All donor screening, recovery and tissue processing is performed by a tissue bank registered with the Food and Drug Administration (FDA) and

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1 All donor screening, recovery and tissue processing is performed by a tissue bank registered with the Food and Drug Administration (FDA) and accredited by the American Association of Tissue Banks (AATB).

2 Quality Control Our experienced professionals have a clear understanding of physician and healthcare facility needs. We strive to bring safe, high quality, innovative biologics to the healthcare market that are capable of maximizing allograft performance. In 2003 the Research and Development center was established, which is a state of the art fully automated 120,000 sq. ft. facility to serve the needs of a now-global footprint to over 30 countries. Quality Management System: ISO13485 certified ISO class 5 clean rooms FDA registered, complies with 21 CFR Part 1270 and 1271 AATB accredited Products are in compliance with: FDA regulation, Title 21, Code of Federal Regulations Part 1271 Human Organs And Tissues Safety And Control Act [Partial modification on January 27, 2005 Act No. 7375] Human Organs And Tissues Safety And Control Executive Order [Partial modification on July 3, Decree of Department of Health & Welfare No. 363] Human Organ And Tissue Safety And Control Decree [Partial modification on June 12, Presidential Decree No.19513] Decree No Food & Drug Administration No

3 Product Information OneFuse is a Patented combination of demineralized cortical bone, and a carrier. The carrier, in recent studies, demonstrated advantageous properties in tissue engineering such as formation of pathways for induction of better cell migration, better delivery of nutrients and bioactive molecules to growing cells and better removal of their wastes, thus providing a better environment for tissue regeneration. As a result OneFuse has a unique characteristic in that it has extremely high cohesiveness while having excellent hydrophilic qualities. DBM Putty Benefits: Donor testing exceeds FDA and AATB criteria High osteoinductivity (Each lot tested by In Vitro Assay) Each lot is tested for BMP s and growth factors (ELISA) Superior handling/molding characteristics High cohesiveness Excellent hydrophilic qualities Easily mixed with complimentary biologics Room temperature storage Comes ready to use Electron beam sterilization DBM Gel Benefits: Donor testing exceeds FDA and AATB criteria High osteoinductivity (Each lot tested by In Vitro Assay) Each lot is tested for BMP s and growth factors (ELISA) Excellent handling/flowable characteristics High cohesiveness Excellent hydrophilic qualities Easily mixed with complimentary biologics Room temperature storage Comes ready to use Electron beam sterilization 3

4 Indications Orthopedic/Spine Surgery Compensation and reconstruction of autograft bone Spine fixation with adequate materials Bone fixation and filling in various sizes and forms of bone defect Spinal fusion Dental Surgery Implantological Indications Extraction site Ridge preservation Sinus floor elevation Socket preservation Wall defect Torus Fenestration defect Dehiscence defect Reconstruction of maxillofacial defect Oncology Joint revision Long bone trauma Distal fracture Small bone procedure Maxillofacial defect Periodontal Indications Periodontal augmentation Exposed implant Periodontal defect Esthetic augmentation 4 Contraindications OneFuse is not intended to provide structural support of the bone during the healing process and the following circumstances: Uncontrolled diabetes Severe degenerative bone disease Active or latent infection in or about the surgical site Renal impairment Vascular disease Neurological disease

5 Growth Factors Each lot of OneFuse is tested for BMP s and growth factors (ELISA) Purpose: This report documents the results of a comparison between the in vitro assay and In vivo results for ten lots. Samples from the same ten lots were tested per Protocol: BMP-2 ELISA. Each donor lot was tested in triplicate BMP-2 concentration was mainly affected by individual factors (gender, age, health condition of donors). As reported in the literature, BMP-2 induces new bone formation at both bony and non-bony sites. A dose-related response was observed and reported as well: higher doses of rhbmp-2 yielded a faster formation of cartilage and bone The BMP-2 concentration of OneFuse was measured and a range of ~ ng BMP-2 in 1cc were detected by ELISA 5

