Jaebum Lee

Evaluation of nano‐technology‐modified zirconia oral implants: a study in rabbits

OBJECTIVE The objective of this study was to screen candidate nano-technology-modified, micro-structured zirconia implant surfaces relative to local bone formation and osseointegration. MATERIALS AND METHODS Proprietary nano-technology surface-modified (calcium phosphate: CaP) micro-structured zirconia implants (A and C), control micro-structured zirconia implants (ZiUnite), and titanium porous oxide implants (TiUnite) were implanted into the femoral condyle in 40 adult male New Zealand White rabbits. Each animal received one implant in each hind leg; thus, 20 animals received A and C implants and 20 animals received ZiUnite and TiUnite implants in contralateral hind legs. Ten animals/group were euthanized at weeks 3 and 6 when biopsies of the implant sites were processed for histometric analysis using digital photomicrographs produced using backscatter scanning electron microscopy. RESULTS The TiUnite surface demonstrated significantly greater bone-implant contact (BIC) (77.6+/-2.6%) compared with the A (64.6+/-3.6%) and C (62.2+/-3.1%) surfaces at 3 weeks (p<0.05). Numerical differences between ZiUnite (70.5+/-3.1%) and A and C surfaces did not reach statistical significance (p>0.05). Similarly, there were non-significant differences between the TiUnite and the ZiUnite surfaces (p>0.05). At 6 weeks, there were no significant differences in BIC between the TiUnite (67.1+/-4.2%), ZiUnite (69.7+/-5.7%), A (68.6+/-1.9%), and C (64.5+/-4.1%) surfaces (p>0.05). CONCLUSION TiUnite and ZiUnite implant surfaces exhibit high levels of osseointegration that, in this model, confirm their advanced osteoconductive properties. Addition of CaP nano-technology to the ZiUnite surface does not enhance the already advanced osteoconductivity displayed by the TiUnite and ZiUnite implant surfaces.

Periodontal Regeneration: Focus on Growth and Differentiation Factors

Several growth and differentiation factors have shown potential as therapeutic agents to support periodontal wound healing/regeneration, although optimal dosage, release kinetics, and suitable delivery systems are still unknown. Experimental variables, including delivery systems, dose, and the common use of poorly characterized preclinical models, make it difficult to discern the genuine efficacy of each of these factors. Only a few growth and differentiation factors have reached clinical evaluation. It appears that well-defined discriminating preclinical models followed by well-designed clinical trials are needed to further investigate the true potential of these and other candidate factors. Thus, current research is focused on finding relevant growth and differentiation factors, optimal dosages, and the best approaches for delivery to develop clinically meaningful therapies in patient-centered settings.

Effect of bone morphogenetic protein‐2, demineralized bone matrix and systemic parathyroid hormone (1‐34) on local bone formation in a rat calvaria critical‐size defect model

AIM To determine the potential of recombinant human bone morphogenetic protein-2 (rhBMP-2) soak-loaded on to an absorbable collagen sponge (ACS) to induce local bone formation compared with the clinical reference demineralized bone matrix (DBM) and to investigate potential additive/synergistic effects of exogenous parathyroid hormone (PTH). METHODS Critical-size (8 mm), through-through calvaria osteotomy defects in 160 adult male Sprague-Dawley rats were randomized to receive one of eight interventions: rhBMP-2/ACS, DBM, ACS, or serve as controls (empty defects) combined or not with systemic PTH. Ten animals from each group were followed for 4 and 8 wks for radiographic and histometric analysis. Multivariable analysis was used to assess the effect of experimental intervention and healing time on local bone formation. RESULTS In the multivariable analysis, rhBMP-2/ACS exhibited significantly greater histologic bone formation than control (β ± SE: 54.76 ± 5.85, p < 0.001) and ACS (β ± SE: 9.14 ± 3.31, p = 0.007) whereas DBM showed significantly less bone formation than control (β ± SE: -32.32 ± 8.23, p < 0.001). Overall, PTH did not show a significant effect on bone formation (β ± SE: 2.72 ± 6.91, p = 0.70). No significant differences in histological defect closure were observed between 4 and 8 wks for all but the control group without PTH. CONCLUSION rhBMP-2/ACS significantly stimulates local bone formation whereas bone formation appears significantly limited by DBM. Systemic application of PTH provided no discernible additive/synergistic effects on local bone formation.

