Dental Graft Materials

6.620.

Dental Graft Materials

C Knabe, Philipps University Marburg, Marburg, Germany P Ducheyne, University of Pennsylvania, Philadelphia, PA, USA M Stiller, Charite´ – University Medical Center Berlin, Berlin, Germany ã 2011 Elsevier Ltd. All rights reserved.

6.620.1. 6.620.2. 6.620.2.1. 6.620.2.2. 6.620.2.3. 6.620.2.4. 6.620.2.5. 6.620.2.6. 6.620.2.7. 6.620.2.8. 6.620.2.9. 6.620.2.10. 6.620.2.10.1. 6.620.2.10.2. 6.620.3. 6.620.3.1. 6.620.3.2. 6.620.3.2.1. 6.620.3.2.2. 6.620.3.2.3. 6.620.3.2.4. 6.620.3.2.5. 6.620.3.2.6. 6.620.3.2.7. 6.620.4. References

Introduction Categories of Dental Grafting Materials Hydroxyapatites TCP Ceramics Bioactive Glass 45S5 Calcium Carbonate Biphasic HA TCP Materials Demineralized Freeze-Dried Bone Allografts and Mineralized Freeze-Dried Bone Allografts Polymer-Based Scaffolds for Craniofacial Tissue Engineering Bone Grafting Cements Combination of Bone Grafting Materials with Platelet-Rich Plasma Combined Use of Grafting Materials and Growth Factors or Other Biologicals Growth factors Enamel matrix derivative Requirements and Novel Developments for Dental Graft Materials Requirements for Dental Graft Materials Novel Developments for Dental Graft Materials Calcium alkali orthophosphate materials The effect of calcium-alkali-orthophosphate ceramics on the expression of the osteoblastic phenotype in vitro The effect of calcium alkali orthophosphates on bone formation and osteoblastic phenotype expression in vivo The effect of calcium alkali orthophosphate ceramics on cell adhesion and intracellular signaling mechanisms The effect of calcium alkali orthophosphate-based bone substitute cements on bone formation and osteogenic marker expression in vivo The effect of b-TCP particles with varying porosity on osteogenesis after sinus floor augmentation in humans Three-dimensional calcium-alkali-phosphate-based scaffolds for bone tissue engineering Summary

Abbreviations BG45S5 BMP CT DFDBAs FDA

6.620.1.

Bioactive glass 45S5 Bone morphogenetic protein Computed tomography Demineralized freeze-dried bone allografts Food and Drug Administration

Introduction

The use of oral implants has become a common treatment to replace missing or lost teeth.1,2 When teeth are missing, the surrounding bone and soft tissue is challenged as a result of the natural resorptive process subsequent to extraction. Furthermore, the prosthodontic requirements for the design of the implant superstructure (rather than the bone volume available) dictate the position in which the dental implants have to be placed. This has been called ‘restoration-driven’ implant placement.1,3–5 Consequently, resorption of the alveolar ridge after tooth extraction frequently mandates site development by augmentation before implants can be placed.1,6–8

HA MFDBA PRP rhBMP TCP TMJ

305 306 306 306 307 307 307 307 308 309 309 309 309 310 310 310 310 310 311 312 314 314 315 318 318 319

Hydroxyapatite Mineralized freeze-dried bone allografts Platelet-rich plasma Recombinant BMP Tricalcium phosphate Temporomandibular joint

The current gold standard for bone reconstruction in implant dentistry and craniomaxillofacila surgery is the use of autogenous bone grafts.9–15 Among the various techniques to reconstruct or enlarge a deficient alveolar ridge, the concept of guided bone regeneration (GBR)12 has become a predictable and well-documented surgical approach.11 The need for localized ridge augmentation prior to the placement of dental implants has been one of the clinical indications for GBR.12 At present, autogenous bone grafts are preferably combined with barrier membranes.9,11,16 These autografts have been used to reduce the defect volume, thereby stabilizing the blood clot,17 and to support the membrane as a space-maintaining device,

305

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thus preventing their collapse into large defects.12,13,18,19 Furthermore, augmentation of the maxillary sinus floor with autogenous bone grafts has become a well-established preimplantology procedure for alveolar ridge augmentation of the posterior maxilla.20,21 The main disadvantages of autogenous bone grafts have been the need for an additional surgical site, increased donor site morbidity, insufficient volume of (intraorally) harvested bone, and the need to use general anesthesia for extraoral bone harvesting.15,22–25 Using biodegradable bone substitutes as a membrane-supporting device would simplify GBR, as it avoids second-site surgery for autograft harvesting.9,13 This is also true for sinus floor elevation procedures.22,23,25 On account of the significant increase in dental implants placed and also in alveolar ridge augmentation procedures performed over the last two decades, there also has been an ever-increasing demand for adequate bone grafting materials for implant dentistry. These bone substitute materials should undergo remodeling and substitution by newly formed functional bone tissue in view of placing dental implants in such augmented sites.9,26–33 Bioactive calcium phosphate ceramics and bioactive glasses are candidate biomaterials which qualify as bone substitutes for this kind of application, as they are widely used in orthopedics.34–38 Alloplastic bone substitute materials are superior to freeze-dried human allografts due to their safety in terms of disease transmission and immunological aspects.9,24,39 Among the ceramics most commonly investigated for use in bone regeneration are b-tricalcium phosphate (b-TCP),36,37,40 hydroxyapatite (HA),37,41–44 and bioactive glass.34,35,45 All of these materials are biocompatible37,38 and osteoconductive.33–35,37,46–51 However, they differ considerably in the rate of resorption and in the rate of bone formation at their surface. Dense HA ceramics resorb very slowly compared to b-TCP37,42,52 and bioactive glass.34,35,50,53

6.620.2.

Categories of Dental Grafting Materials

As mentioned earlier, the majority of the dental grafting materials are calcium phosphate-based. Various HA- and TCP-based dental grafting materials40,54–62 as well as bioactive glasses and glass ceramics63–65 have been investigated and proposed as therapies to augment alveolar bone and to promote periodontal regeneration since the 1970s.

6.620.2.1. Hydroxyapatites Numerous HA-based grafting materials were developed over the last decades. These include HAs, fluorohydroxyapatites, and apatites of coralline origin,27,28,66–84 synthetic HAs41 including nanocrystalline HAs such as an aqueous paste of synthetic nanoparticular HA85–87 as well as bovine deproteinized bone xenograft particles.88–94 Most of these materials have been shown to be osteoconductive.85–87,93,95,96 However, none of these materials exhibit a high biodegradability.85–87,9697 Typical studies report excellent osteoconductivity.18,30,70,71,86,87,93,97–110 In this regard, one of the porous bovine-derived HAs that closely resembles HA of bone, namely Bio-Oss™, has been extensively reported in the scientific literature. Its morphology resembles that of cancellous bone. Its excellent osteoconductive properties have

been described in numerous in vivo preclinical and clinical studies.18,30,70,71,93,97–112 It has been shown, however, that biopsies sampled 20 months after implantation in the human sinus floor still consisted of 29% residual grafting material, which showed close apposition to the newly formed bone.97 With this material also three-dimensional (3D) cancellous blocks are available for the purposes of bone tissue engineering. Various HA block grafts have also been proposed for reconstruction of contour and discontinuity defects in maxillofacial surgery by transplantation of HA-bone composite grafts113–115 and for use as scaffolds in bone tissue engineering procedures.116,117 More recent developments include a peptide-modified HA118–121 named PepGen P-15. P-15 is a highly conserved linear peptide with a 15 amino acid sequence identical to the sequence contained in the residues 766–780 of the a-chain of type I collagen. PepGen P-15 (Dentsply Friadent, Mannheim, Germany) is a combination of a bovine bone-derived hydroxypaptite with P-15. This material has been shown to accelerate bone formation at its surface at the early stages of wound healing; however, after 6 months, no difference compared to the native HA was noted.120 Another development is the use of a nanocrystalline HA embedded in a silica matrix, which is a synthetic HA produced by a sol–gel process in the presence of SiO2. The use of this material is being advocated as a dental graft material, as it has been shown to exhibit good osteoconductivity and to support neovascularization.85,122–125 However, it displays a limited biodegradability.85

6.620.2.2. TCP Ceramics While early b-TCP ceramic products were plagued by insufficient phase purity and inhomogenous solubility characteristics, which led to varying biological and clinical outcomes, more recent improvements in b-TCP ceramics include products with a high phase purity (>99%) and homogenous solubility characteristics, so as to prevent premature separation of microparticles from the structural compound.126 In the past, these types of microparticles have been shown to elicit inflammatory tissue responses.126 Furthermore, the use of TCP particles with increased porosity (65% vs. 35% porosity) has been proposed in order to increase the biodegradability.126–132 These particles exhibit a material structure with pores on different length scales micropores (size: <50 mm), mesopores (size: 50–100 mm), and macropores (size: 100–500 mm), designed to enhance the degradation process. This structure allows for a reduced bulk density. The microporosity allows circulation of biological fluids, increases the specific surface area, and thus accelerates the degradation process. The interconnectivity of the pores creates a capillary force that actively draws cells and nutrients in the center of the particles. The macroporosity is created to encourage the ingrowth of bone by permitting penetration of cells and vascularization.126 Over the last decade, numerous studies have been published regarding the in vivo preclinical and clinical performance of TCP ceramic granules in implant dentistry, confirming the excellent osteoconductivity of various TCP ceramic products (Figure 1).9,13,33,46,47,50,98,127,128,132–154 Long-term results in human patients were shown to be equal to those of autogenous bone grafts.140,155 Recent developments also

Dental Graft Materials

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enhance the osteogenic effect of BG45S5 granules of a narrow size range.175

C

6.620.2.4. Calcium Carbonate

OB

B

200 mm

Figure 1 Resin-embedded human biopsy stained immunohistochemically for osteocalcin after deacrylation. The biopsy was sampled 6 months after augmentation of the sinus floor with b-tricalcium phosphate (b-TCP) particles (C) with 35% porosity. Intense staining of cells and unmineralized fibrous matrix (of the osteogenic mesenchym) lining the newly formed bony trabeculae (B) that are in contact with the TCP particle (C) is evident (arrow). OB (arrow head) – intensely stained osteoblast. These findings demonstrate the good bone-bonding properties of TCP. Furthermore, 6 months after implantation, bone formation and matrix mineralization are still actively progressing in the tissue surrounding the TCP particles. Undecalcified sawed section counterstained with hematoxylin. Bar ¼ 200 mm.

include the clinical use of b-TCP block grafts in implant dentistry and maxillocraniofacial surgery.156 Furthermore, the use of TCP ceramics with zinc or silica additives has been proposed with the goal to further enhance the osteogenic effect of TCPs as well as their mechanical properties.157–159 Even more recently, a TCP putty-like material with kneadable properties has been introduced. It consists of pure, synthetic b-TCP granules of a wide range of particle sizes in a fermented sodium hyaluronate carrier. This material, however, does not set in situ, but with respect to surgical handling is advantageous over granules for a number of surgical uses. Furthermore, autologous blood or its derivates, bone marrow aspirate or bone chips as well as antibiotics can easily be added to the material prior to the surgical application (Figure 2).

6.620.2.3. Bioactive Glass 45S5 Bioactive glass (BG45S5) granules have been used for alveolar ridge augmentation and periodontal repair for more than a decade, and their excellent osteoconductivity, bone-bonding properties, and stimulatory effect on bone formation have been demonstrated by numerous in vivo preclinical and clinical studies since.34,35,50,53,64,129,130,136,146,160–174 Among the various bone grafting materials used in implant dentistry, BG45S5 granules of a narrow size range were the first material, for which extensive and comprehensive histological data regarding their biodegradability derived from human biopsies were reported.50,136,146 These biopsies were sampled at implant placement in clinical studies. Furthermore, the use of preexcavated granules has been proposed in order to even further

Over the last two decades, a madroporic coralline calcium carbonate material (product name: Bio-coral) has been proposed as bone grafting material in implant dentistry, periodontology, and oral and maxillofacial surgery.176–190 This material has been shown to exhibit good osteoconductive properties in combination with a limited biodegradability.178,182 Furthermore, promising long-term clinical results have been demonstrated with respect to bony regeneration of infrabony periodontal defects.189 More recently, this material has also been used for fabricating scaffolds for cell seeding and tissue engineering.190,191

6.620.2.5. Biphasic HA TCP Materials Over the last 5 years, the use of synthetic biphasic HA TCP materials has been introduced for alveolar ridge augmentation. For these materials, a decreasing biodegradability has been demonstrated with increasing HA content.192 A fully synthetic biphasic calcium phosphate consisting of a mixture of 60% HA and 40% of b-TCP (product name: Straumann Bone Ceramic) has been examined in in vivo animal and clinical studies. This material has been shown to display good osteoconductivity and support new bone formation.100,103,192–196 Although this material has been shown to be not fully resorbable, it exhibited greater biodegradability than the bovine-derived HA material Bio-Oss; this, however, was associated with a less favorable bone-bonding behavior.100

6.620.2.6. Demineralized Freeze-Dried Bone Allografts and Mineralized Freeze-Dried Bone Allografts Demineralized freeze-dried bone allografts (DFDBAs) and mineralized freeze-dried bone allografts (MFDBA) have been proposed as substitutes for autologous bone in implant dentistry, periodontology, and oral surgery for more than two decades.162,164,168,197–230 These materials are inferior to synthetic materials in terms of risk of disease transmission and immunological challenges.9,24,231 They have been widely used in the United States, while in several European countries, their use has not been approved for dental applications. Furthermore, conflicting results regarding their osteoconductivity and potential to support new bone formation in clinical settings have been reported.199,218,223,225,228 Schwartz et al.223 showed that a wide variation in commercial bone bank preparations of DFDBA existed and that the ability to induce new bone formation also varied widely. In addition, commercial DFDBA differed in both size and ability to induce new bone formation, but the two were not related. The authors also pointed out that methods or assays for evaluating the ability of DFDBA to induce new bone should be developed and standardized.223 In addition, these materials are not fully resorbable, even 4 years after implantation, residual grafting material was present in the human case.225

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Dentistry, and Oral and Maxillofacial Surgery

(a)

(b)

(c)

Figure 2 Clinical image of maxillary sinus floor augmentation using a tricalcium phosphate (TCP) putty material (a) sinus floor prior to augmentation, (b) TCP putty material which has been mixed with veinous blood, and (c) sinus floor after application of the TCP putty material.

