Integra. Accell Connexus 2 nd Generation Demineralized Bone Matrix Putty (DBM)

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Accell Connexus 2 nd Generation Demineralized Bone Matrix Putty (DBM) Because we are committed to limiting uncertainty, we continuously develop new biologic technologies to complete the Integra biologic product line. Specifications Accell Bone Matrix Superior handling Resist irrigation Integra DBM processing Ready to use E-beam sterilization to enhance safety

Accell Bone Matrix This dispersed form of DBM offers significantly increased surface area, which provides access to natural bone proteins. Superior Handling Accell Connexus Demineralized Bone Matrix incorporates a poloxamer Reverse Phase Medium (RPM), a highly biocompatible carrier. Resist Irrigation The unique thermoreversible RPM carrier allows Accell Connexus Demineralized Bone Matrix to resist irrigation and graft migration. Integra DBM: An Expert Approach to DBM Processing Integra controls the processing of DBM and Accell Bone Matrix (ABM) from start to finish in its state of the art facility. Each lot is tested in a validated in vitro assay to ensure osteoinductive potential. Ready to Use Accell Connexus Demineralized Bone Matrix is ready for implantation directly from the syringe. It does not require any cumbersome or time consuming preoperative preparation such as thawing or mixing. E-beam Sterilization to Enhance Safety Integra utilizes electron beam (e-beam) sterilization to ensure product sterility. This process has been shown to preserve the osteoinductive potential of DBM. All products are e-beam sterilized as the last step in manufacturing prior to being shipped.

Evolution of Integra DBM from First to Third Generation 1 st Generation DBM OrthoBlast II & DynaGraft II 2 nd Generation DBM + ABM Accell Connexus 3 rd Generation Accell EVO3 Demineralized Bone Matrix DBM DBM ABM DBM ABM ABM ABM Early 1990 s First generation Demineralized Bone Matrix (DBM) formulations combined standard processed particulate DBM with an inert carrier for easy handling and graft containment. 2002 A process was developed to transform particulate DBM into a dispersed form of DBM. This Accell Bone Matrix (ABM) is blended with traditional particulate DBM and an inert carrier to create our second generation products. 2008 With Accell Evo3 Demineralized Bone Matrix, Integra optimized the formulation of ABM, DBM, and Reverse Phase Medicum (RPM). This third generation product includes three times the amount of ABM as compared to second generation products with even better handling. Superior Handling The optimized formulation of Accell Connexus Demineralized Bone Matrix contains ABM and DBM combined with a unique poloxamer Reverse Phase Medium (RPM). The result is a graft material with exceptional handling and containment characteristics. The unique RPM carrier becomes more viscous at body temperatures, while it is less viscous at room temperature. Because of the RPM s unique thermoreversible property, the demineralized bone matrix putty Accell Connexus is: Moldable at the time of application Packable into virtually any size or shape defect Mixable with other grafting materials Irrigation-resistant The optimized formulation of Accell Connexus Demineralized Bone Matrix results in a robust, moldable putty that does not stick to surgical gloves. Accell Connexus Demineralized Bone Matrix is ready for implantation directly from the syringe. Resist Irrigation The unique thermoreversible RPM carrier allows Accell Connexus Demineralized Bone Matrix to resist irrigation and graft migration.

