Periodontology 2000, Vol.
17, 1998, 151-1 75
Printed in Denmark All rights reserved
Guided bone regeneration at
oral implant sites
H. F. HAMMERLE
CHRISTOPH KARRING
& THORKILD
Guided bone regeneration is an accepted method
successfully employed in dental practices to increase
the volume of the host bone at sites chosen for im-
plant placement. Originally, the biological principle
leading to the method of guided tissue regeneration
was discovered by Nyman and Karring (103, 104, 131,
133) in the early 1980s as a result of the desire to
regenerate lost periodontal tissues. As a conse-
quence, novel possibilities to regenerate periodontal
tissues with new root cementum, periodontal liga-
ment and alveolar bone became available (70, 71,
130, 134).
Soon, guided tissue regeneration found appli-
cations in other areas, including the regeneration of
bone tissue (129). As a result of animal experiments
(52, 54, 56, 167) and clinical applications in humans
(14, 34, 114, 116, 132, 184), guided tissue regenera-
tion has become a clinically accepted method for
augmenting bone in situations with an inadequate
volume for the placement of endosseous dental im-
plants. The formation of new bone in conjunction
with the placement of dental implants is also a clin-
ically well documented and successful procedure
(13, 51, 53, 100, 112, 116).
There is general agreement that guided bone re-
generation is difficult to perform and demanding re-
garding the skills and experience of the therapist.
Whereas enlargement of jaw bone in conjunction
with implant placement is the most frequent indi-
cation, it has also been used to increase the bone
volume in order to achieve better aesthetics (47).
This chapter discusses the scientific and clinical
aspects of guided bone regeneration based on avail-
able data.
Biological basis of guided bone
regeneration
In principle, four methods have been described to
increase the rate of bone formation and to augment
Copyright 0 Munksgaard 1998
PERIODONTOLOGY 2000
ISSN 0906-6713
the bone volume: osteoinduction by the use of ap-
propriate growth factors (148, 149, 181); osteocond-
uction, where a grafting material serves as a scaffold
for new bone growth (30, 149); distraction osteogen-
esis, by which a fracture is surgically induced and
the two fragments are then slowly pulled apart (91,
92); and finally, guided tissue regeneration, which
allows spaces maintained by barrier membranes to
be filled with new bone (50, 54, 56, 81, 109, 110, 135).
Since biochemical induction of bone formation
is still in an experimental phase, and since distrac-
tion osteogenesis cannot be applied in the healing
of local bone defects in the jaw bones, guided
bone regeneration and the use of bone grafting
materials are the only methods commonly applied
in clinical practice. Among the techniques de-
scribed, guided bone regeneration has shown the
best and most predictable results when employed
to fill peri-implant bone deficits with new bone
(13, 27, 34, 53, 75, 132).
Although bone regeneration using membrane bar-
riers is often successfully achieved in clinical prac-
tice, many problems remain and need to be resolved
to increase predictability. The problems most fre-
quently encountered with guided bone regeneration
include partial or total collapse of the barrier mem-
brane, exposure of membranes due to soft tissue
dehiscences resulting in local infection and incom-
plete bone regeneration within the space provided
by the membrane. In order to overcome these diffi-
culties, often resulting in unsatisfactory clinical re-
sults, various attempts have been made to improve
the devices and the surgical techniques.
It soon became evident that improved knowledge
about the biological mechanisms and the temporal
dynamics of new bone formation under the con-
ditions of guided regeneration is critical. Scientists
and clinicians considered this knowledge a prerequi-
site to better understand the healing steps leading to
regenerated and fully mature bone in order to be
able to beneficially influence healing for further de-
151
Hamnzerle & Karring

152

velopments in the field and for increased predict-
ability of the clinical outcomes.
So far, the type of bone being formed by applying
the principle of guided tissue regeneration has only
been investigated in a few animals (79, 110, 154) and
some human studies (81). Two of these animal
studies were dealing with surgically prepared bone
defects (79, 154). One study focused on tissue heal-
ing in bone defects in the mandible of dogs (154).
The other experiment investigated the temporal and
spatial dynamics of bone regeneration in calvarial
defects in rabbits (79). The third experiment ex-
plored the possibility of augmenting the naturally
present bone volume in the mandible of rats (110).
In all these experiments, a similar basic pattern of
bone formation was observed. Initially, trabeculae of
woven bone proliferated into the defect. In two
studies, the space provided by the membrane was
filled with a newly formed connective tissue matrix
prior to the formation of mineralized bone (79, 81,
154).The investigators concluded that the size of the
defects did not allow for direct formation of mineral-
ized bone, since new bone is only formed at loca-
tions where biomechanical stability is guaranteed,
that is, where pressure and tensile forces are ex-
cluded (177). Otherwise, an intermediate tissue with
appropriate mechanical properties will arise before
ossification.
The mechanism of bone healing being dependent
Fig. 1. a. Newly formed bone trabeculae (purple) closely
follow the pathway given by the proliferating vessels
(brown).b. The new bone (black) consists of irregularly
shaped, delicate trabeculae lined with osteoid seams (0s)
and a layer of cuboidal osteoblasts (arrows). Collagen
fibers (arrow heads) are progressively embedded into the
mineralizing osteoid. c. A newly formed trabeculae of
woven bone is embedded in a highly vascularized connec-
tive tissue. The bright red osteoid seam is covered by a
layer of osteoblasts (arrows).Osteocytes are encircled by
the mineralizing bone (arrowheads). d. Fluorochrome
labeling demonstrates the sequential steps of the re-
generation of mineralized bone. Bone stained in bright
yellow (tetracycline label) is of woven nature (wb).Lamel-
lar bone deposition (arrows) is labeled in red (alizarine
label) and green (calceine label). e. Osteoclasts (Oc) are
resorbing the primarily formed woven bone (Wb). Osteo-
blasts (Ob) in their immediate vicinity deposit layers of
mature lamellar bone on the remnants of the original tra-
becular scaffold. f. Remnants of the dark-stained,primary
trabecular scaffold are covered by new bone lamellae.
g. By continuous apposition of lamellar bone, a primary
osteon (PO) with a central blood vessel is formed. h. As part
of normal bone turnover osteoclasts were resorbing parts
of the cortical bone followed by osteoblastic bone appo-
sition leading to the formation of secondary osteons (so).
Guided bone regeneration at oral implant sites
on the size of the defect has previously been eluci-
dated in an experimental rodent model. In cortical
bone, circular defects of less than 200 pm had the
potential to heal with concentric formation of lamel-
lar bone (97, 155). In larger defects of 200 to 500 pm,
bone healing was characterized by formation of a
trabecular network of woven bone bridging the de-
fect. Subsequently, the spaces between the trabecu-
lae were filled with lamellar bone. However, in de-
fects of 500 pm and larger, bridging by direct forma-
tion of bone did not occur. Following 3 weeks of
healing, such defects exhibited a central area char-
acterized by the presence of connective tissue.
The intermediate connective tissue described in
the two above-mentioned experiments (81, 154) pro-
vided the appropriate mechanical properties necess-
ary to allow for unimpeded ingrowth of blood capil-
laries during angiogenesis (Fig. la), which always
precedes bone formation (162). However, with in-
creasing defect size the biomechanically stable zone
becomes successively limited to the marginal area of
the defect, whereas the central region is exposed to
biomechanical forces presumably preventing bone
formation. This view is supported by experimental
and clinical observations that showed that, in large
bone defects, bone formation is limited to the defect
margins (11, 50, 60, 80, 123).
In the experiment with the augmentation of the
mandibular ramus in rats, in contrast, the new bone
proliferated into the defect space without a nonmin-
eralized connective tissue matrix occupying the en-
tire area for regeneration (110).
Similar observations regarding bone formation
have been reported in canine mandibular and ro-
dent calvarial bone defects (79, 154). The new bone
formation generally originated from the bony bor-
ders of the defect. This new bone appeared as a scaf-
fold of delicate trabeculae comprised of woven bone,
from which several extensions were directed towards
the center of the defects (Fig. lb, c). The surfaces of
the trabeculae were commonly covered by osteoid
seams lined by a dense layer of cuboidal osteoblasts.
The trabeculae were embedded in a well-organized
and vascularized granulation tissue. At various loca-
tions integration of collagen fiber bundles into the
new bone matrix could be detected. In the course of
bone apposition, surrounding connective tissue
fibers became embedded into the osteoid and finally
integrated into the new bone. Within the network of
the trabecular scaffold, numerous blood capillaries
were consistently found connected with the vessels
of the opened bone marrow cavity of the adjacent
bony defect borders. In addition, a considerable
153
Hammerle & Karring
number of proliferating blood capillaries ac-
companied and even preceded the bone trabeculae
growing towards the mid-part of the defect (79, 154,
162).As the mineralized bone grew, blood vessels ly-
ing in its immediate vicinity became incorporated
into the new bone matrix.
The remainder of the defect area, which was not
filled with bone yet, contained loose connective
tissue comprised of scarce collagen fibers without a
preferential orientation. Sparsely distributed cells,
predominantly fibroblasts and macrophages as well
as a moderate number of wide blood capillaries were
seen.
In contrast to the findings in the other studies,
bone islands arose within this fibrovascular tissue in
the calvarial defect model as identified by means of
radiographs and serial sections (79). Their texture
was consistent with that of woven bone, that is, ir-
regular bundles of collagen fibers and extremely nu-
merous, large osteocytes, and they were without
contact with the marginal bone. The proliferation of
new bone in this pattern has not been described pre-
viously, unless a sutural growth area was given ac-
cess to the defect area (11, 60). The investigators
concluded that osseous defect closure arising both
from the margins of the bone defect and as islands
may be a faster healing process than marginal bone
formation alone.
Common to all these experiments was the finding
that the bone volume increased with time and that
the primary intramembranous trabecular scaffold
underwent intense remodeling: numerous osteo-
clasts arose and began to eliminate the primitive
woven bone, whereas a new generation of osteo-
blasts deposited mature lamellar bone layers on the
woven bone remnants (Fig. Id, e). As a consequence
of the continuous remodeling of the primary bony
network, most of the trabeculae contained only a
small, intensely stained core of woven bone sur-
rounded by thick bone layers of regular lamellar tex-
ture and thus comprised the secondary spongiosa
(Fig. If). The continuous growth of the bone tra-
beculae resulted in the narrowing of the intertra-
becular connective tissue and in the formation of
primary osteons containing vascular channels (Fig.
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
bone deposition. Finally, secondary osteons were
formed replacing the previously formed cortical
bone (Fig. lh).
The only available human data on the sequential
154
steps of guided bone regeneration describe bone
healing in the molar area in the mandible (81). Hol-
low titanium test cylinders measuring 3.5 mm in
outer diameter, 2.5 mm in inner diameter and a
height of 4 mm were placed into standardized holes
in the retromolar area of healthy volunteers. The cyl-
inders were placed in such a way that 1.5 to 2 mm
of the test devices was submerged below the level of
the surrounding bone, and 2 to 2.5 mm surpassed
the bone surface. The bone-facing ends of the de-
vices were left open. The soft tissue facing ends were
closed by means of expanded polytetrafluoroethy-
lene membranes (Gore-Tex Periodontal Material@,
Flagstaff, AZ) before the soft tissue flaps were su-
tured for primary healing. After observation times
ranging from 2 to 36 weeks, the cylinders along with
the regenerated tissue were harvested and analyzed.
The tissue generated at 2 and 7 weeks exhibited a
cylindrical shape, whereas the specimens harvested
at 12 weeks and at later time points, yielded the form
of an hourglass. Specimens of 12 weeks and less
healing time almost entirely contained soft tissue.
Specimens with generation times of 4 months and
more contained both soft tissue and increasing
amounts of mineralized bone.
Up to a period of 6 months of healing, new bone
was primarily filling the previously prepared defect
within the host bone. Therefore, by reaching the
level of the surrounding host bone, true regeneration
of bone had occurred. Interestingly, bone formation
did not come to a halt at this point but proceeded
above the borders of the skeleton, thereby altering
the genetically determined form of the mandible.
This formation of new bone beyond the skeletal bor-
ders by applying the method of guided tissue re-
generation was first demonstrated on the calvaria of
rabbits (161). Subsequently, these findings were con-
firmed in other experimental animals such as rab-
bits, rats, and dogs (83, 99, 109, 110, 118, 122, 160).
The first guided bone neogenesis in humans was
demonstrated by applying the novel model system
used in the present study. Furthermore, neoforma-
tion of bone beyond the skeletal borders can also be
achieved by the combined use of bone substitutes
and membranes (78, 159).