6.620.2.7. Polymer-Based Scaffolds for Craniofacial Tissue Engineering Over the last two decades, there have been increasing efforts to develop adequate scaffolds and concepts for bone-tissue engineering in the craniomaxillofacial domain.232 However, only few of these concepts have reached the clinical arena so far. In 2001, the ‘bioseed oral bone’ concept was introduced. Cell-fibrin constructs, that is, pellets made from polylactide, polyglycolide, and/or poly-p-dioxanon, which were coated with fibrin glue and cultured for 4–6 weeks with autologous periost-derived osteoblasts, were used for sinus augmentation of the severely resorbed posterior maxilla.233–235 In clinical studies, this approach resulted in the formation of lamellar bone within 4 months after sinus floor augmentation, thereby providing a reliable basis for dental implant placement. The drawbacks of this approach were the high costs involved and the 4–6 week waiting period between the harvesting of the periosteum and the delivery of the cell-seeded pellets for sinus floor augmentation surgery. This concept, however, is one of the few tissue engineering approaches that has found somewhat wider clinical use in implant dentistry so far. Hollister et al.236–238 developed an image-based and integrated approach for engineering craniofacial scaffolds. This design/fabrication approach can create scaffolds with designed porous architecture to match craniofacial anatomy. These scaffolds were also designed to support bone regeneration for craniofacial reconstruction and, furthermore, to exhibit mechanical properties in the range of those of craniofacial tissue. Using image-based design (IBD) and computer software, precisely sized and shaped scaffolds created via selective laser sintering of polycaprolactone were developed for osseous tissue regeneration.239 This way, polycaprolactone was used to create a condylar ramus unit (CRU) scaffold for application in

temporomandibular joint (TMJ) reconstruction. These scaffolds were used successfully for the reconstruction of the mandibular ramus and TMJ in minipigs.239 IBD and solid free-form (SFF) fabrication was also used to generate scaffolds that are load bearing and match patient and defect site geometry. Using this methodology, poly-L-lactic acid/HA composite scaffolds which were differentially seeded with fibroblasts transduced with an adenovirus expressing bone morphogenetic protein-7 (BMP-7) in the ceramic phase and fully differentiated chondrocytes in the polymeric phase were developed in order to regenerate osteochondral defects and, ultimately, the TMJ.240 3D polycaprolactone scaffolds with controlled microarchitecture were developed for fabricating customized cell-polymer constructs for the repair of calvarial defects using calvarial osteoblasts and mesenchymal progenitor cells in combination with these scaffolds and fibrin glue.241,242 Furthermore, bonemarrow-coated polycaprolactone scaffolds were successfully used for the reconstruction of orbital and craniofacial defects in pigs.243,244 More recently, polycaprolactone-20% TCP scaffolds were utilized in a pilot study in combination with platelet-rich plasma for the treatment of critical-sized defects of the mandible.245 Also, a polycaprolactone-TCP/collagen scaffold loaded with recombinant BMP (rhBMP) was developed for the repair of calvarial bone defects, and the stimulation of healing within a rat calvarial defect was demonstrated.246 Moreover, very recently, successful use of a customized polycaprolactone TCP scaffold fabricated by the rapid prototyping technology fused deposition modeling (CAD/CAM) for calvarial reconstruction in a human case was described.247 Hydrogels were proposed as scaffolds for craniofacial bone tissue engineering and delivery of stem cells and growth factors.248–251 Very recently, calcium cement scaffolds with mesenchymal stem cells were developed for craniofacial tissue

Dental Graft Materials engineering.252,253 Furthermore, the use of rhBMP-2 loaded porous calcium phosphate cements was proposed for craniofacial tissue engineering.254 With most of these tissue engineering approaches, however, controlled clinical studies will have to follow for these concepts to proceed to the clinical arena. Current research efforts in craniofacial tissue engineering also deal extensively with biomaterial matrices and scaffolds with controlled release of signaling cues for stem cells, and integrated tissue engineering approaches255 as well as with ‘guided interplay’ between biomaterial scaffolds, growth factors, and local cell populations toward the restoration of the original architecture and function of complex tissues.256,257 Furthermore, various approaches to pursue adequate vascularization of bioengineered constructs for repair of extensive discontinuity bone defects are being investigated.258–263 This is in addition to optimizing pore-size distribution and poregeometry of various scaffolds.

6.620.2.8. Bone Grafting Cements To fill bone defects, currently available calcium phosphate bone grafting materials are mainly applied as granules. Bone substitutes with improved surgical handling properties include injectable and moldable calcium phosphate cements in paste or putty form that can be introduced into a bony defect with a spatula or injected with a syringe; they subsequently set in situ. These properties make this an intriguing group of materials for bone reconstruction, as by this way, these materials exhibit advantageous surgical handling properties for a number of surgical applications. Consequently, over the last two decades, the use of calcium phosphate-based cements and in a few cases, that of polymer-based cements, have been proposed for craniofacial bone grafting.264–288 With most currently available cements, however, HA or calcium-deficient HA289–292 is formed during setting, which limits their biodegradability.289 This has initiated efforts to develop resorbable cements with improved biodegradability which form TCP or calcium alkali orthophosphates during setting.261,293–298

6.620.2.9. Combination of Bone Grafting Materials with Platelet-Rich Plasma Numerous clinical and animal studies have explored the combined use of bone grafting materials and platelet-rich plasma [PRP] with the intent to enhance bone regeneration. The majority of the studies, however, failed to demonstrate an additional benefit when platelet-rich plasma [PRP] was used in addition to various bone grafting materials. As such, these studies did not show a significant improvement of clinical and histological outcomes.279,280,299–302

6.620.2.10. Combined Use of Grafting Materials and Growth Factors or Other Biologicals 6.620.2.10.1. Growth factors Over the last two decades, numerous preclinical studies have explored the use of rhBMP-2 and -7 for bone regeneration in craniomaxillofacial applications.254,303–321 Furthermore, absorbable collagen sponges and collagen sponges with

309

incorporated HA and TCP particles were proposed as carriers for recombinant human BMP-2, -7, -10 as well as nerve growth factor b for use in craniofacial bone regeneration.322–330 In addition, the use of recombinant human platelet-derived growth factor BB (rhPDGF-BB) and transforming growth factor b (TGF-b) have been investigated.254,331 Preclinical studies have shown that rhBMP-2 and -7 induces normal physiologic bone in clinically relevant defects in the craniofacial skeleton. The newly formed bone develops properties similar to those of the adjacent resident bone and allows placement, osseointegration/re-osseointegration, and functional loading of endosseous implants. Over the last 6 years also, some clinical reports and studies have been published.263,303,304,332–337 A very visible report in this regard was the use of rhBMP-7 for preparing a customized vascularized tissue-engineered mandible, with the patient being used as a living bioreactor.263,335 In this case, rhBMP-7 was combined with bovine-derived HA xenograft particles, bone morrow aspirate, and a titanium mesh shaped after the patient’s mandible. However, further clinical studies optimizing dose and delivery technologies,338,339 including the development of scaffolds with controlled release properties, as well as optimizing conditions for stimulation of bone growth, are needed. The use of rhBMP-2 and -7 for craniomaxillofacial application only received approval in Europe and by the US Food and Drug Administration (FDA) in 2005.340 Furthermore, the aspect of the high costs involved in the use of these growth factors has had a somewhat limiting effect with respect to achieving wide clinical use in implant dentistry and other craniomaxillofacial applications. In 2008, the FDA341 published a safety review communication regarding the use of a PDGF-containing product ‘Regranex’ in cancer patients. An epidemiologic study that was performed to investigate the possibility of an increased risk of cancer in patients with diabetes who applied the product ‘Regranex’ (a topical medicine) directly to their foot and leg ulcers showed that the risk of death from cancer in patients who used three or more tubes of Regranex was 5 times higher than in those patients who did not use Regranex. However, the risk of getting new cancers among Regranex users was not increased compared to nonusers. As BMPs also enhance the vascularization of the regenerated tissue similar to PDGF, this FDA safety review communication raised major concerns with respect to the use of growth factors such as BMPs and PDGF for bone reconstruction and bone tissue engineering in tumor patients. It is useful to point out that tumor patients with major squamous cell carcinomas comprise a major patient population in maxillofacial surgery. This group of patients requires extensive surgery for bone reconstruction of the bone discontinuities arising from tumor resection in major portions of the mandible or maxilla. Thus, the question whether the use of growth factors for bone tissue regeneration in tumor patients increases the risk of relapse or metastases, warrants further investigation. In 2008, the FDA342 published a public health notification regarding life-threatening complications associated with recombinant human BMP application in cervical spine fusion, which involved airway obstruction and compression of major blood vessels and nervous structures in the head-neck region caused by extensive swelling, thereby resulting in patient

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Dentistry, and Oral and Maxillofacial Surgery

fatalities. Consequently, preclinical and clinical studies are needed to ensure that this type of complication can reliably be avoided when using BMPs for major mandibular or craniofacial bone reconstruction. Recently, a b-TCP coated with recombinant human growth and differentiation factor 5 (rhGDF-5) was developed, and the results of a prospective, randomized multicenter clinical trial were recently reported. The authors investigated the potential benefit of rhGDF-5 coated onto b-TCP (rhGDF-5/b-TCP) to support bone formation after sinus floor augmentation.343 rhGDF-5/b-TCP was found to be as effective for sinus floor augmentation as the control treatment with autologous bone, which was mixed with b-TCP. As very low amounts of anti-rhGDF-5 antibodies were transiently detected in some patients who received rhGDF-5, further investigations regarding efficacy and safety will be carried out in larger patient populations.343

6.620.2.10.2. Enamel matrix derivative Some clinical and preclinical animal studies examined the combined use of various bone grafting materials and an enamel matrix derivative (EMD) for bone and periodontal regeneration.221,331,344–346 In these studies, a trend was observed toward more bone formation and improvement in clinical outcomes, when EMD was combined with freeze-dried bone allograft, bovine-derived bone xenograft, and bioactive glass.221,331,344–346 However, larger prospective controlled clinical trials are needed to confirm these findings.221,345,346 Evaluation of various dental grafting materials by comparing them with one another is fraught with uncertainty, as there are only few comparative animal and controlled clinical studies that compare several of these materials in the same study or in studies using identical study designs.347 Furthermore, in order to ultimately prove the superiority of any of these materials or any of these tissue engineering approaches to any other materials/approaches or to autogenous bone graft as the gold standard, long-term, that is, 2-, 5-, and 10-year data from prospective controlled clinical studies would need to be provided, which is a gargantuan task. Such studies would need to show greater regenerated bone volume and higher survival rates for dental implants placed in areas augmented with these grafting materials or tissue engineering approaches, in comparison to areas in which autogenous bone, any other grafting material, or any other tissue engineering approach was used.

6.620.3. Requirements and Novel Developments for Dental Graft Materials 6.620.3.1. Requirements for Dental Graft Materials As outlined earlier, over the last decade, the use of TCP and BG45S5 particles as alloplastic bone graft materials for alveolar ridge augmentation and sinus floor elevation procedures has received increasing attention in implant dentistry.33,46,47,50,136,146,150,151,155 As also outlined earlier, the same is true for bovine deproteinized bone xenograft particles (product name: Bio-Oss®) that closely resemble the native HA of bone, have excellent osteoconductive properties, and exhibit a limited biodegradability.18,30,70,71,97–110 Even with b-TCP, biodegradation has been reported to be

incomplete 9.5 months after grafting in the human mandible.47 Histologic examination of these biopsies revealed that 34% of the biopsy consisted of mineralized bone tissue and 29% of remaining b-TCP.47 Biopsies sampled at 8 months after sinus floor augmentation consisted of 20% mineralized bone and 44% remaining b-TCP.47 With respect to BG45S5 particles of a narrow size range, Tadjoedin et al.50 reported that after grafting in the human sinus floor, BG particles appeared to resorb within 1–2 years. This was by dissolution rather than by osteoclastic activity.50 It is useful to consider, though, that at those time points, these particles are no longer original glass, but calcium phosphate formed in situ out of the glass. When using mixtures of 80%, 90%, and 100% BG particles and 20%, 10%, and 0% autogenous bone, histomorphometric analysis of biopsies harvested at 4, 6, and 15 months showed that the grafts consisted of 27% mineralized bone tissue at 4 months, 36% bone at 6 months, and 42% bone at 15 months. The volume of the biologically transformed BG particles in the biopsies decreased from 29% at 4 months to 15% at 6 months and 8% at 15 months.50 Thus, compared to the bone substitute materials which are currently clinically available,47,50,85,97,100,136,146 there is a significant need for bone substitute materials that degrade more rapidly but still stimulate osteogenesis at the same time.9,26–32 Particularly in non-load-bearing applications such as alveolar ridge augmentation, a biomaterial used as a bone substitute should be a temporary material serving as a scaffold for bone remodeling. The material must degrade in a controlled fashion into nontoxic products that the body can metabolize or excrete via normal physiological mechanisms.37 Moreover, this substance should be resorbable and should undergo remodeling and substitution by newly formed functional bone tissue in view of placing dental implants in such augmented sites.9,26–33 This has initiated an ever-increasing search for bioactive, rapidly resorbable bone grafting materials that exhibit good bone-bonding behavior by stimulating enhanced bone formation at the interface in combination with a high degradation rate. Another important consideration when using grafting materials for sinus floor and alveolar ridge augmentation is the stability of the height and volume of the regenerated bone over time. Consequently, with an ideal grafting material, reduction in height and volume should be minimal and should not exceed that in the presence of autogenous bone grafts. Furthermore, as outlined previously, dental graft materials have been most widely used as granules. However, because of the increasing number of surgical techniques and procedures used for bone regeneration in oral and craniomaxillofacial surgery, there has been a growing demand for resorbable bone grafting materials that can be either injected into defects in paste form or applied as putty that sets in situ. In addition, there is equal demand for biodegradable 3D blocks and scaffolds for bone tissue engineering purposes.

6.620.3.2. Novel Developments for Dental Graft Materials 6.620.3.2.1.

Calcium alkali orthophosphate materials

Thus, considerable efforts have been undertaken to produce rapidly resorbable bone substitute materials that exhibit both excellent bone-bonding behavior by stimulating enhanced

Dental Graft Materials

bone formation and a high degradation rate. This has led to the development of a series of novel, bioactive, rapidly resorbable, glass ceramic calcium-alkali orthophosphate materials.348–350 These are glassy/crystalline calcium alkali orthophosphates which exhibit stable crystalline Ca2KNa(PO4)2 and Ca10[K/ Na](PO4)7 phases.348–351 These materials were designed to exhibit a higher degree of biodegradability compared to TCP348,349,352,353 and therefore could serve as excellent alloplastic materials. In fact, these materials have a higher solubility than TCP. Another approach to increase the solubility and biodegradability of calcium-orthophosphates is by adding diphosphates (Ca2P2O7). Diphosphates have a higher solubility than orthophosphates and they are transiently formed in vivo during the mineralization process of the bone matrix. A number of in vitro and in vivo studies, which examined calcium phosphates to which diphosphates were added, yielded encouraging results.354–357 This prompted Berger to synthesize a calcium alkali orthophosphate ceramic with a small portion of diphosphates.358 He reported that there was an additional effect on the dissolution rate compared to that of the calcium-alkali-orthophosphate. At this time, 3D scaffolds have been fabricated from these calcium alkali orthophosphate ceramic materials, opening interesting perspectives for their use as tissue engineering scaffolds.

