to have important ef- It has been postulated that formation of soft tissue
fects on bone healing (49, 86, 105, 106, 183). Ma- is a step of critical importance in the sequence of

Guided bone regeneration at oral implant sites

events ultimately leading to mature mineralized

bone (78). In a recent experiment, titanium test
tubes were implanted in the retromolar area of
healthy volunteers (81). Regenerating tissue was cap-
able of adhering to the bony base from which it orig-
inated and to the expanded polytetrafluoroethylene
membrane closing the flap facing opening of the
tube and thus separating the soft tissues from the
space inside the tube. The surface of the inner walls
of the tube was made up of polished titanium, pre-
venting cellular adherence (28, 29, 42, 43). In the 2-
week specimens the tissue completely filled the in-
side of the tube, whereas in the 7-week and 12-week Fig. 8. Bone regeneration around deproteinized bovine
ones the newly formed tissues exhibited the shape bone (DBB) from a human specimen. Large areas of the
of an hourglass (Fig. 7a). Apparently, during the graft particles are in direct bone contact (new bone: nb).
phase of fibroplasia, the regenerated soft tissues Some areas are in contact with bone marrow tissue (bm).
Direct deposition of osteoid (0s) produced by osteoblasts
were pulled away from the cylinder walls rendering is occasionally visible. The newly formed bone is sub-
the shape observed. Interestingly, even after obser- jected to remodeling activity as indicated by the presence
vation periods of up to 9 months, when the majority of osteoclasts. Similarly, osteoclasts (arrowheads)are seen
of the space was occupied by new bone, this particu- resorbing the bone substitute.
lar shape was unchanged (Fig. 7b). The investigators
concluded that the outer borders confined by the
mature soft tissue, which arises prior to mineraliza- found in previous studies evaluating sequential
tion, delimit the area ultimately available for bone to stages of guided bone regeneration without the use
form (78, 81). of bone substitutes (79, 109, 154). The fact that the
The observed acceleration of bone formation in pattern of bone formation and the sequence of bone
conjunction with the use of bone substitutes in the remodeling are not negatively influenced by the use
rabbit skull model may be attributed to the higher of this type of bone substitute is of particular im-
amount of osteoblasts found in the test specimens portance for the application of this method in oral
(78, 159). With the increase in osteoblast numbers - implantology. Only lamellar bone, owing to its high
the only cells capable to form bone - the rate of bone biomechanical competence, optimally fulfills the re-
formation rises. The application of the substitute quirements for taking up loading forces transferred
material evidently created an environment that by implants.
allowed earlier immigration of osteoblasts into the There is general agreement that dense synthetic
area intended for guided bone regeneration. By de- hydroxyapatite is nonresorbable in viuo (33, 68, 96,
signing bone substitute materials with appropriate 105,184) and that calcium phosphate compounds as
surface characteristics, this biological mechanism well as coral- or algae-derived materials degrade
may be used with greater benefit in bone regenera- over time (33, 73, 96). Conflicting results, however,
tion procedures. Several studies have indicated that have been published regarding the long-term per-
the use of bone grafts of natural bone mineral does formance of natural bone mineral. Although some
not decrease bone-to-implant contact when used to investigators have reported rare signs of biodegrada-
treat peri-implant defects in guided bone regenera- tion or complete lack of breakdown (57, 78, 1561,
tion procedures as compared with the use of mem- others have described definite graft resorption (24,
branes alone (25, 76, 1881. 76, 96, 107, 188) or documented decrease in area
The physiological pattern of new bone formation density of the graft over time (25). In one of these
with guided bone regeneration in the presence of studies, active resorption of the Bio-Oss particles by
bone substitutes of natural bone mineral has re- osteoclasts was demonstrated unequivocally by
cently been described by Hammerle et al. (78). NO staining with tartrate-resistant acid phosphatase
qualitative differences were detectable in test and (76). Although, the resorption process by osteoclasts
control specimens, indicating that the presence of has thus been documented, no data are available on
the graft material did not alter the basic pattern of the rate of resorption and on the behavior of the re-
bone formation (Fig. 8). These findings were similar sulting spaces.
to the description of the type of bone formation One direction of present research involves the de-

