Sinus Augmentation Studies Methods and Definition

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1 FDA approved indications for Infuse Bone Graft in the Maxillofacial Skeleton Alveolar Ridge Augmentation (Buccal Wall Defects) in the Maxilla Maxillary Sinus Floor augmentation Sinus Augmentation Studies Methods and Definition Prospective, multi-center, randomized, controlled human clinical trials with high level of evidence 220 patients 99 INFUSE Bone Graft patients 30 other rhbmp-2/acs patients 91 autograft patients 21 sites To demonstrate that rhbmp-2/acs: Regenerates or grows normal physiologic bone Provides bone for dental restorations or placement of dental implants Produces stable bone under functional loading To demonstrate safety in oral maxillofacial indications Pre-op Radiograph 1

2 Lateral Window Approach to Sinus Floor Reconstituted rhbmp-2 Placed on ACS Sponge rhbmp-2/acs Sinus Inlay Graft rhbmp-2/acs Graft Graft Placed 2

3 Radiograph showing augmentation in left Maxillary sinus floor Radiograph after implant placement in augmented site CT Scan of de novo Bone Induced by INFUSE Bone Graft All patients had 6 mm or less of native bone in the posterior maxilla. Patients received 13.1 cc of INFUSE Bone Graft per sinus on average ( cc range.) Pre-op 98 out of 99 patients formed bone in their sinus post-infuse Bone Graft placement. 16-weeks Post INFUSE Bone Graft Placement On average, 8.2 mm of new bone (height) was formed in each sinus as measured by CTs. 3

4 CT Scan of de novo Bone Pre-Op (3.9 mm Baseline) 6 Months Post-Op (16.0 mm) Method of Determining bone growth in the Sinus floor Determination of bone growth 4

5 Dental Implant Survival Rate INFUSE Bone Graft Density (mg/cc) Density (mg/cc) Change in Bone Height (mm) Sinus Augmentation Bone Growth Treated with INFUSE Bone Graft (N=98) A significant amount of new bone was formed with INFUSE Bone Graft. As assessed by CTs, all patients but one had formed bone at 6 months. Bone Height Change by Subject 20 Bone Height change mean ± SD = 8.2 ± 3.8 mm Bone Density from CT Scan Sinus Augmentation Dosing Study Density at 4 months Post Grafting Density at 4 months Post Grafting Density at 6 months Post Prosthesis Density at 6 months Post Prosthesis Bone Bone Graft 1.50 mg/ml INFUSE rhbmp-2/acs Bone Graft Graft Bone Graft 1.50 mg/ml INFUSE rhbmp-2/acs Bone Graft Bone induced by INFUSE Bone Graft matured post-prosthesis placement due to normal maturation and remodeling under load (Wolff s Law.) Dental Implant Survival Rate The primary efficacy endpoint of the study for dental implant placement and survival was met There was no significant difference in implant survival either by patient or by implant between the autograft and INFUSE Bone Graft groups over 2 years post-prosthesis placement 100% 90% 80% 70% 60% INFUSE by Implant Bone Graft by Implant A total of 314 implants were placed in each group (628 total implants). The only failures that occurred during loading included: 5 implants in the autograft group at 6 months, and 3 implants in the INFUSE Bone Graft group at 6 and 24 months 50% 40% 30% 20% 10% 0% 6 Months post-prosthesis 5

6 Pre-op imaging of sinus augmentation (1997) Long Term Follow-up Clinical & Radiographic results 13 year follow Pre & Post-op Radiographs

7 Periapical radiographs 14 years after Infuse Augmentation Clinical Photos 14 years after grafting Pre-op Imaging for Pilot study

8 Post op Imaging 16 years after Infuse Grafting Clinical appearance of restorations 16 years after infuse grafting Pre &Post-op Radiographs

9 Bilateral fracture of mandible Atrophic mandible grafted with FDBA & Infuse bone graft Post-op radiographs demonstrating fracture reduction & bone graft 9

