Bone augmentation by means of

barrier membranes
Christoph H. F. Hammerle & Ronald E. Jung
The development of guided bone regeneration (GBR)
has substantially inuenced the possibilities for
using implants. The use of bone augmentation pro-
cedures has extended the use of endosseous implants
to jaw bone areas with insufcient bone volume.
Lack of bone volume may be due to congenital,
post-traumatic, or post-surgical defects or the result
of disease processes. The recently achieved predict-
ability and success of this procedure can change the
treatment of a compromised patient into a nearly
normal challenge.
Based on pioneer experiments investigating heal-
ing of periodontal tissues following surgical therapy,
a principle of tissue healing was discovered by
Nyman & Karring in the early 1980s (60, 62, 87,
88). It was found that cells which have access to
and migrate into a given wound space determine
the type of tissue regenerating in that space. Both
the exclusion of undesired cells from the wound area
and the formation of a wound space into which
desired cells are allowed to migrate were initially
achieved by the placement of barrier membranes
(61). The present understanding of the mechanisms
leading to regeneration of desired tissues is still in
accordance with these initial concepts.
The aim of the present chapter was to review
the techniques and membrane materials applied
for GBR in conjunction with implant based oral reha-
bilitation.
Types of membranes
General aspects
A wide range of membrane materials have been used
in experimental and clinical studies to achieve GBR
including polytetrauoroethylene (PTFE), expanded
PTFE (ePTFE), collagen, freeze-dried fascia lata,
freeze-dried dura mater allografts, polyglactin 910,
polylactic acid, polyglycolic acid, polyorthoester,
polyurethane, polyhydroxybutyrate, calcium sulfate,
micro titanium mesh, and titanium foils. Devices
used for GBR in conjunction with endosseous
implants should be safe and effective. Since no life-
threatening diseases or deciencies are treated, pos-
sible adverse effects emerging from the implanted
devices should be kept to a minimum. At the same
time, documentation of the effectiveness of the pro-
cedures and materials should be available. Certain
critical criteria regarding membranes used for guided
tissue regeneration have been postulated (47): bio-
compatibility, cell occlusiveness, integration by the
host tissues, clinical manageability, and the space
making function. For bioresorbable and biodegrad-
able membranes, additional criteria need to be ful-
lled. Tissue reactions resulting from the resorption
of the membrane should be minimal, these reactions
should be reversible, and they should not negatively
inuence regeneration of the desired tissues (38).
Although GBR is a quite successful procedure, a
better understanding of the factors critical for suc-
cess or failure is mandatory. This understanding
will lead to more rened clinical protocols and to
the manufacture of membrane materials with
improved performance for a given indication. Some
of these factors include the ideal size of membrane
perforations, membrane stability, duration of barrier
function, enhanced access of bone and bone-mar-
row-derived cells to the area for regeneration, ample
blood ll of the space, and prevention of soft tissue
dehiscence.
Non-resorbable membranes
Polytetrafluoroethylene
With the presentation of the rst successful GBR
procedures and the subsequent wide and successful
application of ePTFE membranes, this material
became a standard for bone regeneration. Expanded
PTFE is characterized as a polymer with high stability
36
Periodontology 2000, Vol. 33, 2003, 3653 Copyright
#
Blackwell Munksgaard 2003
Printed in Denmark. All rights reserved
PERIODONTOLOGY 2000
ISSN 0906-6713
in biological systems. It resists breakdown by host
tissues and by microbes and does not elicit immu-
nologic reactions.
A frequent complication with membrane applica-
tion in conjunction with implants is membrane
exposure and infection (98). Wound dehiscence
and membrane exposure have been reported to
impair the amount of bone regenerated in a number
of experimental animal (36, 63, 68) and clinical inves-
tigations (13, 34, 44, 106).
Many of the factors critical for successful bone
formation were identied in experimental studies
applying ePTFE membranes. Furthermore, clinical
protocols regarding surgical procedures, postopera-
tive care and the healing times required were estab-
lished using non-resorbable membranes. Today, as
evidence of the effectiveness of bioresorbable mem-
branes increases, non-resorbable membranes are
losing importance in clinical practice and their use
is increasingly limited to specic indications. Since
the use of ePTFE membranes have been documented
to result in successful GBR therapy, results obtained
using new materials should always be compared with
results of ePTFE membranes.
Titanium-reinforced ePTFE
In situations where bone formation is desired in large
defects or in supracrestal areas, conventional ePTFE
membranes do not adequately maintain space unless
supported by grafting materials. The alternative
approach involves the use of membranes with a sta-
ble form, such as titanium-reinforced membranes.
Titanium-reinforced membranes consist of a double
layer of ePTFE with a titanium framework interposed
(57, 110, 114). Recent research has demonstrated the
successful use of these membranes in vertical ridge
augmentation and in the treatment of large defects in
the alveolar process.
Bioresorbable membranes
An obvious disadvantage of ePTFE materials is that
they are non-resorbable and therefore have to be
removed during a second surgical procedure. With
regard to patient morbidity and psychological stress,
risk of tissue damage, and cost versus benets, the
replacement of non-resorbable by bioresorbable
membranes is highly desirable. Hence, recent experi-
mental research in GBR has aimed at developing
bioresorbable barrier membranes for application in
the clinic (Fig. 1).
