Small animal imaging capsule and bed system

In a small animal imaging system (10) at least one modality (12) and a docking station (36) are provided. The docking station (36) provides a workspace (47) and docking ports (48) for preparation and holding of anesthetized animals that are awaiting imaging. For the duplication of positions, a subject mold (26) is provided that holds the subject in a reproducible position on a subject bed (16). Vital signs monitoring is also provided for subjects awaiting scans. The bed (16) includes fiducials (28) to aid in registration of like modality images and different modality images. A capsule (14) can encapsulate a single bed (16), or for tandem imaging, the capsule can encapsulate multiple-bed configurations, such as two, three, or four beds (16). For better positioning and ease of user access, a positioner (34) positions the capsule (14) from the rear of the modality (12).

The present application relates to diagnostic imaging of small animals. More specifically, it relates to control of imaging variables across many scans to aid in the quantification and reproducibility of imaging studies, and will be described with particular reference thereto. It is to be understood, however, that the present application can also be applied to other diagnostic imaging applications.

Investigation of in vivo models of disease is enhanced if studies are conducted using reproducible imaging of individual or groups of subjects. Objective control over factors that affect the imaging is desired for quantification and validation of results. Various biological functions affect imaging and it is desirable to either control or monitor these functions through potentially long time periods and across heterogeneous imaging steps if the results are to be used in quantitative studies. Existing monitors and controls are tedious and error prone to set up and cannot be moved between imaging procedures.

Small animal imaging modalities, such as PET and CT, provide unique opportunities for imaging of models of disease implanted in genetically altered animals. Small animal PET for example, is a functional imaging modality that provides valuable insights into biochemical, physiological, and pharmacological processes in vivo. Current applications include perfusion, metabolism and substrate utilization in vital organs such as heart and brain, gene expression, tumor biology and angiogenesis, hypoxia and apoptosis, among many others. Small animal CT on the other hand, is a structural imaging modality that provides high bone to soft tissue contrast. It is used for screening of anatomical abnormalities, differentiation of tumors from normal tissues in angiogenesis, visualization of neo-vascularization with the aid of contrast agents, and etc.

Researchers working with small animal PET and small animal CT perform imaging of small animals such as mice and rats. The investigation and validation of in vivo models of disease require serial imaging of the same or groups of animals over time. A common goal of such studies is to compare and track the progression of disease by using the complementary information provided by the two imaging modalities. Consequently, quantification and accurate assessment of experimental results cannot be achieved without image registration that aligns the acquired volumes in the same coordinate space. Given the practical and logistical limitations of current small animal nuclear, CT, and MRI devices, it is customary to image a single animal at a time whereas it would be beneficial to be able to image multiple animals at the same time for the inclusion of one or more control animals and/or to process multiple animals in parallel for increased throughput.

The present application provides a new and improved small animal imaging handler which overcomes the above-referenced problems and others.

In accordance with one aspect, a diagnostic imaging system is provided. At least one imaging module acquires diagnostic imaging data of a subject in an imaging region of the module, the module having at least a first docking interface. A user prepares the subject at a docking station in preparation for imaging in the imaging module. The docking station has at least a second docking interface. At least one animal capsule encapsulates the subject and interfaces with the first and second docking interfaces. The capsule can come in different sizes and shapes, to accommodate different types of animals (e.g. rats, mice) additional animals in the same capsule (e.g. two rats, two, three or four mice) or different modalities.

In accordance with another aspect, a method of diagnostic imaging is provided. A conscious animal is placed in an induction chamber to anesthetize the animal. The anesthetized animal is mounted to a subject support. The animal is secured and positioned with a mold. A cover is placed about the support, encapsulating the animal. The support is docked at a docking interface of a docking station in a time period following preparation of the animal and before imaging of the animal. The support is removed from the docking station and docked with a docking interface of an imaging modality. At least one diagnostic imaging sequence of the animal on the support is initiated. The animal is then removed from the support after the imaging sequence is complete. The animal regains consciousness in a post-anesthesia chamber to allow the animal to recover from anesthesia.

One advantage is increased subject throughput.

Another advantage lies in the ability to control variables that affect the reproducibility or quantifiability of the study, such as but not limited to, body core temperature and depth of anesthesia.

