JBJS | Augmentation of Alveolar Bone and Dental Implant Osseointegration: Clinical Implications of Studies with rhBMP-2 : A Comprehensive Review

The Journal of Bone & Joint Surgery, Volume 83, Issue 1 suppl 2

Clinical Applications of BMPs in Oral and Maxillofacial Surgery | April 01, 2001

Augmentation of Alveolar Bone and Dental Implant Osseointegration: Clinical Implications of Studies with rhBMP-2 : A Comprehensive Review

Ulf M.E. Wikesjö, DDS, PhD; Rachel G. Sorensen; John M. Wozney, PhD

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Laboratory for Applied Periodontal and Craniofacial Regeneration, Department of Periodontology, Temple University School of Dentistry, Philadelphia, Pennsylvania, and Bone Biology and Applications, Musculoskeletal Sciences, Genetics Institute, Inc., Andover, Massachusetts, U.S.A.
Ulf M.E. Wikesjö, DDS, PhD
Temple University School of Dentistry, Laboratory for Applied Periodontal and Craniofacial Regeneration, Department of Periodontology, 3223 North Broad Street, Philadelphia, PA 19140. E-mail address for U.M.E. Wikesjö: uwikesjo@dental.temple.edu

Rachel G. Sorenson
John M. Wozney, PhD
Bone Biology and Applications Group, Genetics Institute, Inc., One Burtt Road, Andover, MA 01810, U.S.A.

The authors did not receive grants or outside funding in support of their research or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

The Journal of Bone & Joint Surgery. 2001; 83:S136-S145

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Abstract

Background: The surgical placement of dental implants is governed primarily by the prosthetic design and secondarily by the morphology and quality of the alveolar bone. Implant placement may be difficult, if at all possible, due to alveolar ridge aberrations. In consequence, prosthetically dictated dental implant positioning often entails augmentation of the alveolar ridge and adjacent structures. The objective of this review is to discuss recent observations of the biologic potential, the clinical relevance, and the perspectives of the application of recombinant human bone morphogenetic protein-2 (rhBMP-2) technology for alveolar bone augmentation and dental implant fixation.

Methods: Our studies use discriminating, critical-size, supraalveolar defects in dogs to evaluate the biologic potential of the rhBMP-2 technology. We also use clinical modeling, including peri-implantitis and alveolar ridge defects and the maxillary sinus in preparation for clinical indications, in dogs and inhuman primates.

Results: The results suggest that rhBMP-2 has substantial potential to augment alveolar bone and support dental implant fixation and functional loading.

Conclusion and Clinical Relevance: Inclusion of rhBMP-2 for alveolar bone augmentation and dental implant fixation will not only enhance the predictability of the existing clinical protocol but will also allow new approaches to these procedures.

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Introduction

Caries and periodontal diseases are the most prevalent diseases of humans. It is generally accepted that the etiology of caries and periodontal disease is infectious in origin; however, variations in host and parasite makeup allow a range of expressions. Invariably, the disease processes result in irreversible tissue loss and thus in disfiguration and dysfunction of the orofacial complex including spreading or loss of teeth, or both, loss of facial height, and phonetic impairment. Ultimately, teeth lost due to caries and periodontal diseases must be prosthetically replaced.

Endosseous dental implants have been used to support single tooth, partial and complete arch dental reconstruction, and maxillofacial reconstruction. Surgical placement of dental implants is governed primarily by the prosthetic design and secondarily by the morphology and quality of the alveolar bone. Implant placement may be difficult, if at all possible, due to alveolar ridge aberrations resulting from tooth loss, systemic bone disease, deficient nutrition, or denture wearing. In consequence, prosthetically dictated dental implant positioning often entails augmentation of the alveolar ridge and adjacent structures. Osseointegration (direct bone-implant contact) is a primary goal following dental implant placement. Such bone anchorage provides stability for functional loading of the implant. Current dental implant technology achieves osseointegration after an initial healing period of several months during which nonloaded implant fixtures interact with and anchor to bone¹.

The objective of this review is to discuss questions regarding current bone augmentation technologies for implant dentistry. Specifically, the recent observations of the biologic potential, the clinical relevance, and the perspectives of recombinant human bone morphogenetic protein-2 (rhBMP-2) technologies for alveolar bone augmentation and dental implant osseointegration will be discussed.

