Clinical Cases Orthopaedics & Trauma

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1 Clinical Cases Orthopaedics & Trauma Inhibition of bacterial growth Osteostimulation* Bioactive bone bonding *non-osteoinduction

2 Mechanism of action (after implantation) BonAlive granules is a resorbable bioactive glass based biomaterial for bone regeneration. Composition: 53% SiO 2, 23% Na 2 O, 20% CaO, 4% P 2 O 5 Surface reaction cascade 1 hour Release of ions increases ph and osmotic pressure (Na, Ca, P, Si) Inhibits bacterial growth on granule surface Si Na Ca P CaP CaP CaP CaP 1 day Silica gel layer forms on granule surface CaP precipitates on surface 1 week CaP crystallizes to natural HA Bonds to bone and promotes osteointegration 1 hour 1 day 1 week 2

Bone formation (scanning electron microscopy images) Hydroxyapatite starts to form on BonAlive granules surface Hydroxyapatite covers BonAlive granules surface BonAlive granules bonds to bone and

3 Bone formation (scanning electron microscopy images) Hydroxyapatite starts to form on BonAlive granules surface Hydroxyapatite covers BonAlive granules surface BonAlive granules bonds to bone and stimulates new bone formation (osteostimulation*) 1 day 1 week 6-12 weeks BonAlive surface Collagen fibres Turku University Hospital, Finland Basis for osteostimulation* Osteostimulation * signifies that BonAlive granules has the capacity to: 1) stimulate the recruitment and differentiation of osteoblasts 2) activate osteoblasts to produce new bone 3) activate specific osteoblast genes as a response to ion dissolution from the material The bioactive glass surface is not only conductive but also osteoproductive in promoting migration, replication, and differentiation of osteogenic cells and their matrix production. (Virolainen et al. 1997) *non-osteoinduction Histological 20 µm-thick section from the mastoid area at 3 months after obliteration with BonAlive granules (human biopsy). Päijät-Häme Central Hospital, Finland 3

Inhibition of bacterial growth A total of 29 aerobic and 17 anaerobic clinically important bacterial species have been tested. Growth was inhibited in all tested species.

faecalis Effective S. pneumoniae Effective Munukka et al. 2008 Aerobic bacteria Growth inhibition Gram negative E. coli Effective P. aeruginosa Effective K. pneumoniae Effective H.

4 Inhibition of bacterial growth A total of 29 aerobic and 17 anaerobic clinically important bacterial species have been tested. Growth was inhibited in all tested species. Selected species are listed below: Test with pigmented P. gingivalis Aerobic bacteria Growth inhibition Gram positive S. epidermidis Effective S. aureus Effective S. aureus (MRSA) Effective E. faecalis Effective S. pneumoniae Effective Munukka et al Aerobic bacteria Growth inhibition Gram negative E. coli Effective P. aeruginosa Effective K. pneumoniae Effective H. influenzae Effective Anaerobic bacteria S. difficile Effective B. adolecentis Effective E. lentum Effective P. gingivalis Effective P. acnes Effective P. anaerobius Effective Growth inhibition Leppäranta et al Bacteria (adherence) Hydroxyapatite (HA) Bacteria (non-adherence) BonAlive granules Stoor P. et al Munukka et al Bactericidal effects of bioactive glasses on clinically important aerobic bacteria. Munukka E. et al. J Mater Sci: Mater Med. 2008;19: Antibacterial effect of bioactive glasses on clinically important anaerobic bacteria in vitro. Leppäranta O. et al. J Mater Sci: Mater Med. 2008;19: Comparison of antibacterial effect on three bioactive glasses. Zhang D. et al. Key Engineering Materials. 2006; : Interactions between bioactive glass and periodontal pathogens. Stoor P. et al. Microbial Ecology in Health and Disease,1996;9: Interactions between the frontal sinusitis-associated pathogen Heamophilus Influenzae and the bioactive glass S53P4. Stoor P. et al. Bioceramics. 1995;8:

$Visual appearance of BonAlive granules vs. CaP Patient: A male with a comminuted calcaneus fracture.$ Infection and fistula formation to the bone was observed and radical debridement was performed.

Infection and fistula formation to the bone was observed and radical debridement was performed.

