demineralized bone matrix with cancellous

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1 onefuse Plus demineralized bone matrix with cancellous TM 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. Tisucor strives to bring safe, high quality, innovative biologics capable of maximizing allograft performance in the healthcare market. In 2003 we established the Research and Development Center, which is a state-of-the-art, fully-automated 120,000 sq. ft. facility, to serve our current global footprint of 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 ] Decree No Food & Drug Administration No

3 Product Information OneFuse Plus is a patented combination of demineralized cortical bone, cancellous bone, and a carrier. In recent studies, the carrier demonstrated advantageous properties in tissue engineering, such as formation of pathways that enable improved cell migration, improved waste removal, improved delivery of nutrients, and improved delivery of bioactive molecules that facilitate cell growth. All of these factors contribute to a more optimized environment for tissue regeneration. As a result OneFuse Plus has the unique characteristic of maintaining extremely high cohesiveness while exhibiting 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 Plus 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 Plus 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 (e.g., 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 OneFusePLUS 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 6

7 OneFuse Plus 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: H 1 Human immunodeficiency i u type 1 BHV - Bovine herpes virus BVDV - Bovine viral diarrhea virus HAV - Hepatitis A virus PPV - Porcine parvovirus OneFuse Plus has undergone and passed the following series of standard tests relating to its biocompatibility: 8 Test Test Overview Cytotoxicity ISO To determined whether leachables extracted from the material would cause cytotoxicity 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 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 Genotoxicity/Bacterial Reverse Mutation Assay (Ames Test) ISO Part 3 Test for Genotoxicity, Carcinogenicity and Reproductive Toxicity. Hemolysis Testing ISO Test the interaction of OneFuse samples with rabbit blood Endotoxin Testing ISO To determine the level of endotoxin in the leachables extracted from the testing material

9 Carrier Information Carboxymethyl Cellulose (CMC) CMC is the sodium salt of carboxymethyl cellulose. It is derived from cellulose, which becomes water-soluble through chemical reactions. The water-solubility is achieved by introducing carboxymethyl groups along the cellulose chain, which makes hydration of the molecule possible. CMC is used to modify or thicken viscosity and to stabilize emulsions in various products. CMC is also known for its excellent water retaining capacity. Studies have shown that porous CMC scaffolds demonstrated advantageous properties in tissue engineering, such as formation of pathways that enable improved cell migration, improved waste removal, improved delivery of nutrients, and improved delivery of bioactive molecules that facilitate cell growth. All of these factors contribute to a more optimized environment for tissue regeneration. 1. Hwang CM, Sant S, Masaeli M, Kachouie NN, Zamanian B, Lee SH, et al. Fabrication of three-dimensional porous cell-laden hydrogel for tissue engineering. Biofabrication. 2010; 2: (12 pp). 9

10 Fusion Study 4 weeks 13 weeks Radiographs of a rabbit spine after posterolateral lumbar arthrodesis using OneFuse Plus he study as conducted to erify the e ecti eness of spinal fusion ith OneFuse Plus 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 Plus putty and gel and the industry leading DBM (control) were implanted into each model. The ability of OneFuse Plus 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 was noted following a progressive activation of new osteoid tissue and bone marrow cavity formation. OneFuse Plus has an e ui alent e ect hen compared to the industry leading. 10

11 Each lot is tested for osteoinductivity (In Vitro Assay) Each lot of OneFuse Plus is tested for BMP s and growth factors (ELISA) The study was conducted to evaluate OneFuse Plus originating from multiple donors. Osteoinductivity Study In Vitro Assay he OneFuse Plus 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 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 Plus was measured. 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 Plus. After 28 days, the mice ere sacrificed. Slides were prepared and examined using various methods including immunology and histology. OneFuse Plus as transplanted in the hip muscle of an athymic rat, and several histological tests were performed to e aluate osteoinducti e a ility. Afterwards the recruitment of osteo lasts and osteoclasts to the sites of osteogenesis was observed. The presence of osteoblasts at these sites could be interpreted as DBM being degraded to form new bone. The results demonstrate that OneFuse Plus has high osteoinductive capacity, contri uting to ne one formation in one defecti e regions. 11

12 Ordering Information onefuse Plus TM demineralized bone matrix with cancellous Please Submit Orders by , Fax or Phone 3OHDVH 6XEPLW 2UGHUV E\ (PDLO )D[ RU 3KRQH (PDLO RUGHUV#WLVXFRU FRP Fax: )D[ Phone: 844-TISUCOR ext. 2 ( ) 3KRQH 7,68&25 H[W PUTTY Volume (cc) Order Number 1.0 TCDBM-PP1 3.0 TCDBM-PP3 5.0 TCDBM-PP TCDBM-PP10 *Note: Price List, Terms & Conditions on Separate Handouts *Note: Price List, Terms & Conditions on Separate Handouts GEL Volume (cc) Order Number 1.0 TCDBM-GP1 3.0 TCDBM-GP3 5.0 TCDBM-GP TCDBM-GP10 *Note: Price List, Terms & Conditions on Separate Handouts *Note: Price List, Terms & Conditions on Separate Handouts tisucor 12 TM Emperor Emperor Blvd. Blvd.Suite Suite Research Research Triangle Triangle Park Park Durham, Durham, NC NC phone:844-tisucor 844-TISUCOR fax: fax: phone: tisucor.com tisucor.com