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Fig. 1:: Figure 1 For the critical-size supraalveolar periodontal defect model (a), the crowns of the third and fourth mandibular premolar teeth in the dog have been reduced in height to just above the crown margin. The alveolar bone has been reduced 6 mm in height around the premolar teeth, creating defect dimensions of clinical relevance (the first and second premolar teeth have been extracted, and the first molar has been reduced to level with the alveolar bone). For the critical-size supraalveolar peri-implant defect model (b), the third and fourth mandibular premolar teeth have been extracted and replaced with three 10-mm titanium dental implants inserted 5 mm into the reduced alveolar crest creating 5-mm discriminating supraalveolar peri-implant defects. For both models, experimental treatments (bone derivatives/substitutes, devices, biologics, or combinations thereof) are placed/molded around the teeth/implants. The mucoperiosteal flaps are then advanced and sutured to cover the teeth on implants for optimized healing conditions.

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Fig. 2:: Figure 2 Representative photomicrographs at 8 weeks after surgery from the critical-size supraalveolar periodontal defect model implanted with recombinant human bone morphogenetic protein-2 (rhBMP-2) in (a) bovine bone mineral matrix (Bio-Oss; Osteohealth); (b) DL-polylactic acid granules (PLA; Drilac, THM Biomedical); (c) allogeneic, freeze-dried, decalcified bone matrix (DBM); and (d) an absorbable type I bovine collagen sponge (ACS; Integra Life Sciences). Relatively limited bone formation can be observed in the region of the Bio-Oss biomaterial. The Bio-Oss particles remain unresorbed. Bone formation appears as a halo around the Bio-Oss implant. Defects receiving the rh-BMP-2/PLA exhibit limited new bone formation. Notably, numerous foamy macrophages are associated with the fragmenting PLA biomaterial, resulting in osteoclastic resorption of the newly formed and the adjacent resident bone. The rhBMP-2/DBM combination shows robust bone formation. New alveolar bone with few residual DBM particles can be observed. The rhBMBP-2/ACS combination shows limited bone formation immediately adjacent to the tooth, without evidence of residual biomaterial. The limited bone formation may be an effect of compression of the ACS biomaterial from or transmitted thorough the mucoperiosteal flaps. The green marking delineates the coronal extension of the resident alveolar bone. (Reprinted, with permission, from Sigurdsson TJ, Nygaard L, Tatakis DN, Fu E, Turek TJ, Jin L, Wozney JM, Wikesjö UM. Periodontal repair in dogs: evaluation of rhBMP-2 carriers. Int J Periodontics Restorative Dent 1996;16:524-37.)

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Fig. 3:: Figure 3 Photomicrographs at 16 weeks after surgery from the critical-size supraalveolar peri-implant defect model implanted with (a) recombinant human bone morphogenetic protein-2 (rhBMP-2/ACS); (b) ACS alone; (c) allogeneic, freeze-dried, decalcified bone matrix (DBM) in conjunction with a purpose-designed guided bone regeneration polytetrafluoroethylene (ePTFE) membrane; and (d) guided bone regeneration with the purpose-designed ePTFE membrane alone. Compare and contrast the regenerative potential of alveolar bone following the various protocols. Notably, the physiologic concentration of bone growth factors including bone morphogenetic proteins (BMPs) sequestered in DBM has no obvious effect on alveolar regeneration; the DBM particles are invested in fibrous connective tissue without apparent evidence of bone metabolic activity. Only pharmacologic relevant concentrations of rhBMP-2 support meaningful alveolar augmentation. The green marking delineates the coronal extension of the resident alveolar bone. (Reprinted, with permission, from Sigurdsson TJ, Fu E, Tatakis DN, Rohrer MD, Wikesjö UM. Bone morphogenetic protein-2 enhances peri-implant bone regeneration and osseointegration. Clin Oral Implants Res. 1997;8:367-74 [ a and b], and from Caplanis N, Sigurdsson TJ, Rohrer MD, Wikesjö UM. Effect of allogeneic, freeze-dried, demineralized bone matrix on guided bone regeneration in supra-alveolar peri-implant defects in dogs. Int J Oral Maxillofac Implants 1997;12:634-42 [c and d].)

