Ulf M E Wikesjö

Publications of Ulf M E Wikesjö

• Maturation of periodontal tissues following implantation of rhGDF-5/β-TCP in one-wall intra-bony defects in dogs: 24-week histological observations.

  Authors: Jung-Seok Lee, Ulf M E Wikesjö, Jung-Chul Park, Yong-Ju Jang, Susanne D Pippig, Patrizia Bastone, Seong-Ho Choi, Chong-Kwan Kim

  Journal of clinical periodontology. 02/2012;

  OBJECTIVE: Although a previous study reported that recombinant human growth/differentiation factor-5 (rhGDF-5) coated onto a β-tricalciumphosphate (β-TCP) significantly enhanced periodontalOBJECTIVE: Although a previous study reported that recombinant human growth/differentiation factor-5 (rhGDF-5) coated onto a β-tricalciumphosphate (β-TCP) significantly enhanced periodontal regeneration, the long-term stability/maturation of the regenerated tissues has not been demonstrated. The objective of this study was to evaluate periodontal regeneration/maturation following application of rhGDF-5/β-TCP using an established periodontal defect model and a 24-week healing interval. MATERIAL & METHODS: Unilateral, surgically created, 4 × 4 × 5 mm (length × width × height), one-wall, critical-size, intra-bony periodontal defects at the mandibular second and fourth premolar teeth in five young adult Beagle dogs received rhGDF-5/β-TCP. Bilateral sites at the fourth premolar in the other four dogs served as pristine controls receiving mucogingival flap surgery without defect induction. The animals were euthanized at 24 weeks for histological analysis. Unpublished data from the previous 8-week study were used to compare tissue maturation between 8 and 24 weeks. RESULTS: Linear histometric observations of cementum and alveolar regeneration showed no significant differences between the 8- and 24-week observation intervals. However, parameters of periodontal tissue maturation showed significant differences between the observation intervals including increased fraction mineralized tissue and lamellar bone (p < 0.05) and decreased osteocyte counts (p < 0.05) at 24 weeks compared with 8 weeks. Although the count inserting Sharpey's fibre did not significantly change, regenerated cementum remote from the intact periodontal ligament appeared more highly mineralized and thicker at 24 weeks compared with 8 weeks, and compared with the pristine cementum. Minimal β-TCP remained. CONCLUSIONS: These 24-week observations suggest that regenerated periodontal tissues in sites receiving rhGDF-5/β-TCP undergo progressive maturation without debilitating aberrant tissue reactions.

• Sinus augmentation using rhBMP-2/ACS in a mini-pig model: relative efficacy of autogenous fresh particulate iliac bone grafts.

  Authors: Jaebum Lee, Cristiano Susin, Nancy A Rodriguez, Jamie de Stefano, Hari S Prasad, Amanda N Buxton, Ulf M E Wikesjö

  Clinical oral implants research. 01/2012;

  BACKGROUND: Implant dentistry in the posterior maxilla often requires bone augmentation. The gold standard, autogenous bone graft, requires additional surgery with associated morbidity, while boneBACKGROUND: Implant dentistry in the posterior maxilla often requires bone augmentation. The gold standard, autogenous bone graft, requires additional surgery with associated morbidity, while bone biomaterials may not support relevant bone formation. Recombinant human bone morphogenetic protein-2 (rhBMP-2) in an absorbable collagen sponge (ACS), however, induces significant, clinically relevant bone formation in several settings including the maxillary sinus floor. OBJECTIVE: The objective of this study was to compare local bone formation and osseointegration following maxillary sinus augmentation using rhBMP-2/ACS or a particulate autogenous cancellous bone graft obtained from the iliac crest in conjunction with immediate placement of dental implants. MATERIALS AND METHODS: Bilateral sinus augmentation using an extraoral approach including rhBMP-2 (0.43 mg/ml)/ACS or the autogenous bone graft, alternated between left and right sinus cavities in five adult male Yucatan mini-pigs, was performed. Two 12-mm dental implants were inserted into the sinus wall protruding approximately 8 mm into the sinus cavity. Surgical sites were closed and sutured in layers; block biopsies collected for histometric analysis at 8 weeks. RESULTS: rhBMP-2/ACS induced bone of significantly greater and consistent quality compared with the iliac crest autogenous bone graft; bone density averaging 51.9 ± 3.0% vs. 32.9 ± 2.5% (P = 0.01). However, there were only numerical differences in augmented bone height (9.3 ± 0.5 vs. 8.6 ± 0.7 mm) and bone-implant contact (37.4 ± 3.0% vs. 30.7 ± 5.9%) between treatments. CONCLUSION: rhBMP-2/ACS induces bone of superior quality compared with an iliac crest particulate autogenous cancellous bone graft when used for maxillary sinus augmentation, and should perhaps be considered the new standard for this indication.

