Giuseppe Polimeni

Alveolar ridge augmentation using implants coated with recombinant human bone morphogenetic protein-2: Histologic observations

BACKGROUNDnStudies using ectopic rodent, orthotopic canine, and non-human primate models show that bone morphogenetic proteins (BMPs) coated onto titanium surfaces induce local bone formation. The objective of this study was to examine the ability of recombinant human BMP-2 (rhBMP-2) coated onto a titanium porous oxide implant surface to stimulate local bone formation including osseointegration and vertical augmentation of the alveolar ridge.nnnMATERIAL AND METHODSnBilateral, critical-size, 5 mm, supra-alveolar, peri-implant defects were created in 12 young adult Hound Labrador mongrel dogs. Six animals received implants coated with rhBMP-2 at 0.75 or 1.5 mg/ml, and six animals received implants coated with rhBMP-2 at 3.0 mg/ml or uncoated control. Treatments were randomized between jaw quadrants. The mucoperiosteal flaps were advanced, adapted and sutured to submerge the implants for primary intention healing. The animals received fluorescent bone markers at weeks 3, 4, 7 and 8 post-surgery when they were euthanized for histologic evaluation.nnnRESULTSnJaw quadrants receiving implants coated with rhBMP-2 exhibited gradually regressing swelling that became hard to palpate disguising the contours of the implants. The histologic evaluation showed robust bone formation reaching or exceeding the implant platform. The newly formed bone exhibited characteristics of the adjoining resident Type II bone including cortex formation for sites receiving implants coated with rhBMP-2 at 0.75 or 1.5 mg/ml. Sites receiving implants coated with rhBMP-2 at 3.0 mg/ml exhibited more immature trabecular bone formation, seroma formation and peri-implant bone remodelling resulting in undesirable implant displacement. Control implants exhibited minimal, if any, bone formation. Thus, implants coated with rhBMP-2 at 0.75, 1.5 and 3.0 mg/ml exhibited significant bone formation (height and area) compared with the sham-surgery control averaging (+/-SD) 4.4+/-0.4, 4.2+/-0.7 and 4.2+/-1.2 versus 0.8+/-0.3 mm; and 5.0+/-2.2, 5.6+/-2.2 and 7.4+/-3.5 versus 0.7+/-0.3 mm(2), respectively (p<0.01). All the treatment groups exhibited clinically relevant osseointegration.nnnCONCLUSIONSnrhBMP-2 coated onto titanium porous oxide implant surfaces induced clinically relevant local bone formation including vertical augmentation of the alveolar ridge and osseointegration. Higher concentrations/doses were associated with untoward effects.

Alveolar ridge augmentation using implants coated with recombinant human bone morphogenetic protein-2: radiographic observations.

OBJECTIVESnEffective carrier technologies and dosing appear critical for the successful use of bone morphogenetic proteins (BMPs). This study evaluated radiographically the potential of a purpose-designed titanium porous-oxide implant surface combined with recombinant human BMP-2 (rhBMP-2) to stimulate alveolar ridge augmentation.nnnMATERIAL AND METHODSnTwelve young-adult Labrador dogs were used. Three 10-mm titanium implants per jaw quadrant were placed 5 mm into the alveolar ridge following extraction of the premolar teeth and reduction of alveolar ridge. Six animals received implants coated with rhBMP-2 at 0.75 or 1.5 mg/ml randomized to contralateral jaw quadrants. Another six animals received implants coated with rhBMP-2 at 3 mg/ml or uncoated control using the same split-mouth design. The mucoperiosteal flaps were advanced, adapted, and sutured to submerge the implants. Radiographic registrations were made immediately postsurgery (baseline), and at weeks 4 and 8 (end of study).nnnRESULTSnrhBMP-2-coated implants exhibited robust radiographic bone formation extending to and above the implant platform from week 4 (P<0.01). Some rhBMP-2-coated implants showed voids within the newly formed bone that gradually resolved and/or implant displacement, being severe in two animals receiving implants coated with rhBMP-2 at 3 mg/ml. Controls showed limited, if any, new bone formation at weeks 4 and 8 postsurgery. There were no significant differences among the rhBMP-2 groups in bone gain.nnnCONCLUSIONSnThe titanium porous-oxide surface serves as an effective carrier for rhBMP-2, showing a clinically significant potential to stimulate local bone formation. With the carrier technology used, therapeutic dosage appears to be in the range of 0.75-1.5 mg/ml.

