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Department ofBiomedical Engineering
Establishing a small animal imaging facility
Design considerations and operation
Julie L Sutcliffe Ph.D.Assistant Professor
Director, Cyclotron and Radiochemistry FacilityThe Center for Molecular and Genomic Imaging
Department ofBiomedical Engineering
Department ofBiomedical Engineering
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, supportthe instrumentation and provide investigators with tools, methods and infrastructure to perform SUCCESSFUL imaging studies is important.
Department ofBiomedical Engineering
Acknowledgements/ DisclaimerTimothy C. Doyle, D.Phil, Scientific Director, Stanford Small Animal Imaging Facility, [email protected]
Chris Flask, Case Center for Imaging Research [email protected]
Jason Lewis, Assistant Professor, Wash U, [email protected]
Martin G. Pomper, M.D., Ph.D., Johns Hopkins Medical Institutions [email protected]
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 [email protected]
Gregory R. Wojtkiewicz, Massachusetts General Hospital / Harvard University [email protected]
Pat Zanzonico, PhD, Memorial Sloan-Kettering Cancer Center, [email protected]
Department ofBiomedical Engineering
Funding opportunitiesWhy these people
They are 8 of the 12 nationally funded centre from SAIR grantsWhat 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.
Department ofBiomedical Engineering
Funding opportunities
“Small Animal Imaging Resources (SAIRs) will enhance capabilities for conductingbasic, translational, and clinical cancer research relevant to the mission of theNCI. Major goals of this initiative are to increase efficiency, synergy, and innovationof such research and to foster research interactions that cross disciplines,approaches, and levels of analysis. Building and strengthening such links holdsgreat potential for better understanding cancer, and ultimately, for better treatmentand 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.
Department ofBiomedical Engineering
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?
Department ofBiomedical Engineering
Modalities continued?
What current instrumentation do you have?microPET : microPET R4, microPET P4, microPET
Focus 120,microPET-Focus 220 MicroPET IImicroCAT : Imtek MicroCAT IISPECT/CT : GammaMedicaOptical : Xenogen IVIS 100Ultrasound: Somoline Antares, Acuson Sequoia,
VisualSonicsMRI : Bruker, Varian, Magnex
What is the most widely used modality?4 of 7 said optical imaging
Department ofBiomedical Engineering
What is the square footage of your facility?This ranged from 1850-6500Use what you haveFlow is critical in small floor plans
How long did your facility take to become operational?1-2 years to become operational3- 5years in the design and build
Do you have a vivarium adjacent to the imaging facility8 of 8 have adjacent barrier facilities with holding areas for hot animals
Facility design
Department ofBiomedical Engineering
How busy are you ?
How many current users do you have20-200 academic users1- 5 industrial users
How many scans are performed/ weekA scan is a single image 30-350Majority of scans being microPET or optical
Department ofBiomedical Engineering
Probe development
Do you have a probe development group?8 of 8 said yes
Do you have a dedicated cyclotron8 of 8 have at least 1 dedicated cyclotron
What are the most frequently used probesFDG, FLT, FIAU, Fmiso, FHBG, 64Cu- ATSM and 64Cu-
antibodies
Department ofBiomedical Engineering
What do you do in terms of infection control?Handling animals in biosafety cabinetsSpraying with antibacterial cleaner before and after each studyUse 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
Department ofBiomedical Engineering
Animal Health Issues
Multi-user, multi-species facilityPotential for spread of infectious diseaseNeeds 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?
Department ofBiomedical Engineering
Why Worry?Infectious contamination can wipe out breeding coloniesEtiologies 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.
Department ofBiomedical Engineering
Common Mouse Pathogens
Mouse Parvoviruses (MPV)MPV leads to persistent infections, especially in
lymph nodesTransmission: fecal and urinary shedStable in environment for months
Mouse Hepatitis VirusRespiratory and enteric symptomsTransmission fecal-oral, aerosol, direct contactMost frequent and contagious pathogen in mice
Murine PinwormsCommon, difficult to get rid of, easily transmitted
Department ofBiomedical Engineering
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
Department ofBiomedical Engineering
StaffingHow many staff do you have in your facility
2-20Manager, computer scientists, lab techs, animal techs, Director, Research associatesOn average 6 people
How do you advertise your facilityWebsite, retreats, free pilot studies, lectures
What sort of training to you have for usersAnimal handling, anesthesia, scanner operation (mainly for optical only) Most centers provide a full service for PET studies.
Department ofBiomedical Engineering
Lessons learnt
Actual usage is always considerably less than projectedFull cost recovery through charges is virtually
impossible to achievePlan for success, make sure the architecture as scope to
expandExternal investigators expect everything to be turn keyProper handling of animals to obtain meaningful and
reproducible dataPeople….hire good onesCleanliness
Department ofBiomedical Engineering
Specific Design and Operation considerations at UCDavis
Facility objectives
Site planning
Radiation Safety
Infection Control
Animal Housing
Data Management System
Recharge
Staffing
Department ofBiomedical Engineering
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 thesame with power, AC and exhaust for anesthesia gas.
Department ofBiomedical Engineering
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
Department ofBiomedical Engineering
Radiation Dose to the Animal
For CT, PET and SPECT can be significantDoses in the range of 1-40 cGy are commonLethal dose for a mouse is several GyBut 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
Department ofBiomedical Engineering
Wear Dosimetry!Run QuickScan to check detectorsPerform Daily Test of dose calibratorEnter the study in the Service/Use log bookCheck that there is sufficient oxygen and isofluraneCHECK 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
Department ofBiomedical Engineering
Scheduling
This is done on line and we are currently booking 2 months in advance
http://imaging.bme.ucdavis.edu/
Animal use and care protocolRUAPrincipal InvestigatorTitle of studyModalities requiredRecharge numberAnimal modelImaging requiredData required
Department ofBiomedical Engineering
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!
Department ofBiomedical Engineering
UC Davis Image Management System
Department ofBiomedical Engineering
Image Download
Department ofBiomedical Engineering
Imaging Center Recharge
Rates established on a per hour basisCover staff costs, supplies and part of maintenanceSame rate for each modality
$$ per mouse quite different due to throughputAssisted and unassisted rates
Unassisted most applicable to optical imagingContrast agents or imaging probes charged at costPer mouse cost ranges from ~$20 to $500+Pilot Study Program ~ 6 free scansCenter supported by some core grants and a campus subsidy for first 3 years
Department ofBiomedical Engineering
Imaging the three Rs of preclinical studies with MicroPET (FDG): Regression, Recurrence, and Resistance
1
10
100
1000
0 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
Func
tiona
lly A
ctiv
e V
olum
e
Time from initial scan (days)
Regression
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)
Department ofBiomedical Engineering
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%