Another advantage is the ability to image multiple animals at the same time to enable comparison studies.

Another advantage lies in improved monitoring of physiological parameters that may be used in evaluating the study results.

Another advantage lies in use of monitored parameters to raise alarms or alerts that may affect imaging results or subject health.

Another advantage lies in the ability of imaging researchers to move freely between imaging steps allowing a more effective use of the laboratory area.

Another advantage lies in more accurate registration of diagnostic images.

Another advantage lies in improved statistical confidence in the analysis of collected imaging data.

Another advantage lies in environmental control of animals awaiting imaging.

Still further advantages of the present invention will be appreciated to those of ordinary skill in the art upon reading and understand the following detailed description.

With reference toFIG. 1, an exemplary small animal imaging system10is shown. The present application contemplates a system with modules for positron emission tomography (PET), Computed Tomography (CT), single photon emission computed tomography (SPECT), other diagnostic imaging modules, animal preparation, and a computer workstation for visualization, image registration, fusion, and analysis capabilities. The various modules are combined within a cover that allows flexible configurations with various combinations of side-by-side configurations, determined by space and throughput issues. A common animal positioner is also contemplated, as well as an animal holder that can be docked and undocked against the positioner. In a side-by side configuration, as shown inFIG. 1, accurate image registration is achieved through the docking feature, which provides positional accuracy and repeatability when the animal holder is docked and undocked. Additional image registration can be obtained through the use of fiducial markers.

With reference toFIG. 2continuing reference toFIG. 1, an imaging modality12is responsible for imaging data acquisition. As mentioned above, the modality12can be any imaging modality, including but not limited to one or more of PET, SPECT, CT, and MRI. Depicted inFIG. 1is a second modality12′, different than the first modality12. An animal capsule14holds one or more animals during imaging sessions. The capsule14typically includes one or more holders, or beds16, a cylindrical cover18, physiological parameter sensors20, provisions for anesthesia22, such as a nose cone into which the animal's nose fits, and a holder-side docking interface24. The docking interface24is preferably designed in such way that minimal insert/twist force is applied when the holder is inserted into the imaging modality12. It is preferable that the position of an animal is not disturbed when it is transferred from one modality to another. The docking interface24provides monitoring, heating and anesthesia interfaces to the capsule14. Detection of animal capsule14attachment and presence of animals inside the handlers can be done based on monitoring results. For example, if there are no ECG or respiration signals coming from a capsule14, it is assumed that there is no animal within the capsule. If no animal is detected within a capsule14, the capsule14can be considered disconnected. This check may result in e.g. adjusting user interface's properties so that all displayed/entered information is limited according to the number of detected animals. Also, this information may be used to recognize the current configuration of the modality12.

This interface24preferably supports up to four animals, but more interfaces are certainly contemplated. By configuring all the modalities and docking stations with a uniform docking interface24, the user can exchange the holder between different modalities and docking stations. Docking interface functionality includes providing monitoring, heating and anesthesia interface to the capsule14. For safety reasons, the anesthesia valves can be automatically shut off when the capsule14is detached and can be reopened when it is attached, e.g. check valves. The capsules are preferably constructed to withstand many cleanings and sterilizations, e.g., alcohol, steam, radiation, and the like.

A single animal capsule14can support several different bed16configurations. One capsule14can accommodate up to two (2) rat beds16, and alternatively, one capsule14can accommodate up to four (4) mouse beds16, that is, one two, three, or four mice could be accommodated in on capsule. A two-bed embodiment is shown inFIG. 3, and a four-bed embodiment is shown inFIG. 4. Apart from at least one bed mount, each of the capsule interfaces24also provides one or more sockets connected with the measurement sensors20, a fluid interface for air and anesthesia, and the like. The beds16can be either profiled beds or flat pallets. For increasing heating efficiency, it is preferable that separate and as small as possible cylinders18be used around each of the animals instead of one large cylinder18covering all the animals, although the latter embodiment is by no means unviable. The cylinders18are preferably easily removable. Holes are also provided, through which it is possible to insert or pull out catheters for isotope injection and/or optional measurements and physical interactions.