Treatment of localized defects of
the alveolar ridge
To date, guided bone regeneration can most success-
fully be used to regenerate localized alveolar defects

with new bone tissue (Fig. 2-4). Although various
attempts have been described aiming at augmenting
the bone over extended areas of the jaw, no valid
technique or clinical procedure has been presented
so far.
Guided bone regeneration prior to implant
placement
In situations with a bone defect at a site, where the
primary stability of an implant cannot be achieved
or when implant placement is not possible in ideal
location for subsequent prosthetic therapy, guided
bone regeneration prior to implantation represents
the method of choice.
Experimental research on ridge augmentation
using guided bone regeneration was presented in the
early 1990s (167). In a dog model, large defects of
the alveolar ridge were surgically prepared both in
the mandible and in the maxilla. The defects were
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).
either covered with expanded polytetrafluoroethy-
lene membranes, covered with membranes and
grafted with porous hydroxyapatite or with a tissue
growth matrix of porous polytetrafluoroethylene,
grafted with these same materials but not covered
with membranes, or finally, neither grafted nor cov-
ered with membranes. Morphological and histologi-
cal analysis revealed that, in sites treated with mem-
branes, with or without the addition of grafts, the
entire space between the membrane and the jaw
bone was filled with bone. In the absence of mem-
branes, bone formation was lacking.
Later, in a similarly designed study, columns of
cortical bone were used to support membranes in-
tended for bone regeneration of previously prepared
alveolar ridge defects in dogs (174). Again, the mem-
branes under this particular experimental situation
proved efficacious in regenerating bone within the
space created, whereas the controls without mem-
branes failed to heal with bone.
155
Hammerle & Karring
Fig. 4. a. After completion of prosthetic treatment, the
mandibular arch is free of edentulous spaces, thus in-
creasing chewing comfort and aesthetics for the patient.
The same clinical procedures were performed in the area
of the second premolar at the mandibular left side.
The conclusions drawn from these and other ex-
periments were that the method of guided bone re-
generation can indeed be successfully employed in
the regeneration of alveolar ridge defects (154, 167,
174).
In the majority of the experimental studies on
guided bone regeneration the effect of this method
was tested in situations in which the ridge defects
had been freshly prepared. One might, however, as-
sume that the reaction of the bone when freshly in-
jured is different than the situation when a state of
tissue equilibrium had been reached in the defect
area. In an animal study, transosseous defects were
156
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.
b. Radiographic examination of the treatment result.
Close adaptation of the marginal bone to the implant
neck. Note that the perforations in the cortical bone are
still visible radiographically.
prepared in the mandibular ramus of rats (55). The
sites of surgery were allowed to heal during a period
of 12 weeks. Upon surgical inspection it was found
that although, some bone regeneration had taken
place at the defect borders, primarily soft connective
tissue had filled the defect. This soft tissue was care-
fully removed and expanded polytetrafluoroethylene
membranes were adapted buccally and lingually to
the bone surrounding the defects. Histological
analysis after 6 weeks demonstrated complete heal-
ing of the previous defects with regenerated bone,
whereas the control defects without membranes
failed to consistently heal with bone. Hence, iso-

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
neighboring soft tissues seems to suffice for success-
ful bone regeneration with guided bone regeneration
(Fig. 5, 6).
In a controlled clinical study in seven patients
with similar contralateral fenestration defects, one
side was treated with guided bone regeneration,
whereas the other one served as control (51). The
results demonstrated that guided bone regeneration
treated dehiscences were consistently filled with new
bone. In the sites where the defect had only been
covered by the mucoperiosteal flap, denuded im-
plant surfaces devoid of bone coverage were ob-
served at re-entry surgery.
On the one hand, lateral ridge augmentation has
been shown to be a method with predictable success
(15, 35-37, 51, 128, 132). On the other hand, the re-
sults regarding vertical augmentation of the alveolar
ridge are controversial.
Implants protruding 4 to 7 mm from the bone
crest were covered with titanium-reinforced ex-
panded polytetrafluoroethylene membranes in a re-
cent study in five patients (172). Biopsies taken 9
months following membrane placement revealed
mineralized bone to have formed up to a level 3 to
4 mm above the previous alveolar crest. Beyond this
level, soft connective tissue was found. Other investi-
gators have reported more vertical gain of bone
(178). Six patients were treated with a similar
method. In contrast to the above study, these thera-
pists grafted the area underneath the titanium-re-
inforced membranes with autogenic bone grafts col-
lected in a suction filter. Twelve months following
membrane placement, an average gain of 5 mm of
Guided bone regeneration at oral implant sites
vertical bone height was measured, reaching up to a
maximum of 7 mm.
In an attempt to augment bone 2.7 mm above the
present crest at titanium implants in dogs, re-
inforced expanded polytetrafluoroethylene mem-
branes showed 1.8 mm of gain, standard expanded
polytetrafluoroethylene membranes revealed 1.9
mm and the bone height increased by 0.5 mm in the
controls without membranes (99). No graft materials
had been incorporated. In both membrane groups,
about 1 mm of nonmineralized tissue was present
between the mineralized bone and the membrane at
its highest point, corroborating the results of Simion
et al. (172). In accordance with these data are the
results obtained with a perforated dome-shaped ti-
tanium space maintainer (150). Although vertical
ridge augmentation with bone did occur, the pres-
ence of nonmineralized connective tissue under-
neath the top of the dome was frequent.
It appears that, depending on the clinical treat-
ment protocol, varying amounts of bone height may
be gained. The factors critical for success or failure
have not been worked out. In addition, no data are
available indicating whether there is a biologically
limited maximum of bone gain, and if so, by what
parameters this maximum is influenced.
On the one hand, according to the law of Frost
(61), bone is resorbed if it is not functionally stimu-
lated. On the other hand, if loading surpasses a criti-
cal level, damage to the implant-supporting bone
my occur. In a recent dog study it was revealed that
occlusal loading of newly regenerated bone may lead
to partial loss of this bone (18). Of the 3-month gain
in bone height of 4.6 mm, the experimental sites
157
Hammerle & Karring

Fig. 6. Excellent bone regeneration is
observed 9 months later. A n implant
with a diameter of 4.1 mm has been
placed into the regenerated bone.
Fig. 7. a. Histological section of a 3-month specimen comprising nonminerd-
ized connective tissue yielding the shape of an hourglass. Note the covering
expanded polytetrafluoroethylene membrane. The polished cylinder walls
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
specimen.

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

158

Guided bone regeneration in conjunction
with implant placement
Following tooth loss, the bone of the alveolar process
has been shown to be subjected to a continuous re-
sorptive process that is most pronounced in the
early phases after tooth removal (4, 6, 41). In order
to reduce the problems resulting from this loss of
bone, dental implants have been placed into fresh
extraction sockets (14, 116, 132).When implants are
placed into extraction sockets, a partial incongru-
ency between the outer surface of the implant and
the bony walls of the socket often results in a bone
deficit in the peri-implant area. Instead of reducing
the height of the alveolar ridge in order to obtain a
sufficient width for implantation (1791, barrier mem-
branes have been demonstrated to be successfully
applied in order to allow the peri-implant area to be
filled with new bone in both animal experiments (13,
20, 184) and clinical studies (14, 19, 27, 53, 63, 75,
100, 101, 112).
The one-stage method of combining implant
placement with guided bone regeneration has been
applied much more frequently in clinical practice
than the two-stage method using guided bone re-
generation prior to implantation. The benefits of the
simultaneous approach are 1) reduced number of
surgical interventions, 2) shortened treatment time,
3) ideal placement of the implant into the alveolar
housing of the lost tooth and 4) reduction of treat-
ment costs.
Guided bone regeneration at submerged implants.
A recent multicenter study evaluated the results of
guided bone regeneration with expanded polyte-
trafluoroethylene membranes for the treatment of
bone defects at implants placed into extraction
sockets (17). Forty-nine implants were placed into
extraction sockets immediately following removal of
the teeth. The reasons for extraction mainly encom-
passed advanced periodontal disease, root fractures
and failed endodontic therapy. Flap incisions prior
to extraction were performed with the aim of
allowing for primary coverage of the membrane and
the two-stage implant. Primary stability was
achieved by preparing implant beds reaching into
pristine bone beyond the socket. Premature removal
of membranes due to exposures, inflammation of
the surrounding tissues or infections of the area was
necessary in 41% of the sites. The 1-year survival rate
of the implants was 93.9%. In the absence of compli-
cations, the mean bony defect fill was very good,
changing from 4.9 mm at the deepest site initially to
Guided bone reeeneration at oral imrtlant sites
0.1 mm at re-entry. However, in the 20 cases with
premature removal of the membranes, a mean re-
sidual bone deficit of 2.4 mm of an initial mean de-
fect depth of 6.4 mm was present at re-entry. The
mean amount of marginal bone loss mesially and
distally of the implants, which amounted to 0.72 mm
over the 7.5 months of observation time, compared
favorably to values for implants placed into pristine
bone (1, 146, 187).This study illustrated that guided
bone regeneration is very successful for implants
that are immediately placed into extraction sockets
in the absence of soft tissue complications during
the healing period.
Exposures and infections are common findings as-
sociated with bone regeneration at immediate im-
plants (8, 17, 157, 170, 184). Conflicting results have
been reported regarding the amount of bone re-
generation in the presence of exposures. Although
some investigators still obtained very good defect fill
with new bone in the presence of membrane ex-
posures (531, it is generally agreed that membrane
exposures lead to compromised results (17, 89, 170,
184, 190, 192) and that proper flap design, a careful
surgical technique and a strict maintenance pro-
gram minimize postoperative complications (14).
One matter of initial discussion dealt with the
question of whether an implant that is placed at the
time of regenerative surgery will actually be osseo-
integrated by the newly formed bone. Subsequent
studies have consistently documented that this pro-
cedure will lead to osseointegration of the exposed
titanium implant surfaces (13, 21, 56, 66, 101, 172,
186).
Depending on the structure of the peri-implant
defect and the presence or absence of bony walls
to support the membrane, different results regarding
bone fill have been reported. In a recent study (16),
sites with a bony wall showed a mean residual lack
of bone of 0.3 mm at re-entry surgery, whereas sites
with dehiscence defects measured 0.6 mm on aver-
age. In situations with extensive bone defects follow-
ing tooth extractions, the two-stage surgical ap-
proach is generally preferred.
Extraction sockets show an excellent tendency for
spontaneous healing with bone (3). One might as-
sume that, in the presence of ideal peri-implant de-
fect structure, the implant will be properly osseo-
integrated without the need for guided bone re-
generation. In a previous study in humans
comparing bone fill in artificially prepared defects
between the test group using an expanded polyte-
trafluoroethylene membrane and a control group
treated without membrane, better results were ob-
159
Hammerle & Karring
tained in the membrane group (138).These findings
are in agreement with results from other human and
animal studies in which the control groups consist-
ently failed to provide as good results as those ob-
tained in the test groups (51, 56). In contrast, other
investigators reported that undisturbed bone forma-
tion in fresh extraction sockets was quite good, so
that only few threads remained uncovered at the
time of abutment connection of submerged immedi-
ate implants (151).
Tissue healing and bone regeneration of extrac-
tion sockets are profoundly influenced by the inser-
tion of implants. The outcome of such a healing pro-
cess cannot be foreseen. Hence, conducting clinical
studies with negative controls is precluded for ethi-
cal reasons.
A disadvantage of combining guided bone re-
generation with implant placement is the fact that,
in case of a compromised treatment outcome re-
garding bone formation, only the more apical part
of the implant will be properly osseointegrated. In
such situations, long-term prognosis is impaired
(58), and the rate of soft tissue complications is in-
creased (117). When the two-stage technique is ap-
plied, then the implant is placed in a second surgical
procedure, at membrane removal, and such a prob-
lem can adequately be dealt with at this moment.
No data are available concerning the long-term
performance of implants placed under these clinical
conditions. Most of the data available represent new
developments with respect to the combination of
implant placement and the guided bone regenera-
tion procedure without the proper validation necess-
ary for general recommendation in patient treat-
ment. During the development period, the surgical
technique, the patient selection and the guidance of
the patient, as well as the proper membrane and, if
applicable, the optimal grafting material are being
tested and appropriately refined. Following this de-
velopment period, the successful treatment ap-
proaches should enter an evaluation period, in
which the implants, placed under these specific pro-
tocols, can be evaluated on a long-term basis. Re-
sulting from this evaluation period, long-term sta-
bility of successfully applied treatment outcomes
can be determined.
Unfortunately, the application of nonresorbable
membranes necessitates a rather extensive second
surgical intervention for their removal. By using re-
sorbable membrane barriers this second surgery
may be limited to the minimum necessary for abut-
ment connection and prosthetic and aesthetic treat-
ment, or not be required at all in the case of trans-
160
mucosal implants (see the section on the benefit of
resorbable membranes in this chapter).
