Maturation of alveolar bone following implantation of an rhGDF-5/PLGA composite into 1-wall intra-bony defects in dogs: 24-week histometric observations.

OBJECTIVE: The aim of this study was to evaluate long-term (24 weeks) alveolar bone maturation following surgical application of recombinant human growth/differentiation factor-5 (rhGDF-5) in an injectable poly-lactide-co-glycolide-acid (PLGA) composite carrier using an established periodontal defect model. METHODS: Routine, bilateral, 4 × 5 mm (width × depth), 1-wall, critical-size, intra-bony periodontal defects were surgically created at the 2nd and 4th mandibular premolar teeth in 10 Beagle dogs. The animals were randomized to receive (split-mouth design; defect sites in the same jaw quadrant getting the same treatment) rhGDF-5/PLGA high dose (188 µg/defect) versus sham-surgery control (5 animals), and rhGDF-5/PLGA low dose (37 µg/defect) versus carrier control (5 animals). The animals were euthanized for histometric analysis following a 24-week healing interval. RESULTS: Clinical healing was uneventful. The rhGDF-5 high dose significantly increased bone formation compared with controls in terms of bone area (p < 0.05), and a high degree of bone maturation was observed in the rhGDF-5/PLGA high dose group. Root resorption/ankylosis or other aberrant healing events were not observed. CONCLUSION: The rhGDF-5/PLGA appears to support alveolar bone healing/regeneration and the rhGDF-5/PLGA high dose uniquely increased maturation of the regenerated bone.

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

OBJECTIVE: Although a previous study reported that recombinant human growth/differentiation factor-5 (rhGDF-5) coated onto a ß-tricalciumphosphate (ß-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/ß-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/ß-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 ß-TCP remained. CONCLUSIONS: These 24-week observations suggest that regenerated periodontal tissues in sites receiving rhGDF-5/ß-TCP undergo progressive maturation without debilitating aberrant tissue reactions.

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.

OBJECTIVE: 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 injectable poly-lactide-co-glycolide-acid (PLGA) composite carrier and an established defect model. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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

OBJECTIVE: 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 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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 implantation of recombinant human growth/differentiation factor-5 (rhGDF-5) in an absorbable collagen sponge carrier into one-wall intrabony defects in dogs: a dose-range study.

AIM: 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 cementum and alveolar bone formation, and aberrant healing events following surgical implantation of rhGDF-5 in an absorbable collagen sponge (ACS) carrier using an established periodontal defect model. MATERIALS AND METHODS: 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. Five animals received 1 microg/defect and five animals 20 microg/defect rhGDF-5 in unilateral defect sites. Contralateral sites received treatments reported elsewhere. Five animals received rhGDF-5/ACS with 0 (buffer control) and 100 microg/defect rhGDF-5 in contralateral defect sites. The animals were euthanized at 8 weeks post-surgery for histologic and histometric evaluation. RESULTS: Surgical implantation of rhGDF-5 stimulated significant periodontal regeneration. Cementum formation was significantly enhanced in sites implanted with rhGDF-5 (1 and 100 microg) compared with control (p<0.05). Similarly, bone formation height was significantly greater in sites receiving rhGDF-5 (1 and 100 microg) compared with control (p<0.05). There were no significant or remarkable differences in bone and cementum formation within the selected dose interval (1, 20 and 100 microg rhGDF-5). None of the control or the rhGDF-5 sites exhibited root resorption, ankylosis, or other aberrant tissue reactions. CONCLUSION: Surgical implantation of rhGDF-5/ACS may be used safely to support periodontal wound healing/regeneration in intrabony periodontal defects without complications.

Superior effect of MD05, beta-tricalcium phosphate coated with recombinant human growth/differentiation factor-5, compared to conventional bone substitutes in the rat calvarial defect model.

BACKGROUND: MD05 consists of beta-tricalcium phosphate (beta-TCP) coated with recombinant human growth/differentiation factor-5 (rhGDF-5) and is under evaluation as an osteoinductive and osteoconductive bone graft material for use in dental and maxillofacial applications. The objective of this study was to compare the bone regenerative properties of MD05 with those of conventional commercially available bone substitutes. METHODS: Full-thickness, 6-mm diameter, calvarial critical-size defects (two per animal) were created in adult Sprague-Dawley rats. Groups of rats were implanted with the following: 1) MD05; 2) bovine bone mineral; 3) bovine bone mineral with collagen; 4) bovine bone mineral with synthetic peptide, 5) beta-TCP (from two different manufacturers); or 6) no filling material (sham controls). Blinded macroscopic analysis, histopathologic analysis, and histomorphometric analysis were carried out 6 weeks after implantation. RESULTS: New bone formation assessed histomorphometrically was about five times greater with MD05 than with the other bone substitutes tested, and bone repair was well advanced in MD05-filled defects after 6 weeks. The extent of fibrous tissue and residual implant were significantly lower in the MD05 group. In contrast to the other materials, the use of MD05 was associated with the complete osseous bridging of the defect and with the presence of normal bone marrow. The osteoinductive effect of rhGDF-5 was apparent from the more pronounced bone ingrowth observed with MD05 compared to the beta-TCP carrier alone. All implants showed good biocompatibility. CONCLUSION: MD05 achieved superior bone regeneration compared to conventional materials and is a promising new bone substitute for dental and maxillofacial applications.