• A phase IIa randomized controlled clinical and histological pilot study evaluating rhGDF-5/β-TCP for periodontal regeneration.

  Authors: Andreas Stavropoulos, Peter Windisch, Istvan Gera, Björn Capsius, Anton Sculean, Ulf M E Wikesjö

  Journal of clinical periodontology. 11/2011; 38(11):1044-54.

  The primary objective of this study was to clinically and histologically evaluate periodontal wound healing/regeneration following surgical implantation of recombinant human growth/differentiationThe primary objective of this study was to clinically and histologically evaluate periodontal wound healing/regeneration following surgical implantation of recombinant human growth/differentiation factor-5 (rhGDF-5) adsorbed onto a particulate β-tricalcium phosphate (β-TCP) carrier rhGDF-5/β-TCP into periodontal defects in man. Twenty chronic periodontitis patients, each with at least one tooth scheduled for extraction exhibiting a probing depth ≥6 mm and an associated intra-bony defect ≥4 mm participated in the study upon written informed consent. Subjects (one defect/patient) were randomized to receive open flap debridement (OFD) + rhGDF-5/β-TCP (n = 10) or OFD alone (control; n = 10). Block biopsies of the defect sites were collected at 6 months post-surgery and prepared for the histological evaluation. Two masked examiners evaluated the deepest aspect of each defect site relative to bone (height/area), periodontal ligament (PDL) and cementum regeneration, and residual β-TCP. Sites receiving rhGDF-5/β-TCP showed numerically greater PD reduction (3.7 ± 1.2 versus 3.1 ± 1.8 mm; p = 0.26), less gingival recession (0.5 ± 0.8 versus 1.4 ± 1.0 mm; p < 0.05) and greater clinical attachment level (CAL) gain (3.2 ± 1.7 versus 1.7 ± 2.2 mm; p = 0.14) at the deepest aspect of the defect compared with OFD alone. One biopsy in the rhGDF-5/β-TCP and four biopsies in the OFD group were deemed as not evaluable. Histologically, bone regeneration height was almost threefold greater for the rhGDF-5/β-TCP treatment compared with OFD alone (2.19 ± 1.59 versus 0.81 ± 1.02 mm; p = 0.08). Similarly an almost twofold increase was observed for PDL (2.16 ± 1.43 versus 1.23 ± 1.07 mm; p = 0.26), cementum (2.16 ± 1.43 versus 1.23 ± 1.07 mm; p = 0.26) and bone regeneration area (0.74 ± 0.69 versus 0.32 ± 0.47 mm(2) ; p = 0.14). Root resorption/ankylosis was not observed. Residual β-TCP occupied 8.4 ± 11.5% of the area of interest in biopsies of patients receiving rhGDF-5/β-TCP. Five biopsies (one rhGDF-5/β-TCP, four OFD) were deemed unsuitable to allow a meaningful histological or histometrical evaluation. Descriptive statistics showed greater PD reduction and CAL gain, and greater alveolar bone regeneration and periodontal regeneration at sites that received rhGDF-5/β-TCP compared to control. However, these differences were not statistically significant. Future studies with larger sample sizes will have to be conducted to verify these findings.

• A phase IIa randomized controlled pilot study evaluating the safety and clinical outcomes following the use of rhGDF-5/β-TCP in regenerative periodontal therapy.

  Authors: Péter Windisch, Andreas Stavropoulos, Bálint Molnár, Dóra Szendröi-Kiss, Emese Szilágyi, Péter Rosta, Attila Horváth, Björn Capsius, Ulf M E Wikesjö, Anton Sculean

  Clinical oral investigations. 09/2011;

