Therapeutic Artificial Organs (TAO) Research and Its .... c n I , b a l d emo –Bi – Clinical Trial Stage (64days in animal test, 87days in clinical trial) • Implantable Bi-ventricular

Therapeutic Artificial Organs (TAO) Research and Its Clinical

Applications in Korea

Prof. Byoung Goo Min

Dept. of Biomedical Engineering, Seoul National University

SMEBA 2006 in KAIST

Biomedical Devices

Biomedical DeviceBiomedical Device

Measurement andDiagnosis Device

Measurement andDiagnosis Device Therapeutic DeviceTherapeutic Device Medical

Information SystemMedical

Information System

X-ray DeviceMRI

Bone Density MeasurementPET

Ultrasound DeviceEndoscope

ElectrocardiographyElectroencephalography

Patient Monitoring SystemBlood Pressure Measurement

(Sphygmomanometer)

X-ray DeviceMRI

Bone Density MeasurementPET

Ultrasound DeviceEndoscope

ElectrocardiographyElectroencephalography

Patient Monitoring SystemBlood Pressure Measurement

(Sphygmomanometer)

Laser Therapy (Nd:YAG, Excimer)

ShockWave Lithotripsy Radiotherapy Device(X-ray therapy device

Gamma-knifeIMRT)

Artificial Organ(Artificial HeartArtificial KidneyArtificial LiverInsulin Pump)

Laser Therapy (Nd:YAG, Excimer)

ShockWave Lithotripsy Radiotherapy Device(X-ray therapy device

Gamma-knifeIMRT)

Artificial Organ(Artificial HeartArtificial KidneyArtificial LiverInsulin Pump)

PACS(Picture Archiving and

Communication System)

PACS(Picture Archiving and

Communication System)

Why Therapeutic Artificial Organs ?

• Many people die of major organ failures– Economical Loss– Social Loss

• Absolute Shortage of Donor Organs– Bridge to Transplantation– Alternative to Transplantation

• From emergency to the surgery and recovery

• Ethical Problems– Xenogenic Organs– Fetal Stem Cells

Artificial Organs

• Artificial Joint• Artificial Valve• Artificial Heart• Artificial Kidney (Dialysis)• Artificial Graft• Artificial Skin• Artificial Blood • Artificial Lung• Artificial Liver• Artificial Eye• Artificial Ear• Artificial Nose• Artificial Bone• Artificial Hand• Artificial Brain• Other Prosthetic Devices

Artificial Heart–Ventricular Assist Devices–Total Artificial Hearts–Korean Artificial Hearts

•Hemopulsa•KorTAH•AnyHeart•T-PLS

Classification of Cardiac Assist Device: Assist Type

• Intra-Aortic Cardiac Assist Device– IABP (Intra-aortic Balloon Pump)

• Ventricular Assist Device (VAD)– LVAD (Left Ventricular Assist Device)– RVAD (Right Ventricular Assist Device)– BVAD/BiVAD (Bi- Ventricular Assist Device)

• Totally Implantable Artificial Heart (TAH)– With weaning natural heart

Classification of Cardiac Assist Device: energy, mechanism, location, pulse

• Energy Source that make actuating motion – Pneumatic– Electronic

• Actuating Force or Mechanism– Pneumatic– Mechanical– Centrifugal

• Location of Device– Implantable– External or Extracorporeal

• Pulsatility of Blood Flow– Pulsatile– non-Pulsatile or Continuous

Intra-aortic Balloon Pump [IABP]

Extracoporeal Centrifugal Pump

• Available since 1977• approved by FDA for cardiopulmonary bypasscardiopulmonary bypass

(CPB)• frequently used as VADs because of availability,

low cost, simplicity

Extracoporeal Pulsatile Pneumatic Ventricular Assist Device

•• Indication: Indication: –– postcardiotomy cardiogenic shockpostcardiotomy cardiogenic shock

•• Application:Application:–– bridge to transplantationbridge to transplantation

• external power supply and console limit patient mobility

Implantable Pulsatile Ventricular Assist Device

• Long-term use• bridge to transplantation• Criteria for circulatory assist

– cardiac output < 2L/min/m2– systolic blood pressure < 90mmHg– atrial pressure > 20mmHg– systemic vascular resistance > 2100 dynes-sec/cm5– urine output < 20ml/hour