These studies showed that several calcium alkali orthophosphate materials supported osteoblast differentiation to a greater extent than did TCP.128,290,291,359 The composition of four of these calcium alkali orthophosphate grafting materials studied, GB14, GB9, GB9/25, and 352i, whose main crystalline phase is either the phase Ca2KNa(PO4)2348,349,351 or Ca10[K/Na](PO4)7358, is indicated in Tables 1 and 2. Glass ceramics GB14, GB9, and GB9/25 contain the crystalline phase Ca2KNa(PO4)2.348,349 They contain an amorphous phase, silica phosphate (GB9 and GB9/25), or magnesium potassium phosphate (GB14), respectively. Crystallization occurs spontaneously from the melt, and thus, these bioceramics can be fabricated easily. The dissolution rate of the calcium-alkali orthophosphates depends on the amount of added ions such as Na, K, or Mg. Importantly, GB 9/25358 also contains a small portion of diphosphates (Ca2P2O7), unlike GB9, which does not. This further increases the dissolution rate in comparison to this previously described GB9.290,348,349,360 More recently, it was demonstrated that the glass ceramic calcium alkali orthophosphate material GB9 had a significantly greater stimulatory effect on osteoblastic proliferation and differentiation when compared to b-TCP, preconditioned BG45S5, and other calcium-alkali-orthophosphate materials of varying composition, that is, GB14, GB9/25, and 352i (Table 1).128,290,359 45S5 discs were preconditioned by a two-step procedure, which resulted in the transformation of the BG surface into a crystalline, carbonated calcium phosphate apatite onto which serum proteins were adsorbed in a second step. Hence, the conditioning treatment of BG produced an in situ-formed calcium phosphate surface layer. Figure 3 shows that osteoblastic cells grown for 14 days on GB9 expressed significantly higher levels of the osteogenic markers type I collagen, alkaline phosphatase, osteopontin, osteonectin, and bone sialoprotein than when the same

6.620.3.2.2. The effect of calcium-alkali-orthophosphate ceramics on the expression of the osteoblastic phenotype in vitro In recent years, several studies examined the effect of rapidly resorbable calcium alkali orthophosphate bone substitute materials on the expression of osteogenic markers characteristic of the osteoblastic phenotype and compared this behavior to that of the currently clinically used materials b-TCP and BG45S5.

Table 1

311

Description of novel calcium-alkali-orthophosphate ceramic bone substitute materials, TCP, and bioglass 45S5

GB14

GB9

GB9/25

352i

b-TCP

Bioglass 45S5™

Calcium-alkaliorthophosphate: Ca2KNa(PO4)2 crystalline phase with a small amorphous portion containing magnesium potassium phosphate

Calcium-alkaliorthophosphate: Ca2KNa(PO4)2 crystalline phase with a small amorphous portion containing silica phosphate

Diphosphate containing calcium-alkaliorthophosphate: Ca2KNa(PO4)2 crystalline phase and Ca2P2O7

Diphosphate containing calcium-alkaliorthophosphate: Ca10[K/Na](PO4)7, crystalline phase with small addition of SiO2

Tricalciumphosphate Ca3(PO4)2

(Bioactive glass45S5) Composition (wt%): SiO2 45.0 CaO 24.5 P2O5 6.0 Na2O 24.5

Table 2

Composition of novel calcium-alkali-orthophosphate ceramic bone grafting materials, TCP, and bioglass 45S5

Bone grafting materials

CaO

P2O5

Na2O

K2O

MgO

SiO2

GB14 Ca1.8KMg0.4Na(PO4)2 GB9 Ca2KNa(PO4)2 þ Mg2SiO4 GB9/25 Ca2KNa(PO4)2 þ Mg2SiO4 Ca2P2O7 352i Ca10[K/Na](PO4)7 þ SiO2 TCP Ca3(PO4)2 Bioglass 45S5

30.67 32.25 29.25 40–45

43.14 40.81 44.81 45–48

9.42 8.91 8.41 5–8

14.32 13.54 13.04 1–2

2.45 2.57 2.57 1–1.5

1.92 1.92 1–2

24.5

6.0

24.5

45.0

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Absorbance = 405 nm

2.5 2.0 1.5 1.0 0.5 0.0 Col I

ALP TCP

OP OC Antibodies BG

GB14

GB9

ON GB9/25

BSP 352i

Figure 3 The temporal expression of osteogenic proteins by osteoblasts cultured on different calcium phosphate materials for 14 days. Intracellular protein expression by human osteoblasts is at 14 days of culture on tricalcium phosphate (TCP), bioactive glass 45S5 (BG) GB14, GB9, GB9/25, and 352i. Results are normalized to the internal control b-actin protein for each substratum. All values are meanstandard deviation of eight measurements. Col I, type I collagen; ALP, alkaline phosphatase; OP, osteopontin; OC, osteocalcin; ON, osteonectin; and BSP, bone sialoprotein.

cells were grown in parallel on b-TCP and BG 45S5. Furthermore, BG 45S5 and GB14 induced significantly greater expression of the majority of these osteogenic markers when compared to b-TCP.128,163

6.620.3.2.3. The effect of calcium alkali orthophosphates on bone formation and osteoblastic phenotype expression in vivo Correlating in vitro data with in vivo phenomena is important in order to test the hypothesis that enhanced osteoblastic cell differentiation in vitro leads to more and more expeditious and more copious bone formation at the bone–biomaterial interface in vivo. This includes (1) correlating quantitative expression of the osteogenic markers in vitro with the amount of bone formed after bioceramics implantation and (2) quantifying the expression of these markers in histological sections obtained from in vivo experiments in comparison to the expression of the various markers in vitro. To this end, a study was performed in which the effect of the same selection of bioactive ceramics (Table 1) on the expression of osteogenic markers was studied in vitro as well as in vivo.128–131,163,361 This required the development of an adequate hard tissue histology technique. Histological evaluation of the bone–biomaterial interface requires undecalcified poly(methylmethacrylate) (PMMA) sections. While various assays have been developed which permit studying the effect of calcium phosphate biomaterials on the expression of osteogenic markers in vitro,290,291,359,362 there have been considerable difficulties to visualize the expression of these markers in undecalcified implant material containing sections of bone obtained from in vivo studies.363 In recent years, a new technique has been developed that facilitates immunohistochemical analysis of osteogenic markers on undecalcified sawed sections of bone which contain ceramic implant materials.129,364 This rendered it possible to study the effect of ceramic bone substitute materials on osteoblast differentiation and tissue maturation on ex vivo specimens by visualizing active

osteoblasts in their different stages of differentiation at the bone–biomaterials interface. This experimental capability was in addition to visualizing the expression of various osteogenic markers in the mineralized and unmineralized extracellular matrix components.129,130 Utilization of this hard tissue technology rendered it possible to study the effect of identical bioactive ceramics on the expression of osteogenic markers in vitro and in vivo and to test the aforementioned hypothesis.130,163,298,361,365–367 In this study, calcium alkali orthophosphate ceramic bone substitute materials (Table 1) were implanted in the sheep mandible and sinus floor and compared to currently clinically used synthetic bone substitute materials (b-TCP, BG 45S5).130,131,163 These materials were selected, because previous in vitro studies demonstrated that they stimulated greater differentiation of osteoblasts compared to cells grown on TCP ceramic.128,290,359 The various calcium phosphate materials with a particle size range of 300–355 mm were implanted in the sheep mandible for 1, 4, 12, and 24 weeks with the goal to regenerate critical size membrane-protected defects as described by von Arx et al.9 Autogenous bone chips and empty defects, which were filled with collagen sponges, served as controls.130,163,361 This study examined the aforementioned calcium alkali orthophosphate materials GB9 and GB14. As described previously, GB9, followed by GB14, displayed a significantly greater stimulatory effect on osteoblast proliferation and differentiation in vitro compared to TCP, BG 45S5, and other calcium alkali orthophosphates.128,290,359 It was found that the in vitro findings correlated with enhanced bone formation and bone-particle-contact (i.e., bone-bonding behavior) in vivo (Figure 4(a) and 4(b)). This in its turn was associated with enhanced expression of type I collagen, osteopontin, osteocalcin, osteonectin, and bone sialoprotein in vivo (Figure 5(a) and 5(b)).130,361 This was associated with a significantly greater decrease in particle area fraction over time, that is, a significantly greater biodegradation (Figure 4(c)).130,361 Staining for tartrate-resistant

Dental Graft Materials

acid phosphatase showed that biodegradation of the various calcium alkali orthophosphates as well as TCP occurred by dissolution rather than by osteoclastic activity.130,163,361 Furthermore, it is noteworthy that GB9 displayed a significantly greater bone-particle-contact than all other calcium phosphates after only 4 weeks (Figure 4(b)). By 12 weeks, the defects that were augmented using GB9 showed greater bone formation in comparison to those defects that were augmented with autogenous bone chips.130,163 These findings are clinically very significant, by virtue of autogenous bone being the gold standard. BG 45S5 and TCP displayed good bone-regenerative capacities and bone-bonding behavior (Figures 4(a,b) and 6). However, the biodegradability was lower in comparison to GB9 (Figure 4(c)).130,163

With respect to augmentation of the ovine sinus floor, the materials GB9/25 and 352i were studied and compared to TCP. Among these materials, GB9/25 facilitated the greatest extent of bone formation (Figure 7(a)) in combination with the highest biodegradability (Figure 7(b)). This finding was in addition to a more enhanced effect on osteogenic marker expression (Figure 8). The studies summarized here demonstrate that among the various bioceramic bone grafting materials studied, the calcium alkali orthophosphate material GB9 displayed the greatest stimulatory effect on osteogenesis in vitro and in vivo, in combination with a high biodegradability, and that in this it was followed by the materials GB14 (Figure 9) and GB9/25.

100 90 80

Percent

70 60 50 40 30 20 10 0 12 weeks Bone area fraction

4 weeks (a)

24 weeks

TCP

BG

GB14

GB9

GB9/25

352i

Aut. bone

Collagen sponge

120 100

Percent

80 60 40 20 0 4 weeks

12 weeks

TCP

Figure 4 (Continued)

24 weeks

Bone-particle-contact

(b) BG

313

GB14

GB9

GB9/25

352i

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70 60 50 Percent

40 30 20 10 0 4 weeks

1 week

−10

12 weeks

24 weeks

Particle area fraction

(c) TCP

GB14

BG

GB9

GB9/25

352i

80 000.0 70 000.0 60 000.0

mm2

50 000.0 40 000.0 30 000.0 20 000.0 10 000.0 0.0 (d)

1 week

4 weeks

12 weeks

24 weeks

TCP

BG

GB14

GB9

GB9/25

352i

Figure 4 Histomorphometric results of mandibular defects augmented with various calcium phosphates after 1, 4, 12, and 24 weeks of implantation: (a) bone area fraction in the augmented defect area and (b) bone-particle-contact after 1, 4, 12, and 24 weeks of implantation. (c) Particle area fraction and (d) particle size. All values are meanstandard deviation of five measurements. TCP, tricalcium phosphate; BG, bioactive glass; aut. bone, autogenous bone chips; collagen, empty hole defects filled with a collagen sponge.

6.620.3.2.4. The effect of calcium alkali orthophosphate ceramics on cell adhesion and intracellular signaling mechanisms Cell adhesion and intracellular signaling events which are associated with this stimulatory effect of some of the calcium alkali orthophosphate materials on osteogenesis in vitro and in vivo are not yet fully understood. Developing this understanding has been hampered by the inadequacy of the experimental techniques that could be used. Recently, however, new molecular biological methods have been brought to bear on similar problems of osteogenesis and they have been combined with insight generated using powerful surface analysis techniques. Consequently, we performed a series of experiments to study the mechanisms by which these novel bioactive bone substitutes stimulate the intracellular signaling pathways that regulate osteoblast differentiation and cell

survival.131,163,298,366,368 This included investigating (1) solution-mediated surface transformations, (2) serum protein adsorption events, (3) integrin-mediated cell adhesion mechanisms, and (4) intracellular signaling mechanisms. These studies are described in greater detail in Chapter 1.114, Bioactivity: Mechanisms to which the interested reader is referred here.

6.620.3.2.5. The effect of calcium alkali orthophosphate-based bone substitute cements on bone formation and osteogenic marker expression in vivo Bone substitutes with improved surgical handling properties include moldable calcium phosphate cements in paste form that can be either introduced into a bony defect with a spatula or injected with a syringe; they subsequently set in situ, which makes them an attractive group of materials for bone reconstruction.163,295 Over the past decade, various bioactive

Dental Graft Materials

315

B GB 9

(a)

(b)

Figure 5 (a) Histomicrograph of GB9 particle 4 weeks after augmentation of a critical-size defect in the sheep mandible with GB9. Immunodetection of type I collagen in deacrylated sawed section of mandibular defect. Already after 4 weeks, the GB9 particle is almost fully covered by newly formed bone tissue. Strong staining of the newly formed bone matrix (B) in contact with the particle is present (block arrow). In addition, moderate cellular staining of osteocytes is visible (arrow heads). Moreover, strong staining of the osteoid and bone matrix lining the periphery of the newly formed bone is evident (small arrow). This is indicative that bone formation and matrix mineralization are actively progressing both at the surface of the degrading particle and on the periphery of the newly formed bone. These findings demonstrate the excellent bone-bonding and bone-regenerative capacities of the calcium alkali orthophosphate material GB9, which is capable of stimulating bone formation at its surface as early as 4 weeks after implantation. Undecalcified sawed section counterstained with hematoxylin. Bar ¼ 200 mm. (b) Immunodetection of osteocalcin in deacrylated section of mandibular defect 12 weeks after implantation of GB9. Histomicrograph of residual GB9 particle fragment and surrounding bone tissue. In general, only very few particle fragments are present at 12 weeks. Areas with strong osteocalcin staining of cells and mineralized bone matrix (arrow) in contact with the degrading particle which displays new bone formation in its center are present. These findings show that after 12 weeks, bone formation, matrix mineralization, and particle degradation are still actively progressing at the surface of this degrading particle. Undecalcified sawed section counterstained with hematoxylin. Bar ¼ 100 mm.