6 Serological Testing Prior to donation all donor medical/social history is screened for medical conditions or diseases that would contraindicate the donation of tissue in accordance with the current regulations established by the FDA (21 CFR 1270) and standards set forth by AATB. All donor tissue utilized for processing is provided by recovery agencies registered with the FDA and accredited by AATB. Screening criteria exceeds requirements established by the FDA and AATB. Serological tests are performed in accordance to FDA regulations and AATB standards. In accordance ith regulations set forth y the FDA and standards y AA, donor lood samples are collected at the time of reco ery and serological testing is performed on each tissue donor see elo y a IA certified laboratory. Anti odies to the human immunodeficiency irus, type 1 and type 2 anti-hi -1 and anti-hi -2 Nucleic acid test (NAT) for HIV-1 Hepatitis B surface antigen (HBsAg) otal anti odies to hepatitis core antigen anti-h c-total, meaning Ig and Ig Antibodies to the hepatitis C virus (anti-hcv) Nucleic acid test (NAT) for HCV Syphilis 6

7 OneFuse additional screening: Clinically significant metabolic bone disease Tuberculosis (clinically active) Gonorrhea (clinically active) Active genital herpes Illicit drug use, injected drugs Cancer (see chart below) Leprosy (Hansen s disease) Encephalitis (clinically active) Polyarteritis nodosa Endocarditis (clinically active) Rabies High risk behavior Rheumatoid arthritis Illicit drug use, non-injected drugs Sarcoidosis Meningitis (clinically active) Systemic lupus erythematosus Multiple sclerosis Systemic mycosis Poliomyelitis Tissue Donor Selection/Screening Tissue cultures collected during the recovery process are tested for the following microbial contaminants: Aerobic Anaerobic Fungal 7

8 Viral Inactivation and Biocompatibility Tissue processing procedures have been validated to inactivate and eliminate the following viruses: HI -1 - Human immunodeficiency irus type 1 BHV - Bovine herpes virus BVDV - Bovine viral diarrhea virus HAV - Hepatitis A virus PPV - Porcine parvovirus OneFuse has undergone and passed the following series of standard tests relating to its biocompatibility: 8 Cytotoxicity Test Test Overview Maximization/Hypersensitivity Testing Irritation/Intracutaneous Reactivity Testing Acute Systemic Toxicity Study in Mouse Muscle Implantation/Biological Suitability Testing in Rabbits Implantation Test in Rabbit Bone Genotoxicity/Bacterial Reverse Mutation Assay (Ames Test) Hemolysis Testing Endotoxin Testing ISO To determined whether leachables extracted from the material would cause cytotoxicity ISO Part (E) Tests for Irritation and Delayed-type Hypersensitivity ISO Part (E) Tests for Irritation and Delayed-type Hypersensitivity ISO10993 Part (E) Test for Systemic Toxicity USP 28[88] To evaluate the local effect of implanted OneFuse samples in the paravertebral muscle ISO To evaluate the biocompatibility and local effect of OneFuse over a 12 week period ISO Part 3 Test for Genotoxicity, Carcinogenicity and Reproductive Toxicity. ISO Test the interaction of OneFuse samples with rabbit blood ISO To determine the level of endotoxin in the leachables extracted from the testing material

9 Carrier Information Carboxymethyl Cellulose (CMC) Is sodium salt of car o ymethyl cellulose. It is deri ed from cellulose, hich is made ater-solu le y a chemical reaction. he ater-solu ility is achie ed y introducing car o ymethyl groups along the cellulose chain, hich ma es hydration of the molecule possi le. is used as a iscosity modifier or thic ener, and to sta ili e emulsions in various products. CMC is also known for its excellent water retaining capacity. Studies ha e sho n that porous sca olds demonstrated ad antageous properties in tissue engineering such as formation of path ays for induction of etter cell migration, etter deli ery of nutrients and ioacti e molecules to gro ing cells and etter remo al of their astes, thus pro iding a etter en ironment for tissue regeneration. [1] 1. H ang, Sant S, asaeli, achouie NN, amanian, ee SH, et al. Fa rication of three-dimensional porous cell-laden hydrogel for tissue engineering. Biofabrication. 2010;2: (12 pp) 9