Guided bone regeneration at transmucosal im-
plants. In the studies discussed above, surgery was
performed to submerge both the implant and the
membrane under the soft tissue flap, thus aiming at
healing by primary intention.
The technique of guided bone regeneration has
recently been used in conjunction with the place-
ment of transmucosal implants into fresh extraction
sockets (27, 45, 112, 180). Case reports using this
method were first presented in 1993 (45). The critical
difference from the above-mentioned procedures is
that the implant was deliberately left in a transmu-
cosal position during the entire phase of bone re-
generation. In a prospective study involving 16 con-
secutively treated patients with 25 implants over an
observation period of 2.5 years, the details of this
method were described (112). As opposed to the
above-described methods for immediate implan-
tation in conjunction with guided bone regenera-
tion, this technique does not aim at primary closure
of the flap completely covering both membrane and
implant. In contrast, the flap is adapted around the
neck of the implant, thus indeed covering the mem-
brane but leaving the implant in transmucosal posi-
tion.
The results of a study on 10 patients with surgical
re-entries 6 months following guided bone regenera-
tion therapy demonstrated successful bone gener-
ation into defects around transmucosal implants
(75). The mean fill of the defects with bone
amounted to 94%, which is in the upper range of the
defect fill reported in earlier investigations. Pre-
viously, mean bone fill was reported to amount to
75% (511, 90% (1001, 94% (19) and 82% (53).
Comparison between the clinical results of im-
mediate transmucosal implants and implants placed
under standard conditions at 1 year following incor-
poration of fixed prostheses revealed favorable con-
ditions for the 20 patients in each of the two groups
(27). Low plaque and mucositis scores, similar
amounts of recession, probing pocket depth and
clinical attachment levels were registered.
It has previously been claimed that primary
wound closure following guided bone regeneration
surgery was a prerequisite for the formation of min-
eralized bone (34, 184).This statement was based on
the finding that bone formation was less favorable
when dehiscences occurred, compared with situ-
ations in which the soft tissues remained intact dur-
ing the entire regenerative period (17, 34, 89, 170,

184, 192). As a consequence of these results, it was
concluded that a flap dehiscence following primary
wound closure represents a complication usually
leading to a compromised healing outcome. How-
ever, on the one hand, implants placed in a transmu-
cosal position do not impair the successful outcome
of the bone regeneration process per se (27, 45, 75,
112). On the other hand, in accordance with the re-
sults of studies evaluating guided bone regeneration
at submerged implants, defect fill with new bone in
the presence of flap dehiscence, inflammation and
infection was not as successful as when a flap dehis-
cence did not occur (75). Hence, infection control
appears to be the key factor for an optimal treatment
outcome rather than the mere situation of sub-
merged or transmucosal implant position.
Attempts to fill defects around freshly placed sub-
merged implants with bone have consistently been
documented to lead to osseointegration of the ex-
posed titanium implant surfaces (13, 21, 56, 66, 101,
186). Osseointegration has not been documented
following bone regeneration around transmucosal
implants. However, regeneration of the periodontal
apparatus is predictably achieved around teeth in
spite of the fact that teeth are located transmucosally
(102, 145). Numerous articles have been published
documenting the intimate contact between the pre-
viously exposed root surface and the newly formed
cementum with inserting collagen fibers. Based on
these results from periodontal regeneration studies,
it is reasonable to assume that previously exposed
implant surfaces can become osseointegrated during
bone regeneration in cases of transmucosal implant
position.
The method of achieving regeneration around
transmucosal implants can be particularly beneficial
when the combination of implantation and re-
sorbable membranes may eliminate the need for a
second surgical procedure. However, further studies
testing resorbable membranes are necessary before
definite recommendations can be made.
Guided bone regeneration in the treatment of
peri-implant defects
Research suggests that peri-implant tissue destruc-
tion may be caused by bacterial infection and that
the concomitant inflammation seen is similar to that
in periodontal disease (113, 119, 127, 163, 164). Peri-
implant tissue breakdown and actual loss of some
implants as a consequence of occlusal overload have
recently been reported in an animal experiment (93,
94). It is important to note, however, that truly ex-
Guided bone reaeneration at oral imalant sites
cessive forces in very unfavorable biomechanical
situations were applied and lead to these findings.
Evidence in favor of bacterial causes of late peri-im-
plant tissue breakdown is most overwhelming (115).
Since the causes and pathogenesis of peri-implant
and periodontal lesions are similar, it is reasonable
to anticipate that the treatment should be the same.
Antimicrobial and regenerative therapies are estab-
lished for the treatment of periodontal disease (69,
108, 1451, and antimicrobial treatment can be used
in the treatment of early peri-implantitis (59, 126).
In two early studies on guided bone regeneration
in the treatment of peri-implant bone loss, ligature-
induced tissue breakdown was initiated around ti-
tanium implants in beagle dogs (72). After 5 months,
the ligatures were removed and regenerative therapy
conducted. Membranes of expanded polytetrafluo-
roethylene were applied to isolate the defects from
the flap tissue and half of the implants were left in a
transmucosal and half in a submerged healing situ-
ation. Plaque control using antiseptics was per-
formed for 1 week. At the transmucosal implant sites
mechanical brushing was initiated after 1 week. Soft
tissue complications were frequent and the mem-
branes were removed 4 weeks following placement.
Histological analysis revealed a complete failure of
the attempt to regenerate the peri-implant bone (72,
165).
From these and other studies it may be concluded
that, in accordance with the situation in peri-
odontics, regenerative therapies are not suitable for
the treatment of infectious diseases such as peri-
odontitis or peri-implantitis. They can successfully
be applied, however, in the treatment of the sequelae
of such disease processes: to regenerate the de-
stroyed periodontal or peri-implant tissues. It is,
therefore, of paramount importance to realize that
the infectious disease process has to be adequately
treated, prior to regenerative surgery.
Successful re-osseointegration of bacterially con-
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
tissue had been removed surgically. Subsequently,
the implant surface was allowed to be colonized by
pathogenic bacteria during 12 weeks of undisturbed
ligature induced plaque accumulation. Guided tissue
regeneration therapy was then performed. Histologi-
cal analysis of the specimens retrieved after 2
months showed that new bone formation occurred
in the space underneath the membrane and fulfilled
the histological criteria for osseointegration (2).
More recent experimental data, however, have
161
Hammerle & Karrina
questioned the possibility that implant surfaces once
exposed to plaque accumulation can be successfully
reosseointegrated (140). Following ligature-induced
peri-implant tissue breakdown, an antibiotic regi-
men was initiated. Three weeks later, flaps were
raised on the test sides, the granulation tissue within
the bone craters was curetted away and the implants
were carefully cleaned with a detergent. After place-
ment of expanded polytetrafluoroethylene mem-
branes and new cover screws, the flaps were sutured
for primary healing. On the control side no local
treatment was performed. Histological analysis dem-
onstrated no resolution of the defects and signs of
inflammation on the control side. On the test side
tissue healing had taken place, including bone re-
generation into the previous defect area. On the one
hand, a connective tissue capsule 200-300 pm thick
was consistently found in contact with the implant
surface previously exposed to plaque accumulation.
On the other hand, the regenerating bone had grown
into contact with the newly placed pristine cover
screws. These results demonstrate that the healing
and regenerative capacity of the peri-implant tissues
following experimental bacterial breakdown are not
impaired, but the applied treatment - debridement
and cleaning with a detergent - had not rendered
the implant surface biologically acceptable for bone
to grow into contact with it.
In a recent study the effect of guided bone re-
generation alone or in combination with various
bone substitutes was evaluated in the treatment of
peri-implant defects (87).Following ligature-induced
tissue breakdown, the defects were debrided and the
exposed implant surfaces cleaned with an air-pow-
der abrasive instrument. Histological data revealed
varying amounts of bone regeneration depending on
the clinical procedure. The best results were ob-
tained with the combination of guided bone re-
generation and bone substitutes. Furthermore, the
investigators reported consistent contact between
regenerated bone and the previously exposed im-
plant surfaces. In contrast to previous investigations
(1401, the treatment regimen for decontamination of
the implant chosen in this study had rendered the
surface biologically acceptable for new bone to grow
into contact with it.
Human studies of the regeneration of tissues after
destruction due to peri-implantitis are limited to a
few recent case reports documenting the use of
guided bone regeneration in the treatment of early
and late implant failures (77).Although the re-estab-
lishment of bone-to-implant contact on the surface
previously exposed to plaque accumulation could
162
obviously not be demonstrated in any of these
studies, stability of the clinical result over a period
of 1.5 years was documented radiographically in one
study (77). Successful bone regeneration was ob-
tained in spite of the fact that the implants remained
transmucosal during the entire treatment period.
Before guided bone regeneration treatment for
late peri-implant failures can be recommended for
routine use in practice, some aspects of the clinical
procedures still have to be established. These as-
pects include the appropriate antimicrobial therapy
in terms of the choice of medication, the dosage, the
duration of this treatment and the optimal manipu-
lations of the implant surface, the ideal membrane
material - resorbable or nonresorbable - the defects
most amenable to treatment and the proper time
frame of the regeneration period.
The use of bone grafts and
substitute materials
Classification of bone graft materials
Bone grafts have long been used in reconstructive
surgery with the aim of increasing the bone volume
in the previous defect area. Bone grafts and bone
substitute materials may be classified into two main
groups: autogenic and xenogenic materials. The
term autogenic graft refers to tissues that are trans-
planted within one and the same organism. Auto-
genic bone is the most frequently used material in
this group. Xenogenic grafts encompass all materials
of an origin other than the recipients organism and
may further be divided into materials from the same
species but different individuals, materials from
other species and products of nonorganic origin. De-
mineralized freeze-dried bone represents an allograft
material, that is, from the same species, but not the
same individual, which has widely been used in
bone augmentation procedures.
Biological behavior
Introduction. A wide variety of graft materials have
been employed in experimental studies or in clinical
practice. The range of materials used encompass
autogenic cancellous or cortical human bone, xen-
ogenic bone transplants such as demineralized
freeze-dried human bone and xenogenic bone sub-
stitute materials such as natural and synthetic hy-
droxyapatite, deproteinized bovine bone mineral
and calcium-phosphate compounds (73, 75, 78, 84,

86, 105, 106, 136, 141-144, 159). The rationale for
using bone grafts in combination with guided bone
regeneration encompasses factors such as support-
ing the membrane in situations in which the defect
morphology will not adequately do so, to offer a
scaffold for ingrowth of capillaries and perivascular
tissue, in particular osteoprogenitor cells, and to
provide a carrier for factors enhancing bone forma-
tion. Although mechanical support can also be
achieved by the use of stiffer membranes, pins, mini-
screws or metal reinforcements of membranes (15,
34, 82, 991, the possible biological benefits of filler
materials cannot be achieved in other ways.
Bone substitutes should exhibit biocompatible
material properties. They should not elicit allergic or
immune reactions. They should be well tolerated
and integrated by the host tissues and ideally pro-
vide a scaffold for new bone to grow onto. It has
been postulated that they should gradually be re-
placed by newly formed bone. Their three-dimen-
sional structure should most closely resemble that of
natural bone with respect to macro- and micro-
porosities. Finally, they should compartmentalize
larger defects into smaller fragments comparable to
that of natural human bone (31).
Unfortunately, many of the products presently
available lack adequate scientific documentation to
recommend their general use in conjunction with
guided bone regeneration procedures. It is therefore
difficult, to critically appraise many of the obtainable
bone substitute materials.
Bone-inductive materials. The most intriguing
method of enhancing the local bone volume is by
inducing pluripotent mesenchymal cells to bone-
forming cells. Theoretically, this can be accom-
plished by supplying growth factors or suitable pro-
teins into the defect area. Demineralized freeze-
dried bone allograft is a substance that has been
widely used with the purpose of achieving osteoind-
uction. However, data from both animal experiments
and from human clinical studies are controversial
with respect to the bone-inducing effect of this ma-
terial. Although some earlier publications have pro-
vided encouraging data (141, 148, 149, 181), more
recent experiments have questioned the ability of
demineralized freeze-dried bone allograft to induce
new bone formation (5, 20-23, 142, 143).In this con-
text it appears that both the rank on the phylogen-
etic ladder as well as the source and the preparation
of the demineralized freeze-dried bone allograft pro-
foundly influence the final outcome. Animals rank-
ing high on the phylogenetic ladder are character-
Guided bone reEeneration at oral irndant sites
ized by a low metabolic index and hence form bone
at a slower rate than lower-ranking animals (48). In
addition, they have been documented to exhibit
lower reactivity to osteoinductive stimuli (153). Both
factors may contribute to the confusion resulting
from contradictory results presented in different
studies. Whereas bone induction by demineralized
freeze-dried bone allograft has been shown in ro-
dents, this has not been conclusively demonstrated
in higher species such as dogs, monkeys or humans.
