Periodontology 2000, Vol.

17, 1998, 151-1 75 Printed in Denmark All rights reserved

Copyright 0 Munksgaard 1998

PERIODONTOLOGY 2000
ISSN 0906-6713

Guided bone regeneration at oral implant sites

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

Biological basis of guided bone regeneration

In principle, four methods have been described to increase the rate of bone formation and to augment

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velopments in the field and for increased predictability of the clinical outcomes. So far, the type of bone being formed by applying the principle of guided tissue regeneration has only been investigated in a few animals (79, 110, 154) and some human studies (81). Two of these animal studies were dealing with surgically prepared bone defects (79, 154). One study focused on tissue healing in bone defects in the mandible of dogs (154). The other experiment investigated the temporal and spatial dynamics of bone regeneration in calvarial defects in rabbits (79). The third experiment explored the possibility of augmenting the naturally present bone volume in the mandible of rats (110). In all these experiments, a similar basic pattern of bone formation was observed. Initially, trabeculae of woven bone proliferated into the defect. In two studies, the space provided by the membrane was filled with a newly formed connective tissue matrix prior to the formation of mineralized bone (79, 81, 154).The investigators concluded that the size of the defects did not allow for direct formation of mineralized bone, since new bone is only formed at locations where biomechanical stability is guaranteed, that is, where pressure and tensile forces are excluded (177). Otherwise, an intermediate tissue with appropriate mechanical properties will arise before ossification. The mechanism of bone healing being dependent

Fig. 1. a. Newly formed bone trabeculae (purple) closely follow the pathway given by the proliferating vessels (brown).b. The new bone (black) consists of irregularly shaped, delicate trabeculae lined with osteoid seams (0s) and a layer of cuboidal osteoblasts (arrows). Collagen fibers (arrow heads) are progressively embedded into the mineralizing osteoid. c. A newly formed trabeculae of woven bone is embedded in a highly vascularized connective tissue. The bright red osteoid seam is covered by a layer of osteoblasts (arrows).Osteocytes are encircled by the mineralizing bone (arrowheads). d. Fluorochrome labeling demonstrates the sequential steps of the regeneration of mineralized bone. Bone stained in bright yellow (tetracycline label) is of woven nature (wb).Lamellar bone deposition (arrows) is labeled in red (alizarine label) and green (calceine label). e. Osteoclasts (Oc) are resorbing the primarily formed woven bone (Wb). Osteoblasts (Ob) in their immediate vicinity deposit layers of mature lamellar bone on the remnants of the original trabecular scaffold. f. Remnants of the dark-stained,primary trabecular scaffold are covered by new bone lamellae. g. By continuous apposition of lamellar bone, a primary osteon (PO) with a central blood vessel is formed. h. As part of normal bone turnover osteoclasts were resorbing parts of the cortical bone followed by osteoblastic bone apposition leading to the formation of secondary osteons (so).

on the size of the defect has previously been elucidated in an experimental rodent model. In cortical bone, circular defects of less than 200 pm had the potential to heal with concentric formation of lamellar bone (97, 155). In larger defects of 200 to 500 pm, bone healing was characterized by formation of a trabecular network of woven bone bridging the defect. Subsequently, the spaces between the trabeculae were filled with lamellar bone. However, in defects of 500 pm and larger, bridging by direct formation of bone did not occur. Following 3 weeks of healing, such defects exhibited a central area characterized by the presence of connective tissue. The intermediate connective tissue described in the two above-mentioned experiments (81, 154) provided the appropriate mechanical properties necessary to allow for unimpeded ingrowth of blood capillaries during angiogenesis (Fig. la), which always precedes bone formation (162). However, with increasing defect size the biomechanically stable zone becomes successively limited to the marginal area of the defect, whereas the central region is exposed to biomechanical forces presumably preventing bone formation. This view is supported by experimental and clinical observations that showed that, in large bone defects, bone formation is limited to the defect margins (11, 50, 60, 80, 123). In the experiment with the augmentation of the mandibular ramus in rats, in contrast, the new bone proliferated into the defect space without a nonmineralized connective tissue matrix occupying the entire area for regeneration (110). Similar observations regarding bone formation have been reported in canine mandibular and rodent calvarial bone defects (79, 154). The new bone formation generally originated from the bony borders of the defect. This new bone appeared as a scaffold of delicate trabeculae comprised of woven bone, from which several extensions were directed towards the center of the defects (Fig. lb, c). The surfaces of the trabeculae were commonly covered by osteoid seams lined by a dense layer of cuboidal osteoblasts. The trabeculae were embedded in a well-organized and vascularized granulation tissue. At various locations integration of collagen fiber bundles into the new bone matrix could be detected. In the course of bone apposition, surrounding connective tissue fibers became embedded into the osteoid and finally integrated into the new bone. Within the network of the trabecular scaffold, numerous blood capillaries were consistently found connected with the vessels of the opened bone marrow cavity of the adjacent bony defect borders. In addition, a considerable

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number of proliferating blood capillaries accompanied and even preceded the bone trabeculae growing towards the mid-part of the defect (79, 154, 162).As the mineralized bone grew, blood vessels lying in its immediate vicinity became incorporated into the new bone matrix. The remainder of the defect area, which was not filled with bone yet, contained loose connective tissue comprised of scarce collagen fibers without a preferential orientation. Sparsely distributed cells, predominantly fibroblasts and macrophages as well as a moderate number of wide blood capillaries were seen. In contrast to the findings in the other studies, bone islands arose within this fibrovascular tissue in the calvarial defect model as identified by means of radiographs and serial sections (79). Their texture was consistent with that of woven bone, that is, irregular bundles of collagen fibers and extremely numerous, large osteocytes, and they were without contact with the marginal bone. The proliferation of new bone in this pattern has not been described previously, unless a sutural growth area was given access to the defect area (11, 60). The investigators concluded that osseous defect closure arising both from the margins of the bone defect and as islands may be a faster healing process than marginal bone formation alone. Common to all these experiments was the finding that the bone volume increased with time and that the primary intramembranous trabecular scaffold underwent intense remodeling: numerous osteoclasts arose and began to eliminate the primitive woven bone, whereas a new generation of osteoblasts deposited mature lamellar bone layers on the woven bone remnants (Fig. Id, e). As a consequence of the continuous remodeling of the primary bony network, most of the trabeculae contained only a small, intensely stained core of woven bone surrounded by thick bone layers of regular lamellar texture and thus comprised the secondary spongiosa (Fig. If). The continuous growth of the bone trabeculae resulted in the narrowing of the intertrabecular connective tissue and in the formation of primary osteons containing vascular channels (Fig. lg). The presence of osteoid seams with overlying osteoblasts indicated continuation of the osteogenic process. At the defect borders facing the membranes cortical bone was formed by continuous lamellar bone deposition. Finally, secondary osteons were formed replacing the previously formed cortical bone (Fig. lh). The only available human data on the sequential