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

BACKGROUND Implants coated with recombinant human bone morphogenetic protein-2 (rhBMP-2) induce relevant bone formation but also resident bone remodelling. OBJECTIVES To compare the effect of implants fully or partially coated with rhBMP-2 on new bone formation and resident bone remodelling. MATERIALS AND METHODS Twelve, 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. RESULTS Clinical 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). CONCLUSION Local 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.

Wound healing following surgical and regenerative periodontal therapy.

Clinical studies have evaluated the effect of conventional periodontal surgical therapy. In general, although some clinical gain in tissue support may be attained, these therapies do not support regeneration of the periodontal attachment. Even though the biological possibility of periodontal regeneration has been demonstrated, the clinical application of this intrinsic potential appears difficult to harness; thus also conceptually most intriguing candidate protocols face clinical challenges. In this review, we explore the bioclinical principles, condiciones sine quibus non, that unleash the innate potential of the periodontium to achieve clinically meaningful periodontal regeneration (i.e. space-provision, wound stability and conditions for primary intention healing). Moreover, limiting factors and detrimental practices that may compromise clinical and biological outcomes are reviewed, as is tissue management in clinical settings.

Effect of rhBMP‐2 dose on bone formation/maturation in a rat critical‐size calvarial defect model

BACKGROUND Application of recombinant human bone morphogenetic protein-2 (rhBMP-2) has been associated with significant adverse events in craniofacial settings, including swelling and seroma formation. Recent work has demonstrated an inverse relationship between bone formation/maturation and rhBMP-2 dose, frequency/severity of adverse events increasing with rising dose. OBJECTIVE The objective of this study was to determine the most effective dose for rhBMP-2 soak-loaded onto an absorbable collagen sponge (ACS) carrier for bone formation/maturation using an established defect model. METHODS One hundred sixty-eight outbred male Sprague-Dawley rats, age 11-13 weeks, weight 325-375 g randomized into seven groups of 24 subdivided into groups of eight, were used to provide radiographic and light microscopy observations of bone formation/maturation and aberrant healing events at 2, 4 and 8 weeks following application of rhBMP-2/ACS into critical-size, ø8-mm, through-through, calvarial osteotomy defects for a dose of 1.25, 2.5, 5.0, 10.0 and 20.0 μg rhBMP-2/defect, or serve as ACS or sham-surgery controls. RESULTS rhBMP-2 dosages ≥ 2.5 μg/defect showed histological defect closure >90% within 2 weeks, and complete resolution within 4 weeks. Adverse healing events including swelling, excessive bone formation or seroma formation could not be determined with certainty in this defect model. Notably ACS control sites showed complete defect closure at the 8-week healing interval. CONCLUSIONS rhBMP-2/ACS accelerates local bone formation in the rat critical-size through-through calvarial defect model once reaching an osteoinductive dose threshold. This threshold may already be reached at a 1.25-/2.5-μg dose in this model. No further enhancement to bone formation/maturation may be observed adding rhBMP-2 above the 2.5-μg dose. The 1.25-20.0 μg dose range did not invoke appreciable aberrant healing events.

Growth/differentiation factor‐5: pre‐clinical and clinical evaluations of periodontal regeneration and alveolar augmentation – review

AIM Growth/differentiation factor-5 (GDF-5) plays critical roles in mesenchymal cell differentiation and stimulates human periodontal ligament cell proliferation. Potentially, GDF-5 may also play roles in wound healing including periodontal regeneration and alveolar augmentation. The objective of this review was to provide up-to-date information from pre-clinical/clinical studies evaluating GDF-5 for these indications. METHODS A comprehensive search using PubMed and Google search engines was conducted to identify reports on GDF-5 applied to periodontal and alveolar indications. Two reviewers independently screened the titles and abstracts from a total of 479 reports. Full-length articles of 17 pre-clinical and four clinical studies were selected and reviewed. RESULTS Canine-, porcine- and non-human primate-based models as well as human clinical trials were used in the evaluation of GDF-5 in support of periodontal regeneration and alveolar augmentation. An absorbable collagen sponge (ACS), β-tricalcium phosphate (β-TCP) and a poly(lactic-co-glycolic) acid (PLGA) were evaluated as candidate carriers for GDF-5 using various dose and healing intervals demonstrating significantly enhanced periodontal regeneration/alveolar augmentation including cementum, periodontal ligament and alveolar bone with limited, if any, adverse effects. CONCLUSION Growth/differentiation factor-5 supports periodontal regeneration/alveolar augmentation without aberrant healing events documented in qualified pre-clinical models and clinical pilot studies. In perspective, GDF-5 appears a promising technology for periodontal regeneration/alveolar augmentation.