BG

Figure 6 Immunodetection of bone sialoprotein in deacrylated section of mandibular defect 24 weeks after augmentation of a critical-size defect in the sheep mandible with BG45S5. Histomicrograph of residual excavated BG45S5 particle and surrounding bone tissue. Areas with strong osteocalcin staining of cells and mineralized bone matrix in contact with the particle are present (arrowheads). This shows that bone formation, matrix mineralization, and particle transformation are still actively progressing at the surface of the degrading particle 24 weeks after implantation. Undecalcified sawed section counterstained with hematoxylin. Bar ¼ 200 mm.

calcium phosphate cements have been developed. In most cases, HA is formed during setting, which limits their biodegradability. More recent developments include cements which form calcium alkali phosphates during setting, which, as outlined previously, have been shown to have a stimulatory effect on osteogenesis in vitro and in vivo.128,130,163,290 These cements are designed for higher biodegradability.295 Thus, an animal study was performed to evaluate the effect of four calcium alkali orthophosphate cements as compared to TCP particles

on osteogenesis in vivo after implantation in critical size effects in rabbit femora for 1, 3, 6, and 12 months.261 Of the various bone substitute cements studied, the GB9 cement showed the best bone-bonding behavior and had the greatest stimulatory effect on bone formation and expression of osteogenic markers, while exhibiting the highest biodegradability.261 After 12 months, the original trabecular structure of the rabbit femur was almost fully restored (Figure 10). The biodegradability of the GB9-cement, however, was lower than that of the TCP granules.261 Hence, current efforts deal with increasing the porosity of the cement during setting in order to accelerate the biodegradation and studying moldable calcium-alkaliorthophosphate-based putty-like cements for restoring outer bony contours.261,294

6.620.3.2.6. The effect of b-TCP particles with varying porosity on osteogenesis after sinus floor augmentation in humans By virtue of the importance to correlate findings from preclinical (animal) studies with data from clinical studies, a study was conducted in which the effect of various TCP particulate bone grafting materials with varying porosity on bone formation and osteogenic marker expression was examined in biopsies sampled 6 months after sinus floor augmentation in patients.129,132,163 These studies demonstrated that greater porosity of the TCP particles (65% vs. 35% porosity) resulted in greater bone formation and particle degradation.129,132,163 Moreover, 6 months after implantation of both types of b-TCP particles, bone formation and matrix mineralization was still actively progressing in the tissue surrounding the particles (Figure 1). Both TCP materials supported bone formation and exhibited excellent bone-bonding behavior (Figure 1).

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90 80 70

Percent

60 50 40 30 20 10 0

4 weeks

12 weeks

24 weeks

Bone area fraction

(a)

TCP

352i

GB9/25

90 80 70 Percent

60 50 40 30 20 10 0 4 weeks

12 weeks

24 weeks

Bone-particle-contact

(b)

TCP

GB9/25

352i

80 70

Percent

60 50 40 30 20 10 0 4 weeks (c)

12 weeks Particle area fraction TCP

Figure 7 (Continued)

GB9/25

352i

24 weeks

Dental Graft Materials

317

90 000.0 80 000.0 70 000.0

µm2

60 000.0 50 000.0 40 000.0 30 000.0 20 000.0 10 000.0 0 (d)

4 weeks

12 weeks TCP

GB9/25

24 weeks 352i

Figure 7 Histomorphometric results of the ovine sinus floor augmented with various calcium phosphates after 1, 4, 12, and 24 weeks of implantation: (a) bone area fraction in the augmented sinus; (b) bone-particle-contact after 4, 12, and 24 weeks of implantation; (c) particle area fraction; and (d) particle size. All values are meanstandard deviation of five measurements. TCP, tricalcium phosphate.

GB 14 GB9/25

GB9/25

GB 14

B B Figure 8 Histomicrograph of GB9/25 particles 3 months after implantation in the ovine sinus floor directly underneath the Schneiderian membrane. Immunodetection of osteopontin (OP) in deacrylated sawed section of the sinus floor. After 12 weeks, new bone formation (B) is visible at the surface of these particles (GB9/25) in combination with strong expression of OP in the mineralized bone matrix (white arrows) at the particle surface as well as in the not-yet mineralized fibrous matrix (gray arrowheads) in contact with the degrading particles and particle fragments. In addition, osteoblasts with strong OP expression (black arrows) are visible at the surface of these particle fragments which show excellent bone-bonding behavior (green arrowheads). These findings demonstrate the excellent bone-bonding and bone-regenerative capacities of the calcium alkali orthophosphate material GB9/25, which is capable of stimulating bone formation at its surface in this location underneath the Schnederian membrane, that is, at a great distance from the original resident bone of the sinus floor. Undecalcified sawed section counterstained with hematoxylin. Bar ¼ 320 mm.

With the more porous particles, however, bone formation, osteogenic marker expression, and particle degradation had already reached a more advanced stage at 6 months. Consequently, a greater porosity appears to be advantageous for enhancing bone formation and particle degradation.129,163 These studies provide a valuable insight into the performance of synthetic bone graft materials in the human case and can

Figure 9 Immunodetection of bone sialoprotein in deacrylated section of mandibular critical-size defect 12 weeks after augmentation with GB14. Histomicrograph of residual GB14 particle fragments and surrounding bone tissue. Strong staining of osteoblasts (black arrows) is present at the particle surface in combination with moderate staining of the mineralized matrix (white arrows) in contact with these particles. This is indicative that after 12 weeks of implantation, bone formation, matrix mineralization, and particle degradation are still actively progressing at the surface of the degrading particles. Undecalcified sawed section counterstained with hematoxylin. Bar ¼ 100 mm.

form the basis for designing controlled clinical studies and selecting appropriate model parameters. Such studies are needed to advancing new bone grafting materials to the clinic in an evidence-based fashion. This clinical study also confirms the validity of any animal model by correlating in vivo animal findings to those obtained from human biopsies. In fact, excellent correspondence between animal data and clinical findings suggests comparable in vivo response, a useful finding for any animal study.129,130,163 Current research efforts focus on dealing with efforts toward personalized medicine questions, in that the influence of age, gender, and hormone status-related parameters in 120 boneregeneration patients (after sinus floor augmentation with TCP

318

Dentistry, and Oral and Maxillofacial Surgery

bone grafting materials) are examined. Such studies have the potential to provide powerful predictive tools toward the therapeutic outcome in any future patient and thereby facilitate tailoring individual bone augmentation treatment regimens for individual patients. Additional research involves computed tomography (CT) and Synchroton-CT methodology for volumetric determination of the newly formed bone and the residual

grafting material after sinus floor and alveolar ridge augmentation.132 This is described in greater detail in Chapter 3.304, Developments in High-Resolution CT: Studying Bioregeneration by Hard X-ray Synchrotron-Based Microtomography.

6.620.3.2.7. Three-dimensional calcium-alkali-phosphatebased scaffolds for bone tissue engineering Current research also deals with optimizing 3D calcium-alkaliphosphate-based scaffolds350 in which mesenchymal stem cells are cultured under perfusion bioreactor conditions for bone tissue engineering purposes, that is, repair of large segmental defects. This includes various approaches to achieve adequate angiogenesis. These scaffolds are fabricated from calcium alkali orthophosphates using a free form fabrication technique, that is, 3D printing as well as a method utilizing combustible polyurethane sponges as temporary templates (Schwartzwald–Somers-technique) (Figure 11).350

C

6.620.4. 2000 µm

Summary

Insertion of dental implants has become a common treatment in modern dentistry. However, the resorptive processes following tooth extraction often mandate site development by alveolar ridge augmentation before implants can be placed. Although the current gold standard, namely autogenous bone grafts, serves this function, there has been an ever-increasing search for excellent synthetic bone grafting materials, in order to avoid second-site surgery for autograft harvesting.

Figure 10 Histomicrograph of GB9 calcium alkali phosphate cement after 336 days after implantation in the rabbit femur. The defect area is circled. The highly cancellous original bone structure or the rabbit femur has been widely restored with only a very small amount of residual cement (C) being present which displays high bone-cement contact (arrow), that is, excellent bone-bonding behavior. Undecalcified sawed section stained with Giemsa surface staining. Bar ¼ 2000 mm.

(b)

(a)

(d)

0.25 mm/div

(c)

Figure 11 (a, b) Three-dimensional calcium-alkali-orthophosphate-based scaffold fabricated utilizing the Schwartzwald–Somers-technique, (magnification 50), (c, d) 3D calcium-alkali-orthophosphate-based scaffold fabricated by 3D printing.

Dental Graft Materials

Furthermore, the significant increase in the number of dental implants placed and alveolar ridge augmentation procedures performed over the last two decades resulted in an everincreasing demand for adequate bone grafting materials for implant dentistry. Numerous bone grafting materials have been developed and studied since the late 1970s. The majority of these grafting materials are calcium phosphate-based materials. Various HAand TCP-based dental grafting materials, as well as bioactive glasses and glass ceramics have been proposed for use in therapies to augment alveolar bone and to promote periodontal regeneration. These materials include synthetic as well as coralline and bovine-derived HAs, nanocrystalline or peptidemodified HAs, TCP ceramics, biphasic HA-TCPs, calcium carbonates, BG45S5, glass ceramics, and DFDBAs. Most of these materials have been shown to be osteoconductive but exhibit limited biodegradability. DFDBAs are inferior to synthetic materials in terms of the risk of disease transmission and immunological challenges. While for these DFDBAs a wide variation in commercial bone bank preparations of DFDBA and conflicting results regarding their osteoconductivity and potential to support new bone formation have been reported in combination with a low biodegradability, excellent osteoconductive properties have been demonstrated by numerous in vivo and clinical studies for one of the porous bovine-derived HAs that closely resembles the native HA of bone and whose morphology, in addition, resembles that of cancellous bone. This material, however, also exhibits only limited biodegradability. For other HAs, varying degrees of osteoconductivity and bone-bonding behavior have been reported. Both TCP ceramics and BG45S5 have been shown to possess excellent osteoconductivity, bone-regenerative capacity, and bonebonding behavior in combination with a higher biodegradability than various HAs. More recently, injectable and moldable resorbable bone substitute cements as well as scaffolds for craniofacial bone tissue engineering have been developed. Furthermore, the combination of grafting materials with growth factors and other biologicals has been explored. Compared to the bone substitute materials which are currently clinically available, there is a significant need for bone grafting materials that degrade more rapidly but at the same time stimulate osteogenesis. This prompted a search for bioactive, rapidly resorbable bone grafting materials that exhibit good bone-bonding behavior by stimulating enhanced bone formation at the interface. They also exhibit a high degradation rate. This led to the development of calcium alkali orthophosphate materials. Current research efforts include the optimization of resorbable bone grafting cements and of scaffolds for various tissue engineering approaches that integrate concepts to achieve adequate vascularization when restoring large segmental defects.

Acknowledgments Support over the years from various agencies is gratefully acknowledged. Part of the work was supported by the German Research Foundation DFG (KN 377/2-1, KN377/3-1, KN377/ 5-1, KN377/8-1), the Osteology Foundation, Robert Mathys

319

Foundation, and by the European Union (EFRE-ProFIT grants # 10136206, 10141914). Furthermore, the authors thank the numerous colleagues who contributed to the work presented in this chapter. They are Prof. Dr. I. Shapiro, Dr. G. Berger, Dr. G. Gildenhaar, Prof. Dr. C. R. Howlett, Dr. A. Houshmand, Dr. Ch. Koch, Dr. A. Rack, Dr. A. Bednarek, Dr. S. Jonscher, Dr. K. Reiter, PD Dr. Ch. Mu¨ller-Mai, Dr. H. Renz, Dr. S. Radin, Ms. A. Kopp, Ms. I. Borchert, Mrs. K. Schulze-Dirksen, Ms. E. Rieger-Ru¨diger, and Mrs. I. Schwarz.

References 1. Belser, U. C.; Mericske-Stern, R.; Bernard, J. P.; Taylor, T. D. Clin. Oral Implants Res. 2000, 11(Suppl. 1), 126–145; Review. 2. Bornstein, M. M.; Lussi, A.; Schmid, B.; Belser, U. C.; Buser, D. Int. J. Oral Maxillofac. Implants 2003, 18, 659–666. 3. Garber, D. A.; Belser, U. C. Compend. Contin. Educ. Dent. 1995, 16, 796; 798–802, 804. 4. Garber, D. A. J. Am. Dent. Assoc. 1995, 126, 319–325. 5. Taylor, T. D.; Belser, U.; Mericske-Stern, R. Clin. Oral Implants Res. 2000, 11 (Suppl. 1), 101–107; Review. 6. Ganz, S. D.; Valen, M. J. Oral Implantol. 2002, 28, 178–183. 7. Winkler, S. J. Oral Implantol. 2002, 28, 226–229. 8. Eisig, S. B.; Ho, V.; Kraut, R.; Lalor, P. J. Oral Maxillofac. Surg. 2003, 61, 347–353. 9. von Arx, T.; Cochran, D. L.; Hermann, J. S.; Schenk, R. K.; Buser, D. Clin. Oral Implants Res. 2001, 12, 260–269. 10. von Arx, T.; Cochran, D. L.; Schenk, R. K.; Buser, D. Int. J. Oral Maxillofac. Surg. 2002, 31, 190–199. 11. Buser, D.; Dula, K.; Hess, D.; Hirt, H. P.; Belser, U. C. Periodontol. 2000 1999, 19, 151–163; Review. 12. Buser, D.; Dula, K.; Hirt, H. P.; Berthold, H. In Guided Bone Regeneration in Implant Dentistry; Buser, D., Dahlin, C., Schenk, R. K., Eds.; Quintessenz: Chicago, IL, 1994; pp 189–233. 13. Buser, D.; Hoffmann, B.; Bernard, J. P.; Lussi, A.; Mettler, D.; Schenk, R. K. Clin. Oral Implants Res. 1998, 9, 137–150. 14. Klijn, R. J.; Meijer, G. J.; Bronkhorst, E. M.; Jansen, J. A. Tissue Eng. B Rev. 2010, 16(5), 493–507. 15. Klijn, R. J.; Meijer, G. J.; Bronkhorst, E. M.; Jansen, J. A. Tissue Eng. B Rev. 2010, 16(3), 295–303; Review. 16. Buser, D.; Dula, K.; Hirt, H. P.; Schenk, R. J. Oral Maxillofac. Surg. 1996, 54, 420–432. 17. Friedmann, A.; Strietzel, F. P.; Maretzki, B.; Pitaru, S.; Bernimoulin, J. P. Clin. Oral Implants Res. 2002, 13(6), 587–594. 18. Ha¨mmerle, C. H. F.; Chiantella, G. C.; Karring, T.; Lang, N. P. Clin. Oral Implants Res. 1998, 9, 151–162. 19. Kohal, R. J.; Mellas, P.; Hu¨rzeler, M. B.; Trejo, P. M.; Morrison, E.; Caffesse, R. G. J. Periodontol. 1998, 69(8), 927–937. 20. Stricker, A.; Voss, P. J.; Gutwald, R.; Schramm, A.; Schmelzeisen, R. Clin. Oral Implants Res. 2003, 14, 207–212. 21. Timmenga, N. M.; Raghoebar, G. M.; van Weissenbruch, R.; Vissink, A. Clin. Oral Implants Res. 2003, 14, 322–328. 22. Kalk, W. W.; Raghoebar, G. M.; Jansma, J.; Boering, G. J. Oral Maxillofac. Surg. 1996, 54, 1424–1429. 23. Kaptein, M. L.; Hoogstraten, J.; de Putter, C.; de Lange, G. L.; Blijdorp, P. A. Clin. Oral Implants Res. 1998, 9, 321–326. 24. Orsini, G.; Ricci, J.; Scarano, A.; et al. J. Biomed. Mater. Res. 2004, 68B, 199–208. 25. Wheeler, S. L. J. Oral Maxillofac. Surg. 1997, 55, 1287–1293; Review. 26. Groeneveld, E. H. J.; van den Bergh, J. P. A.; Holzmann, P.; ten Bruggenkate, C. M.; Tuinzing, D. B.; Burger, E. H. Clin. Oral Implants Res. 1999, 10, 499–509. 27. Hu¨rzeler, M. B.; Kirsch, A.; Ackermann, K. L.; Quinones, C. R. Int. J. Oral Maxillofac. Implants 1996, 11, 466–475. 28. Hu¨rzeler, M. B.; Kirsch, A.; Ackermann, K. L.; Quin˜ones, C. R. Int. J. Oral Maxillofac. Implants 1996, 11(4), 466–475. 29. Lorenzetti, M.; Mozzati, M.; Campanino, P. P.; Valente, G. Int. J. Oral Maxillofac. Implants 1998, 13, 69–76.

