TMoneFuse Plusdemineralized bone matrix with cancellous

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).

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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, 2006. Decree of Department of Health & Welfare No. 363]• Human Organ And Tissue Safety And Control Decree [Partial modification on June 12, 2006. Presidential Decree No. 19513]• Decree No. 2005-16 Food & Drug Administration No. 2005-16

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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

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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 SurgeryImplantological Indications• Extraction site• Ridge preservation• Sinus floor elevation• Socket preservation• Wall defect• Torus• Fenestration defect• Dehiscence defect• Reconstruction of maxillofacial defect

Contraindications

• Uncontrolled diabetes• Severe degenerative bone disease• Active or latent infection in or about the surgical site

• Oncology• Joint revision• Long bone trauma• Distal fracture• Small bone procedure• Maxillofacial defect

Periodontal Indications• Periodontal augmentation• Exposed implant• Periodontal defect• Esthetic augmentation

• Renal impairment• Vascular disease• Neurological disease

OneFuse Plus is not intended to provide structural support of the bone during the healing processand the following circumstances:

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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 42.48 ~ 123.50 ng BMP-2 in 1cc were detected by ELISA.

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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.

Inaccordance�ithregulationssetforth�ytheFDAandstandards�yAA��,donor�loodsamplesarecollectedatthetimeofreco�eryandserologicaltestingisperformedoneachtissuedonor�see�elo���ya��IA-certifiedlaboratory.

� Anti�odiestothehumanimmunodeficiency�irus,type1andtype2anti-HI�-1andanti-HI�-2• Nucleic acid test (NAT) for HIV-1• Hepatitis B surface antigen (HBsAg)� �otalanti�odiestohepatitis�coreantigenanti-H c-total,meaningIgandIg• Antibodies to the hepatitis C virus (anti-HCV)• Nucleic acid test (NAT) for HCV

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Clinically significant metabolic bone diseaseGonorrhea (clinically active) Illicit drug use, injected drugsLeprosy (Hansen’s disease)Polyarteritis nodosaRabiesRheumatoid arthritisSarcoidosisSystemic lupus erythematosusSystemic mycosis

Tuberculosis (clinically active)Active genital herpesCancer (see chart below)Encephalitis (clinically active)Endocarditis (clinically active)High risk behaviorIllicit drug use, non-injected drugsMeningitis (clinically active)Multiple sclerosisPoliomyelitis

Tissue cultures collected during the recovery process are tested for the following microbial contaminants:

• Aerobic• Anaerobic• Fungal

OneFuse Plus additional screening

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Tissue processing procedures have been validated to inactivate and eliminate the following viruses:

� H���1�Humanimmunodeficiency�i�u�type1• 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:

Test Test OverviewISO 10993-5 To determined whether leachables extracted from the material would cause cytotoxicityISO 10993 Part 10 2002(E) Tests for Irritation and Delayed-type HypersensitivityISO 10993 Part 10 2002(E) Tests for Irritation and Delayed-type HypersensitivityISO10993 Part 11 2002(E) Test for Systemic ToxicityUSP 28[88] To evaluate the local effect of implanted OneFuse samples in the paravertebral muscleISO 10993-6 To evaluate the biocompatibility and local effect of OneFuse over a 12 week periodISO 10993 Part 3 Test for Genotoxicity, Carcinogenicity and Reproductive Toxicity.ISO 10993-4 Test the interaction of OneFuse samples with rabbit bloodISO 10993-12 To determine the level of endotoxin in the leachables extracted from the testing material

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

Genotoxicity/Bacterial Reverse Mutation Assay (Ames Test)

Hemolysis Testing

Endotoxin Testing

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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; 2:035003 (12 pp).

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�hestudy�asconductedto�erifythee�ecti�enessofspinalfusion�ithOneFuse Plusanditsa�ilitytostimulate 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 andinter�odyspinalfusion�ase�aluatedat4,8and13�ee�safterimplantation�yconductingalongitudinalradiologice�aluation,�iomechanicalandhistologytest.�hera��itsmodels�eree�aluatedforradiologicfindings,fusionrate,�iomechanicalstrengthandhistologicalfindings�graftmaterialresiduerate,ne��oneformationrate�.The results indicate biocompatibility and proved a gradual density growth along with successful bone remodeling. Fusion�aso�ser�edafter13�ee�sinthe�4���section.Inhistologicale�aluation,compact�one

OneFuse Plushasane�ui�alente�ect�hencomparedtotheindustryleading���.

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Radiographs of a rabbit spine after posterolateral lumbar arthrodesis using OneFuse Plus

continuity was noted following a progressive activation of new osteoid tissue and bone marrow cavity formation.

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The study was conducted to evaluate OneFuse Plus originating from multiple donors.

In Vitro Assay• �heOneFusePlus samplesusedforthise�aluationoriginatedfromtendi�erentdonors.�heunits�eresterili�ed �y electron beam• Samples from the same ten lots were tested per Protocol: BMP-2 ELISA. Each donor lot was tested in triplicate• ����2concentration�asmainlya�ected�yindi�idualfactors�genderandage�.Asreportedintheliterature, 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.• After28days,themice�eresacrificed.• Slides were prepared and examined using various methods including immunology and histology.

OneFusePlus �astransplantedinthehipmuscleofanathymicrat, and several histological tests were performed to e�aluateosteoinducti�ea�ility.Afterwardstherecruitmentofosteo�lastsandosteoclaststothesitesof 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�utingtone��oneformationin�one�defecti�eregions.

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Each lot is tested for osteoinductivity (In Vitro Assay)

Each lot of OneFuse Plus is tested for BMP’s and growth factors (ELISA)

*Note: Price List, Terms & Conditions on Separate Handouts

*Note: Price List, Terms & Conditions on Separate Handouts

Ord

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TMtisucor

1.0 TCDBM-PP1

3.0 TCDBM-PP3

5.0 TCDBM-PP5

10.0 TCDBM-PP10

1.0 TCDBM-GP1

3.0 TCDBM-GP3

5.0 TCDBM-GP5

10.0 TCDBM-GP10

Volume (cc) Order Number

Volume (cc) Order Number

12

*Note: Price List, Terms & Conditions on Separate Handouts

*Note: Price List, Terms & Conditions on Separate Handouts

GEL

PUTTY

4819 Emperor Blvd. Suite 400 | Research Triangle Park | Durham, NC 27703

phone: 844-TISUCOR | 844-847-8267 | fax: 844-497-9800tisucor.com

4819 Emperor Blvd. Suite 400 | Research Triangle Park | Durham, NC 27703

phone: 844-TISUCOR | 844-847-8267 | fax: 844-497-9800

tisucor.com

Please Submit Orders by Email, Fax or Phone

Email: orders@tisucor.comFax: 844-497-9800

Phone: 844-TISUCOR ext. 2 (844-847-8267)

TMoneFuse Plusdemineralized bone matrix with cancellous