Breast cancer is the most common cancer among women worldwide and ranks second in terms of overall cancer deaths. One of the difficulties associated with treating breast cancer is that it is a heterogeneous disease with variations in benign and pathologic tissue composition, which contributes to disease development, progression, and treatment response. Many of these phenotypes are uncharacterized and their presence is difficult to detect, in part due to the sparsity of methods to correlate information between the cellular microscale and the whole-breast macroscale. Quantitative multiscale imaging of the breast is an emerging field concerned with the development of imaging technology that can characterize anatomic, functional, and molecular information across different resolutions and fields of view. It involves a diverse collection of imaging modalities, which touch large sections of the breast imaging research community. Prospective studies have shown promising results, but there are several challenges, ranging from basic physics and engineering to data processing and quantification, that must be met to bring the field to maturity. This paper presents some of the challenges that investigators face, reviews currently used multiscale imaging methods for preclinical imaging, and discusses the potential of these methods for clinical breast imaging.

Cardiovascular disease is the global leading cause of death. One route to address this problem is using biomedical imaging to measure the molecules and structures that surround cardiac cells. This cellular microenvironment, known as the cardiac extracellular matrix, changes in composition and organization during most cardiac diseases and in response to many cardiac treatments. Measuring these changes with biomedical imaging can aid in understanding, diagnosing, and treating heart disease. This chapter supports those efforts by reviewing representative methods for imaging the cardiac extracellular matrix. It first describes the major biological targets of ECM imaging, including the primary imaging target of fibrillar collagen. Then it discusses the imaging methods, describing their current capabilities and limitations. It categorizes the imaging methods into two main categories: organ-scale noninvasive methods and cellular-scale invasive methods. Noninvasive methods can be used on patients, but only a few are clinically available, and others require further development to be used in the clinic. Invasive methods are the most established and can measure a variety of properties, but they cannot be used on live patients. Finally, the chapter concludes with a perspective on future directions and applications of biomedical imaging technologies.

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Changes in the multi-level physical structure of biological features going from cellular to tissue level composition is a key factor in many major diseases. However, we are only beginning to understand the role of these structural changes because there are few dedicated multiscale imaging platforms with sensitivity at both the cellular and macrostructural spatial scale. A single platform reduces bias and complications from multiple sample preparation methods and can ease image registration. In order to address these needs, we have developed a multiscale imaging system using a range of imaging modalities sensitive to tissue composition: Ultrasound, Second Harmonic Generation Microscopy, Multiphoton Microscopy, Optical Coherence Tomography, and Enhanced Backscattering. This paper details the system design, the calibration for each modality, and a demonstration experiment imaging a rabbit eye.

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High-frequency quantitative ultrasound is a potential non-invasive source of imaging cell-tissue scale biomarkers for major diseases such as heart disease, cancer, and preterm birth. However, one of the barriers to developing such biomarkers is that it is labor-intensive to compare quantitative ultrasound images to optical images of the tissue structure. We have previously developed a multiscale imaging system that can obtain registered qualitative ultrasound and optical images, but there are further technical challenges to obtaining quantitative data: System-specific details of obtaining and processing data with Verasonics high-frequency transducers; the need for high-frequency reference phantoms; and off-axis clutter from imaging above a glass coverslip. This paper provides a characterization of the Verasonics ultrasound system with the 18.5 MHz L22-14v and 28.5 MHz L38-22v transducers, describes the construction of high-frequency reference phantoms, and details methods for reducing off-axis clutter. The paper features a demonstration multiscale image of a wild type mouse mammary gland that incorporates quantitative ultrasound with both transducers and second harmonic generation microscopy. These advances demonstrate a way to obtain, on a single system with a cohesive and integrated pipeline, quantitative ultrasound data that is correlated with optical imaging without the need for extensive sample preparation.

Mueller polarimetry is a quantitative polarized light imaging modality that is capable of label-free visualization of tissue pathology, does not require extensive sample preparation, and is suitable for wide-field tissue analysis. It holds promise for selected applications in biomedicine, but polarimetry systems are often constrained by limited end-user accessibility and/ or long-imaging times. In order to address these needs, we designed a multiscale-polarimetry module that easily couples to a commercially available stereo zoom microscope. This paper describes the module design and provides initial polarimetry imaging results from a murine preclinical breast cancer model and human breast cancer samples. The resultant polarimetry module has variable resolution and field of view, is low-cost, and is simple to switch in or out of a commercial microscope. The module can reduce long imaging times by adopting the main imaging approach used in pathology: scanning at low resolution to identify regions of interest, then at high resolution to inspect the regions in detail. Preliminary results show how the system can aid in region of interest identification for pathology, but also highlight that more work is needed to understand how tissue structures of pathological interest appear in Mueller polarimetry images across varying spatial zoom scales.

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