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Fig. 4:: Figure 4 Intrasurgery view of a recombinant human bone morphogenetic protein-2 (rhBMP)-2/decalcified bone matrix (DBM) onlay in the edentulous posterior mandible (a). Clinical view at 8 weeks after surgery, showing the extent of the ridge augmentation (b). Implant placement into the newly formed ridge at 8 weeks after surgery (c). Note the clinically significant vertical and horizontal gain of alveolar bone. Representative photomicrographs from 8 (d) and 16 (e) weeks following implant placement. The implants are mainly implanted into rhBMP-2 induced bone. Only the most apical aspect contacts resident alveolar bone. The green marking approximates the coronal extension of the resident alveolar bone. Illustrations courtesy of Dr. Thorarinn J. Sigurdsson.

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Fig. 5:: Figure 5 Computerized tomography (CT) scan before surgery of the maxillary sinuses in a cynomolgus monkey (a). T and C delineate sites to be treated with recombinant human bone morphogenetic protein-2 (rhBMP-2)/ACS or ACS alone, respectively. CT scan after surgery (3 months) following sinus augmentation using the lateral wall approach (b). Bone formation is significantly increased in the site that received the rhBMP-2/ACS implant compared with the site receiving ACS alone. (Reprinted, with permission, from Hanisch O, Tatakis DN, Rohrer MD, Wöhrle PS, Wozney JM, Wikesjö UM. Bone formation and osseointegration stimulated by rhBMP-2 following subantral augmentation procedures in nonhuman primates. Int J Oral Maxillofac Implants 1997;12:785-92.)

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Fig. 6:: Figure 6 Clinical view following surgical exposure and debridement of peri-implant defects (a). Reentry surgery at 4 months following placement of recombinant human bone morphogenetic protein-2 (rhBMP-2)/ACS into the peri-implant defects (b). Note the substantial apparent bone fill of the circumferential defects. Photomicrograph from 4 months following implantation of rhBMP-2/ACS into the peri-implant defects (c). Note extensive new bone formation coronal to the base of the defect (indicated by the arrows) approaching the top surface of the dental implant. Also note evidence of re-osseointegration to the previously orally exposed implant surface. (Reprinted, with permission, from Hanisch O, Tatakis DN, Boskovic MM, Rohrer MD, Wikesjö UM. Bone formation and reosseointegration in peri-implantitis defects following surgical implantation of rhBMP-2. Int J Oral Maxillofac Implants 1997;12:604-10.)

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Fig. 7:: Figure 7 Prosthetically reconstructed dental implants placed into recombinant human bone morphogenetic protein-2 (rhBMP-2)/ACS-induced and into native resident bone in the dog (a). The dental implants were allowed to osseointegrate for 4 months before reconstruction and 12 months of functional loading. Representative photomicrographs of dental implants placed into rhBMP-2/ACS induced (b) and into native resident bone (c) following 12 months functional loading from the same animal. Note the similar morphology and osseointegration between the implant sites. Illustrations courtesy of Dr. Sascha A. Jovanovic.

Bone, Bone Derivatives, and Substitutes

Benefits from the osteogenic potential of autograft bone, the treatment of choice or "gold standard" for skeletal reconstruction, are restricted due to limited tissue resources and donor morbidity^?2,3. In addition, bone modeling may result in undesirable alterations in tissue volume and geometry. In perspective, commonly considered undecalcified/decalcified allogeneic bone or xenogeneic bone mineral preparations appear attractive to support bone reconstruction in the craniofacial skeleton.

Considerable work concerning the efficacy and safety of allogeneic bone preparations has been presgented^4-6. It has been suggested that allogeneic bone, lyophilized and decalcified, may support regeneration of alveolar bone^7,8. An increasing body of evidence, however, questions the clinical relevance and the osteoconductive and regenerative potential of such bone preparations. Studies evaluating lyophilized, decalcified, allogeneic bone preparations in a variety of orthotopic models including long bones, calvaria, and alveolar ridge in experimental animals and clinical cases provide little, if any, histologic evidence of a short-term or long-term benefit of these biomaterials^9-16. Xenogeneic bone mineral preparations incorporate into bone; however, their slow resorption rates impact on the quality of the newly formed bone and ultimately on their clinical relevance^17-20. In addition, the public perception of allogeneic or xenogeneic cadaver materials reduces their acceptance for elective procedures. The potential for immunologic reactions, fear of disease transmission, and uncertain outcomes thus limit the acceptance and utility of allogeneic or xenogeneic bone derivatives.