steps of guided bone regeneration describe bone healing in the molar area in the mandible (81). Hollow titanium test cylinders measuring 3.5 mm in outer diameter, 2.5 mm in inner diameter and a height of 4 mm were placed into standardized holes in the retromolar area of healthy volunteers. The cylinders were placed in such a way that 1.5 to 2 mm of the test devices was submerged below the level of the surrounding bone, and 2 to 2.5 mm surpassed the bone surface. The bone-facing ends of the devices were left open. The soft tissue facing ends were closed by means of expanded polytetrafluoroethylene membranes (Gore-Tex Periodontal Material@, Flagstaff, AZ) before the soft tissue flaps were sutured for primary healing. After observation times ranging from 2 to 36 weeks, the cylinders along with the regenerated tissue were harvested and analyzed. The tissue generated at 2 and 7 weeks exhibited a cylindrical shape, whereas the specimens harvested at 12 weeks and at later time points, yielded the form of an hourglass. Specimens of 12 weeks and less healing time almost entirely contained soft tissue. Specimens with generation times of 4 months and more contained both soft tissue and increasing amounts of mineralized bone. Up to a period of 6 months of healing, new bone was primarily filling the previously prepared defect within the host bone. Therefore, by reaching the level of the surrounding host bone, true regeneration of bone had occurred. Interestingly, bone formation did not come to a halt at this point but proceeded above the borders of the skeleton, thereby altering the genetically determined form of the mandible. This formation of new bone beyond the skeletal borders by applying the method of guided tissue regeneration was first demonstrated on the calvaria of rabbits (161). Subsequently, these findings were confirmed in other experimental animals such as rabbits, rats, and dogs (83, 99, 109, 110, 118, 122, 160). The first guided bone neogenesis in humans was demonstrated by applying the novel model system used in the present study. Furthermore, neoformation of bone beyond the skeletal borders can also be achieved by the combined use of bone substitutes and membranes (78, 159).

Treatment of localized defects of the alveolar ridge

To date, guided bone regeneration can most successfully be used to regenerate localized alveolar defects

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Fig. 2. a . Insufficient bone volume to place an implant under standard conditions in the right premolar region of the mandibular arch in a 22-year-old caries-free patient. b. 'Ityosupporting screws of the Memfix system have been placed in order to augment the local bone volume laterally. c. The cortical bone has been perforated at multiple locations to allow for bleeding from the bone marrow spaces. d. An expanded polytetrafluoroethylene membrane has been carefully adapted to the bony borders of the defect being draped over the two supporting screws. Stabilization of the membrane has been achieved by placing three Memfix fixation screws (Institut Straumann, Waldenburg, Switzerland).

with new bone tissue (Fig. 2-4). Although various attempts have been described aiming at augmenting the bone over extended areas of the jaw, no valid technique or clinical procedure has been presented so far. Guided bone regeneration prior to implant placement In situations with a bone defect at a site, where the primary stability of an implant cannot be achieved or when implant placement is not possible in ideal location for subsequent prosthetic therapy, guided bone regeneration prior to implantation represents the method of choice. Experimental research on ridge augmentation using guided bone regeneration was presented in the early 1990s (167). In a dog model, large defects of the alveolar ridge were surgically prepared both in the mandible and in the maxilla. The defects were

either covered with expanded polytetrafluoroethylene membranes, covered with membranes and grafted with porous hydroxyapatite or with a tissue growth matrix of porous polytetrafluoroethylene, grafted with these same materials but not covered with membranes, or finally, neither grafted nor covered with membranes. Morphological and histological analysis revealed that, in sites treated with membranes, with or without the addition of grafts, the entire space between the membrane and the jaw bone was filled with bone. In the absence of membranes, bone formation was lacking. Later, in a similarly designed study, columns of cortical bone were used to support membranes intended for bone regeneration of previously prepared alveolar ridge defects in dogs (174). Again, the membranes under this particular experimental situation proved efficacious in regenerating bone within the space created, whereas the controls without membranes failed to heal with bone.

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Fig. 3 .a . At membrane removal surgery 9 months later, excellent bone formation is observed. b. A hollow-cylinder implant can be placed in perfect location under standard conditions.

Fig. 4. a. After completion of prosthetic treatment, the mandibular arch is free of edentulous spaces, thus increasing chewing comfort and aesthetics for the patient. The same clinical procedures were performed in the area of the second premolar at the mandibular left side.

b. Radiographic examination of the treatment result.

Close adaptation of the marginal bone to the implant neck. Note that the perforations in the cortical bone are still visible radiographically.

The conclusions drawn from these and other experiments were that the method of guided bone regeneration can indeed be successfully employed in the regeneration of alveolar ridge defects (154, 167, 174). In the majority of the experimental studies on guided bone regeneration the effect of this method was tested in situations in which the ridge defects had been freshly prepared. One might, however, assume that the reaction of the bone when freshly injured is different than the situation when a state of tissue equilibrium had been reached in the defect area. In an animal study, transosseous defects were

prepared in the mandibular ramus of rats (55). The sites of surgery were allowed to heal during a period of 12 weeks. Upon surgical inspection it was found that although, some bone regeneration had taken place at the defect borders, primarily soft connective tissue had filled the defect. This soft tissue was carefully removed and expanded polytetrafluoroethylene membranes were adapted buccally and lingually to the bone surrounding the defects. Histological analysis after 6 weeks demonstrated complete healing of the previous defects with regenerated bone, whereas the control defects without membranes failed to consistently heal with bone. Hence, iso-

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Guided bone regeneration at oral implant sites Fig. 5. a. The minimal width of the ridge (arrows) in this patient with a completely edentulous maxilla precludes standard implant therapy. b. A titanium-reinforcedexpanded polytetrafluoroethylene membrane has been adapted to the surrounding bone in such a way that a space is created between the membrane and the knife-like ridge. The membrane is secured in place by use of titanium pins.

