Establishing a small animal imaging facility Design considerations - - PowerPoint PPT Presentation

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Establishing a small animal imaging facility Design considerations and operation

Julie L Sutcliffe Ph.D. Assistant Professor Director, Cyclotron and Radiochemistry Facility The Center for Molecular and Genomic Imaging

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Is a dedicated small animal imaging facility necessary?

Increasing number of dedicated small animal imaging systems e.g. microPET, microCAT, microSPECT etc Increasing number of mouse models of human disease Increasingly sophisticated and specific multi modal molecular probes Multimodality imaging facilities that can house animals, support the instrumentation and provide investigators with tools, methods and infrastructure to perform SUCCESSFUL imaging studies is important.

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Acknowledgements/ Disclaimer

Timothy C. Doyle, D.Phil, Scientific Director, Stanford Small Animal Imaging Facility, timbo@pmgm2.stanford.edu Chris Flask, Case Center for Imaging Research flask@uhrad.com Jason Lewis, Assistant Professor, Wash U, LewisJas@mir.wustl.edu Martin G. Pomper, M.D., Ph.D., Johns Hopkins Medical Institutions mpomper@jhmi.edu Steve Rendig, Manager, Center for Molecular and Genomic Imaging, UCDavis David Stout, Ph.D., Director, Crump Small Animal Imaging Facility, UCLA Crump Institute for Molecular Imaging DStout@mednet.ucla.edu Gregory R. Wojtkiewicz, Massachusetts General Hospital / Harvard University gwojtkiewicz@PARTNERS.ORG Pat Zanzonico, PhD, Memorial Sloan-Kettering Cancer Center, zanzonip@mskcc.org

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Funding opportunities

Why these people They are 8 of the 12 nationally funded centre from SAIR grants What is a SAIR grant? Small Animal Imaging Resource Program (U24) (RFA) Number: RFA-CA-07-004 http://grants1.nih.gov/grants/guide/rfa-files/RFA-CA-07-004.html The SAIR Program (SAIRP) was established in 1999 with the funding of five sites. These grants support: (a) shared imaging resources to be used by cancer investigators (b) research related to small animal imaging technology or methodology (c) training of both professional and technical support personnel interested in the science and techniques of small animal imaging.

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Funding opportunities

“Small Animal Imaging Resources (SAIRs) will enhance capabilities for conducting basic, translational, and clinical cancer research relevant to the mission of the

• NCI. Major goals of this initiative are to increase efficiency, synergy, and innovation
• f such research and to foster research interactions that cross disciplines,

approaches, and levels of analysis. Building and strengthening such links holds great potential for better understanding cancer, and ultimately, for better treatment and prevention.” The total amount to be awarded is $18 million over 5 years. The NCI anticipates awarding eight small animal imaging resource grants in FY 2007. Current recipients include Memorial Sloan-Kettering Cancer Center, Johns Hopkins University, Massachusetts General Hospital/Harvard University, Duke University, Stanford University, University of Michigan, University of Arizona, University of Pennsylvania, Washington University, Case Western Reserve University, UCLA and UCDavis.

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Is your centre a dedicated small animal facility? 8 of 8

• What imaging modalities do you use?

microPET 8 of 8 microCT 8 of 8 SPECT/CT 6 of 8 Optical 8 of 8 Ultrasound 5 of 8 MRI 5 of 8

Modalities?

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Modalities continued?

What current instrumentation do you have?

microPET : microPET R4, microPET P4, microPET Focus 120,microPET-Focus 220 MicroPET II microCAT : Imtek MicroCAT II SPECT/CT : GammaMedica Optical : Xenogen IVIS 100 Ultrasound: Somoline Antares, Acuson Sequoia, VisualSonics MRI : Bruker, Varian, Magnex What is the most widely used modality? 4 of 7 said optical imaging

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What is the square footage of your facility?

