Mohammed Qahash

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

BACKGROUND Studies 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. MATERIAL AND METHODS Bilateral, 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. RESULTS Jaw 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. CONCLUSIONS rhBMP-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.

OBJECTIVES Effective 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. MATERIAL AND METHODS Twelve 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). RESULTS rhBMP-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. CONCLUSIONS The 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.

Bone formation at recombinant human bone morphogenetic protein‐2‐coated titanium implants in the posterior mandible (Type II bone) in dogs

BACKGROUND Conventional oral/maxillofacial implants reach osseointegration over several months during which the titanium fixtures interact with alveolar bone. The objective of this study was to determine if adsorbing recombinant human bone morphogenetic protein-2 (rhBMP-2) onto a titanium porous oxide (TPO) implant surface might enhance or accelerate local bone formation and support osseointegration in a large animal oral/maxillofacial orthotopic model. MATERIAL AND METHODS Endosseous implants with a TPO surface were installed into the edentulated posterior mandible in eight adult Hound Labrador mongrel dogs. The implant surface had been adsorbed with rhBMP-2 at 0.2 or 4.0 mg/ml. TPO implants without rhBMP-2 served as control. Treatments were randomized between jaw quadrants. Mucosal flaps were advanced and sutured leaving the implants submerged. Clinical and radiographic evaluations were made immediately post-surgery, at day 10 (suture removal), and week 4 and 8 post-surgery. The animals received fluorescent bone markers at week 3, 4, and at week 8 post-surgery, when they were euthanized for histologic analysis. RESULTS TPO implants coated with rhBMP-2 exhibited dose-dependent bone remodelling including immediate resorption and formation of implant adjacent bone, and early establishment of clinically relevant osseointegration. The resulting bone-implant contact, although clinically respectable, appeared significantly lower for rhBMP-2-coated implants compared with the control [rhBMP-2 (0.2 mg/ml) 43.3+/-10.8%versus 71.7+/-7.8%, p<0.02; rhBMP-2 (4.0 mg/ml) 35.4+/-10.6%versus 68.2+/-11.0%, p<0.03]. CONCLUSIONS rhBMP-2 adsorbed onto TPO implant surfaces initiates dose-dependent peri-implant bone re-modelling resulting in the formation of normal, physiologic bone and clinically relevant osseointegration within 8 weeks.

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

BACKGROUND Pre-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. MATERIALS AND METHODS Bilateral, 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. RESULTS Without 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. CONCLUSIONS rhBMP-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

OBJECTIVES In 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. MATERIALS AND METHODS Bilateral, 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. RESULTS The 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. CONCLUSIONS rhGDF-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.

Histological and biomechanical evaluation of phosphorylcholine‐coated titanium implants

OBJECTIVE Compounds considered for drug delivery from oral implant surfaces in support of local bone formation might themselves influence osseointegration. Phosphorylcholine (PC) polymers have been shown to enhance the biocompatibility of medical devices and to serve as drug delivery systems. The objective of this study was to evaluate local bone formation and osseointegration at PC and positively charged PC (PC+)-coated endosseous implants in an established rabbit model. MATERIAL AND METHODS Sixteen adult female New Zealand White rabbits were used. Eight animals received PC-coated and control titanium porous oxide surface implants placed in the left and right distal femural condyle (trabecular bone) and proximal tibial metaphysis (cortical bone) using aseptic routines. The remaining eight animals similarly received PC+ and control implants. One implant was placed in each femural condyle and two implants in each tibial metaphysis. Experimental and control implants were alternated between the left and right hind legs. Fascia and skin were closed in layers. The animals were euthanized following a 6-week healing interval for biomechanical (removal torque) and histometric analyses. RESULTS Peri-implant bone density was considerably greater at tibial compared with femoral sites within as well as immediately outside the implant threads. However, there were no significant differences in bone density among PC, PC+, and control implants. Nevertheless, bone-implant contact was significantly lower at PC compared with PC+ and control implants in cortical bone (p<0.05). Numerical differences in trabecular bone did not reach statistical significance. The removal torque evaluation revealed significantly lower values for PC compared with PC+ and control sites (p<0.05). CONCLUSION The histometric and biomechanical analyses suggest that PC coating may influence biological processes and ultimately osseointegration of endosseous implants. Apparently, incorporation of cationic charges may reverse or compensate for this scenario. Nevertheless, both PC coatings exhibited clinically acceptable osseointegration. In perspective, PC technology appears to be a viable candidate delivery system for agents in support of local bone formation at endosseous implant surfaces.

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

OBJECTIVES Application 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. MATERIAL AND METHODS Twelve 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. RESULTS rhGDF-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. CONCLUSIONS rhGDF-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.