Advances in Noninvasive Functional Imaging of Bone

The demand for functional imaging in clinical medicine is comprehensive. Although the gold standard for the functional imaging of human bones in clinical settings is still radionuclide-based imaging modalities, nonionizing noninvasive imaging technology in small animals has greatly advanced in recent decades, especially the diffuse optical imaging to which Britton Chance made tremendous contributions. The evolution of imaging probes, instruments, and computation has facilitated exploration in the complicated biomedical research field by allowing longitudinal observation of molecular events in live cells and animals. These research-imaging tools are being used for clinical applications in various specialties, such as oncology, neuroscience, and dermatology. The Bone, a deeply located mineralized tissue, presents a challenge for noninvasive functional imaging in humans. Using nanoparticles (NP) with multiple favorable properties as bioimaging probes has provided orthopedics an opportunity to benefit from these noninvasive bone-imaging techniques. This review highlights the historical evolution of radionuclide-based imaging, computed tomography, positron emission tomography, and magnetic resonance imaging, diffuse optics–enabled in vivo technologies, vibrational spectroscopic imaging, and a greater potential for using NPs for biomedical imaging.

The Evolution of Structural Imaging to Functional and Molecular Imaging of Bone

Bone is a composite material consisting primarily of hydroxyapatite crystal and type I collagen, which accounts for ∼90% of the organic component. Because bone has high mineral content and higher attenuation of x-rays than the surrounding soft tissue, conventional roentgenography was, when introduced in 1895, the first noninvasive structural imaging modality for bone. Because of the advances in physics, digital geometric processing, and computational power, computed tomography (CT) and magnetic resonance imaging (MRI) can process a large array of digital data to reconstruct virtual three-dimensional (3D) images of bone and soft tissue . However, functional changes usually precede structural changes in disease process, and molecular signaling aberrations are fundamental to most diseases. Therefore, clinical demands for advanced imaging technology capable of providing functional and molecular information are urgent.

From the functional point of view, physiological bone homeostasis, repair, and pathologic changes are mediated by a balance of positive and negative remodeling processes. Noninvasive functional imaging of bone includes in vivo imaging of bone formation, resorption, inflammation, vascularization, and mechanical properties. At the molecular level, the bone-remodeling kinetics involves a complex molecular interaction network between the cells and the cell–matrix. Appropriate functional and molecular imaging systems with sufficient spatial and temporal resolution provide valuable information to advance bone research and clinical frontiers.

Functional imaging, compared to structural imaging, unravels physiological and pathologic activities, and it has been widely used both in basic medical research and in clinical settings. The scope of functional imaging is shown in Figure 1 . Functional imaging senses signals from biological tissue and reconstructs the information into registered images that reflect regional changes in the blood supply, metabolism, chemical constituents, or physical properties. Decades ago, the introduction of intravascular contrast agents not only allowed physicians to distinguish vessels from other tubular structures in the human body but also shed a light on functional imaging . Contrast-enhanced CT has been used to assess vascularity and permeability to distinguish between benign and malignant lesions in orthopedics and other clinical specialties .

Molecular imaging , an integral part of functional imaging, is recognized as an important medical advance toward personalized medicine to optimize disease treatment. Detecting subtle functional changes at the molecular level provides advanced diagnoses and clues to therapeutic strategies. The development of molecular probes and new sensing and image processing technologies has contributed to the emergence of molecular imaging. To map the molecular events in vivo, the imaging probes consist of a targeting unit that directs the probe to the site of interest and a reporter unit that emits signals spontaneously or on specific stimulation.

The Targeting Unit of Bone-imaging Probes

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The Reporter Unit of Bone-imaging Probes: From Radionuclides to Near-infrared Fluorophores to Nanomaterials

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Table 1

Current Noninvasive Functional Imaging Modalities in Orthopedic Clinics and Research

Modality 99m Tc-MDP SPECT 18 F-NaF PET Contrast-enhanced CT Dual-energy CT Proton MRI Doppler Ultrasound Image acquisition time Minutes Shorter than SPECT Minutes Minutes Minutes to hours 10–30 milliseconds Spatial resolution ∗ 7–15 mm 6–10 mm 0.5–2.0 mm <1 mm 10–100 μm 50 μm Detection depth Whole body Whole body Whole body Whole body Whole body Centimeters Sensitivity † 10 −10 to 10 −11 mol 10 −11 to 10 −12 mol

Greater than CT 10 −3 to 10 −5 mol for Gd contrast agent

10 −6 to 10 −9 mol for selective nanoparticles — Specificity Low Greater than SPECT

High High — Volumetric quantification Relative Absolute Absolute Absolute Absolute — Cost of infrastructure High Higher than SPECT Moderate Moderate High Low Cost of each use Moderate High Low Low Low Low Detection applications

Major advantages

Major disadvantages

CT, computed tomography; MDP, methylenediphosphonate; MRI, magnetic resonance imaging; NaF, sodium fluoride; PET, positron emission tomography; SPECT, single photon emission computed tomography.

Data are integrated from the previous studies .