lation of the defect and the adjacent bone from the neighboring soft tissues seems to suffice for successful bone regeneration with guided bone regeneration (Fig. 5, 6). In a controlled clinical study in seven patients with similar contralateral fenestration defects, one side was treated with guided bone regeneration, whereas the other one served as control (51). The results demonstrated that guided bone regeneration treated dehiscences were consistently filled with new bone. In the sites where the defect had only been covered by the mucoperiosteal flap, denuded implant surfaces devoid of bone coverage were observed at re-entry surgery. On the one hand, lateral ridge augmentation has been shown to be a method with predictable success (15, 35-37, 51, 128, 132). On the other hand, the results regarding vertical augmentation of the alveolar ridge are controversial. Implants protruding 4 to 7 mm from the bone crest were covered with titanium-reinforced expanded polytetrafluoroethylene membranes in a recent study in five patients (172). Biopsies taken 9 months following membrane placement revealed mineralized bone to have formed up to a level 3 to 4 mm above the previous alveolar crest. Beyond this level, soft connective tissue was found. Other investigators have reported more vertical gain of bone (178). Six patients were treated with a similar method. In contrast to the above study, these therapists grafted the area underneath the titanium-reinforced membranes with autogenic bone grafts collected in a suction filter. Twelve months following membrane placement, an average gain of 5 mm of

vertical bone height was measured, reaching up to a maximum of 7 mm. In an attempt to augment bone 2.7 mm above the present crest at titanium implants in dogs, reinforced expanded polytetrafluoroethylene membranes showed 1.8 mm of gain, standard expanded polytetrafluoroethylene membranes revealed 1.9 mm and the bone height increased by 0.5 mm in the controls without membranes (99). No graft materials had been incorporated. In both membrane groups, about 1 mm of nonmineralized tissue was present between the mineralized bone and the membrane at its highest point, corroborating the results of Simion et al. (172). In accordance with these data are the results obtained with a perforated dome-shaped titanium space maintainer (150). Although vertical ridge augmentation with bone did occur, the presence of nonmineralized connective tissue underneath the top of the dome was frequent. It appears that, depending on the clinical treatment protocol, varying amounts of bone height may be gained. The factors critical for success or failure have not been worked out. In addition, no data are available indicating whether there is a biologically limited maximum of bone gain, and if so, by what parameters this maximum is influenced. On the one hand, according to the law of Frost (61), bone is resorbed if it is not functionally stimulated. On the other hand, if loading surpasses a critical level, damage to the implant-supporting bone my occur. In a recent dog study it was revealed that occlusal loading of newly regenerated bone may lead to partial loss of this bone (18). Of the 3-month gain in bone height of 4.6 mm, the experimental sites

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Fig. 6. Excellent bone regeneration is observed 9 months later. A n implant with a diameter of 4.1 mm has been placed into the regenerated bone.

Fig. 7. a. Histological section of a 3-month specimen comprising nonminerdized connective tissue yielding the shape of an hourglass. Note the covering expanded polytetrafluoroethylene membrane. The polished cylinder walls prevented cellular attachment, thus allowing the tissue to be pulled away from the walls. b. Histological section of a %month specimen. The height of the mineralized tissue has reached 80% of the cylinder space. Note the unchanged shape resembling an hourglass in comparison with the %month specimen.

showed 1.8 mm of regenerated bone height still intact at 6 months, whereas the control sites exhibited 4.3 mm of 4.8 mm initially still intact. Other investigators have reported a loss in total bone volume following membrane removal but an increase in area density of mineralized bone at titanium implants in rabbit tibia over an observation period of 6 months (147). The loss in volume observed in this study may well be compensated by the documented increase in area density of mineralized bone, thus providing the peri-implant bone with a higher capacity to bear loading forces. In contrast, implants placed entirely into regenerated bone in another dog model were either restored and subjected to loading forces or not restored (39). All implants were osseointegrated to a similar degree, and no apparent differences were reported with respect to bone-remodeling activities. Control sites that were augmented, but where no implants had been placed, demonstrated bone atrophy underneath the membranes. The investigators concluded that placement of an implant represents a stimulus sufficient to maintain regenerated bone and that the regenerated bone was able to withstand the loading forces in this model system. The contrasting findings

between this study and the experiment discussed above (18) may be based on the difference in healing time allowed to the regenerated bone before loading. In the former study, this time amounted to 9 months, whereas loading was initiated after 3 months in the latter. Evidence emerging from clinical studies also suggests that the regenerated bone is capable of withstanding the occlusal loading forces exerted by functional forces and is hence stable over time. A clinical follow-up study of 626 titanium implants that had either been placed into regenerated bone or adjacent to which bone had been regenerated at their placement revealed an overall cumulative success rate of 93.8% (62). The observation periods ranged from 6 to 51 months. A prospective study involving 12 implants over the observation period of 5 years demonstrated stable peri-implant marginal bone levels with an average 0.3 mm of cumulative bone loss (38). This bone loss is within the range of bone loss measured for implants placed into pristine bone (187). These preliminary data indicate that bone generated by guided bone regeneration reacts to implant placement and to functional loading like natural jaw bone.

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Guided bone regeneration in conjunction with implant placement Following tooth loss, the bone of the alveolar process has been shown to be subjected to a continuous resorptive process that is most pronounced in the early phases after tooth removal (4, 6, 41). In order to reduce the problems resulting from this loss of bone, dental implants have been placed into fresh extraction sockets (14, 116, 132).When implants are placed into extraction sockets, a partial incongruency between the outer surface of the implant and the bony walls of the socket often results in a bone deficit in the peri-implant area. Instead of reducing the height of the alveolar ridge in order to obtain a sufficient width for implantation (1791, barrier membranes have been demonstrated to be successfully applied in order to allow the peri-implant area to be filled with new bone in both animal experiments (13, 20, 184) and clinical studies (14, 19, 27, 53, 63, 75, 100, 101, 112). The one-stage method of combining implant placement with guided bone regeneration has been applied much more frequently in clinical practice than the two-stage method using guided bone regeneration prior to implantation. The benefits of the simultaneous approach are 1) reduced number of surgical interventions, 2) shortened treatment time, 3) ideal placement of the implant into the alveolar housing of the lost tooth and 4) reduction of treatment costs. Guided bone regeneration at submerged implants. A recent multicenter study evaluated the results of guided bone regeneration with expanded polytetrafluoroethylene membranes for the treatment of bone defects at implants placed into extraction sockets (17). Forty-nine implants were placed into extraction sockets immediately following removal of the teeth. The reasons for extraction mainly encompassed advanced periodontal disease, root fractures and failed endodontic therapy. Flap incisions prior to extraction were performed with the aim of allowing for primary coverage of the membrane and the two-stage implant. Primary stability was achieved by preparing implant beds reaching into pristine bone beyond the socket. Premature removal of membranes due to exposures, inflammation of the surrounding tissues or infections of the area was necessary in 41% of the sites. The 1-year survival rate of the implants was 93.9%. In the absence of complications, the mean bony defect fill was very good, changing from 4.9 mm at the deepest site initially to