Bone morphogenetic proteins for periodontal and alveolar indications; biological observations – clinical implications

Surgical placement of endosseous oral implants is governed by the prosthetic design and by the morphology and quality of the alveolar bone. Nevertheless, often implant placement may be complexed, if at all possible, by alveolar ridge irregularities resulting from periodontal disease, and chronic and acute trauma. In consequence, implant positioning commonly necessitates bone augmentation procedures. One objective of our laboratory is to evaluate the biologic potential of bone morphogenetic proteins (BMP) and other candidate biologics, bone biomaterials, and devices for alveolar ridge augmentation and implant fixation using discriminating large animal models. This focused review illustrates the unique biologic potential, the clinical relevance and perspectives of recombinant human BMP-2 (rhBMP-2) using a variety of carrier technologies to induce local bone formation and implant osseointegration for inlay and onlay indications. Our studies demonstrate a clinically relevant potential of a purpose-designed titanium porous oxide implant surface as stand-alone technology to deliver rhBMP-2 for alveolar augmentation. In perspective, merits and shortcomings of current treatment protocol including bone biomaterials and guided bone regeneration are addressed and explained. We demonstrate that rhBMP-2 has unparalleled potential to augment alveolar bone, and support implant osseointegration and long-term functional loading. Inclusion of rhBMP-2 for alveolar augmentation and osseointegration will not only enhance predictability of existing clinical protocol but also radically change current treatment paradigms.

Histopathological Observations of a Polylactic Acid‐Based Device Intended for Guided Bone/Tissue Regeneration

BACKGROUNDnBarrier devices have been shown to support alveolar bone and periodontal regeneration, a procedure also known as guided bone/tissue regeneration (GBR/GTR). Popular demand and clinical convenience have raised an interest in bioresorbable barrier devices. Tissue reactions to such bioresorbable devices are, however, generally not well explored.nnnPURPOSEnThe objective of this study was to evaluate short- and long-term tissue reactions following implantation of a bioresorbable polylactic acid (PLA)-based barrier device using a rat model.nnnMATERIALS AND METHODSnTwenty-one young adult male Sprague-Dawley rats were used. The animals were divided into three groups including 15 animals receiving the PLA device and animals serving as sham surgery (five) or nonoperated (one) controls. Using aseptic techniques, the PLA device was surgically implanted in direct contact with the calvarial bone. Animals receiving the PLA device were sacrificed at 3, 5, 7, and 12 months postsurgery to provide longitudinal histopathological observations of tissue and biomaterials reactions. Control animals were sacrificed at 3 months.nnnRESULTSnAnimals were maintained without adverse events. Sham surgery and nonoperated control animals showed no signs of new bone formation or resorption, or signs of inflammatory reactions in adjoining soft tissues. In contrast, extensive amounts of residual biomaterial with evidence of foreign body reactions and bone resorption were observed in animals receiving the PLA device over 12 months.nnnCONCLUSIONSnThe results suggest that the PLA device may induce bone resorbing foreign body reactions. Importantly, the PLA device does not resorb within a 12-month healing interval. These biomaterials properties may influence new bone formation and maintenance when applying the device for GBR/GTR.

