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Editorials |
1 From the Department of Radiology, Mayo Clinic, 200 First St SW, Rochester, MN 55902 (R.L.E.); Medical College of Wisconsin, Milwaukee, Wis (W.R.H.); Mallinckrodt Institute of Radiology, Washington University, St. Louis, Mo (M.J.W.); Department of Radiology, University of Michigan, Ann Arbor, Mich (N.R.D.); Radiological Society of North America, Oak Brook, Ill (L.B.B.); Department of Radiology, University of California, San Francisco, Calif (R.L.A.); Department of Radiology, University of Pennsylvania, Philadelphia, Pa (S.B.); Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY (H.H.); and Department of Radiology, Massachusetts General Hospital, Boston, Mass (J.H.T.). Received January 9, 2007; final version accepted January 16. Supported by the Academy of Radiology Research, American Roentgen Ray Society, and the Radiological Society of North America. Address correspondence to R.L.E. (e-mail: ehman.richard{at}mayo.edu).
In testimony before the U.S. Congress in April 2003, Director of the National Institutes of Health (NIH) Elias A. Zerhouni, MD, observed
We have witnessed nothing short of a revolution in science over the past 5 years. Some may see this year as the grand finale. I think of it more as the overture. As the 21st century begins to unfold, we are poised to make quantum leaps in our knowledge about how to improve people's health.
Today the understanding of biological processes in human health and disease is deeper and richer than it was 3 years ago when Dr Zerhouni offered his testimony, and far deeper and richer than it was at the close of the previous century. The action of Congress in doubling the NIH research budget has greatly accelerated the rate of discovery of new knowledge in biomedical research. The process of discovery is providing greater insight into human biology and into the mechanisms of human illness and injury that lead to disease, disability, and death. The knowledge about human health and disease gained over the past decade is one of the great success stories in the modern era of science.
Challenges remain, however, in translating new knowledge gained through biomedical research into improved human health and into earlier and more effective interventions in human disease and disability. That is, the discovery process that has been so successful in unraveling the complexity of human biology must be conjoined with an enhanced development process that translates new knowledge into innovative products and services used to enhance the health and welfare of people from all walks of life, both in the United States and around the world. Then, improved delivery mechanisms must be designed to facilitate the distribution of new products and services from the research laboratory to the bedsides of patients who need them. Biomedical research is a continuum that starts with the discovery of new knowledge; moves through the development stage, where new products and services are designed from the new knowledge; and ends with the delivery of new products and services to all those who can benefit from them.
This continuum of biomedical research is reflected in the NIH Roadmap for Medical Research announced in 2003 by Dr Zerhouni (1). The NIH Roadmap initiative pursues three fundamental objectives:
1. Stimulate the development of novel approaches to unravel the complexity of biological systems and their regulation (the "New Pathways to Discovery" theme);
2. Explore ways to reduce the cultural and administrative barriers that often impede research on novel approaches (the "Research Teams of the Future" theme);
3. Initiate renovations in translational and clinical research that include a robust, bidirectional flow of information among basic, translational, and clinical scientists (the "Re-engineering the Clinical Research Enterprise" theme).
Attainment of the third objective is being pursued by the NIH in part through the Institutional Clinical and Translational Science Awards that were announced by Dr Zerhouni in the late fall of 2005 (2).
Biomedical imaging is one arena that has the potential to accelerate progress in biomedical science and technology development across all three of the NIH Roadmap objectives. Imaging science and technology are major contributors to the discovery of new knowledge about cellular and human biology—from the molecular and intracellular levels, through studies in cells and the macroscopic realms of whole animals, and into population genetics.
Imaging science and technology also enhance the development of new health care products and services, including mechanisms such as design and screening of new pharmaceuticals, construction of early measures for assessing the effectiveness of new procedures and processes to prevent and intervene in disease, and demarcation of biomarkers to identify patients at risk for specific diseases and disabilities.
Finally, imaging science and technology can help accelerate the process whereby effective new products and services for disease identification and intervention can be made available to all those who need them, in the United States and around the world.
Realizing the potential of imaging science and technology to accelerate progress in the discovery of new knowledge and in the development and delivery of new products and services to improve the health and welfare of people is a major challenge to the biomedical research enterprise. This challenge was the core reason for a meeting in September 2005 that brought leading thinkers across a broad range of disciplines together to develop the Blueprint for Imaging in Biomedical Research. The foundations of medical imaging were laid more than a century ago, but remarkable advances in the past several decades have vastly expanded the structure that is now known as biomedical imaging science. The goal of this document is to provide a blueprint or map of this discipline, the opportunities that it offers to advance other areas of biomedical research, and the emerging outlines of the imaging science of the future.