Apart from the fact that the surgical intervention
for removal of the membrane is omitted, bioresorb-
able membranes offer some additional advantages
(Table 1). Among these are improved soft tissue heal-
ing, the incorporation of the membranes by the host
tissues (depending on material properties), and a
quick resorption in case of exposure, thus eliminat-
ing open microstructures prone to bacterial contam-
ination (72, 130).
In general, soft tissue healing is improved in the
presence of bioresorbable compared to non-resorb-
able membranes (69, 70, 130). However, some inves-
tigators have reported contrasting ndings (72). With
ePTFE membranes, 22% (GTAM) and 47% (TR-
GTAM) of sites showed dehiscences, while 50% of
sites treated with a bioresorbable membrane (self-
reinforced polyglycolic acid) became dehiscent (72).
The average gain of bone was decreased in cases
with dehiscences compared to an uneventful sub-
merged regeneration period. Both in the presence
and in the absence of soft tissue problems the
amount of bone ll of the defects was greater with
the ePTFE membranes.
Several studies have compared bioresorbable
membranes to non-resorbable membranes made of
ePTFE. In situations where no membrane exposures
were noted, the results regarding the relative amount
of bone formation were usually more favorable using
the ePTFE membranes compared to the bioresorb-
able ones (55, 81, 83, 109).
Various reasons for the generally lower defect ll
with bioresorbable membranes as compared to
ePTFE membranes include:
the better space-making capacity of ePTFE;
controlled time of barrier function;
lack of a resorption process and lack of the gen-
eration of resorption products that negatively
affect bone formation;
longer experience with ePTFE membranes resulting
in surgical protocols better tailored for their use.
In summary, it appears that bioresorbable mem-
branes in general allow for more bone regeneration
than non-resorbable ePTFE membranes. However, if
soft tissue dehiscences can be avoided, the ePTFE
membranes allow for slightly more bone regenera-
tion than bioresorbable ones.
Choice of material
Obviously, choice of material is very critical when it
comes to bioresorbable membranes for GBR. A vari-
ety of bioresorbable and non-resorbable devices for
GBR have been evaluated in a recent animal and
clinical experiments. Depending on the material,
inammatory reactions have been documented in
Barrier membranes
37
Fig. 1. a) Radiographic view of a single tooth gap in the
anterior maxilla following extraction of a partially
resorbed central incisor. b) A screw implant (ITI
1
Dental
Implant System, Straumann AG, Waldenburg, Switzer-
land) has been placed at the location of the right central
incisor of the maxilla. A dehiscence defect is visible expos-
ing part of the buccal aspect of the rough surfaced implant
body. c) A bioresorbable collagen membrane (Bio-Gide,
Geistlich AG, Wolhusen, Switzerland) supported by a
deproteinized bovine bone mineral (Bio-Oss, Geistlich)
has been placed in an attempt to augment the bone buc-
cal to the implant, thus integrating the titanium surface.
d).At the reentry surgery 6 months later, the initially
exposed surface of the implant is completely covered by
newly formed bone. The buccal bone plate is of sufcient
width to adequately support the soft tissues. e) Radio-
graphic view of the implant following incorporation of
the nal reconstruction. Note the excellent height of
the crestal bone and the adaptation of the bone to the
implant surface.
38
Hammerle & Jung
the tissues adjacent to bioresorbable membranes,
ranging from mild (1, 93, 97) to severe (37). Another
recent study reported on therapeutic failures using
polylactic membranes for bone regeneration at peri-
implant defects in dogs (98). Soft tissue complica-
tions were frequent, and the results did not reveal
any improvement over control sites without the use
of membranes.
Bioresorbable membranes that are commercially
available at present are not capable of maintaining
adequate space unless the defect morphology is very
favorable (77). Even if the membranes initially seem
able to maintain space, they generally lose their
mechanical strength soon after implantation into
the tissues. Only in situations where the bony bor-
ders of the defects adequately support the membrane
have favorable results been reported. When defects
are not space making by themselves, failure of bone
regeneration results (82, 126). Therefore, they need to
be supported in one way or another.
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 (41, 43, 100).
New bone was demonstrated to form underneath the
membrane beyond the borders of the former calvar-
ium. On the one hand, this experiment demonstrated
that, in principle, stiff, bioresorbable membranes are
conducive to bone regeneration and bone neoforma-
tion. On the other hand, after the observation period
of 4 months, no overt signs of breakdown of the
membrane were reported. In many clinical situations
a resorption time not extending beyond 612 months
is mandatory in order not to lose the advantages of
resorbability.
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
polyglycolide and/or polylactide or copolymers
thereof (for review see (54)).
Convincing results of bone regeneration in animal
experiments have been reported for collagen mem-
branes (53, 125). Furthermore, reports of human
cases or case series (45) as well as controlled clinical
studies (130) have been presented describing the
successful use of collagen membranes for GBR at
exposed implant surfaces.
In two recent experiments, a polylactic acid (PLA)
membrane was tested for its ability to increase the
bone volume in conjunction with an autogenous
bone graft; this was compared to controls that were
grafted only (74, 75). Both experiments showed more
bone formation when the membranes were applied.
These results and results from other investigations
(83, 109) demonstrate that soft PLA or polyglycoid
acid (PGA) membranes are suitable for GBR proce-
dures in conjunction with autogenic grafts.