0.1 mm at re-entry. However, in the 20 cases with premature removal of the membranes, a mean residual bone deficit of 2.4 mm of an initial mean defect depth of 6.4 mm was present at re-entry. The mean amount of marginal bone loss mesially and distally of the implants, which amounted to 0.72 mm over the 7.5 months of observation time, compared favorably to values for implants placed into pristine bone (1, 146, 187).This study illustrated that guided bone regeneration is very successful for implants that are immediately placed into extraction sockets in the absence of soft tissue complications during the healing period. Exposures and infections are common findings associated with bone regeneration at immediate implants (8, 17, 157, 170, 184). Conflicting results have been reported regarding the amount of bone regeneration in the presence of exposures. Although some investigators still obtained very good defect fill with new bone in the presence of membrane exposures (531, it is generally agreed that membrane exposures lead to compromised results (17, 89, 170, 184, 190, 192) and that proper flap design, a careful surgical technique and a strict maintenance program minimize postoperative complications (14). One matter of initial discussion dealt with the question of whether an implant that is placed at the time of regenerative surgery will actually be osseointegrated by the newly formed bone. Subsequent studies have consistently documented that this procedure will lead to osseointegration of the exposed titanium implant surfaces (13, 21, 56, 66, 101, 172, 186). Depending on the structure of the peri-implant defect and the presence or absence of bony walls to support the membrane, different results regarding bone fill have been reported. In a recent study (16), sites with a bony wall showed a mean residual lack of bone of 0.3 mm at re-entry surgery, whereas sites with dehiscence defects measured 0.6 mm on average. In situations with extensive bone defects following tooth extractions, the two-stage surgical approach is generally preferred. Extraction sockets show an excellent tendency for spontaneous healing with bone (3). One might assume that, in the presence of ideal peri-implant defect structure, the implant will be properly osseointegrated without the need for guided bone regeneration. In a previous study in humans comparing bone fill in artificially prepared defects between the test group using an expanded polytetrafluoroethylene membrane and a control group treated without membrane, better results were ob-

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tained in the membrane group (138).These findings are in agreement with results from other human and animal studies in which the control groups consistently failed to provide as good results as those obtained in the test groups (51, 56). In contrast, other investigators reported that undisturbed bone formation in fresh extraction sockets was quite good, so that only few threads remained uncovered at the time of abutment connection of submerged immediate implants (151). Tissue healing and bone regeneration of extraction sockets are profoundly influenced by the insertion of implants. The outcome of such a healing process cannot be foreseen. Hence, conducting clinical studies with negative controls is precluded for ethical reasons. A disadvantage of combining guided bone regeneration with implant placement is the fact that, in case of a compromised treatment outcome regarding bone formation, only the more apical part of the implant will be properly osseointegrated. In such situations, long-term prognosis is impaired (58), and the rate of soft tissue complications is increased (117). When the two-stage technique is applied, then the implant is placed in a second surgical procedure, at membrane removal, and such a problem can adequately be dealt with at this moment. No data are available concerning the long-term performance of implants placed under these clinical conditions. Most of the data available represent new developments with respect to the combination of implant placement and the guided bone regeneration procedure without the proper validation necessary for general recommendation in patient treatment. During the development period, the surgical technique, the patient selection and the guidance of the patient, as well as the proper membrane and, if applicable, the optimal grafting material are being tested and appropriately refined. Following this development period, the successful treatment approaches should enter an evaluation period, in which the implants, placed under these specific protocols, can be evaluated on a long-term basis. Resulting from this evaluation period, long-term stability of successfully applied treatment outcomes can be determined. Unfortunately, the application of nonresorbable membranes necessitates a rather extensive second surgical intervention for their removal. By using resorbable membrane barriers this second surgery may be limited to the minimum necessary for abutment connection and prosthetic and aesthetic treatment, or not be required at all in the case of trans-

mucosal implants (see the section on the benefit of resorbable membranes in this chapter). Guided bone regeneration at transmucosal implants. In the studies discussed above, surgery was performed to submerge both the implant and the membrane under the soft tissue flap, thus aiming at healing by primary intention. The technique of guided bone regeneration has recently been used in conjunction with the placement of transmucosal implants into fresh extraction sockets (27, 45, 112, 180). Case reports using this method were first presented in 1993 (45). The critical difference from the above-mentioned procedures is that the implant was deliberately left in a transmucosal position during the entire phase of bone regeneration. In a prospective study involving 16 consecutively treated patients with 25 implants over an observation period of 2.5 years, the details of this method were described (112). As opposed to the above-described methods for immediate implantation in conjunction with guided bone regeneration, this technique does not aim at primary closure of the flap completely covering both membrane and implant. In contrast, the flap is adapted around the neck of the implant, thus indeed covering the membrane but leaving the implant in transmucosal position. The results of a study on 10 patients with surgical re-entries 6 months following guided bone regeneration therapy demonstrated successful bone generation into defects around transmucosal implants (75). The mean fill of the defects with bone amounted to 94%, which is in the upper range of the defect fill reported in earlier investigations. Previously, mean bone fill was reported to amount to 75% (511, 90% (1001, 94% (19) and 82% (53). Comparison between the clinical results of immediate transmucosal implants and implants placed under standard conditions at 1 year following incorporation of fixed prostheses revealed favorable conditions for the 20 patients in each of the two groups (27). Low plaque and mucositis scores, similar amounts of recession, probing pocket depth and clinical attachment levels were registered. It has previously been claimed that primary wound closure following guided bone regeneration surgery was a prerequisite for the formation of mineralized bone (34, 184).This statement was based on the finding that bone formation was less favorable when dehiscences occurred, compared with situations in which the soft tissues remained intact during the entire regenerative period (17, 34, 89, 170,

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184, 192). As a consequence of these results, it was concluded that a flap dehiscence following primary wound closure represents a complication usually leading to a compromised healing outcome. However, on the one hand, implants placed in a transmucosal position do not impair the successful outcome of the bone regeneration process per se (27, 45, 75, 112). On the other hand, in accordance with the results of studies evaluating guided bone regeneration at submerged implants, defect fill with new bone in the presence of flap dehiscence, inflammation and infection was not as successful as when a flap dehiscence did not occur (75). Hence, infection control appears to be the key factor for an optimal treatment outcome rather than the mere situation of submerged or transmucosal implant position. Attempts to fill defects around freshly placed submerged implants with bone have consistently been documented to lead to osseointegration of the exposed titanium implant surfaces (13, 21, 56, 66, 101, 186). Osseointegration has not been documented following bone regeneration around transmucosal implants. However, regeneration of the periodontal apparatus is predictably achieved around teeth in spite of the fact that teeth are located transmucosally (102, 145). Numerous articles have been published documenting the intimate contact between the previously exposed root surface and the newly formed cementum with inserting collagen fibers. Based on these results from periodontal regeneration studies, it is reasonable to assume that previously exposed implant surfaces can become osseointegrated during bone regeneration in cases of transmucosal implant position. The method of achieving regeneration around transmucosal implants can be particularly beneficial when the combination of implantation and resorbable membranes may eliminate the need for a second surgical procedure. However, further studies testing resorbable membranes are necessary before definite recommendations can be made. Guided bone regeneration in the treatment of peri-implant defects Research suggests that peri-implant tissue destruction may be caused by bacterial infection and that the concomitant inflammation seen is similar to that in periodontal disease (113, 119, 127, 163, 164). Periimplant tissue breakdown and actual loss of some implants as a consequence of occlusal overload have recently been reported in an animal experiment (93, 94). It is important to note, however, that truly ex-