Ceramic and polymeric bone substitutes, potentially osteoconductive, have also been evaluated in the reconstruction of bone. A variety of resorbable or non-resorbable biomaterials including calcium-based ceramics, bioactive glass, and synthetic polymers are commercially available for alveolar reconstruction²¹. In selecting ceramic or polymeric bone substitutes, the clinician must carefully consider the mechanical and biological qualities of these materials. Early resorption of an implanted material must not significantly interfere with bone formation. Late resorption must not significantly compromise bone maintenance.

It appears critical that any implanted biomaterial, whether derived from allogeneic or xenogeneic bone or of ceramic or polymeric origin, must not compromise bone formation by obstructing the wound space or negating or delaying the native osteogenic potential of the site. Its long-term residence must not compromise the mechanical properties of bone, including load-bearing and dental implant osseointegration.

Guided Tissue/Guided Bone Regeneration

Other studies have explored and taken advantage of the native regenerative potential of alveolar bone by employing passive membrane devices that separate tissues during healing^22,23. This enabling technology has been termed guided tissue regeneration or guided bone regeneration and represents one basic tenet of tissue engineering: providing and maintaining a space to allow regeneration from specific tissue sources and preventing scar formation. Following extensive development of biomaterials and surgical techniques, guided tissue/guided bone regeneration is now a widely accepted regenerative procedure in periodontics and implant dentistry. Since the clinical application is generally restricted to defects offering space-providing morphology and wound stability, its broader application is limited²³. Moreover, compromised wound closure or early mechanical wound failure, which exposes the membrane to the oral cavity, restricts regenerative outcomes even in well defined defects^24-26.

Preclinical Models for Evaluation of Bone Regeneration

The search for effective and safe therapies for bone reconstruction requires an evaluation to estimate their biologic potential, efficacy, and safety prior to clinical application and introduction. Candidate therapies should first be evaluated in well characterized rodent screening models for biologic potential and safety^27,28. Therapies exhibiting biologic potential and safety should be evaluated for clinical potential and efficacy in discriminating preclinical models designated as critical-size defect models in larger animals, including canines or nonhuman primates. Critical-size defects are defects that must not spontaneously regenerate following reconstructive surgery without adjunctive measure²⁹. Critical-size defects must also allow clinically relevant regeneration induced or supported by implanted biologics, biomaterials, or devices compared with that in a surgical control³⁰. Our laboratories have developed and characterized the critical-size supraalveolar periodontal defect model (Fig. 1)³¹. This model has proved to represent a litmus test for candidate therapies for periodontal regeneration³⁰. Subsequently, we have modified the supraalveolar periodontal defect model to study regeneration of alveolar bone and dental implant osseointegration and thus introduced the critical-size supraalveolar peri-implant defect model (Fig. 1)³⁰.

Once a candidate therapy has an established record of biologic potential and safety and a clinically relevant effect in a discriminating large animal model, successful therapies may become subject to clinical modeling. Clinical type defects that may not necessarily be discriminating critical-size defects but are recognized as difficult to successfully manage are produced in large animals to evaluate the efficacy and application of a candidate therapy. Examples of clinical modeling used to evaluate rhBMP-2 in the craniofacial skeleton include mandibular segmental defect reconstruction^32-36, cleft palate reconstruction^37-39, zygoma bone gap reconstruction⁴⁰, subantral augmentation^41-43, alveolar ridge augmentation^44-46, peri-implantitis defect reconstruction⁴⁷, and dental implant functional loading⁴⁸. In the following, we present studies evaluating the effect of rhBMP-2 in discriminating, critical-size defect models and in clinical modeling.