This ranged from 1850-6500 Use what you have Flow is critical in small floor plans How long did your facility take to become operational? 1-2 years to become operational 3- 5years in the design and build Do you have a vivarium adjacent to the imaging facility 8 of 8 have adjacent barrier facilities with holding areas for hot animals Facility design

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How busy are you ? How many current users do you have 20-200 academic users 1- 5 industrial users How many scans are performed/ week A scan is a single image 30-350 Majority of scans being microPET or optical

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Probe development Do you have a probe development group? 8 of 8 said yes Do you have a dedicated cyclotron 8 of 8 have at least 1 dedicated cyclotron What are the most frequently used probes FDG, FLT, FIAU, Fmiso, FHBG, 64Cu- ATSM and 64Cu- antibodies

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What do you do in terms of infection control? Handling animals in biosafety cabinets Spraying with antibacterial cleaner before and after each study Use isolation chambers

Allows for reproducible positioning, constant gas anesthesia, multi-modality imaging capability (PET, CT, MR), barrier for immunocompromised mice and rats and temperature

• control. The optical chamber provides gas anesthesia and barrier conditions. Heating is

provided externally. microPET-CT Isolation Chamber Optical Imaging Isolation Chamber

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Animal Health Issues

Multi-user, multi-species facility Potential for spread of infectious disease Needs thought regarding What animals come into the facility? How are they are handled within the facility? How are surfaces in the facility cleaned? Where and how are animals kept for longitudinal studies?

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Why Worry? Infectious contamination can wipe out breeding colonies Etiologies fall into 5 categories:

– Those that the animal lives with as normal flora. Do not cause any clinical problems and not known to have direct affect on research. Example: Normal gut flora. – Those that the animal becomes infected by without clinical signs or evidence of disease, but can have impact on research. Example: Mouse parvovirus. – Those that the animal becomes infected by that are opportunistic, normally don’t cause clinical signs but based on research or immune status can cause clinical signs and disease and directly affect research Example: Pneumocystis sp.. – Those that the animal becomes infected by that can cause clinical signs and have direct affects on research Example: Mouse Hepatitis Virus – Those that the animal becomes infected by without clinical signs or evidence of disease, but can have impact on specific types of research and are difficult to manage or prevent spread. Example: Pinworms.

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Common Mouse Pathogens

Mouse Parvoviruses (MPV) MPV leads to persistent infections, especially in lymph nodes Transmission: fecal and urinary shed Stable in environment for months Mouse Hepatitis Virus Respiratory and enteric symptoms Transmission fecal-oral, aerosol, direct contact Most frequent and contagious pathogen in mice Murine Pinworms Common, difficult to get rid of, easily transmitted

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What physiological monitoring do you perform? Temperature, respiration rate, ECG What sampling do you perform during a study Blood sampling via cardiac puncture post sacrifice, tail nick, retro-orbital venous plexus, arterial lines, carotid/femoral arteries How do you inject contrast agent? Directly into tail vein, catheter, warm the tail, awake and asleep Animal monitoring and intervention

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Staffing How many staff do you have in your facility 2-20 Manager, computer scientists, lab techs, animal techs, Director, Research associates On average 6 people How do you advertise your facility Website, retreats, free pilot studies, lectures What sort of training to you have for users Animal handling, anesthesia, scanner operation (mainly for optical only) Most centers provide a full service for PET studies.

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Lessons learnt

Actual usage is always considerably less than projected Full cost recovery through charges is virtually impossible to achieve Plan for success, make sure the architecture as scope to expand External investigators expect everything to be turn key Proper handling of animals to obtain meaningful and reproducible data People….hire good ones Cleanliness

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Specific Design and Operation considerations at UCDavis

Facility objectives Site planning Radiation Safety Infection Control Animal Housing Data Management System Recharge Staffing

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microPET The microPET(r) R4 (12 cm bore) The microPET(r) P4 (22 cm bore) The microPET(r) Focus 120 (12 cm bore) The microPET(r) Focus 220 (22 cm bore size) Inveon PET (12 cm bore). The site planning for all is about the same with power, AC and exhaust for anesthesia gas.