Hammerle & Karring

Guided bone regeneration at oral implant sites

velopment of resorbable grafting materials chemic- generation, the newly developed and successful
ally based on synthetic polymers (185). These com- treatment approaches should enter a validation
pounds offer a number of advantages over presently period, in which the implants, for the placement of
used fillers. They can be custom made regarding re- which the incorporation of bone grafts and substi-
sorption time, stability and rigidity, three-dimen- tutes was indicated, should be evaluated on a long-
sional structure and pore size, and finally they can term basis with respect to the stability of the suc-
be used as carriers for compounds enhancing bone cessfully obtained treatment outcomes.
The benefit of
Clinical applications resorbable membranes
Human clinical studies on the use of bone grafts and
Material developments and experimental studies
of bone substitutes are scarce. Available data are
mostly limited to case reports and reports of case With the presentation of the first successful guided
series (16, 37, 57, 84, 128, 173), some of which report bone regeneration procedures and the subsequent
test and control procedures (22, 65, 170, 192, 193). wide and successful application of expanded polyte-
Controlled long-term clinical studies are lacking. trafluoroethylene membranes, this material became
So far, autogenic bone grafts in conjunction with standard for bone regeneration. An obvious disad-
guided bone regeneration have yielded the best re- vantage of this material is that it is nonresorbable
sults with high predictability (16, 37). However, and, therefore, has to be removed with a second sur-
studies involving harvesting of autogenic bone for gical procedure. Regarding patient morbidity, risk for
transplantation should not only present data on the tissue damage, and from a cost-benefit point of view,
success of the treatment at the regenerated site but the replacement of nonresorbable by resorbable
should also provide information about the morbidity membranes would be desirable. Hence, recent ex-
and the discomfort caused to the patient by the har- perimental research in guided bone regeneration has
vesting procedure. Not before this aspect has been aimed at developing resorbable barrier membranes
included in the evaluation process should a compre- for application in the clinic.
hensive benefit-risk analysis of the various concepts Bioresorbable materials that may be used for the
for grafting in guided bone regeneration be con- fabrication of membranes all belong to the groups
ducted. of natural or synthetic polymers. The best known
Most of the data available with respect to the use groups of polymers used for medical purposes are
of bone grafts and bone substitute materials repre- collagen and aliphatic polyesters. Currently tested
sent presentations of new developments. In accord- and used membranes are made of collagen or of po-
ance with the sequence of analysis described for im- lyglycolide and/or polylactide or copolymers thereof
plants placed in conjunction with guided bone re- (90) (Fig. 9a-h).
Several design criteria have been postulated for
membranes as being favorable for their use in
Fig. 9. a. Due to failed endodontic treatment, tooth num- guided bone regeneration. Thus, it was postulated
ber 34 has to be extracted. Therapy with an immediate that the membrane barrier should be permeable for
implant and guided bone regeneration is favored over a exchange of critical fluid substances with putative
conventional bridge due to inappropriate adjacent poten-
tial abutment teeth. b. Eight weeks following extraction of nutritive or instructive function. It was later shown
the root, the soft tissues have healed over the extraction in an animal experiment on the rabbit skull that
socket. c. Careful flap elevation has exposed the alveolar membrane permeability is not a prerequisite for
process with the tooth socket. d. A full-body plasma- guided bone regeneration, as new bone had formed
sprayed implant has been placed with primary stability in both the test and control chambers (160).
into the alveolus. e. A bone substitute of natural bone
mineral is use to support a collagen membrane. The results of another animal experiment have
f. The collagen membrane has carefully been adapted to shown that occlusive bioresorbable membranes
the bony walls surrounding the defect and has been made of polylactic or polyglycolic acid are equally
punched and slipped over the shoulder of the implant. successful as expanded polytetrafluoroethylene
g. At re-entry surgery 6 months later, regenerated hard membranes in regenerating bone in transosseous
tissue is found in the previous defect area around the co-
ronal part of the implant. h. Radiographic control of the defects in the rabbit mandibular ramus (152). How-
implant and the surrounding regenerated bone prior to ever, bone formation in the defects separated by the
initiation of prosthetic treatment. resorbable membranes was associated with chondral