Evaluation of rhBMP-2 Candidate Carriers

The use of a carrier appears essential for delivery, retention, and release of BMPs at a defect site. Successful carrier systems must enable vascular and cellular invasion, allowing the BMP to act as a differentiation factor. The carrier should be reproducible, nonimmunogenic, moldable, and space-providing to define the contours of the resulting bone. Moreover, the carrier should resorb completely following the initiation of bone induction, thus ensuring bone formation. Various biomaterials have been tested as candidate carriers for BMPs. They include collagen^{43-45,47,49,50}, decalcified bone matrix (DBM)^32,51,52, hyaluronan⁵³, hydroxyapatite^50,54,55, calcium phosphates^56,57, a hydroxyapatite-collagen composite⁵⁸, various poly(α-hydroxy acids)^33,37,59-63, and titanium^64-68.

Using the critical-size, supraalveolar periodontal defect model, Sigurdsson et al.⁶⁹ showed that biomaterials used as candidate carriers for rhBMP-2 may significantly influence bone formation. The biomaterials included allogeneic, freeze-dried DBM, bovine bone mineral matrix (Bio-Oss; Osteohealth), and DL-polylactic acid granules (PLA; Drilac, THM Biomedical), all mixed with autologous blood. We also evaluated an absorbable type I bovine collagen sponge (ACS; Integra Life Sciences) and 50:50 polylactic acid-polyglycolic acid-copolymer microparticles (BEP; Genetics Institute) mixed with 6% carboxymethyl cellulose in aqueous glycerol in this study. Briefly, supraalveolar periodontal defects in contralateral jaw quadrants in six beagle dogs were randomly assigned to receive rhBMP-2/DBM, rhBMP-2/ACS, rhBMP-2/Bio-Oss, rhBMP-2/PLA, rhBMP-2/BEP, or a DBM control (rhBMP-2 at 0.2 mg/ml; Genetics Institute). A qualitative and quantitative histologic evaluation was performed on the block sections of the defect sites following an 8-week healing interval.

Treatment outcome was carrier-dependent. The Bio-Oss biomaterial remained unresorbed at the 8-week observation, clearly obstructing bone formation. Bone formation resembled an eggshell that surrounded the outside boundaries of the Bio-Oss carrier, thereby expanding the implanted site (Fig. 2). This carrier property appears unacceptable, since the unresorbed Bio-Oss matrix compromises the quality of bone and the volume of implanted site cannot be predicted.

The BEP carrier supported acceptable bone quality; however, bone quantity varied, probably due to the poor space-providing capacity of this biomaterial. The PLA carrier exhibited poor bone quality and quantity. This implant resulted in formation of sparsely trabeculated bone undergoing aggressive resorption. An accumulation of foamy macrophages dominated the implanted site; this was most likely a response to fragmentation of the PLA material undergoing biodegradation (Fig. 2). These characteristics make these polymers undesirable carriers for BMPs and probably undesirable to support bone reconstruction.

Histologic evaluation of the rhBMP-2/DBM implant revealed extensive bone formation expanding the boundaries of the implanted site. The quality of the newly formed bone assumed characteristics of the immediate resident bone (Fig. 2). Thus, the DBM carrier exhibited advantages over the Bio-Oss and the PLGA and PLA carrier systems. Its clinical use, however, may be limited by the lack of an adequate and reproducible supply and by the possible transmission of infectious agents. Finally, the ACS biomaterial also failed to meet the requirements of an ideal carrier in this model system. Despite desirable clinical handling, it lacked the ability to adequately provide or maintain space, resulting in limited bone formation when it was used as an onlay (Fig. 2).

None of the carriers were considered optimal in all aforementioned criteria. Demands on a carrier system may differ between indications and between sites; therefore, the search for alternative carriers continues. Naturally space-providing defects without the concerns of tissue compression may well be served by the use of plastic biomaterials as inlays. In contrast, candidate carriers for rhBMP-2 must include space definition and space maintenance when used as an onlay, as in the supraalveolar periodontal defect model described. Such biomaterials must resist compression from surrounding tissues to delineate the shape of the rhBMP-2 induced bone. Also, orthopaedic indications may demand biomaterials that provide early mechanical (weight-bearing) stability in addition to supporting bone formation. Indications, such as those in the craniofacial complex, may better benefit from plastic biomaterials that can be conveniently contoured into the awkward shapes needed in plastic, oral/maxillofacial, and periodontal surgery. Candidate biomaterials that are non-resorbable or that exhibit resorption profiles that may negatively influence bone formation or maintenance, or both, thereby compromising the biomechanical properties of bone (including weight-bearing and dental implant osseointegration) should not be considered.

