& tissue botiss regeneration biomaterials

cerabone® Natural bovine bone grafting material Scientific and clinical evidence

natural

safe

pure hard tissue 1 Bone and regeneration techniques

maxresorb® flexbone* collacone®..max

Augmentation Preservation hard tissue

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® B maxresorb n or bone atrophy following loss of teeth or inflammatory processes. Autologous: cerabone® mucoderm® - Patient‘s own bone, mostly For the filling of bone defects, the patient‘s own (autologous) bone Osseous harvested intraorally or from Integration Remodeling Hig ng is considered the „gold standard“, because of its biological activity the iliac crest h Quality Learni - Intrinsic biological activity SCIENCE due to vital cells and growth factors. Nevertheless, the harvesting of

CLINIC botiss academy EDUCATION bone & tissue days autologous bone requires a second surgical site associated with an Allogenic: - Bone from human donors additional bony defect and potential donor site morbidity. (multi- donors or femoral cerabone® 0.5 - 1.0 mm heads of living donors) In addition, the quantity of autologous bone is limited. Today, due to ...... - Natural bone composition and a constant development, bone graft materials provide a reliable and Development / Production / Distribution structure safe alternative to autologous bone grafts. Clinicians can choose between a variety of different bone graft Xenogenic: materials and augmentation techniques. Bone graft materials are - From other organisms, mainly classified by their origin into four groups. bovine origin - Long-term volume stability The GBR/GTR technique

The principle of Guided Bone Regeneration (GBR) maintain the space for controlled regeneration of Alloplastic: or Guided Tissue Regeneration (GTR) is based bone. - Synthetically produced, cerabone® maxresorb® maxresorb® inject maxgraft® maxgraft® bonering / maxgraft® on the separation of the grafted site from the sur- The application of a bone graft material into the preferably calcium phosphate bonebuilder maxgraft® cortico rounding soft tissue by application of a barrier. defect prevents a collapse of the membra- ceramics Natural bovine bone graft Synthetic biphasic calcium Synthetic injectable bone Patient matched allogenic Allogenic bone ring / Processed allogenic Collagen membranes act as a resorbable matrix ne, acting as a place holder for the regenerating - No risk of disease phosphate paste bone implant Processed allogenic bone bone graft plate to avoid the ingrowth of the faster proliferating fibro- bone and as an osteoconductive scaffold for the transmission blasts and/or epithelium into the defect, and to ingrowth of blood vessels and bone forming cells.

Guided Tissue Regeneration (GTR) Guided Bone Regeneration (GBR) For large defects a mixture of autologous or allogenic bone, which has excellent biological ® collacone® max maxresorb® Jason fleece / collprotect® Jason® mucoderm® potential, and a bone graft flexbone* collacone® membrane membrane material for volume stability Alveolar cone Flexible block Collagenic haemostat Native collagen membrane Native pericardium 3D-stable soft tissue of the grafting site, is recom- (CaP / Collagen composite) (CaP / Collagen composite) (Sponge / Cone) GBR / GTR membrane (Collagen) graft mended.

2 * Coming soon 3 Indications for cerabone®

cerabone® product family ......

Histology of cerabone® six months after sinus lift; optimal Xenogenic bone graft materials integration and bone healing ...... Xenogenic bone grafts are derived from animals, preferably of bo- SEM: cerabone® macro- and micropores vine origin. Bovine bone materials are deproteinized by heating resembling human bone Periodontology (sintering) to minimize the risk of allergic reactions and disease transmission1. Bovine bone materials have a long tradition, are very well documen- Intraosseous defects (1 - 3 walls) ted, and their clinical application has found wide-ranging accep- Furcation defects (class I - II) tance. The removal of all transforms them into biologically SEM picture of human bone derived ceramics. They are characterized by their Implantology and Oral and CMF Surgery preserved three-dimensional natural bone structure with intercon- - Sinus floor elevation necting pores, strongly resembling the human bone structure. Their guided osseous integration rather than rapid resorption leads to ex- - Horizontal augmentation cellent volume stability of the graft, with the formation of new bone - Vertical augmentation on the highly structured bovine bone surface...... - Ridge preservation