10 Pre and post op radiographs Healed bilateral mandibular 9 months Radiograph 1 year after osseous reconstruction 10

11 Ameloblastoma Pre-Op Medical Model Exposure of the mandible 11

12 Specimen 12

13 Infuse and cancellous allograft Post op radiograph Post op day 1 13

14 Six Months Post-op Intra 0ral Views of Defect and Dentition 14

15 Radiograph of failing implants Clinical picture after Implants are removed 15

16 Model preparation and mesh adaptation Site exposure and grafting using titanium mesh and Infuse BMP-2 SPONGES RIDGE FORM AT 4 MONTHS 16

17 BEFORE GRAFT AFTER BMP-2 AND TI MESH Excellent height &width was achieved Imaging showing implants in grafted bone 17

18 Three Months Post Operative EXCELLENT BONE HEIGHT AND TISSUE HEALTH 18

19 FINALRESULT Safety Concerns with Infuse Bone Graft Questions have been raised regarding the association between the clinical use of Infuse Bone Graft and ithe incidence of Cancer. Concerns about the potential for rhbmp-2 to promote Cancer growth due to a broad range of expected cellular responses ie. cell recruitment, differentiation, and new blood vessel formation. Critical molecule in embryological development Scientific Evidence Summary There is no evidence that rhbmp-2 is Carcinogenic or Mutagenic. Clinical evidence for use of Infuse in approved applications does not suggest an increase incidence of Cancer. Unknown whether direct implantation of rhbmp- 2 on the ACS carrier into a tumor site could affect tumor growth rate. In an in vivo study the implantation of Infuse had no impact on the aggressiveness of distant malignant tumors 19

20 Scientific Evidence Summary However, Infuse Bone Graft should not be used in the vicinity of any active malignancy or patients undergoing treatment for malignancy. Scientific Evidence Resnick D, Boznic KJ, Meta Analysis of Recombinant Human bone MorphogeneticProtein-2. Annals Intern Med 2013;158: Simmonds MC, Brown JVE, Heirs MK, Higgins PT, Mannion RJ, Rodgers MA, Stewart LA. Safety and Effectiveness of Recombinant Human Bone Morphogenetic Protein-2 for Spinal Fusion. Ann Intern Med:158: Fu R, Selph S, McDonagh M, Peterson K, Tiwari A, Chou R, Helfand M.Effectiveness and Harms of Recombinant Human Bone MorphogneneticProtein-2 in Spine Fusion. Ann Intern Med. 2013; 158: Laine C et al. Closing in on the Truth About Recombinant Human Bone Morphogenetic Protein-2: Evidence Synthesis, Data Sharing, Peer Review and Reproducible Research. Ann Intern Med 2013;158:

21 Clinical Applications Of Recombinant Human Bone Morphogenetic Protein- 2 (rhbmp-2) April 17, 2014 University of Miami Miller School Of Medicine Tissue Engineering Advantages in Reconstructive Surgery Robert E. Marx, DDS Professor of Surgery Director of Research University of Miami Miller School of Medicine 1

22 Disclosure - Active 1. Medtronics Consultant 2. KLS Martin Residency support 3. Synthes CMF Residency support 4. Bio-Met Microfixation Residency support 5. Biomet 3i Residency support What Is rhbmp-2/acs? 1. An alternate to autogenous bone grafting 2. Enhancer of soft tissue healing 3. Maybe combined and enhances bone regeneration with: a. autogenous grafts b. allogeneic/xenogeneic grafts c. synthetics Matrix Cells Signal 2

23 In-Situ Tissue Engineering Bone Regeneration Without Autogenous Bone Or Free Vascular Fibulas rhbmp 2 Dimer 32K protein 2 chains of approximately 250 amino acids each Cysteines in yellow 3

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25 Bone Precursor Cells 1. Endosteal osteoblasts 2. Marrow stem cells * Transplanted * Circulating rhbmp-2 induces physiologically normal trabecular bone. 5

26 Role Of BMP In Nature 1. Embryogenesis histodifferentiation migration development of the skeleton 2. Adult bone remolding (reforms bone after osteoclastic resorption) Why recombinant technology? BMP In Bone 20ug in 10Kg Bone 2X ,000, ,000,02% 1/500,000,000. 6