A flat pallet bed type allows animal technicians to work with non-standard measurements or with non-commonly used animals or animal configurations. The technicians can freely place different animals of different sizes and weights. The nosecone22on the pallet bed16preferably is interchangeable to accommodate different sizes of animals. The nosecone22is preferably radio-translucent and tightly covers the animal's head. Additionally, the nosecone22can be removed, e.g. if an injected anesthesia is used. The pallet bed16is equipped with holes at each side for mounting motion restraints.

In another embodiment, the bed16is a form fitting, profiled bed. The profiled bed16preferably comes in a few types, each adjusted to different animal category (rats, mice) and sizes (small, medium, large). The bed curves allows for easy and repeatable animal positioning, both with the same subject in temporally remote scans, or with different subjects. Motion restraints are integrated into the bed to prevent re-arrangement of the subject during or between scans. Restraints integrated with the bed16are also contemplated in lieu of traditional taping and un-taping.

With reference toFIG. 5, for purposes of positioning subjects in reproducible positions, and to aid registration of images, a mold26is made of a subject. Silicone rubbers are contemporary materials available for making molds and have a very good chemical resistance and a high temperature resistance (205° C. and higher). Small animals such as mice and rats are substantially standard in weight and have very small variation in size and shape. For example, the average body weight of an athymic mouse is 20 grams with a small standard deviation of 2 grams. By placing an animal on the larger end of the scale in a container of silicone rubber a technician can produce an external mold26of the animal body. The mold26is then cured and attached to the small animal imaging bed16. A set of molds custom fitted to general shape of the imaged animals (e.g. mice, rats, guinea pigs, etc.) can be prepared similarly and used interchangeably as needed. Imaging different animals placed in the same mold26on the imaging bed16keeps their shape, orientation, and position relatively similar, significantly simplifying intra-subject rigid or elastic matching of serially acquired volumes of the same animal as well as inter-subject registration.

To further aid registration of both intra- and inter-subject images, non-radioactive fiducial markers28are attached to the bed16to provide support for image based rigid or elastic registration techniques. An exemplary fiducial marker28is shown inFIG. 6. Solid copper may serve as a fiducial marker in CT, PET, and SPECT. Small spheres or wires of copper30are visible in CT while neutron activation of these same markers produces positron-emitting Copper-64 for detection by PET and SPECT. Copper is easily machined into desirable shapes, and prior to activation, is easy and safe to handle. The center of fiducial markers28with spherical shapes is easily detected by a Hough transform or another image processing technique such as edge detection followed by a centroid calculation. The process is fully automatic, robust and reliable. After the centers of the fiducial markers28are detected, a least squares algorithm for rigid registration can be applied to serially acquired images to correct for a global rigid alignment. Once the partial images are brought into rough alignment, elastic matching can be applied to correct the non-rigid deformations between the volumes that in this case will be constrained by the holder mold26custom fitted to the shape of the imaged animal. A base32of the fiducial markers28can be made in such a way that allows the markers28to be attached only if needed. It is also preferred that the fiducials28are placed in non-linear and non-planar locations. Optionally, the fiducial28includes a hollow copper sphere filled with an MR imageable substance, such as copper sulfate, doped water, hydrogen containing gel or plastic, or the like.

The sensors20, such as ECG and respiration probes are preferably integrated with the bed16. Alternately, sensors can be applied to the subject manually. SpO2and heating elements may also be parts of the bed16. Position marks on the bed (i.e. ruler-like markings) assist in reproducing positions when mounting subjects to the bed16. Given that exact repositioning is desirable in brain imaging, a stereotactic frame may be included. To allow access to the subject without disturbing the subject's position while it is fixed to the bed16, it is preferable to leave the animal's tail, legs, and eyes accessible while the animal is fixed to the bed16. It is desirable to autoclave elements that have been in contact with animals, so those particular components are preferably resistant to high temperature steam cleaning and disinfection.

The beds are independently removable to facilitate access to subjects in multi-animal configurations. With rat and mouse subjects, heated tail holders are preferable because they help prevent tail veins from contracting in a cold environment and altering blood flow rates. Moreover, the beds16include heating mechanisms33for controlling the subject's temperature while attached to the bed16. This can be built-in tubing for temperature control, such as embedded tubes in the base of the bed16that would allow for the circulation of heated water or air. In another embodiment the bed could include resistive coils and electrical connections. The temperature of the bed can be controlled by a thermostat that can turn on or off the heating of water, air, or resistive coils.