The Accell Technology Advantage Skeletally mature sheep model Cylindrical 5 mm metatarsal defect created in tibial diaphysis Results after 4 weeks Control - Empty 1 st Generation DBM Accell Technology Minimal bone regeneration observed at 4 weeks. Healing limited to area adjacent to host bone. Bone regeneration occurs throughout the defect, caused by the presence of osteoinductive DBM particles. The inert carrier has been metabolized. (DynaGraft II DBM) Significantly more bone formation is evident immediately adjacent to the bone repair surfaces and within the interior of the defect. The Accell Technology Advantage What s the Difference? Accell Connexus Demineralized Bone Matrix combines ABM and particulate DBM. Particulate DBM ABM Standard Process Accell Bone Matrix Process 30x Standard particulate DBM is dense and requires more time to break down. Until these dense particles break down, access to natural bone proteins is limited. Ground Cortical Bone Combined to form Accell Connexus Demineralized Bone Matrix 30x Accell Bone Matrix (ABM) is an open-structured, dispersed form of DBM, which provides accessibility to bone proteins without the need to be broken down. As a result this creates a favorable environment for the formation of bone. 30x The combination of ABM and particulate DBM provides for both immediate and sustained accessibility to bone proteins which are important for osteogenesis.

What is our Accell Bone Matrix? Particulate DBM ABM Particulate DBM is formed by removing the mineral component of ground cortical bone. Accell Bone Matrix is transformed from particulate DBM using the Accell process. At higher magnification, DBM can be seen as a dense matrix. At higher magnification, ABM can be seen as a white, highly porous matrix. Particulate DBM consists of a highly dense matrix of Type-I collagen and naturally occurring growth factors, with limited accessibility. ABM consists of an open pore structure with high surface area. The resultant scaffold provides accessibility to bone proteins, which creates a favorable environment for the formation of bone. Graphically shown, wavy lines represent Type-I collagen. The blue and red symbols denote naturally occurring growth factors in bone. Accell Bone Matrix s increased surface area provides access to natural bone proteins. Natural bone protein content of ABM and particulate DBM was measured in vitro over time using an Enzyme Linked ImmunoSorbent Assay (ELISA). The results are shown graphically and indicate that bone protein was detectable in a saline solution containing ABM at earlier time points compared to that of particulate DBM. The higher surface area and more open pore structure of ABM provides accessibility to the bone protein, without the need to be broken down. This analysis shows that while ABM provided early accessibility of natural bone protein, particulate DBM provides for accessibility of natural bone protein at later time points. Osteoinductive Potential In Vitro Measurement Accell Bone Matrix (ABM) vs. Demineralized Bone Matrix (DBM)

www.integraorthobiologics.com Reference Description 02-3000-005 0.5 cc syringe 02-3000-010 1 cc syringe 02-3000-025 2.5 cc syringe 02-3000-050 5 cc syringe 02-3000-100 10 cc syringe Integra LifeSciences Services (France) SAS Sales & Marketing EMEA Immeuble Séquoia 2 97 allée Alexandre Borodine Parc technologique de la Porte des Alpes 69800 Saint Priest FRANCE phone +33 (0)4 37 47 59 00 fax +33 (0)4 37 47 59 99 emea.info@integralife.com integralife.eu Distributed by Customer Service International: +1 (949) 595 8710 Fax: +1 (949) 595 8717 irvine.customerservice@integralife.com IsoTis Orthobiologics 2 Good Year Suite A Irvine, CA 92618 United States of America Phone: +1 (949) 595 8710 Fax: +1 949 595 8711 97 2011 Integra LifeSciences Corporation. All rights reserved. ILS 07-01-020-01-11 PRODUCTS FOR SALE IN EUROPE, MIDDLE-EAST and AFRICA ONLY Availability of these products might vary from a given country or region to another, as a result of specific local regulatory approval or clearance requirements for sale in such country or region. Always refer to the appropriate instructions for use for complete clinical instructions. Non contractual document. The manufacturer reserves the right, without prior notice, to modify the products in order to improve their quality. WARNING: Applicable laws restrict these products to sale by or on the order of a physician. Accell Connexus, Accell Evo3, DynaGraft, OrthoBlast, Accell, Accelerating innovation in orthobiologics, Integra and the Integra logo are trademarks of Integra LifeSciences Corporation or its subsidiaries. All the references numbers mentioned on this document are CE marked according to European council directive 93/42/EEC on medical devices, unless specifically identified as NOT CE MARKED.