  To present the safety profile, the early healing phase and the clinical outcomes at 24 weeks following treatment of human intrabony defects with open flap debridement (OFD) alone or with OFD andTo present the safety profile, the early healing phase and the clinical outcomes at 24 weeks following treatment of human intrabony defects with open flap debridement (OFD) alone or with OFD and rhGDF-5 adsorbed onto a particulate β-tricalcium phosphate (β-TCP) carrier. Twenty chronic periodontitis patients, each with at least one tooth exhibiting a probing depth ≥6 mm and an associated intrabony defect ≥4 mm entered the study. Ten subjects (one defect/patient) were randomized to receive OFD alone (control) and ten subjects OFD combined with rhGDF-5/β-TCP. Blood samples were collected at screening, and at weeks 2 and 24 to evaluate routine hematology and clinical chemistry, rhGDF-5 plasma levels, and antirhGDF-5 antibody formation. Plaque and gingival indices, bleeding on probing, probing depth, clinical attachment level, and radiographs were recorded pre- and 24 weeks postsurgery. Comparable safety profiles were found in the two treatment groups. Neither antirhGDF-5 antibody formation nor relevant rhGDF-5 plasma levels were detected in any patient. At 6 months, treatment with OFD + rhGDF-5/β-TCP resulted in higher but statistically not significant PD reduction (3.7 ± 1.2 vs. 3.1 ± 1.8 mm; p = 0.26) and CAL gain (3.2 ± 1.7 vs. 1.7 ± 2.2 mm; p = 0.14) compared to OFD alone. In the tested concentration, the use of rhGDF-5/β-TCP appeared to be safe and the material possesses a sound biological rationale. Thus, further adequately powered, randomized controlled clinical trials are warranted to confirm the clinical relevance of this new approach in regenerative periodontal therapy. rhGDF-5/β-TCP may represent a promising new techology in regenerative periodontal therapy.

• Wound healing/regeneration using recombinant human growth/differentiation factor-5 in an injectable poly-lactide-co-glycolide-acid composite carrier and a one-wall intra-bony defect model in dogs.

  Authors: Cheon-Ki Min, Ulf M E Wikesjö, Jung-Chul Park, Gyung-Joon Chae, Susanne D Pippig, Patrizia Bastone, Chang-Sung Kim, Chong-Kwan Kim

  Journal of clinical periodontology. 03/2011; 38(3):261-8.

  The purpose of this study was to evaluate the effect of recombinant human growth/differentiation factor-5 (rhGDF-5) on periodontal wound healing/regeneration using an injectableThe purpose of this study was to evaluate the effect of recombinant human growth/differentiation factor-5 (rhGDF-5) on periodontal wound healing/regeneration using an injectable poly-lactide-co-glycolide-acid (PLGA) composite carrier and an established defect model. Bilateral 4 × 5 mm (width × depth) one-wall, critical-size, intra-bony periodontal defects were surgically created at the second and the fourth mandibular pre-molar teeth in 15 Beagle dogs. The animals were randomized to receive (using a split-mouth design; defect sites in the same jaw quadrant getting the same treatment) rhGDF-5 high dose (188 μg/defect) versus sham-surgery control (five animals), rhGDF-5 mid dose (37 μg/defect) versus carrier control (five animals), and rhGDF-5 low dose (1.8 μg/defect) versus treatment reported elsewhere (five animals). The animals were euthanized for histometric analysis following an 8-week healing interval. Clinical healing was uneventful. The rhGDF-5/PLGA construct was easy to assemble and apply. The rhGDF-5 high dose supported significantly increased bone formation compared with the low-dose, sham-surgery, and carrier controls (p<0.05) and induced significantly increased cementum formation compared with the controls (p<0.05). Root resorption/ankylosis or other aberrant healing events were not observed. rhGDF-5 appears to effectively support periodontal wound healing/regeneration in a dose-dependent order; the PLGA composite appears to be an effective ease-of-use candidate for carrier technology.

• 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.

  Authors: John F Decker, Jaebum Lee, Carlo Alberto Cortella, Giuseppe Polimeni, Michael D Rohrer, John M Wozney, Jan Hall, Cristiano Susin, Ulf M E Wikesjö

  Journal of periodontology. 12/2010; 81(12):1839-49.

  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.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. 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. 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). 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.

• Implant osseointegration in the absence of primary bone anchorage: a clinical report.

  Authors: Roberto Villa, Giuseppe Polimeni, Ulf M E Wikesjö

  The Journal of prosthetic dentistry. 11/2010; 104(5):282-7.