Moreover, some of the contrast in the results from
various studies possibly originates from the fact that
demineralized freeze-dried bone allograft prepara-
tions from different bone banks and from different
batches from the same bank may respond quite dif-
ferently (166).Therefore, it has been postulated that
assays should be developed to standardize the activ-
ity of demineralized freeze-dried bone allograft.
Another source of confusion may arise from the
fact that evidence that demineralized freeze-dried
bone allograft promotes bone formation has gener-
ally been provided at two different levels: the clinical
and the histological level. There is general agreement
that the histological data are more reliable than clin-
ical measurements. Studies combining histological
and clinical data have recently reported a disparity
between the two methods of assessing the results of
regeneration (21). Hence, conclusions drawn from
purely clinical evaluation of demineralized freeze-
dried bone allograft should be interpreted with cau-
tion.
Finally, there are contradictory results regarding
the resorbability of demineralized freeze-dried bone
allograft in the host tissues (20, 23, 142).
In conclusion, although demineralized freeze-
dried bone allograft holds some promise as an osteo-
inductive material for use in guided bone regenera-
tion procedures, it should be used with caution until
it can be provided in a well-standardized and con-
trolled form from the bone banks, and until its effi-
cacy in bone induction has been proven in nonhu-
man primates and in humans.
Transplantation of autogenic bone. It has long been
claimed that autogenic bone is the ideal material to
increase the bone volume of the jaw bone (31). Be-
fore the advent of guided bone regeneration, intra-
oral bone augmentation was commonly performed
by the use of autogenic bone transplants preferen-
tially taken from the iliac crest. Such a procedure is
very demanding regarding operator skills and logis-
tical support for the surgical intervention, is highly
stressful for the patient and causes considerable
163
Hammerle & Karring
post-operative pain, and the treatment is very costly.
Ridge augmentation using bone grafts without mem-
branes is subjected to extensive resorption of the
graft (111, 175). Loss of graft volume in the magni-
tude of 50% have been reported during healing over
the period of 6 months.
One of the possible indications for guided bone
regeneration is the replacement of such procedures.
A recent study (95) has demonstrated that the results
of guided bone regeneration, when combined with
autogenic bone grafts, are superior to the traditional
method of transplanting bone without adequate
protection by barrier membranes. In this dog study
demineralized freeze-dried bone allograft and
cortico-cancellous iliac autografts with and without
barrier membranes of expanded polytetrafluoroe-
thylene were compared. The best results were ob-
tained with the combination of the autogenic graft
and the membrane in terms of the graft volume in-
corporated as well as the direct bone-to-implant
contact.
In a recent clinical article (371, the successful com-
bination of autogenic cortico-cancellous bone grafts
and guided bone regeneration has been shown. A
group of 40 patients consecutively treated with this
method demonstrated a very low frequency of soft
tissue complications and successful ridge augmenta-
tion in 66 sites. A mean gain in crest width of 3.5
mm was measured allowing implant placement in
proper position in all 66 sites.
These very good results may be used as a standard
against which new developments, aiming at reduc-
ing efforts necessary to obtain successful treatment
outcomes, can be tested.
Xenogenic bone substitutes. Xenogenic bone sub-
stitutes of hydroxyapatite have recently been de-
veloped. Experimental studies have dealt with ma-
terials manufactured synthetically (68, 86, 105, 144),
derived from corals or algae (73, 96, 105, 106, 144) or
originated from natural bone mineral (25, 46, 64, 76,
78, 96, 107, 156, 159, 176, 188). These materials are
considered biocompatible and osteoconductive.
Nevertheless, considerable differences in their be-
havior based on material properties have been re-
ported.
Integration of natural bone mineral has been
shown to be superior to coral- or algae-derived hy-
droxyapatite products (96). One of the reasons for
these differences may be the three-dimensional
structures, including the porosities of bone grafts,
which have been documented to have important ef-
fects on bone healing (49, 86, 105, 106, 183). Ma-
164
~~~ ~
terials exhibiting large surface areas showed better
bone-graft contact than materials with a compara-
tively small surface area (86, 105, 106).Deproteinized
bone mineral in its unaltered form has presumably
ideal architecture for use as a bone graft material.
However, due to manipulations during the purifi-
cation process, different tissue integration properties
of the natural bone mineral may result. Thus, bo-
vine-derived bone mineral exhibiting natural crystal-
linity (Bio-Oss, Geistlich, Wolhusen, Switzerland)
yielded increased bone-to-graft contact compared
with a product of the same origin but with larger
crystal size (Endobon, Merck Biomaterials, Darm-
stadt, Germany) (96).
The results regarding bone-to-graft contact and
hence the osteoconductive properties attributed to
the materials tested vary considerably between dif-
ferent studies, rendering interpretation and com-
parison difficult (76, 78, 85, 86, 96).
Bone-to-graft contact also depends, among other
factors, on the density of bone in the vicinity of the
graft. In order to ameliorate interpretation of results,
this factor should be taken into consideration in the
assessment of the osteoconductive properties of a
bone substitute. Recently, an osteoconductivity
index has been proposed, which was calculated by
using a model to detect phase association from the
direct bone-to-graft contact and the area density of
bone in the vicinity of the graft (76). It was postu-
lated that values above 1.0 indicate that the bone
grows preferentially in contact with the graft,
whereas values of less than 1.0 indicate that the
bone-to-graft contact is taking place at a level less
than what could be expected by randomly occurring
contact, and therefore, the bone is being hampered
from making graft contact. Thus an index that equals
1.0 indicates that bone-to-implant contact is occur-
ring at random. In that study, this parameter reached
values of 2.9 at the sites treated with membrane and
deproteinized bovine bone mineral and of 2.6 for the
sites treated with deproteinized bovine bone mineral
group, indicating high osteoconductivity of the graft
(76).
Recent studies have evaluated a deproteinized bo-
vine bone mineral as a filler in a guided bone re-
generation procedure model on the rabbit skull (78,
159). In combination with a stiff bioresorbable mem-
brane made of polylactic acid, this substitute im-
proved the amount of initial soft tissue formation
and initially increased the rate of mineralized bone
formation compared with blood-filled controls.
It has been postulated that formation of soft tissue
is a step of critical importance in the sequence of

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
ones the newly formed tissues exhibited the shape
of an hourglass (Fig. 7a). Apparently, during the
phase of fibroplasia, the regenerated soft tissues
were pulled away from the cylinder walls rendering
the shape observed. Interestingly, even after obser-
vation periods of up to 9 months, when the majority
of the space was occupied by new bone, this particu-
lar shape was unchanged (Fig. 7b). The investigators
concluded that the outer borders confined by the
mature soft tissue, which arises prior to mineraliza-
tion, delimit the area ultimately available for bone to
form (78, 81).
The observed acceleration of bone formation in
conjunction with the use of bone substitutes in the
rabbit skull model may be attributed to the higher
amount of osteoblasts found in the test specimens
(78, 159). With the increase in osteoblast numbers -
the only cells capable to form bone - the rate of bone
formation rises. The application of the substitute
material evidently created an environment that
allowed earlier immigration of osteoblasts into the
area intended for guided bone regeneration. By de-
signing bone substitute materials with appropriate
surface characteristics, this biological mechanism
may be used with greater benefit in bone regenera-
tion procedures. Several studies have indicated that
the use of bone grafts of natural bone mineral does
not decrease bone-to-implant contact when used to
treat peri-implant defects in guided bone regenera-
tion procedures as compared with the use of mem-
branes alone (25, 76, 1881.
The physiological pattern of new bone formation
with guided bone regeneration in the presence of
bone substitutes of natural bone mineral has re-
cently been described by Hammerle et al. (78). NO
qualitative differences were detectable in test and
control specimens, indicating that the presence of
the graft material did not alter the basic pattern of
bone formation (Fig. 8). These findings were similar
to the description of the type of bone formation
Guided bone regeneration at oral implant sites
Fig. 8. Bone regeneration around deproteinized bovine
bone (DBB) from a human specimen. Large areas of the
graft particles are in direct bone contact (new bone: nb).
Some areas are in contact with bone marrow tissue (bm).
Direct deposition of osteoid (0s) produced by osteoblasts
is occasionally visible. The newly formed bone is sub-
jected to remodeling activity as indicated by the presence
of osteoclasts. Similarly, osteoclasts (arrowheads)are seen
resorbing the bone substitute.
found in previous studies evaluating sequential
stages of guided bone regeneration without the use
of bone substitutes (79, 109, 154). The fact that the
pattern of bone formation and the sequence of bone
remodeling are not negatively influenced by the use
of this type of bone substitute is of particular im-
portance for the application of this method in oral
implantology. Only lamellar bone, owing to its high
biomechanical competence, optimally fulfills the re-
quirements for taking up loading forces transferred
by implants.
There is general agreement that dense synthetic
hydroxyapatite is nonresorbable in viuo (33, 68, 96,
105,184) and that calcium phosphate compounds as
well as coral- or algae-derived materials degrade
over time (33, 73, 96). Conflicting results, however,
have been published regarding the long-term per-
formance of natural bone mineral. Although some
investigators have reported rare signs of biodegrada-
tion or complete lack of breakdown (57, 78, 1561,
others have described definite graft resorption (24,
76, 96, 107, 188) or documented decrease in area
density of the graft over time (25). In one of these
studies, active resorption of the Bio-Oss particles by
osteoclasts was demonstrated unequivocally by
staining with tartrate-resistant acid phosphatase
(76). Although, the resorption process by osteoclasts
has thus been documented, no data are available on
the rate of resorption and on the behavior of the re-
sulting spaces.
One direction of present research involves the de-
165
Hammerle & Karring

166

velopment of resorbable grafting materials chemic-
ally based on synthetic polymers (185). These com-
pounds offer a number of advantages over presently
used fillers. They can be custom made regarding re-
sorption time, stability and rigidity, three-dimen-
sional structure and pore size, and finally they can
be used as carriers for compounds enhancing bone
formation.
Clinical applications
Human clinical studies on the use of bone grafts and
of bone substitutes are scarce. Available data are
mostly limited to case reports and reports of case
series (16, 37, 57, 84, 128, 173), some of which report
test and control procedures (22, 65, 170, 192, 193).
Controlled long-term clinical studies are lacking.
So far, autogenic bone grafts in conjunction with
guided bone regeneration have yielded the best re-
sults with high predictability (16, 37). However,
studies involving harvesting of autogenic bone for
transplantation should not only present data on the
success of the treatment at the regenerated site but
should also provide information about the morbidity
and the discomfort caused to the patient by the har-
vesting procedure. Not before this aspect has been
included in the evaluation process should a compre-
hensive benefit-risk analysis of the various concepts
for grafting in guided bone regeneration be con-
ducted.
Most of the data available with respect to the use
of bone grafts and bone substitute materials repre-
sent presentations of new developments. In accord-
ance with the sequence of analysis described for im-
plants placed in conjunction with guided bone re-
Fig. 9. a. Due to failed endodontic treatment, tooth num-
ber 34 has to be extracted. Therapy with an immediate
implant and guided bone regeneration is favored over a
conventional bridge due to inappropriate adjacent poten-
tial abutment teeth. b. Eight weeks following extraction of
the root, the soft tissues have healed over the extraction
socket. c. Careful flap elevation has exposed the alveolar
process with the tooth socket. d. A full-body plasma-
sprayed implant has been placed with primary stability
into the alveolus. e. A bone substitute of natural bone
mineral is use to support a collagen membrane.
f. The collagen membrane has carefully been adapted to
the bony walls surrounding the defect and has been
punched and slipped over the shoulder of the implant.
g. At re-entry surgery 6 months later, regenerated hard
tissue is found in the previous defect area around the co-
ronal part of the implant. h. Radiographic control of the
implant and the surrounding regenerated bone prior to
initiation of prosthetic treatment.
Guided bone regeneration at oral implant sites
generation, the newly developed and successful
treatment approaches should enter a validation
period, in which the implants, for the placement of
which the incorporation of bone grafts and substi-
tutes was indicated, should be evaluated on a long-
term basis with respect to the stability of the suc-
cessfully obtained treatment outcomes.
The benefit of
resorbable membranes
Material developments and experimental studies
With the presentation of the first successful guided
bone regeneration procedures and the subsequent
wide and successful application of expanded polyte-
trafluoroethylene membranes, this material became
standard for bone regeneration. An obvious disad-
vantage of this material is that it is nonresorbable
and, therefore, has to be removed with a second sur-
gical procedure. Regarding patient morbidity, risk for
tissue damage, and from a cost-benefit point of view,
the replacement of nonresorbable by resorbable
membranes would be desirable. Hence, recent ex-
perimental research in guided bone regeneration has
aimed at developing resorbable barrier membranes
for application in the clinic.