Clinical outcome: At 12 months post-op the healing was uneventful and clear osteointegration could be seen in the area of the

5 Visual appearance of BonAlive granules vs. CaP Patient: A male with a comminuted calcaneus fracture. Operation: The hardware was removed at 8 weeks post-op and CaP cement was applied to a bone defect. Infection and fistula formation to the bone was observed and radical debridement was performed. The bone cavity was filled with BonAlive granules (3 months after hardware removal). Clinical outcome: At 12 months post-op the healing was uneventful and clear osteointegration could be seen in the area of the BonAlive granules. X-ray MRI CT CaP cement 5 months post-op BonAlive granules 2 months post-op CaP cement 5 months post-op BonAlive granules 2 months post-op CaP cement 15 months post-op BonAlive granules 12 months post-op Helsinki University Central Hospital, Finland 5

Aneurysmal bone cyst (ABC) in the proximal phalanx in a child Patient: A three year old child with a recurrent aneurysmal bone cyst of the proximal phalanx of the index finger.

6 Aneurysmal bone cyst (ABC) in the proximal phalanx in a child Patient: A three year old child with a recurrent aneurysmal bone cyst of the proximal phalanx of the index finger. Operation: The bone tumour was removed and the defect was grafted with 2 cc/ mm BonAlive granules and two 2-3 mm pieces of autogenous bone. Clinical outcome: Follow-up was at 1, 3, 12 and 24 months post-op. At 24 months, no cavity was observed and the homogenous region resembled normal trabecular bone. The phalanx had grown in length and remodelled to almost normal shape. BonAlive granules does not disturb the natural growth of bone in children. Pre-op X-ray 1 month post-op X-ray 3 months post-op X-ray 12 months post-op X-ray 24 months post-op X-ray 6 Treatment of a recurrent aneurysmal bone cyst with bioactive glass in a child allows for good bone remodelling and growth. Lindfors N. Bone, 2009;45(2):

7 Large aneurysmal bone cyst (ABC) in the proximal femur in a child Immediate post-op X-ray 7-month post-op X-ray Patient: 16-year old male with a large aneurysmal bone cyst in the proximal femur. Operation: In the 1 st operation the cavity was filled with autograft and the 2 nd time with a CaP based synthetic bone graft. In both cases the grafts had resorbed. In the 3 rd operation 60 cc/ mm BonAlive granules was used for the grafting. Clinical outcome: Healing could be observed due to the osteostimulative* and slow resorbtion properties of BonAlive granules. *non-osteoinductive Helsinki University Central Hospital, Finland 7

8 Large pelvic aneurysmal bone cyst (ABC) Patient: 15-year old girl with a large pelvic aneurysmal bone cyst. Operation: The large bone cyst was evacuated, the defect was fenolized and filled with 60 cc/ mm BonAlive granules. Clinical outcome: At 9 months post-op the patient had fully healed and was free of any symptoms and signs of recurrence of the ABC. Pre-op X-ray Immediate post-op X-ray 9-month post-op X-ray Clinical peri-operative picture illustrating an egg shell thin cortex surrounding the ABC Department of Paediatric Orthopedic Surgery, Turku University Hospital, Finland 8

9 Depressed tibial plateau fracture Patient: 57-year old male with a depressed lateral tibial plateau fracture. Operation: 15 cc/ mm of BonAlive granules was used to fill the defect. Clinical outcome: No complications, current status is excellent. BonAlive granules is a slowly resorbing biomaterial, but has completely remodelled to bone during the 11-year follow-up. Immediate post-op X-ray 12-month post-op X-ray 11-year post-op X-ray 11-year post-op X-ray BonAlive has fully remodelled Turku University Hospital, Finland Patient included in the following study: Bioactive glass S53P4 and autograft bone in treatment of depressed tibial plateau fractures. A prospective randomized 11-year follow-up. Pernaa K. et al. J Long-term Eff Med Impl. 2011;21(2):

$Ulnar fracture with post-op chronic infection Patient: 45-year old male with an ulnar fracture. Bacterial species: Staphylococcus epidermis.$ A two-stage revision was performed using antibiotic beads, radical debridement and grafting with BonAlive granules (1.0-2.0 mm).

A two-stage revision was performed using antibiotic beads, radical debridement and grafting with BonAlive granules (1.0-2.0 mm).