  The authors identified no report describing implant primary stability obtained by external fixation as a means to achieve osseointegration in craniofacial settings. This article describes a situationThe authors identified no report describing implant primary stability obtained by external fixation as a means to achieve osseointegration in craniofacial settings. This article describes a situation in which an implant was placed without direct contact with the resident bone; primary stability was provided by an external device. An edentulous patient was restored with 5 endosseous titanium implants to support a mandibular fixed prosthesis. An implant placed in the right central incisor position was removed after 48 hours and replaced with a shorter and narrower implant without contact with resident bone. Thus, primary stability for the implant was provided by rigid fixation to the prosthesis rather than by bone anchorage. At recall examinations after 6 and 27 months, all implants, including the implant in the right central incisor position, showed clinical and radiographic signs of osseointegration. Resonance frequency analysis indicated acceptable stability and osseointegration for all implants. Observations of this patient suggest that implant osseointegration can be achieved by providing primary stability using a fixed complete denture. Primary bone anchorage/contact does not appear to be critical to the osseointegration process.

• Single flap approach with and without guided tissue regeneration and a hydroxyapatite biomaterial in the management of intraosseous periodontal defects.

  Authors: Leonardo Trombelli, Anna Simonelli, Mattia Pramstraller, Ulf M E Wikesjö, Roberto Farina

  Journal of periodontology. 09/2010; 81(9):1256-63.

  The single flap approach (SFA) is a minimally invasive procedure designed for periodontal reconstructive procedures of intraosseous periodontal defects characterized by a dominant unilateral, buccalThe single flap approach (SFA) is a minimally invasive procedure designed for periodontal reconstructive procedures of intraosseous periodontal defects characterized by a dominant unilateral, buccal or oral, extension. This study evaluates the adjunctive effect of guided tissue regeneration (GTR) combined with a hydroxyapatite (HA) biomaterial in the management of intraosseous periodontal defects accessed with SFA compared to SFA alone. Twenty-four intraosseous defects (in 24 patients) were randomly allocated to treatment with SFA or SFA + HA/GTR. Clinical outcomes were assessed 6 months post-surgery. Five sites in the SFA + HA/GTR group showed incomplete closure at week 2, which resolved spontaneously. There were no statistically significant or clinically meaningful differences in mean (+/-SD) clinical attachment gain (4.7 +/- 2.5 versus 4.4 +/- 1.5 mm), probing depth reduction (5.3 +/- 2.4 versus 5.3 +/- 1.5 mm), and gingival recession increase (0.4 +/- 1.4 versus 0.8 +/- 0.8 mm) between the SFA + HA/GTR and SFA groups. SFA with and without HA/GTR seems to be a valuable minimally invasive approach in the treatment of deep intraosseous periodontal defects. Under the present experimental conditions, the additional HA/GTR protocol offers no significant adjunctive effect.

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

  Authors: Giuseppe Polimeni, Ulf M E Wikesjö, Cristiano Susin, Mohammed Qahash, Richard H Shanaman, Hari S Prasad, Michael D Rohrer, Jan Hall

  Journal of clinical periodontology. 08/2010; 37(8):759-68.

  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 recombinantIn 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. 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. 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. 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.

• Growth/differentiation factor-5 significantly enhances periodontal wound healing/regeneration compared with platelet-derived growth factor-BB in dogs.

  Authors: Hyuk-Rak Kwon, Ulf M E Wikesjö, Jung-Chul Park, Young-Taek Kim, Patrizia Bastone, Susanne D Pippig, Chong-Kwan Kim

  Journal of clinical periodontology. 08/2010; 37(8):739-46.