Bioresorbable materials that may be used for the
fabrication of membranes all belong to the groups
of natural or synthetic polymers. The best known
groups of polymers used for medical purposes are
collagen and aliphatic polyesters. Currently tested
and used membranes are made of collagen or of po-
lyglycolide and/or polylactide or copolymers thereof
(90) (Fig. 9a-h).
Several design criteria have been postulated for
membranes as being favorable for their use in
guided bone regeneration. Thus, it was postulated
that the membrane barrier should be permeable for
exchange of critical fluid substances with putative
nutritive or instructive function. It was later shown
in an animal experiment on the rabbit skull that
membrane permeability is not a prerequisite for
guided bone regeneration, as new bone had formed
in both the test and control chambers (160).
The results of another animal experiment have
shown that occlusive bioresorbable membranes
made of polylactic or polyglycolic acid are equally
successful as expanded polytetrafluoroethylene
membranes in regenerating bone in transosseous
defects in the rabbit mandibular ramus (152). How-
ever, bone formation in the defects separated by the
resorbable membranes was associated with chondral
167
Hammerle & Karrinn
bone formation, whereas the defects treated with ex-
panded polytetrafluoroethylene membranes were
associated with bone formation along the desmal
pathway. Based on an earlier study (169),the investi-
gators concluded that since the impermeable mem-
branes had prevented oxygen from passing from the
soft tissues into the area intended for bone regenera-
tion, the low oxygen tension in the defect area had
resulted in cartilage formation as an intermediary
step prior to bone formation (152).
In accordance with these findings are the results
of an experiment evaluating the effect of different
pore sizes of expanded polytetrafluoroethylene
membranes in guided bone regeneration on the rat
skull (191). It was found that the dome-shaped
membranes exhibiting internodal distances of less
than 8 pm showed delayed bone fill compared with
membranes, where these distances ranged from 20-
25 pm or were in the range of 100 pm. In addition,
soft tissue integration and peripheral sealing associ-
ated with the small internodal distance were re-
ported to be inferior. Nevertheless, after 12 weeks,
a similar degree of bone fill was observed with the
different membrane types.
From these studies it may be concluded that
membrane porosities are indeed no prerequisite for
bone formation, but optimal pore sizes are advan-
tageous regarding nutrient flow, wound stabilization
and peripheral sealing to prevent ingrowth of soft
tissue-forming cells.
Unfortunately, most of the available resorbable
membranes are not capable of maintaining space.
Therefore, they need to be supported in one way or
another. The most commonly used method for
membrane support is to sustain it with autogenic
grafts or with bone substitutes (9, 139, 158, 192, 193),
whereas other methods such as screws, pins and re-
inforcements have also occasionally been applied
(67, 109).
Several animal experiments have demonstrated
the successful use of bioresorbable membranes in
guided bone regeneration (44, 78, 109, 120, 121, 123,
152, 158, 159, 168), whereas only few have reported
failures (12, 32, 67, 157, 189). In two recent experi-
ments, a polylactic acid membrane was tested in its
ability to increase the bone volume in conjunction
with an autogenous bone graft compared to controls
that were grafted only (120, 121). Both experiments
showed more bone formation when the membranes
were applied. These results demonstrate that soft
polylactic acid membranes are suitable for guided
bone regeneration procedures in conjunction with
autogenous grafts.
168
A different approach was taken in experimental
studies evaluating a form-stable bioresorbable mem-
brane made of polylactic acid in conjunction with a
bone substitute in a rabbit skull model (78, 159).
New bone was demonstrated to form underneath
the membrane beyond the borders of the former cal-
varium. On the one hand, this experiment demon-
strated that, in principle, stiff, bioresorbable mem-
branes are conducive to bone regeneration and bone
neoformation. On the other hand, after the obser-
vation period of 2 months, no overt signs of break-
down of the membrane were reported. In many clin-
ical situations a resorption time between 6 and 12
months is mandatory in order not to lose the advan-
tages of resorbability.
Results of clinical applications
Beginning in the early 1990s and thereafter, reports
of cases or case series were presented describing the
use of resorbable membranes for guided bone re-
generation at exposed implant surfaces (10, 88, 89,
124, 125, 137, 139, 193). Later, controlled clinical
studies were published (171, 192). In all of these re-
ports a low rate of complications involving inflam-
mation of the flap covering the site of regeneration
and exposures of membranes were observed. In two
studies involving a larger number of consecutively
treated patients, the results with respect to bone re-
generation were very favorable. Bony defect fill
ranged from 83% (193) to 92% (89). Similar results
were reported in the treatment of dehiscence and
fenestration defects at threaded implants with the
use of bioabsorbable membranes made of polyglyco-
lide and polylactide (125).Even though no bone graft
or bone graft substitutes were used, 14 out of 17 de-
fects showed complete bone fill at re-entry.
In one of the controlled clinical studies, a collagen
membrane was tested against an expanded polyte-
trafluoroethylene membrane (192). At the re-entry
operation 4 to 6 months following guided bone re-
generation surgery, 57% of the 39 defects treated
with collagen and 57% of 14 defects treated with ex-
panded polytetrafluoroethylene membranes showed
complete bone fill. Incomplete bone regeneration
was found in 39% of the test sites and 29% of the
control sites. No gain of new bone was found in 5%
of the test sites and 15% of the control sites. A high
percentage of exposure of membranes (19%) leading
to early removal occurred in sites treated with ex-
panded polytetrafluoroethylene membranes. Al-
though, the possibility for early resorption of colla-
gen membranes is mentioned in the article in cases

of incomplete wound closure, unfortunately, no data
are presented with respect to this complication.
In the most recent controlled clinical study, 18 im-
plants with exposed threads were divided into two
groups (171). In both groups the defects were filled
with autogenous bone. In the test group a resorbable
polylactic or polyglycolic acid membrane was
adapted, whereas in the control group a standard ex-
panded polytetrafluoroethylene membrane was
placed. Neither in the test nor in the control group
were any flap dehiscences or membrane exposures
registered. Six to seven months later, both groups re-
vealed excellent bone regeneration, with values of
89% and 98% defect fill. Although the test group
yielded less bone fill and exhibited a higher vari-
ability of the results, no statistically significant differ-
ence was found.
In conclusion, these case reports and initial con-
trolled clinical studies demonstrate that resorbable
membranes can be used successfully for bone re-
generation at implants with exposed surface areas.
However, before the methods can be recommended
for widespread clinical practice, the fine points of
the treatment protocols have to be worked out, and
the treatment approaches presented will have to be
validated in larger, well-controlled studies.
References
1. Adell R, Lekholm U, Rockler B, Brinemark P-I, Lindhe J,
Eriksson B, Sbordone L. Marginal tissue reactions at
osseointegrated titanium fixtures. Int J Oral Maxillofac
Surg 1990: 15: 39-52.
2. Albrektsson T, Brlnemark P-I, Hansson HA, Lindstrom J.
Osseointegrated titanium implants. Requirements for en-
suring a long-lasting direct bone anchorage in man. Acta
Orthop Scand 1981: 52: 155-170.
3. Amler MH. The time sequence of tissue regeneration in
human extraction wounds. Oral Surg Oral Med Oral
Pathol Oral Radio1 Endod 1969: 27: 309-318.
4. Amler MH, Johnson PL, Salman I. Histological and histo-
chemical investigation of human alveolar socket healing
in undisturbed extraction wounds. J Am Dent Assoc 1960:
61: 32-44.
5. Aspenberg P, Kalebo P, Albrektsson T. Rapid bone healing
delayed by bone matrix implantation. Int J Oral Maxillo-
fac Implants 1988: 3: 123-127.
6. Atwood DA. Postextraction changes in the adult mandible
as illustrated by microradiographs of midsagittal sections
and serial cephalometric roentgenograms. J Prosthet Dent
1963: 13: 810-824.
7. Aufdemorte T, Fox C, Boyce B, Triplett G, Poser J, Moore
G, Holt R. A novel orthopaedic implant to repeatedly
sample cancellous bone for histomorphometric analysis.
In: Takahaski HE, ed. Bone morphometry. Niigata: Nishi-
mura, 1990: 260-263.
Guided bone regeneration at oral imdant sites
8. Augthun M, Yildirim M, Spiekermann H, Biesterfeld S.
Healing of bone defects in combination with immediate
implants using the membrane technique. Int J Oral Maxi-
lofac Implants 1995: 10: 421-428.
9. Avera SI: Stampley WA, McAllister BS. Histologic and clin-
ical observation of resorbable and nonresorbable barrier
membranes used in maxillary sinus graft containment.
Int J Oral Maxillofac Implants 1997: 12: 88-94.
10. Balshi TJ, Hernandez RE, Cutler RH, Hertzog CE Treat-
ment of osseous defects using Vicryl mesh (polyglactin
910) and the Brlnemark implant: a case report. Int 1 Oral
Maxillofac Implants 1991: 6: 87-91.
11. Beck LS, Amento El? Xu Y, Deguzman L, Lee Wr: Nguyen
T, Gillett NA. TGF-P1 induces bone closure of skull de-
fects: temporal dynamics of bone formation in defects ex-
posed to rh TGF-P1. J Bone Miner Res 1993: 8 : 753-761.
12. Becker J, Meissner T, Reichart PA. Gesteuerte Knochen-
regeneration mit Membranen aus Polyesterurethan. Im-
plantologie 1995: 2: 151-161.
13. Becker W, Becker B, Handelsman M, Ochsenbein C, Al-
brektsson T. Guided tissue regeneration for implants
placed into extraction sockets: a study in dogs. J Peri-
odontol 1991: 62: 703-709.
14. Becker W, Becker BE. Guided tissue regeneration for im-
plants placed into extraction sockets and for implant
dehiscences: surgical techniques and case reports. Int J
Periodontics Restorative Dent 1990: 10: 377-391.
15. Becker W, Becker BE, McGuire MK. Localized ridge aug-
mentation using absorbable pins and ePTFE barrier
membranes: a new surgical approach. Int J Periodontics
Restorative Dent 1994: 14: 48-61.
16. Becker W, Becker BE, Polizzi G, Bergstrom C. Autogenous
bone grafting of bone defects adjacent to implants placed
into immediate extraction sockets in patients: a prospec-
tive study. Int J Oral Maxillofac Implants 1994: 9: 389-396.
17. Becker W, Dahlin C, Becker BE, Lekholm U, van Steen-
berghe D, Higuchi K, Kultje S. The use of e-PTFE barrier
membranes for bone promotion around titanium im-
plants placed into extraction sockets: a prospective multi-
center study. Int J Oral Maxillofac Implants 1994: 9: 31-
40.
18. Becker W, Lekholm U, Dahlin C, Becker B, Donath K. The
effect of clinical loading on bone regenerated by GTAM
barriers: a study in dogs. Int J Oral Maxillofac Implants
1994: 9: 305-313.
19. Becker W, Lekholm U, Dahlin C, Becker B, Higuchi K, van
Steenberghe D. Immediate placement of titanium im-
plants into fresh extraction sockets protected by e-PTFE
membrane barriers. A clinical multicenter study. Int J Oral
Maxillofac Implants 1994: 9: 31-40.
20. Becker W, Lynch SE, Lekholm U, Becker BE, Caffesse R,
Donath K, Sanchez R. A comparison of ePTFE mem-
branes alone or in combination with platelet-derived
growth factors and insulin-like growth factor-I or demin-
eralized freeze-dried bone in promoting bone formation
around immediate extraction socket implants. J Peri-
odontol 1992: 63: 929-940.
21. Becker W, Schenk R, Higuchi K, Lekholm U, Becker BE.
Variations in bone regeneration adjacent to implants aug-
mented with barrier membranes alone, or with demin-
eralized freeze-dried bone or autologous grafts: a study in
dogs. Int J Oral Maxillofac Implants 1995: 10: 143-154.
22. Becker W, Urist M, Becker BE, Jackson W, Parry DA, Bar-
169
Hammerle & Karring
told M, Vincenzzi G, DeGeorges D, Niederwanger M. Clin-
ical and histologic observations of sites implanted with
intraoral autologous bone grafts or allografts. 15 human
case reports. J Periodontol 1996: 67: 1025-1033.
23. Becker W, Urist MR, Tucker LM, Becker BE, Ochsenbein
C. Human demineralized freeze-dried bone: inadequate
induced bone formation in athymic mice. A preliminary
report. J Periodontol 1995: 66: 822-828.