Biomedical imaging is a complex enterprise concerned with the presentation of multidimensional data in ways that facilitate rapid and accurate interpretation of information. Imaging is the principal way that humans and many other primates relate to and make sense of an external world replete with complex scenes, discordant signals, and friendly and hostile environments. Using this knowledge and skill to interpret biomedical images is the task of the biomedical researcher, employing imaging techniques such as confocal microscopy and electron spin resonance to understand biological systems at the biochemical and molecular levels. It is the task of clinicians, using imaging techniques such as multi–detector row computed tomography (CT) and duplex Doppler ultrasonography (US), to understand human health and disease at the level of physiologic systems and the whole organism.
Biomedical imaging is a science and an art that requires years of education and training for the expertise and skill of its practitioner to fully develop. It is becoming increasingly complex and multidisciplinary, and it depends on knowledge not only of the biological systems to which it is applied but also of the physics, chemistry, and computer science that underlie the technology and its multivariate uses.
The Blueprint for Imaging in Biomedical Research is only a beginning. It offers a vision of the potential of imaging to accelerate and enhance all phases of biomedical research, and it presents a framework through which colleagues in all areas of science contribute to this acceleration and enhancement. Each section of the Blueprint reflects the contributions of leading scientists from different fields to realizing the potential of biomedical imaging.
This point in history is pivotal in the use of biomedical imaging to enhance knowledge and human health in areas as diverse as genetics and proteomics; molecular structure and interactions; molecular and cell biology; organ and systems physiology; infectious, acute, and chronic disease; and public and population health. Imaging promises to accelerate disease diagnosis at pre-symptomatic levels; enhance understanding of the pathways of drug action and effectiveness; improve the use of physical, chemical, genetic, and biological methods to arrest the ravages of human disease and disability; and assist in evaluating the effectiveness of therapeutic measures of all types. Finally, biomedical imaging has the potential to help contain the exploding costs of health care through early identification and intervention in disease and through the development of improved therapeutic measures. The Blueprint for Imaging in Biomedical Research and the NIH Roadmap for Medical Research are closely linked; biomedical imaging can contribute in a substantive manner to the human and research objectives of the NIH and its Roadmap.
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Many clear messages emerged from the Blueprint meeting, one of which was: Imaging encompasses more than any one discipline or any one level of analysis.
Imaging allows one to visualize individual genes and gene sequences, the presence and activity of individual molecules in the cell, the development and growth of organs, and the function of physiologic systems at the level of the whole animal. Continued development of these technologies and applications requires a translational link between basic and clinical researchers, as well as an interactive network integrating physical and computer scientists, mathematicians, and engineers into the biomedical imaging arena.
The linear model of research that moved discoveries from the bench to the bedside is no longer—and in fact, probably never was—viable. Modern biomedical research requires a multi-investigator multidisciplinary effort that advances research frontiers through evolution of new technologies and research methods but also pulls new developments into the clinical arena in response to challenges articulated by physicians, nurses, and other care providers in clinical and public health environments. Biomedical imaging is at the nexus of this evolutionary change. It unites researchers from many disciplines to develop new approaches and technologies that address unmet clinical needs and to advance the discovery-development-delivery continuum of biomedical research.
Stakeholders
Imaging brings a wide spectrum of stakeholders to the table. These stakeholders help advance the evolution of biomedical imaging, as well as its contributions to improved knowledge about fundamental biological processes and to advances in human health and disease prevention and intervention. Just as important, biomedical imaging helps all of these stakeholders in their pursuit of research objectives, advances in new knowledge, and improvements in the human condition.
Government agencies are important drivers in the development of biomedical imaging through support of biomedical research and through policy guidance on the ethical responsibilities of investigators, especially those using animals and human participants in research. Government support of research in biomedical imaging is critical to the growth of new knowledge and to new applications of this knowledge in the clinical arena. The NIH, with its Roadmap for Medical Research, is essential to the strategy for future developments in imaging research and to achieving the objective of re-engineering the biomedical research enterprise in support of the discovery-development-delivery continuum.