- Peri-implant defects cerabone® – natural bovine bone grafting material - Socket preservation cerabone® is derived from bovine bone in an established high- - Bone defect augmentation temperature heating process (sintering) guaranteeing high safety. Beside safety and reliablity of the product and the production pro- cess, the material fulfills all other important requirements for the clinical success of a bovine bone graft material: Product Specifications - Phase pure hydroxyapatite without organic components cerabone® granules

Article No. Particle Size Content - Rough and open porous structure comparable to native human bone 1510 0.5 - 1.0 mm 1 x 0.5 ml - Excellent hydrophilicity enabling a rapid uptake of blood 1511 0.5 - 1.0 mm 1 x 1.0 ml 1512 0.5 - 1.0 mm 1 x 2.0 ml - Optimal biocompatibility proven in various in vitro and in vivo tests 1515 0.5 - 1.0 mm 1 x 5.0 ml - Rapid and controlled osseous integration 1520 1.0 - 2.0 mm 1 x 0.5 ml 1521 1.0 - 2.0 mm 1 x 1.0 ml cerabone® has excellent biofunctionality; These characteristics are the base for the excellent clinical results of superior hydrophilicity and blood uptake 1522 1.0 - 2.0 mm 1 x 2.0 ml ...... cerabone® demonstrated by high volume stability at the graft site, 1525 1.0 - 2.0 mm 1 x 5.0 ml complete integration into newly formed bone matrix with high bone density2. cerabone® block

cerabone® Article No. Dimension Content packaging ...... 1720 20 x 20 x 10 mm 1 x block 1 Murugan et al. (2003). Heat-deproteinated xenogeneic bone from 2 Rothamel et al. (2011). Sinus floor Elevation using a sintered, slaughterhouse waste: Physico-chemical properties. Bull Mater Sci natural bone mineral. zzi 27(1). 26:523–528. 4 5 cerabone®: cerabone®: Safety and reliability facts 100% pure mineral bone phase

made in Germany cerabone® consists of the pure mineral phase of bovine bone.

No other phases besides hydroxyapatite are detectable. The high

phase purity leads to maximal volume stability. In addition, the

absence of organic components ensures the high safety of cer-

abone®. Sintering Safety ...... Results from Prof. Dr. C. Vogt, University of Hannover Heating up cerabone® is made of cancellous bone from the 160 X-ray diffractometry: mineral phases and crystallinity. to 1250°C 140 3 femoral heads of domestic cattle. The processes 120 Narrow peaks and low baseline . 100 cerabone® shows high crystallinity and 100% purity. of procurement and processing/production of 80 60

this bovine material meets strict safety require- Intensity/cts 40 20 1.2 ments. Thus the risk of BSE ransmission can be 0 5 15 25 35 45 55 1

considered negligible. Threefold sterility Diffraction angle/° 2 O 0.8 O-H-peak ...... 0.6 Infrared spectroscopy: 0.4 molecular fingerprint. transmission Characteristic peaks of phosphate and 0.2 Patented manufacturing process P-O-peaks hydroxy groups of the hydroxyapatite3. 0 Both, product and process of procurement of the raw material as 4000 3400 2800 2200 1600 1000 400 No other organic phases detectable. wave number/cm-1 well as the production process are fulfilling the German and EU- regulatory and security requirements for bovine bone grafts inclu- ...... ding EN ISO 22442-1, -2 and -3, as well as Commission Regulation room Thermogravimetric analysis showing combustion of cerabone® (EU) No 722/2012. temperature organic components. unsintered The proprietary manufacturing process of cerabone® is based on bovine bone No mass loss by heating cerabone® up to 1000°C4. graft high-temperature heating (sintering) and special surface treatment Complete removal of organic components 1000°C that result in: ...... (cells, collagen) by sintering process. - Cell-friendly, biomimetically structured, rough surface 80% 82% 84% 86% 88% 90% 92% 94% 96% 98% 100% - Complete removal of organic components and albuminous mass impurities - No risk of allergic reactions or rejection CE marking Particle size 1.0 - 2.0 mm 0.5 - 1.0 mm - CE certification of cerabone® was issued in 2002 - The product is on the market since January 2002