24. Bereiter H, Melcher GA, Gautier E, Huggler AH. Erfah-
rungen mit Bio-Oss, einem bovinen Apatit, bei verschied-
enen klinischen Indikationsbereichen. Hefte Unfallheilkd
1991: 216: 118-126.
25. Berglundh T, Lindhe J. Healing around implants placed in
bone defects treated with Bio-Oss@. An experimental
study in the dog. Clin Oral Implants Res 1997: 8: 117-124.
26. Boyne PJ, Cole MD, Stringer D, Shafqat JP. A technique
for osseous restoration of deficient edentulous maxillary
ridges. J Oral Maxillofac Surg 1985: 43: 87-91.
27. Bragger U, Hammerle CHF, Lang NE! Immediate transmu-
cosal implants using the principle of guided tissue re-
generation. 11. A cross-sectional study comparing the clin-
ical outcome 1 year after immediate to standard implant
placement. Clin Oral Implants Res 1996: 7: 268-276.
28. Brunette DM. The effects of implant surface topography
on the behavior of cells. Int J Oral Maxillofac Implants
1988: 3: 231-246.
29. Brunette DM, Chehroudi B, Gould TRL. Electron micro-
scopic observations on the effects of surface topography
on the behavior of cells attached to percutaneous and
subcutaneous implants. In: Laney WR, Tolman DE, ed.
Proceedings of the Second International Congress o n
Tissue Integration in Oral, Orthopedic, and Maxillofacial
Reconstruction. Carol Stream. IL: Quintessence Pub-
lishing Co., 1990: 21-31.
30. Buch E Albrektsson T, Herbst E. The bone growth
chamber for quantification of electrically induced osteo-
genesis. J Orthop Res 1986: 4: 194-203.
31. Burchardt H. The biology of bone graft repair. Clin Orthop
1983: 174: 28-42.
32. Busch 0, Solheim E, Bang B, Tornes K. Guided tissue re-
generation and local delivery of insulinlike growth factor I
by bioerodible polyorthoester membranes in rat calvarial
defects. Int J Oral Maxillofac Implants 1996: 11: 498-505.
33. Buser D, Bernard JI? Hofmann B, Lussi A, Mettler D,
Schenk RK. Evaluation of bone filling materials in mem-
brane-protected defects of the mandible. A histomorpho-
metric study in miniature pigs. Clin Oral Implants Res (in
press).
34. Buser D, Bragger U, Lang NI: Nyman S. Regeneration and
enlargement of jaw bone using guided tissue regenera-
tion. Clin Oral Implants Res 1990: 1: 22-32.
35. Buser D, Dula K, Belser U, Hirt HP, Berthold H. Localized
ridge augmentation using guided bone regeneration. I.
Surgical procedures in the maxilla. Int J Periodontics Re-
storative Dent 1993: 13: 13-29.
36. Buser D, Dula K, Belser UC, Hirt H-I: Berthold H. Local-
ized ridge augmentation using guided bone regeneration.
11. Surgical procedure in the mandible. Int J Periodontics
Restorative Dent 1995: 15: 11-29,
37. Buser D, Dula K, Hirt HI: Schenk RK. Lateral ridge aug-
mentation using autografts and barrier membranes. A
clinical study in 40 partially edentulous patients. Int J Oral
Maxillofac Surg 1996: 54: 420-432.
170
38. Buser D, Dula K, Lang NI: Nyman S. Long-term stability
of osseointegrated implants in bone regenerated with the
membrane technique. Clin Oral Implants Res 1996: 7:
175-183.
39. Buser D, Ruskin J, Higginbottom E Hardwick R, Dahlin C,
Schenk RK. Osseointegration of titanium implants in
bone regenerated in membrane-protected defects: a his-
tologic study in the canine mandible. Int J Oral Maxillofac
Implants 1995: 10: 666-681.
40. Buser D, Weber HP, Donath K, Fiorellini JI: Paquette DW,
Williams RC. Soft tissue reactions to non-submerged un-
loaded titanium implants in beagle dogs. J Periodontol
1992: 63: 225-235.
41. Carlsson GE, Thilander H, Hedegdrd B. Histologic
changes in the upper alveolar process after extractions
with or without insertion of an immediate full denture.
Acta Odontol Scand 1967: 25: 21-43.
42. Chehroudi B, Gould TRL, Brunette DM. Effects of a
grooved titanium coated implant surface on epithelial cell
behavior in uitro and in uiuo. J Biomed Mater Res 1989:
23: 1067-1085.
43. Chehroudi B, Gould TRL, Brunette DM. Titanium-coated
micromachined grooves of different dimensions affect
epithelial and connective-tissue cells differently in uivo. J
Biomed Mater Res 1990: 24: 1203-1219.
44. Chung CI: Kim DK, Park YJ, Nam KH, Lee SJ. Biological
effects of drug-loadable biodegradable membranes for
guided bone regeneration. J Periodont Res 1997: 32: 172-
175.
45. Cochran DL, Douglas HB. Augmentation of osseous tissue
around non-submerged endosseous dental implants. Int
J Periodontics Restorative Dent 1993: 13: 506-519.
46. Cohen RE, Mullarky RH, Noble B, Comeau RL, Neiders
ME. Phenotypic characterization of mononuclear cells
following anorganic bovine bone implantation in rats. J
Periodontol 1994: 65: 1008-1015.
47. Cortellini I: Bartolucci E, Clauser C, Pini Prato GP. Local-
ized ridge augmentation using guided tissue regeneration
in humans. A report of nine cases. Clin Oral Implants Res
1993: 4: 203-209.
48. Coulson RA. Relationship between fluid flow and O2 de-
mand in tissues in uiuo and in uitro. Perspect Biol Med
1983: 27: 121-126.
49. Daculsi G, Passuti N. Effect of the macroporosity for oss-
eous substitution of calcium phosphate ceramics. Bio-
materials 1990: 11: 86-87.
50. Dahlin C, Alberius P, Linde A. Osteopromotion for cranio-
plasty. An experimental study in rats using a membrane
technique. J Neurosurg 1991: 74: 487-491.
51. Dahlin C, Andersson L, Linde A. Bone augmentation at
fenestrated implants by an osteopromotive membrane
technique. A controlled clinical study. Clin Oral Implants
Res 1991: 2: 159-165.
52. Dahlin C, Gottlow J, Linde A, Nyman S. Healing of maxil-
lary and mandibular bone defects by a membrane tech-
nique: an experimental study in monkeys. Scand J Plast
Reconstr Hand Surg 1990: 24: 13-19.
53. Dahlin C, Lekholm U, Becker W, Becker B, Higuchi K, Cal-
lens A, van Steenberghe D. Treatment of fenestration and
dehiscence bone defects around oral implants using the
guided tissue regeneration technique: a prospective
multicenter study. Int J Oral Maxillofac Implants 1995: 10:
312-318.

54. Dahlin C, Linde A, Gottlow J, Nyman S. Healing of bone
defects by guided tissue regeneration. Plast Reconstr Surg
1988: 81: 672-677.
55. Dahlin C, Sandberg E, Alberius P, Linde A. Restoration of
mandibular nonunion bone defect. Int J Oral Maxillofac
Surg 1994: 23: 237-242.
56. Dahlin C, Sennerby L, Lekholm U, Linde A, Nyman S.
Generation of new bone around titanium implants using
a membrane technique: an experimental study in rabbits.
Int J Oral Maxillofac Implants 1989: 4: 19-25.
57. Diks E Etienne D, Bou Abboud N, Ouhayoun J-P Bone
regeneration in extraction sites after immediate place-
ment of an e-PTFE membrane with or without a bio-
material. A report of 12 consecutive cases. Clin Oral Im-
plants Res 1996: 7: 277-285.
58. Dietrich U, Lippold R, Dirmeier T, Behneke W, Wagner W.
Statistische Ergebnisse zur Implantatprognose am Beispi-
el von 2017 IMZ-Implantaten unterschiedlicher Indikat-
ionen der letzten 13 Jahre. Z Zahnarztl Implant01 1993: 9:
9-18.
59. Ericsson I, Persson LG, Berglundh T, Edlund T, Lindhe J.
The effect of antimicrobial therapy on periimplantitis
lesions. An experimental study in the dog. Clin Oral Im-
plants Res 1996: 7: 320-328.
60. Frame JW. A convenient animal model for testing bone
substitute materials. J Oral Surg 1980: 38: 176-180.
61. Frost HM. Bone remodeling dynamics. Springfield, IL: CC
Thomas, 1963.
62. Fugazzotto PA. Success and failure rates of osseointe-
grated implants in function in regenerated bone for 6 to
51 months: a preliminary report. Int J Oral Maxillofac Im-
plants 1997: 12: 17-24.
63. Fugazzotto PA, Shanaman R, Manos T, Shectman R. Ges-
teuerte Knochenregeneration um Titanimplantate: Be-
richt uber die Behandlung von 1503 Stellen mit klinisch-
em Reentry. Int J Oral Maxillofac Implants 1997: 17: 277-
283.
64. Fukuta K, Har-Shai Mv; Collares MV, Lichten JB, Jackson
IT. Comparison of inorganic bovine bone mineral par-
ticles with porous hydroxyapatite granules and cranial
bone dust in the reconstruction of full thickness skull de-
fect. J Craniofac Surg 1992: 3: 25-29.
65. Gher ME, Quintero G, Assad D, Monaco E, Richardson AC.
Bone grafting and guided bone regeneration for immedi-
ate dental implants in humans. J Periodontol 1994: 65:
881-99 1.
66. Gotfredsen K, Nimb L, Buser D, Hjorting-Hansen E.
Evaluation of guided bone regeneration around implants
placed into fresh extraction sockets. An experimental
study in dogs. J Oral Maxillofac Surg 1993: 51: 879-884.
67. Gotfredsen K, Nimb L, Hjorting-Hansen E. Immediate im-
plant placement using a biodegradable barrier, poly-
hydroxybutyrate-hydroxyvaleratereinforced with poly-
glactin 910. Clin Oral Implants Res 1994: 5: 83-91.
68. Gotfredsen K, Warrer K, Hjorting-Hansen E, Karring T. Ef-
fect of membranes and porous hydroxyapatite on healing
in bone defects around titanium dental implants. An ex-
perimental study in monkeys. Clin Oral Implants Res
1991: 2: 172-178.
69, Gottlow J. Periodontal regeneration - a review. In: Lang
NP, Karring T, ed. First European Workshop on Periodon-
tology. Carol Stream, I L Quintessence Publishing Co.,
1994: 172-192.
Guided bone regeneration at oral implant sites
70. Gottlow J, Nyman S, Karring T, Lindhe J. New attachment
formation as the result of controlled tissue regeneration.
J Clin Periodontol 1984: 11: 494-503.
71. Gottlow J, Nyman S, Lindhe J, Karring T, Wennstrom J.
New attachment formation in the human periodontium
by guided tissue regeneration. Case reports. J Clin Peri-
odontol 1986: 13: 604-616.
72. Grunder U, Hurzeler MB, Schiipbach P, Strub JR. Treat-
ment of ligature-induced peri-implantitis using guided
tissue regeneration: a clinical and histologic study in the
beagle dog. Int J Oral Maxillofac Implants 1993: 8: 282-
293.
73. Guillemin G, Patat J.-L, Fournie J, Chetail M. The use of
coral as a bone graft substitute. J Biomed Mater Res 1987:
21: 557-567.
74. Hammerle CHF, Bragger U, Burgin W, Lang NP The effect
of the subcrestal placement of the polished surface of IT1
implants on the marginal soft and hard tissues. Clin Oral
Implants Res 1996: 7: 111-119.
75. Hammerle CHF, Bragger U, Schmid B, Lang NP Successful
bone formation at immediate transmucosal implants. Int
J Oral Maxillofac Implants (in press).
76. Hammerle CHF, Chiantella GC, Karring T, Lang NP The
effect of a deproteinized bovine bone mineral on bone
regeneration around titanium dental implants. Clin Oral
Implants Res (in press).
77. Hammerle CHF, Fourmousis I, Winkler JR, Weigel C, Brag-
ger U, Lang NP Successful bone fill in late peri-implant
defects using guided tissue regeneration. A short com-
munication. J Periodontol 1995: 66: 303-308.
78. Hammerle CHF, Olah AJ, Schmid J, Fliickiger L, Winkler
JR, Gogolowski S, Lang NP The biological effect of depro-
teinized bovine bone on bone neoformation on the rabbit
skull. Clin Oral Implants Res 1997: 8: 198-207.
79. Hammerle CHF, Schmid J, Lang NP, Olah AJ. Temporal
dynamics of healing in rabbit cranial defects using guided
bone regeneration. J Oral Maxillofac Surg 1995: 53: 167-
174.