Implantable Continuous System

• Disadvantages of pulsatile mechanical assist devices– size– noise– infection of the power/vent line

• Advantages of continuous flow pump– small size– low noise– absence of a compliance chamber– small priming volume

Total Artificial Heart

• Mechanical & Polymeric Parts– Actuator– Blood Sac– Valves

• Electrical Parts– Implantable Controller– Wireless Energy Transmission

System– Wireless Information Transmission

System– Internal & External Battery– Portable Monitoring System

무선정보전송장치

무선에너지전달장치

체외 감시장치체내외 축전지 시스템

이식형 제어장치

인공심장Wireless information transmission system

Wireless Energy Transmission System

Internal & External Battery

Portable Monitoring System

Implantable Controller

Artificial Heart

History of Korean Artificial Heart

• Extracorporeal Ventricular Assist Device (Hemopulsa) (1991 – )

– Biomedlab, Inc.

– Clinical Trial Stage (64days in animal test, 87days in clinical trial)

• Implantable Bi-ventricular Assist Device (KAH AnyHeart) (1984 – )

– Biomedlab, Inc.

– Clinical Trial Stage (34day in animal test, 12days in clinical trial)

• Pulsatile Extracorporeal Cardiopulmonary Bypass Pump (T-PLS)

(2000 – )– NewheartBio, Inc.

– Approved in KFDA and CE

– Approved in SDA (China)

ImbeddedECG Monitor

2nd controller

1st controller

AutoS/W

Bellow-type Pumping Sac

Pusher-plate

DC motor

Heart

Left Atrium

Aorta

Blood chamberBlood chamber

ActuatorActuator

Integrated ControllerIntegrated Controller

Hemopulsa, Biomedlab, Korea- Extracorporeal Ventricular Assist Device

Water

Hemopulsa, Biomedlab, Korea- Extracorporeal Ventricular Assist Device

Driving UnitDriving Unit

Disposable Unit, ChannyDisposable Unit, Channy--200200

KAH, Seoul National Univ., Korea- Total Artificial Heart (TAH)

AnyHeart, Seoul National Univ., Korea- Implantable BiVentricular Assist Device

Cactus Pump

BVAD Configuration LVAD Configuration

TAH Configuration



Size : 167 x 170 x 68 mmWeight : 750 gVolume : 600 ccMax Pumping Output : 9 L/min


• Control & Electrical Technologies of AnyHeart®– Integrated Controller

• 70 mm diameter 35 mm x 30 mm size

– TET• Efficiency : average 80%• Maximum supply output: 90 W• Li-ion battery system

– Telemetry• RF communication



• 12 Days Clinical Experience, Korea Univ. Hospital, 2001

Right Pump : 3.5 ~ 4.5 L/minLeft Pump : 4.5 ~ 5.5 L/min

Artificial Valve, Seoul National Univ., Korea- Polymer Valve

• SNU Polymer Valve– Since late 1980s – Floating Polyurethane Valve [FPV]

• Membrane – partially-open shape in resting state– to minimize the pressure difference across the artificial valve

• Membrane & frame : concave shape– quickly open and completely close when working

• Spokes of valve frame : wedge shape– minimize thrombus formation due to flow separation

– Biocompatible Materials and Surface Modifications• Polyurethane membrane and frame• Lumbrokinase coating with plasma process


Pin Ring Membrane Membrane + Ring* adhesive : Pellethane solution

Frame Polymer Valve


Normal

Floating

Flapping

Closed

T-PLS, NewHeartBio, Korea


• T-PLS® (NewheartBio. Inc., Seoul, Korea)– Pulsatile, percutaneous, portable, extracorporeal cardio-pulmonary bypass pump– Versatile Extracorporeal Blood Pump

• ECMO + CPB + PCPS + (VAD)

PCPS

CPB

VAD

ECMO


Core Technology of AnyHeart®

Core Technology of AnyHeart®

Moving Actuator TypePumping Mechanism

Moving Actuator TypePumping Mechanism

BiocompatiblePolymer ValveBiocompatiblePolymer Valve

Pulsatile Flow Control & Safety ManagementPulsatile Flow Control & Safety Management

