history of embolotherapy 1904 dawbain - inject melted wax/carotid 1930 brooks - inject muscle/int....

History of EmbolotherapyHistory of Embolotherapy

1904 Dawbain - inject melted wax/carotid1904 Dawbain - inject melted wax/carotid

1930 Brooks - inject muscle/int. carotid1930 Brooks - inject muscle/int. carotid

1960 Lussenhop & Spence - MM spheres1960 Lussenhop & Spence - MM spheres

1971 PVA Plug1971 PVA Plug

1972 Hemorrhage controlled auto-clot1972 Hemorrhage controlled auto-clot

1974 Serbinenko -Detachable balloons1974 Serbinenko -Detachable balloons

History of EmbolotherapyHistory of Embolotherapy

White et. al. - flow directed cath w/det. Bal.White et. al. - flow directed cath w/det. Bal.

1974 Gel Foam1974 Gel Foam

1975 Wool Coil1975 Wool Coil

1981 Ethanol used kidney infarction1981 Ethanol used kidney infarction

1982 Amplatz - boiled contrast1982 Amplatz - boiled contrast

Improvements in Visualization, Catheter Improvements in Visualization, Catheter Technology, Embolic AgentsTechnology, Embolic Agents

Embolic Agent VariablesEmbolic Agent Variables

DeliveryDelivery Mechanical EffortMechanical Effort Tortuousity of VesselsTortuousity of Vessels Procedure Time - Radiation, ContrastProcedure Time - Radiation, Contrast

PlacementPlacement Flow directedFlow directed Proximal or distalProximal or distal In-vivo sizingIn-vivo sizing Reflux tendencyReflux tendency

Embolic Agent VariablesEmbolic Agent Variables

RadiopacityRadiopacity Additives tantulum, barium, et. al.Additives tantulum, barium, et. al. MRI CompatibilityMRI Compatibility

ActivationActivation ToxicityToxicity Expansion Expansion NecrosisNecrosis

Embolic Agent VariablesEmbolic Agent Variables

SizingSizing Ranges and toleranceRanges and tolerance

Inflammatory ResponseInflammatory Response Local mild or giant cell reactionLocal mild or giant cell reaction

Pain on AdministrationPain on Administration Alcohol, gelfoam, PVAAlcohol, gelfoam, PVA

Permanent or TemporaryPermanent or Temporary Auto-lysisAuto-lysis

RecanalizationRecanalization

Vessels recanalizeVessels recanalize

Embolic can “wash-out”Embolic can “wash-out”

Vessel with embolic can remodelVessel with embolic can remodel

Not important in pre-op embosNot important in pre-op embos

Timing is the key variableTiming is the key variable

Embolic Agent VariablesEmbolic Agent Variables

CostCost Total procedure cost and patient lifeTotal procedure cost and patient life

Occlusion MechanismOcclusion Mechanism MechanicalMechanical ThrombusThrombus

HemodynamicsHemodynamics Large vs. small vesselsLarge vs. small vessels High flow or slower flowHigh flow or slower flow

ParticlesParticles

Irregular shapeIrregular shape Induce an inflammatory responseInduce an inflammatory response Auto-lysisAuto-lysis Some are temporarySome are temporary Occlusion sustainabilityOcclusion sustainability ThrombogenicThrombogenic May be difficult to handleMay be difficult to handle

Mechanical DevicesMechanical Devices

CoilsCoils ThrombogenicThrombogenic Size and deliverySize and delivery PermanentPermanent

BalloonsBalloons Latex or siliconeLatex or silicone Mechanical occlusionMechanical occlusion

Liquid EmbolsLiquid Embols

Ethanol and Ethibloc are painfulEthanol and Ethibloc are painful Results can take time post Results can take time post

procedureprocedure Can be difficult to handleCan be difficult to handle Obliteration, permanentObliteration, permanent Extensive necrosis possibleExtensive necrosis possible

GluesGlues

Acrylates used but not approved Acrylates used but not approved Polymerize upon contact with Polymerize upon contact with

ionic solutionsionic solutions Some use Acetic acid or heavy water to delaySome use Acetic acid or heavy water to delay

High inflammatory responseHigh inflammatory response PermanentPermanent Experience is criticalExperience is critical Difficult to handleDifficult to handle

Embolic AgentsEmbolic Agents

Spheres Particles Mechanical Liquid Sclerosant

Embosphere PVA Coils NBCA Ethanol

Therasphere Gelfoam Balloons Hydrogel Acetic acid

Hepasphere Sotradecol

Contour SE Ethibloc

Beadblock

SpheresSpheres

CalibratedCalibrated Radio-pacity Radio-pacity Flow directedFlow directed CarrierCarrier Dry or wetDry or wet Polymer, hydrogel, glassPolymer, hydrogel, glass Mechanical occlusionMechanical occlusion