80. Hammerle CHF, Schmid J, Olah AJ, Lang NP Osseous
healing of experimentally created defects in the calvaria
of rabbits using guided bone regeneration. Clin Oral Im-
plants Res 1992: 3: 144-147.
81. Hammerle CHF, Schmid J, Olah AJ, Lang NP A novel
model system for the study of experimental bone forma-
tion in humans. Clin Oral Implants Res 1996: 7: 38-47.
82. Hardwick R, Scantlebury Tv, Sanchez R, Whitley N,
Ambruster J. Membrane design criteria for guided bone
regeneration of the alveolar ridge. In: Buser D, Dahlin C,
Schenk RK, ed. Guided bone regeneration in implant den-
tistry. Carol Stream, IL: Quintessence, 1994: 101-136.
83. Hjorting-Hansen E, Helbo M, Aaboe M, Gotfredsen K,
Pinholt EM. Osseointegration of subperiosteal implant via
guided tissue regeneration. A pilot study. Clin Oral Im-
plants Res 1995: 6 : 149-154.
84. Hjorting-Hansen E, Worsaae N, Lemons JE. Histologic re-
sponse after implantation of porous hydroxylapatite cer-
amic in humans. Int J Oral Maxillofac Implants 1990: 5:
255-263.
85. Holmes RE, Bucholz RW, Mooney V. Porous hydroxyapa-
tite as a bone-graft substitute in metaphyseal defects. A
histometric study. J Bone Joint Surg 1986: 6 6 A 904-911.
86. Holmes RE, Bucholz RW, Mooney V. Porous hydroxyapa-
tite as a bone graft substitute in diaphyseal defects: a his-
tometric study. J Orthop Res 1987: 5: 114-121.
171
Hammerle & Karring
87. Hurzeler MB, Quifiones CR, Schupbach P, Morrison EC,
Caffesse RG. Treatment of peri-implantitis using guided
bone regeneration and bone grafts, alone or in combi-
nation, in beagle dogs. 2. Histologic findings. Int J Oral
Maxillofac Implants 1997: 12: 168-175.
88. Hurzeler MB, Strub JR. Guided bone regeneration around
exposed implants: a new bioresorbable device and biore-
sorbable membrane pins. Pract Periodontics Aesthet Dent
1995: 7: 37-47.
89. Hurzeler MB, Weng D, Hutmacher D. Knochenregener-
ation um Implantate - eine klinische Studie mit einer
neuen resorbierbaren Membran. Dtsch Zahnarztl Z 1996:
51: 2-7.
90. Hutmacher D, Hurzeler MB, Schliephake H. A review of
material properties of biodegradable and bioresorbable
polymers and devices for GTR and GBR applications. Int
J Oral Maxillofac Implants 1996: 11: 667-678.
91. Ilizarov GA. The tension-stress effect on the genesis and
growth of tissues. I. The influence of stability of fixation
and soft tissue preservation. Clin Orthop 1989: 238: 249-
281.
92. Ilizarov GA. The tension-stress effect on the genesis and
growth of tissues. 11. The influence of the rate and fre-
quency of distraction. Clin Orthop 1989: 239: 263-285.
93. Isidor F. Loss of osseointegration caused by occlusal load
of oral implants. A clinical and radiographic study in
monkeys. Clin Oral Implants Res 1996: 7: 143-152.
94. Isidor F. Histological evaluation of peri-implant bone at
implants subjected to occlusal overload or plaque ac-
cumulation. Clin Oral Implants Res 1997: 8: 1-9.
95. Jensen OT, Greer RO, Johnson L, Kassebaum D. Vertical
guided bone-graft augmentation in a new canine man-
dibular model. Int J Oral Maxillofac Implants 1995: 10:
335-344.
96. Jensen SS, Aaboe M, Pinholt EM, Hj~rting-HansenE,
Melsen E Ruyter IE. Tissue reaction and material charac-
teristics of four bone substitutes. Int J Oral Maxillofac Im-
plants 1996: 11: 55-66.
97. Johner R. Zur Knochenheilung in Abhangikeit von der De-
fektgrosse. Helv Chir Acta 1972: 39: 409-411.
98. Jovanovic SA, Kenney EB, Carranza FA, Donath K. The re-
generative potential of plaque-induced periimplant bone
defects treated by a submerged membrane technique: an
experimental study. Int J Oral Maxillofac Implants 1993:
8: 13-18.
99. Jovanovic SA, Schenk RK, Orsini M, Kenney EB. Supracres-
tal bone formation around dental implants: an experi-
mental dog study. Int J Oral Maxillofac Implants 1995: 10:
23-31.
100. Jovanovic SA, Spiekermann H. Bone regeneration around
titanium dental implants in dehisced defect sites: a clin-
ical study. Int J Oral Maxillofac Implants 1992: 7: 233-245.
101. Jovanovic SA, Spiekermann H, Richter EJ, Koseoglu M.
Guided tissue regeneration around titanium dental im-
plants. In: Laney WR, Tolman DE, ed. Tissue integration of
oral, orthopedic and maxillofacial reconstruction. Carol
Stream, IL: Quintessence Publishing Company, 1992: 208-
215.
102. Karring T, Nyman S, Gottlow J, Laurel1 L. Development
of the biological concept of guided tissue regeneration -
animal and human studies. Periodonto12000 1993: 1: 26-
35.
103. Karring T, Nyman S, Lindhe J. Healing following implan-
172
tation of periodontitis affected roots into bone tissue. J
Clin Periodontol 1980: 7: 96-105.
104. Karring T, Nyman S, Lindhe J, Sirirat M. Potential for root
resorption during periodontal healing. J Clin Periodontol
1984: 11: 41-52.
105. Kasperk C, Ewers R. Tierexperimentelle Untersuchungen
zur Einheilungstendenz synthetischer, koralliner und aus
Algen gewonnener (phykogener) Hydroxylapatitmateriali-
en. Z Zahnarztl Implantol 1986: 2: 242-248.
106. Kasperk C, Ewers R, Simons B, Kasperk R. Algae-derived
(phycogene) hydroxylapatite. Int J Oral Maxillofac Im-
plants 1988: 17: 319-324.
107. Hinge B, Alberius F: Isaksson S, Jonsson AJ. Osseous re-
sponse to implanted natural bone mineral and synthetic
hydroxylapatite ceramic in the repair of experimental
skull bone defects. J Oral Maxillofac Surg 1992: 50: 241-
249.
108. Kornman KS. The role of antimicrobials in prevention and
treatment of periodontal disease. In: American Academy
of Periodontology, ed. Perspectives on oral antimicrobial
therapeutics. Littleton: PSG Publishing Company, 1987:
37-46.
109. Kostopoulos L, Karring T. Augmentation of the rat man-
dible using guided tissue regeneration. Clin Oral Implants
Res 1994: 5: 75-82.
110. Kostopoulos L, Karring T, Uraguchi R. Formation of jaw-
bone tuberosities by guided tissue regeneration. An ex-
perimental study in the rat. Clin Oral Implants Res 1994:
5: 245-253.
111. Krekeler G, ten Bruggenkate CM, Oosterbeek HS. Verbes-
serung des Implantatbettes durch Augmentation mit au-
tologem Knochen. Z Zahnarztl Implantol 1993: 9: 231-
236.
112. Lang NF: Bragger U, Hammerle CHF. Immediate transmu-
cosal implants using the principle of guided tissue re-
generation (GTR). I. Rationale, clinical procedures, and 2
1/2-year results. Clin Oral Implants Res 1994: 5: 154-163.
113. Lang NP, Bragger U, Walther D, Beamer B, Kornman KS.
Ligature-induced peri-implant infection in cynomolgus
monkeys. I. Clinical and radiographic findings. Clin Oral
Implants Res 1993: 4: 2-11.
14. Lang NP, Hammerle CHE Bragger U, Lehmann B, Nyman
SR. Guided tissue regeneration in jawbone defects prior
to implant placement. Clin Oral Implants Res 1994: 5: 92-
97.
15. Lang NP, Mombelli A, Tonetti MS, Bragger U, Hammerle
CHF. Clinical trials on therapies for peri-implant infec-
tions. Ann Periodontol 1997: 2: 343-356.
16. Lazzara RM. Immediate implant placement into extrac-
tion sites: surgical and restorative advantages. Int J Peri-
odontics Restorative Dent 1989: 9: 333-343.
17. Lekholm U, Adell R, Lindhe J. Marginal tissue reactions
at osseointegrated titanium fixtures. 11. A cross-sectional
retrospective study. Int J Oral Maxillofac Surg 1986: 15:
53-61.
18. Linde A, T h o r h C, Dahlin C, Sandberg E. Creation of new
bone by a n osteopromotive membrane technique. An ex-
perimental study in rats. J Oral Maxillofac Surg 1993: 51:
892-897.
119. Lindhe J, Berglundh T, Ericsson I, Liljenberg B, Marinello
C. Experimental breakdown of peri-implant and peri-
odontal tissues. A study in the beagle dog. Clin Oral Im-
plants Res 1992: 3: 9-16.

120. Lundgren AK,Lundgren D, Sennerby L, Taylor 8, Gottlow
J, Nyman S. Augmentation of skull bone using a biore-
sorbable barrier supported by autologous bone grafts.
Clin Oral Implants Res 1997: 8: 90-95.
121. Lundgren AK, Sennerby L, Lundgren D, Taylor 8, Gottlow
J, Nyman S. Bone augmentation at titanium implants
using autologous bone grafts and a bioresorbable barrier.
Clin Oral Implants Res 1997: 8: 82-89.
122. Lundgren D, Lundgren AK, Sennerby L, Nyman S. Aug-
mentation of intramembranous bone beyond the skeletal
envelope using an occlusive titanium barrier. An experi-
mental study in the rabbit. Clin Oral Implants Res 1995:
6: 67-72.
123. Lundgren D, Nyman S, Mathiesen T, Isaksson S, Kling B.
Guided bone regeneration of cranial defects, using biode-
gradable barriers: a n experimental pilot study in the rab-
bit. J Craniomaxillofac Surg 1992: 20: 257-260.
124. Lundgren D, Sennerby L, Falk H, Friberg B, Nyman S. The
use of a new bioresorbable barrier for guided bone re-
generation in connection with implant installation. Clin
Oral Implants Res 1994: 5: 177-184.
125. Mayfield L, Nobreus N, Attstrom R, Linde A. Guided bone
regeneration in dental implant treatment using a bioab-
sorbable membrane. Clin Oral Implants Res 1997: 8: 10-
17.
126. Mombelli A, Lang NP. Antimicrobial treatment of peri-im-
plant infections. Clin Oral Implants Res 1992: 3: 162-168.
127. Mombelli A, Van Oosten MAC, Schurch E, Lang Nl? The
microbiota associated with successful or failing osseo-
integrated titanium implants. Oral Microbiol Immunol
1987: 2: 145-151.
128. Nevins M, Mellonig JT. The advantages of localized ridge
augmentation prior to implant placement. A staged event.
Int J Periodontics Restorative Dent 1994: 14: 97-111.
129. Nyman S. Bone regeneration using the principle of guided
tissue regeneration. I Clin Periodontol 1991: 18: 494-498.
130. Nyman S, Gottlow J, Karring T, Lindhe J. The regenerative
potential of the periodontal ligament. An experimental
study in the monkey. J Clin Periodontol 1982: 9: 257-265.
131. Nyman S, Karring T, Lindhe J, Planten S. Healing following
implantation of periodontitis affected roots into gingival
connective tissue. J Clin Periodontol 1980: 7: 394-401.
132. Nyman S, Lang NP, Buser D, Bragger U. Bone regeneration
adjacent to titanium dental implants using guided tissue
regeneration. A report of 2 cases. Int J Oral Maxillofac Im-
pIants 1990: 5: 9-14.
133. Nyman S, Lindhe J, Karring T. Reattachment - new attach-
ment. In: Lindhe J, ed. Textbook of clinical periodonto-
logy. 2nd edn. Copenhagen: Munksgaard, 1989: 450-473.
134. Nyman S, Lindhe J, Karring T, Rylander H. New attach-
ment following surgical treatment of human periodontal
disease. J Clin Periodontol 1982: 9: 290-296.
135. Nyman SR, Lang NF! Guided tissue regeneration and den-
tal implants. Periodontol 2000 1994: 4: 109-118.
136. Nystrom E, Legrell PE, Forssell A, Kahnberg K-E. Com-
bined use of bone grafts and implants in the severely re-
sorbed maxilla. Int J Oral Maxillofac Surg 1995: 24: 20-25.
137. Pajarola GF, Sailer HE Studer S. Steuerung der Knochen-
regeneration um Implantatpfeiler durch eine resorbierba-
re Folie. Z Zahnarztl Implant01 1993: 9: 181-183.