cessive forces in very unfavorable biomechanical situations were applied and lead to these findings. Evidence in favor of bacterial causes of late peri-implant tissue breakdown is most overwhelming (115). Since the causes and pathogenesis of peri-implant and periodontal lesions are similar, it is reasonable to anticipate that the treatment should be the same. Antimicrobial and regenerative therapies are established for the treatment of periodontal disease (69, 108, 1451, and antimicrobial treatment can be used in the treatment of early peri-implantitis (59, 126). In two early studies on guided bone regeneration in the treatment of peri-implant bone loss, ligatureinduced tissue breakdown was initiated around titanium implants in beagle dogs (72). After 5 months, the ligatures were removed and regenerative therapy conducted. Membranes of expanded polytetrafluoroethylene were applied to isolate the defects from the flap tissue and half of the implants were left in a transmucosal and half in a submerged healing situation. Plaque control using antiseptics was performed for 1 week. At the transmucosal implant sites mechanical brushing was initiated after 1 week. Soft tissue complications were frequent and the membranes were removed 4 weeks following placement. Histological analysis revealed a complete failure of the attempt to regenerate the peri-implant bone (72, 165). From these and other studies it may be concluded that, in accordance with the situation in periodontics, regenerative therapies are not suitable for the treatment of infectious diseases such as periodontitis or peri-implantitis. They can successfully be applied, however, in the treatment of the sequelae of such disease processes: to regenerate the destroyed periodontal or peri-implant tissues. It is, therefore, of paramount importance to realize that the infectious disease process has to be adequately treated, prior to regenerative surgery. Successful re-osseointegration of bacterially contaminated implant surfaces by the use of guided tissue regeneration was reported in a recent animal study (98). In this experiment the peri-implant bone tissue had been removed surgically. Subsequently, the implant surface was allowed to be colonized by pathogenic bacteria during 12 weeks of undisturbed ligature induced plaque accumulation. Guided tissue regeneration therapy was then performed. Histological analysis of the specimens retrieved after 2 months showed that new bone formation occurred in the space underneath the membrane and fulfilled the histological criteria for osseointegration (2). More recent experimental data, however, have

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questioned the possibility that implant surfaces once exposed to plaque accumulation can be successfully reosseointegrated (140). Following ligature-induced peri-implant tissue breakdown, an antibiotic regimen was initiated. Three weeks later, flaps were raised on the test sides, the granulation tissue within the bone craters was curetted away and the implants were carefully cleaned with a detergent. After placement of expanded polytetrafluoroethylene membranes and new cover screws, the flaps were sutured for primary healing. On the control side no local treatment was performed. Histological analysis demonstrated no resolution of the defects and signs of inflammation on the control side. On the test side tissue healing had taken place, including bone regeneration into the previous defect area. On the one hand, a connective tissue capsule 200-300 pm thick was consistently found in contact with the implant surface previously exposed to plaque accumulation. On the other hand, the regenerating bone had grown into contact with the newly placed pristine cover screws. These results demonstrate that the healing and regenerative capacity of the peri-implant tissues following experimental bacterial breakdown are not impaired, but the applied treatment - debridement and cleaning with a detergent - had not rendered the implant surface biologically acceptable for bone to grow into contact with it. In a recent study the effect of guided bone regeneration alone or in combination with various bone substitutes was evaluated in the treatment of peri-implant defects (87).Following ligature-induced tissue breakdown, the defects were debrided and the exposed implant surfaces cleaned with an air-powder abrasive instrument. Histological data revealed varying amounts of bone regeneration depending on the clinical procedure. The best results were obtained with the combination of guided bone regeneration and bone substitutes. Furthermore, the investigators reported consistent contact between regenerated bone and the previously exposed implant surfaces. In contrast to previous investigations (1401, the treatment regimen for decontamination of the implant chosen in this study had rendered the surface biologically acceptable for new bone to grow into contact with it. Human studies of the regeneration of tissues after destruction due to peri-implantitis are limited to a few recent case reports documenting the use of guided bone regeneration in the treatment of early and late implant failures (77).Although the re-establishment of bone-to-implant contact on the surface previously exposed to plaque accumulation could

obviously not be demonstrated in any of these studies, stability of the clinical result over a period of 1.5 years was documented radiographically in one study (77). Successful bone regeneration was obtained in spite of the fact that the implants remained transmucosal during the entire treatment period. Before guided bone regeneration treatment for late peri-implant failures can be recommended for routine use in practice, some aspects of the clinical procedures still have to be established. These aspects include the appropriate antimicrobial therapy in terms of the choice of medication, the dosage, the duration of this treatment and the optimal manipulations of the implant surface, the ideal membrane material - resorbable or nonresorbable - the defects most amenable to treatment and the proper time frame of the regeneration period.

The use of bone grafts and substitute materials

Classification of bone graft materials
Bone grafts have long been used in reconstructive surgery with the aim of increasing the bone volume in the previous defect area. Bone grafts and bone substitute materials may be classified into two main groups: autogenic and xenogenic materials. The term autogenic graft refers to tissues that are transplanted within one and the same organism. Autogenic bone is the most frequently used material in this group. Xenogenic grafts encompass all materials of an origin other than the recipients organism and may further be divided into materials from the same species but different individuals, materials from other species and products of nonorganic origin. Demineralized freeze-dried bone represents an allograft material, that is, from the same species, but not the same individual, which has widely been used in bone augmentation procedures.