In contrast, unfavorable results were obtained
using a bioresorbable barrier composed of poly
(d,l-lactic)-co-trimethylene carbonate (52). Control
sites treated with ePTFE showed signicantly better
bone regeneration. Generally, only a mild inamma-
tory reaction was found associated with the mem-
branes. Five months following implantation, some of
the membranes had only just started to lose their
original integrity, while others were completely
resorbed. This high variability in resorption kinetics
complicates clinical use of the material. Similar unfa-
vorable ndings were documented in another study
using the same PLA membrane (98).
In summary, animal experiments, human case
reports and initial controlled clinical studies demon-
strate that bioresorbable collagen, PLA and PGA
membranes can be used successfully for bone regen-
eration at implants with exposed surface areas.
Table 1. Characteristics of bioresorbable membranes
Advantages
No need for membrane removal surgery
Simplified surgical procedure with an implant system with two-stage surgical approach
Wider range of surgical techniques possible at abutment connection (which coincides with membrane removal for non-
resorbable membranes)
Better cost-effectiveness
Decreased patient morbidity
Disadvantages
Uncontrolled duration of barrier function
Resorption process possibly interfering with wound healing and bone regeneration
Need for membrane supporting material
39
Barrier membranes
Types of bone defects
Horizontal bone defects include dehiscence, fenes-
tration and infra bony defects.
A large number of animal experiments have
demonstrated the successful use of bioresorbable
membranes in GBR (7, 24, 43, 64, 74, 75, 76, 97, 99,
100, 104, 125), whereas others have reported failures
(28, 37, 72, 98, 123).
Horizontal bone defects
Since the early 1990s, various studies have been
published describing the successful clinical employ-
ment of bioresorbable PLA and PGA membranes for
GBR at exposed implant surfaces (8, 77, 79, 89, 109).
In contrast, some investigators have reported a
reduced defect ll when applying bioresorbable
(60%) compared to non-resorbable (8184%) mem-
branes (72).
In one of these studies, 18 implants with exposed
surfaces were treated in nine patients (109). In the
test sites, bioresorbable membranes of polylactic and
polyglycolic acid (PLA/PGA) were used, whereas
non-resorbable membranes of ePTFE (GTAM) were
applied in the control sites. In addition, autogenic
bone was placed to cover the exposed implant
threads prior to membrane adaptation. The results
at reentry 67 months later revealed a more favorable
healing using ePTFE (98% defect ll) compared to
the bioresorbable group (89% defect ll). This pattern
of increased bone formation resulting from the use of
ePTFE membranes compared to PLA/PGA mem-
branes has been demonstrated in a histologic study
in humans (108).
Vertical bone defects
The indications for vertical ridge augmentation
include situations where the remaining bone height
is too small for proper anchorage of oral implants;
unfavorable crown to implant ratios and unfavorable
esthetic outcomes will result from the lack of remain-
ing hard and soft tissues.
Data from animal experiments have clearly
demonstrated that growth of bone above the external
borders of the skeleton was possible using GBR (43,
64, 65, 74, 78, 100, 101).
In a recently presented model system, vertical
growth of bone has been studied experimentally in
humans (42). Titanium hollow cylinders were placed
in the retromolar area of healthy subjects. The regen-
erating tissue was harvested at different time points.
The results revealed that up to 12 weeks soft tissue
was lling the cylinder space, while increasing
amounts of mineralized bone was lling the space
at later time points up to 9 months.
In the rst attempt to augment bone above the
borders of the alveolar crest at titanium implants in
dogs, reinforced ePTFE membranes showed a gain of
1.8 mm, standard ePTFE membranes revealed a gain
of 1.9 mm, and in the controls without membranes
the bone height increased by 0.5 mm (58). No graft
materials had been placed. In both membrane
groups, about 1 mm of non-mineralized tissue was
present between the mineralized bone and the mem-
brane at its highest point. Non-mineralized tissue
has been reported in contact with the inner surfaces
of membranes in other studies as well (57, 106).
In the rst clinical study on vertical ridge augmen-
tation in humans, a titanium-reinforced ePTFE
membrane was used to cover implants that were
allowed to protrude up to 7 mm above the crest
(107). The results after 9 months of submerged heal-
ing showed bone formation reaching up to 4 mm
above the previous border of the alveolar crest. The
remainder of the space between the newly formed
bone and the membrane was occupied by non-
mineralized tissue. Within the area of the newly
formed bone, osseointegration of the implants had
occurred as demonstrated by histologic analysis of
experimentally retrieved test implants.
In another study, six patients were treated with
titanium-reinforced membranes and autogenic bone
collected in a suction lter (114). Twelve months
following membrane placement, an average gain of
5 mm of vertical bone height was measured, reach-
ing up to a maximum of 7 mm.
Later studies reported improved amounts of verti-
cal bone gain when using autogenous bone grafts or
bone substitute materials in addition to the titanium-
reinforced ePTFE membranes (110, 115).
The ePTFE/tissue interface has recently been char-
acterized in humans (31). The tissue layer in contact
with the membrane was described as non-minera-
lized, rich in cells and vessels, and containing irre-
gularly distributed collagen bers. According to the
investigators, this tissue layer may have developed
due to micro movements or broblasts penetrating
through the membrane from the covering soft tissue
ap. The phenomenon of non-mineralized tissue in
contact with membrane surfaces has been reported
for bioresorbable materials as well (94, 100). The
reasons for this are not fully understood and need
clarication. Furthermore, it has been postulated
40
Hammerle & Jung
that lack of adequate stability of membranes will
prevent complete bone formation.
