Myron Nevins

Pivotal, Randomized, Parallel Evaluation of Recombinant Human Bone Morphogenetic Protein-2/Absorbable Collagen Sponge and Autogenous Bone Graft for Maxillary Sinus Floor Augmentation

PURPOSE The purpose of this prospective study was to evaluate the safety and effectiveness of recombinant human morphogenetic protein-2 (rhBMP-2) on an absorbable collagen sponge (ACS) compared with an autogenous bone graft when used for 2-stage maxillary sinus floor augmentation. The study assessed new bone formation, placement integration, and functional loading after 6 months and long term for 2 years. MATERIALS AND METHODS A total of 160 subjects were randomized, enrolled, and followed from January 1999 to February 2004 at 21 centers in the United States. The subjects with less than 6 mm of native bone height were treated with 1.50 mg/mL rhBMP-2/ACS or with an autograft. The height and density measurements were quantified by computed tomography scans. Core biopsies were obtained at dental implant placement and used for histological analysis. Safety was evaluated by oral examinations, radiographs, serum chemistries, and hematology. RESULTS A significant amount of new bone was formed by 6 months postoperatively in each group. The mean change in bone height in the rhBMP-2/ACS subjects was 7.83 +/- 3.52 mm versus 9.46 +/- 4.11 mm for the bone graft subjects. At 6 months after dental restoration, the induced bone in the rhBMP-2/ACS group was significantly denser than that in the bone graft group. No marked differences were found in the histologic parameters evaluated between the 2 groups. The new bone was comparable to the native bone in density and structure in both groups. The success rate for the rhBMP-2/ACS group was 79% (64 of 81 subjects), and 201 of 251 implants placed in the bone graft group and 199 of 241 implants placed in the rhBMP-2/ACS group were integrated, retained, and functional at 6 months after loading. No adverse events were deemed related to the rhBMP-2/ACS treatment. The autograft group was noted to have a 17% rate of long-term parasthesia, pain, or gait disturbance related to the bone graft harvest. CONCLUSIONS The results of our multicenter, randomized, prospective, clinical trial have shown the effectiveness and safety of rhBMP-2/ACS compared with bone graft for sinus floor augmentation. The studys primary endpoint was exceeded, and the implants placed in rhBMP-2/ACS and bone graft groups performed similarly after functional loading.

Platelet-derived growth factor applications in periodontal and peri-implant bone regeneration

Introduction: Achieving successful tissue regeneration following traditional therapeutic protocols, combining bone grafts and barrier membranes, may be challenging in certain clinical scenarios. A deeper understanding of periodontal and peri-implant wound healing and recent advances in the field of tissue engineering have provided clinicians with novel means to obtain predictable clinical outcomes. The use of growth factors such as recombinant human platelet-derived growth factor-BB (rhPDGF) with biocompatible matrices to promote tissue regeneration represents a promising approach in the disciplines of periodontology and implantology. Areas covered: This review covers the basic principles of bone and periodontal regeneration, and provides an overview of the biology of PDGF and its potential to predictably and reproducibly promote bone regeneration in regular clinical practice. The results of preclinical and clinical human studies evaluating the effectiveness of growth-factor-enhanced matrices are analyzed and discussed. Expert opinion: Current available evidence supports the use of rhPDGF-enhanced matrices to promote periodontal and peri-implant bone regeneration.

Adaptive growth factor delivery from a polyelectrolyte coating promotes synergistic bone tissue repair and reconstruction