Biological behavior Introduction. A wide variety of graft materials have been employed in experimental studies or in clinical practice. The range of materials used encompass autogenic cancellous or cortical human bone, xenogenic bone transplants such as demineralized freeze-dried human bone and xenogenic bone substitute materials such as natural and synthetic hydroxyapatite, deproteinized bovine bone mineral and calcium-phosphate compounds (73, 75, 78, 84,

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86, 105, 106, 136, 141-144, 159). The rationale for using bone grafts in combination with guided bone regeneration encompasses factors such as supporting the membrane in situations in which the defect morphology will not adequately do so, to offer a scaffold for ingrowth of capillaries and perivascular tissue, in particular osteoprogenitor cells, and to provide a carrier for factors enhancing bone formation. Although mechanical support can also be achieved by the use of stiffer membranes, pins, miniscrews or metal reinforcements of membranes (15, 34, 82, 991, the possible biological benefits of filler materials cannot be achieved in other ways. Bone substitutes should exhibit biocompatible material properties. They should not elicit allergic or immune reactions. They should be well tolerated and integrated by the host tissues and ideally provide a scaffold for new bone to grow onto. It has been postulated that they should gradually be replaced by newly formed bone. Their three-dimensional structure should most closely resemble that of natural bone with respect to macro- and microporosities. Finally, they should compartmentalize larger defects into smaller fragments comparable to that of natural human bone (31). Unfortunately, many of the products presently available lack adequate scientific documentation to recommend their general use in conjunction with guided bone regeneration procedures. It is therefore difficult, to critically appraise many of the obtainable bone substitute materials. Bone-inductive materials. The most intriguing method of enhancing the local bone volume is by inducing pluripotent mesenchymal cells to boneforming cells. Theoretically, this can be accomplished by supplying growth factors or suitable proteins into the defect area. Demineralized freezedried bone allograft is a substance that has been widely used with the purpose of achieving osteoinduction. However, data from both animal experiments and from human clinical studies are controversial with respect to the bone-inducing effect of this material. Although some earlier publications have provided encouraging data (141, 148, 149, 181), more recent experiments have questioned the ability of demineralized freeze-dried bone allograft to induce new bone formation (5, 20-23, 142, 143).In this context it appears that both the rank on the phylogenetic ladder as well as the source and the preparation of the demineralized freeze-dried bone allograft profoundly influence the final outcome. Animals ranking high on the phylogenetic ladder are character-

ized by a low metabolic index and hence form bone at a slower rate than lower-ranking animals (48). In addition, they have been documented to exhibit lower reactivity to osteoinductive stimuli (153). Both factors may contribute to the confusion resulting from contradictory results presented in different studies. Whereas bone induction by demineralized freeze-dried bone allograft has been shown in rodents, this has not been conclusively demonstrated in higher species such as dogs, monkeys or humans. Moreover, some of the contrast in the results from various studies possibly originates from the fact that demineralized freeze-dried bone allograft preparations from different bone banks and from different batches from the same bank may respond quite differently (166).Therefore, it has been postulated that assays should be developed to standardize the activity of demineralized freeze-dried bone allograft. Another source of confusion may arise from the fact that evidence that demineralized freeze-dried bone allograft promotes bone formation has generally been provided at two different levels: the clinical and the histological level. There is general agreement that the histological data are more reliable than clinical measurements. Studies combining histological and clinical data have recently reported a disparity between the two methods of assessing the results of regeneration (21). Hence, conclusions drawn from purely clinical evaluation of demineralized freezedried bone allograft should be interpreted with caution. Finally, there are contradictory results regarding the resorbability of demineralized freeze-dried bone allograft in the host tissues (20, 23, 142). In conclusion, although demineralized freezedried bone allograft holds some promise as an osteoinductive material for use in guided bone regeneration procedures, it should be used with caution until it can be provided in a well-standardized and controlled form from the bone banks, and until its efficacy in bone induction has been proven in nonhuman primates and in humans. Transplantation of autogenic bone. It has long been claimed that autogenic bone is the ideal material to increase the bone volume of the jaw bone (31). Before the advent of guided bone regeneration, intraoral bone augmentation was commonly performed by the use of autogenic bone transplants preferentially taken from the iliac crest. Such a procedure is very demanding regarding operator skills and logistical support for the surgical intervention, is highly stressful for the patient and causes considerable

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post-operative pain, and the treatment is very costly. Ridge augmentation using bone grafts without membranes is subjected to extensive resorption of the graft (111, 175). Loss of graft volume in the magnitude of 50% have been reported during healing over the period of 6 months. One of the possible indications for guided bone regeneration is the replacement of such procedures. A recent study (95) has demonstrated that the results of guided bone regeneration, when combined with autogenic bone grafts, are superior to the traditional method of transplanting bone without adequate protection by barrier membranes. In this dog study demineralized freeze-dried bone allograft and cortico-cancellous iliac autografts with and without barrier membranes of expanded polytetrafluoroethylene were compared. The best results were obtained with the combination of the autogenic graft and the membrane in terms of the graft volume incorporated as well as the direct bone-to-implant contact. In a recent clinical article (371, the successful combination of autogenic cortico-cancellous bone grafts and guided bone regeneration has been shown. A group of 40 patients consecutively treated with this method demonstrated a very low frequency of soft tissue complications and successful ridge augmentation in 66 sites. A mean gain in crest width of 3.5 mm was measured allowing implant placement in proper position in all 66 sites. These very good results may be used as a standard against which new developments, aiming at reducing efforts necessary to obtain successful treatment outcomes, can be tested. Xenogenic bone substitutes. Xenogenic bone substitutes of hydroxyapatite have recently been developed. Experimental studies have dealt with materials manufactured synthetically (68, 86, 105, 144), derived from corals or algae (73, 96, 105, 106, 144) or originated from natural bone mineral (25, 46, 64, 76, 78, 96, 107, 156, 159, 176, 188). These materials are considered biocompatible and osteoconductive. Nevertheless, considerable differences in their behavior based on material properties have been reported. Integration of natural bone mineral has been shown to be superior to coral- or algae-derived hydroxyapatite products (96). One of the reasons for these differences may be the three-dimensional structures, including the porosities of bone grafts, which have been documented to have important effects on bone healing (49, 86, 105, 106, 183). Ma-

terials exhibiting large surface areas showed better bone-graft contact than materials with a comparatively small surface area (86, 105, 106).Deproteinized bone mineral in its unaltered form has presumably ideal architecture for use as a bone graft material. However, due to manipulations during the purification process, different tissue integration properties of the natural bone mineral may result. Thus, bovine-derived bone mineral exhibiting natural crystallinity (Bio-Oss, Geistlich, Wolhusen, Switzerland) yielded increased bone-to-graft contact compared with a product of the same origin but with larger crystal size (Endobon, Merck Biomaterials, Darmstadt, Germany) (96). The results regarding bone-to-graft contact and hence the osteoconductive properties attributed to the materials tested vary considerably between different studies, rendering interpretation and comparison difficult (76, 78, 85, 86, 96). Bone-to-graft contact also depends, among other factors, on the density of bone in the vicinity of the graft. In order to ameliorate interpretation of results, this factor should be taken into consideration in the assessment of the osteoconductive properties of a bone substitute. Recently, an osteoconductivity index has been proposed, which was calculated by using a model to detect phase association from the direct bone-to-graft contact and the area density of bone in the vicinity of the graft (76). It was postulated that values above 1.0 indicate that the bone grows preferentially in contact with the graft, whereas values of less than 1.0 indicate that the bone-to-graft contact is taking place at a level less than what could be expected by randomly occurring contact, and therefore, the bone is being hampered from making graft contact. Thus an index that equals 1.0 indicates that bone-to-implant contact is occurring at random. In that study, this parameter reached values of 2.9 at the sites treated with membrane and deproteinized bovine bone mineral and of 2.6 for the sites treated with deproteinized bovine bone mineral group, indicating high osteoconductivity of the graft (76). Recent studies have evaluated a deproteinized bovine bone mineral as a filler in a guided bone regeneration procedure model on the rabbit skull (78, 159). In combination with a stiff bioresorbable membrane made of polylactic acid, this substitute improved the amount of initial soft tissue formation and initially increased the rate of mineralized bone formation compared with blood-filled controls. It has been postulated that formation of soft tissue is a step of critical importance in the sequence of