Absorbent materials can be included to handle excretion during imaging sessions; the bed design can accommodate disposable materials, or they can be integrated into the bed16. The bed16can be designed with all or most of desired probes embedded into the bed16. Alternately, the bed can be designed with all probes flexible enough to be placed wherever they are required by the operator. The integrated sensors20are useful for standardized imaging, specifically where throughput is an issue. External probes can be used, e.g., in complex research scenarios, where it is more desirable to execute a given scenario with maximum accuracy.

With reference again toFIG. 1, the system10also includes an animal positioner34capable of receiving and docking the capsule14. The positioner34is used to position the animal capsule14optimally in an imaging region of the scanner12during an imaging session. The capsule14has an identifier to provide a unique holder identity to the system. The identity can be read when the capsule14is connected to the animal positioner34, e.g. a bar code that moves past a reader during insertion. Fixed laser devices can also be used to aid in registration. A docking station36provides anesthesia and monitoring while the animal capsule14is attached awaiting a scan. As shown, the docking station may include storage space38for storage of additional beds16cylinders18or other devices when not in use. Although the animal preparation and imaging modules are contemplated and shown side by side, animal preparation and imaging may be located in separate rooms.

A side-by-side configuration of the modules12,12′,36is preferred because it facilitates ease of workflow. The user does not have to be constantly walking back and forth across a room, or between rooms. An exemplary workflow is depicted inFIG. 7. In particular, it is a workflow for a PET imaging sequence. In such a workflow, there is potential for down time when the animal is actually being scanned. The radioisotope only decays so fast. In such a workflow, it becomes advantageous to prepare subsequent animals while one is being imaged, so that when the first scan is complete, a subsequent animal is ready to be imaged with no additional prep time. The workflow ofFIG. 7, or one similar to it, happens for each animal, but the docking station36allows these workflows to substantially overlap, reducing overall work time, and increasing subject throughput.

In an illustrative example, say a typical animal scan takes ten minutes, which includes five minutes of prep time, and five minutes of scan time. To scan six animals would take an hour, if the workflow were repeated from start to finish for each animal. This includes time when the scanner is not scanning. The docking station36allows pre-preparation of the animals. While the first animal is being scanned, the second animal will be prepped and held at the docking station36. Thus, the same task of scanning six animals is performed in only 35 minutes, with the only down time of the scanner being while the first animal is being prepped.

In the embodiment ofFIG. 1, the system10includes three modules, namely first and second acquisition modules12,12′ and the animal preparation module, that is, the docking station36. Of course, fewer or greater numbers of modules are contemplated. Preferably, the docking station36adds several aspects of functionality. With reference toFIG. 8, an animal monitoring and anesthesia (AMA) system40is shown. An induction chamber42provides an area in which a conscious animal is placed so it can be anesthetized before it is mounted on the animal bed16. Before an imaging session can begin, the animal is placed in the induction chamber42where it is given preliminary anesthesia before further preparations will take place. Anesthetic agent is provided via a coarse anesthesia interface44. The subject's temperature is coarsely maintained with the use of heaters that rely on the environment or heater temperature. This control path is executed over a coarse temperature regulation interface46.

A physical workspace47is provided at the docking station36to attach the subject to a bed16and install the required sensors20, after the subject has been anesthetized in the induction chamber40. Docking ports48for continuation of life support and anesthesia of the subject between studies are provided at the docking station36within close proximity to the positioner34. Preferably, the number of docking ports48in the docking station matches the number of modalities available in the imaging facility (i.e. one docking slot per one available modality). Early preparation of a greater number of animals would not increase the imaging throughput, as imaging time is typically fixed, and is the factor that limits throughput. This way, the prepared animals spend no more time anesthetized than is necessary.

A post anesthesia chamber50or “wake up box” provides life support during wake-up of the subjects. Here, the subject's temperature is coarsely maintained via a coarse wakeup temperature regulator52in the same manner as it is done for subject in the induction chamber42. The post anesthesia chamber50is preferably well ventilated to speed the subject's recovery from anesthesia.

