Bone augmentation by means ofbarrier membranesChristoph H. F. Hammerle & Ronald E. Jung

The development of guided bone regeneration (GBR)

has substantially influenced the possibilities for

using implants. The use of bone augmentation pro-

cedures has extended the use of endosseous implants

to jaw bone areas with insufficient 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 polytetrafluoroethylene (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 deficiencies 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-

filled. Tissue reactions resulting from the resorption

of the membrane should be minimal, these reactions

should be reversible, and they should not negatively

influence 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 refined 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 fill of the space, and prevention of soft tissue

dehiscence.

Non-resorbable membranes

Polytetrafluoroethylene

With the presentation of the first 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 2000ISSN 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 identified 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 specific 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 benefits, 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 findings (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 fill 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 fill

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 resultingin 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,

inflammatory reactions have been documented in

Barrier membranes

37

Fig. 1. a) Radiographic view of a single tooth gap in theanterior maxilla following extraction of a partiallyresorbed central incisor. b) A screw implant (ITI1 DentalImplant System, Straumann AG, Waldenburg, Switzer-land) has been placed at the location of the right centralincisor of the maxilla. A dehiscence defect is visible expos-ing part of the buccal aspect of the rough surfaced implantbody. c) A bioresorbable collagen membrane (Bio-Gide,Geistlich AG, Wolhusen, Switzerland) supported by adeproteinized 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 initiallyexposed surface of the implant is completely covered bynewly formed bone. The buccal bone plate is of sufficientwidth to adequately support the soft tissues. e) Radio-graphic view of the implant following incorporation ofthe final reconstruction. Note the excellent height ofthe crestal bone and the adaptation of the bone to theimplant 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 significantly better

bone regeneration. Generally, only a mild inflamma-

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 findings 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

AdvantagesNo 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 fill 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 fill) compared to

the bioresorbable group (89% defect fill). 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 filling the cylinder space, while increasing

amounts of mineralized bone was filling the space

at later time points up to 9 months.

In the first 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 first 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 filter (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 fibers. According to the

investigators, this tissue layer may have developed

due to micro movements or fibroblasts penetrating

through the membrane from the covering soft tissue

flap. 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

clarification. 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 first

surgical intervention. After the appropriate time for

healing, the implants are then placed into a site of

sufficient 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 coveredwith 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 filled 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 refinement 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 first 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 sufficient 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 significantly less

resorption had occurred. This controlled clinical

study confirms 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 fixed 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 thatonly one surgical intervention is necessary;

decreased treatment time since regeneration andimplantation 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 ascrew implant (TiUnite Mk III Branemark1, Nobel Biocare,Gothenburg, Sweden) showing a buccal and oral dehis-cence. (c: occlusal view; d: buccal view). The defect sitehas been grafted with a deproteinized bovine bone mineral(Bio-Oss, Geistlich) and autogenous bone harvested fromthe surrounding area. A titanium reinforced non-resorbableePTFE membrane (Gore-Tex TR, W.L. Gore & Associates,Inc., Flagstaff, USA) has been trimmed and shaped to coverthe bone substitute materials and the implant. The

membrane has been secured at the buccal aspect by twonon-resorbable pins. (e: occlusal view; f: buccal view). Sixmonths after implantation and regeneration, a significantgain of the buccal contour is discernable. (g: occlusal view;h: buccal view). At membrane removal surgery, the surfaceof the implant is completely covered with new bone (i). Apronounced 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 zirconiumoxide abutment screwed onto the implant. Note the closeadaptation of the bone at the surface of the implant and thecrestal bone level being located coronal to the fist 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 confirmed the findings 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 fulfilled 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 fill 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 deficit is

due to the area of tissue penetration of the tooth

prior to extractions. Hence, in order to obtain pri-

mary closure, the buccal flap 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 flap 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 flap (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 filling materials or

membranes were applied. Control implants were

inserted into sites with sufficient 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 fill 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

fill was not as predictable as reported in other studies

using membranes (108), the majority of the initial

defect area was filled 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 filled 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 flap 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 simplifies the

surgical technique for flap 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

first 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 significantly 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 significant

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 significant 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 benefits and

risks when planning GBR therapy. Based on the

reports in the literature, there is general agreement

that GBR is a difficult 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 difficult 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 first 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 fill 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 fill 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-term results

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 from 97.5% 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 significant 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 fixed reconstructions, a 100% survi-

val rate was found for both test and control implants

and no significant 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 field of therapeutic options

will be opened.

Growth and differentiation factors in oralsurgery

In the past decade a number of basic science experi-

ments and clinical studies have clarified 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),

fibroblast 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-

ified 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 fibrous 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 benefit 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-

plifies 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 augmentationprocedures

Further developments in bone augmentation proce-

dures can be related either to simplification of the

clinical handling or to influencing 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 specific procedures for mechanical fixation

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 therapyto be a predictable and successful procedure to

augment bone in a horizontal direction at sites

exhibiting insufficient 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 demonstratesbioresorbable 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 significantly higher surface frac-tion of the bone substitute particles in direct contact withnewly formed bone compared to a site treated withBio-Oss alone (b). Lamellar bone (lb); woven bone (wb);non-mineralized tissue (nt), bone substitute particles (bo).(Original magnification 100; toluidine blue stain).

48

Hammerle & Jung

Some studies indicate that implant placementimmediately 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 survivalrate of implants partly resting in augmented bone

is similar to implants placed in native bone.

It is expected that bone regeneration using growthand differentiation factors will play an important

role in the future.

The literature on GBR for implant placementis mostly limited to compromised sites and studies

evaluating this procedure in compromised

patients are not available.

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