Making Molecular Imaging Clea r Integrated high ... · Making Molecular Imaging Clea r Integrated...

Making Molecular Imaging Clear

Integrated high performance 4x4D imaging:SPECT, PET, Optical & X-ray CT

Why seeing more matters in molecular imaging

Why seeing more matters in molecular imaging

Seeing more by imaging less:With MILabs’ imaging platform, you can gain more by imaging less. The unique capabilities such as simultaneous multi-isotope PET and PET/SPECT acquisitions, high resolution theranostic a and b imaging, and optical tomography allow you to study different functions at the same time, under identical physiological and physical conditions.

Breakthrough translational image resolution:MILabs’ systems have the ability to image and quantitate smaller structures more than any other nuclear imaging system. Imaging with SPECT down to 0.15 mm and PET down to 0.6 mm resolution give you the power to image mice with unprecedented visual acuity. Moreover, it is the only PET that can image 124I at sub-mm resolution.

Higher sensitivity for 4D imaging applications:The high sensitivity of MILabs’ four imaging modalities enables obtaining multiple registered 4D live streaming image videos, showing e.g. fast beating mouse hearts, blood flow in organs and vessels, the uptake and wash-out of molecular tracers, the biodistribution of new disease markers and more.

Enhanced by diagnostic X-ray CT:MILabs’ integrated adaptive diagnostic CT, extends the role of CT beyond co-registration of hybrid images. With the finest resolution, the lowest dose, and fastest acquisitions in the industry, MILabs X-ray CT adds many new diagnostic capabilities to your molecular research and includes dual-gated, multi-energy, and dynamic contrast enhanced CT.

Image courtesy of Imanis Life Sciences

Cutting edge molecular imaging research demands cutting edge technology. At MILabs, we design products to make molecular and structural imaging clearer, sharper and more cost-effective. Through continuous innovation, we have now achieved a higher-order of multimodal imaging, called 4x4D imaging. Four modalities, each with four-dimensional tomographic imaging capabilities, will enable you to improve diagnostics and therapy development through analysis of complementary, data-rich, co-registered images. What’s more, each modality by itself will give you data beyond the capabilities of any other stand-alone system.

Value from innovation: 4x4D high-performance multimodal imaging

Table of contentsWhy seeing more matters in molecular imaging 2

MILabs’ 4x4D super-resolution multimodal imaging 4

Modular and upgradable systems 5

SPECT-CT 6

EXIRAD-3D: automated quantitative 3D autoradiography 8

Clinical SPECT for large animals 9

PET-CT 10

Simultaneous multi-isotope PET & SPECT: VECTor-CT 12

Optical imaging: bioluminescence, fluorescence, and Cherenkov 14

Optical fluorescence and bioluminescence tomography 16

Stand-alone or integrated X-ray CT 18

Animal handling 22

Fully integrated software platform 23

E-Class entry-level systems 24

Awards and partnerships 25

MILabs’ 4x4D super-resolution multimodal imaging

Large field-of-viewfull-ring stationary

PET- SPECT detectorsProprietary

collimation and magnification

High precision XYZ stage

Temperature controlled

animal cell with physiological monitoring

Optical imaging:bioluminescence,

fluorescence, Cherenkov & Optical Tomography

Proprietary user-friendly touchscreen image

acquisition

Low-dose diagnostic X-ray CT


• Integrated high performance PET/SPECT/CT• Best PET resolution: 18F at 0.6mm; 124I at 0.75mm• Best SPECT resolution: < 0.15 mm• Dynamic PET & SPECT:

< 1 s organ and < 8 s total body frame rate• Simultaneous multi-isotope PET and PET-SPECT• Radio-theranostics up to 1000 keV

• Integrated high performance SPECT/CT• Best SPECT resolution: < 0.15 mm • Dynamic SPECT: < 1 s organ and < 8 s total body frame rate• Ultra-low dose and quantitative SPECT• Easily upgradeable with full PET capabilities• High-energy SPECT

• Ultra-high resolution stand-alone or integrated CT• Unprecedented scanning speed: < 3.5 s total body

imaging at low dose down to < 2 mGy• Cardiac- and respiratory-gated 4D imaging

• Exclusive integrated Optical Imaging and high performance CT

• Bioluminescence, fluorescence, Cherenkov imaging• Optical Tomography

U-CT: diagnostic X-Ray CT

VECTor6CT: PET/SPECT/CT U-SPECT6CT

U-OI6CT

Modular and upgradable systems

MILabs’ systems have a modular set up where PET, SPECT, Optical or CT functionality can be delivered separately or in any combination. After initial installation, additional functionalities can be added to the platform.

CT

SPECT

Optical PET

CTCT

Optical

CT

SPEC

T

PET CT

CT

PET

Optic

al

SPECT

User adaptable: 15 possible platform configurations

CT

PET

SPECT CT

Optical

Example configurations:

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U-SPECT6CT

7 mm

U-SPECT Histology

U-SPECT Autoradiography

U-SPECT μCT

0.25 mm

Scientifically validated high-resolution SPECT performance

• Spatial Resolution: proven best in vivo SPECT resolution in the market: < 0.25 mm [1]. Enables quantifying dynamic processes in tiny sub-compartments of mouse organs and tumors in vivo.

• < 0.15 mm resolution: 3D Autorad option (see p. 8).

• Temporal resolution: proven best SPECT total body and organ time resolution (< 8 s and < 1 s respectively). Perfect for assessing fast pharmacokinetics.

• Sensitivity: proven best sensitivity allows for < 0.10

MBq (~3 μCi) total body SPECT and fast screening of tracers.

