Week 4. Image guided therapies

2012.10.30.

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Multimodal Imaging in Neurosciences Course

Image guided therapies inneurological sciences and VRDr. András Jakab, MD, PhD

COURSE FAQ

Forthcoming lectures:16. October – „IGT lecture”23. October – NO LECTURE, holiday30. October – MR Spectroscopy6. November – PET + Final Test

Test:- Basic imaging techniques, what are they- 5-10 easy, simple choice questions- If November 6. is not good for everyone, I will organize extra

time for getting the short test done

Study material:Lecture material will be distributed in PDF 2 wks before thetest.

Diagnostic neuroimaging modalities

CT – Computed TomographyBrain anatomyStereotactic reference frame

Structural MRIFine brain anatomyVascular structure

Diffusion, perfusion MRIFine pathologicalinformation

Intra-operative imagingmodalities, open MRI, low-field

MR SpectroscopyBrain metabolismBiochemical mapping

Positron EmissionTomography PETBrain metabolismBrain function

Functional MR imaging fMRIBrain function

Electro encephalography, LORETTA, Magnetoencephalography

Using multi-modal imaging for planningimage-guided neurological interventions

What is multimodality?Combining images and information from multipleimaging tools, devicesAnatomical alignment of imagesFusion display, co-analysis of multipleinformation sources

What is needed for multimodality?What is needed for multimodality?CT, PET, MRI, SPECT, EEG, …Hybrid devices – PET-CT, PET-MRIImage processing skills to create image fusions, etc.

Overview of the lecture

1. Image guided therapy – basicsand the modalities used

2. Stereotactic functionalneurosurgeryR di d l i3. Radiosurgery and planning

4. Focused ultrasoundneurosurgery

5. VR applications in surgery

1 Image guided therapy -1. Image guided therapy -basics

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Image guidance• Using preoperative images

to define target volumes ina reference space

• Using intraoperativeimaging to monitor treatment– Intraoperative

ultrasound– Intraoperative low-field

MRI– Intraoperative high-field

open MRI Intraoperative open MRI, Brighamand Women’s Hospital, Harvard, Boston (credits: Prof. Ferenc Jolesz)

AMIGO – Harvard, Boston

Surgical robot for biopsies

Treatment planning w/ preoperative imaging

Intraoperative imaging withMRI

Surgical robot for biopsies

Intraoperative MR imaging

• Medtronic Polestar• Low field (0.1-0.3T)• Brain shift – a real problem• Use of nonmagnetic tools 2 Stereotaxy in functional2. Stereotaxy in functional

neurosurgery

What is stereotactic?• Space, spatial• Coordinate frame

of the brain:– Intrinsic– extrinsic

Why use stereotaxy inneurosurgery?

• Very high (<1-2mm) precision needed• Minimal invasive procedures

– Electrode implantation for ablationElectrode implantation for ablation– Permanent electrode implantation (DBS)– Biopsy sampling from the brain

• Procedures without opening the skull– Radiosurgery, LINAC, Gamma Knife,

Cyberknife– Focused ultrasound surgery

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Brain biopsy• Indications

– Tumor suspect (enhancing CT, MRI, lesion)– Inflammation, Neurodegeneration, unknown

• Procedure (1-2 hours):St f tt h t– Stereo frame attachment

– Computed tomography– Planning– General anaesthesia– Small craniotomy– Dexamethasone– Control scan(s)

Imaging for brain biopsy

• CT• MRI (T1/T2+Contrast)• Pathology+Radiological

consultation – where to takeh l f ?the sample from?

Functional neurosurgery

• Alleviating symptoms by modifyingfunctional areas of the brain, subcortical areas

• Two main approaches:• Two main approaches:– Permanently cutting fiber pathways,

destroying specific nuclei

– Retuning / stimulating fiber pathways, specificnuclei in the brain

Thermoablation

Deep brain stimulation

Thalamotomy / pallidotomy• Parkinson disease – associated tremor

alleviation• Essential tremor (unkown ethiology)

Targets:VIM nucleusSubthalamicnucleus, PTTVentral Pallidum

Thalamotomy• Fantom pain (after amputation)• Intractable tumor / stroke pain in limbs etc.• CL / CM nucleus – central lateralis / centré median