Alveolar ridge augmentation using implants coated with recombinant human bone morphogenetic protein‐7 (rhBMP‐7/rhOP‐1): histological observations

BACKGROUNDnPre-clinical studies have shown that recombinant human bone morphogenetic protein-2 (rhBMP-2) coated onto purpose-designed titanium porous-oxide surface implants induces clinically relevant bone formation and osseointegration. The objective of this study was to examine the potential of rhBMP-7, also known as recombinant human osteogenic protein-1 (rhOP-1), coated onto titanium porous-oxide surface implants to support vertical alveolar ridge augmentation and implant osseointegration.nnnMATERIALS AND METHODSnBilateral, critical-size, 5 mm, supraalveolar peri-implant defects were created in six young adult Hound Labrador mongrel dogs. The animals received implants coated with rhBMP-7 at 1.5 or 3.0 mg/ml randomized to contra-lateral jaw quadrants. The mucoperiosteal flaps were advanced, adapted, and sutured to submerge the implants for primary intention healing. The animals received fluorescent bone markers at 3, 4, 7, and 8 weeks post-surgery when they were euthanized for histological evaluation.nnnRESULTSnWithout striking differences between treatments, the implant sites exhibited a swelling that gradually regressed to become hard to palpation disguising the implant contours. The histological evaluation showed robust bone formation; the newly formed bone assuming characteristics of the contiguous resident bone, bone formation (height and area) averaging 4.1+/-1.0 versus 3.6+/-1.7 mm and 3.6+/-1.9 versus 3.1+/-1.8 mm(2); and bone density 56%versus 50% for implants coated with rhBMP-7 at 1.5 and 3.0 mg/ml, respectively. Both treatments exhibited clinically relevant osseointegration, the corresponding bone-implant contact values averaging 51% and 47%. Notable peri-implant resident bone remodelling was observed for implants coated with rhBMP-7 at 3.0 mg/ml.nnnCONCLUSIONSnrhBMP-7 coated onto titanium porous-oxide surface implants induces clinically relevant local bone formation including osseointegration and vertical augmentation of the alveolar ridge, the higher concentration/dose associated with some local side effects.

Alveolar ridge augmentation using implants coated with recombinant human growth/ differentiation factor-5: histologic observations

OBJECTIVESnIn vitro and in vivo preclinical studies suggest that growth/differentiation factor-5 (GDF-5) may induce local bone formation. The objective of this study was to evaluate the potential of recombinant human GDF-5 (rhGDF-5) coated onto an oral implant with a purpose-designed titanium porous oxide surface to stimulate local bone formation including osseointegration and vertical augmentation of the alveolar ridge.nnnMATERIALS AND METHODSnBilateral, critical-size, 5 mm, supraalveolar peri-implant defects were created in 12 young adult Hound Labrador mongrel dogs. Six animals received implants coated with 30 or 60 microg rhGDF-5, and six animals received implants coated with 120 microg rhGDF-5 or left uncoated (control). Treatments were alternated between jaw quadrants. The mucoperiosteal flaps were advanced, adapted, and sutured to submerge the implants for primary intention healing. The animals received fluorescent bone markers at weeks 3, 4, 7, and 8 post-surgery when they were euthanized for histologic evaluation.nnnRESULTSnThe clinical examination showed no noteworthy differences between implants coated with rhGDF-5. The cover screw and implant body were visible/palpable through the alveolar mucosa for both rhGDF-5-coated and control implants. There was a small increase in induced bone height for implants coated with rhGDF-5 compared with the control, induced bone height averaging (+/-SD) 1.6+/-0.6 mm for implants coated with 120 microg rhGDF-5 versus 1.2+/-0.5, 1.2+/-0.6, and 0.6+/-0.2 mm for implants coated with 60 microg rhGDF-5, 30 microg rhGDF-5, or left uncoated, respectively (p<0.05). Bone formation was predominant at the lingual aspect of the implants. Narrow yellow and orange fluorescent markers throughout the newly formed bone indicate relatively slow new bone formation within 3-4 weeks. Implants coated with rhGDF-5 displayed limited peri-implant bone remodelling in the resident bone; the 120 microg dose exhibiting more advanced remodelling than the 60 and 30 microg doses. All treatment groups exhibited clinically relevant osseointegration.nnnCONCLUSIONSnrhGDF-5-coated oral implants display a dose-dependent osteoinductive and/or osteoconductive effect, bone formation apparently benefiting from local factors. Application of rhGDF-5 appears to be safe as it is associated with limited, if any, adverse effects.