138. Palmer RM, Floyd PD, Palmer PJ, Smith BJ, Johansson CB,
Albrektsson T. Healing of implant dehiscence defects with
and without expanded polytetrafluoroethylene mem-
Guided bone reaeneration at oral imulant sites
branes: a controlled clinical and histological study. Clin
Oral Implants Res 1994: 5: 98-104.
139. Parodi R, Santarelli G, Carusi G. Application of slow-re-
sorbing collagen membrane to periodontal and peri-im-
plant guided tissue regeneration. Int J Periodontics Re-
storative Dent 1996: 16: 174-185.
140. Persson LG, Ericsson I, Berglundh T, Lindhe J. Guided
bone regeneration in the treatment of periimplantitis.
Clin Oral Implants Res 1996: 7: 366-372.
141. Pinholt EM, Bang G, Haanaes HR. Alveolar ridge augmen-
tation by osteoinduction in rats. Scand J Dent Res 1990:
98: 43441.
142. Pinholt EM, Haanaes HR, Donath K, Bang G. Titanium
implant insertion into dog alveolar ridges augmented by
allogenic material. Clin Oral Implants Res 1994: 5: 213-
219.
143. Pinholt EM, Haanaes HR, Roervik M, Donath K, Bang G.
Alveolar ridge augmentation by osteoinductive materials
in goats. Scand J Dent Res 1990: 100: 361-365.
144. Pinholt EM, Ruyter IE, Haanaes HR, Bang G. Chemical,
physical, and histologic studies on four commercial apa-
tites used for alveolar ridge augmentation. J Oral Maxillo-
fac Surg 1992: 50: 859-867.
145. Quifiones CR, Caffesse RG. Current status of guided peri-
odontal tissue regeneration. Periodonto12000 1995: 9: 55-
68.
146. Quirynen M, Naert I, van Steenberghe D. Fixture design
and overload influence marginal bone loss and fixture
success in the Brlnemark system. Clin Oral Implants Res
1992 3: 104-111.
147. Rasmusson L, Sennerby L, Lundgren D, Nyman S.
Morphological and dimensional changes after barrier re-
moval in bone formed beyond the skeletal borders at ti-
tanium implants. A kinetic study in the rabbit tibia. Clin
Oral Implants Res 1997: 8: 103-116.
148. Reddi AH. Cell biology and biochemistry of endochondral
bone development. Coll Re1 Res 1981: 1: 209-226.
149. Reddi AH, Weintroub S, Muthukumaran N. Biologic prin-
ciples of bone induction. Orthop Clin North Am 1987: 18:
207-2 12.
50. Renvert S, Claffey N, Orafi H, Albrektsson T. Supracrestal
bone growth around partially inserted titanium implants
in dogs. A pilot study. Clin Oral Implants Res 1996: 7: 360-
365.
51. Rosenquist 3, Grenthe B. Immediate placement of im-
plants into extraction sockets: implant survival. Int J Oral
Maxillofac Implants 1996: 11: 205-209.
52. Sandberg E, Dahlin C, Linde A. Bone regeneration by the
osteopromotion technique using bioabsorbable mem-
branes. An experimental study in rats. J Oral Maxillofac
Surg 1993: 51: 1106-1114.
153. Sato K, Urist MR. Induced regeneration of calvaria by
bone morphogenetic protein (BMP) in dogs. Clin Orthop
1985: 197: 301-311.
154. Schenk RK, Buser D, Hardwick WR, Dahlin C. Healing pat-
tern of bone regeneration in membrane-protected de-
fects: a histologic study in the canine mandible. Int J Oral
Maxillofac Implants 1994: 9: 13-29.
155. Schenk RK, Willenegger HR. Zur Histologie der primaren
Knochenheilung. Modifikationen und Grenzen der Spal-
theilung in Abhangigkeit von der Defektgrosse. Unfallheil-
kunde 1977: 80: 155-160.
156. Schlickewei W, Riede UN, Yu J , Ziechmann W, Kuner EH,
173
Hammerle & Karring
Seubert B. Influence of humate o n calcium hydroxyapa-
tite implants. Arch Orthop Trauma Surg 1993: 112: 275-
279.
157. Schliephake H, Kracht D. Vertical ridge augmentation
using polylactic membranes in conjunction with immedi-
ate implants in periodontally compromised extraction
sites: an experimental study in dogs. Int J Oral Maxillofac
Implants 1997:12:325-334.
158. Schliephake H, Neukam FW, Hutmacher D, Becker J. En-
hancement of bone ingrowth into a porous hydroxylapa-
tite-matrix using a resorbable polylactic membrane. An
experimental pilot study. J Oral Maxillofac Surg 1994: 52:
57-63.
159. Schmid J, Hammerle CHF, Fluckiger L, Gogolewski S,
Winkler JR, Rahn B, Lang Nl? Blood filled spaces with and
without filler materials in guided bone regeneration. A
comparative experimental study in the rabbit using biore-
sorbable membranes. Clin Oral Implants Res 1997:8: 75-
81.
160. Schmid J, Hammerle CHF, Olah AJ, Lang Nl? Membrane
permeability is unnecessary for guided generation of new
bone. Clin Oral Implants Res 1994: 5: 125-130.
161. Schmid J, Hammerle CHE Stich H, Lang NP. Suprapl-
ant@,a novel implant system based on the principle of
guided bone generation. Clin Oral Implants Res 1991: 2:
199-202.
162. Schmid J, Wallkamm B, Hammerle CHE Gogolewski S,
Lang NP: The significance of angiogenesis in guided bone
regeneration. Clin Oral Implants Res 1997:8: 244-248.
163. Schou S, Holmstrup E: Hjnrting-Hansen E, Lang N.
Plaque-induced marginal tissue reactions of osseointe-
grated oral implants: a review of the literature. Clin Oral
Implants Res 1992:3: 149-161.
164. Schou S, Holmstrup P, Keiding N, Fiehn N-E. Micro-
biology of ligature-induced marginal inflammation
around osseointegrated implants and ankylosed teeth in
cynomolgus monkeys (Mucacafuscicularis). Clin Oral Im-
plants Res 1996:7: 190-200.
165. Schupbach P, Hurzeler M, Grunder U. Implant-tissue in-
terfaces following treatment of peri-implantitis using
guided tissue regeneration. Clin Oral Implants Res 1994:
5: 55-65.
166. Schwartz 2, Mellonig JT, Carnes DR, De La Fontaine J,
Cochran DL, Dean DD, Boyan BD. Ability of commercial
demineralized freeze-dried bone allograft to induce new
bone formation. J Periodontol 1996:67:918-926.
167. Seibert J, Nyman S. Localized ridge augmentation in dogs:
a pilot study using membranes and hydroxyapatite. J Peri-
odontol 1990:3: 157-165.
168. Sevor JJ, Meffert RM, Cassingham RJ. Regeneration of de-
hisced alveolar bone adjacent to endosseous dental im-
plants utilizing a resorbable collagen membrane: clinical
and histologic results. Int J Periodontics Restorative Dent
1993:13: 71-83.
169. Shaw JK, Basset CAL. The effect of varying oxygen con-
centrations on osteogenesis and embryonic cartilage in
vitro. J Bone Joint Surg Am 1967:49: 73-80.
170. Simion M, Baldoni M, Rossi P, Zaffe D. A comparative
study of the effectiveness of e-PTFE membranes with and
without early exposure during the healing period. Int J
Periodontics Restorative Dent 1994: 14: 167-180.
171. Simion M, Misitano U, Gionso L, Salvato A. Treatment of
dehiscences and fenestrations around dental implants
174
using resorbable and nonresorbable membranes associ-
ated with bone autografts: a comparative clinical study.
Int J Oral Maxillofac Implants 1997: 12: 159-167.
172. Simion M,Trisi P, Piattelli A. Vertical ridge augmentation
using a membrane technique associated with osseointe-
grated implants. Int J Periodontics Restorative Dent 1994:
14:497-511.
173. Skoglund A, Hising P, Young C. A clinical and histologic
examination in humans of the osseous response to im-
planted natural bone mineral. Int J Oral Maxillofac Im-
plants 1997: 12: 194-199.
174. Smukler H, Porto Barboza E, Burliss C. A new approach
to regeneration of surgically reduced alveolar ridges in
dogs: a clinical and histologic study. Int J Oral Maxillofac
Implants 1995: 10:537-551.
175. ten Bruggenkate CM, Kraaijenhagen HA, van der Kwast
WAM, Krekeler G, Oosterbeek HS. Autogenous maxillary
bone grafts in conjunction with placement of IT1 endos-
seous implants: a preliminary report. Int J Oral Maxillofac
Surg 1992:21: 81-84.
176. Thaller SR, Hoyt J, Borjeson K, Dart A, Tesluk H. Recon-
struction of calvarial defects with anorganic bovine bone
mineral (Bio-Oss) in a rabbit model. J Craniofac Surg
1993:4: 79-84.
177. Tillmann T. Skelettsystem. In: Leonhardt H, Tillmann B,
Tondury G, Zilles K, ed. Anatomie des Menschen.
Stuttgart: Thieme, 1987:51-90.
178. Tinti C, Parma-Benfenati S, Polizzi G. Vertical ridge aug-
mentation: what is the limit? Int J Periodontics Restora-
tive Dent 1996: 16:220-229.
179. Tolman DE, Keller EE. Endosseous implant placement im-
mediately following dental extraction and alveoloplasty:
preliminary report with 6-year follow-up. Int J Oral Maxil-
lofac Implants 1991:6:24-28.
180. Tritten CB, Bragger U, Fourmousis I, Hammerle CHE
Transmukosale Direktimplantate: Einzelzahnsofortversor-
gung. Schweiz Monatsschr Zahnmed 1994:2: 122-126.
181. Urist MR. Bone: formation by autoinduction. Science
1965: 150:893-899.
182. van Drie HJY, Beertsen W, Grevers A. Healing of the gin-
giva following installment of Biotes" implants in beagle
dogs. In: de Putter C, de Lange GL, de Groot K, Lee AJC,
ed. Advances in biomaterials. Amsterdam: Elsevier
Science Publishers, 1988:485-490.
183. van Eeden SR Ripamonti U. Bone differentiation in po-
rous hydroxyapatite in baboons is regulated by the ge-
ometry of the substratum: implications for reconstructive
craniofacial surgery. Plast Reconstr Surg 1994: 93: 959-
966.
184. Wachtel HC, Langford A, Bernimoulin JP, Reichart l?
Guided bone regeneration next to osseointegrated im-
plants in humans. Int J Oral Maxillofac Implants 1991:6:
127-135.
185. Wallkamm B, Schmid J, Hammerle CHF, Gogolewski S,
Lang NE! Effect of a bioresorbable foam (Polyfoam") on
experimental bone neoformation. J Dent Res (in press:
IADR abstract).
186. Warrer K, Gotfredsen K, Hjmting-Hansen E, Karring T.
Guided tissue regeneration ensures osseointegration of
dental implants placed into extraction sockets. An experi-
mental study in monkeys. Clin Oral Implants Res 1991:2:
166-1 71.
187. Weber H, Buser D, Fiorellini J, Williams R. Radiographic

evaluation of crestal bone levels adjacent to nonsub-
merged titanium implants. Clin Oral Implants Res 1992:
3: 181-188.
188. Wetzel AC, Stich H, Caffesse RG. Bone apposition onto
oral implants in the sinus area filled with different graft-
ing materials. A histological study in beagle dogs. Clin
Oral Implants Res 1995: 6: 155-163.
189. Wildfang J, Merten AH, Schafer E Vergleichende Untersu-
chung zur GTR rnit resorbierbaren und nicht resorbier-
baren Folien. Z Zahnarztl Implant01 1994: 10: 137-143.
190. Zablotsky M, Meffert R, Caudill R, Evans G. Histological
and clinical comparisons of guided tissue regeneration on
dehisced hydroxylapatite-coated and titanium endosse-
Guided bone reKeneration at oral implant sites
ous implant surfaces: a pilot study. Int J Oral Maxillofac
Implants 1991: 6: 294-303.
191. Zellin G, Linde A. Effects of different osteopromotive
membrane porosities on experimental bone neogenesis
in rats. Biomaterials 1996: 17: 695-702.
192. Zitzmann N, Naef R, Scharer I? Gesteuerte Knochenregen-
eration und Augmentation in der Implantatchirurgie mit
Bio-Oss und Membrantechniken. Dtsch Zahnarztl Z 1996:
51: 36&369.
193. Zitzmann NU, Naef R, Schiipbach Scharer I? Sofort-
oder verzogertes Sofortimplantat versus Spatimplantat
bei Anwendung der Prinzipien der gesteuerten Knochen-
regeneration. Acta Med Dent Helv 1996: 1: 221-227.
175