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

BACKGROUND Endosseous 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. METHODS Twelve 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. RESULTS Clinical 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). CONCLUSIONS Local 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.

Comparative study of Chinese hamster ovary cell versus Escherichia coli-derived bone morphogenetic protein-2 using the critical-size supraalveolar peri-implant defect model.

BACKGROUND Chinese hamster ovary (CHO) cell-derived recombinant human bone morphogenetic protein-2 (rhBMP-2) has been introduced for spine, long bone, and craniofacial indications. Escherichia coli- (E. coli) derived rhBMP-2 displays comparable efficacy to CHO cell-derived rhBMP-2 in vitro and in small-animal models. The objective of this study is to evaluate the efficacy of E. coli-derived rhBMP-2 compared to the benchmark CHO cell-derived rhBMP-2 using an established large-animal model. METHODS Contralateral, critical-size supraalveolar peri-implant defects in six adult male Hound Labrador mongrel dogs received CHO cell- or E. coli-derived rhBMP-2 (0.2 mg/mL) in an absorbable collagen sponge (ACS) carrier. In each quadrant, three dental implants were placed. A titanium mesh device was used to support space provision. The animals received fluorescent bone markers for qualitative evaluations. Animals were euthanized at 8 weeks for histopathologic and histometric evaluation. RESULTS Clinical healing included significant swelling, but none of the animals experienced wound dehiscences. CHO cell- and E. coli-derived rhBMP-2 supported comparable bone formation (new bone area, 35.8 ± 3.6 versus 30.1 ± 2.2 mm(2); bone density, 31.8% ± 1.6% versus 35.6% ± 2.5%; and osseointegration, 32.9% ± 7.4% versus 33.7% ± 8.1%) without statistically significant differences between treatments. Newly formed immature delicate trabecular bone in fibrovascular marrow filled the space underneath the titanium mesh and extended coronally above the mesh. Seroma formation was frequently observed. There were no discernable qualitative histologic differences between treatments. CONCLUSION CHO cell- and E. coli-derived rhBMP-2 in an ACS carrier appear equally effective at inducing local bone formation in support of dental implant osseointegration.

Crestal remodelling and osseointegration at surface‐modified commercially pure titanium and titanium alloy implants in a canine model

BACKGROUND Ti-6Al-7Nb alloys exhibit enhanced mechanical properties and corrosion resistance and may represent an improvement to present commercially pure (CP) titanium oral implant technology. OBJECTIVES To evaluate crestal remodelling and osseointegration at CP titanium compared with Ti-6Al-7Nb alloy oral implants using a canine model. METHODS Two threaded anodized CP titanium and two Ti-6Al-7Nb alloy anodized oral implants (ø4.5 × 6.1 mm) were placed into each jaw quadrant in the edentulated posterior mandible in six adult male Hound Labrador mongrel dogs. Abutments were placed onto the implants, and the mucogingival flaps were adapted and sutured for transmucosal wound healing. Block biopsies were collected for histometric analysis following an 8-week healing interval. RESULTS Healing was uneventful. Bone density outside and within the root of the threads averaged (± SE) 49.0 ± 4.5% and 38.7 ± 5.1% for CP titanium implants and 43.2 ± 3.6% and 34.2 ± 4.8% for Ti-6Al-7Nb alloy implants. Mean osseointegration reached 68.0 ± 4.4% and 62.8 ± 2.5% for CP titanium and Ti-6Al-7Nb alloy implants, respectively. Although crestal resorption at lingual sites averaged 0.2 ± 0.1 mm for both technologies, crestal resorption at buccal sites averaged 0.9 ± 0.2 and 1.0 ± 0.6 mm for CP titanium and Ti-6Al-7Nb alloy implants, respectively. There were no statistically significant differences between implant technologies for any parameter assessed. Notably, advanced/advancing buccal crestal resorption exposing the implant threads was observed in 50% of the implants (four of six animals) regardless of implant technology; osteoclastic resorption still observed at 8 weeks following implant placement. CONCLUSION Within the limitations of study, anodized Ti-6Al-7Nb alloy implants may represent a feasible alternative to benchmark anodized CP titanium implants. Remodelling of the buccal crestal plate resulting in advanced bone loss appears a major impediment to oral implant osseointegration and possibly, in extension, implant maintenance.