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Inveon dedicated PETMicroPET

Engineering spec Unit weight 275 kg Unit height 150 cm Unit width 83 cm Unit depth 139 cm Operating room temp 45-80F (7-27C) Operating humidity 30-70% (non- condensing) Power requirements 9.5A @110V 5.0A @ 220 V Room size minimum 15 x 15

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Radiation Dose to the Animal For CT, PET and SPECT can be significant Doses in the range of 1-40 cGy are common Lethal dose for a mouse is several Gy But at cGy level can have biological effects that may interfere with what is being measured. Efforts should be made to keep dose to a minimum – PET/SPECT: inject less tracer – CT: lower x-ray tube current, more filtration, fewer views

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• Wear Dosimetry!
• Run QuickScan to check detectors
• Perform Daily Test of dose calibrator
• Enter the study in the Service/Use log book
• Check that there is sufficient oxygen and isoflurane
• CHECK THAT THERE IS SUFFICIENT DISK SPACE

AVAILABLE ON F: DRIVE.

• Wipe test PETNET container, log into Receiving Form, and

fill in the Log-In form.

• Check any radioactive waste from the previous day with a

survey meter and dispose if it’s at background level; finish the entry on the Log-In form

• AFTER ISOTOPE INJECTION, PUT RADIOACTIVE TAPE

LABELED WITH THE ISOTOPE, ACTIVITY, DATE AND SURVEY DATE ON THE BAG OF RADIOACTIVE WASTE AND THE ANIMAL’S CAGE!

MicroPET Daily Set-up Procedures

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Scheduling This is done on line and we are currently booking 2 months in advance http://imaging.bme.ucdavis.edu/ Animal use and care protocol RUA Principal Investigator Title of study Modalities required Recharge number Animal model Imaging required Data required

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Study documentation Date: Operator: Session ID: Animal ID : Scan Region: PI: Project: Animal Position: Species: Weight (g): Sex: Fast (hr): Breed: Glucose (mg/dL): Anesthetic: Route: Maintenance Dose: Isotope: Pre-

• Inj. uCI: Post-Inj. uCI: Dose: Injector: Chemical

Form: Measurement Time: Measurement Time: Injection Time: Cal. Time: Injection Site: Injection Volume: Drawn By: Acquire.Time =Frames x What do we document? AS MUCH AS POSSIBLE!

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UC Davis Image Management System

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Image Download

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Imaging Center Recharge Rates established on a per hour basis Cover staff costs, supplies and part of maintenance Same rate for each modality $$ per mouse quite different due to throughput Assisted and unassisted rates Unassisted most applicable to optical imaging Contrast agents or imaging probes charged at cost Per mouse cost ranges from ~$20 to $500+ Pilot Study Program ~ 6 free scans Center supported by some core grants and a campus subsidy for first 3 years

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Imaging the three Rs of preclinical studies with MicroPET (FDG): Regression, Recurrence, and Resistance

1 10 100 1000 7 14 21 28 35 42 49 Average: Controls Average: Treated 1 cm Scan 1 Scan 2 Scan 3 Scan 4 Scan 5 Scan 6 Scan 7 Scan 8

Functionally Active Volume Time from initial scan (days)

R e g r e s s i

• n

Resistance Recurrence

First Treatment Period Second Treatment Period

• A. Longitudinal Images (Animal 6525)

Coronal MIP

• B. Quantitative Estimates (Treatment and Control Cohorts)

Transverse Slice (through lesions)

Craig Abbey and Jeff Greg (UC Davis and UCSB)

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Novel molecular imaging agents

FDG [18F]FBA-Peptide

αvβ6

• αvβ6

+ αvβ6

• αvβ6

+

[18F]FBA-Peptide 15 min 30 min 45 min 120 min 180 min 0% 100%