Significance A critical challenge in the field of tissue repair is effective bone repair and reconstruction. The clinical standard of extracting bone from another area in the body or from donors is severely hampered by short supply, pain, and concerns about disease transmission. In this study, we developed a polymer-based nanolayered coating that carries active biological drugs in physiologically relevant amounts for tissue repair, with tunable release properties to induce bone repair. Using a rodent model, we observed that these coatings yield mature, mechanically stable bone that bridges large defects and restores the native form. This system is a potent strategy for safe and precise tissue repair and has the potential to significantly boost successful outcomes for bone repair. Traumatic wounds and congenital defects that require large-scale bone tissue repair have few successful clinical therapies, particularly for craniomaxillofacial defects. Although bioactive materials have demonstrated alternative approaches to tissue repair, an optimized materials system for reproducible, safe, and targeted repair remains elusive. We hypothesized that controlled, rapid bone formation in large, critical-size defects could be induced by simultaneously delivering multiple biological growth factors to the site of the wound. Here, we report an approach for bone repair using a polyelectrolye multilayer coating carrying as little as 200 ng of bone morphogenetic protein-2 and platelet-derived growth factor-BB that were eluted over readily adapted time scales to induce rapid bone repair. Based on electrostatic interactions between the polymer multilayers and growth factors alone, we sustained mitogenic and osteogenic signals with these growth factors in an easily tunable and controlled manner to direct endogenous cell function. To prove the role of this adaptive release system, we applied the polyelectrolyte coating on a well-studied biodegradable poly(lactic-co-glycolic acid) support membrane. The released growth factors directed cellular processes to induce bone repair in a critical-size rat calvaria model. The released growth factors promoted local bone formation that bridged a critical-size defect in the calvaria as early as 2 wk after implantation. Mature, mechanically competent bone regenerated the native calvaria form. Such an approach could be clinically useful and has significant benefits as a synthetic, off-the-shelf, cell-free option for bone tissue repair and restoration.

Platelet-Derived Growth Factor Promotes Periodontal Regeneration in Localized Osseous Defects: 36-Month Extension Results From a Randomized, Controlled, Double-Masked Clinical Trial

BACKGROUND Recombinant human platelet-derived growth factor (rhPDGF) is safe and effective for the treatment of periodontal defects in short-term studies up to 6 months in duration. We now provide results from a 36-month extension study of a multicenter, randomized, controlled clinical trial evaluating the effect and long-term stability of PDGF-BB treatment in patients with localized severe periodontal osseous defects. METHODS A total of 135 participants were enrolled from six clinical centers for an extension trial. Eighty-three individuals completed the study at 36 months and were included in the analysis. The study investigated the local application of β-tricalcium phosphate scaffold matrix with or without two different dose levels of PDGF (0.3 or 1.0 mg/mL PDGF-BB) in patients possessing one localized periodontal osseous defect. Composite analysis for clinical and radiographic evidence of treatment success was defined as percentage of cases with clinical attachment level (CAL) ≥2.7 mm and linear bone growth (LBG) ≥1.1 mm. RESULTS The participants exceeding this composite outcome benchmark in the 0.3 mg/mL rhPDGF-BB group went from 62.2% at 12 months, 75.9% at 24 months, to 87.0% at 36 months compared with 39.5%, 48.3%, and 53.8%, respectively, in the scaffold control group at these same time points (P <0.05). Although there were no significant increases in CAL and LBG at 36 months among all groups, there were continued increases in CAL gain, LBG, and percentage bone fill over time, suggesting overall stability of the regenerative response. CONCLUSION PDGF-BB in a synthetic scaffold matrix promotes long-term stable clinical and radiographic improvements as measured by composite outcomes for CAL gain and LBG for patients possessing localized periodontal defects ( ClinicalTrials.gov no. CT01530126).

Angiogenic Biomarkers and Healing of Living Cellular Constructs

The use of intra-oral soft-tissue-engineered devices has demonstrated potential for oral mucosa regeneration. The aim of this study was to investigate the temporal expression of angiogenic biomarkers during wound healing of soft tissue reconstructive procedures comparing living cellular constructs (LCC) with autogenous free gingival grafts. Forty-four human participants bilaterally lacking sufficient zones of attached keratinized gingiva were randomly assigned to soft tissue surgery plus either LCC or autograft. Wound fluid samples were collected at baseline and weeks 1, 2, 3, and 4 post-operatively and analyzed for a panel of angiogenic biomarkers: angiogenin (ANG), angiostatin (ANT), PDGF-BB, VEGF, FGF-2, IL-8, TIMP-1, TIMP-2, GM-CSF, and IP-10. Results demonstrated a significant increase in expression of ANT, PDGF-BB, VEGF, FGF-2, and IL-8 for the LCC group over the autograft group at the early stages of wound repair. Although angiogenic biomarkers were modestly elevated for the LCC group, no clinical correlation with wound healing was found. This human investigation demonstrates that, during early wound-healing events, expression of angiogenic-related biomarkers is up-regulated in sites treated with LCC compared with autogenous free gingival grafts, which may provide a safe and effective alternative for regenerating intra-oral soft tissues (ClinicalTrials.gov number, NCT01134081).