• Reliability: patented robust stationary SPECT detector design ensures unprecedented reliability, virtually no down time and very long system life.

• Energy range: 20-1000# keV for single and multitracer SPECT.

• Quantitation: unrivaled accuracy due to advanced

correction methods for scatter, attenuation and partial volume effects.

123I-FP-CIT DAT SPECT of mouse brain vs. autoradiography [3].

Cardiac perfusion SPECT vs. μCT shows a) left ventricle, b) right ventricle, and c) right atrium [4].

Quarter-mm resolution in vivo SPECT and high-resolution μCT [1].

U-SPECT accurately shows heterogeneous antibody distribu-tion within tumors [2].

Validation of image resolution of in vivo U-SPECT [1].

U-SPECT μCT

c

ba

c

ba

U-SPECT Reference

Unmatched SPECT performance

1. Quarter-mm resolution molecular mouse imaging with U-SPECT+, O. Ivashchenko et al., Mol. Imaging. 20142. 3D histological validation of high-resolution SPECT of antibody distributions within xenografts. W. Branderhorst, et al., J. Nucl. Med. 20143. Movies of dopamine transporter occupancy with ultra-high resolution focusing pinhole SPECT. B. Vastenhouw, et al., Mol Psychiatry 20074. Comparison of 4D-MicroSPECT and MicroCT for Murine Cardiac Function, N.T. Befera, C.T. Badea, G.A. Johnson, Mol. Imaging Biol. 2013# With VECTor upgrade

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for highly quantitative and ultra-fast dynamic imaging

Adaptive SPECT with proprietary multi-pinhole collimation

Different sizes of collimators are available: 3D Autorad, mouse, mouse/rat and Medium Size Animal (MSA) collimators.

Superior system performance for a wide range of applications is achieved through MILabs’ patented multi-pinhole collimators. A wide range of scientifically validated collimators is available to enable ultra-high resolution (< 0.15 mm) or ultra-sensitive (> 30000 cps/MBq) imaging, providing incredibly detailed, low dose or ultra-fast imaging.

Better than a quarter-mm resolution in vivo SPECT imaging [1].

Quarter-minute SPECT imaging combined with quarter MBq (< 7 mCi) enables fast 4D pharmacokinetic analysis [5] and whole-body quick and easy in vivo biodistribution analysis [6]

0 300 600 900 1200 1500 1800

10 mm

1 mm

Ultra-high resolution SPECT

Ultra-fast and ultra-low dose SPECT

Small specimen to larger animalsU-SPECT6 offers the highest commercially available resolution for small specimens up to medium-sized animals, showing mouse bone scans below 0.15 mm and rabbit kidney scans at 2 mm resolutions [7].

5. Whole-body sub-half-minute 4D pharmacokinetic SPECT in mice, R. Ramakers et al., J. Nucl. Med. 20136. Ultra-High-Sensitivity Submillimeter Mouse SPECT, O. Ivashchenko et al., J. Nucl. Med. 20157. High-resolution medium-sized animal multi-pinhole SPECT with stationary detectors, F. van der Have et al., EANM 2014

EXIRAD-3D SPECTRabbitSPECT

Mouse99mTc-HDP

0.25 MBq

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EXIRAD-3D SPECT/CT

By scanning cryo-cooled tissue samples, such as complete organs, with a dedicated super-resolution SPECT option, researchers can finally eliminate many tedious, time-consuming, and error-prone steps from quantitative 3D autoradiography. Thanks to excellent energy resolving capabilities of the detectors, one can scan multiple isotopes at the same time to image 3D distributions of different molecules simultaneously, with < 0.15 mm resolution.

Mouse knee imaged with super-resolution 99mTc-MDP SPECT (left) and 99mTc-MDP SPECT/CT (right) with high definition X-ray CT. These extreme resolution SPECT and CT capabilities enable studying the spatial distribution of a selected function marker and relate this one-to-one to anatomical microstructures imaged in 3D.

EXIRAD-3D multi-isotope autoradiography is fast, saves tremendous amounts of labor, and reduces costs. And best of all, results are truly quantitative. On your image analysis workstation, undistorted quantitative EXIRAD-3D images can be re-sliced in any direction over and over, and can be perfectly overlaid with automatically registered ultra-high resolution CT images obtained in the same multi-modal acquisition or with other 3D images of the specimen. With EXIRAD-3D, MILabs’ U-SPECT6CT and VECTor6CT systems offer a unique single-system solution to translate research results from ex vivo to in vivo analysis and vice-versa.

EXIRAD-3D SPECT

EXIRAD-3D SPECT 1 mm1 mm

Cryo-microtome Microtome slicing Autoradiography slicesManually co-

registered stack of autoradiographs

EXIRAD-3D Automated 3D Autoradiography

Reconstructed quantitative

3D Autorad imageEXIRAD-3D sample holder with cryo-cooling

Automated quantitative 3D autoradiography

OldNew

Making Molecular Imaging ClearClinical G-SPECT* for large animalsGyro-free SPECT; from mouse to man

Unmatched SPECT performance

• Stunning image quality: with a ten-fold volumetric resolution improvement over current state-of-the-art large animal and clinical SPECT [8], G-SPECT outperforms dedicated PET systems for organ-specific imaging.

• Adaptive SPECT: user-exchangeable collimators allow for adapdation of resolution to any animal size to facilitate translation from mouse to large animal to humans without any information loss.

• Slash costs: thanks to the breakthrough full-ring, gyro-free, detector technology, G-SPECT can cut down tracer dose with a factor of ten without affecting image quality.

• Extra insight with dynamic SPECT: the high sensitivity of G-SPECT and the absence of detector rotation, enables truly dynamic determination of tracer uptake.