  Recombinant human growth/differentiation factor-5 (rhGDF-5) in a particulate beta-tricalcium phosphate (beta-TCP) carrier is being evaluated to support periodontal regeneration. The objective of thisRecombinant human growth/differentiation factor-5 (rhGDF-5) in a particulate beta-tricalcium phosphate (beta-TCP) carrier is being evaluated to support periodontal regeneration. The objective of this study was to evaluate periodontal wound healing/regeneration following an established clinical (benchmark) protocol including surgical implantation of rhGDF-5/beta-TCP in comparison with that following implantation of recombinant human platelet-derived growth factor-BB (rhPDGF) combined with a particulate beta-TCP biomaterial using an established canine defect model. Bilateral, 4 x 5 mm (width x depth), one-wall, critical-size, intrabony periodontal defects were surgically created at the mandibular second and fourth pre-molar teeth in five adult Beagle dogs. Defect sites were randomized to receive rhGDF-5/beta-TCP or the rhPDGF construct followed by wound closure for primary intention healing. The animals were sacrificed following an 8-week healing interval for histological and histometric examination. Clinical healing was generally uneventful. Sites receiving rhGDF-5/beta-TCP exhibited a significantly enhanced cementum formation compared with sites receiving the rhPDGF construct, averaging (+/-SD) 4.49+/-0.48 versus 2.72+/-0.91 mm (p<0.001). Similarly, bone regeneration height and area were significantly enhanced at sites receiving rhGDF-5/beta-TCP versus that of the rhPDGF construct averaging, 3.08+/-0.74 versus 1.29+/-0.78 mm (p<0.001) and 6.03+/-1.28 versus 2.98+/-2.61 mm(2) (p<0.01), respectively. Cementum regeneration included cellular/acellular mixed (extrinsic/intrinsic) fibre cementum at sites receiving rhGDF-5/beta-TCP; sites receiving the rhPDGF/beta-TCP showed a pre-dominantly acellular cementum. Newly formed cementum generally extended above the adjoining alveolar bone. Both protocols displayed beta-TCP residues apparently undergoing resorption. Application of both materials appears safe, as they were associated with limited, if any, adverse events. rhGDF-5/beta-TCP shows a significant potential to support/accelerate periodontal wound healing/regeneration. Application of rhGDF-5/beta-TCP appears safe and should be further evaluated in human clinical trials.

• Periodontal wound healing/regeneration following the application of rhGDF-5 in a beta-TCP/PLGA carrier in critical-size supra-alveolar periodontal defects in dogs.

  Authors: David H Kwon, Frederick C Bisch, Robert W Herold, Cornelius Pompe, Patrizia Bastone, Nancy A Rodriguez, Cristiano Susin, Ulf M E Wikesjö

  Journal of clinical periodontology. 07/2010; 37(7):667-74.

  The objective of this study was to evaluate the effect of a novel recombinant human GDF-5 (rhGDF-5) construct intended for onlay and inlay indications on periodontal woundThe objective of this study was to evaluate the effect of a novel recombinant human GDF-5 (rhGDF-5) construct intended for onlay and inlay indications on periodontal wound healing/regeneration. Contralateral, surgically created, critical-size, 6-mm, supra-alveolar periodontal defects in five adult Hound Labrador mongrel dogs received rhGDF-5 coated onto beta-tricalcium phosphate (beta-TCP) particles and immersed in a bioresorbable poly(lactic-co-glycolic acid) (PLGA) composite or the beta-TCP/PLGA carrier alone (control). The rhGDF-5 and control constructs were moulded around the teeth and allowed to set. The gingival flaps were then advanced; flap margins were adapted 3-4 mm coronal to the teeth and sutured. The animals were euthanized at 8 weeks post-surgery when block biopsies were collected for histometric analysis. Healing was generally uneventful. A few sites exhibited minor exposures. Three control sites and one rhGDF-5 site (in separate animals) experienced more extensive wound dehiscencies. The rhGDF-5 and control constructs were easy to apply and exhibited adequate structural integrity to support the mucoperiosteal flaps in this challenging onlay model. Limited residual beta-TCP particles were observed at 8 weeks for both rhGDF-5/beta-TCP/PLGA and beta-TCP/PLGA control sites. The rhGDF-5/beta-TCP/PLGA sites showed significantly greater cementum (2.34 +/- 0.44 versus 1.13 +/- 0.25 mm, p=0.02) and bone (2.92 +/- 0.66 versus 1.21 +/- 0.30 mm, p=0.02) formation compared with the carrier control. Limited ankylosis was observed in four of five rhGDF-5/beta-TCP/PLGA sites but not in control sites. Within the limitations of this study, the results suggest that rhGDF-5 is a promising candidate technology in support of periodontal wound healing/regeneration. Carrier and rhGDF-5 dose optimization are necessary before further advancement of the technology towards clinical evaluation.

• Influence of defect dimensions on periodontal wound healing/regeneration in intrabony defects following implantation of a bovine bone biomaterial and provisions for guided tissue regeneration: an experimental study in the dog.

  Authors: Andreas Stavropoulos, Ulf M E Wikesjö

  Journal of clinical periodontology. 06/2010; 37(6):534-43.