10 Ulnar fracture with post-op chronic infection Patient: 45-year old male with an ulnar fracture. Bacterial species: Staphylococcus epidermis. Operation: The fracture was stabilised and CaP cement was applied to the bone defect. At 2 months post-op, fistula formation to CaP with Staphylococcus epidermis infection was observed. A two-stage revision was performed using antibiotic beads, radical debridement and grafting with BonAlive granules ( mm). Clinical outcome: At 7 months after revision surgery the patient had healed well and the clinical outcome was considered to be good. Pre-op X-ray 2-month post-op X-ray 7-month post-op X-ray CaP 2 months post-op BonAlive granules 7 months post-op Helsinki University Central Hospital, Finland 10

11 Chronic osteomyelitis in the distal tibia Immediate post-op X-ray 2.5-year post-op X-ray Patient: 36-year old male with a chronic osteomyelitis in the distal tibia. After surgical debridement the defect size was 100 cc. Operation: The patient received a pilon fracture in a car crash and the fracture was stabilised with an anterior plate in the distal tibia. The patient was diagnosed with severe chronic osteomyelitis with extensive pus formation in the distal tibia. The anterior fixation plate was removed and the area was surgically cleaned through radical debridement. The defect was filled with BonAlive granules 48 cc/ mm mixed with an equal amount of autologous bone. Clinical outcome: The soft tissue healed well. Although a significant part of the anterior cortex of the distal tibia was removed, new cortical bone was formed. At 2.5 years post-op the fusion was stabile and the patient outcome continued to be successful. Turku University Hospital, Finland 11

$Chronically infected non-union of the distal tibia Patient: 32-year old female, type A host, was in a car crash and received an exposed pilon fracture that was stabilized with an$ Operation: The patient was diagnosed with septic non-union 9 months after trauma. The patient refused new external fixation.

Operation: The patient was diagnosed with septic non-union 9 months after trauma. The patient refused new external fixation.

12 Chronically infected non-union of the distal tibia Patient: 32-year old female, type A host, was in a car crash and received an exposed pilon fracture that was stabilized with an external fixator. Bacterial species: Staphylococcus aureus. Surgeon: Prof. Carlo Romanó, Istituto Ortopedico Galeazzi, Milan, Italy. Operation: The patient was diagnosed with septic non-union 9 months after trauma. The patient refused new external fixation. The external fixator was removed and, after 15 days, an osteotomy of the fibula, debridement of the non-union septic focus, local application of BonAlive granules (20 cc/ mm granules) and intramedullary nailing were performed. Pre-op Pre-op X-ray Istituto Ortopedico Galeazzi, Italy 12

Clinical outcome: Bone healing was achieved in 6 months from

Dynamisation of the nail was performed 14 months post-op and

13 Clinical outcome: Bone healing was achieved in 6 months from implantation. The soft tissue healed well, with no clinical or laboratory signs of infection recurrence. Dynamisation of the nail was performed 14 months post-op and the nail was removed 24 months post-op. Immediate post-op X-ray 14-month post-op X-ray 24-month post-op X-ray Istituto Ortopedico Galeazzi, Italy 13

Chronic osteomyelitis in the spine Patient: 75-year old female, abscess formation in the spine. Bacterial species: Mycobacterium tuberculosis.

decompression and reconstruction. Posterolateral fusion and application of BonAlive granules and autograft bone (50/50) around the anterior cage.

14 Chronic osteomyelitis in the spine Patient: 75-year old female, abscess formation in the spine. Bacterial species: Mycobacterium tuberculosis. Operation: Posterior decompression L2-L3 and L3-L4, spondylodesis L2-L5, lumbotomy, canalisation of paravertebral abscess, resection of L3-L4, anterior decompression and reconstruction. Posterolateral fusion and application of BonAlive granules and autograft bone (50/50) around the anterior cage. Pre-op MRI Pre-op CT Abscess formation in L III Helsinki University Central Hospital, Finland 14 Bioactive glass S53P4 as bone graft substitute in treatment of osteomyelitis. Lindfors NC, J. Bone. 2010;47:

Lateral view Anteroposterior view Immediate post-op X-ray 2-year post-op CT

15 Clinical outcome: Complete fusion at 2 years post-op. The patient was fully healed. Lateral view Anteroposterior view Immediate post-op X-ray 2-year post-op CT Post-op X-ray 2-year post-op CT BonAlive granules BonAlive BonAlive granules Helsinki University Central Hospital, Finland New bone formation New bone formation 15