Sterile and storable cerabone® is available as granules and in block form. The product is packed in sterile vials, sealed in primary and secondary blister packaging and sterilized with gamma irradiation. cerabone® can be 3 Prof. C. Vogt, Leibniz University Hanover, Proto- stored at room temperature for up to three years. col on the analysis of bone graft material, 2012. 4 Tadic et al. (2004). A thorough physicochemi- cal characterisation of 14 calcium phosphate- based bone substitution materials in compari- son to natural bone. Biomaterials 25:987–994. 6 7 Topography and cerabone® serves as an hydrophilicity excellent matrix as key success factors for bone regeneration

cerabone® and growth factors ...... In vitro experiments from Prof. Dr. H. Jennissen und Dr. M. Laub Bone biology: University of Duisburg-Essen/Morphoplant GmbH

Loading capacity for BMP-2 1.5 A (n=3, mean +_ SD) In vitro experiments show Scientific results ® 1.2 that cerabone can be

) from in vitro ® loaded with up to 1 mg 0.9 BMP-2/g. experiments 0.6 Bound rhBMP-2 (mg/g cerabone 0.3

0.0 Optimal adhesion and ingrowth of cells, 0 0.3 0.6 0.9 1.2 1.5 proteins and blood vessels B 0.8 Two-phase exponential release Two-phase controlled ex- of bound BMP-2; (n=3, mean +_ SD) ponential release of BMP-2 Scanning electron microscope (SEM) pictures show the highly struc- 0.6

) ®

® may provide cerabone with tured surface of cerabone® as well as the macro and micropores. Pore distribution of cerabone®5 burst phase: half-life 1.0 day

Percentage distribution of pores (%) pores of distribution Percentage enhanced osseointegration 800 100 0.4 700 90 (Morphoplant GmbH; 80 patent application WO 600 Bound rhBMP-2 70 (mg/g cerabone 0.2 sustained release phase: 500 60 half-life 35 days 2009/056567). 400 50 0.0 BMP-2 structure 300 40 0 5 10 15 20 25 30 200 time (days) 20 ...... 100 10 ® ® Number of pores 0 0 Growth of and on cerabone Colonialization of cerabone by osteoblasts Prof. Dr. Dr. Daniel Rothamel The macroporous structure enab- The capillary effect of the micropo- The rough surface ensures an <150 150- 300- 600- 900- 1200- 1500- 1800- >2100 In vitro results from Prof. Dr. Dr. D. Rothamel, University of Düsseldorf les migration of cells, penetration res leads to a quick blood uptake excellent and homogenous surface 300 600 900 1200 1500 1800 2100 of blood vessels and integration of of the material adhesion of cells and proteins Pore size (µm) and Dr. C. Reichert, University of Bonn the particles The rough surface also promotes the adhesion of serum proteins and cells onto the surface. -like cells Excellent hydrophilicity of cerabone® quickly adhere to the cerabone® particles. Only attached osteoblasts can start to produce new bone matrix leading cerabone®´s rapid and complete hydration with Its strong capillary action facilitates fast and to the osseous integration of the cerabone® particles. In blood or saline solution is crucial for superior efficient penetration of the material particles with another study, good adherence of osteoclasts promoted handling characteristics, new bone formation and fluids, nutrients and blood through the three- the superficial remodeling of the particles. for the final clinical success. dimensional, porous trabecular bone network, resulting in excellent handling, reliability and pre- Proliferation of osteoblasts on cerabone® dictability in the daily clinical use. 600