T-PLS®T-PLS®

Animal & Clinical Experiences

Animal & Clinical Experiences


• Product Specification– Weight : 60kg– Dimension (Main body) : 456*437*665 (mm)– Pump mechanism : Tubular-occlusion Mechanism– Designed Stroke Volume : 70 cc– Priming Volume : 300 cc– Maximum flow rate : 6 L/min– Pump rate control : 0-80 BPM(+1/-1 step)

• Auto Control function – Auto Priming setup – Suction Protect mode– Electrical Motor : 50 W brushless DC motor– Battery (UPS) : Lithium-Ion Battery for 4hrs– Tube : Medical-grade silicone rubber– Connector : Medical-grade polycarbonate– Polymer Valve (4EA)


T-PLS®

Oxygen

HeatExchanger

AterialFilter

Oxygenator

Reservoir

Femoral VeinCatheter(21Fr.)

Femoral ArteryCatheter(17Fr.)

GasBlender

Air

T-PLS, Three-stage Successive Treatment from Cardogenic Shock to Recovery

CardiogenicShock

Treatment(PTCA, CABG orStent Insertion)

Recovery

EmergentCardiopumonary

SupportAs PCPS

Surgical SupportAs CPB

Heart RecoveryAssist

As VAD

Heart and LungSupportAs ECMO

T-PLS®

T-PLS : Clinical Trial

• Multiple Purpose Pulsatile Blood Pump for Cardiac Surgery and Emergency Treatment– Support during high-risk PTCA– Safeguard against cardiogenic shock pre- and post-PTCA– artial circulatory support in beating CABG surgery with minimal hemodilution– Emergency standby in cases of cardiac arrest during interventional and surgical procedures(Extra-corporeal life

support)– Support the heart during other cardiac surgery(Cardiopulmonary bypass)– ARDS(Acute respiratory distress syndrome)– Hemoperfusion for toxication

Versatile Applications of Dual Pulsatile Blood Pumping Mechanism

Cardiopulmonary Support

Hemoperfusion

Artificial Liver

Hemodialysis

Hemofiltration

Dual Pulsatile Blood Pumping Mechanism

Hemodialysis System(Artificial Kidney)

Hemodialysis System(Artificial Kidney)

• Acute Renal Failure• Chronic Renal Failure

– Peritoneal Dialysis• Mass Transfer through

Peritoneal

– Hemodialysis• Mass Transfer through

Hollow Fiber Membrane– Excessive water– Waste : Urea, Creatine– Required ions– Required dextrose

Hemodialysis Machine

The Principles of Hemodialysis System

Diffusion and Convection through Hollow Fiber

Membrane

Blood

Dialysate

Hollow fiber membrane

Required IonRequired Dextrose

Excessive WaterWaste : Urea, Creatine

Vascular Access of Hemodialysis System

• Vascular Access– AV-fistula

• Requiring vascular surgery

– Implantable venous catheters

Issues of Hemodialysis System

• Development Issues– High-Efficiency Dialysis– High-Flux Dialysis– Daily Dialysis– Home Dialysis– Pulsatile Hemodialysis– Implantable Vascular Access Device– Dialysate Reusable System

The Prospect of Hemodialysis System

• High-Efficiency , High-Flux Dialysis– Incresing middle-size molecule clearance– Incresing water ultrafiltration rate

• A : Membrane with numerous small pores that allow high water flux but no middle-size molecule transport.

• B : Membrane with a smaller surface area and fewer pores, with the pore size sufficiently large to allow middle-size molecule transport.

Silicone o-ring

Conventional Conventional high flux high flux dialyzer, dialyzer,

CHFDCHFD

Modified high Modified high flux dialyzer, flux dialyzer,

MHFDMHFD


• Design of Modified Dialyser– Enhanced Ultrafiltration– Enhanced Molecule

Clearance(Patent Pending)


• Daily-Home Hemodilysis– Benefits of Daily-Hemodialysis

• Better well-being and energy • Better nutritional indices • Higher hemoglobin, less transfusions or erythropoietin requirements • Better blood-pressure control, less blood pressure medications • Much improved intra-dialysis tolerance with fewer: cramps, crashes,

nausea-vomiting, headaches • Less post-dialysis fatigue, cramps, lightheadedness • Better quality of life ratings