16 References Mechanism of action (osteostimulation*) Osteoblast response to continuous phase macroporous scaffolds under static and dynamic culture conditions. Meretoja VV, Malin M, Seppälä JV, Närhi TO. J Biomed Mater Res. 2008;89A(2): Molecular basis for action of bioactive glasses as bone graft substitute. Välimäki VV, Aro HT. Scandinavian Journal of Surgery. 2006;95(2): Intact surface of bioactive glass S53P4 is resistant to osteoclastic activity. Wilson T, Parikka V, Holmbom J, Ylänen H, Penttinen R. J Biomed Mater Res. 2005;77A(1): Granule size and composition of bioactive glasses affect osteoconduction in rabbit. Lindfors NC, Aho AJ. J Mater Sci: Mater Med. 2003;14(4): Osteoblast differentiation of bone marrow stromal cells cultured on silica gel and sol-gelderived titania. Dieudonné SC, van den Dolder J, de Ruijter JE, Paldan H, Peltola T, van t Hof MA, Happonen RP, Jansen JA. Biomaterials. 2002;23(14): Histomorphometric and molecular biologic comparison of bioactive glass granules and autogenous bone grafts in augmentation of bone defect healing. Virolainen P, Heikkilä J, Yli-Urpo A, Vuorio E, Aro HT. J Biomed Mater Res. 1997;35(1):9-17. *non-osteoinduction The reputation of BonAlive is built on solid clinical evidence Over 20 peer-reviewed published clinical articles More than a decade of human prospective randomized clinical data Inhibition of bacterial growth Antibacterial effects and dissolution behavior of six bioactive glasses. Zhang D, Leppäranta O, Munukka E, Ylänen H, Viljanen MK, Eerola E, Hupa M, Hupa L. J Biomed Mater Res. 2010;93A(2): Bactericidal effects of bioactive glasses on clinically important aerobic bacteria. Munukka E, Leppäranta O, Korkeamäki M, Vaahtio M, Peltola T, Zhang D, Hupa L, Ylänen H, Salonen JI, Viljanen MK, Eerola E. J Mater Sci: Mater Med. 2008;19(1): Antibacterial effect of bioactive glasses on clinically important anaerobic bacteria in vitro. Leppäranta O, Vaahtio M, Peltola T, Zhang D, Hupa L, Ylänen H, Salonen JI, Viljanen MK, Eerola E. J Mater Sci: Mater Med. 2008;19(2): In situ ph within particle beds of bioactive glasses. Zhang D, Hupa M, Hupa L. Acta Biomaterialia. 2008;4(5): Factors controlling antibacterial properties of bioactive glasses. Zhang D, Munukka E, Hupa L, Ylänen H, Viljanen MK, Hupa M. Key Engineering Materials. 2007; : Comparison of antibacterial effect on three bioactive glasses. Zhang D, Munukka E, Leppäranta O, Hupa L, Ylänen H, Salonen J, Eerola E, Viljanen MK, Hupa M. Key Engineering Materials. 2006; : Interactions between the bioactive glass S53P4 and the atrophic rhinitis-associated microorganism Klebsiella ozaenae. Stoor P, Söderling E, Grenman R. J Biomed Mater Res. 1999;48(6): Antibacterial effects of a bioactive glass paste on oral micro-organisms. Stoor P, Söderling E, Salonen JI. Acta Odontol Scand. 1998;56(3): Interactions between the frontal sinusitis-associated pathogen Heamophilus Influenzae and the bioactive glass S53P4. Stoor P, Söderling E, Andersson OH, Yli-Urpo A. Bioceramics. 1995;8:

