Yuval Ramot, Yael S. Schiffenbauer, Robert Maronpot, and Abraham Nyska

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Practical magnetic resonance imaging for use in investigative and preclinical toxicology studies is now feasible. Newly developed, self-containing imaging systems provide an efficient and cost-effective means to rapidly obtain in vivo and ex vivo magnetic resonance imaging images to improve how we perform toxicology and toxicologic pathology.

Drug development is a lengthy and highly expensive endeavor involving high risk and uncertainty. Animal studies are a crucial part of this process, both for the evaluation of drug efficacy and for drug safety assessment. For financial and ethical reasons, it is important to find ways to reduce the number of study animals needed in preclinical testing. Since preclinical assessments should be done in a timely manner and in a strictly regulated environment, the question of how to optimize the process so that resources may be prudently allocated is a major concern for all drug developers (Jekunen, 2014). If data gathering is modified by adding imaging to preclinical studies, the drug development process can become more efficient with an added benefit of providing an approach that may be translatable to the clinical setting. Imaging technologies have made tremendous advances in the last 3–4 decades (Ying and Monticello, 2006) and can be readily used to facilitate drug development. In addition to X-ray and ultrasound, preclinical imaging modalities available now for researchers include magnetic resonance imaging (MRI), microcomputed tomography, micro positron emission tomography and single-photon emission computed tomography and in vivo optical imaging, while additional new and combinatory technologies continue to develop (Ettlin, 2013; Ying and Monticello, 2006).

Magnetic Resonance Imaging In Drug Development And Toxicity Studies

Magnetic resonance imaging is one of the main technologies that holds great promise for preclinical research and animal studies in support of drug development and safety assessment, and, indeed, for use in general investigative biomedical research. Laboratory animal MRI has been utilized in toxicologic pathology for almost 30 years (Delnomdedieu et al., 1996; Johnson and Maronpot, 1989; Maronpot et al., 2004) and is an excellent modality for noninvasive in vivo, as well as ex vivo, imaging due to its high soft tissue contrast and spatial resolution. It allows sensitive detection of pathologic changes in soft tissues, provides quantitative three-dimensional data, and its use in longitudinal studies allows noninvasive monitoring of the genesis, progression, and regression of chemically induced changes (Dixon et al., 1988). By using MRI there is reduced need, and sometimes no need, for interim sacrifice as the same animal can be repeatedly and sequentially imaged over time, and can even serve as its own control when imaged before start of treatment.

The use of MRI in animal studies has also set the stage for the development of the new concept of magnetic resonance histology (MRH) (Johnson et al., 1993). MRH is the use of MR imaging on formalin-fixed tissues for high resolution characterization of tissue structure (Johnson et al., 2002). It is a highly valuable complementary adjunct to conventional histopathology, as it permits a thorough examination to be performed through multiple digital slices of an entire organ, while leaving the formalin-fixed specimen intact for subsequent definitive conventional diagnostic histopathology.

The Introduction Of Compact, Self-contained MRI Systems

While the advantages of using MRI in preclinical testing are evident, it is still underutilized and widespread adoption of MRI in preclinical investigations has been hampered by the high purchase price, the expense of siting and installation, and operating and maintenance costs of conventional superconducting MRI systems. In addition, there are significant safety concerns, infrastructure, and logistical issues associated with use of superconducting MRI systems. Consequently, use of MRI imaging in preclinical safety assessment studies has previously been limited to large research centers that could afford to acquire and maintain superconducting MRI equipment as well as to employ educated and trained staff to operate these expensive superconducting MRI magnets.

This situation has changed with the introduction of a portable, relatively inexpensive, self-contained, and self-shielded compact MRI system (Figure 1A) (Tempel-Brami et al., 2015). This new MRI imaging system can be placed in any laboratory or research facility without requiring specially shielded rooms, cryogens or coolants, or a dedicated electrical or plumbing supply. The portability of the compact MRI imaging equipment allows it to be easily moved into an animal room so that animals need not be removed from the animal facility. The ease of use of compact MRI equipment provides an opportunity for toxicologists and pathologists to obtain diagnostic-quality in vivo MRI and ex vivo MRH images of experimental rodents and tissue samples, thereby greatly enhancing conventional preclinical studies. Basically, the convenience of this type of MRI facilitates the development and use of rodent models of human disease without the cost, complexity, infrastructure, and safety issues traditionally associated with superconducting MRI systems (Geninatti-Crich et al., 2011; Schmid et al., 2013). Table 1 provides a comparison between compact MRI systems and traditional superconducting MRI systems.

FIG. 1




A, View of a high performance compact MRI system. B, Two-dimensional views of the same focal liver lesions using different MRI image acquisition settings. C, MRI rendering and segmentation of a whole liver showing multiple focal lesions developing in an Mdr −/− KO mouse. D, Hematoxylin and eosin-stained section of one of the focal lesions in the liver of the Mdr −/− KO mouse.


A Comparison Between the Main Characteristics of Compact MRI and Traditional Superconducting MRI Systems

Permanent Magnet Compact MRI Traditional Superconducting MRI
Size Compact Not compact
Field strength 1 T 4.7–9.4 T
Resolution Limited to 60 microns ex vivo and 100 microns in vivo Down to 20 microns ex vivo and 30 microns in vivo
Scan time Typical 5 min for in vivo At least 3 times faster
Cryogenic operation of magnet No Yes
Price Low (starts from 300K US$) At least 3 times more
Upfront site preparations Negligible Significant
No dedicated power supply, no RF shielded room, no cryogens Infrastructure adaptations required (shielded/isolated room/water cooling/3-phase electricity/substantial HVAC)
Safety Very Safe Restricted
Practically no fringe field, allowing no restrictions with magnet location Special attention is required. May have extensive 5 Gauss stray field
Siting and moving flexibility Flexible Limited flexibility
The instrument is wheeled and can be easily moved Support infrastructure may make it problematic to move
Animal handling for imaging Instrument can be moved into animal facility Animals must be removed from animal facility for imaging
Electricity and water cooling Single-phase power outlet Three Phase electricity
No water cooling required Cryogenic infrastructure; compressor and cryogens
Ongoing maintenance considerations and running costs Negligible Considerable
Electronics can be switched off overnight for zero energy costs System is ON 24/7. Cryogenic infrastructure must be periodically serviced
System operation Routine operation, high throughput. Behind the barrier operation Often requires MRI expertise
Advanced MRI protocols Limited Available
Acoustic noise Negligible acoustic noise Substantial (may require acoustic shielding)

HVAC, heating, ventilating, and air-conditioning.

In the system described by Tempel-Brami et al. (2015), in vivo images were acquired with acquisition times ranging from 2 to 10 min and ex vivo MRH images on fixed tissue were batch loaded for automatic image acquisition. The short acquisition times and automatic image acquisition on fixed