• Reliable and stable: no wear-and-tear from rotating detectors and no instability or calibration problems caused by positioning inaccuracies.

• List-mode acquisitions: eliminate rescans caused by movement by retrospectively deleting the list data portion subject to motion

Clearer images at reduced doses

*Clinical availability depends on final local registrations, including FDA and CE clearance.

8. G-SPECT-I: a full ring high sensitivity and ultra-fast clinical molecular imaging system with <3 mm resolution. Beekman F.J. et al. Eur J Nucl Med Mol Imaging. 2015;42 Suppl 1:S209

The award-winning large animal G-SPECT’s design is based on the same proven gyro-free technology used in U-SPECT6. The result is a robust, fast, and cost-effective solution with unprecedented image quality for scanning large animals and humans.

0.03 kg 0.3 kg 3.0 kg 5.5 kg 20-100 kg 70-150 kg

Current, state-of-the-art clinical SPECT systems

Gyro-free, MILabs G-SPECT system

7 mm

2.5

mm

MILabs offers gyro-free SPECT for any size animal

G-SPECT: Hoffman Brain phantom image details.

U-PET6CTUniform super-resolution PET with improved S/N

• Resolution: uniform spatial resolution down to 0.6 mm for 18F and 0.75 mm for 124I, unrivaled by any other preclinical PET system [9].

• Molecular sensitivity: with excellent molecular sensitivity [9] and superior spatial resolution, U-PET’s patented Adaptive Stationary Clustered Pinhole PET (SCP-PET) outperforms other preclinical PET designs for a wide range of preclinical imaging applications [10,11].

• Dynamic PET: excellent organ- or tissue-specific (< 1 s) and whole-body time resolution (< 8 s) with uniform resolution and S/N across the full selected region of interest.

• Sub-mm at all energies*: unique sub-mm imaging for high energy isotopes including radio-therapeutic isotopes, e.g. < 0.55 mm for 131I [11], < 0.7 mm for 213Bi [12] and < 0.85 mm for 211Rn/211At/ 209At [18].

• Extended application range: with sub-mm resolution and improved S/N characteristics, U-PET6 enables accurate quantitation at the organ substructure level in mice and rats. Performance will not be affected by co-injected SPECT tracers, enabling applications beyond the capabilities of conventional coincidence-based PET systems [14].

Simultaneous multi-isotope PET & 124I without positron range blurring

Unmatched PET performance

9. VECTor: A Pre-clinical Imaging System for Simultaneous Sub-mm SPECT-PET, M C. Goorden, et al., J. Nucl. Med., 201310. Craig S. Levin. New Imaging Technologies to Enhance the Molecular Sensitivity of Positron Emission Tomography. Proceeding of the IEEE, Vol. 96, 0018-921911. Performance Assessment of a Preclinical PET Scanner with Pinhole Collimation by Comparison to a Coincidence-Based Small-Animal PET Scanner, M.D. Walker, et al., J. Nucl. Med. 201412. High-resolution Clustered-Pinhole 131Iodine SPECT Imaging in Mice, F. van der Have et al., Nucl. Med. Biol. 201613. Utilizing High-Energy γ-Photons for High-Resolution 213Bi SPECT in Mice, J. de Swart et al., J. Nucl. Med. 201614. Performance Characteristics of a Novel Clustered Multi-pinhole Technology for Simultaneous High-resolution SPECT/PET, K. Miwa et al., Ann. of Nucl. Med. 201515. 18F-Trifluoromethylation of Unmodified Peptides with 5-18F- (Trifluoromethyl)dibenzothiophenium Trifluoromethanesulfonate, S. Verhoog et al., J Am Chem Soc. 201816. 18F-FDG as an inflammation biomarker for imaging dengue virus infection and treatment response, A. Chacko et al., JCI Insight 2017* With VECTor upgrade

The excellent performance of Adaptive PET is further illustrated by the ability to image 124I without positron range blurring at 0.75mm resolution, and to perform simultaneous dual tracer 18F/124I imaging. Now you can exploit the long half-life of an easy-to-label PET isotope for immunoPET, neurology and other studies.

Culmination of years of research on improving preclinical PET

1. S. Cherry et al, UC Davis, 2003; 2. R.E. Schmitz et al, University of Washington, 2007; 3. Y.C. Tai et al, University of Washington, 2008; 4. J. Zhou et al (S. Cherry group), UC Davis, 2011; 5. S.D. Metzler et al, University of Pennsylvania, 2013; 6. D. Brasse et al, Siemens Healthcare, 2014; 7. M. Goorden et al, MILabs, 2015.

1241 resolution improvement by using Adaptive PET rather than coincidence-based PET (left picture) and simultaneous dual-istope acquisitions of 18F and 124I (right picture) .

0,75 mm + 0,75

mm

18F 124I

>3.0 mm

0,75 mm

124ICoincidence PET

124IVECTor6 PET

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Why Adaptive SCP-PET outperforms coincidence-based PET

Adaptive PET offers many unique advantages over coincidence PET

System capabilities AdaptiveSCP-PET

CoincidencePET

Elimination of randoms x

Low scatter noise x

Uniform sensitivity x

Linear dose response ++ --

Demagnification of blurring x

Elimination non-collinearity x

Uniform sub-mm resolution x

Energy resolution ++ (8%) -- (>20%)

Eliminate positron range 124I x

Radiotherapy imaging x

Simultaneous 18F/124I x

Simultaneous PET/SPECT x

By eliminating random and scatter coincidence noise, Adaptive SCP-PET significantly improves both S/N ratio and count-rate linearity (or Noise Equivalent Count Rate - NECR) [14].