17 Orthopaedics & trauma Trauma Bioactive glass S53P4 and autograft bone in treatment of depressed tibial plateau fractures. A prospective randomized 11-year follow-up. Pernaa K, Koski I, Mattila K, Gullichsen E, Heikkilä J, Aho AJ, Lindfors N. J Long-term Eff Med Impl. 2011;21(2): Bioactive glass granules: a suitable bone substitute material in the operative treatment of depressed lateral tibial plateau fractures: a prospective, randomized 1 year follow-up study. Heikkilä JT, Kukkonen J, Aho AJ, Moisander S, Kyyrönen T, Mattila K. J Mater Sci: Mater Med. 2011;22(4): Instrumented spondylodesis in degenerative spondylolisthesis with bioactive glass and autologous bone. A prospective 11-year follow-up. Frantzén J, Rantakokko J, Aro H, Heinänen J, Kajander S, Koski I, Gullichsen E, Kotilainen E, Lindfors N. J Spinal Disorder Tech. 2011;24(7): Posterolateral spondylodesis using bioactive glass S53P4 and autogenous bone in instrumented unstable lumbar spine burst fractures - A prospective 10-year follow-up study. Rantakokko J, Frantzén J, Heinänen J, Kajander S, Kotilainen E, Gullichsen E, Lindfors N. Scan J Surg. 2012;101(1): Benign bone tumour A prospective randomized 14-year follow-up study of bioactive glass and autogenous bone as bone graft substitutes in benign bone tumors. Lindfors NC, Koski I, Heikkilä JT, Mattila K, Aho AJ. J Biomed Mater Res. 2010;94B(1): Treatment of a recurrent aneurysmal bone cyst with bioactive glass in a child allows for good bone remodelling and growth. Lindfors NC. Bone. 2009;45: Bioactive glass and autogenous bone as bone graft substitutes in benign bone tumors. Lindfors NC, Heikkilä J, Koski I, Mattila K, Aho AJ. J Biomed Mater Res. 2009;90B(1): Chronic osteomyelitis Through the looking glass; bioactive glass S53P4 (BonAlive ) in the treatment of chronic osteomyelitis. McAndrew J, Efrimescu C, Sheehan E, Niall D. Ir J Med Sci. 2013;182(3): Clinical Experience on Bioactive Glass S53P4 in Reconstructive Surgery in the Upper Extremity Showing Bone Remodelling, Vascularization, Cartilage Repair and Antibacterial Properties of S53P4. Lindfors NC. J Biotechnol Biomaterial. 2011;1(5). (An open access journal.) Bioactive glass S53P4 as bone graft substitute in treatment of osteomyelitis. Lindfors NC, Hyvönen P, Nyyssönen M, Kirjavainen M, Kankare J, Gullichsen E, Salo J. Bone. 2010;47: Preclinical publications Bioactive glass as bone-graft substitute for posterior spinal fusion in rabbit. Lindfors NC, Tallroth K, Aho AJ. J Biomed Mater Res. 2002;63B(2): Tissue response to bioactive glass and autogenous bone in the rabbit spine. Lindfors NC, Aho AJ. Eur Spine J. 2000;9: Bioactive glass and calcium carbonate granules as filler material around titanium and bioactive glass implants in the medullar space of the rabbit tibia. Turunen T, Peltola J, Helenius H, Yli-Urpo A, Happonen, R. Clin Oral Impl Res. 1997;8: Long term behaviour of bioactive glass cone and granules in rabbit bone. Heikkilä JT, Salonen H, Yli-Urpo A, Aho AJ. Bioceramics. 1996;9: Protein adsorption properties of bioactive glasses compared to their behaviour in rabbit tibia. Brink M, Söderling E, Turunen T, Karlsson KH. Bioceramics. 1995;8: Bone formation in rabbit cancellous bone defects filled with bioactive glass granules. Heikkilä JT, Aho HJ, Yli-Urpo A, Happonen R, Aho AJ. Acta Orthopaedica. 1995;66(5):

5 cc BonAlive granules in large applicator Ref. no Granule size Unit size 13130 0.5-0.

18 Products 1 cc 2.5 cc 5 cc 10 cc BonAlive granules in small applicator Ref. no Granule size Unit size mm (small) 1 cc mm (small) 2.5 cc BonAlive granules in large applicator Ref. no Granule size Unit size mm (small) 5 cc mm (small) 10 cc mm (medium) 5 cc mm (medium) 10 cc mm (large) 5 cc mm (large) 10 cc 18

Instructions for use Figure 1 Peel open the pouch and aseptically remove

Figure 2 Moisten the granules by injecting sterile physiological saline

Figure 3 Screw tightly the shovel onto the applicator body, turn the

19 Instructions for use Figure 1 Peel open the pouch and aseptically remove the sterile tray. Figure 2 Moisten the granules by injecting sterile physiological saline slowly through the cap membrane. Figure 3 Screw tightly the shovel onto the applicator body, turn the applicator to a horizontal position, and push the plunger rod to slide the moistened granules onto the shovel. Move the applicator to the defect site and implant the moistened granules from the shovel into the defect with the aid of a sterile instrument. For complete instructions for use, see package insert. 19