Time frame of implantation
In relation to GBR surgery
In principle, attempts at regenerating bone for
improved anchorage of oral implants may be per-
formed in conjunction with the placement of the
implants or during a surgical intervention prior to
implant placement.
The staged approach is primarily chosen in situa-
tions with large bone defects. Such situations often
do not allow obtaining primary stability of the
implants in the prosthetically desired position.
Hence, the alveolar ridge is augmented in a rst
surgical intervention. After the appropriate time for
healing, the implants are then placed into a site of
sufcient bone volume.
Staged approach
Experimental research on ridge augmentation using
GBR was presented in the early 1990s (103). In a dog
model, large defects of the alveolar ridge were surgi-
cally prepared both in the mandible and in the max-
illa to allow for four different treatment modalities.
The defects were treated one of the following ways:
covered with ePTFE membranes;
covered with membranes and grafted with porous
hydroxyapatite or with a tissue growth matrix of
porous PTFE;
grafted with these same materials but not covered
with membranes;
neither grafted nor covered.
Morphological and histologic analysis revealed that
in sites treated with membranes, with or without the
addition of grafts, the entire space between the mem-
brane and the jawbone was lled with bone. In the
absence of membranes, bone formation did not occur.
More recently, studies in humans and animals have
lead to further development and renement of this
method. In a clinical study involving 40 partially eden-
tulous patients lateral ridge augmentations were
performed prior to implant placement (21). Ridge
width at the rst surgical intervention precluded
implant placement in prosthetically proper position.
Autogenous cortico-cancellous block grafts and parti-
culate bone were used in conjunction with ePTFE
membranes for ridge augmentation. At the reentry
surgery 9 months later, the bone volume had
increased to values sufcient for implant placement
in all cases. The investigators concluded that the
combination of autogenous bone grafts and ePTFE
membranes rendered predictable success.
The effect of barrier membranes on the resorption
of bone block grafts has recently been studied in an
animal experiment (6). Resorption of the grafted
bone occurred to various degrees at sites not covered
with ePTFE membranes, whereas at the sites with
membranes no loss of graft volume due to resorption
was recorded.
The necessity for membranes was tested in a pro-
spective randomized clinical study involving 13
patients (3). Patients were either treated with onlay
bone grafts alone or additionally covered by ePTFE
membranes. The width of the ridges was clinically
evaluated immediately following graft placement
and at the time of membrane removal 6 months
later. In the group with membranes signicantly less
resorption had occurred. This controlled clinical
study conrms animal experimental data and is in
accordance with previous case series reporting the
occurrence of pronounced resorption of bone grafts
(4, 121, 27).
Grafts of autogenous bone have traditionally been
used for augmentaion of narrow ridges prior to
implant placement. In a recent clinical study a
deproteinized bovine bone mineral was applied in
conjunction with a bioresorbable collagen mem-
brane (128). Spongiosa granules of 0.251 mm parti-
cle size were mixed with sterile saline and
tetracycline powder and applied to the defect. The
grafting material was subsequently covered with a
collagen membrane, which was xed to the adjacent
bone by use of titanium pins. Flaps were adapted and
sutured for primary healing. After 67 months, reen-
try surgeries were carried out. Biopsies taken from
the augmented sites reveal the grafted particles to be
well integrated into the newly formed bone.
In another study the sites were augmented with
bioactive glass immediately following tooth extrac-
tion. Membranes were not used in all cases. An overall
success rate of 88.6% was reported for the implants
after a mean period of function of 29.2 months. For-
mation of new bone in association with the grafting
particles was histologically documented.
These newer studies indicate that provided the
appropriate protocols are developed, ridge augmen-
tation without the use of autogenous block grafts
could possibly evolve into a standard procedure.
Combined approach
Compared to the staged approach the combined
method offers some advantages:
41
Barrier membranes
decreased patient morbidity due to the fact that
only one surgical intervention is necessary;
decreased treatment time since regeneration and
implantation are performed at the same time;
decreased costs.
Based on these advantages it has been postulated
that the combined approach is to be preferred when-
ever the clinical situation allows doing so (Fig. 2).
One of the key points of discussion regarding
combined implantation and regeneration was the
Fig. 2. Preoperative view of a single tooth gap in the ante-
rior maxilla following extraction of a central incisor. (a:
occlusal view; b: buccal view). Intraoperative view of a
screw implant (TiUnite Mk III Branemark
1
, Nobel Biocare,
Gothenburg, Sweden) showing a buccal and oral dehis-
cence. (c: occlusal view; d: buccal view). The defect site
has been grafted with a deproteinized bovine bone mineral
(Bio-Oss, Geistlich) and autogenous bone harvested from
the surrounding area. A titaniumreinforced non-resorbable
ePTFE membrane (Gore-Tex TR, W.L. Gore & Associates,
Inc., Flagstaff, USA) has been trimmed and shaped to cover
the bone substitute materials and the implant. The
membrane has been secured at the buccal aspect by two
non-resorbable pins. (e: occlusal view; f: buccal view). Six
months after implantation and regeneration, a signicant
gain of the buccal contour is discernable. (g: occlusal view;
h: buccal view). At membrane removal surgery, the surface
of the implant is completely covered with new bone (i). A
pronounced gain of bone also in buccal direction is obser-
ved following uncovering of the closure screw(j). Radiogra-
phic view of the implant with an individualized zirconium
oxide abutment screwed onto the implant. Note the close
adaptation of the bone at the surface of the implant and the
crestal bone level being located coronal to the st thread.