Resolution at physical PET limits Improved S/N in small structures

MILabs’ Adaptive SCP-PET collimation introduces the geometric considerations and the associated magnification advantages of physical collimation into PET, rather than the fixed geometry of coincidence-based collimation.This approach eliminates resolution degradation by the non-collinearity of dual-photon coincidence detection and enables the use of strong magnification. The spatial resolution of the detection system is therefore dramatically improved by demagnifying the effects of light spreading due to depth-of-interaction (DOI) effects. As a result, the 0.6 mm 18F PET resolution of MILabs’ PET systems approaches the physical limits for small-bore PET scanners set by positron range.

Physical rather than electronic coincidence-based collimation, can reduce sensitivity loss due to coincidence noise. While collimation always results in certain loss of detected photons, physical collimation yields a system with favorable S/N characteristics. Noise sources random and scatter coincidences are virtually eliminated. Moreover, low S/N characteristics are applied to smaller resolution cells, thus yielding improved detection sensitivities for small structures.

Activity (MBq)

Rat

e (c

ount

s/s)

x 1

0 fo

r SC

P-PE

T

0 10 20 30 40 50

1000k

800k

600k

400k

200k

18F-FDG PET/CT dynamic evolution of inflammatory foci for imaging dengue virus infection and treatment response [16].

18F-NaF images of a phantom and a mouse (image courtesy NIRS-Japan).

Dynamic low dose whole-body PET

Whole-body low-dose dynamic PET imaging of 18F-RGD [15] on the left, and 89Zr-RGD peptide imaging on the right (image courtesy of University of Saskatchewan).

0.6 mm

PET & SPECT: VECTor6CTSimultaneous multi-isotope PET and SPECT imaging

• Unmatched PET/SPECT/CT performance: sub-mm PET and SPECT resolution even when imaged simultaneously in space and time. Anatomical co-registration with fast, ultra-high resolution, low-dose X-ray CT.

• Exclusive spatial and temporal co-registration of PET and SPECT images. Sub-mm imaging of co-injected PET and SPECT tracers enables exploring different physiological and molecular functions at the same time, under identical physiological and physical conditions. Allows to switch between SPECT- and PET-based approaches at any time.

• Unmatched molecular sensitivity for PET and SPECT imaging enables targeting specific biological processes with low-dose PET and/or SPECT tracers.

• Dynamic PET and SPECT: excellent whole-body (< 8 s) and organ (< 1 s) time resolution.

• Advanced theranostics applications: the ability to image all high-energy isotopes at sub-mm resolution including radiotherapeutic Auger e-, a-emitters, and b-emitters such as 131I [12], 188Re [17], 213Bi [13], 209At [18] and 225Ac [19] can be combined with simultaneous imaging of their therapeutic effect using almost any other PET or SPECT tracer.

VECTor: 18F-NaF PET and 99mTc-HDP SPECT co-registered in time and space obtained in a single mouse scan.

Simultaneous PET/SPECT of co-injected tracers

PET SPECT

The only system with true tri-modality imaging capabilities

Multi-isotope, simultaneous SPECT and PET imaging [20].

With VECTor6CT, you can investigate virtually any radiotherapy or theranostic isotope, even those with high energies, at sub-mm resolution

99mTc-HDP111In-pentetreotide123I-NaI

18F-FDG

Radiotherapy and theranostics

3 mm

188Re 131I

213Bi213Bi 209At

0.55 mm 0.50 mm

0.70 mm 0.85 mm


17. 188Re image performance assessment using small animal multi-pinhole SPECT/PET/CT system, P. L. Esquinas et al., Physica Medica, 201718. Evaluation of 209At as a theranostic isotope for 211At-radiopharmaceutical development using high-energy SPECT, JR Crawford et al., Phys. Med. Biol., 201819. Multi-isotope SPECT imaging of the 225Ac decay chain: feasibility studies, A. Robertson et al. Phys Med Biol, 201720. Integration of Small Animal SPECT and PET with Other Imaging Modalities, P.E.B. Vaissier et al., TvNG 201321. 99mTc-Duramycin SPECT imaging of early tumor response to targeted therapy: a comparison with 18F-FDG PET, F. Elvas et al., Journal of Nuclear Medicine, November 201622. In Vivo Simultaneous Imaging of Vascular Pool and Hypoxia with a HT-29 Tumor Model: the Application of Dual-Isotope SPECT/PET/CT, N. Adachi et al., IJSBAR 2016

Multiple tracers with spatial and temporal co-registration

VECTor6CT extends nuclear imaging applications beyond the capabilities of any other preclinical system• Theranostics: high-energy SPECT with PET/SPECT

treatment follow-up [11, 12].

• Comparing immuno-PET (e.g. 89Zr) and immuno-SPECT (e.g. 111In).

• DAT-SPECT and FDG-PET to differentiate typical from atypical parkinsonian syndromes.

• Combined PET/SPECT monitoring of pharmacokinetics and treatment response (e.g. using 99mTc-Duramycin or 18F-FDG) [21].

• Simultaneous 124I-immunoPET and tumor 18F-FDG/FLT scans

• Simultaneous perfusion and metabolism imaging to enhance the diagnostic value of cardiac imaging.

• Alzheimer imaging: SPECT (e.g. 99mTc-HMPAO) with PET (e.g. 11C-PIB).

• Simultaneous vascularity (99mTc-HSA) and hypoxia (64Cu-ATSM) imaging in tumors [22].

• Single scan comparisons of “identical” SPECT and PET tracers: e.g. labeled with 67Ga vs 68Ga, 125I/123I/131I vs 124I, 111In vs 64Cu

• Comparing long-lived 124I to short-lived 18F tracers using both spatial and temporal coregistration.