An improved relationship between the biomedical imaging community and the U.S. Food and Drug Administration (FDA) is needed to expedite the approval and dissemination of new image-guided interventional procedures, as well as new imaging probes and pharmaceuticals. The imaging community has an obligation to work with the FDA to ensure that new imaging pharmaceuticals, technologies, and interventions are safe, effective, and available to patients who need them in the shortest time possible. Much drug research and development is now being targeted to subpopulations of patients; imaging has the potential to make this process less expensive and more effective. Biomedical imaging also has an important role to play in the promotion of evidence-based medicine and in the drive to "cross the quality chasm"—a need identified by the Institute of Medicine (3).
Scientific and professional societies are also essential partners in the expansion of biomedical imaging and in developing and delivering imaging innovations. The education of members, scientists, and health care providers from other disciplines, as well as patients and the public, about new imaging technologies and their benefits for biomedical research and clinical medicine is a responsibility best shouldered by scientific and professional societies. Joint meetings of imaging organizations with their counterparts in other disciplines are an effective way to disseminate the educational process.
Academic institutions are the home of most basic and translational research in biomedical imaging. They are also the training ground for the next generation of basic and clinical imaging scientists. These institutions have historically tended to create "research silos," with little cross-collaboration of research scientists and little cross-dissemination of research data. In the past couple of decades, this tendency has diminished as the need for interdisciplinary and interinstitutional biomedical research has become apparent. It is imperative to build networks for research collaboration among imaging investigators from different disciplines and institutions if imaging science are to advance optimally, as it is for biomedical research and clinical medicine in general. These networks help establish the culture of creativity, interdisciplinary learning, and teamwork that is essential to address fundamental questions in biomedical research and to educate the next generation of scientific investigators within a paradigm of interdisciplinary research collaboration and cooperation.
Corporations are also important stakeholders and innovators in the area of biomedical imaging. Companies developing imaging probes—radiopharmaceuticals, optical agents, and magnetic resonance (MR), US, and CT contrast agents—and imaging device companies have invested millions of dollars in a research infrastructure to support the development process. Pharmaceutical and biotechnology companies have also invested in preclinical and clinical imaging facilities to assist in drug development. Translational research sponsored by these companies focuses on validating imaging applications and bridging the gap between preclinical research and applications in patient care. Advances in these areas are best achieved by processes to encourage and promote communication, collaboration, and co-development of technologies and applications through public-private partnerships.
Foundations and voluntary health agencies also play important roles in the development of new technologies and therapies to benefit patients and the public. They can help facilitate two-way communication between researchers and those who use the products and services of research, including clinicians and patients. They also can promote the support of biomedical research within the public sector, which in turn can influence the appropriation of adequate research funding for federal agencies such as the NIH.
The ultimate stakeholders in biomedical imaging are, of course, patients and the public. Because of rapidly emerging advances in molecular biology, genetics, and proteomics, it is likely that health care as we know it today will be transformed tomorrow into a more effective and cost-efficient process that benefits patients and all of society. Biomedical imaging will play a major role in bringing this potential to fruition for the betterment of the nation and the world.
Interdisciplinary Research in Biomedical Imaging
Improved spatial and temporal resolution of contemporary imaging technologies enable investigators to draw inferences about fundamental biological processes at the level of genes, cells, and organ systems, leading to a tremendous opportunity to apply imaging methods in basic biomedical research. Functional imaging is opening new frontiers in neuroscience, cardiovascular science, and cancer biology, and molecular imaging allows investigators to identify and track cell migration in human subjects, as well as in model systems of disease (4–10). Without question, imaging methods are essential tools in biomedical research, and discoveries using these tools are advancing not only basic knowledge about biological processes but also the further evolution of imaging technologies that will contribute to improvements in clinical medicine.
Imaging technologies are also finding increasingly robust applications in translational and clinical research. Imaging biomarkers are able to establish the presence and severity of disease and the response of patients to treatment (11,12). They can guide patient selection in clinical trials and serve as surrogate endpoints in clinical trials (13). The design, development, and testing of new pharmaceuticals are becoming increasingly dependent on functional imaging technologies as a pathway to earlier, more cost-effective decision making about the potential of a drug to meet clinical needs.