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events ultimately leading to mature mineralized bone (78). In a recent experiment, titanium test tubes were implanted in the retromolar area of healthy volunteers (81). Regenerating tissue was capable of adhering to the bony base from which it originated and to the expanded polytetrafluoroethylene membrane closing the flap facing opening of the tube and thus separating the soft tissues from the space inside the tube. The surface of the inner walls of the tube was made up of polished titanium, preventing cellular adherence (28, 29, 42, 43). In the 2week specimens the tissue completely filled the inside of the tube, whereas in the 7-week and 12-week ones the newly formed tissues exhibited the shape of an hourglass (Fig. 7a). Apparently, during the phase of fibroplasia, the regenerated soft tissues were pulled away from the cylinder walls rendering the shape observed. Interestingly, even after observation periods of up to 9 months, when the majority of the space was occupied by new bone, this particular shape was unchanged (Fig. 7b). The investigators concluded that the outer borders confined by the mature soft tissue, which arises prior to mineralization, delimit the area ultimately available for bone to form (78, 81). The observed acceleration of bone formation in conjunction with the use of bone substitutes in the rabbit skull model may be attributed to the higher amount of osteoblasts found in the test specimens (78, 159). With the increase in osteoblast numbers the only cells capable to form bone - the rate of bone formation rises. The application of the substitute material evidently created an environment that allowed earlier immigration of osteoblasts into the area intended for guided bone regeneration. By designing bone substitute materials with appropriate surface characteristics, this biological mechanism may be used with greater benefit in bone regeneration procedures. Several studies have indicated that the use of bone grafts of natural bone mineral does not decrease bone-to-implant contact when used to treat peri-implant defects in guided bone regeneration procedures as compared with the use of membranes alone (25, 76, 1881. The physiological pattern of new bone formation with guided bone regeneration in the presence of bone substitutes of natural bone mineral has recently been described by Hammerle et al. (78). NO qualitative differences were detectable in test and control specimens, indicating that the presence of the graft material did not alter the basic pattern of bone formation (Fig. 8). These findings were similar to the description of the type of bone formation

Fig. 8. Bone regeneration around deproteinized bovine bone (DBB) from a human specimen. Large areas of the graft particles are in direct bone contact (new bone: nb). Some areas are in contact with bone marrow tissue (bm). Direct deposition of osteoid (0s) produced by osteoblasts is occasionally visible. The newly formed bone is subjected to remodeling activity as indicated by the presence of osteoclasts. Similarly, osteoclasts (arrowheads)are seen resorbing the bone substitute.

found in previous studies evaluating sequential stages of guided bone regeneration without the use of bone substitutes (79, 109, 154). The fact that the pattern of bone formation and the sequence of bone remodeling are not negatively influenced by the use of this type of bone substitute is of particular importance for the application of this method in oral implantology. Only lamellar bone, owing to its high biomechanical competence, optimally fulfills the requirements for taking up loading forces transferred by implants. There is general agreement that dense synthetic hydroxyapatite is nonresorbable in viuo (33, 68, 96, 105,184) and that calcium phosphate compounds as well as coral- or algae-derived materials degrade over time (33, 73, 96). Conflicting results, however, have been published regarding the long-term performance of natural bone mineral. Although some investigators have reported rare signs of biodegradation or complete lack of breakdown (57, 78, 1561, others have described definite graft resorption (24, 76, 96, 107, 188) or documented decrease in area density of the graft over time (25). In one of these studies, active resorption of the Bio-Oss particles by osteoclasts was demonstrated unequivocally by staining with tartrate-resistant acid phosphatase (76). Although, the resorption process by osteoclasts has thus been documented, no data are available on the rate of resorption and on the behavior of the resulting spaces. One direction of present research involves the de-

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velopment of resorbable grafting materials chemically based on synthetic polymers (185). These compounds offer a number of advantages over presently used fillers. They can be custom made regarding resorption time, stability and rigidity, three-dimensional structure and pore size, and finally they can be used as carriers for compounds enhancing bone formation. Clinical applications Human clinical studies on the use of bone grafts and of bone substitutes are scarce. Available data are mostly limited to case reports and reports of case series (16, 37, 57, 84, 128, 173), some of which report test and control procedures (22, 65, 170, 192, 193). Controlled long-term clinical studies are lacking. So far, autogenic bone grafts in conjunction with guided bone regeneration have yielded the best results with high predictability (16, 37). However, studies involving harvesting of autogenic bone for transplantation should not only present data on the success of the treatment at the regenerated site but should also provide information about the morbidity and the discomfort caused to the patient by the harvesting procedure. Not before this aspect has been included in the evaluation process should a comprehensive benefit-risk analysis of the various concepts for grafting in guided bone regeneration be conducted. Most of the data available with respect to the use of bone grafts and bone substitute materials represent presentations of new developments. In accordance with the sequence of analysis described for implants placed in conjunction with guided bone re-

generation, the newly developed and successful treatment approaches should enter a validation period, in which the implants, for the placement of which the incorporation of bone grafts and substitutes was indicated, should be evaluated on a longterm basis with respect to the stability of the successfully obtained treatment outcomes.