PET SPECT

18F-FDG PET 123I-FP-CIT

Brain

Gated cardiac

Spine

Wholebody

Tumor

Intravenous co-injection

of PET and SPECT tracers

PET

SPECT

18F-FDG PET

99mTc- Tetrofosmin

99mTc-HDP

111In-pentetreotide

123I-NaI

18F-FDG

SPECTPET

18F-NaF 99mTc-HDPTherapy response

PETSPECT

99mTc-Duramycin 18F-FDG

Pre- and post-therapy Pre- and post-therapy

0,75 mm

18F 124I

+ 0,75 mm

Optical imaging: bioluminescence, fluorescence,

Unmatched OI versatility

The next step in hybrid Optical Imaging with U-OI

Advancing the translation of optical imaging agents into the clinic

Since the U-OI wavelength range covers Cherenkov Luminescence (CL) or Secondary Cherenkov-induced Fluorescence Imaging (SCIFI), the system can be used to image radionuclides that emit charged particles such as b−. This ability further complements the theranostic applications of VECTor6 by enabling 90Y radiotherapy imaging.

• Industry-leading optical camera embedded on a multi-modal platform: the U-OI system features a proprietary large area sensor with multi-stage thermo-electric cooling, enabling the camera to operate at an unprecedented -100°C without the aggravation of liquid nitrogen or compressed gas cooling. This no-compromise optical design delivers exceptional sensitivity for imaging optical probes, both in stand-alone and multi-modal configuration.

• Suited for optical reporters across the blue to near infrared wavelength region: the U-OI system uses a computer-controlled filter wheel with narrow band-pass emission filters for multi-spectral bioluminescence and fluorescence imaging. In fluorescence mode, a broadband halogen light source is filtered by a set of computer-controlled narrow band-pass excitation filters.

• Automated single-pass U-OI/CT imaging: by mounting the U-OI system on an industry-leading stage for in vivo animal imaging including temperature and anesthesia control, the system offers flexible and sensitive optical multi-modal preclinical imaging capabilities with a one-step operation and automated co-registration of images. Multispectral OI/CT images of up to three mice at once can be obtained in a single system pass.

U-OI can scan up to five mice in a single system pass in the standalone system, three in the integrated system, and can also scan 96-well plates and microscopy slides. It is upgradable to U-OI/CT and 3D fluorescence and bioluminescence tomography (FLT/CT and BLT/CT).

By acquiring images with multiple narrow-band excitation and emission filters, the acquired spectra of multiple probes can be unmixed using the spectral unmixing feature of MILabs’ optional Imalytics Software.

• Automated U-OI/CT/PET/SPECT imaging: the U-OI system can also be offered as an upgrade to MILabs’ PET/SPECT/CT system and includes fluorescence, bioluminescence, and Cherenkov imaging. Now you can translate your in vitro and ex vivo research to in vivo using the VECTor6 system with fused optical and complete nuclear capabilities (PET and SPECT).

96-well plate 5-mouse holder

Spectral Unmixing


Example of complementary registered bioluminescent, fluorescent, and nuclear images in one scanning session with a single dose of anesthesia [23].

23. U-SPECT-BioFluo: An Integrated Radionuclide, Bioluminescence, and Fluorescence Imaging Platform. M.N. van Oosterom, EJNMMI Research, 2014

Bioluminescence60 s

Fluorescence300 ms

SPECT MIP30 min

Improving OI translational power with single-pass multi-modal imaging

In a single scanning session, and with a single dose of anesthesia, VECTor6OI/CT enables complementary registration of bioluminescent, fluorescent, CT, PET, and SPECT images.

A scalable Optical Imaging platform

Enhancing OI with diagnostic CT

As the only optical imaging system with an integrated CT with diagnostic capabilities, VECTor6 enables to:

• Include spatial priors from X-ray CT to significantly improve the reconstructed image quality of multi-spectral bioluminescence measurements.

• Use DCE-CT to determine whether light intensity changes in tumors are actually due to treatment effects or caused by acute hypoxia due to rapid growth or inadequate blood supply.

and Cherenkov

Optical tomography: Fluorescence (FLT/CT) andA breakthrough in hybrid Optical/CT tomography

The powerful combination of two industry-leading modalities with the best image analysis and segmentation software (Imalytics Preclinical [24]) enables quantitative optical tomography imaging with fluorescence and bioluminescence.

Hybrid FLT/CT goes beyond the capabilities of standalone FLT (also called Fluorescence Molecular Tomography, FMT) by using the heterogeneous optical absorption and scattering maps of the animal for improved fluorescence reconstruction [27].

Hybrid FLT/CT

24. Imalytics Preclinical: Interactive Analysis of Biomedical Volume Data, F. Gremse et al.,Theranostics 2016, Vol. 6, Issue 325. Method for reconstructing the image of an object scanned with a laser imaging apparatus, Rohler et al., US patent 6,130,958; Oct.10,200026. Non-Invasive Optical Imaging of Nanomedicine Biodistribution, Sijumon Kunjachan, Felix Gremse et al., ACS Nano. 2013 Jan 22; 7(1): 252–262.27. Spectrally resolved bioluminescence optical tomography, H. Dehghani et al., Optics Letters Vol. 31, Issue 3, pp. 365-367 (2006)

Hybrid BLT/CT uses the same 3D bioluminescent lightcorrection approach as FLT by using segmented CTpriors, but reconstructs the initial 3D BLT image byimaging bioluminescence at multiple wavelenghts [26].