20 Contact details Headquarters BonAlive Biomaterials Ltd Tel (0) Fax +358 (0) Biolinja Turku, Finland Distributors EUROPE AUSTRIA Olympus Biotech Österreich GmbH Tel com Museumstraße 5/ Wien, Austria BENELUX Leander Healthcare B.V. Tel info@leanderhealthcare.com Postbus AD Vleuten The Netherlands DENMARK Mediplast A/S Tel info.dk@mediplast.com Valhøjs Allé Rødovre, Denmark FINLAND BonAlive Biomaterials Ltd Tel orders@bonalive.com Biolinja Turku, Finland FRANCE Olympus Biotech Europe SAS Tel obicustomercare@olympusbiotech. com 62 Quai Charles De Gaulle Lyon, France GERMANY Olympus Biotech Deutschland GMBH Tel obicustomercare@olympusbiotech. com Neuer Wall 50, Hamburg, Germany IRELAND Olympus Biotech International Tel obicustomercare@olympusbiotech. com Raheen Business Park Limerick, Ireland ITALY Medix Italia Tel commerciale@medixitaliasrl.it Via Roma n Torino, Italy NORWAY Mediplast Innova AS Tel info.no@mediplast.com Enebakkveien 302a 1188 Oslo, Norway POLAND Medical Communications Tel bonalive@medical.pl ul. Powsinska , Warszawa, Poland PORTUGAL Atos Medical Spain SL.Sucursal em Portugal Tel info.pt@atosmedical.com Avenida da Liberdade, Nº78-1ºB Vale de Milhaços Corroios Portugal ROMANIA GTS Solution SRL Tel. +40 (21) office@gotosolution.com 24, Nicolae Rosu Street District 3, Bucharest, Romania SPAIN Bemed Productos Y Distribuciones, S.L. Tel jnbemed@gmail.com Lauaxeta Olekari, 46 C - 1º B Munguia, Spain SWEDEN Mediplast AB Tel mediplast.info@mediplast.com Kantyxegatan 29 SE Malmö, Sweden SWITZERLAND Medeco-CH Sàrl Tel info@medeco-ch.com Route de Trélex Duillier, Switzerland TURKEY Fiksmed Tic. Ltd. Sti Tel sanem@fiksmed.com.tr Kizilirmak Mah.Muhsin yazicioglu cad asmalibache apt no:7/1 Cukurambar Ankara, Turkey UNITED KINGDOM Olympus Biotech UK Limited Tel obicustomercare@olympusbiotech. com Seven Gables House 30 Letchmore Road Radlett, Herts, WD7 8HT, U MIDDLE EAST/ ASIA-PACIFIC AUSTRALIA Device Technologies Australia Pty Ltd Tel customers@device.com.au 8/25 Frenchs Forest Road Frenchs Forest, NSW 2086, Australia INDIA Shreyaas Health Care Tel info@shreyaas.net No. 73, II Floor, Lal Bagathur Colony, Peelamedu Coimbatore, Tamilnadu, India ISRAEL Da-Mor Ltd. Tel da_mor@012.net.il 19 Beeri Street Herzeliya, Israel KINGDOM OF SAUDI-ARABIA Husn Al Emirat Est Tel marketingmgr@husnksa.com PO Box 93341, Riyadh Kingdom of Saudi Arabia MALAYSIA Malex Medical Asia (M) Sdn Bhd Tel enquiries@malexmedical.com No.19-1, Block E1, Jalan PJU 1/42 Dataran Prima, Petaling Jaya Selangor, Malaysia NEW ZEALAND Device Technologies New Zealand Tel sales@device.co.nz 47 Arrenway, Albany Auckland, New Zealand TAIWAN Chi Fu Trading Co. Ltd. Tel info@chifupharma.com 69, Lane 77, Xin Ai Road 7th Floor, Neihu District Taipei 11494, Taiwan UNITED ARAB EMIRATES Bayan Medical Co. Tel saed@bayanmed.com Office 320, Emarat Atrium Bldg, Sheikh Zayed Road Dubai, United Arab Emirates AMERICAS BRAZIL Ossis Medical Tel info@ossis.com.br R.Domingos Lopes da Silva, 890- Cj , São Paulo, SP, Brasil CENTRAL AMERICA AND CARIBBEAN Kaisermed SA de CV Tel info@kmed-ca.net Santa Tecla, LL El Salvador CHILE International Medical Products Chile Tel cperez@impchile.cl Av Sucre N 1389 Ñuñoa Santiago, Chile AFRICA SOUTH-AFRICA Stratmed Tel di@stratmed.co.za 7 Thicket road, Rosebank 7705, Cape Town, South-Africa OTHER REGION 91316f/2

BonAlive Clinical Cases

BonAlive Clinical Cases Inhibition of bacterial growth Osteostimulation* Bioactive bone bonding *Non-osteoinduction BonAlive mechanism of action BonAlive composition: 53% SiO 2, 23% Na 2 O, 20% CaO, 4%