The preferred method of docking the capsule14to the receiving system is through a positive locking mechanism that is engaged through axial force applied by means of an actuator placed in the positioner34. Again, engagement of the actuator should not require disturbance of the animal. The docking interface24on each capsule14includes leads to engage the AMA system40, including electrical and gas connections. The anesthesia connection includes an “auto shut-off on disconnection” function to prevent loss of anesthesia to the environment.

During a procedure the subject is located on the imaging bed16and attached to either the docking station36or the imaging modality12. Its physiological parameters are monitored via a vital signs probes interface54. Anesthesia is supplied and controlled via an anesthesia interface56. This interface56can be a pneumatic interface that delivers anesthetic agent to the animal in the capsule14and extracts waste gases, but it can also include electrical (automatic) control of the agent concentration. Also the animal's core temperature is maintained with a temperature regulation interface58based on the current temperature measurement and desired target temperature value. The temperature regulation interface58preferably carries control signals that drive the heating elements working on per animal basis.

The AMA40also interfaces with one or more imaging modalities12. In the preferred embodiment, the modality's operation does not depend on the AMA40. For certain studies, however, physiological gating information is required in order to correctly build an image. A gating signal can be passed over a gating interface60that is the same for all imaging modalities. The gating interface60is preferably a TTL (0-12V) interface that accepts an active state as a gate event for image reconstruction.

An acquisition, reconstruction and control subsystem62also interfaces with the AMA40. The subsystem62has at least two functions related to the AMA40. These functions include presentation and storage of acquired vital signs data, control of monitoring and anesthesia functions, image reconstruction, correlation of vital signs data with image data, and the like. These commands and data are sent over a monitoring status and control interface64. The interface64can handle all monitoring data, status and control commands. It is to be understood that acquisition, reconstruction, and control are logical components that are physically distributed over different parts of the system10. A power distribution unit66distributes electric power to all subsystems.

The system also includes a computer workstation68. The workstation68includes a computer that controls main system functions and provides an interface for a user to work with the image and vital signs data. The workstation68includes acquisition control to allow starting, pausing, resuming and stopping an image acquisition and showing status and progress info on the acquisition. The workstation68also interfaces with the AMA40in order to display vital signs for multiple animals scanned across several modalities and stages of animal preparation on the workstation. Additionally, acquisition control and a reconstruction user interface reside on the workstation68. Multimodality function is included on the workstation68such as PET-CT non-rigid registration. In such a situation, interfacing with a CT Acquisition control can to be done via the workstation68. It is preferable that the workstation68provides a migration path for all applications of the system10to use a common platform for infrastructure services and operation. Naturally, the workstation68can be upgraded as new preparation techniques, scanning techniques, software, hardware, and the like become available. Alternatively, the AMA40is capable of running without an associated workstation68; however, functionality and accessibility to the AMA40would be more limited.

The workstation68presents information to the user and allows the user to enter data into the system. Optionally, the workstation68itself does not process information, it merely passes and receives it to/from behind-the-scenes processing70, storing and retrieving data from databases72, and the like. The workstation's68tasks include presenting results of monitoring and anesthesia, entering animal identification and tracer injection times, configuring gating signal, and the like. For entering experiment information and configuration settings an input device, such as a keyboard or mouse, is used. The workstation need not be a PC; it could be, for example, a display74on the modality12such as a touch screen.FIG. 9shows, in schematic form, one possible implementation of the system10.

In another embodiment, a portable AMA can be provided. To increase docking station's usage flexibility it is preferable that function in this embodiment is limited to docking capabilities. Preparation stations may vary significantly by size and complexity between different imaging facilities, therefore, it is preferred that the facility organizes the station wherever it suits them and their own needs. Then, the docking station can be placed either aside the preparation station providing storage for prepared animals, or it can be placed aside modalities, which often can be in different rooms, offering temporary storage for longer studies or when animal is exchanged between different modalities. Portability of such a unit would allow it to be placed wherever it is convenient. Also, its functional similarity to the normal AMA unit would allow technicians for early detection of wrong animal setup or monitoring and anesthesia defects.