Alveolar Augmentation and Dental Implant Osseointegration

This section presents preclinical studies evaluating surgical implantation of rhBMP-2 constructs used as onlays or inlays in clinically demanding alveolar ridge defects, with or without dental implants.

Sigurdsson et al.⁷⁰ first demonstrated that rhBMP-2/ACS used as an onlay supported by titanium dental implants induced significant alveolar bone augmentation (Fig. 3). Ten-millimeter-long endosseous dental implants (Nobel Biocare) were inserted 5 mm into the surgically reduced edentulous mandibular ridge, creating 5-mm critical-size supraalveolar peri-implant defects in five beagle dogs. rhBMP-2/ACS (rhBMP-2 at 0.4 mg/ml) or buffer/ACS was implanted into peri-implant defects in contralateral jaw quadrants. The animals were euthanized for histometric evaluation of the implant sites following a 16-week healing interval. Defects receiving rhBMP-2 exhibited significantly increased bone formation along the exposed implant surface compared with controls (4.2 ± 1.0 compared with 0.5 ± 0.3 mm, p < 0.002). The rhBMP-2 induced bone often constituted only a thin layer on the dental implant surface. Apparently, the rhBMP-2/ACS construct was ineffective in producing a space for adequate bone volume. Bone-implant contact was, as may be expected, lower than that in resident alveolar bone following the relatively short healing interval.

The significance of the observations by Sigurdsson et al.⁷⁰ becomes even more valuable when compared with those of Caplanis et al.¹². They evaluated the surgical implantation of allogeneic, freeze-dried DBM in conjunction with guided bone regeneration or guided bone regeneration alone, both representing common clinical practice. Contralateral 5-mm critical-size supraalveolar peri-implant defects, each including two titanium implants (Nobel Biocare), received a purpose-designed guided bone regeneration expanded polytetrafluoroethylene (ePTFE) membrane (WL Gore) or guided bone regeneration using the ePTFE membrane alone. Tissue blocks including the implant sites were harvested and prepared for histometric analysis following a 16-week healing interval (Fig. 3). DBM was discernible in all defects receiving this treatment. The DBM particles appeared solidified within a dense connective tissue matrix and in close contact to the implants, without evidence of osseointegration. Bone formation along the exposed implant surfaces was limited to 1.5 ± 0.9 and 1.1 0.4 mm for the guided bone regeneration/DBM and guided bone regeneration alone protocols, respectively. There were no significant differences between experimental conditions for any parameter examined. The results suggest that DBM has no relevant bone inductive or adjunctive effect to guided bone regeneration in supraalveolar peri-implant defects and that guided bone regeneration has a limited potential to augment alveolar bone.

Notably, the physiologic concentration of bone growth factors and BMPs sequestered in the DBM had no relevant effect on alveolar bone augmentation, given that the DBM particles were invested in fibrous connective tissue without apparent evidence of bone metabolic activity. Only pharmacologic concentrations of rhBMP-2 have been shown to support meaningful alveolar bone augmentation in this discriminating defect model.

In a subsequent study, Sigurdsson et al.⁷¹ showed that rhBMP-2 in an allogeneic, freeze-dried DBM/autologous blood carrier may have substantial clinical utility to augment demanding alveolar ridge defects and to allow early placement and osseointegration of dental implants (Fig. 4). Bilateral, critical-size (5-6 mm), supraalveolar ridge defects in five beagle dogs received an unsupported rhBMP-2/DBM/blood onlay (rhBMP-2 at 0.2 mg/ml). Non-submerged 10-mm dental implants (Straumann) were placed into the rhBMP-2 induced alveolar ridge at weeks 8 and 16 after surgery. The animals were euthanized for histometric evaluation of the implant sites at week 24 after surgery. Approximately 90% of the bone-anchoring surface of the implants was invested in rhBMP-2 induced bone. Similar levels of bone-implant contact (~55%) were observed in induced and resident bone irrespective of the osseointegration interval (8 or 16 weeks). There was no significant difference in bone density between rhBMP-2 induced and resident bone.