320

Dentistry, and Oral and Maxillofacial Surgery

30. Valentini, P.; Abensur, D. Int. J. Periodontics Restorative Dent. 1997, 17, 233–241. 31. Wallace, S. S.; Froum, S. J.; Tarnow, D. P. Int. J. Periodontics Restorative Dent. 1996, 16, 47–51. 32. Wetzel, A. C.; Stich, H.; Caffesse, R. G. Clin. Oral Implants Res. 1995, 6, 155–163. 33. Wiltfang, J.; Merten, H. A.; Schlegel, K. A.; et al. J. Biomed. Mater. Res. 2002, 63, 115–121. 34. Hench, L. L. J. Am. Ceram. Soc. 1998, 81, 1705–1728; Review. 35. Ducheyne, P. In Hip Surgery: New Materials and Developments; Sedel, L., Cabanela, M., Eds.; Martin Dunitz: London, 1998; pp 75–82. 36. Metsger, D. S.; Driskell, T. D.; Paulsrud, J. R. J. Am. Dent. Assoc. 1982, 105, 1035–1038; Review. 37. Yaszemski, M. J.; Payne, R. G.; Hayes, W. C.; Langer, R.; Mikos, A. C. Biomaterials 1996, 17, 175–185. 38. Hollinger, J. O.; Schmitz, J. P.; Mizgala, J. W.; Hassler, C. J. Biomed. Mater. Res. 1989, 23(1), 17–29. 39. Wenz, B.; Oesch, B.; Horst, M. Biomaterials 2001, 22(12), 1599–1606. 40. Saffar, J. F.; Colombier, M. L.; Detienville, R. J. Periodontol. 1990, 61, 209–216. 41. Ducheyne, P.; de Groot, K. J. Biomed. Mater. Res. 1991, 15, 441–445. 42. Eggli, P. S.; Muller, W.; Schenk, R. K. Clin. Orthop. Relat. Res. 1988, 232, 127–138. 43. Jarcho, M. Clin. Orthop. Relat. Res. 1981, 157, 259–278. 44. Daculsi, G.; Le Geros, R. Z.; Mitre, D. Calcif. Tissue Int. 1989, 45, 95–103. 45. Hench, L. L.; Paschall, H. A. J. Biomed. Mater. Res. 1973, 7, 25–42. 46. Schliephake, H.; Kage, T. J. Biomed. Mater. Res. 2001, 56, 128–136. 47. Zerbo, I. R.; Bronckers, A. L.; de Lange, G. L.; van Beek, G. J.; Burger, E. H. Clin. Oral Implants Res. 2001, 12, 379–384. 48. Merten, H. A.; Wiltfang, J.; Grohmann, U.; Hoenig, J. F. J. Craniofac. Surg. 2001, 12(1), 59–68. 49. Cordioli, G.; Mazzocco, C.; Schepers, E.; Brugnolo, E.; Majzoub, Z. Clin. Oral. Implants Res. 2001, 12, 270–278. 50. Tadjoedin, E. S.; de Lange, G. L.; Holzmann, P. J.; Kulper, L.; Burger, E. H. Clin. Oral Implants Res. 2000, 11, 334–344. 51. Davies, J. E. Int. J. Prosthodont. 1998, 11, 391–401. 52. Holmes, R. E.; Bucholz, R. W.; Mooney, V. J. Orthop. Res. 1987, 5(1), 114–121. 53. Schepers, E. J.; Ducheyne, P. J. Oral Rehabil. 1997, 24, 171–181. 54. Barney, V. C.; Levin, M. P.; Adams, D. F. J. Periodontol. 1986, 57(12), 764–770. 55. Chanavaz, M. J. Oral Implantol. 1990, 16(3), 199–209. 56. Desilets, C. P.; Marden, L. J.; Patterson, A. L.; Hollinger, J. O. J. Craniofac. Surg. 1990, 1(3), 150–153. 57. Hempton, T. J.; Fugazzotto, P. A. Implant Dent. 1994, 3(1), 35–37. 58. Hollinger, J. O.; Schmitz, J. P.; Mizgala, J. W.; Hassler, C. J. Biomed. Mater. Res. 1989, 23(1), 17–29. 59. Klein, C. P.; Driessen, A. A.; de Groot, K.; van den Hooff, A. J. Biomed. Mater. Res. 1983, 17(5), 769–784. 60. Misch, C. E.; Dietsh, F. Implant Dent. 1993, 2(3), 158–167; Review. 61. Riess, G.; Heide, H.; Ko¨ster, K.; Reiner, R. Dtsch Zahna¨rztl. Z. 1978, 33(4), 287. 62. Swart, J. G.; Feenstra, L.; Ponssen, H.; de Groot, K. Ned. Tijdschr. Geneeskd 1979, 123(33), 1421–1425. 63. Bunte, M.; Strunz, V. J. Maxillofac. Surg. 1977, 5(4), 303–309. 64. Schepers, E.; de Clercq, M.; Ducheyne, P.; Kempeneers, R. J. Oral Rehabil. 1991, 18(5), 439–452. 65. Strunz, V.; Bunte, M.; Stellmach, R.; et al. Dtsch Zahna¨rztl. Z. 1977, 32(4), 287–290. 66. Davis, W. H.; Hochwald, D.; Daly, B.; Owen, W. F., 3rd J. Prosthet. Dent. 1990, 64(5), 583–588; Review. 67. Ewers, R. J. Oral Maxillofac. Surg. 2005, 63(12), 1712–1723. 68. Haas, R.; Baron, M.; Zechner, W.; Mailath-Pokorny, G. Int. J. Oral Maxillofac. Implants 2003, 18(5), 691–696. 69. Hjorting-Hansen, E.; Worsaae, N.; Lemons, J. E. Int. J. Oral Maxillofac. Implants 1990, 5(3), 255–263. 70. Hu¨rzeler, M. B.; Quinones, C. R.; Kirsch, A.; et al. Clin. Oral Implants Res. 1997, 8(5), 401–411. 71. Hu¨rzeler, M. B.; Quin˜ones, C. R.; Kirsch, A.; et al. Clin. Oral Implants Res. 1997, 8(5), 401–411. 72. Krejci, C. B.; Bissada, N. F.; Farah, C.; Greenwell, H. J. Periodontol. 1987, 58(8), 521–528. 73. Noppe, C. Quintessenz 1987, 38(6), 1053–1063. 74. Otto, K.; Schopper, C.; Ewers, R.; Lambrecht, J. T. Schweiz. Monatsschr. Zahnmed. 2004, 114(10), 996–1002. 75. Prokic, B.; Lekovic, V.; Weingart, H.; Kleber, B. M. Zahn Mund Kieferheilkd Zentralbl. 1990, 78(7), 597–601.

76. Quin˜ones, C. R.; Hu¨rzeler, M. B.; Schu¨pbach, P.; et al. Clin. Oral Implants Res. 1997, 8(6), 487–496. 77. Roos-Jansa˚ker, A. M.; Renvert, H.; Lindahl, C.; Renvert, S. J. Clin. Periodontol. 2007, 34(7), 625–632. 78. Schopper, C.; Moser, D.; Wanschitz, F.; et al. J. Long Term Eff. Med. Implants 1999, 9(3), 203–213. 79. Small, S. A.; Zinner, I. D.; Panno, F. V.; Shapiro, H. J.; Stein, J. I. Int. J. Oral Maxillofac. Implants 1993, 8(5), 523–528. 80. Smiler, D. G.; Johnson, P. W.; Lozada, J. L.; et al. Dent. Clin. North Am. 1992, 36(1), 151–186. 81. Thompson, D. M.; Rohrer, M. D.; Prasad, H. S. Implant Dent. 2006, 15(1), 89–96. 82. Ripamonti, U. J. Craniofac. Surg. 1992, 3(3), 149–159. 83. Schopper, C.; Moser, D.; Wanschitz, F.; et al. J. Long Term Eff. Med. Implants. 1999, 9(3), 203–213. 84. Bertoli, F. Dent. Cadmos 1989, 57(1), 68–71. 85. Canullo, L.; Dellavia, C. Clin. Implant Dent. Relat. Res. 2009, 11(Suppl. 1), e7–e13. 86. Spies, C.; Schnu¨rer, S.; Gotterbarm, T.; Breusch, S. Z. Orthop. Unfall. 2008, 146(1), 64–69. 87. Spies, C. K.; Schnu¨rer, S.; Gotterbarm, T.; Breusch, S. Arch. Orthop. Trauma. Surg. 2009, 129(7), 979–988. 88. Al Ruhaimi, K. A. Int. J. Oral Maxillofac. Implants 2001, 6(1), 105–114. 89. Froum, S. J.; Tarnow, D. P.; Wallace, S. S.; Rohrer, M. D.; Cho, S. C. Int. J. Periodontics Restorative Dent. 1998, 18(6), 528–543. 90. Ha¨mmerle, C. H.; Olah, A. J.; Schmid, J.; et al. Clin. Oral Implants Res. 1997, 8(3), 198–207. 91. Landi, L.; Pretel, R. W., Jr.; Hakimi, N. M.; Setayesh, R. Int. J. Periodontics Restorative Dent. 2000, 20(6), 574–583. 92. Schmid, J.; Ha¨mmerle, C. H.; Flu¨ckiger, L.; et al. Clin. Oral Implants Res. 1997, 8(2), 75–81. 93. Tapety, F. I.; Amizuka, N.; Uoshima, K.; Nomura, S.; Maeda, T. Clin. Oral Implants Res. 2004, 15(3), 315–324. 94. Al Ruhaimi, K. A. Int. J. Oral Maxillofac. Implants 2000, 15(6), 859–864. 95. Busenlechner, D.; Tangl, S.; Mair, B.; et al. Biomaterials 2008, 29(22), 3195–3200. 96. Smeets, R.; Grosjean, M. B.; Jelitte, G.; et al. Schweiz. Monatsschr. Zahnmed. 2008, 118(3), 203–212. 97. Traini, T.; Degidi, M.; Sammons, R.; Stanley, P.; Piattelli, A. J. Periodontol. 2008, 79(7), 1232–1240. 98. Artzi, Z.; Kozlovsky, A.; Nemcovsky, C. E.; Weinreb, M. J. Clin. Periodontol. 2005, 32(2), 193–199. 99. Berglundh, T.; Lindhe, J. Clin. Oral Implants Res. 1997, 8(2), 117–124. 100. Cordaro, L.; Bosshardt, D. D.; Palattella, P.; Rao, W.; Serino, G.; Chiapasco, M. Clin. Oral Implants Res. 2008, 19(8), 796–803. 101. de Vicente, J. C.; Herna´ndez-Vallejo, G.; Bran˜a-Abascal, P.; Pen˜a, I. Clin. Oral Implants Res. 2010, 21(4), 430–438. 102. Ferreira, C. E.; Novaes, A. B.; Haraszthy, V. I.; Bittencourt, M.; Martinelli, C. B.; Luczyszyn, S. M. J. Periodontol. 2009, 80(12), 1920–1927. 103. Froum, S. J.; Wallace, S. S.; Cho, S. C.; Elian, N.; Tarnow, D. P. Int. J. Periodontics Restorative Dent. 2008, 28(3), 273–281. 104. Gutwald, R.; Haberstroh, J.; Kuschnierz, J.; et al. Br. J. Oral Maxillofac. Surg. 2010, 48(4), 285–290. 105. Klinge, B.; Alberius, P.; Isaksson, S.; Jonsson, J. J. Oral Maxillofac. Surg. 1992, 50(3), 241–249. 106. Simunek, A.; Kopecka, D.; Somanathan, R. V.; Pilathadka, S.; Brazda, T. Int. J. Oral Maxillofac. Implants 2008, 23(5), 935–942. 107. Sohn, D. S.; Kim, W. S.; An, K. M.; Song, K. J.; Lee, J. M.; Mun, Y. S. Implant Dent. 2010, 19(3), 259–270. 108. van Steenberghe, D.; Callens, A.; Geers, L.; Jacobs, R. Clin. Oral Implants Res. 2000, 11(3), 210–216. 109. Yildirim, M.; Spiekermann, H.; Biesterfeld, S.; Edelhoff, D. Clin. Oral Implants Res. 2000, 11(3), 217–229. 110. Zitzmann, N. U.; Naef, R.; Scha¨rer, P. Int. J. Oral Maxillofac. Implants 1997, 12(6), 844–852. 111. Jensen, S. S.; Broggini, N.; Hjrting-Hansen, E.; Schenk, R.; Buser, D. Clin. Oral Implants Res. 2006, 17(3), 237–243. 112. Valentini, P.; Abensur, D. J. Int. J. Oral Maxillofac. Implants 2003, 18(4), 556–560. 113. Schliephake, H.; Neukam, F. W.; Hutmacher, D.; Becker, J. J. Oral Maxillofac. Surg. 1994, 52(1), 57–63. 114. Schliephake, H.; Neukam, F. W.; Hutmacher, D.; Wu¨stenfeld, H. J. Oral Maxillofac. Surg. 1995, 53(1), 46–51; discussion 52.