Regenerative potential and healing dynamics of the periodontium: A critical-size supra-alveolar periodontal defect study

OBJECTIVESnThe nature and characteristics of the newly formed periodontium obtained following regenerative procedures remain a matter of controversy. The objective of this study was to evaluate the regenerative potential of the periodontal attachment and healing dynamics as observed from the spatial distribution of newly formed cementum, periodontal ligament (PDL) and alveolar bone following optimal circumstances for wound healing/regeneration in a discriminating animal model.nnnMATERIAL AND METHODSnCritical-size, 6-mm, supra-alveolar, periodontal defects were surgically created in six young adult Beagle dogs. Space-providing ePTFE devices with 300-microm laser-drilled pores were implanted to support wound stability and space provision in one jaw quadrant/animal. Treatments were alternated between left and right jaw quadrants in subsequent animals. The gingival flaps were advanced to submerge the defect sites for primary intention healing. Histometric analysis followed an 8-week healing interval.nnnRESULTSnHealing was uneventful in all animals. The histometric analysis showed that cementum regeneration (2.99 +/- 0.22 mm) was significantly greater than PDL (2.54 +/- 0.18 mm, p=0.03) and bone regeneration (2.46 +/- 0.26 mm, p=0.03). The wound area showed significant positive non-linear effect on cementum (log beta=1.25, p<0.001), PDL (log beta=1.24, p<0.001) and new bone formation (log beta=1.36, p<0.001). A high degree of concordance and significant linear relationship was observed between cementum, PDL and bone regeneration indicating that their formation virtually occurred in parallel.nnnCONCLUSIONSnCementum, PDL and alveolar bone virtually regenerate in parallel under optimal circumstances for periodontal wound healing/regeneration. Moreover, space provision positively influences the extent of periodontal regeneration.

Evaluation of implants coated with rhBMP‐2 using two different coating strategies: a critical‐size supraalveolar peri‐implant defect study in dogs

BACKGROUNDnImplants coated with recombinant human bone morphogenetic protein-2 (rhBMP-2) induce relevant bone formation but also resident bone remodelling.nnnOBJECTIVESnTo compare the effect of implants fully or partially coated with rhBMP-2 on new bone formation and resident bone remodelling.nnnMATERIALS AND METHODSnTwelve, male, adult, Hound Labrador mongrel dogs were used. Critical-size, supraalveolar, peri-implant defects received titanium porous oxide surface implants coated in their most coronal aspect with rhBMP-2 (coronal-load/six animals) or by immersion of the entire implant in an rhBMP-2 solution (soak-load/six animals) for a total of 30 mug rhBMP-2/implant. All implants were air-dried. The animals were euthanized at 8 weeks for histometric evaluation.nnnRESULTSnClinical healing was uneventful. Supraalveolar bone formation was not significantly affected by the rhBMP-2 application protocol. New bone height and area averaged (+/- SE) 3.4 +/- 0.2 versus 3.5 +/- 0.4 mm and 2.6 +/- 0.4 versus 2.5 +/- 0.7 mm(2) for coronal-load and soak-load implants, respectively (p>0.05). The corresponding bone density and bone-implant contact (BIC) recordings averaged 38.0 +/- 3.8%versus 34.4 +/- 5.6% and 25.0 +/- 3.8%versus 31.2 +/- 3.3% (p>0.05). In contrast, resident bone remodelling was significantly influenced by the rhBMP-2 application protocol. Bone density outside the implants threads averaged 74.7 +/- 3.8% and 50.8 +/- 4.1% for coronal-load and soak-load implants, respectively (p<0.05); bone density within the thread area averaged 51.8 +/- 1.2% and 37.8 +/- 2.9%, and BIC 70.1 +/- 6.7% and 43.3 +/- 3.9% (p<0.05).nnnCONCLUSIONnLocal application of rhBMP-2 appears to be a viable technology to support local bone formation and osseointegration. Coronal-load implants obviate resident bone remodelling without compromising new bone formation.