  To evaluate the influence of defect dimensions on periodontal wound healing/regeneration in intrabony defects following implantation of a deproteinized bovine bone/collagen matrix under provisionsTo evaluate the influence of defect dimensions on periodontal wound healing/regeneration in intrabony defects following implantation of a deproteinized bovine bone/collagen matrix under provisions for guided tissue regeneration. Material and Contra-lateral one-wall intrabony [6 x 6 mm (wide/deep) versus 4 x 4 mm (narrow/shallow)] periodontal defects were surgically created at the edentulated mesial aspect of the mandibular first molars in three Labradors, i.e., three defects in each category. The defects were implanted with the bovine bone/collagen matrix and covered with a collagen membrane. Histologic/histometric analysis followed an 18-month healing interval. New cementum encompassed the entire intrabony component in both wide/deep (5.6 +/- 0.5 mm) and narrow/shallow (4.2 +/- 0.1 mm) defects; bone formation amounted to 5.6 +/- 0.6 and 4.0 +/- 0.8 mm, respectively. Mineralized bone encompassed 57.5%versus 65% and the bone biomaterial 11.6%versus 13.1% of the defect space. A periodontal ligament with a width and composition similar to that of the resident periodontal ligament encompassing the entire aspect of the defects was observed. Root resorption/ankylosis was rare. Both wide/deep and narrow/shallow intrabony defects showed a substantial potential for periodontal regeneration in this pre-clinical model. The contribution of the bovine bone/collagen matrix and guided tissue regeneration to this regenerative potential is not clear.

• Periodontal healing following reconstructive surgery: effect of guided tissue regeneration using a bioresorbable barrier device when combined with autogenous bone grafting. A randomized-controlled trial 10-year follow-up.

  Authors: Per Nygaard-Østby, Vibeke Bakke, Oddny Nesdal, Cristiano Susin, Ulf M E Wikesjö

  Journal of clinical periodontology. 04/2010; 37(4):366-73.

  The objective of this 10-year randomized-controlled trial follow-up was to evaluate the stability of treatment outcomes following the implantation of autogenous bone graft with or without guidedThe objective of this 10-year randomized-controlled trial follow-up was to evaluate the stability of treatment outcomes following the implantation of autogenous bone graft with or without guided tissue regeneration (GTR) in the treatment of deep intra-bony periodontal defects. Forty patients exhibiting deep intra-bony periodontal defects were included in a randomized-controlled trial evaluating the adjunctive effect of GTR to autogenous bone graft. Twenty-six of 39 patients completing the original study were available for follow-up 10 years post-treatment. The patients had been included in a structured maintenance programme and were evaluated using the criteria of the original study by the same investigators. Significant improvements in the probing depth and clinical attachment level were observed for both groups between baseline and 9 months. Whereas the autogenous bone graft+GTR group showed significant improvements in probing bone levels and increased gingival recession at 9 months, no significant differences were observed for the autogenous bone graft group. Nine-month within-group results were maintained throughout the 10-year follow-up. Nevertheless, between-group comparisons at 10 years showed that the autogenous bone graft+GTR group exhibited significantly greater probing depth reduction (mean +/- SE: 4.2 +/- 0.5 versus 2.7 +/- 0.5 mm, p=0.023) and probing bone-level gain (3.9 +/- 0.8 versus 1.3 +/- 0.9 mm, p=0.034) than the autogenous bone graft group. Borderline significant differences between the autogenous bone graft+GTR and the autogenous bone graft groups were observed for clinical attachment level gain at 10 years (3.8 +/- 0.5 versus 2.2 +/- 0.7 mm, p=0.067), whereas no significant differences were observed for gingival recession (0.7 +/- 0.3 versus 0.6 +/- 0.5 mm, p>0.05). The results of this randomized study suggest that statistically significant differences were found with the adjunct use of GTR to an autogenous bone graft at 10 years. Nevertheless, these results should be interpreted with caution in light of its clinical relevance and biological rationale. Importantly, resolution of deep intra-bony periodontal defects can be maintained in the presence of a structured maintenance programme emphasizing high oral hygiene standards.

• Periodontal wound healing/regeneration following implantation of recombinant human growth/differentiation factor-5 in a beta-tricalcium phosphate carrier into one-wall intrabony defects in dogs.

  Authors: Jung-Seok Lee, Ulf M E Wikesjö, Ui-Won Jung, Seong-Ho Choi, Susanne Pippig, Michael Siedler, Chong-Kwan Kim

  Journal of clinical periodontology. 04/2010; 37(4):382-9.