Jovanovic et al.²⁶ showed a rhBMP-2/ACS inlay to be an effective treatment when it is implanted into space-providing alveolar ridge defects. Combining rhBMP-2/ACS with guided bone regeneration provided no additional value. Surgically created mandibular, alveolar ridge, full-thickness, 15 10-mm saddle-type defects (two defects/jaw quadrant) in seven hound dogs were randomly assigned to receive rhBMP-2/ACS, rhBMP-2/ACS combined with guided bone regeneration (rhBMP-2 at 0.2 mg/ml), or control treatments. The guided bone regeneration protocol used ePTFE membranes. The animals were euthanized at 12 weeks after surgery for histologic evaluation. Complications after surgery included wound failure in 44% of the defects receiving guided bone regeneration, with or without rhBMP-2. Histologic analysis revealed bone fill averaging 101% for defects receiving rhBMP-2/ACS or rhBMP-2 combined with guided tissue regeneration (without wound failure) and 92% for defects receiving guided tissue regeneration alone (without wound failure). Bone fill for the surgical controls averaged 60%.

Similar observations have been made by Cochran et al.⁴⁵ in more limited intrabone defects. Bilateral 4-mm intrabone defects were surgically created around endosseous dental implants (Straumann) in the edentulous mandible in six foxhounds. rhBMP-2/ACS (rhBMP-2 at 0.2 mg/ml) or buffer/ACS (control) was placed into the defects. Half of the defect sites were additionally prepared for guided bone regeneration with use of ePTFE membranes. The animals were euthanized at 4 and 12 weeks after surgery. Implantation of rhBMP-2 resulted in enhanced defect resolution compared with that in controls (47 compared with 34%) as early as 4 weeks after surgery.

These observations demonstrate that rhBMP-2 may be used to augment alveolar bone when used as an onlay and as an inlay. The observations also point to the importance of space provision for rhBMP-2 induced bone formation. Alveolar defects, such as the critical-size supraalveolar periodontal or peri-implant defect model, may require rhBMP-2 constructs to provide space for alveolar augmentation. In contrast, space-providing alveolar defects such as the saddle-type defect and the intrabone peri-implant defect may be treated successfully with use of rhBMP-2 constructs with lesser biomechanical properties. The addition of guided bone regeneration membranes does not provide additional value to the rhBMP-2 technology. Notably, guided bone regeneration membranes introduce an increased risk for wound failure and appear to decelerate the regenerative potential of rhBMP-2^26,45,72.

Subantral Augmentation

Model selection appears critical in the study of biologics and biomaterials for subantral augmentation. Differences in morphologic characteristics between preclinical models and the human subantral space, including the proximity of sinus walls and relationship between the maxillary sinus and the alveolar ridge, may complicate the translation of preclinical observations to clinical application. Nonhuman primate clinical modeling appears a relevant model since the appositional bone formation rate in the cynomolgus monkey closely parallels that in humans^73,74.

Hanisch et al.⁴³ first provided evidence for considerable vertical bone gain in the subantral space following surgical implantation of rhBMP-2, consequently allowing for the placement and osseointegration of dental implants in the cynomolgus monkey. Bilateral rhBMP-2/ACS (rhBMP-2 at 0.4 mg/ml) and buffer/ACS (control) constructs were surgically implanted into the subantral space in four animals (Fig. 5). Following a 12-week healing interval, dental implants (Nobel Biocare) were placed into the augmented subantral space and into native bone anterior to the sinus. Histologic analysis was performed after an additional 12 weeks of healing. Significantly greater bone gain was observed in rhBMP-2 augmented sites than in controls (6.0 ± 0.3 compared with 2.6 ± 0.3 mm, respectively; p < 0.002). Bone density and bone-implant contact were similar in rhBMP-2 augmented, surgical control, and the native bone anterior to the augmented subantral space.