The benefit of resorbable membranes

Material developments and experimental studies With the presentation of the first successful guided bone regeneration procedures and the subsequent wide and successful application of expanded polytetrafluoroethylene membranes, this material became standard for bone regeneration. An obvious disadvantage of this material is that it is nonresorbable and, therefore, has to be removed with a second surgical procedure. Regarding patient morbidity, risk for tissue damage, and from a cost-benefit point of view, the replacement of nonresorbable by resorbable membranes would be desirable. Hence, recent experimental research in guided bone regeneration has aimed at developing resorbable barrier membranes for application in the clinic. Bioresorbable materials that may be used for the fabrication of membranes all belong to the groups of natural or synthetic polymers. The best known groups of polymers used for medical purposes are collagen and aliphatic polyesters. Currently tested and used membranes are made of collagen or of polyglycolide and/or polylactide or copolymers thereof (90) (Fig. 9a-h). Several design criteria have been postulated for membranes as being favorable for their use in guided bone regeneration. Thus, it was postulated that the membrane barrier should be permeable for exchange of critical fluid substances with putative nutritive or instructive function. It was later shown in an animal experiment on the rabbit skull that membrane permeability is not a prerequisite for guided bone regeneration, as new bone had formed in both the test and control chambers (160). The results of another animal experiment have shown that occlusive bioresorbable membranes made of polylactic or polyglycolic acid are equally successful as expanded polytetrafluoroethylene membranes in regenerating bone in transosseous defects in the rabbit mandibular ramus (152). However, bone formation in the defects separated by the resorbable membranes was associated with chondral

Fig. 9. a. Due to failed endodontic treatment, tooth number 34 has to be extracted. Therapy with an immediate implant and guided bone regeneration is favored over a conventional bridge due to inappropriate adjacent potential abutment teeth. b. Eight weeks following extraction of the root, the soft tissues have healed over the extraction socket. c. Careful flap elevation has exposed the alveolar process with the tooth socket. d. A full-body plasmasprayed implant has been placed with primary stability into the alveolus. e. A bone substitute of natural bone mineral is use to support a collagen membrane. f. The collagen membrane has carefully been adapted to the bony walls surrounding the defect and has been punched and slipped over the shoulder of the implant. g. At re-entry surgery 6 months later, regenerated hard tissue is found in the previous defect area around the coronal part of the implant. h. Radiographic control of the implant and the surrounding regenerated bone prior to initiation of prosthetic treatment.

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bone formation, whereas the defects treated with expanded polytetrafluoroethylene membranes were associated with bone formation along the desmal pathway. Based on an earlier study (169),the investigators concluded that since the impermeable membranes had prevented oxygen from passing from the soft tissues into the area intended for bone regeneration, the low oxygen tension in the defect area had resulted in cartilage formation as an intermediary step prior to bone formation (152). In accordance with these findings are the results of an experiment evaluating the effect of different pore sizes of expanded polytetrafluoroethylene membranes in guided bone regeneration on the rat skull (191). It was found that the dome-shaped membranes exhibiting internodal distances of less than 8 pm showed delayed bone fill compared with membranes, where these distances ranged from 2025 pm or were in the range of 100 pm. In addition, soft tissue integration and peripheral sealing associated with the small internodal distance were reported to be inferior. Nevertheless, after 12 weeks, a similar degree of bone fill was observed with the different membrane types. From these studies it may be concluded that membrane porosities are indeed no prerequisite for bone formation, but optimal pore sizes are advantageous regarding nutrient flow, wound stabilization and peripheral sealing to prevent ingrowth of soft tissue-forming cells. Unfortunately, most of the available resorbable membranes are not capable of maintaining space. Therefore, they need to be supported in one way or another. The most commonly used method for membrane support is to sustain it with autogenic grafts or with bone substitutes (9, 139, 158, 192, 193), whereas other methods such as screws, pins and reinforcements have also occasionally been applied (67, 109). Several animal experiments have demonstrated the successful use of bioresorbable membranes in guided bone regeneration (44, 78, 109, 120, 121, 123, 152, 158, 159, 168), whereas only few have reported failures (12, 32, 67, 157, 189). In two recent experiments, a polylactic acid membrane was tested in its ability to increase the bone volume in conjunction with an autogenous bone graft compared to controls that were grafted only (120, 121). Both experiments showed more bone formation when the membranes were applied. These results demonstrate that soft polylactic acid membranes are suitable for guided bone regeneration procedures in conjunction with autogenous grafts.

A different approach was taken in experimental studies evaluating a form-stable bioresorbable membrane made of polylactic acid in conjunction with a bone substitute in a rabbit skull model (78, 159). New bone was demonstrated to form underneath the membrane beyond the borders of the former calvarium. On the one hand, this experiment demonstrated that, in principle, stiff, bioresorbable membranes are conducive to bone regeneration and bone neoformation. On the other hand, after the observation period of 2 months, no overt signs of breakdown of the membrane were reported. In many clinical situations a resorption time between 6 and 12 months is mandatory in order not to lose the advantages of resorbability.

Results of clinical applications Beginning in the early 1990s and thereafter, reports of cases or case series were presented describing the use of resorbable membranes for guided bone regeneration at exposed implant surfaces (10, 88, 89, 124, 125, 137, 139, 193). Later, controlled clinical studies were published (171, 192). In all of these reports a low rate of complications involving inflammation of the flap covering the site of regeneration and exposures of membranes were observed. In two studies involving a larger number of consecutively treated patients, the results with respect to bone regeneration were very favorable. Bony defect fill ranged from 83% (193) to 92% (89). Similar results were reported in the treatment of dehiscence and fenestration defects at threaded implants with the use of bioabsorbable membranes made of polyglycolide and polylactide (125).Even though no bone graft or bone graft substitutes were used, 14 out of 17 defects showed complete bone fill at re-entry. In one of the controlled clinical studies, a collagen membrane was tested against an expanded polytetrafluoroethylene membrane (192). At the re-entry operation 4 to 6 months following guided bone regeneration surgery, 57% of the 39 defects treated with collagen and 57% of 14 defects treated with expanded polytetrafluoroethylene membranes showed complete bone fill. Incomplete bone regeneration was found in 39% of the test sites and 29% of the control sites. No gain of new bone was found in 5% of the test sites and 15% of the control sites. A high percentage of exposure of membranes (19%) leading to early removal occurred in sites treated with expanded polytetrafluoroethylene membranes. Although, the possibility for early resorption of collagen membranes is mentioned in the article in cases

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of incomplete wound closure, unfortunately, no data are presented with respect to this complication. In the most recent controlled clinical study, 18 implants with exposed threads were divided into two groups (171). In both groups the defects were filled with autogenous bone. In the test group a resorbable polylactic or polyglycolic acid membrane was adapted, whereas in the control group a standard expanded polytetrafluoroethylene membrane was placed. Neither in the test nor in the control group were any flap dehiscences or membrane exposures registered. Six to seven months later, both groups revealed excellent bone regeneration, with values of 89% and 98% defect fill. Although the test group yielded less bone fill and exhibited a higher variability of the results, no statistically significant difference was found. In conclusion, these case reports and initial controlled clinical studies demonstrate that resorbable membranes can be used successfully for bone regeneration at implants with exposed surface areas. However, before the methods can be recommended for widespread clinical practice, the fine points of the treatment protocols have to be worked out, and the treatment approaches presented will have to be validated in larger, well-controlled studies.

8. Augthun M, Yildirim M, Spiekermann H, Biesterfeld S.

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