  Recombinant human growth/differentiation factor-5 (rhGDF-5) is being evaluated as a candidate therapy in support of periodontal regeneration. The objective of this study was to evaluate periodontalRecombinant human growth/differentiation factor-5 (rhGDF-5) is being evaluated as a candidate therapy in support of periodontal regeneration. The objective of this study was to evaluate periodontal wound healing/regeneration following the application of rhGDF-5 on a particulate beta-tricalcium phosphate (beta-TCP) carrier using an established defect model. Bilateral 4 x 5 mm (width x depth), one-wall, critical-size, intrabony periodontal defects were surgically created at the mandibular second and fourth pre-molar teeth in 15 Beagle dogs. Unilateral defects in five animals received rhGDF-5/beta-TCP (Scil Technology GmbH); five animals received beta-TCP solo; and five animals served as sham-surgery controls. Contralateral sites received treatments reported elsewhere. The animals were sacrificed following an 8-week healing interval for histological examination. Clinical healing was generally uneventful. Sites implanted with rhGDF-5/beta-TCP exhibited greater enhanced cementum and bone formation compared with beta-TCP and sham-surgery controls; cementum regeneration averaged (+/- SD) 3.83 +/- 0.73 versus 1.65 +/- 0.82 and 2.48 +/- 1.28 mm for the controls (p<0.05). Corresponding values for bone regeneration height averaged 3.26 +/- 0.30 versus 1.70 +/- 0.66 and 1.68 +/- 0.49 mm (p<0.05), and bone area 10.45 +/- 2.26 versus 6.31 +/- 2.41 and 3.00 +/- 1.97 mm(2) (p<0.05). Cementum regeneration included cellular/acellular cementum with or without a functionally oriented periodontal ligament. A non-specific connective tissue attachment was evident in the sham-surgery control. Controls exhibited mostly woven bone with primary osteons, whereas rhGDF-5/beta-TCP sites showed a noticeable extent of lamellar bone. Sites receiving rhGDF-5/beta-TCP or beta-TCP showed some residual beta-TCP granules apparently undergoing biodegradation without obvious differences between the sites. Sites receiving beta-TCP alone commonly showed residual beta-TCP granules sequestered in the connective tissue or fibrovascular marrow. rhGDF-5/beta-TCP has a greater potential to support the regeneration of the periodontal attachment. Long-term studies are necessary to confirm the uneventful maturation of the regenerated tissues.

• Evaluation of an injectable rhGDF-5/PLGA construct for minimally invasive periodontal regenerative procedures: a histological study in the dog.

  Authors: David H Kwon, William Bennett, Samuel Herberg, Patrizia Bastone, Susanne Pippig, Nancy A Rodriguez, Cristiano Susin, Ulf M E Wikesjö

  Journal of clinical periodontology. 04/2010; 37(4):390-7.

  To evaluate the injectability, biocompatibility, safety, and periodontal wound healing/regeneration following application of a novel bioresorbable recombinant human growth/differentiation factor-5To evaluate the injectability, biocompatibility, safety, and periodontal wound healing/regeneration following application of a novel bioresorbable recombinant human growth/differentiation factor-5 (rhGDF-5)/poly(lactic-co-glycolic acid) (PLGA) construct. Periodontal pockets (3 x 6 mm, width x depth) were surgically created over the buccal roots of the second and fourth mandibular pre-molars in eight adult Hound Labrador mongrel dogs. Surgeries including injection of the rhGDF-5/PLGA construct into the pockets were sequenced that four animals provided 2-/4-week and four animals 6-/8-week observations of sites receiving rhGDF-5/PLGA or serving as sham-surgery control. The rhGDF-5/PLGA construct was easy to prepare and apply. Approximately 0.2 ml (93 microg rhGDF-5)/tooth was used. Clinical and radiographic healing was exemplary without adverse events. Healing was characterized by a non-specific connective tissue attachment, acellular/cellular cementum, periodontal ligament (PDL), bone regeneration, and a junctional epithelium. PLGA fragments were observed in 4/7, 2/8, and 1/8 sites at 2, 4, and 6 weeks, respectively. Associated inflammatory reactions exhibited no limiting effect on periodontal wound healing/regeneration. Root resorption/ankylosis was not observed. Bone formation showed apparent increased maturity (lamellar bone) at 6 weeks in sites receiving rhGDF-5/PLGA compared with the control. Both protocols exhibited significant increases in PDL, cementum, and bone regeneration over time, without significant differences between treatments. In time, PDL and cementum regeneration was twofold greater for the control at 4 weeks (p=0.04) while increased bone formation was observed at sites receiving rhGDF-5/PLGA (p<0.01). In conclusion, the rhGDF-5/PLGA construct appears to be a safe technology for injectable, ease-of-use application of rhGDF-5-stimulated periodontal wound healing/regeneration. Additional work to optimize the polymer carrier and rhGDF-5 release kinetics/dose might be required before evaluating the efficacy of this technology in clinical settings using minimally invasive approaches.