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Deep brain stimulation (DBS)

• FDA approval: 1997

• Implant in brain+ subcutaneous+ subcutaneousstimulator(~pacemaker)

• Retuningfunctionalpathways(„arrhythmia”)

Deep brain stimulation

• Indications:– Chronic pain, PD tremor,

ET, dystonia– Tourette, OCD, Major

d idepression

– Parkinsons• Subthalamic nucleus• Globus pallidus interna• Zona incerta• Pallidothalamic fibers

Procedure• Localization,

stereotaxy• Electrode trajectory: • Trials and

monitoring• Pre/postop imaging

Targeting scheme• 1. Target definition using stereotactic atlas

of the human thalamus and basal ganglia(histology)

Getting x,y,z coordinatesfor yourtarget

Reference: AC-PC coordinatesystem

Targeting scheme• 2. Defining targets on the patient’s coordinate frame (using CT+MRI)

Manually finding AC, PC points on scans

Finding landmarks of the reference frame(stereotactic frameattached to the head)

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3. Radiosurgery

Gamma ART 6000N Rotating Gamma SystemAmerican Radiosurgery Inc., San Diego, CA,

USA

•only 30 Co60 sources•Rotating sources•Collimator size:

4, 8, 14, 18 mm•Stereotactic frame required•0,3 mm accuracy•Source half-life approx. 5 yrs

Challenges

• Morphological imaging by MRI– 3D isotrop voxel acquisitio

• Good tissue contrast• Good signal-to-noise• Minimal image distortion• Optimal image resolution

– MRI as reference system?• Robust CT method is necessary

Challenges of multimodality

– fMRI– DTI, fibertracking– MRS, MRSI

• Postprocessing– Registration, image fusion (need fast)

• PET, SPECT

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3D T1 weighted images• 1,2x1,2x1,2 mm• 140 slices• 6 minutes• Gd contrast agent

3D T2 weighted images

• 0,7x0,7x0,7 mm• 40-60 slices• 4 minutes

3D TOF acquisition• 1,2x1,2x1,2 mm• 190 slices• 6 minutes• Gd contrast agentg

Our imaging protocolls(+indications)

• Metastasis, meningeoma• AVM• Cavernoma• Cavernoma• Acustic neurinoma• Hypophysis microadenoma

AVM MRA Automatic radiologic image processing

CT/T1/T2

T1

Automated CT/MRI registration(gammaknife, neurosurgery

automatedstandardization, segmentation

(neurosurgery, neurology)

DIC

OM

server

ImageSorter

DWI, T1

fMRI, T1, T2

automatedTensor space calculations and

regularization(neurosurgery, neurology)

automatedSPM analízisfMRI, T1, T2automated

SPM analízisfMRI, T1, T2automated

SPM analysis(neurosurgery, neurology)

Pet & Mriautomated

PET-MR registrationand roi analysis

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T1-CT registration for radiosurgery(gamma-knife)

- Automatic (maximalisation relative entropy)- Manual correction (with internal „landmarks”)To this time, manual correction was necessary in 60% of

the cases- Optimalised automatic registration

Image registration, alignmentgamma knife

T1-CT Fiesta-CT TOF-CT

Extracranial metastasis Extracranial metastasis (epipharynx)(epipharynx)

Acoustic neurinoma treatment plan

• 1 kezelési tervet betenni

Acustic neurinoma

Pre-treatment 6 months post 12 months post

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Treating trigeminal neuralgiaTrigeminal neuralgia

CT and FIESTA imaging

Service available via a DICOM-serverDataflow

• 2D fusion

BrainCAD:•Dicom-minc conversion

MNI and M3I tools:

• 2D fusion

• 3D fusion

• Fiber visualizationSPM-analysis

INTERACTIVEIMAGE PROCESSING

•Segmentation

•Automatic registration

•Spatial standardization

•Automatic region analysis

AUTOMATICIMAGE PROCESSING PRESENTATION

(neuronavigation)

Validation of the T1-CT optimized registration method

S01

REFERENCE IMAGES AUTOMATICALLY REGISTERED IMAGES

S02

S03

SnMRI data revision by experts

(occassionaly manual registrations)

Comparison using normalized relative entropy

Further fancy options

PET/SPECT imagesT2, PD etc.