Hybrid BLT/CT

Absorption + fluorescence emission images

FLT CT

CT priors

HybridFLT/CT

DiagnosticX-ray CT

with or without contrast agent

CT image priors (e.g. body shape, lung, bone, fat) are segmented based on X-ray CT data and used for improved FLT reconstruction. Additional segmentations (e.g. kidneys, liver, and tumor) can be performed interactively for quantification [24,25].

Ultra-sensitive Optical

Imaging with optional NIR

laser scanning for FLT

Making Molecular Imaging ClearBioluminescence (BLT/CT) in 3D/4DQuantitative Optical Tomography that rivals PET/SPECT

Why hybrid FLT/CT is superior?Light scattering and absorption are heterogeneous in the body of an animal. These light characteristics depend on the “darkness” of the organ/tissue from where the optical probe emits light. As illustrated below, accurate optical tomography is not possible without correcting for these heterogeneities.

These images and graphical results illustrate the erroneous reconstruction results of simple fused FLT/CT (or FMT/CT) imaging. Simple co-registration of FLT images with CT does not take into account the heterogeneous light absorption within the animal tissues (left images). The images on the right and data results below illustrate the substantial underestimation of fluorescence intensity in the so-called dark organs: heart, liver and kidneys (orange arrows) [28].

Conc

entra

tion

[nM

]

100

0

200

300

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Heart Liver Kidney Muscle Tumor

Homogeneous absorption

Heterogeneous absorption

Imalytics Preclinical segmentationand analysis softwareImalytics Preclinical [24] image segmentation software is excellent for preclinical applications. Results have been published in numerous peer-reviewed articles for:• Organ segmentation for biodistribution studies• Bone segmentation and labeling• Segmentation of blood vessels• Fat segmentation (visceral and sub-cutaneous)• Hybrid FLT/CT & BLT/CT analysis and renderings

Hybrid FLT/CT versus PET/MRIHybrid FLT/CT and PET/MRI images and analyses show the biodistribution in separate cohorts of nude mice bearing subcutaneous tumors, two hours post injection of anti-EGFR compounds. In vivo analyses correlated well with ex vivo quantitation for both modalities [29].

Homogeneousabsorption

Heterogeneous absorption

28. Absorption reconstruction improves biodistribution of fluorescent nanoprobes using hybrid fluorescence tomography, F. Gremse et al., Theranostics 2014.29. Comparison of the accuracy of FMT/CT and PET/MRI for the assessment of antibody biodistribution in squamous cell carcinoma xenografts, C. Hage et al., J Nucl Med, 2017

FLT/CT

PET/MRI

Alexa750-labeled anti-EGFR antibody [29].

64Cu-NODAGA-labeled anti-EGFR antibody [29].

MILabs U-OI features OI Hybrid OI/CT2D bioluminescence, fluor-esscence, and Cherenkov imaging

Maximum number of animals 5 3

96-well plate imaging

Spectral unmixing Optional* Optional*

In-line X-ray CT Optional

3D FLT/CT and BLT/CT N/A Optional*

Imalytics Preclinical Optional Optional* Requires Imalytics Preclinical software

U-CT: stand-alone or integrated X-ray CTThe only CT system that will fit your needs - Today, tomorrow

Industry-leading 3D/4D adaptive X-ray CT

MILabs’ U-CT is extremely fast and offers ultra-high resolution at low X-ray doses enabling demanding multispecies 3D/4D in vivo applications, including dynamic contrast-enhanced (DCE) CT imaging.

Many steps ahead in preclinical CT: • Stand-alone or integrated CT, field-upgradable

with SPECT, PET, and 2D/3D Optical imaging• With variable isotropic voxel resolution down to

2.5 μm, the U-CT system is also suited for ex vivo applications

• Ultra-fast whole body scanning down to 3.5 s• Ultra-low dose, down to 2 mGy whole-body mouse

Cardiac- and respiratory-gated CT

Unique DCE-CT & PET/SPECT/CT

From small specimen to larger animalsMILab's U-CT is a true multispecies microCT system capable of imaging ex vivo specimen as well as a range of in vivo animals. The FOV is large enough to image entire mice, rats and optionally, ferrets and rabbits.

With fast, high-resolution, and optional dual-energy acquisitions, U-CT is uniquely suited for diagnostic DCE-CT applications. Moreover, MILabs' unique attenuation correction enables hybrid PET/SPECT/CT imaging, even for gated acquisitions [30].

Accurate CT reconstruction in cardiac and respiratory research requires motion elimination from the heart and diaphragm. U-CT uses dual-gated acquisitions and freeze-frame to avoid image blurring.

Respiratory- and cardiac-gated “freeze-frame” image.

DCE-CT* of tumor vasculature [31]. U-PET/CT 18F-FDG and Exitron

Virtual lung endoscopy of a ferret.

Dos

e (m

Gy)

Noise (HU)

201816141210

86420

0 10 20 30 40 50

Unrivaled in vivo dose efficiencyInverse-square dose-to-noise relationship

By combining cutting-edge CMOS technology with a thick scintillation layer and on-the-fly readout, U-CT sets new low-dose benchmarks without compromising image quality.

U-CT

Conventional microCT


and beyond...

U-CT image of mouse brain vasculature* Detailed image mouse eye*In vivo mouse knee

MILabs’ U-CT system will adapt to your applications so you don’t have to adapt your research. Why invest in multiple systems for speed and resolution, for in vivo and ex vivo applications, or for molecular CT with SPECT, PET or OI, if you can start your research with a single U-CT today and expand by adding modalities over time?