Hammerle & Karrinn

bone formation, whereas the defects treated with ex- A different approach was taken in experimental
panded polytetrafluoroethylene membranes were studies evaluating a form-stable bioresorbable mem-
associated with bone formation along the desmal brane made of polylactic acid in conjunction with a
pathway. Based on an earlier study (169),the investi- bone substitute in a rabbit skull model (78, 159).
gators concluded that since the impermeable mem- New bone was demonstrated to form underneath
branes had prevented oxygen from passing from the the membrane beyond the borders of the former cal-
soft tissues into the area intended for bone regenera- varium. On the one hand, this experiment demon-
tion, the low oxygen tension in the defect area had strated that, in principle, stiff, bioresorbable mem-
resulted in cartilage formation as an intermediary branes are conducive to bone regeneration and bone
step prior to bone formation (152). neoformation. On the other hand, after the obser-
In accordance with these findings are the results vation period of 2 months, no overt signs of break-
of an experiment evaluating the effect of different down of the membrane were reported. In many clin-
pore sizes of expanded polytetrafluoroethylene ical situations a resorption time between 6 and 12
membranes in guided bone regeneration on the rat months is mandatory in order not to lose the advan-
skull (191). It was found that the dome-shaped tages of resorbability.
membranes exhibiting internodal distances of less
than 8 pm showed delayed bone fill compared with
Results of clinical applications
membranes, where these distances ranged from 20-
25 pm or were in the range of 100 pm. In addition, Beginning in the early 1990s and thereafter, reports
soft tissue integration and peripheral sealing associ- of cases or case series were presented describing the
ated with the small internodal distance were re- use of resorbable membranes for guided bone re-
ported to be inferior. Nevertheless, after 12 weeks, generation at exposed implant surfaces (10, 88, 89,
a similar degree of bone fill was observed with the 124, 125, 137, 139, 193). Later, controlled clinical
different membrane types. studies were published (171, 192). In all of these re-
From these studies it may be concluded that ports a low rate of complications involving inflam-
membrane porosities are indeed no prerequisite for mation of the flap covering the site of regeneration
bone formation, but optimal pore sizes are advan- and exposures of membranes were observed. In two
tageous regarding nutrient flow, wound stabilization studies involving a larger number of consecutively
and peripheral sealing to prevent ingrowth of soft treated patients, the results with respect to bone re-
tissue-forming cells. generation were very favorable. Bony defect fill
Unfortunately, most of the available resorbable ranged from 83% (193) to 92% (89). Similar results
membranes are not capable of maintaining space. were reported in the treatment of dehiscence and
Therefore, they need to be supported in one way or fenestration defects at threaded implants with the
another. The most commonly used method for use of bioabsorbable membranes made of polyglyco-
membrane support is to sustain it with autogenic lide and polylactide (125).Even though no bone graft
grafts or with bone substitutes (9, 139, 158, 192, 193), or bone graft substitutes were used, 14 out of 17 de-
whereas other methods such as screws, pins and re- fects showed complete bone fill at re-entry.
inforcements have also occasionally been applied In one of the controlled clinical studies, a collagen
(67, 109). membrane was tested against an expanded polyte-
Several animal experiments have demonstrated trafluoroethylene membrane (192). At the re-entry
the successful use of bioresorbable membranes in operation 4 to 6 months following guided bone re-
guided bone regeneration (44, 78, 109, 120, 121, 123, generation surgery, 57% of the 39 defects treated
152, 158, 159, 168), whereas only few have reported with collagen and 57% of 14 defects treated with ex-
failures (12, 32, 67, 157, 189). In two recent experi- panded polytetrafluoroethylene membranes showed
ments, a polylactic acid membrane was tested in its complete bone fill. Incomplete bone regeneration
ability to increase the bone volume in conjunction was found in 39% of the test sites and 29% of the
with an autogenous bone graft compared to controls control sites. No gain of new bone was found in 5%
that were grafted only (120, 121). Both experiments of the test sites and 15% of the control sites. A high
showed more bone formation when the membranes percentage of exposure of membranes (19%) leading
were applied. These results demonstrate that soft to early removal occurred in sites treated with ex-
polylactic acid membranes are suitable for guided panded polytetrafluoroethylene membranes. Al-
bone regeneration procedures in conjunction with though, the possibility for early resorption of colla-
autogenous grafts. gen membranes is mentioned in the article in cases

Guided bone regeneration at oral imdant sites

of incomplete wound closure, unfortunately, no data 8. Augthun M, Yildirim M, Spiekermann H, Biesterfeld S.

Healing of bone defects in combination with immediate
are presented with respect to this complication.
implants using the membrane technique. Int J Oral Maxi-
In the most recent controlled clinical study, 18 im- lofac Implants 1995: 10: 421-428.
plants with exposed threads were divided into two 9. Avera SI: Stampley WA, McAllister BS. Histologic and clin-
groups (171). In both groups the defects were filled ical observation of resorbable and nonresorbable barrier
with autogenous bone. In the test group a resorbable membranes used in maxillary sinus graft containment.
polylactic or polyglycolic acid membrane was Int J Oral Maxillofac Implants 1997: 12: 88-94.
10. Balshi TJ, Hernandez RE, Cutler RH, Hertzog CE Treat-
adapted, whereas in the control group a standard ex-
ment of osseous defects using Vicryl mesh (polyglactin
panded polytetrafluoroethylene membrane was 910) and the Brlnemark implant: a case report. Int 1 Oral
placed. Neither in the test nor in the control group Maxillofac Implants 1991: 6: 87-91.
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registered. Six to seven months later, both groups re- T, Gillett NA. TGF-P1 induces bone closure of skull de-
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vealed excellent bone regeneration, with values of
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89% and 98% defect fill. Although the test group 12. Becker J, Meissner T, Reichart PA. Gesteuerte Knochen-
yielded less bone fill and exhibited a higher vari- regeneration mit Membranen aus Polyesterurethan. Im-
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