Precise T1-CT registration

Structures defined in the space of a brain atlasDTI parametric images

SPM images

CT-DTI registration

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CT-DTI registration

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DTI + MRI data in the CT frame. Metastaticdisease, 55/M

( Gamma Radiosurgery Centre, Debrecen )

Proton therapy

100%

60%

PHOTONSMedulloblastoma“dose bath”

60%

10%

PROTONS

The proton advantage:Nasopharynx

Photons (IMRT) Protons

Dose bath

The proton advantage:Paraspinal

Photons Protons

Dose bath

4 Focused ultrasound4. Focused ultrasoundneurosurgery

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Energy Conversion and Transport in Biosystems (09.12.10)

Non-invasiveInterventions with

Beat WernerMR-CenterUniversity Children‘s HospitalZurich

Focused Ultrasound

WelcomeWelcome

Beat WernerMR-CenterUniversity Children’s Hospital Zurich

www.kispi.uzh.ch/mrbeat werner@kispi uzh [email protected]

dipl. phys. ETH

MR-Physics

HIFU surgery since 2005, research project as part of NCCR Co-Me

Slide credits: Beat Werner, Ernst Martin

Intro: Image guided interventionsIntro: Image guided interventions


Intro: Image guided interventionsIntro: Image guided interventionsImage Guided Interventions

Improve accuracyDecrease intervention risks Minimally invasive / Non-invasive Interventions

Planning and navigation Complex interventions in cranio-maxillo-facial surgery. Slide credits: Beat Werner, Ernst Martin

Intro: Image guided interventionsIntro: Image guided interventions"Multimodal" Imaging

Multimodal: US, CT, MR, ...Multidomain: Anatomical, physiological, statistical information Multi-Timescales: Static (Pre-/intra-intervention), RealtimeRealtimeAugmented reality: condition, fuse, modelEnhanced visualization: 2D, 3D, ..., force feedback

Computer-assisted support in ORL surgerySlide credits: Beat Werner, Ernst Martin

Intro: Image guided interventionsIntro: Image guided interventionsEnabling technologies used here:

MRClosed-loop intervention controlUS field calibration

Focused UltrasoundMechanical / Thermal therapy(Targeted) drug delivery(Targeted) drug activation

Nano-ParticlesMolecular markersContrast agentsDrug carriersTherapeutic devicesSlide credits: Beat Werner, Ernst Martin

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Motivation: NonMotivation: Non--invasive HIFU Surgeryinvasive HIFU Surgery


Motivation: Clinical value of Motivation: Clinical value of MR guided Focused US SurgeryMR guided Focused US Surgery

Excellent soft tissue contrast for target localizationLocal therapyNon-invasiveNon invasiveNo dose accumulation effectsNo long term toxicityImmediate result –no radiation necrosisTreatments can be repeated Closed-loop image guidance Real time monitoring

Imaging (Diagnostics): want wide field of view with uniform low acoustic intensity

Imaging <Imaging <--> Focused Ultrasound> Focused Ultrasound

HIFU (Intervention / Therapy): want small focal spot with high acoustic intensitySlide credits: Beat Werner, Ernst Martin

Phased-Array Transducer = Array of TransducersEach transducer element controlled individually Transducer phases define superposition pattern of waves -> Electronic steering

PhasedPhased--Array TransducersArray Transducers

Constructive Destructive Shift


Beam Forming / FocusingBeam Forming / Focusing

Geometric focusing Lens focusing

Electronic beam forming Electronic steering


PhasedPhased--Array TransducersArray TransducersLinear Array -> Plane Wave

Spherical Array -> Focus


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Spherical Array

Pressure Distribution Temperature Distribution



Spherical Array

Electronic Steering


The effects of Ultrasound on biological tissue are a field of active researchMany effects are not well understoodEffects include:

Biological EffectsBiological Effects

th l non thermalultrasoundthermal mechanisms

non-thermal mechanisms

cavitation mechanismsnon-cavitation mechanisms

non-inertial cavitation inertial cavitationtemperature increase radiation force

energy absorption

ablation enhanced Delivery lithothripsy


Medical applicationsMedical applications

LithotrypsyPhysiotherapyHIFU Surgery (Tissue ablation)Blood-Brain-Barrier-OpeningCell sonoporation Targeted Cell sonoporationLocal drug activationVessel occlusionThrombolysisNerve activation / blockage

gdrug delivery


1880 1880 Piezoelectric effect (P. & J. Curie)Piezoelectric effect (P. & J. Curie)1918 1918 Sonar (Langevin)Sonar (Langevin)1927 1927 Effects on biological tissues (Looms, Wood)Effects on biological tissues (Looms, Wood)1942 1942 First HIFU lesions in animal brains (J.Lynn, T.Putnam)First HIFU lesions in animal brains (J.Lynn, T.Putnam)19501950––2000 2000 Pioneer work on (a) HIFU effects on tissue (brain Pioneer work on (a) HIFU effects on tissue (brain

tumors) and (b) LIU for soft tissue visualization (W Frytumors) and (b) LIU for soft tissue visualization (W Fry

Development of HIFU TechnologyDevelopment of HIFU Technology

tumors) and (b) LIU for soft tissue visualization (W.Fry tumors) and (b) LIU for soft tissue visualization (W.Fry & F.Fry).& F.Fry).

19511951––1960 1960 Technical development at MGH (Cosman)Technical development at MGH (Cosman)19511951––1967 1967 HIFU stereotactic neurosurgery against pain, psychoHIFU stereotactic neurosurgery against pain, psycho--

neuroses, anxiety, depression and epilepsy (Lindstrom) neuroses, anxiety, depression and epilepsy (Lindstrom) and Radiosurgery (Leksell) gamma knife and Radiosurgery (Leksell) gamma knife

Mid Mid 19701970ss First stereotactic HIFU brain surgery with open cranium First stereotactic HIFU brain surgery with open cranium (F.Fry & R.Heimburger).(F.Fry & R.Heimburger).


W.Fry, circa 1960, with 4W.Fry, circa 1960, with 4--beam HIFU system for neurobeam HIFU system for neuro--surgery in his surgery in his bioacoustics bioacoustics laboratory.laboratory.



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First US-image guided HIFU system to treat brain cancer patients.W.Fry in the 1970s

F.Fry and R.Heimburger 1974



Image guidanceImage guidance

US-ImagingCheapLimited feedback

MRMRExpensiveHigh-resolution imagingClosed loop process


Key technologies: Key technologies: 1.1. Phased array transducersPhased array transducers2.2. Acoustic field modellingAcoustic field modelling33. MR imaging for accurate real time monitoring. MR imaging for accurate real time monitoring

ll 990990 l d h d ( )l d h d ( )


Early Early 19901990s s Ultrasound phased arrays (Hynynen)Ultrasound phased arrays (Hynynen)MidMid––19901990s s MRI thermometry (Jolesz)MRI thermometry (Jolesz)20012001 First integrated MRgHIFU system (InSightec)First integrated MRgHIFU system (InSightec)20012001 Fibroadenoma of Breast and Uterine FibroidsFibroadenoma of Breast and Uterine Fibroids20042004 FDA approval for Uterine Fibroid ApplicationFDA approval for Uterine Fibroid Application……20082008 Functional NeurosurgeryFunctional Neurosurgery


HIFU Surgery for Uterine FibroidsHIFU Surgery for Uterine Fibroids


InSightec Exablate InSightec Exablate 20002000

InSightec Haifa, IsraelTechnology originally GE

FDA approvedFirst & only worldwide

GE MR-ScannersCa. 200 systems installed


Treatment process for Treatment process for Uterine FibroidsUterine Fibroids

benign (non-cancerous) tumors most common pelvic tumors in women20-40% in women of reproductive age Classical procedure: Hysterectomy


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Patient interfacePatient interfaceMR-coil

Patient

Transducer

Ultrasound

Coupling Target


TransducerTransducer16 element array

vertical electronic steeringfocal depth 12cm – 19cm

Mechanical positioning4 axesComputer controlled

MR-compatibleCeramic step motors


Safety checksSafety checks

Air bubbles?Metallic clips?Scars?Bowels?Bl dd ?Bladder?Nerves?