Company HistoryCompany History

Microspheres developed to purify Human Serum Microspheres developed to purify Human Serum Albumin and antibodies -1970sAlbumin and antibodies -1970s

IBF-French Biological Industries and later IBF-French Biological Industries and later Biosepra produce microspheres for drug Biosepra produce microspheres for drug purification - 1980spurification - 1980s

Microspheres used to produce albumin, insulin, Microspheres used to produce albumin, insulin, and genetically engineered human growth and genetically engineered human growth hormone - 1980shormone - 1980s

First use of microsphere as a human implant at First use of microsphere as a human implant at LRB in Paris, 1989 LRB in Paris, 1989

Early 1990s:Early 1990s:

Microspheres used to produce biotech drugs Microspheres used to produce biotech drugs such as TPA, AT3, gene therapy vaccinessuch as TPA, AT3, gene therapy vaccines

Sepracor purchases BiosepraSepracor purchases Biosepra

Company HistoryCompany History

Biosepra spins off from Sepracor, 1994Biosepra spins off from Sepracor, 1994

Biosepra, through its French distributor, obtains Biosepra, through its French distributor, obtains CE Mark for Embosphere, 1997CE Mark for Embosphere, 1997

Biosepra sells chromatography business, 1998Biosepra sells chromatography business, 1998

Biosepra purchases majority share of Biosphere Biosepra purchases majority share of Biosphere Medical SA and changes corporate name to Medical SA and changes corporate name to Biosphere Medical, 1999Biosphere Medical, 1999

BSMD files 510k, 1999BSMD files 510k, 1999

Company HistoryCompany History

Management team nucleus hired, 1999Management team nucleus hired, 1999

IDE filed for UAE clinicals, 1999IDE filed for UAE clinicals, 1999

European distribution expanded, 1999European distribution expanded, 1999

Australia and Canada approve Embosphere, 2000Australia and Canada approve Embosphere, 2000

PIPEs completed, 2000PIPEs completed, 2000

FDA clearance for Embosphere, 2000FDA clearance for Embosphere, 2000

Sales force recruited, 2000Sales force recruited, 2000

Company HistoryCompany History

Embosphere® Microspheres are precisely calibrated, spherical, hydrophilic, micro-porous beads made of a cross-linked acrylic co-polymer which is then cross-linked with gelatin.

• Cross-linked acrylic beadsCross-linked acrylic beads• Precisely calibratedPrecisely calibrated• Micro-porousMicro-porous• Embedded with gelatinEmbedded with gelatin

• CompliantCompliant• HydrophilicHydrophilic• Non-clumpingNon-clumping• Patented and proprietaryPatented and proprietary

• Spherical Spherical • Non AggregatingNon Aggregating• Uniform occlusionUniform occlusion• Predictable penetrationPredictable penetration

• Irregular shape Irregular shape • ClumpingClumping• Non-uniform occlusion Non-uniform occlusion • More proximal occlusionMore proximal occlusion

EmbosphereEmbosphere

PVAPVA

A Precise CalibrationA Precise Calibration

PVA type 1

50-150 microns

PVA type 2

50-150 microns

Embosphere Microspheres -

Biosphere Medical

100-300 microns

Ultra-Drivalon 50-150m

Particle diameter (m)

1 10 100 1000

% (

volu

me)

0

10

20

30

Contour Emboli 45-150m

Particle diameter (m)1 10 100 1000

% (

volu

me)

0

10

20

30

Microspheres 100-300m

Particle diameter (m)1 10 100 1000

% (

volu

me)

0

10

20

30

Ultra-Drivalon 50-150m

Particle diameter (m)

1 10 100 1000

% (

volu

me)

0

10

20

30

Contour Emboli 45-150m

Particle diameter (m)1 10 100 1000

% (

volu

me)

0

10

20

30

Microspheres 100-300m

Particle diameter (m)1 10 100 1000

% (

volu

me)

0

10

20

30

U ltra-d riv alon – N ycom e d 5 0-1 5 0 m

C o nto u r em b oli - Targe t 5 0-1 5 0 m

E M B O SP HE R E - B iosp he re M e dical 1 00 -3 00 m

% V

olum

e%

Vol

ume

% V

olum

e

A Precise calibrationA Precise calibration

The only particulate embolic The only particulate embolic material you can trust !material you can trust !

ES 1

00/3

00ES

300

/500

ES 5

00/7

00ES

700

/900

0

100

200

300

400

500

600

Ves

sel d

iam

eter

(µ

)

PVA

150

/250

PVA

250

/400

PVA

400

/600

PVA

600

/100

00

100

200300

400

500

600

700

800

Competitive Advantage Competitive Advantage

“Controlled Vessel Targeting”

Embolization efficiencyEmbolization efficiency

ES

100/

300

ES

300/

500

ES

500/

700

ES

700/

900

PVA

150

/250

PVA

250

/400

PVA

400

/600

PVA

600

/100

00

2.5

5

7.5

10

12.5

15

17.5

20

22.5

Num

ber

of p

arti

cles

PVA

Embosphere

Perfectly sphericalPerfectly spherical

A direct correlation between the A direct correlation between the size of the vesselssize of the vessels

andand

the size of embolic !the size of embolic !