Hydrophobicity of a non sintered bovine bone graft material3 400

Good hydrophilicity and fast blood uptake of cerabone® 3 200 cells/well

0 Osteoclastic resorption of cerabone® day 0 day 3 day 7 Dr. C. Reichert, University of Bonn6 ...... 5 Seidel and Dingeldein (2004). Cerabone® - Bovine Based Spongiosa 6 Konermann et al. (2014). Bone substitute material composition and morphology differentially modulate calcium and Ceramic. Mat.-wiss. u. Werkstofftech. 35:208–212. phosphate release through -like cells. International journal of oral and maxillofacial surgery 43:514–521. 8 9 Stem cell research Maximal stability and good osseous ® Interaction of cerabone® with stem cells integration of cerabone In vitro results from Prof. Dr. B. Zavan, University of Padova cerabone® supports the differentiation of attached stem cells into Histological studies on cerabone® ...... osteoblasts that produce new bone matrix. Immunofluorescence staining of stem cells Collagen, osteopontin, osteonectin and osteocalcin are proteins of ...... the extracellular bone matrix that can be used as markers for bone Compressive force (N) 1670±120 4510±770 In vivo formation. Their detection 14 days after seeding stem cells on cera- Compressive resistance (N/cm2) 420±32 564±96 Results from bone® indicate the correct differentiation of the cells. Shear force (N/cm2) 124±35 338±200 Prof. Dr. Z. Artzi, dimension (mm) University of Tel Aviv 7

40 20 1.5 20 20 1.4 20 40 1.3 1.2 Endodontics 1.1 optical density cerabone® – osteoconduction and bony regeneration colla- osteo- osteo- osteo- Stem cells seeded on cerabone® gen I pontin nectin calcin ......

Optimal bone regeneration after bone defect treatment with

cerabone® was demonstrated in an animal study. Tissue integration and cellular degradation In vivo data from a mouse model by Dr. Dr. S. Ghanaati, University of Mainz Bony defects following apicoectomy, were filled with cerabone®. and University of Frankfurt a. M. The histological examination showed a complete bridging of the Section of maxillary block stained with 15 days after implantation into the subcutaneous tissue (CT) of mice, Stevenels blue and Van Gieson’s picro osteotomy orifice after three months and a well established new fuchsin cerabone® (CB) is embedded within a well vascularized granulation bone (NB) and formation (CEM) around the cerabone® tissue (blood vessels marked by arrows). No fibrous encapsulation particles...... or inflammatory reactions are observed. Mononuclear and multinu- clear cells (arrow heads) indicate the onset of cellular degradation of the cerabone® particles. Implantology cerabone® – osseous integration and optimal stability Sinus lift study from Prof. Dr. Dr. D. Rothamel, University of Düsseldorf 8

...... A study on 12 patients showed that cerabone® acts as an osteoconductive material that supports the regeneration of bone after sinus floor elevation surgery. After six months the particles of all biop-

new bone sies were completely integrated into the newly for- cerabone® med bone matrix, while the grafted area showed excellent volume stability.

Biopsy taken six months after sinus floor elevation. cerabone® particles are covered by a layer of newly formed bone matrix ......

7 Artzi et al. (2012). Effect of Guided Tissue Regeneration on Newly 8 Rothamel et al. (2011). Sinus floor elevation using a sintered, natu- Formed Bone and Cementum in Periapical Tissue Healing after ral bone mineral - A histological case report study. zzi 27(1): 60. Endodontic Surgery: An In Vivo Study in the Cat. Journal of Endo- dontics 38:163–169.