Autonomous X-ray CT gantry, the key reason for maintaining

true diagnostic CT performance on a scalable multimodal platform

Molecular CTw/SPECT, PET, OI

Mice, Rats & RabbitsPlus Exirad-3D specimen

Ultra-High Resolution2.5 micron voxel size

Fast ScanningWhole-body in 3.5 s

Low Dose< 2 mGy whole-body

Whole-body mouse*

*Imaged using ExiTron nano 12000 – nanoPET Pharma GmbH.

Dual-gated cardiac CT*

30. Oral contrast enhances the SPECT/CT resolution of in-life NIS reporter gene imaging, L. Suksanpaisan et al, Mayo Clinic, Cancer Gene Therapy, Nature Publishing 201331. Courtesy of Dr. Sean Smart and Dr. Veerle Kersemans, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford

U-SPECT/CTIn vivo mouse knee

U-CTIn vivo mouse spine

U-CTIn vivo mouse chest

U-CTIn civo cardiac/gated mouse*

HLA

VLA

SA

End diastole End systole

U-CTIn vivo mouse

U-CT: X-ray CT beyond the application capabilitiesBest resolution, highest speed, and lowest dose for in vivo imaging, plus scaleable to image small specimen as well as larger animals including rabbits. In addition, upgradable with in-line OI and/or PET and SPECT plus the unique ability to handle DCE-CT and attenuation-corrected PET/CT and SPECT/CT, including gated multi-modality acquisitions. The system allows for dual-gated cardiac- and respiratory imaging with freeze-frame acquisitions and is equipped with an on-screen dose estimator. Add to this the flexibility to tailor configurations to your research needs and you will agree that there are no other X-ray CT systems that can bring as much diagnostic CT power to your preclinical imaging applications.


X-Ray CT system/module Standard HR UHR XUHRSmallest isotropic voxel size 30 μm 10 μm 4 μm 2.5 μmFocal spot size 25 μm 25 μm 7 μm 7 μmTotal body mouse scanning time < 5 s < 5 s < 3.5 s < 3.5 sTotal body mouse dose < 5 mGy < 5 mGy < 2 mGy < 2 mGyMaximum field of view (FOV) Ø 75 mm Ø 75 mm Ø 75 mm Ø 75 mmFocused scanning Focused scanning in ex vivo specimen holder Circular and helical scanning Mouse Rat Medium sized animal (FOV Ø 130 mm) Optional Optional Optional OptionalDual-energy CT Optional Optional Optional OptionalDynamic (multi-frame) imaging Optional Optional Optional OptionalRespiratory and cardiac gating Optional Optional Optional Optional

MILabs’ images are fully compatible with existing software based on international image format standards and work seamlessly with post-processing image analysis software packages such as PMOD, Imalytics, InviCRO, Amira, ImageJ, and OsiriX. In vivo images acquired by U-CT can be analyzed and quantified in high detail using the user’s favored software. For example, bone parameters like trabecular thickness and structure model index can be easily extracted. Additionally, images can be exported to STL file format for detailed surface rendering and analysis while all packages allow advanced image visualization in 2D, 3D, and even 4D.

32 Sample courtesy of Prof. A.J. Sinusas, MD and Zhenwu Zhuang, MD, MS, Yale School of Medicine, USA33. Samples courtesy of Prof. R. Jayakumar, Amrita Center for Nanosciences and Molecular Medicine, India

Mouse heart perfused with radiopaque contrast agent [32]

U-CT rat knee

Stainless steel implant rat femoral bone [33]Bone regeneration in rat cranial vault [22]

Mouse mandible

Mouse knee

of other preclinical CT systems

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An integrated system is available for animal monitoring, automatic animal temperature regulation, and multiple physiological event triggering. This enables flexible triggering, e.g. combined respiratory and cardiac gating.

AnesthesiaAnimals can be anesthetized with the optional Univentor gas anesthesia system with built-in vaporizer and flow meter. Precise automatic control of anesthetic and air minimizes anesthetic consumption.

Animal handling

MILabs’ transparent animal imaging beds can be easily converted to closed imaging U-cells™ for pathogen-free imaging. They are equipped with anesthesia cones and heater pads for optimal animal comfort. The beds can easily be mounted onto, and removed from MILabs’ systems and also facilitate smooth transfer to other modalities such as MRI. The beds allow for open access to the animal during acquisition or can be closed. There is continuous visual monitoring of the animal by four optical cameras. Custom beds are available upon request.

Gating, heating and monitoring

Animal beds and cells

Docking station

Animals can easily be positioned, injected and prepared using movable docking stations. These can be used either on the bench or inside a fume-hood.

Dedicated animal cells and monitoring systems

Medium size animal bed for animals up to 5 kg.

Rat bed with anesthesia nose cone, heating and gating connections.

Multi-mouse bed, for scanning 2, 3 or 4 animals simultaneous.

U-cell™ providing closed environment, suited for immuno-compromised or contagious mice.

Mouse bed optimized for comfort, reproducibility, and reliability.

Ferret bed with anesthesia nose cone, heating and gating connections.

Holder for stand-alone OI and hybrid OI/CT (max. three mice).

Plate/slide holder Multi-mouse holders

Animal holders for hybrid FLT/CT and BLT/CT imaging.

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Image acquisition, reconstruction, and visualization

Fully integrated software platform

34. Targeted Multi-pinhole SPECT. W. Branderhorst, B., et al., Eur J Nucl Med Mol Imaging, 201135. Pixel-based Subsets for Rapid Multi-pinhole SPECT Reconstruction. W. Branderhorst, et al., Phys Med Biol., 201036. Similarity-regulation of OS-EM for accelerated SPECT reconstruction P. Vaissier, et al., Phys Med Biol. 2016

Visualization, analysis and storage

An enterprise-wide license for the visualization and analysis software platform comes with every system installation. Image data storage and handling is in full accordance with the latest DICOM standard. Other data formats include BMP, TIFF, JPG, AVI, and NIFTI which makes import into image analysis software packages such as Imalytics Preclinical, PMOD, InviCRO-VivoQuant, Amira, ImageJ, OsiriX and MILabs’ BoneJ analysis software easy.