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Table 2

Current Noninvasive Functional Imaging Modalities in Orthopedic Research Only

Modality Bioluminescence Imaging (BLI) Fluorescence Reflectance Imaging (FRI) ∗ Fluorescence Molecular Tomography (FMT) Photoacoustic Imaging (PAI) Energy source Chemical luminescence

Near-infrared Near-infrared laser Image acquisition time Seconds to minutes Seconds to minutes Minutes Milliseconds Spatial resolution 3–5 mm 1–3 mm <1 mm ∼100 μm Detection depth <3 cm <1 cm <20 cm ∼5 cm Sensitivity 10 −15 to 10 −17 mol 10 −9 to 10 −12 mol 10 −13 mol

Specificity High High High High with targeting contrast Volumetric quantification Relative Relative Absolute Relative Cost of infrastructure Moderate Moderate Moderate Low Cost of each use Low Low Low Low Detection capability Molecular

Major advantages

Major disadvantages

Longer image processing time than BLI and FRI Relatively lower sensitivity

NIR, near-infrared; 2D, two-dimensional; 3D, three-dimensional.

Data are integrated from the previous studies .

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Imaging modalities for the skeletal system

Radionuclide Imaging of Bone Metabolic Activity

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Fluorescence Reflectance Imaging and Fluorescence Molecular Tomography

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Optical Imaging of Osteoblastic Activity

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Optical Imaging of Osteoclastic Activity

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Raman Spectroscopic Imaging

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Table 3

Current Noninvasive “Bone Quality” Imaging Modalities

Modality Dual-energy X-ray Absorptiometry Quantitative Computed Tomography Quantitative Ultrasound High-resolution Magnetic Resonance Imaging Raman Spectroscopic Imaging Variable derived from bone tissue Bone mineral density per unit projection body surface area

Skeleton assessed Central (hip and spine) Central and peripheral Peripheral (calcaneus, radius, phalanges, and tibia) Central and peripheral Peripheral Image acquisition time Minutes Minutes Seconds to minutes Minutes to hours Minutes Ionizing radiation exposure Low (0.08–4.6 μSv for pencil beam; 6.7–31 μSv for fan beam)

No No No Portability Poor Poor Good Poor Moderate Application Clinical standard Clinical Clinical Research Research

Data are integrated from the previous studies .

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Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy for Functional Imaging of Bone

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Ultrasound for Functional Imaging

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Nanomedicine-enabled imaging in orthopedics

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Nanomaterials for Magnetic Resonance Imaging Probes

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Gold NPs in Computed Tomography and Photoacoustic Imaging

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Other Optically Active Nanomaterials for Optical Imaging

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Organic Materials for Bone Imaging

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Upconversion NPs

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Developing functional imaging technologies

The Modular Design in Targeting

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Multimodal Imaging Contrast Agents

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Conclusion

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Table 4

Comparison of Nanoparticle (NP) Imaging Probes for Functional Imaging in Clinical and Research Use

Probes Imaging Modality Mechanism Advantages/Disadvantages Clinical and Research Implications References Gold nanoparticles Fluorescence microscopy or FRI Plasmon-based photoluminescence

Dark-field microspectroscopy Strong and characteristic light scattering Optical coherence tomography Strong light scattering CT Photon absorption MRI contrast enhancer

PAI Strong light absorption Surface-enhanced Raman spectroscopy Huge increase of the Raman signal, by a factor of about 10 14 to 10 15 to allow single molecular detection Superparamagnetic iron oxide NP MRI Disturbance of magnetic field

Quantum dot (QD) Fluorescence reflectance imaging Quantum confinement effect

Lanthanide-doped upconversion nanoparticle (UCNP) Optical imaging

CT, computed tomography; FRI, fluorescence reflectance imaging; MRI, magnetic resonance imaging; NIR, near-infrared; PAI, photoacoustic imaging.

Common charateristics for NPs listed in the table: (1) surface modification for multiple biological and chemical functions, (2) integrated properties for multimodality imaging, (3) good photostability, (4) adaptive physicochemical and biological properties for various imaging modalities.

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Advances in Noninvasive Functional Imaging of Bone

The Evolution of Structural Imaging to Functional and Molecular Imaging of Bone

The Targeting Unit of Bone-imaging Probes

The Reporter Unit of Bone-imaging Probes: From Radionuclides to Near-infrared Fluorophores to Nanomaterials

Imaging modalities for the skeletal system

Radionuclide Imaging of Bone Metabolic Activity

Fluorescence Reflectance Imaging and Fluorescence Molecular Tomography

Optical Imaging of Osteoblastic Activity

Optical Imaging of Osteoclastic Activity

Raman Spectroscopic Imaging

Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy for Functional Imaging of Bone

Ultrasound for Functional Imaging

Nanomedicine-enabled imaging in orthopedics

Nanomaterials for Magnetic Resonance Imaging Probes

Gold NPs in Computed Tomography and Photoacoustic Imaging

Other Optically Active Nanomaterials for Optical Imaging

Organic Materials for Bone Imaging

Upconversion NPs

Developing functional imaging technologies

The Modular Design in Targeting

Multimodal Imaging Contrast Agents

Conclusion

References

Further Reading

Adaptable Near-Infrared Spectroscopy Fiber Array for Improved Coupling to Different Breast Sizes During Clinical MRI

Blood Flow Reduction in Breast Tissue due to Mammographic Compression

Britton Chance