10 11 Clinical application of cerabone® Clinical application of cerabone®

Clinical case by Clinical case by Dr. Marius Steigmann, Neckargemünd, Germany Dr. Viktor Kalenchuk, Chernivtsi, Ukraine

cerabone® for coverage of implant dehiscence and ridge augmentation Ridge augmentation with cerabone® and collprotect® membrane

Extraction of tooth 21 after Application of collacone® for Buccal bone defect after eight A periodontal probe demons- Clinical situation with narrow 3.5 mm dental implants inserted Implants inserted and cortical Alveolar ridge form and size endodontic treatment stabilization of the blood clot weeks healing time trates the vertical extension of alveolar ridge in the lower jaw with inefficient immersion of bone perforated, vestibular view renewal around implants with the defect dental implant platforms cerabone®

Implant placed into the former Surface of the implant is Coverage of the autologous Covering of the bone substitute cerabone® particles size Covering augmentation site with Situation at re-entry six months Implants uncovered, good extraction socket covered with autologous bone bone with cerabone® with Jason® membrane 0.5 - 1.0 mm in place collprotect® membrane post-operative, implants partly integration of cerabone® (0.5 - 1.0 mm) covered by new bone matrix particles

Particle Size Closure of the site using single Tension-free suturing maintains Abutment installation after Final prosthetic restoration with Small cerabone® particles (0.5 - 1.0 mm) allow sutures after slitting undisturbed healing implant uncovering, six a full-ceramic crown a good adaptation to surface contours; they months after implantation are especially useful for lateral augmentations or to fill voids when working with autologous bone blocks. Contour maintenance Rehydration For sinus lift and extensive augmentations the For augmentations in the aesthetic region cerabone® provides Due to its excellent hydrophilicity, cerabone® particles adhere to use of cerabone® particle size 1.0 - 2.0 mm is re- long-term dimensional stability and therefore a good bone bed each other after mixing with blood or sterile saline solution, allowing commended. The increased space between the to support an optimal contour of the soft tissue and sustained optimal handling and good adaptation to surface contours. large particles enables a better vascularization aesthetic result. and improves the regeneration of larger defects. 12 13 Clinical application of cerabone® Clinical application of cerabone®

Clinical case by Clinical case by Dr. Marius Steigmann, Neckargemünd, Germany Dr. Derk Siebers, Berlin, Germany

cerabone® for horizontal augmentation Socket management/ridge preservation with cerabone® and Jason® membrane

Atrophic alveolar ridge in the After mucoperiosteal flap eleva- Clinical view six months after Pre-operative OPG, tooth 25 Large defect of the buccal wall Jason® membrane placed to Socket filled with cerabone® and left mandible tion, the extensive bone resorp- augmentation reveals healthy planned for extraction visible after tooth extraction close the mouth-antrum con- augmentation of the buccal wall tion is visible soft tissue situation nection

Pre-operative cone beam scan Excellent bone regeneration The wide ridge allows for stable Situation after healing of the Covering of augmentation site Augmentation site covered Jason® membrane protecting Jason® fleece placed over revealing good osseous forma- six months after application of insertion of the two implants soft tissue with Jason® membrane with Jason® membrane in the socket membrane tion of the augmented site cerabone® particles and Jason® double layer membrane

Insertion of gingiva formers Final prosthetic restoration with ceramic bridge Jason® fleece left exposed for Situation two weeks after healing Soft tissue situation after four Implant insertion 12 months allow for soft tissue maturation open healing months healing time after augmentation

Antibiotic prophylaxis Make sure that the patient's blood contains a sufficient concen- tration of antibiotics before starting the augmentation (especially for larger augmentation volumes), e.g. by starting the antibiosis one day prior to surgery or at least one hour before by ingestion Final prosthetic restoration, Final prosthetic restoration, of a full daily dose. occlusal view vestibular view

14 15 Clinical application of cerabone® Clinical application of cerabone®

Clinical case by Clinical case by Prof. Dr. Dr. Daniel Rothamel, Düsseldorf, Germany Dr. Damir Jelušić, Opatija, Croatia