• Korea Artificial Organ Center , Seoul National University & Newheartbio Co.– C-PAK(Compact-Pulatile Aritificial Kidney) & N-PAK(Nocturnal)

• Home/Portable Homedialysis• Pulsatile Blood Pumping• Implantable Vascular Access Device• Dialysate Reusable System• Web-based Remote Monitor & Control

PHS system®, AKSYS, USA Prototype of C-PAK9.3 kg


• C-PAK

Design of C-PAK

Configuration of C-PAK during animal experiment

Weight : 9.3 kg

Pulsatile Blood Pump : 0 – 700 ml/min

Fluid Pump : 0 - 5 l/h (2EA)

Air-bubble Detector (ultrasonic)

Blood Leak Sensor (laser)

Blood Pressure Sensor

Main Controller : Samsung ARM9 2410

4.0 inch Color Touch Display

• C-PAK : Animal Experiment– Daily hemofiltration without dialysate– Blood urea nitrogen profile

0

10

20

30

40

50

60

70

80

90

0 50 100 150 200 250

Time [hr]

BU

N [

mg

/dl]

, B

od

y W

eig

ht

[kg

]

Body Weight

BUN(cheju)

BUN(E1)

Artificial Liver

E-liver System

Artificial Liver - Bridge System

• Artificial liver is ‘bridge system’ for the patients who need time until…– liver transplantation surgery; Lack of donor liver;

Waiting list of liver transplantation is increasing every year.

– recovery of liver function.

• In some fulminant hepatic failure (FHF) cases, the lethality reaches 85%.– Proper liver assist device which can replace liver

function is essential.

Types of Artificial Liver

• Non-biological artificial liver

• Biological artificial liver• Hybrid bioartificial liver;

BAL

Liver Support System

• Nonbiological liver system – only toxin removal

• Plasma exchange• Hemodialysis• Hemofiltration• Hemoperfusion• Hemodiadorption

• Biological liver support system – Toxin removal and metabolism– Extracorporeal circulation

• Extracorporeal perfusion with animal or human liver• Artificial liver support systems using hepatocytes (BAL)

– Hepatocyte transplantation• Transgenic xenotransplantation• Human hepatocytes transplantation directly to splenic bed

Bioartificial Liver (BAL)

• DefinitionAll kinds of liver-assist devices which are using hepatocytescome from mammalian animals or human

• BAL - ‘Hybrid system’

- Inorganic bioreactor vessel + Functioning living cells or tissue

- Detoxification + Functional liver support

SNU Artificial Liver System

• E-Liver system – PSAF(Plasma Separation-Absorption-Filtration) – Patent Pending

P1

Water soluble toxins removalElectrolytes balancing

Albumin bound toxins Water soluble toxins

Absoprtion50~150 ml/min

Blood circuit100~300 ml/min

Hemofiltration30 ml/min

Plasm

a Sep

Replacement fluid30 ml/min

P3

Hem

ofilterA

dsorber

P2

plasma circuit50~150 ml/min

SNU Artificial Liver System

• E-Liver– Mock-circulation

Test

Prospect of Artificial Organs Research

• Development of combined treatment of cell-therapy and therapeutic artificial organ

HeartHeartAttackAttack

LifeLife--savingsavingUsing Using

ArtificialArtificialOrganOrgan

(VAD/ECLS)(VAD/ECLS)

ExtractingExtractingMuscle cell Muscle cell

from Patientfrom Patient’’ssLeg MuscleLeg Muscle

Culture Culture MuscleMuscle

Cell into HeartCell into HeartMuscle CellMuscle Cell

For 3~4 weeksFor 3~4 weeks

TransplantTransplantCulturedCultured

MucsleMucsle CellCellOn Patient On Patient

HeartHeart

Differentiation/Differentiation/DevelopmentDevelopment

Of transplantedOf transplantedMuscle cellMuscle cell

Recovery ofRecovery ofDamaged Damaged Heart cellHeart cell

Weaning Weaning Artificial Artificial

OrganOrgan(VAD/ECLS)(VAD/ECLS)

Thank you

Documents

Therapeutic Artificial Organs (TAO) Research and Its .... c n I , b a l d emo –Bi – Clinical Trial Stage (64days in animal test, 87days in clinical trial) • Implantable Bi-ventricular