42
Hammerle & Jung
question whether or not implant surfaces initially
not covered by bone can successfully be osseointe-
grated by the regenerating bone under GBR. A
large number of animal experimental studies have
histologically demonstrated that such surfaces are
truly osseointegrated during the process of bone
regeneration (10, 11, 63, 118). In addition, studies
in humans have conrmed the ndings reported
in the animal experiments mentioned above (91,
92, 122).
In relation to tooth extraction
With respect to loss or extraction of teeth, implants
may be placed in an immediate, a delayed or a late
fashion. The time requirements for immediate
Fig. 2. continued
43
Barrier membranes
implant placement are fullled when the implant is
placed into an extraction socket during the same
surgical intervention as the removal of the tooth to
be replaced by the implant. The delayed approach
indicates that several weeks, usually up to a maxi-
mum of 12 weeks, have passed between tooth extrac-
tion and implant placement. In situations where
more time elapses between tooth extraction and
implant placement the term late implant placement
is appropriate.
In a recent retrospective study immediate, delayed
and late implant placements were compared using
survival data as well as clinical and radiographic
parameters (119). The survival rate for all groups
was above 97% 2 years after implantation. In another
investigation, no difference regarding bone ll was
found between immediate and delayed implant pla-
cement at reentry surgery (130). In this study the
defects had been treated by collagen membranes
and a deproteinized bovine bone mineral.
Immediate implant placement
Increasing numbers of clinical studies demonstrate
that the immediate placement of implant into extrac-
tion sockets is a method that renders success rates
similar to the ones reported for conventional implant
placement. Success rates usually well above 90%
have been reported in a large number of studies
(14, 16, 18, 33, 35, 102).
A problem encountered when placing implants
immediately into extraction sockets is a lack of soft
tissues for primary healing. This soft tissue decit is
due to the area of tissue penetration of the tooth
prior to extractions. Hence, in order to obtain pri-
mary closure, the buccal ap is often mobilized by
vertical and horizontal releasing incisions. However,
as a result the soft tissue contours, in particular the
level of the mucogingival line, are altered and the
esthetic outcome may be hampered. Consequently,
techniques have recently been published aimed at
facilitating primary ap closure through the place-
ment of pedicle or free grafts (23, 32, 84, 96). Closure
of the wound over an immediate implant can suc-
cessfully be obtained by connective tissue grafts,
eliminating the need for excessive mobilization of
the buccal ap (23, 32). In addition, this technique
increases the amount of keratinized tissue and thus
provides better conditions for an optimal esthetic
result.
Immediate implants without regeneration
Whereas controlled human studies have demon-
strated enhanced bone regeneration when exposed
implant surfaces are treated with barrier membranes
(29, 90), other investigators have reported adequate
bone formation in extraction sockets without the use
of membranes (12, 92, 102, 112, 122).
In a prospective controlled human clinical trial,
test implants were placed into extraction sockets
immediately after tooth extraction (92). Implants
were located in the premolar and molar region of
maxilla and mandible. The diameter of the experi-
mental implants was chosen with the aim of obtain-
ing as much contact with the socket walls as possible.
Thus, the distance from the bone to the implant sur-
face was consistently kept at values smaller than
2 mm. The neck of the implants was located at the
level of the alveolar crest. No lling materials or
membranes were applied. Control implants were
inserted into sites with sufcient bone volume. Pri-
mary wound closure was performed at both test and
control implants. Six months after implant place-
ment, a second stage surgery was performed and
healing caps were inserted. After another 6 months,
test and control implants were removed with an
appropriate trephine drill. Results of clinical mea-
surements, radiographic assessments of bone levels,
histologic analysis of crestal bone levels and surface
fraction of the implants in direct bone contact
revealed no difference between test and control
implants. In only three out of 48 test implants was a
crestal zone of connective tissue contact discernible
extending 1.52 mm. The investigators concluded that
implant placement immediately into extraction sock-
ets leads to tissue integration similar to the one
obtained with implants placed into intact alveolar
crests provided the gap width is smaller than 2 mm.
In a human study treating more demanding
defects including dehiscence defects with a mean
depth of 7 mm, a deproteinized bovine bone was
used to ll the gaps between the implants and the
bony walls of the defects (112). Again, no membranes
were used to cover the defect areas. Although, defect
ll was not as predictable as reported in other studies
using membranes (108), the majority of the initial
defect area was lled with new bone at the 6-month
reentry surgery. Compromised results were asso-
ciated with exposure and loss of the grafting material.
There seems to be some consistent results that a
gap width of less than 2 mm between the implant
and the socket wall will be lled with bone in the
absence of membranes. However, more research is
needed to characterize the clinical conditions, where
membranes in bone regeneration procedures are not
necessary and where they are necessary for predict-
able success.