Evaluation of Implants Coated With Recombinant Human Bone Morphogenetic Protein-2 and Vacuum-Dried Using the Critical-Size Supraalveolar Peri-Implant Defect Model in Dogs

BACKGROUNDnEndosseous implants coated with recombinant human bone morphogenetic protein-2 (rhBMP-2) in a laboratory bench setting and air-dried induce relevant bone formation but also resident bone remodeling. Thus, the objective of this study is to evaluate the effect of implants fully or partially coated with rhBMP-2 and vacuum-dried using an industrial process on local bone formation and resident bone remodeling.nnnMETHODSnTwelve male adult Hound Labrador mongrel dogs were used. Critical-size, supraalveolar, peri-implant defects received titanium porous oxide surface implants coated in their most coronal aspect with rhBMP-2 (coronal-load, six animals), or by immersion of the entire implant in a rhBMP-2 solution (soak-load, six animals) for a total of 30 μg rhBMP-2 per implant. All implants were vacuum-dried. The animals were sacrificed at 8 weeks for histometric evaluation.nnnRESULTSnClinical healing was unremarkable. Bone formation was not significantly affected by the rhBMP-2 application protocol. New bone height and area averaged (± SE) 3.2 ± 0.5 versus 3.6 ± 0.3 mm, and 2.3 ± 0.5 versus 2.6 ± 0.8 mm(2) for coronal-load and soak-load implants, respectively (P >0.05). The corresponding bone density and bone-implant contact registrations averaged 46.7% ± 5.8% versus 31.6% ± 4.4%, and 28% ± 5.6% versus 36.9% ± 3.4% (P >0.05). In contrast, resident bone remodeling was significantly influenced by the rhBMP-2 application protocol. Peri-implant bone density averaged 72.2% ± 2.1% for coronal-load versus 60.6% ± 4.7% for soak-load implants (P <0.05); the corresponding bone-implant contact averaged 70.7% ± 6.1% versus 47.2% ± 6.0% (P <0.05).nnnCONCLUSIONSnLocal application of rhBMP-2 and vacuum-drying using industrial process seems to be a viable technology to manufacture implants that support local bone formation and osseointegration. Coronal-load implants obviate resident bone remodeling without compromising local bone formation.

Alveolar ridge augmentation using implants coated with recombinant human growth/differentiation factor -5 (rhGDF-5). Radiographic observations

OBJECTIVESnApplication of growth factors onto dental implant surfaces is being considered to support local bone formation. Bone morphogenetic protein-2 (BMP-2) and BMP-7 have been shown to support local bone formation, but are also associated with adverse events including seroma formation, extensive bone remodeling, and implant displacement captured in the radiographic evaluation. This report presents mineralized tissue formation and associated adverse events following implantation of recombinant human growth/differentiation factor-5 (rhGDF-5) coated onto a purpose-designed titanium porous-oxide implant surface.nnnMATERIAL AND METHODSnTwelve young adult Labrador dogs were used. Three 10-mm titanium implants/jaw quadrant were placed 5 mm into the alveolar ridge in the posterior mandible following surgical extraction of the premolar teeth and reduction of the alveolar ridge. Six animals received implants coated with rhGDF-5 at 30 or 60 μg/implant in contralateral jaw quadrants. Six animals received implants coated with rhGDF-5 at 120 μg/implant or uncoated implants (sham-surgery control) using the same split-mouth design. The mucoperiosteal flaps were advanced, adapted, and sutured to submerge the implants. Radiographic recordings were made immediately postsurgery (baseline), and at week 4 and 8 (end of study). Two masked examiners performed the analysis using computer enhanced radiographic images.nnnRESULTSnrhGDF-5 coated implants displayed mineralized tissue formation significantly exceeding that of the sham-surgery control in a dose-dependent order. The greatest increase was observed for implants coated with rhGDF-5 at 60 μg and 120 μg amounting to approximately 2.2 mm for both groups at 8 weeks. Importantly, none of the implants showed evidence of peri-implant bone remodeling, implant displacement, or seroma formation. The newly formed mineralized tissues assumed characteristics of the resident bone.nnnCONCLUSIONSnrhGDF-5 coated onto a titanium porous-oxide implant surface exhibits a dose-dependent potential to stimulate local mineralized tissue formation. Application of rhGDF-5 appears safe as it is associated with limited, if any, adverse events.