Establishing interdisciplinary research teams and creating a model for biomedical research that fosters a pathway for progress across the discovery-development-delivery continuum are crucial to the full exploitation of biomedical imaging in basic and translational research, as well as to making image-driven improvements in health care delivery available to patients who need them. As an example, an interdisciplinary research team in molecular imaging may include biological scientists, imaging scientists, physicists, chemists, mathematicians, computer scientists, and electrical and biomedical engineers. The biological scientists may be seeking a solution to a fundamental problem, such as development of tumor vasculature or characterization of plaque formation in an atherosclerosis model. They may be assisted by imaging scientists with expertise in the development of molecular probes or in the acquisition, display, and interpretation of images. Physicists and engineers with knowledge of detector systems and chemists with skills in the formulation of imaging probes and contrast agents could be partnered with mathematicians and computer scientists who are knowledgeable about image reconstruction and analysis. Interdisciplinary teams of individuals who complement each other's knowledge and who focus on a common objective of unraveling the mystery of an important biological question form an incredibly strong approach to discovering new knowledge, developing new technologies and procedures, and delivering new methods to improve the care of patients.
The interdisciplinary approach to biomedical research is a self-reinforcing process. As improved imaging methods are developed by interdisciplinary teams of scientists, engineers, mathematicians, and clinicians, intriguing questions invariably arise that demand investigation with improved imaging methods. Each round of investigation stimulates the next round of improvements in imaging technologies and procedures. Active dialogue among team members stimulates and accelerates this ever-reinforcing process and leads to continuous progress in the application of imaging science and technology to biomedical research and clinical medicine.
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While much has been accomplished in recent years, it is clear that many new opportunities exist for additional innovations in imaging technology that offer extraordinary potential to promote health, improve the treatment of disease, and further accelerate the pace of scientific inquiry in medical science. The following sections outline some areas of opportunity for advancing biomedical imaging.
Discovery and Development of Imaging Technologies
X-ray–based imaging.—It has been more than a century since Roentgen's discovery of the "mysterious rays" that launched the modern field of biomedical imaging (14). Recent research into x-ray–based imaging is providing new capabilities that are only now being realized. For example, the advanced solid-state x-ray detectors that can be assembled into large, highly sensitive flat-panel arrays promise to revolutionize "conventional" x-ray–based imaging in applications as diverse as breast cancer screening and coronary imaging (15,16).
Many imaging devices exploit the wavelike nature of light to generate information. Until recently, available technologies for x-ray–based imaging have not been able to make use of this important property. Advances in basic physics now suggest that it may be possible to develop laserlike devices that can generate highly ordered and coherent x-ray beams; these devices can be used with novel diffraction-based x-ray optics to probe biological systems with unprecedented resolution at the molecular and cellular levels (17,18).
CT imaging.—Introduced in the 1970s, CT furnishes cross-sectional images of the body, providing information that previously could only be obtained by means of exploratory surgery. In the space of a few decades, CT and related cross-sectional imaging technologies have fundamentally changed the practice of medicine by providing extraordinary capabilities to investigators who study disease processes and treatment. For example, multidetector CT is demonstrating a remarkable potential to enable visualization of the coronary arteries (virtual coronary angiography), thereby reducing the need for invasive coronary angiography in many patients (19,20).
Recent technical advances in CT have dramatically increased the speed with which CT imaging can be performed. Multi–detector row CT systems can acquire detailed imaging data for large regions of the body in only a few seconds. This rapid acquisition makes it possible to generate three-dimensional images of rapidly moving structures, such as the heart, and to capture the transitory movement of contrast material through blood vessels (21–23). Advances in thin-section CT are yielding improvements in diverse areas such as safe and reliable diagnosis of pulmonary emboli, detailed three-dimensional structural information in patients with complex skeletal trauma, and screening for colon cancer (24–27).
Radionuclide imaging.—Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are powerful technologies capable of imaging biochemical processes in vivo in real-time by depicting low-density target proteins by using a small dose of radionuclide-labeled probe. PET and SPECT imaging methods are improving the diagnosis and treatment of psychiatric, neurologic, and cardiac disorders (28,29). An area of great promise is the use of PET and SPECT in monitoring the presence and activity of disease as a function of treatment, particularly in oncology (30).
Research using PET and SPECT in neurology and cognitive neuroscience has been concentrated on creating new knowledge at the molecular level, whereas oncologic research has been concentrated on monitoring therapy and predicting the efficacy of chemotherapy and radio-immunotherapy.