44
Hammerle & Jung
Delayed implantation
Since ap dehiscence and resulting membrane expo-
sure are the most frequent complications using the
immediate implantation protocol, differing treatment
concepts have been developed. In contrast to immedi-
ate implantation following tooth extraction, the
delayed approach is aimed at allowing soft tissue
healing prior to the surgical intervention. The in-
creased amount of soft tissue present simplies the
surgical technique for ap closure. Furthermore, it
renders esthetically optimal results more predictable.
Since the resorption processes of bone are rather
small, the loss in bone volume occurring during the
rst 12 weeks will usually not hamper placement of
the implant and can be compensated by the planned
regeneration procedure.
In a recent study a comparison between the fre-
quency of membrane exposures was done between
three treatment groups: immediate implantation,
delayed implantation, and late implantation (130).
The results demonstrated that in particular when
using non-resorbable ePTFE membranes, the inci-
dence of membrane exposure was signicantly ele-
vated when using the immediate (60%) as compared
to the delayed approach (17%). The late approach,
however, was associated with even fewer exposures
than the delayed approach. Although still present,
these differences were less pronounced when a bior-
esorbable collagen membrane was used.
The disadvantages of the delayed approach
include the increased treatment time, the need for
an additional surgical intervention, the fact that the
excellent bone regenerative potential of the fresh
extraction socket can no longer fully be taken advan-
tage of, and the decreased bone volume resulting
from the occurring bone resorption during soft tissue
healing.
Late implantation
Late implant placement is performed in situations
where teeth have been extracted months before. Clin-
ical experience shows that many implantation proce-
dures can be performed in a standard way without the
need for GBR. Such procedures would qualify for the
term late implantation. However, the focus of this
review lies on treatment using GBR for compromised
sites. In situations where the late approach is chosen
and the need for GBR is still present, no signicant
advantages have been described compared to GBR
using the delayed approach.
However, it has been reported that the incidence of
soft tissue dehiscence and subsequent membrane
exposure is somewhat smaller when using the late
approach compared to the delayed one (130). This
difference may have signicant effects since bone
formation is generally less favorable when dehis-
cences occur, compared to situations where the soft
tissues remain intact during the entire regeneration
period (13, 20, 44, 51, 67, 106, 117, 127).
Soft tissue dehiscences represent an important
complication during GBR with ePTFE membranes.
They range from a minor problem affecting only a
few percent of membranes up to a serious complica-
tion leading to a high rate of complete treatment
failures, impaired results, and suffering for the
patient (30, 72, 109, 117, 127, 129). This emphasizes
the importance of carefully balancing benets and
risks when planning GBR therapy. Based on the
reports in the literature, there is general agreement
that GBR is a difcult procedure to perform and that
the skills and experience of the clinician are a critical
factor in the success of treatment. Recently, evidence
of lower rates of dehiscences associated with biore-
sorbable membranes compared to non-resorbable
membranes has been presented, further promoting
the use of bioresorbable membranes.
Clinical mode of healing
Submerged implants
In general, when GBR is performed in conjunction
with implant placement a submerged mode of heal-
ing is attempted. The rationale for attempting a sub-
merged mode of healing includes the prevention of
bacterial contamination of the implant and the
membrane surfaces by bacteria from the oral cavity.
In addition, in esthetically difcult regions an addi-
tional soft tissue volume is present at the initiation of
the prosthetic procedures, which increases the range
of therapeutic possibilities to reach an optimal
esthetic result. Finally, a submerged implant has
been claimed to be optimally protected from adverse
loading forces (2).
In contrast, recent studies have demonstrated that
successful treatment outcomes may also be obtained
when implants are kept in a transmucosal location
during bone regeneration and tissue integration (18,
25, 40, 45, 66). Furthermore, histologic data obtained
in animal experiments as well as from human speci-
mens demonstrate osseointegration of the previously
exposed surface areas (63, 122).
In contrast to the submerged approach, transmu-
cosal healing eliminates the surgical intervention
45
Barrier membranes
necessary to obtain access to the implant head for
performing the prosthetic procedures.
Transmucosal implants
The technique for transmucosal positioning of
implants during GBR procedures was rst described
in a clinical report of a series of cases (25). Subse-
quently, another series of cases using ePTFE mem-
branes for regeneration of bone around implant
immediately placed into extraction sockets was pre-
sented (66). In this study a treatment regimen includ-
ing the directions for meticulous plaque control was
described involving both mechanical means and
chemical agents. The results demonstrated 20 out
of 21 implants with complete defect ll with new
bone upon membrane removal surgery. In a retro-
spective controlled study, transmucosal implants
with GBR were compared with transmucosal
implants that did not need any GBR procedures
(18). No differences were found regarding the pre-
sence of plaque, the prevalence of bleeding on prob-
ing, values for the level of the mucosal margin, or
probing depths around the implants.
Two recent studies presented a defect ll of 94%
when using ePTFE membranes (40) and 86% when
using bioresorbable membranes (45) for GBR at
transucosal implants. Measurements were taken at
the time of implant placement and 6 months later.
In summary, although studies on bone regenera-
tion at transmucosal implants are still not very
numerous, the available data demonstrate that GBR
at transmucosal implants is a successful procedure.
Hence, primary closure of the site of implantation
and regeneration is not a prerequisite for successful
treatment outcomes. However, investigators report-
ing on the transmucosal technique stress the impor-
tance of meticulous plaque control during the
regeneration period.