Statements from the Estepona Consensus Meeting on Peri-implantitis

† The great majority of well-documented oralimplants show very good long-term clinical results.† A limited amount of crestal bone loss (CBL) ormarginal bone loss may be a biologic response toimplant placement.† CBL may occur for reasons other than infection.† CBL may occur around implants and can have along-termimpactontheoutcomeof thoseimplants.† Some implants can demonstrate substantial boneloss, but a steady state may be reached and nofurther clinically significant bone loss observed.† There is an adaptive change of the crestal bone levelafter placement and restoration.† Peri-implantitis is an unsuitable term to describe allCBL.† The term peri-implantitis is here defined as aninfection with suppuration associated with clini-cally significant progressing CBL after the adaptivephase.† In contrast, peri-implant mucositis is defined asinflammation of the peri-implant mucosa withoutdiscernibly progressing CBL.† Bone remodeling including CBL is influenced byinflammation.† Implant-, clinician-, and patient-related factors aswell as foreign body reactions may contribute toCBL. Implant factors: material, surface properties,and design (e.g., ease of plaque removal); clinicianfactors: surgical and prosthodontic experience,skills, and ethics; patient factors: systemic diseaseand medication, oral disease (e.g., untreated orrefractory periodontal disease, local infections),behavior (e.g., patient compliance with oral hygieneand maintenance, smoking), and site-related factors(e.g., bone volume and density, soft tissue quality);and foreign body reactions (e.g., corrosion by-products, excess cement in soft tissues).† A radiograph does not give an absolutely accuratepicture of the bone-implant contact or the crestalbone situation. However, the periapical radiographis an important clinical tool to be used at im-plant placement, implant loading, and repeatedlythereafter.† Radiographs taken longitudinally may assist the cli-nician to monitor changes in crestal bone levels.† Peri-implant examinations that include bleedingon probing and probing depths do not by

Statements from the Estepona Consensus Meeting on Peri-implantitis, February 2–4, 2012

† The great majority of well-documented oralimplants show very good long-term clinical results.† A limited amount of crestal bone loss (CBL) ormarginal bone loss may be a biologic response toimplant placement.† CBL may occur for reasons other than infection.† CBL may occur around implants and can have along-termimpactontheoutcomeof thoseimplants.† Some implants can demonstrate substantial boneloss, but a steady state may be reached and nofurther clinically significant bone loss observed.† There is an adaptive change of the crestal bone levelafter placement and restoration.† Peri-implantitis is an unsuitable term to describe allCBL.† The term peri-implantitis is here defined as aninfection with suppuration associated with clini-cally significant progressing CBL after the adaptivephase.† In contrast, peri-implant mucositis is defined asinflammation of the peri-implant mucosa withoutdiscernibly progressing CBL.† Bone remodeling including CBL is influenced byinflammation.† Implant-, clinician-, and patient-related factors aswell as foreign body reactions may contribute toCBL. Implant factors: material, surface properties,and design (e.g., ease of plaque removal); clinicianfactors: surgical and prosthodontic experience,skills, and ethics; patient factors: systemic diseaseand medication, oral disease (e.g., untreated orrefractory periodontal disease, local infections),behavior (e.g., patient compliance with oral hygieneand maintenance, smoking), and site-related factors(e.g., bone volume and density, soft tissue quality);and foreign body reactions (e.g., corrosion by-products, excess cement in soft tissues).† A radiograph does not give an absolutely accuratepicture of the bone-implant contact or the crestalbone situation. However, the periapical radiographis an important clinical tool to be used at im-plant placement, implant loading, and repeatedlythereafter.† Radiographs taken longitudinally may assist the cli-nician to monitor changes in crestal bone levels.† Peri-implant examinations that include bleedingon probing and probing depths do not by

Ridge Augmentation Using Recombinant Bone Morphogenetic Protein-2 Techniques: An Experimental Study in the Canine