Dental Graft Materials

115. Schliephake, H.; Neukam, F. W.; Hutmacher, D. Fortschr. Kiefer Gesichtschir. 1994, 39, 190–193. 116. Chu, T. M.; Hollister, S. J.; Halloran, J. W.; Feinberg, S. E.; Orton, D. G. Ann. NY Acad. Sci. 2002, 961, 114–117. 117. Chu, T. M.; Orton, D. G.; Hollister, S. J.; Feinberg, S. E.; Halloran, J. W. Biomaterials 2002, 23(5), 1283–1293. 118. Degidi, M.; Piattelli, M.; Scarano, A.; Iezzi, G.; Piattelli, A. J. Oral Implantol. 2004, 30(6), 376–383. 119. Hole, B. B.; Schwarz, J. A.; Gilbert, J. L.; Atkinson, B. L. J. Biomed. Mater. Res. A 2005, 74(4), 712–721. 120. Thorwarth, M.; Schultze-Mosgau, S.; Wehrhan, F.; Kessler, P.; Srour, S.; Wiltfang, J. Biomaterials 2005, 26(28), 5648–5657. 121. Thorwarth, M.; Wehrhan, F.; Srour, S.; et al. Br. J. Oral Maxillofac. Surg. 2007, 45(1), 41–47. 122. Abshagen, K.; Schrodi, I.; Gerber, T.; Vollmar, B. J. Biomed. Mater. Res. A 2009, 91(2), 557–566. 123. Go¨tz, W.; Gerber, T.; Michel, B.; Lossdo¨rfer, S.; Henkel, K. O.; Heinemann, F. Clin. Oral Implants Res. 2008, 19(10), 1016–1026. 124. Brandt, J.; Henning, S.; Michler, G.; Hein, W.; Bernstein, A.; Schulz, M. J. Mater. Sci. Mater. Med. 2010, 21(1), 283–294. 125. Heinemann, F.; Mundt, T.; Biffar, R.; Gedrange, T.; Goetz, W. J. Physiol. Pharmacol. 2009, 60(Suppl. 8), 91–97. 126. Peters, F.; Reif, D. Materialwiss. Werkst. 2004, 35, 203–207. 127. Bednarek, A. Dissertation; Charite´ University Medical Center: Berlin, Germany, 2010. 128. Knabe, C.; Houshmand, A.; Berger, G.; et al. J. Biomed. Mater. Res. A 2008, 84, 856–868. 129. Knabe, C.; Koch, C.; Rack, A.; Stiller, M. Biomaterials 2008, 29, 2249–2258. 130. Knabe, C.; Berger, G.; Gildenhaar, R.; et al. In (Oral Presentation) Transactions of the 8th World Biomaterials Congress, Amsterdam, The Netherlands, May 28–Jun 1, 2008 p 035. 131. Knabe, C.; Stiller, M.; Berger, G.; et al. In Society for Biomaterials Transactions 2008 Translational Biomaterial Research Symposium, Atlanta, GA, Sept 11–13, 2008 p 215. 132. Stiller, M.; Rack, A.; Zabler, S.; et al. Bone 2009, 44(4), 619–628. 133. Aguirre Zorzano, L. A.; Rodrı´guez Tojo, M. J.; Aguirre Urizar, J. M. Med. Oral Patol. Oral Cir. Bucal 2007, 12(7), E532–E536. 134. Artzi, Z.; Weinreb, M.; Givol, N.; et al. Int. J. Oral Maxillofac. Implants 2004, 19(3), 357–368. 135. Bornstein, M. M.; Chappuis, V.; von Arx, T.; Buser, D. Clin. Oral Implants Res. 2008, 19(10), 1034–1043. 136. Cordioli, G.; Mazzocco, C.; Schepers, E.; Brugnolo, E.; Majzoub, Z. Clin. Oral Implants Res. 2001, 12, 270–278. 137. Damron, T. A. Nanomedicine (Lond.) 2007, 2(6), 763–775; Review. 138. Fiorellini, J. P.; Kim, D. M.; Nakajima, Y.; Weber, H. P. Int. J. Periodontics Restorative Dent. 2007, 27(3), 287–294. 139. Horch, H. H.; Sader, R.; Pautke, C.; Neff, A.; Deppe, H.; Kolk, A. Int. J. Oral Maxillofac. Surg. 2006, 35(8), 708–713; 16(7), 2343–2354. 140. Meyer, C.; Chatelain, B.; Benarroch, M.; Garnier, J. F.; Ricbourg, B. Rev. Stomatol. Chir. Maxillofac. 2009, 110(2), 69–75. 141. Nakajima, Y.; Fiorellini, J. P.; Kim, D. M.; Weber, H. P. Int. J. Periodontics Restorative Dent. 2007, 27(2), 151–159. 142. Ormianer, Z.; Palti, A.; Shifman, A. Implant Dent. 2006, 15(4), 395–403. 143. Suba, Z.; Taka´cs, D.; Matusovicz, D.; Fazekas, A.; Szabo´, G.; Baraba´s, J. Fogorv. Sz. 2006, 99(1), 21–28. 144. Suba, Z.; Taka´cs, D.; Matusovits, D.; Baraba´s, J.; Fazekas, A.; Szabo´, G. Clin. Oral Implants Res. 2006, 17(1), 102–108. 145. Szabo´, G.; Suba, Z.; Hraba´k, K.; Baraba´s, J.; Ne´meth, Z. Int. J. Oral Maxillofac. Implants 2001, 16(5), 681–692. 146. Tadjoedin, E. S.; de Lange, G. L.; Holzmann, P. J.; Kulper, L.; Burger, E. H. Clin. Oral Implants Res. 2000, 11, 334–344. 147. Tetsch, J.; Tetsch, P.; Lysek, D. A. Clin. Oral Implants Res. 2010, 21(5), 497–503. 148. Uckan, S.; Deniz, K.; Dayangac, E.; Araz, K.; Ozdemir, B. H. J. Oral Maxillofac. Surg. 2010, 68(7), 1642–1645. 149. Velich, N.; Ne´meth, Z.; To´th, C.; Szabo´, G. J. Craniofac. Surg. 2004, 15(1), 38–41. 150. Zerbo, I. R.; Zijderveld, S. A.; de Boer, A.; et al. Clin. Oral Implants Res. 2004, 15(6), 724–732. 151. Zijderveld, S. A.; Zerbo, I. R.; van den Bergh, J. P.; Schulten, E. A.; ten Bruggenkate, C. M. Int. J. Oral Maxillofac. Implants 2005, 20(3), 432–440. 152. Artzi, Z.; Weinreb, M.; Carmeli, G.; Lev-Dor, R.; Dard, M.; Nemcovsky, C. E. Clin. Oral Implants Res. 2008, 19(7), 686–692.

321

153. Ne´meth, Z.; Suba, Z.; Hraba´k, K.; Baraba´s, J.; Szabo´, G. Orv. Hetil. 2002, 143(25), 1533–1538. 154. Szabo´, G.; Huys, L.; Coulthard, P.; et al. Int. J. Oral Maxillofac. Implants 2005, 20(3), 371–381. 155. Zijderveld, S. A.; Schulten, E. A.; Aartman, I. H.; ten Bruggenkate, C. M. Clin. Oral Implants Res. 2009, 20(7), 691–700. 156. Yamauchi, K.; Takahashi, T.; Funaki, K.; Hamada, Y.; Yamashita, Y. Int. J. Oral Maxillofac. Surg. 2010, 39(10), 1000–1006. 157. Bohner, M. Biomaterials 2009, 30(32), 6403–6406; Review. 158. Komlev, V. S.; Mastrogiacomo, M.; Pereira, R. C.; Peyrin, F.; Rustichelli, F.; Cancedda, R. Eur. Cell Mater. 2010, 19, 136–146. 159. Lin, K.; Chang, J.; Shen, R. Biomed. Mater. 2009, 4(6), 065009 Epub. 160. Carmagnola, D.; Abati, S.; Celestino, S.; Chiapasco, M.; Bosshardt, D.; Lang, N. P. Clin. Oral Implants Res. 2008, 19(12), 1246–1253. 161. Galindo-Moreno, P.; Avila, G.; Ferna´ndez-Barbero, J. E.; Mesa, F.; O’Valle-Ravassa, F.; Wang, H. L. Clin. Oral Implants Res. 2008, 19(8), 755–759. 162. Hall, E. E.; Meffert, R. M.; Hermann, J. S.; Mellonig, J. T.; Cochran, D. L. J. Periodontol. 1999, 70(5), 526–535. 163. Knabe, C.; Ducheyne, P. In Handbook of Bioceramics and Their Applications; Kokubo, T., Ed.; Woodhead: Cambridge, UK, 2008; pp 133–164. 164. Lovelace, T. B.; Mellonig, J. T.; Meffert, R. M.; Jones, A. A.; Nummikoski, P. V.; Cochran, D. L. J. Periodontol. 1998, 69(9), 1027–1035. 165. Low, S. B. Dent. Implantol. Update 1998, 9(9), 65–67. 166. Nevins, M. L.; Camelo, M.; Nevins, M.; et al. Int. J. Periodontics Restorative Dent. 2000, 20(5), 458–467. 167. Norton, M. R.; Wilson, J. Int. J. Oral Maxillofac. Implants 2002, 17(2), 249–257. 168. Reynolds, M. A.; Aichelmann-Reidy, M. E.; Branch-Mays, G. L.; Gunsolley, J. C. Ann. Periodontol. 2003, 8(1), 227–265; Review. 169. Zamet, J. S.; Darbar, U. R.; Griffiths, G. S.; et al. J. Clin. Periodontol. 1997, 24(6), 410–418. 170. Ducheyne, P.; Bianco, P.; Radin, S.; Schepers, E. In Bone-Bioactive Biomaterials; Ducheyne, P., Kokubo, T., van Blitterswijk, C. A., Eds.; Reed Healthcare Communications: Leiderdorp, Netherlands, 1993; pp 1–12. 171. Ducheyne, P.; Qiu, Q. Biomaterials 1999, 20, 2287–2303; Review. 172. Effah, E.; Bianco, P.; Ducheyne, P. J. Biomed. Mater. Res. 1995, 29, 73–80. 173. El-Ghannam, A.; Ducheyne, P.; Shapiro, I. M. J. Orthop. Res. 1999, 17, 340–345. 174. Strunz, V.; Bunte, M.; Stellmach, R.; et al. Dtsch Zahna¨rztl. Z. 1976, 31(1), 69–70. 175. Radin, S.; Ducheyne, P.; Falaize, S.; Hammond, A. J. Biomed. Mater. Res. 2000, 49(2), 264–272. 176. Bottura, G.; Mongiorgi, R.; Valdre`, G.; et al. Minerva Stomatol. 1995, 44(1–2), 33–42. 177. Figueiredo, M.; Henriques, J.; Martins, G.; Guerra, F.; Judas, F.; Figueiredo, H. J. Biomed. Mater. Res. B Appl. Biomater. 2010, 92(2), 409–419. 178. Hippolyte, M. P.; Fabre, D.; Peyrol, S. J. Parodontol. 1991, 10(3), 279–286. 179. Molly, L.; Vandromme, H.; Quirynen, M.; Schepers, E.; Adams, J. L.; van Steenberghe, D. J. Periodontol. 2008, 79(6), 1108–1115. 180. Mongiorgi, R.; Valdre`, G.; Bertocchi, G.; et al. Minerva Stomatol. 1995, 44(1–2), 3–11. 181. Penel, G.; Pottier, E. C.; Leroy, G. Bull. Group. Int. Rech. Sci. Stomatol. Odontol. 2003, 45(2–3), 56–59. 182. Piattelli, A.; Podda, G.; Scarano, A. Biomaterials 1997, 18(8), 623–627. 183. Pretorius, J. A.; Melsen, B.; Nel, J. C.; Germishuys, P. J. Int. J. Oral Maxillofac. Implants 2005, 20(3), 387–398. 184. Sa`ndor, G. K.; Kainulainen, V. T.; Queiroz, J. O.; Carmichael, R. P.; Oikarinen, K. S. Dent. Traumatol. 2003, 19(4), 221–227. 185. Scarano, A.; Degidi, M.; Iezzi, G.; et al. Implant Dent. 2006, 15(2), 197–207. 186. Soost, F.; Reisshauer, B.; Herrmann, A.; Neumann, H. J. Mund Kiefer Gesichtschir. 1998, 2(2), 96–100. 187. Soost, F. Chirurg 1996, 67(11), 1193–1196. 188. Valdre`, G.; Mongiorgi, R.; Ferrieri, P.; Corvo, G.; Cattaneo, V.; Tartaro, G. P. Minerva Stomatol. 1995, 44(1–2), 55–68. 189. Yukna, R. A.; Yukna, C. N. J. Clin. Periodontol. 1998, 25(12), 1036–1040. 190. Zhu, H.; Schulz, J.; Schliephake, H. Clin. Oral Implants Res. 2010, 21(2), 182–188. 191. Mangano, C.; Piattelli, A.; Mangano, A.; et al. Clin. Implant Dent. Relat. Res. 2009, 11(Suppl. 1), e92–e102.