Long-termresults
Survival rate of implants placed into sites with regen-
erated/augmented bone using barrier membranes
have been reported to vary between 79% and 100%
with the majority of studies indicating more than 90%
after at least 1 year of function. Thus, in a number of
studies a total of 656 implants treated with GBR
yielded survival rates ranging from97.5% to 100% after
a 2-year observation period (19, 29, 73, 80, 86, 73).
Three studies reported 5-year data (15, 22, 131).
Survival rates were 79.4% for 37 implants with dehis-
cence/fenestration defects treated with ePTFE mem-
branes (15), 92.6% for 41 implants treated with
ePTFE membranes (131), 93.9% for 33 implants in
extraction sites treated with ePTFE membranes (15)
95.4% for 112 implants treated with a collagen mem-
brane (131), and 100% for 12 implants treated with
e-PTFE membranes (22).
In a 5-year prospective controlled study, implants
placed into pristine bone were compared with
implants associated with bone regeneration (131).
No signicant differences were found regarding the
cumulative implant survival rates in the three groups:
sites augmented with a collagen membrane and a
deproteinized bovine bone mineral (95.4%), sites
augmented with an e-PTFE membrane and a depro-
teinized bovine bone mineral (92.6%), and sites with-
out augmentation (97.3%).
Another study providing controls reported on 38
implants in seven patients (80). In this study, 21
implants were placed in conjunction with GBR and
17 could be placed into the host bone without the
need for regenerative therapy. A polylactic, polygly-
colic acid membrane was used in all regenerative
procedures. After an average of 25 months following
incorporation of xed reconstructions, a 100% survi-
val rate was found for both test and control implants
and no signicant difference in marginal bone levels
was recorded between the two groups.
A multicenter evaluation of implants inserted at
the time or after vertical ridge augmentation revealed
stable crestal bone levels over a period of 15 years
(111). Initially, 123 implants had been placed. At the
follow-up examination one implant had been lost,
while the remainder could be reexamined. Augmen-
tation had been performed using ePTFE membranes
in conjunction with a blood clot, with demineralized
freeze-dried bone allografts or with autografts. Stable
crestal bone levels were reported in the majority of
the implants. Only two implants demonstrated an
increased crestal bone loss of 3.5 mm and 4 mm,
respectively. The investigators concluded that verti-
cally regenerated bone reacts to implant placement
in a manner similar to non-regenerated bone.
Although the data are derived from a small number
of studies showing an adequate design, survival rates
similar to the ones generally reported for implants
placed conventionally into sites without the need for
bone augmentation have been documented.
Outlook into the future
In recent years, many developments in medicine
have been based on a better understanding of
46
Hammerle & Jung
the development of diseases at the cellular and
the molecular level. This is a key step to the devel-
opment of new strategies and materials in medicine.
The strategies in most of the medical disciplines
are changing in character from a mechanical to a
more biological one. The aim is to come up with
more effective techniques that predictably promote
the bodys natural ability to regenerate lost tissue
instead of using external materials to repair lost
tissue.
The most intriguing method currently being inves-
tigated is the application of polypeptide or natural
proteins that regulate wound and tissue regenera-
tion. With the improvements in cellular and molecu-
lar technologies to isolate, sequence and produce
these molecules, a new eld of therapeutic options
will be opened.
Growth and differentiation factors in oral
surgery
In the past decade a number of basic science experi-
ments and clinical studies have claried biological
mechanisms of several growth and differentiation
factors in the regeneration of oral soft and hard tissue
(49). Growth and differentiation factors currently
believed to contribute to periodontal and alveolar
ridge augmentation include platelet-derived growth
factor (PDGF), insulin-like growth factor (IGF-I and -
II), transforming growth factor beta (TGF-a and -b),
broblast growth factor (a- and b-FGF), and bone
morphogenetic proteins (BMPs 1-15). Of these, bone
morphogenetic protein is the most widely studied in
the dental literature. In 1965, Urist discovered the
inductive bone capacity of a protein extracts
from demineralized bone (116). This protein extract
was termed bone morphogenetic protein (BMP). The
induction process triggered by BMPs involves
chemotaxis, proliferation and differentiation of
mesenchymal progenitor cells (124). Recombinant
biotechnology has made it possible to characterize
at least 15 BMPs and to produce quantities of pur-
ied recombinant protein for therapeutic application
(39). Recombinant human BMP-2 (rhBMP-2) has
been found to exhibit very high osteogenic activity
in experimental (26, 46, 48, 105) and clinical studies
(17, 46).
Local delivery of molecules
The regenerative potential of growth and differentia-
tion factors depends upon the carrier material (50,
105). The effect of such proteins is dependent upon a
carrier material, which serves as a delivery system
and as a scaffold for cellular ingrowth (95).
Collagen has been extensively studied as a carrier
material for growth factors applied to promote bone
formation in different kinds of indications (17, 49,
85). Different studies (9) using rhBMP-2 in an
absorbable collagen sponge (ACS) for alveolar ridge
augmentation gained only small amounts of bone.