Inert biocompatible materialInert biocompatible material

Cross-linked acrylic bead impregnated Cross-linked acrylic bead impregnated with gelatinwith gelatin Chromatography media Chromatography media Cell-culturing history Cell-culturing history

Acute and chronic animal testing Acute and chronic animal testing Strong safety profileStrong safety profile

Six year implantSix year implant Complete mechanical occlusionComplete mechanical occlusion Inert material Inert material Remains unchanged over timeRemains unchanged over time

6 year implant

PVA DegradationPVA Degradation

Chronic inflammatory response

Histology slides courtesy of Dr. Alex Laurent, Hopital Lariboisiere, Paris

Non-uniform occlusion

LLong-term tolerance - Facial AVMong-term tolerance - Facial AVM

1 year

Female patientFemale patient. 25 yrs.. 25 yrs. 1989 sept Embolization with ES 500-700 & 1989 sept Embolization with ES 500-700 &

700-900700-900 1990 march1990 march Surgery Surgery 6M6M 1990 oct 1990 oct SurgerySurgery 1Y1Y 1993 feb 1993 feb SurgerySurgery 1995 oct 1995 oct Surgery Surgery 6Y6Y

6 years

6 years

Long term Long term tolerance tolerance

Facial AVM Facial AVM

Male patient, 31 yo, lip AVM1988 Embolization PVA1990 dec Embolization ES 800-10001992 nov Surgery (23 M)

23 Months

*

*

*

ES

ESES

PVA particle

23 Months* = Macrophages

BiocompatibilityBiocompatibility

PermanentPermanent

DurableDurable

CompleteComplete

MechanicalMechanical

OcclusionOcclusion

Compressible and HydrophilicCompressible and Hydrophilic

Elastic shape and hydrophilic surface prevent aggregation within the catheter, simplifying handling and promoting accurate delivery to the target vessel.

Compressible and HydrophilicCompressible and Hydrophilic

Assume 33% compression

gets backin roundshape

Embosphere and 3F CathetersEmbosphere and 3F Catheters

Brand I.D. Embosphere size in m

Micro Ferret .018 300-500

Rapid Transit .021 500-700

Turbo Tracker .021 500-700

Renegade .021 500-700

GT Leggiero .023 500-700

Tracker 325 .024 700-900

Slip Cath .025 700-900

SP Cath .025 700-900

Mass Transit .027 700-900

Trademarks and product names are exclusiveproperties of their manufacturers.Here above information is purely given as indications.

A unique ease of useA unique ease of use

A superior catheter patencyA superior catheter patency

Compressible and HydrophilicCompressible and Hydrophilic

Summary of Competitive AdvantagesSummary of Competitive Advantages

Embosphere (ES) PVA ES Advantage

Spherical shape, Narrow size range

Irregular shape, wide range of sizes

Targeted and controlled Complete, permanent occlusion

Elastic structure Non-elastic structure

Microcatheters Non-fragmentation Minimizes untargeted tissue necrosis

Hydrophilic/ Charged surface

Non-hydrophilic/ Non-charged

No clumping Ease of use No migration

Key Features & BenefitsKey Features & Benefits

FeaturesFeatures RoundRound CalibratedCalibrated InertInert CompressibleCompressible HydrophilicHydrophilic

BenefitsBenefits Complete lumen fillingComplete lumen filling Control and targetingControl and targeting BiocompatibleBiocompatible Catheter patencyCatheter patency Easy to injectEasy to inject

Platform technologyPlatform technology

The proven embolicThe proven embolic

Embosphere® microspheres:First generation of calibrated microspheres

The new Gold StandardThe new Gold Standard

EmboGold™ microspheres:User-friendly stained calibrated microspheres

Embosphere® microspheres

From right to left

40-120µm100-300µm300-500µm500-700µm700-900µm900-1200µm

Embosphere® microspheres

Calibrated microspheres available in1ml or 2ml

sizes Product codes

40-120µm 110GH 120GH100-300µm 210GH 220GH300-500µm 410GH 420GH500-700µm 610GH 620GH700-900µm 810GH 820GH900-1200µm 1010GH 1020GH

EmboGold™ microspheres

New pre-filled syringe under peel-off blister tray

Calibrated microspheresStained with Gold

100-300µm 300-500µm500-700µm 700-900µm900-1200µm

EmboGold™ microspheres

VisibilityConvenience

Performance

Stained calibrated microspheres available in PFS1ml or 2ml

sizes Product codes

100-300µm S210EG S220EG300-500µm S410EG S420EG500-700µm S610EG S620EG700-900µm S810EG S820EG900-1200µm S1010EG S1020EG