322

Dentistry, and Oral and Maxillofacial Surgery

192. Jensen, S. S.; Bornstein, M. M.; Dard, M.; Bosshardt, D. D.; Buser, D. J. Biomed. Mater. Res. B Appl. Biomater. 2009, 90(1), 171–181. 193. Frenken, J. W.; Bouwman, W. F.; Bravenboer, N.; Zijderveld, S. A.; Schulten, E. A.; ten Bruggenkate, C. M. Clin. Oral Implants Res. 2010, 21(2), 201–208. 194. Friedmann, A.; Dard, M.; Kleber, B. M.; Bernimoulin, J. P.; Bosshardt, D. D. Clin. Oral Implants Res. 2009, 20(7), 708–714. 195. Jensen, S. S.; Yeo, A.; Dard, M.; Hunziker, E.; Schenk, R.; Buser, D. Clin. Oral Implants Res. 2007, 18(6), 752–760. 196. Dietze, S.; Bayerlein, T.; Proff, P.; Hoffmann, A.; Gedrange, T. Folia Morphol. (Warsz) 2006, 65(1), 63–65. 197. Anderegg, C. R.; Martin, S. J.; Gray, J. L.; Mellonig, J. T.; Gher, M. E. J. Periodontol. 1991, 62(4), 264–268. 198. Becker, W.; Schenk, R.; Higuchi, K.; Lekholm, U.; Becker, B. E. Int. J. Oral Maxillofac. Implants 1995, 10(2), 143–154. 199. Becker, W.; Urist, M.; Becker, B. E.; et al. J. Periodontol. 1996, 67(10), 1025–1033. 200. Becker, W.; Urist, M. R.; Tucker, L. M.; Becker, B. E.; Ochsenbein, C. J. Periodontol. 1995, 66(9), 822–828. 201. Blank, B. S.; Levy, A. R. Int. J. Periodontics Restorative Dent. 1999, 19(5), 481–487. 202. Boe¨ck-Neto, R. J.; Gabrielli, M.; Lia, R.; Marcantonio, E.; Shibli, J. A.; Marcantonio, E., Jr. J. Periodontol. 2002, 73(3), 266–270. 203. Bowen, J. A.; Mellonig, J. T.; Gray, J. L.; Towle, H. T. J. Periodontol. 1989, 60(12), 647–654. 204. Brugnami, F.; Then, P. R.; Moroi, H.; Leone, C. W. J. Periodontol. 1996, 67(8), 821–825. 205. De Leonardis, D.; Garg, A. K.; Pedrazzoli, V.; Pecora, G. E. J. Periodontol. 1999, 70(1), 8–12. 206. Die`s, F.; Etienne, D.; Abboud, N. B.; Ouhayoun, J. P. Clin. Oral Implants Res. 1996, 7(3), 277–285. 207. Froum, S.; Cho, S. C.; Rosenberg, E.; Rohrer, M.; Tarnow, D. J. Periodontol. 2002, 73(1), 94–102. 208. Fucini, S. E.; Quintero, G.; Gher, M. E.; Black, B. S.; Richardson, A. C. J. Periodontol. 1993, 64(9), 844–847. 209. Hanisch, O.; Lozada, J. L.; Holmes, R. E.; Calhoun, C. J.; Kan, J. Y.; Spiekermann, H. Int. J. Oral Maxillofac. Implants 1999, 14(3), 329–336. 210. Harasty, L. A.; Brownstein, C. N.; Deasy, M. J. Periodontal Clin. Investig. 1999, 21(1), 10–17. 211. Klepp, M.; Hinrichs, J. E.; Eastlund, T.; Schaffer, E. M. J. Clin. Periodontol. 2004, 31(7), 534–544. 212. Kohal, R. J.; Mellas, P.; Hu¨rzeler, M. B.; Trejo, P. M.; Morrison, E.; Caffesse, R. G. J. Periodontol. 1998, 69(8), 927–937. 213. Kolerman, R.; Hirsh, A.; Shapira, L. Refuat Hapeh Vehashinayim 2001, 18(2), 24–32; 60. 214. Ku¨bler, N. R.; Will, C.; Depprich, R.; et al. Mund Kiefer Gesichtschir. 1999, 3(Suppl. 1), S53–S60. 215. Landi, L. Compend. Contin. Educ. Dent. 1998, 19(12), 1221–1223; 1226–1230. 216. Olson, J. W.; Dent, C. D.; Morris, H. F.; Ochi, S. Ann. Periodontol. 2000, 5(1), 152–156. 217. Parashis, A.; Andronikaki-Faldami, A.; Tsiklakis, K. Int. J. Periodontics Restorative Dent. 2004, 24(1), 81–90. 218. Piattelli, A.; Scarano, A.; Corigliano, M.; Piattelli, M. Biomaterials 1996, 17(11), 1127–1131. 219. Piemontese, M.; Aspriello, S. D.; Rubini, C.; Ferrante, L.; Procaccini, M. J. Periodontol. 2008, 79(5), 802–810. 220. Reynolds, M. A.; Bowers, G. M. J. Periodontol. 1996, 67(2), 150–157. 221. Rosen, P. S.; Reynolds, M. A. J. Periodontol. 2002, 73(8), 942–949. 222. Rummelhart, J. M.; Mellonig, J. T.; Gray, J. L.; Towle, H. J. J. Periodontol. 1989, 60(12), 655–663. 223. Schwartz, Z.; Mellonig, J. T.; Carnes, D. L., Jr.; et al. J. Periodontol. 1996, 67(9), 918–926. 224. Schwartz, Z.; Somers, A.; Mellonig, J. T.; et al. J. Periodontol. 1998, 69(4), 470–478. 225. Simion, M.; Trisi, P.; Piattelli, A. Int. J. Periodontics Restorative Dent. 1996, 16(4), 338–347. 226. Trejo, P. M.; Weltman, R.; Caffesse, R. J. Periodontol. 2000, 71(12), 1852–1861. 227. Wallace, S. C.; Gellin, R. G.; Miller, M. C.; Mishkin, D. J. J. Periodontol. 1994, 65(3), 244–254. 228. Xiao, Y.; Parry, D. A.; Li, H.; Arnold, R.; Jackson, W. J.; Bartold, P. M. J. Periodontol. 1996, 67(11), 1233–1244.

229. Yamamichi, N.; Itose, T.; Neiva, R.; Wang, H. L. Int. J. Periodontics Restorative Dent. 2008, 28(2), 163–169. 230. Bowers, G. M.; Chadroff, B.; Carnevale, R.; et al. J. Periodontol. 1989, 60(12), 683–693. 231. Ouhayoun, J. P. ‘Risques de transmission a` l’homme de pathologies virale par de substituts oseux d’origine humaine ou animale’. In Rapport sur l’ e´tat des recherches concernant les risques associe´s a` l‘utilisation a` des fins the´rapeutiques de produits d‘origine humaine ou de produits et proce´de´s de substitution, Paris, Edition INSERM, 1995; pp 224–230. 232. Shaug, S. L.; Crane, G. M.; Miller, M. J.; Yasko, A. W.; Yaszemski, M. J.; Mikos, A. G. J. Bone Miner. Res. 1997, 36, 17–28. 233. Schimming, R.; Schmelzeisen, R. J. Oral Maxillofac. Surg. 2004, 62(6), 724–729. 234. Schmelzeisen, R.; Schimming, R.; Sittinger, M. J. Craniomaxillofac. Surg. 2003, 31(1), 34–39. 235. Schmelzeisen, R.; Schimming, R.; Sittinger, M. Ann. R. Australas. Coll. Dent. Surg. 2002, 16, 50–53. 236. Hollister, S. J.; Levy, R. A.; Chu, T. M.; Halloran, J. W.; Feinberg, S. E. Int. J. Oral Maxillofac. Surg. 2000, 29(1), 67–71. 237. Hollister, S. J.; Lin, C. Y.; Saito, E.; et al. Orthod. Craniofac. Res. 2005, 8(3), 162–173. 238. Feinberg, S. E.; Hollister, S. J.; Halloran, J. W. Shanghai Kou Qiang Yi Xue 2000, 9(1), 34–38. 239. Smith, M. H.; Flanagan, C. L.; Kemppainen, J. M.; et al. Int. J. Med. Robot. 2007, 3(3), 207–216. 240. Schek, R. M.; Taboas, J. M.; Hollister, S. J.; Krebsbach, P. H. Orthod. Craniofac. Res. 2005, 8(4), 313–319. 241. Schantz, J. T.; Hutmacher, D. W.; Lam, C. X.; et al. Tissue Eng. 2003, 9(Suppl. 1), S127–S139. 242. Schantz, J. T.; Teoh, S. H.; Lim, T. C.; Endres, M.; Lam, C. X.; Hutmacher, D. W. Tissue Eng. 2003, 9(Suppl. 1), S113–S126. 243. Rohner, D.; Hutmacher, D. W.; Cheng, T. K.; Oberholzer, M.; Hammer, B. J. Biomed. Mater. Res. B Appl. Biomater. 2003, 66(2), 574–580. 244. Rohner, D.; Hutmacher, D. W.; See, P.; et al. Mund Kiefer Gesichtschir. 2002, 6(3), 162–167. 245. Rai, B.; Ho, K. H.; Lei, Y.; Si-Hoe, K. M. J. Oral Maxillofac. Surg. 2007, 65(11), 2195–2205. 246. Sawyer, A. A.; Song, S. J.; Susanto, E.; et al. Biomaterials 2009, 30(13), 2479–2488. 247. Probst, F. A.; Hutmacher, D. W.; Mu¨ller, D. F.; Machens, H. G.; Schantz, J. T. Handchir. Mikrochir. Plast. Chir. 2010, 42(6), 369–373. 248. Betz, M. W.; Caccamese, J. F.; Coletti, D. P.; Sauk, J. J.; Fisher, J. P. J. Biomed. Mater. Res. A 2009, 90(3), 819–829. 249. Docherty-Skogh, A. C.; Bergman, K.; Waern, M. J.; et al. Plast. Reconstr. Surg. 2010, 125(5), 1383–1392. 250. Kretlow, J. D.; Young, S.; Klouda, L.; Wong, M.; Mikos, A. G. Adv. Mater. 2009, 21(32–33), 3368–3393. 251. Salinas, C. N.; Anseth, K. S. J. Dent. Res. 2009, 88(8), 681–692; Review. 252. Weir, M. D.; Xu, H. H. J. Biomed. Mater. Res. B Appl. Biomater. 2010, 93(1), 93–105. 253. Xu, H. H.; Zhao, L.; Weir, M. D. J. Dent. Res. 2010, 89(12), 1482–1488. 254. Jansen, J. A.; Vehof, J. W.; Ruhe´, P. Q.; et al. J. Control. Release 2005, 101(1–3), 127–136. 255. Moioli, E. K.; Clark, P. A.; Xin, X.; Lal, S.; Mao, J. J. Adv. Drug Deliv. Rev. 2007, 59(4–5), 308–324; Review. 256. Mikos, A. G.; Herring, S. W.; Ochareon, P.; et al. Tissue Eng. 2006, 12(12), 3307–3339; Review. 257. Chan, W. D.; Perinpanayagam, H.; Goldberg, H. A.; et al. J. Can. Dent. Assoc. 2009, 75(5), 373–377. 258. Fuchs, S.; Hofmann, A.; Kirkpatrick, C. J. Tissue Eng. 2007, 13(10), 2577–2588. 259. Fuchs, S.; Jiang, X.; Schmidt, H.; et al. Biomaterials 2009, 30(7), 1329–1338. 260. Kirkpatrick, C. J. In Proceedings BIOMED 2009, 15th International Biomedical Science and Technology Symposium, Gu¨zelyurt, Turkey, Aug 16–19, 2009 p 17. 261. Knabe, C.; Berger, G.; Gildenhaar, R.; et al. In Transactions of the 36th Annual Meeting of the Society for Biomaterials USA, Seattle, WA, Apr 21–24, 2010 p 10. 262. Tilkorn, D. J.; Bedogni, A.; Keramidaris, E.; et al. Tissue Eng. A 2010, 16(1), 165–178. 263. Warnke, P. H.; Springer, I. N.; Wiltfang, J.; et al. Lancet 2004, 364(9436), 766–770.

Dental Graft Materials

264. Aral, A.; Yalc¸in, S.; Karabuda, Z. C.; Anil, A.; Jansen, J. A.; Mutlu, Z. Clin. Oral Implants Res. 2008, 19(6), 612–617. 265. Bell, R. B. Oral Maxillofac. Surg. Clin. North Am. 2009, 21(2), 227–242; Review. 266. Bifano, C. A.; Edgin, W. A.; Colleton, C.; Bifano, S. L.; Constantino, P. D. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 1998, 85(5), 512–516. 267. Bohner, M.; Gbureck, U. J. Biomed. Mater. Res. B Appl. Biomater. 2008, 84(2), 375–385. 268. Brown, G. D.; Mealey, B. L.; Nummikoski, P. V.; Bifano, S. L.; Waldrop, T. C. J. Periodontol. 1998, 69(2), 146–157. 269. Cole, I.; Dan, N.; Anker, A. Aust. NZ J. Surg. 1996, 66(7), 469–472. 270. Ding, S. J.; Shie, M. Y.; Hoshiba, T.; Kawazoe, N.; Chen, G.; Chang, H. C. Tissue Eng. A 2010, 16(7), 2343–2354. 271. Fujimura, K.; Bessho, K.; Okubo, Y.; Segami, N.; Iizuka, T. Clin. Oral Implants Res. 2003, 14(5), 659–667. 272. Lew, D.; Farrell, B.; Bardach, J.; Keller, J. J. Oral Maxillofac. Surg. 1997, 55(12), 1441–1449; discussion 1449–1451. 273. Mazor, Z.; Peleg, M.; Garg, A. K.; Chaushu, G. J. Periodontol. 2000, 71(7), 1187–1194. 274. Nakadate, M.; Amizuka, N.; Li, M.; et al. Microsc. Res. Tech. 2008, 71(2), 93–104. 275. Reddi, S. P.; Stevens, M. R.; Kline, S. N.; Villanueva, P. J. Craniomaxillofac. Trauma 1999, 5(1), 7–12. 276. Shirakata, Y.; Setoguchi, T.; Machigashira, M.; et al. J. Periodontol. 2008, 79(1), 25–32. 277. Sinikovic´, B.; Kramer, F. J.; Swennen, G.; Lu¨bbers, H. T.; Dempf, R. Int. J. Oral Maxillofac. Surg. 2007, 36(1), 54–61. 278. Van Damme, P. A. J. Craniomaxillofac. Surg. 2005, 33(2), 75–78. 279. Wiltfang, J.; Kessler, P.; Buchfelder, M.; Merten, H. A.; Neukam, F. W.; Rupprecht, S. J. Oral Maxillofac. Surg. 2004, 62(1), 29–35. 280. Wiltfang, J.; Kloss, F. R.; Kessler, P.; et al. Clin. Oral Implants Res. 2004, 15(2), 187–193. 281. Wolff, K. D.; Swaid, S.; Nolte, D.; Bo¨ckmann, R. A.; Ho¨lzle, F.; Mu¨ller-Mai, C. J. Craniomaxillofac. Surg. 2004, 32(2), 71–79. 282. Wright, S.; Bekiroglu, F.; Whear, N. M.; Grew, N. R. Br. J. Oral Maxillofac. Surg. 2006, 44(6), 531–533. 283. Arisan, V.; Ozdemir, T.; Anil, A.; Jansen, J. A.; Ozer, K. Int. J. Oral Maxillofac. Implants 2008, 23(6), 1053–1062. 284. Cavalcanti, S. C.; Pereira, C. L.; Mazzonetto, R.; de Moraes, M.; Moreira, R. W. J. Craniomaxillofac. Surg. 2008, 36(6), 354–359. 285. Habraken, W. J.; de Jonge, L. T.; Wolke, J. G.; Yubao, L.; Mikos, A. G.; Jansen, J. A. J. Biomed. Mater. Res. A 2008, 87(3), 643–655. 286. Kroese-Deutman, H. C.; Wolke, J. G.; Spauwen, P. H.; Jansen, J. A. J. Biomed. Mater. Res. A 2006, 79(3), 503–511. 287. Link, D. P.; van den Dolder, J.; van den Beucken, J. J.; et al. J. Biomed. Mater. Res. A 2009, 90(2), 372–379. 288. Zuo, Y.; Yang, F.; Wolke, J. G.; Li, Y.; Jansen, J. A. Acta Biomater. 2010, 6(4), 1238–1247. 289. Khairoun, I.; Boltong, M. G.; Driessens, F. C. M.; Planell, J. A. Biomaterials 1997, 18, 1535–1539. 290. Knabe, C.; Berger, G.; Gildenhaar, R.; et al. J. Biomed. Mater. Res. 2004, 69A, 145–154. 291. Knabe, C.; Berger, G.; Gildenhaar, R.; Howlett, C. R.; Markovic, B.; Zreiqat, H. Biomaterials 2004, 25, 335–344. 292. Ooms, E. M.; Wolke, J. G.; van der Waerden, J. P.; Jansen, J. A. J. Biomed. Mater. Res. 2002, 61, 9–18. 293. Cuisinier, F. J. G.; Wieber, A.; Tenenbaum, H.; van Landuyt, P.; Lemaitre, J. J. Appl. Biomater. Biomech. 2003, 1, 186–193. 294. Dombrowski, F.; Ploska, U.; Berger, G.; Gildenhaar, R.; Stiller, M.; Knabe, C. Bioceramics Key Eng. Mater. 2009, 422–429, 863–866. 295. Gildenhaar, R.; Berger, G.; Lehmann, E.; Knabe, C. Key Eng. Mater. 2008, 361–363, 331–334. 296. Jo¨rn, D.; Gildenhaar, R.; Berger, G.; Stiller, M.; Knabe, C.; Schlau, S. Biomaterialien 2008, 9(3/4), 178. 297. Jo¨rn, D.; Gildenhaar, R.; Berger, G.; Stiller, M.; Knabe, C. Key Eng. Mater. 2009, 396–398, 213–216. 298. Knabe, C.; Berger, G.; Gildenhaar, R.; Ducheyne, P.; Stiller, M. In Vicenzini, P., Ed.; Advances in Science and Technology; Trans Tech: Switzerland, 2010; Vol. 76, pp 214–223. 299. Broggini, N.; Hofstetter, W.; Hunziker, E.; et al. Clin. Implant Dent. Relat. Res. 2011, 13(1), 1–12. 300. Esposito, M.; Grusovin, M. G.; Rees, J.; et al. Eur. J. Oral Implantol. 2010, 3(1), 7–26; Review.