Nevins et al.⁴¹ and Kirker-Head et al.⁴² also evaluated sinus augmentation using rhBMP-2. Contralateral sites in six Alpine-Saanen goats were implanted with rhBMP-2/ACS (1.7 mg rhBMP-2) or buffer/ACS. The animals were euthanized at 4, 8, or 12 weeks after surgery. Computerized tomography (CT) over the 3-month healing interval suggested increasing radiopacity in sites receiving rhBMP-2/ACS compared with those receiving buffer/ACS. Histologic evaluation revealed increased amounts of new bone in sites receiving rhBMP-2 compared with controls, with an apparent normal progression of bone formation. Clinical observations did not reveal any serious adverse reactions toward the rhBMP-2 construct including toxicity or significant immunologic reactions.

The studies by Hanisch et al.⁴³, Nevins et al.⁴¹, and Kirker-Head et al.⁴² demonstrate that the implantation of rhBMP-2/ACS is a safe and effective treatment allowing for the placement and osseointegration of endosseous dental implants. This treatment negates the need for autologous bone grafts or bone derivatives or substitutes for sinus augmentation procedures.

Peri-Implantitis Defects

Hanisch et al.⁴⁷ were the first to show bone fill and renewed bone-implant contact (dental implant re-osseointegration) in bone defects resulting from long-term peri-implant infection (peri-implantitis). Ligature-induced peri-implantitis lesions were created around hydroxyapatite-coated titanium dental implants in the posterior mandible and maxilla over 11 months in four adult Rhesus monkeys. The induced peri-implantitis lesions exhibited a microbiota similar to that of advanced human peri-implantitis and periodontal disease and a complex, vertical-horizontal, defect morphology⁷⁵. At defect reconstruction (Fig. 6), the defects were surgically debrided and the implant surfaces were properly cleaned prior to surgical implantation of rhBMP-2/ACS (rhBMP-2 at 0.4 mg/ml). Control defects in contralateral mandibular and maxillary jaw quadrants received buffer/ACS. Histometric analysis performed following a 16-week healing interval revealed a 3-fold greater vertical bone gain in rhBMP-2 treated defects than in controls (p < 0.01). rhBMP-2 treated defects exhibited convincing evidence of re-osseointegration.

The results from this demanding nonhuman primate model suggest that surgical implantation of rhBMP-2 may have significant clinical utility in the reconstruction of peri-implantitis defects and of alveolar defects of lesser complexity.

Functional Loading

Jovanovic et al.⁴⁸ showed that rhBMP-2 induces normal physiologic bone, allowing for the installation, osseointegration, and long-term functional loading of titanium dental implants. Mandibular, alveolar ridge, full-thickness, 15 x 10-mm saddle-type defects, two per jaw quadrant, were surgically induced in six young adult American foxhounds. The defects were immediately implanted with rhBMP-2/ACS (rhBMP-2 at 0.2 mg/ml). Healing was allowed to progress for 3 months, when titanium dental implants (Nobel Biocare) were installed into the rhBMP-2 induced bone and into the adjacent resident bone. After 4 months of osseointegration, the implants were exposed to receive abutments and prosthetic reconstruction (Fig. 7). The prosthetically reconstructed implants were exposed to functional loading for 12 months, and the animals were euthanized for histometric analysis. The rhBMP-2 induced bone exhibited features of the resident bone, including a re-established cortex. Dental implants exposed to functional loading for 12 months exhibited some crestal resorption. The implants exhibited a mean bone contact approximating 50% in rhBMP-2 induced bone compared with 75% in resident bone. There were no significant differences between dental implants placed into rhBMP-2 induced bone and resident bone for any parameter.

Although previous preclinical studies have convincingly demonstrated clinically relevant alveolar bone augmentation following surgical implantation of rhBMP-2 and dental implant osseointegration, this study is the first to show the functional utility of rhBMP-2 induced bone in implant dentistry.

Conclusions

Preclinical studies have shown that rhBMP-2 induces normal physiologic bone in clinically relevant defects in the craniofacial skeleton. The newly formed bone assumes characteristics of the adjacent resident bone and allows placement, osseointegration, and functional loading of dental implants. Clinical studies optimizing the dose, mechanism of delivery, and conditions for stimulation of bone growth will bring about a new era in implant dentistry. The ability to predictably promote osteogenesis through the use of rhBMP-2 technology is not far from becoming a clinical reality and will no doubt have a profound effect on the way in which dentistry is practiced.

Note: Earlier versions of this text have been published. The text has undergone several revisions and updating for reviews in journals and book chapters.

References

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