The investigators concluded that the compromised
results were due to the failure of the ACS to ade-
quately support the supra-alveolar wound space. In
order to overcome this lack of structural strength, rh-
BMP-2/ACS has been combined with hydroxyapatite
in an experiment attempting lateral ridge augmenta-
tion (9). In contrast to rhBMP-2/ACS alone, a signif-
icant clinical improvement in ridge width was
observed with the addition of HA to rhBMP-2/ACS.
However, the hydroxyapatite particles were largely
encapsulated by brous tissue and they appeared
to partially obstruct bone formation. The investiga-
tors concluded that space maintenance in BMP-
induced bone formation is an important factor (9).
Previous animal studies indicated that a xenogenic
bone substitute mineral performed well as carrier
material for osteoinductive proteins (105, 113). A
recent study demonstrated that the results of GBR
procedures in human could be improved by the addi-
tion of rhBMP-2 to a xenogenic bone substitute
mineral. This improvement was documented by a
higher degree of bone maturation and an increased
graft to bone contact fraction at the BMP-treated
sites (59) (Fig. 3). In addition, the xenogenic bone
substitute mineral has some therapeutic advantages
over HA due to its three-dimensional structure and
its resorbability (56). Synthetic polymers, on the
other hand, offer possibilities for being combined
with biologic factors. Synthetic polymers can repro-
ducibly be fabricated and the growth factors can be
incorporated under controlled manufacturing condi-
tions (120).
However, the ideal carrier material, which is easy
to apply, able to provide space for regeneration, bior-
esorbable, and allows controlled release of the bioac-
tive molecules has not yet been discovered. Further
research is needed to determine the ideal combina-
tion of factors for regeneration, the best delivery sys-
tem, and the optimum doses.
Membranes
The benet of using both barrier membranes and
BMP for bone augmentation remains controversial
(26, 49, 59, 71). In a recent study it was found that
47
Barrier membranes
non-resorbable ePTFE membrane initially inhibited
bone formation with rhBMP-2 (4 weeks) but not at
later time points (12 weeks) (26). It has been shown
that bone induction by rhBMP-2 occurs at early time
points and that rhBMP-2 undergoes rapid clearance.
Hence, the use of a membrane may potentially
reduce the bone-forming effect of rhBMP-2 due to
limited availability of inducible cells. Another animal
study in rats reported no difference in bone healing
with the combination of rhBMP-2 and an ePTFE
membrane compared to rhBMP-2 alone (71). From
a clinical point of view, the use of a membrane sim-
plies the handling and the stabilization of the bone
substitute mineral at the time of bone augmentation,
but from a biological point of view the use of a
membrane may block the recruitment of cells from
the environment.
The question whether or not bioactive molecules
are best used in conjunction with membranes or in
the absence of membranes has not been answered
conclusively yet. On the one hand, it is reasonable to
apply them as adjunctive agents to GBR therapy to
accelerate the membrane-guided bone regeneration.
On the other hand, it may be hypothesized that their
mode of action is best taken advantage of when
membranes are not simultaneously applied, thus
allowing all inducible cells from the wound environ-
ment access to the area to be regenerated.
Developments in bone augmentation
procedures
Further developments in bone augmentation proce-
dures can be related either to simplication of the
clinical handling or to inuencing of biological pro-
cesses. To simplify clinical handling, new materials
should comprise a matrix with optimal cell ingrowth
capacities and good mechanical properties, provid-
ing space for tissue regeneration. No membrane and
no specic procedures for mechanical xation
should be necessary. This would reduce the techni-
que sensitivity and increase the predictability of bone
augmentation.
From a biological point of view the growth and
differentiation factors may induce earlier bone
growth into the area to be regenerated. Thus, the
area of regeneration would be stabilized at an earlier
time point. Furthermore, the use of such materials
would allow treatment of extended bone defect
volumes. At present, large bone defects are regularly
augmented with autogenous block grafts and mem-
branes (5). The use of synthetic materials would
result in lower surgical risks and lower morbidity in
augmentation procedures and would represent an
important step forward in simplifying bone regenera-
tion techniques.
Conclusions
Presently available data demonstrate GBR therapy
to be a predictable and successful procedure to
augment bone in a horizontal direction at sites
exhibiting insufcient bone volume for implant
placement under standard conditions.
Although data are not plentiful, vertical augmenta-
tion using this technique has successfully been
performed by various groups of investigators.
An increasing body of literature demonstrates
bioresorbable membranes to render success rates
similar to the ones obtained with non-resorbable
membranes for the treatment of horizontal defects.
Fig. 3. Histologic section of a site treated with Bio-Oss and
rhBMP-2 (a) showing a signicantly higher surface frac-
tion of the bone substitute particles in direct contact with
newly formed bone compared to a site treated with
Bio-Oss alone (b). Lamellar bone (lb); woven bone (wb);
non-mineralized tissue (nt), bone substitute particles (bo).
(Original magnication 100; toluidine blue stain).
48
Hammerle & Jung
Some studies indicate that implant placement
immediately following tooth extraction without
the use of membranes may lead to complete bone
regeneration of the gap between the implant and
the socket wall, provided this gap does not surpass
a certain distance.
A few long-term studies indicate that the survival
rate of implants partly resting in augmented bone
is similar to implants placed in native bone.
It is expected that bone regeneration using growth
and differentiation factors will play an important
role in the future.
The literature on GBR for implant placement
is mostly limited to compromised sites and studies
evaluating this procedure in compromised
patients are not available.
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