323

301. Mooren, R. E.; Dankers, A. C.; Merkx, M. A.; Bronkhorst, E. M.; Jansen, J. A.; Stoelinga, P. J. Int. J. Oral Maxillofac. Surg. 2010, 39(4), 371–378. 302. Klongnoi, B.; Rupprecht, S.; Kessler, P.; et al. J. Clin. Periodontol. 2006, 33(7), 500–509. 303. Costello, B. J.; Shah, G.; Kumta, P.; Sfeir, C. S. Oral Maxillofac. Surg. Clin. North Am. 2010, 22(1), 33–42; Review. 304. Davies, S. D.; Ochs, M. W. Oral Maxillofac. Surg. Clin. North Am. 2010, 22(1), 17–31; Review. 305. Hallman, M.; Thor, A. Periodontol. 2000 2008, 47, 172–192; Review. 306. Hanisch, O.; Sorensen, R. G.; Kinoshita, A.; Spiekermann, H.; Wozney, J. M.; Wikesjo¨, U. M. J. Periodontol. 2003, 74(5), 648–657. 307. Hanisch, O.; Tatakis, D. N.; Boskovic, M. M.; Rohrer, M. D.; Wikesjo¨, U. M. Int. J. Oral Maxillofac. Implants 1997, 12(5), 604–610. 308. Hanisch, O.; Tatakis, D. N.; Rohrer, M. D.; Wo¨hrle, P. S.; Wozney, J. M.; Wikesjo¨, U. M. Int. J. Oral Maxillofac. Implants 1997, 12(6), 785–792. 309. Leach, J. K.; Mooney, D. J. Expert Opin. Biol. Ther. 2004, 4(7), 1015–1027; Review. 310. Rolda´n, J. C.; Jepsen, S.; Miller, J.; et al. Bone 2004, 34(1), 80–90. 311. Rolda´n, J. C.; Jepsen, S.; Schmidt, C.; et al. Clin. Oral Implants Res. 2004, 15(6), 716–723. 312. Ruhe´, P. Q.; Kroese-Deutman, H. C.; Wolke, J. G.; Spauwen, P. H.; Jansen, J. A. Biomaterials 2004, 25(11), 2123–2132. 313. Terheyden, H.; Jepsen, S.; Mo¨ller, B.; Rueger, D. Laryngorhinootologie 2001, 80(1), 47–51; German. 314. Terheyden, H.; Jepsen, S.; Vogeler, S.; Tucker, M.; Rueger, D. C. Mund Kiefer Gesichtschir. 1997, 1(5), 272–275. 315. Terheyden, H.; Knak, C.; Jepsen, S.; Palmie, S.; Rueger, D. R. Int. J. Oral Maxillofac. Surg. 2001, 30(5), 373–379. 316. Terheyden, H.; Menzel, C.; Wang, H.; Springer, I. N.; Rueger, D. R.; Acil, Y. Int. J. Oral Maxillofac. Surg. 2004, 33(2), 164–172. 317. Terheyden, H.; Warnke, P.; Dunsche, A.; et al. Int. J. Oral Maxillofac. Surg. 2001, 30(6), 469–478. 318. Wang, H. L.; Greenwell, H.; Fiorellini, J.; et al. J. Periodontol. 2005, 76(9), 1601–1622; Review. 319. Warnke, P. H.; Bolte, H.; Schu¨nemann, K.; et al. J. Craniomaxillofac. Surg. 2010, 38(1), 54–59. 320. Warnke, P. H.; Wiltfang, J.; Springer, I.; et al. Biomaterials 2006, 27(17), 3163–3167. 321. Wikesjo¨, U. M.; Sorensen, R. G.; Kinoshita, A. J. Clin. Periodontol. 2004, 31(8), 662–670. 322. Arosarena, O. A.; Collins, W. L. Otolaryngol. Head Neck Surg. 2005, 132(4), 592–597. 323. Barboza, E. P.; Cau´la, A. L.; Cau´la Fde, O.; et al. J. Periodontol. 2004, 75(5), 702–708. 324. Bessa, P. C.; Casal, M.; Reis, R. L. J. Tissue Eng. Regen. Med. 2008, 2(2–3), 81–96; Review. 325. Dunn, C. A.; Jin, Q.; Taba, M., Jr.; Franceschi, R. T.; Bruce Rutherford, R.; Giannobile, W. V. Mol. Ther. 2005, 11(2), 294–299. 326. Letic-Gavrilovic, A.; Piattelli, A.; Abe, K. J. Mater. Sci. Mater. Med. 2003, 14(2), 95–102. 327. Smith, D. M.; Afifi, A. M.; Cooper, G. M.; Mooney, M. P.; Marra, K. G.; Losee, J. E. J. Craniofac. Surg. 2008, 19(5), 1315–1322. 328. Wikesjo¨, U. M.; Xiropaidis, A. V.; Thomson, R. C.; Cook, A. D.; Selvig, K. A.; Hardwick, W. R. J. Clin. Periodontol. 2003, 30(8), 715–725. 329. Wikesjo¨, U. M.; Xiropaidis, A. V.; Thomson, R. C.; Cook, A. D.; Selvig, K. A.; Hardwick, W. R. J. Clin. Periodontol. 2003, 30(8), 705–714. 330. Moore, J. C.; Matukas, V. J.; Deatherage, J. R.; Miller, E. J. Int. J. Oral Maxillofac. Surg. 1990, 19(3), 172–176. 331. Trombelli, L.; Farina, R. J. Clin. Periodontol. 2008, 35(Suppl. 8), 117–135; Review. 332. Esposito, M.; Grusovin, M. G.; Coulthard, P.; Worthington, H. V. Int. J. Oral Maxillofac. Implants 2006, 21(5), 696–710; Review. 333. Smeets, R.; Maciejewski, O.; Gerressen, M.; et al. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 2009, 108(4), e3–e12. 334. Springer, I. N.; Ac¸il, Y.; Kuchenbecker, S.; et al. Bone 2005, 37(4), 563–569. 335. Warnke, P. H.; Springer, I. N.; Acil, Y.; et al. Biomaterials 2006, 27(7), 1081–1087. 336. Wikesjo¨, U. M.; Huang, Y. H.; Polimeni, G.; Qahash, M. Oral Maxillofac. Surg. Clin. North Am. 2007, 19(4), 535–551; vi–vii, Review. 337. Abu-Serriah, M. M.; Odell, E.; Lock, C.; Gillar, A.; Ayoub, A. F.; Fleming, R. H. Br. J. Oral Maxillofac. Surg. 2004, 42(5), 410–418. 338. Haidar, Z. S.; Hamdy, R. C.; Tabrizian, M. Biotechnol. Lett. 2009, 31(12), 1825–1835.

324

Dentistry, and Oral and Maxillofacial Surgery

339. Haidar, Z. S.; Hamdy, R. C.; Tabrizian, M. Biotechnol. Lett. 2009, 31(12), 1817–1824; Review. 340. Food and Drug Administration, HHS. Fed. Regist. 2005, 70(81), 21947–21950. 341. FDA Communication of Jun 6, 2008: Follow-up to the Mar 27, 2008, Communication About the Ongoing Safety Review of Regranex (Becaplermin). 342. FDA Public Health Notification: Life-Threatening Complications Associated with Recombinant Human Bone Morphogenetic Protein in Cervical Spine Fusion, July 1, 2008. 343. Koch, F. P.; Becker, J.; Terheyden, H.; Capsius, B.; Wagner, W. Clin. Oral Implants Res. 2010, 21(11), 1301–1308. 344. Potijanyakul, P.; Sattayasansakul, W.; Pongpanich, S.; Leepong, N.; Kintarak, S. J. Oral Implantol. 2010, 36(3), 195–204. 345. Scheyer, E. T.; Velasquez-Plata, D.; Brunsvold, M. A.; Lasho, D. J.; Mellonig, J. T. J. Periodontol. 2002, 73(4), 423–432. 346. Velasquez-Plata, D.; Scheyer, E. T.; Mellonig, J. T. J. Periodontol. 2002, 73(4), 433–440; Erratum in J. Periodontol. 2002, 73(6), 684. 347. Merkx, M. A.; Maltha, J. C.; Stoelinga, P. J. Int. J. Oral Maxillofac. Surg. 2003, 32(1), 1–6. 348. Berger, G.; Gildenhaar, R.; Ploska, U. In Wilson, J., Hench, L. L., Greenspan, D. C., Eds.; Bioceramics; Butterworth-Heinemann: Oxford, UK, 1995; Vol. 8, pp 453–456. 349. Berger, G.; Gildenhaar, R.; Ploska, U. Biomaterials 1995, 16, 1241–1248. 350. Berger, G.; Mu¨cke, U.; Harbich, K. W. In Ben-Nissan, B., Sher, D., Walsh, W. R., Eds.; Key Engineering Materials; Trans Tech: Zurich, Switzerland, 2003; Vols. 240–242, pp 469–472. 351. Schneider, M.; Gildenhaar, R.; Berger, G. Cryst. Res. Technol. 1994, 29, 671–675. 352. Berger, G.; Gildenhaar, R.; Ploska, U. In LeGeros, R. Z., LeGeros, J. P., Eds.; Bioceramics; World Scientific: Singapore, Malaysia, 1998; Vol. 11, pp 121–124. 353. Berger, G.; Gildenhaar, R.; Ploska, U.; Willfahrt, M. In Sedel, L. C., Rey, C., Eds.; Bioceramics; Elsevier Science: Oxford, UK, 1997; Vol. 10, pp 367–370.

354. 355. 356. 357. 358. 359. 360. 361. 362. 363. 364. 365.

366.

367.

368.

369.

Crawford, R.; et al. J. Bone Joint Surg. Br. 1999, 81, 552–554. Sun, J. S.; et al. J. Arthroplasty 2003, 18(3), 352–360. Sun, J. S.; et al. J. Biomed. Mater. Res. 1997, 37, 324–334. Sun, J. S.; et al. Artif. Organs 1999, 23(4), 331–338. Berger, G. In Federal Institute for Materials Research and Testing (BAM) Annual Report, BAM: Berlin, Germany, 2003; pp 34–43. Knabe, C.; Stiller, M.; Berger, G.; et al. Clin. Oral Implants Res. 2005, 16, 119–127. Knabe, C.; Gildenhaar, R.; Berger, G.; et al. J. Mater. Sci. Mater. Med. 1998, 9, 337–345. Knabe, C.; Berger, G.; Gildenhaar, R.; et al. In Transactions of the 32nd Annual Meeting of the Society for Biomaterials USA, Chicago, IL, Apr 18–21, 2007 p 262. El-Ghannam, A.; Ducheyne, P.; Shapiro, I. M. J. Biomed. Mater. Res. 1997, 36(2), 167–180. Roeser, K.; Johansson, C. B.; Donath, K.; Albrektsson, T. J. Biomed. Mater. Res. 2000, 51, 280–291. Knabe, C.; Kraska, B.; Koch, Ch.; Gross, U.; Zreiqat, H.; Stiller, M. Biotech. Histochem. 2006, 81, 31–39. Knabe, C.; Berger, G.; Gildenhaar, R.; et al. In Transactions of the 35th Annual Meeting of the Society for Biomaterials USA, San Antonio, TX, Apr 22–25, 2009 p 262. Knabe, C.; Kim, J.; Chen, C.; Meausoone, V.; Radin, S.; Ducheyne, P. In Transactions of the 35th Annual Meeting of the Society for Biomaterials USA, San Antonio, TX, Apr 22–25, 2009 p 359. Knabe, C.; Berger, G.; Gildenhaar, R.; Ducheyne, P.; Stiller, M. In Advances in Science and Technology; Vicenzini, P., Ed.; Trans Tech Publications: Switzerland, 2010; Vol. 76, pp 214–223. Kim, J.; Berger, G.; Gildenhaar, R.; Shapiro, I.; Ducheyne, P.; Knabe, C. In Transactions 36th Annual Meeting of the Society for Biomaterials USA. April 21–24, Seattle, Washington, USA, 2010; p 830. Ohgushi, H.; Dohi, Y.; Susumu, T.; Tabata, S. J. Biomed. Mater. Res. 1993, 27, 1401–1407.