10 Fusion Study 4 Weeks weeks 13 Weeks weeks Radiographs of a rabbit spine after posterolateral lumbar arthrodesis using OneFuse he study as conducted to erify the e ecti eness of spinal fusion ith OneFuse and its a ility to stimulate new bone formation. The spinal fusion models of rabbits were prepared following posterolateral intertransverse process arthrodesis bilaterally at L4-L5 section of the lumbar vertebrae. Equivalent amounts of OneFuse putty and gel and the industry leading DBM (control) were implanted into each model. The ability of OneFuse to stimulate new bone formation and inter ody spinal fusion as e aluated at 4, 8 and 13 ee s after implantation y conducting a longitudinal radiologic e aluation, iomechanical and histology test. he ra its models ere e aluated for radiologic findings, fusion rate, iomechanical strength and histological findings graft material residue rate, ne one formation rate. The results indicate biocompatibility and proved a gradual density growth along with successful bone remodeling. Fusion as o ser ed after 13 ee s in the 4 section. In histological e aluation, compact one continuity as noted following a progressive activation of new osteoid tissue and bone marrow cavity formation. OneFuse has an e ui alent e ect hen compared to the industry leading. 10

11 Pu se ste st B ste st une e nne t e t ssue e ne B Each lot is tested for osteoinductivity (In Vitro Assay) Each lot of OneFuse is tested for BMP s and growth factors (ELISA) The study was conducted to evaluate OneFuse originating from multiple donors. Osteoinductivity Study u y In Vitro Assay he OneFuse samples used for this e aluation originated from ten di erent donors. he units ere sterili ed y electron beam Samples from the same ten lots were tested per Protocol: BMP-2 ELISA. Each donor lot was tested in triplicate P-2 concentration as mainly a ected y indi idual factors gender and age. As reported in the literature, BMP-2 induces new bone formation at both bony and non-bony sites. [6.1] A dose-related response was observed and reported as well: higher doses of rhbmp-2 yielded a faster formation of cartilage and bone The BMP-2 concentration of OneFuse was measured n Samples from the same ten lots were implanted per Protocol: In vivo Osteoinductivity Assessment using an Ectopic Bone Formation Model. Each lot of tissue was implanted into three mice with each mouse receiving approximately 0.3cc of OneFuse After 28 days, the mice ere sacrificed Slides were prepared and examined using various methods including immunology and histology n us ns OneFuse as transplanted in the hip muscle of an athymic rat, and several histological tests were performed for e aluation of osteoinducti e a ility. onse uently, the recruitment of osteo lasts and osteoclasts in the sites hich contribute to osteogenesis were observed. The osteoblasts which were observed in the site might be interpreted as DBM being degraded to form new bone. The results show that OneFuse has high osteoinductive capacity in a mouse model, contri uting to ne one formation in one-defecti e regions. 11

12 Ordering Information P e se u t e s y P ne : e s t su : P ne: e t PUTTY Volume (cc) Order Number 1.0 TCDBM-P1 3.0 TCDBM-P3 5.0 TCDBM-P TCDBM-P10 *Note: Price List, Terms & Conditions on Separate Handouts GEL Volume (cc) Order Number 1.0 TCDBM-G1 3.0 TCDBM-G3 5.0 TCDBM-G TCDBM-G10 *Note: Price List, Terms & Conditions on Separate Handouts 12 tisucor TM 4819 Emperor Blvd. Suite 400 Research Triangle Park Durham, NC phone: 844-TISUCOR fax: tisucor.com