27 rhbmp-2/acs (Infuse ) Now FDA Cleared For: 1. Maxillary sinus augmentation 2. Ridge preservation (socket grafting) Off Label Applications Of rhbmp-2/acs (Infuse ) rhbmp-2/acs Use 1. Ridge Augmentation 2. Continuity Defects 7

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56 Prosthetic Phase Overbar Denture Final Restoration 36

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58 Reconstruction Of Large Vertical Ridge Augmentations 1. Crushed cancellous allogeneic bone 2. Platelet rich plasma 3. rhbmp-2/acs Maxillary Vertical Ridge Augmentation rhbmp-2/acs Autograft P N Bone Regeneration TBA 72% 64% 0.95 Osseointegrated Implants 137/148 (92.6%) 140/156 (89.7%) Donor Site N/A 40/ Average Cost $5,700 $5, Average Time of Procedure 48 minutes 78 minutes P=0.05 rhbmp is an alternative to autogenous bone. 38

59 Conclusions 1. An improved scaffold is required for predictable bone regeneration and greater bone density 2. rhbmp-2/acs + CCFDAB+PRP will equal autogenous bone results in the OR or office setting Matrix Cells Signal In-Situ Tissue Engineering Bone Regeneration Without Autogenous Bone Or Free Vascular Fibulas 39

60 Tumor Related Defects & Continuity Defects 40

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64 Reconstruction Of Large Non-Continuity Defects 1. Crushed cancellous allogeneic bone 2. Platelet rich plasma 3. rh-bmp-2/acs 44

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70 Reconstruction Of Large Non-Continuity Defects 1. Crushed cancellous allogeneic bone 2. Platelet rich plasma 3. rh-bmp-2/acs Can rhbmp-2/acs reconstruct continuity defects? 50

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85 Bone Marrow Aspirate Concentrates (BMAC) Stem Cells And Osteoprogenitor Cells 65

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91 An Update On Management Of Bisphosphonate Induced Osteonecrosis 71

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93 Grafted With 1. rhbmp-2/acs 12 mg 2. BMAC 10 ml, TNC=798 x 10 6, CD34+=7.68 x CC freeze dried allogeneic bone Matrix Cells Signal 73

94 Contribution 1. Cells: osteoprogenitor cells in BMAC (i.e., CD34+, CD44+, CD105+) 2. Signal: rhbmp-2 3. Matrix: a. CCFDAB b. cell adhesion molecules in BMAC Bone Marrow Aspirate Concentrates 1. Osteoprogenitor cells 2. Mesenchymal stem cells (CD44 +, CD90 +, CD Platelets 4. Cell adhesion molecules 74

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96 rhbmp-2/acs Edema 1. Will be twice as much 2. Will last twice as long 3. Will not be reduced very much by steroids Cause Of rhbmp-2/acs Edema 1. High protein content in confined space hypertonic 2. Chemo attraction of connective tissue/bone cells: responds minimally to steroids 76

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99 Success In Continuity Defects 1. Continuity 2. Alveolar height 3. Alveolar width 4. Arch coordination 5. Implantable bone BMP (OMFS) On Label: 1. Socket grafts 2. Sinus augmentation Off Label: 1. Alveolar clefts 2. Ridge augmentation 3. Interpositional grafts 4. Continuity defects 79

100 BMP Advantages 1. Predictable bone regeneration 2. No bone harvest 3. Decreased pain 4. Reduced operating time BMP Disadvantages 1. Increased edema 2. Cost 3. Preparation of rhbmp- 2/ACS (20 minutes) 4. Mesh exposures Continuity Defects In-Situ TE PBCCM Fibula N Bone Regeneration 49 (98%) 48 (96%) 20 (86%) HND (6 months) TBA 67% 63% N/A Donor Site 0 50/50 23/23 Avg. Hospital Stay 1.7 days 4.2 days 11.3 days Avg. Costs $19,200 $41,300 $67,700 Avg. Time of Procedure 3.7 hrs 5.7 hours 10.4 hrs 80

101 The End 81