Treatment planningTreatment planning

Delineate region of treatmentSystem createstreatment planp(array of sonicationsto be done)Plan can be changed manuallyby operator


RealReal--time temperature monitoringtime temperature monitoringMR-ThermometryProton resonance frequency shift ~ TemperaturePhase difference ~ Temperature difference

1.1 seconds 4.5 seconds 7.9 seconds 11.3 seconds


Treatment assessmentTreatment assessment

Very good agreement

Blue dots = Cell ablation as calculated by thermal dose

Treatment control by contrast enhanced MR


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MRgFUS = Magnetic Resonance guidedFocused UltraSound

Closed loop controlClosed loop control

Planing Safetychecks

Real-TimeMonitoring

Assement

Closed LoopSlide credits: Beat Werner, Ernst Martin Slide credits: Beat Werner, Ernst Martin

Clinical applications and researchClinical applications and research

Brain Tumors

Breast Cancer

Brain Functional

Liver TumorsUterine Fibroids

Prostate

Bone Tumors


T1w contrast enhanced image before treatment

T2w planning

Uterine fibroidsUterine fibroids

Courtesy of Sheba Medical Center, Tel Aviv, Israel

T1w contrast enhanced image immediately post-treatment

T2w planning image with dose overlay


Treatment effects in canine prostate

Prostate Prostate

Thermal dose estimate

T1w contrast enhanced image imaging

TTC stained tissue

Courtesy InSightec Slide credits: Beat Werner, Ernst Martin

Liver tumors Liver tumors

Courtesy of St. Mary’s Hospital, London, UK

Sagittal, Axial and coronal post treatment dose maps (in blue) and post treatment T1W+C


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IDECaution-Investigational Device

Limited by United States Law to Investigational Use.

Breast Cancer Breast Cancer

Pre treatment T1w+C MIP image

2 weeks post treatment T1w+C MIP image

Courtesy of Breastopia Namba Hospital, Japan Slide credits: Beat Werner, Ernst Martin

10.0Screening

Bone tumors (Pain palliation) Bone tumors (Pain palliation)

1.5

7

0

1.5

00.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

9.0

0 10 20 30 40 50 60 70 80 90

Days post treatment

VAS

scor

e

ScreeningAverage

1 Month Follow Up

3 Months Follow Up

Courtesy InSightec Slide credits: Beat Werner, Ernst Martin

NonNon--invasive neuroinvasive neuro--surgery surgery in the MRin the MR--suitesuite

Skull: Anisotropic AberrationSkull: Anisotropic Aberration

Focused waves are distrorted after skull

Courtesy of ESPCI, Paris, F

Focused waves … … are distrorted after skull

Phase corrected waves … … are refocused after skull

InSightec ExAblate InSightec ExAblate 40004000FrontendAmplifier

3D-Positioner

InSightec ExAblate 4000 / 3.0T GE Signa HDxHemispheric 1024-element phased-array transducer (650kHz)

Transducer

(650kHz)Stereotactic frameWater cooling of skull surfaceCT-based acoustic modelingPRS-ThermometryInstallation June 2006

Degassed water used for acoustic coupling & coolingStereotactic frame for patient immobillization

PatientPatient InterfaceInterface

Sealing membraneSealing membraneTransducerTransducer

WaterWater Stereotactic frameStereotactic frame

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MRIMRI--HIFU ConsoleHIFU Console Clinical phase I studyClinical phase I studyCentro-Lateral Thalamotomy against chronic, therapy resistant, neuropathic pain

Established procedure: RF-ablationo minimally invasiveo n (pain) > 100 interventions

New procedure: Non-invasive TcMRgHIFUo Minimize intervention risks (Collateral

damage, infections, bleeding, tissue shift)

o Enhanced efficacy (no trajectory restrictions, anatomically adapted volume ablation, image guidance)

o Outpatient process

Bildfolge der Behandlung (sonication procedure)Bildfolge der Behandlung (sonication procedure)

X+20’: Stereotactic frame

Bildfolge der Behandlung (sonication procedure)Bildfolge der Behandlung (sonication procedure)

X+50: Positioning

X+1h20: Imaging X+3h: Verification sonications

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X+3h: Verification sonications X+4h: Ablation