BACKGROUND The use of recombinant bone morphogenetic protein-2 (rhBMP-2) with a collagen carrier material has severe limitations in regards to space maintenance. The aim of this study was to test whether rhBMP-2 combinations with allografts or a mesh enhance the regeneration of missing bone and the subsequent placement of dental implants. METHODS In five dogs, surgically created ridge defects were augmented using one of the following treatment modalities: 1) rhBMP-2/absorbable collagen sponge (ACS) under a titanium mesh (Mesh); 2) rhBMP-2/ACS plus canine freeze-dried bone allograft; 3) rhBMP-2/ACS plus canine demineralized freeze-dried bone allograft (DFDBA); or 4) rhBMP-2/ACS wrapped around a canine cancellous allograft block (Block Allograft). Eight weeks later, dental implants were placed in the augmented areas. The dogs were sacrificed 16 weeks after bone augmentation and specimens obtained for histologic and histomorphometric analyses. RESULTS All sites augmented with DFDBA, and one site with Block Allograft did not allow placement of dental implants. In all other sites, dental implants were placed. The area of regenerated bone ranged between 23.40 mm(2) (freeze-dried bone allograft) and 35.16 mm(2) (Block Allograft). The greatest amount of bone was regenerated in the Block Allograft group ranging from 4.54 mm (at 1.5 mm), to 4.95 mm (at 3 mm), to 5.14 mm (at 4.5 mm). The least amount of bone was regenerated by the DFDBA group with values of 2.24 mm (at 1.5 mm), 2.84 mm (at 3 mm), and 3.34 mm (at 4.5 mm). Statistically significant differences were observed between DFDBA and block allograft at all three levels (P <0.001). CONCLUSION The combination of rhBMP-2 and a block allograft provides the greatest ridge width of the four treatment options used in this canine ridge augmentation model.

A Prospective, Randomized Controlled Preclinical Trial to Evaluate Different Formulations of Biphasic Calcium Phosphate in Combination With a Hydroxyapatite Collagen Membrane to Reconstruct Deficient Alveolar Ridges

Many patients and clinicians would prefer a synthetic particulate bone replacement graft, but most available alloplastic biomaterials have limited osteogenic potential. An alloplast with increased regenerative capacity would be advantageous for the treatment of localized alveolar ridge defects. This prospective, randomized controlled preclinical trial utilized 6 female foxhounds to analyze the osteogenic impact of different formulations of biphasic calcium phosphate (BCP) in combination with an hydroxyapatite-collagen membrane and their ability to reconstruct deficient alveolar ridges for future implant placement. The grafted sites were allowed to heal 3 months, and then trephine biopsies were obtained to perform light microscopic and histomorphometric analyses. All treated sites healed well with no early membrane exposure or adverse soft tissue responses during the healing period. The grafted sites exhibited greater radiopacity than the surrounding native bone with BCP particles seen as radiopaque granules. The graft particles appeared to be well-integrated and no areas of loose particles were observed. Histologic evaluation demonstrated BCP particles embedded in woven bone with dense connective tissue/marrow space. New bone growth was observed around the graft particles as well as within the structure of the graft particulate. There was intimate contact between the graft particles and newly formed bone, and graft particles were bridged by the newly formed bone in all biopsies from the tested groups. The present study results support the potential of these BCP graft particulates to stimulate new bone formation. Clinical studies are recommended to confirm these preclinical findings.

The Combination of Purified Recombinant Human Platelet-Derived Growth Factor-BB and Equine Particulate Bone Graft for Periodontal Regeneration

BACKGROUND The objective of this study is to evaluate the potential for periodontal regeneration of a critical-sized defect with the application of recombinant human platelet-derived growth factor (rhPDGF-BB) combined with either a particulate equine or a β-tricalcium phosphate (β-TCP) matrix. METHODS Critical-sized intrabony 2-wall defects were created bilaterally on the distal surface of the second premolar and the mesial surface of the first molar in nine hounds. Twelve defects received rhPDGF-BB/equine treatment, 12 defects received rhPDGF-BB/β-TCP treatment, and the remaining 12 sites served as sham-surgery controls. The animals were sacrificed after a 10-week healing period. RESULTS Clinical healing was uneventful without obvious signs of overt gingival inflammation. Histologic and histomorphometric analyses revealed statistically that there were differences among the three groups in terms of new bone formation (P <0.001). The amount of test material for both rhPDGF-BB/equine and rhPDGF-BB/β-TCP groups was comparable, but the amount of newly formed bone was significantly higher (P <0.01) in favor of the rhPDGF-BB/equine group. The amount of new cementum formed for the rhPDGF-BB/equine group (4.8 ± 1.3 mm) was significantly higher (P =0.001) than the sham-surgery control group (1.7 ± 1.9 mm). CONCLUSION Both rhPDGF-BB/equine and rhPDGF-BB/β-TCP have the potential to support the regeneration of the periodontal attachment apparatus.