Two-stage sinus lift with cerabone® and Jason® membrane Sinus floor elevation with cerabone® and Jason® membrane

Clinical situation before surgery Surgical presentation of the Preparation of lateral sinus Filling of the sinus cavity with Pre-operative OPG Preparation of a lateral window Perforation of the Schneiderian Jason® fleece introduced into atrophic alveolar ridge window cerabone® for sinus floor elevation membrane visible after prepara- the sinus cavity to cover the tion of the lateral window Schneiderian membrane

Additional lateral augmentation Covering of the augmentation Tension-free wound closure Detail of OPG showing radio- Filling of the sinus cavity with Simultaneous placement of Jason® fleece covering the Additional horizontal augmen- with cerabone® site with the slowly resorbing pacity of cerabone® cerabone® (particle size three implants lateral sinus window tation with cerabone® (particle Jason® membrane 1.0 - 2.0 mm) size 1.0 - 2.0 mm)

Very good integration of Implant placed in sufficient bone Trephine biopsy taken at Detail of the histology showing Covering of the augmentation Re-opening six months after Placement of gingiva formers Good situation after removal of cerabone® particles without matrix implant insertion cerabone® particles covered by site with Jason® membrane implantation, stable integration ginigva formers, six weeks after soft tissue encapsulation newly formed bone matrix of the cerabone® particles re-opening

Schneiderian membrane perforation In case of a small perforation (< 5 mm) of the Schneiderian membrane during sinus floor elevation, the application of a collagen membrane (e.g. Jason® membrane or collprotect® membrane) is a use- Membrane coverage ful tool for perforation coverage. Instruct the patient to avoid sneezing for two weeks and prescribe For better and more predictable results we always recommend to cover the aug- antibiotics and swelling prophylaxis (e.g. xylomethazoline). Never continue if you find an acute mentation area (and the lateral sinus window after sinus floor elevation) with a sinusitis with presence of pus. collagen membrane (e.g. collprotect® membrane or Jason® membrane). 16 17 Clinical application of cerabone® Clinical application of cerabone®

Clinical case by Clinical case by Dr. Damir Jelušić, Opatija, Croatia Dr. Raluca Cosgarea and Prof. Dr. Dr. Anton Sculean, Cluj-Napoca, Romania and Bern, Switzerland Socket preservation with cerabone® Regeneration of intrabony defects with cerabone® and collprotect® membrane

Pre-operative CT of teeth eleven Teeth eleven and 21 not worth Situation after extraction of the Jason® membranes placed Pre-operative defect measure- Pre-operative x-ray showing Defect presentation after prepa- Rehydration of cerabone® and 21 after endodontic treat- saving and planned for front teeth within in the extraction sockets, ment intrabony defect ration of mucoperiosteal flap particles ment extraction covering the vestibular wall

Filling of the sockets with Jason® membrane turned down Post-operative CT four months Flapless implant placement collprotect® membrane cut to Filling of intrabony defect with collprotect® membrane in place Wound closure cerabone® over the socket and sutured after extraction, good preserva- (punch technique) four months shape cerabone® tion of the ridge after socket preparation; com- plete integration of cerabone® particles

Placement of gingiva formers Final prosthetic situation with Individualized zirconium Final prostethic restoration X-ray control X-ray at 24 Final prosthetic restoration individual emergence profile abutments with ceramic crowns at 12 months months post- created with provisional crowns post-operative operative (Four months post implantation) Sterile application Pay attention to sterile application of the substitute, e.g. by using new instruments Density for granule insertion (and trimming of Avoid to compress the cerabone® particles excessively at the de- membranes). Prior contact to saliva may fect site. Open space between the particles permits blood vessel contaminate your graft. ingrowth and the formation of new bone matrix. 18 19 bone & tissue botiss regeneration biomaterials

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Rev.: CBen-09/2016-10 20