Dosemap Dosemap 17 17 CEM CEM 4343°°CC

Dosemap Dosemap 240 240 CEM CEM 4343°°CC

X+6h: End of treatment

X+7h: Happy End

Patient #Patient #44immediately afterimmediately afterthe interventionthe intervention

Patient #Patient #2248 48 h afterh afterthe interventionthe intervention

Trigeminal neuralgiaTrigeminal neuralgia Chronic lumbar pain syndrome Chronic lumbar pain syndrome following disc hernia op Lfollowing disc hernia op L44/L/L5 5


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TT11WI + GdWI + Gd TT11WI + GdWI + Gd



DTIDTI DTIDTI

TumorvolumeTumorvolume

HIFUHIFU--AblationAblation

Combined Tumor therapy:Combined Tumor therapy:HIFUHIFU--Ablation & LIFU BBBDAblation & LIFU BBBD

McDannold et al. McDannold et al. Neurosurgery 2010 Neurosurgery 2010

BBBBBB--Opening with Low Intensity Opening with Low Intensity Focused Ultrasound (LIFU)Focused Ultrasound (LIFU)and Adjuvant Chemotherapyand Adjuvant Chemotherapy


Blood Brain BarrierBlood Brain BarrierBrain protected by BBB:

Structural and functional barrier in the vessel wallsControls transport and diffusion from the vasculature to the central nervous system Severely limits ability to deliver drugs to the brain


Reversible BBBReversible BBB--Disruption using Disruption using FUS and Microbubble UCAFUS and Microbubble UCA

MicrobubblesPhospholipid / Hexafluorid (2-4um)Commercial CE / FDA

Lipid monolayer

Reversible opening of BBB byCavitationShear stress (Acoustic streaming, radiation force, ...)Slide credits: Beat Werner, Ernst Martin

TcMRgFUS BBBTcMRgFUS BBB--DisruptionDisruptionUS freq. 220kHz – 1MHzAcc.Power < 1WSonication 10 – 200sDuty cycle 1%Tail vein injection

Inj.

Dru

g

Inj. Micro bubbles

MR

I

His

to

MR

I

Low Intensity US (Bursts of 10ms/1000ms)

MR-contrast agent / drugMicro bubbles

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TcMRgFUS BBBTcMRgFUS BBB--DisruptionDisruption

P iti MR C il

MR-Scanner: GE 3.0TTransducer: Imasonic (Aperture 8cm, f# 0.8)Microbubbles: Bracco

WatertankTransducer

Positioner MR-Coil

Mouse

TcMRgFUS BBBTcMRgFUS BBB--DisruptionDisruptionDuration

several hours

ApplicationNeuro-PhamacologyPhamacologyTumorsAlzheimerNeuron regeneration

Targeted Drug DeliveryTargeted Drug DeliveryTargeted Drug Delivery

Bubble constructsAdd specificityAdd payloadRemote activation

Targeted Drug DeliveryTargeted Drug DeliveryTarget specificCarries contrast agents (Dye, fluorescent, magnetic, ...)Carries drugsRemote activation

Targeted Drug DeliveryTargeted Drug DeliveryReleasing drug by Ultrasound

HeatCavitation

Gene DeliveryGene Delivery

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Gene Activation: hspGene Activation: hsp--8080


SummarySummaryImage guided FUS is a new modality for non-invasive interventions deep in soft tissueThermal ablation clinically establishedIntense research on treatment strategies based on mechanical effectsVery promising results in animal models for targetedVery promising results in animal models for targeted drug delivery based on transient BBBD / SonoporationIntense research on development of nano-constructs for imaging and therapy Clinical studies to come soon


Targeted Drug Delivery

In-vitro T2W MRI before [l] and after[r] sonication

Clot Lyses for StrokeNeurological Disorders

OutlookOutlook


Thank you !


Thank you for your attention!

Presentation credits:

Dr. András Jakab, M.D. Ph.D.Dr. Ervin Berényi, M.D. Ph.D.Dr. Miklós Emri (Nuclear Medicine Institute, UD)Prof. Ernst Martin – Uni. Zürich (Focused Ultrasound)Beat Werner – Uni. Zürich (Focused Ultrasound)

Documents

Week 4. Image guided therapies