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

  Authors: Jaebum Lee, John F Decker, Giuseppe Polimeni, Carlo Alberto Cortella, Michael D Rohrer, John M Wozney, Jan Hall, Cristiano Susin, Ulf M E Wikesjö

  Journal of clinical periodontology. 03/2010; 37(6):582-90.

  Implants coated with recombinant human bone morphogenetic protein-2 (rhBMP-2) induce relevant bone formation but also resident bone remodelling. To compare the effect of implants fully or partiallyImplants coated with recombinant human bone morphogenetic protein-2 (rhBMP-2) induce relevant bone formation but also resident bone remodelling. To compare the effect of implants fully or partially coated with rhBMP-2 on new bone formation and resident bone remodelling. Materials and 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. 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). 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.

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

  Authors: Cristiano Susin, Mohammed Qahash, Giuseppe Polimeni, Ping Hung Lu, Hari S Prasad, Michael D Rohrer, Jan Hall, Ulf M E Wikesjö

  Journal of clinical periodontology. 03/2010; 37(6):574-81.

  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 bonePre-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. 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. 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. 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.

• Periodontal regeneration: focus on growth and differentiation factors.

  Authors: Jaebum Lee, Andreas Stavropoulos, Cristiano Susin, Ulf M E Wikesjö

  Dental clinics of North America. 01/2010; 54(1):93-111.

  Several growth and differentiation factors have shown potential as therapeutic agents to support periodontal wound healing/regeneration, although optimal dosage, release kinetics, and suitableSeveral 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.

• The critical-size supraalveolar peri-implant defect model: reproducibility in histometric data acquisition of alveolar bone formation and osseointegration.

  Authors: Jaebum Lee, Quoc Tran, Gary Seeba, Ulf M E Wikesjö, Cristiano Susin

  Journal of clinical periodontology. 12/2009; 36(12):1067-74.

  OBJECTIVE: The objective of this report is to present the reproducibility of outcomes assessments in the Critical-Size Supraalveolar Peri-Implant Defect Model. MATERIALS AND METHODS: Two examinersOBJECTIVE: The objective of this report is to present the reproducibility of outcomes assessments in the Critical-Size Supraalveolar Peri-Implant Defect Model. MATERIALS AND METHODS: Two examiners without specific experience in histological analysis and one experienced examiner performed the histometric evaluation. A comprehensive training program in data acquisition and histological analysis was established, the inexperienced examiners underwent approximately 12 h of training over multiple sessions. A custom-designed image analysis software macro and a computer-based image system were used to analyse digital images generated by a microscope camera system. Nine parameters for newly formed and resident bone were evaluated. Examiners performed histometric analysis using 36 histologic sections selected from critical-size supraalveolar peri-implant defects in 12 male Hound Labrador Mongrel dogs. Buccal and lingual measurements were performed in 72 sites. Intra- and inter-examiner reproducibility were evaluated using the concordance correlation coefficient (CCC) and means +/- SD of the differences. Systematic errors were evaluated using an F-test for equality of means and variances. RESULTS: Intra-examiner reproducibility was high for all parameters evaluated, the lowest CCC observed being 0.87. Inter-examiner reproducibility was also high, most CCCs exceeding 0.90. Minor systematic errors for intra- and inter-examiner comparisons were occasionally observed. The results imply a high temporal stability because recordings were performed 3 months apart. Measurement errors were stable throughout the range of observations for all parameters. CONCLUSIONS: High examiner reproducibility and temporal stability can be achieved for histometric data acquisition using the Critical-Size Supraalveolar Peri-Implant Defect Model. Examiner reproducibility should be routinely assessed, reported, and accounted for to assure the quality of evidence generated by preclinical studies.

• Evaluation of nano-technology-modified zirconia oral implants: a study in rabbits.

  Authors: Jaebum Lee, Janet H Sieweke, Nancy A Rodriguez, Peter Schüpbach, Håkan Lindström, Cristiano Susin, Ulf M E Wikesjö

  Journal of clinical periodontology. 07/2009; 36(7):610-7.

  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. MATERIALSOBJECTIVE: 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.