MILabs’ systems are provided with advanced proprietary acquisition, reconstruction, fusion, and analysis software. The software is intuitive and extremely user-friendly, so imaging with MILabs´s systems can typically be mastered by a technician or a student in a single day.

GUI-based list-mode acquisitionsThe patented acquisition graphical user interface (GUI) is displayed on a touch screen. Unique interactive sliders enable easy and accurate selection of the field-of-view in three orthogonal directions. The scan volume is selected from either three X-ray or optical camera views and helps improve signal strength from the tissues of interest [34]. True List Mode (TLM) acquisitions facilitate quantitative multi-isotope imaging with a virtually unlimited number of energy windows. With the VECTor6CT, a PET isotope can easily be imaged simultaneously with a combination of several different SPECT isotopes. Furthermore, with TLM, background windows can be defined retrospectively to accurately correct for scatter and spill-over effects, and stored accumulated counts can be fractioned to study the effect on image quality, thus enabling dose planning without rescanning.

Novel reconstruction algorithms such as model based ML-EM, OS-EM, Pixel-based OS-EM (P-OS-EM) [35] or statistically regulated OS-EM (SR-OS-EM) [36] are used for SPECT and PET reconstruction. These reconstruction algorithms are up to 30 times faster than traditional OS-EM while accuracy is improved [36].

Reconstruction software

Exclusive True List Mode acquisition facilitates quantitative multi-isotope imaging and dose-planning.

Field-of-view selection from total body and organs using optical and/or X-ray CT images exploits MILabs´ fast-focused 3D acquisition [34].

MILabs´ SR-OS-EM [36] provides fast high-fidelity image reconstruction

Fast &Accurate

MILabs’SR-OS-EM

FastInaccurate

TraditionalOS-EM

SlowAccurate

ML-EM

Imalytics Preclinical [24] software for hybrid FLT/CT and BLT/CT. From left to right: biodistribution, bone segmentation, vessel segmentation, tumor vascularity, and fat segmentation.

E-Class preclinical imaging sytems

Built to meet the future needs of researchers, MILabs has designed economical, high-performance, integrated, and expandable PET, SPECT & CT systems. Using the same proven technology as the industry-leading VECTor, these systems were refined to be more cost-efficient with easy scalability and re-designed for researchers with a limited budget to start now and upgrade later.

The result is: E-Class.

Start small, think big, scale fast

PET• 0.75 mm resolution 18F and 124I• Best image contrast ratio• Mice and rats• Static and dynamic PET• Simultaneous multi-isotope PET• Simultaneous PET/SPECT*

SPECT• Sub-0.5 mm resolution• Superb sensitivity• Static and dynamic SPECT• Mice, rats and small rabbits• 3D auto-radiography*• α & β radiotherapy*

CT• 30 μm voxel resolution• 5 sec whole-body mouse• < 5 mGy whole-body mouse• Mice and rats• Dual-gated acquisitions*• Dual-energy and DCE-CT*

Economical: You can start small in preclinical imaging as long as your system enables you to do big things. No matter what modality, PET, SPECT or CT, your entry-level MILabs E-Class imaging system will keep costs low and image quality high.

Exceptional: You can expect no less from MILabs, a combination of exceptional performance and outstanding utility: SPECT and PET at sub-mm resolution, and ultra-fast X-ray CT at low dose levels.

Expandable: Start small, think big, scale fast. Not by adding more imaging systems, but by upgrading your entry-level system to 4x4D omni-tomography (including optical) without animal shuttling.

Essential: Exclusive capabilities to expand your diagnostic and therapeutic research including; single-pass simultaneous PET and SPECT, dynamic CT, fluorescence & bioluminescence, and exclusive theranostic imaging with α & β radiotherapy.

Evidence-based performance and application reach. Based on technology proven in over 100 global installations for preclinical applications documented in hundreds of peer-reviewed publications.

Easy-to-use: Master acquisition & reconstruction in one day.

*denotes options

Optical Imaging*

All specifications are subject to change without notice. June 2018 MILabs B.V. The Netherlands 51000-05.10

Heidelberglaan 100, STR 4.205 3584 CX Utrecht The NetherlandsPhone: +31 88 756 5343 Fax: +31 88 755 0094www.milabs.com Making Molecular Imaging Clear

MILabs is committed and supportive to the scientific and medical community by providing the best possible imaging solutions on the market. MILabs is proud that world leading academic partners have chosen MILabs’ systems. MILabs collaborates with many institutes worldwide through joint grant applications, sharing of expertise, organizing workshops and developing customized imaging solutions with a single goal in mind: to facilitate and perform the best research and diagnostics.

MILabs’ ground breaking imaging platforms have received several international awards, including the New Product Innovation Award for Diagnostics and Imaging by Frost & Sullivan, the FOM Valorization Award 2013 as well as several awards from the Society of Nuclear Medicine. Each year MILabs significantly invests in new technologies such as software and hardware upgrades to ensure that MILabs’ customers can continuously expand their cutting edge research.

Dutch Science Foundation:FOM Valorization Award 2013

Frost & Sullivan: MedicalInnovation Product Award

Society of Nuclear Medicine: Animal Image of the Year

... but value customer partnerships most

We appreciate industry awards...

Soc. Nucl. Med. & Mol. Im.:Hoffman Memorial Award 2017

World Molecular Imaging Society

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