An especially promising area of research is the development of biomarkers for measuring the effectiveness of targeted drugs. PET- and SPECT-targeted probes can measure drug occupancy at receptor sites for validation of initial targeting and guiding the choice of the right drug for the right patient in personalized medicine.
MR imaging.—MR imaging is a versatile medical imaging technology, with steadily expanding applications in clinical medicine and biomedical research. MR imaging is valued for its capability to provide high-contrast definition of normal and abnormal tissues. It also allows a freely oriented plane-of-section, making it a key tool in brain and musculoskeletal imaging and for diagnosing and staging cancer.
A remarkable aspect of MR imaging is the extent to which imaging scientists have steadily developed and added new capabilities since introducing the technology in the early 1980s. For example, specially developed MR imaging technology can now be used to diagnose arterial disease, sparing patients the discomfort, risk, and high cost of invasive angiography (31,32).
Newly invented MR imaging techniques have opened large fields of research. In the 1990s, for example, an MR imaging–based method was introduced to identify areas of increased neuronal activity in the brain that was based on blood oxygenation level–dependent, or BOLD, imaging (functional MR imaging). This method has provided a critical and accessible tool for brain functional mapping, drawing hundreds of investigators from multiple disciplines into functional mapping of the brain. This area of research is now regarded as one of the key approaches to the study of brain function (33–35).
The richness of the physics of MR is allowing researchers to develop MR imaging–based methods to quantitatively image a diverse range of tissue properties, including vessel density in tumors, fat content in liver cells, metabolite concentrations, volumetric blood flow in arteries, cerebral perfusion measures, dynamic myocardial strain, water proton diffusion, tissue viscoelasticity, and cellular orientation and morphology (36–44). All of these evolving capabilities have potential applications as diagnostic methods and as tools for research.
US imaging.—US is a widely used, cost-effective diagnostic imaging tool that is valued for its real-time imaging capability, usefulness in characterizing tissues, and absence of ionizing radiation. In cardiovascular imaging, Doppler processing of echo data provides real-time measurements of blood flow.
New capabilities of US are being sought in many areas. Researchers are developing advanced, multidimensional ultrasound transducer arrays that provide three-dimensional images in real-time (45,46). Smarter and more complex real-time data processing methods are being developed to aid tissue characterization with US (47,48). Investigators are developing several ultrasound-based methods to characterize the elasticity of tissues, with important potential applications ranging from detecting tumors to noninvasively diagnosing liver disease (49–52). Researchers have developed microscopic "bubble" US contrast agents that can be injected into the blood, can be easily visualized, and can even be manipulated with an ultrasound beam, enabling targeted delivery of therapeutic or other materials contained within the bubbles (53,54).
Optical imaging.—Optical imaging uses fluorescent and bioluminescent probes that emit radiation of visible or near-infrared wavelengths, which can be scanned by optical cameras. Although fluorescence imaging in the visible range can penetrate tissue only to a depth of 1–2 mm, fluorescence in the near-infrared region can penetrate up to several centimeters of tissue, enabling imaging at greater depths (55). Progress has been enabled by advances in three technologies: the development of new probes, the development of new imaging modalities, and advances in genomic sciences that allow genetically targeted probes.
Advances in probe design include probes that respond to cellular activity, inorganic probes with increased photostability, and probes that emit in the near-infrared region (56,57). New optical imaging techniques include optical coherence tomography, multiphoton microscopy, total internal reflection fluorescence, and speckle microscopy. Green fluorescent protein, which was originally introduced as a tool for tracking cells, has quickly evolved into a tool for following proteins and for reporting on a plethora of cellular activities and signaling pathways (58–60).
Imaging of biological specimens and materials.—Many evolving imaging technologies used in clinical medicine and biomedical research are designed to evaluate samples of biological material rather than imaging the living bodies of humans and animals.
It can be argued that, other than the naked eye, the earliest biomedical imaging device was the magnifying glass. The optical microscope revolutionized biological science, and in the past century advances in microscope technology have substantially improved spatial, contrast, and temporal resolution (61–64). These advances included phase contrast, fluorescence, and confocal laser-scanning microscopy. The expanding fields of imaging science and digital image processing have contributed greatly to the advance of optical microscopy.
Electron microscopy became an essential imaging tool for biology in the latter half of the 20th century, providing a way to visualize structures beyond the resolution of conventional optical microscopy. Electron imaging can provide images of single molecules or other assemblies; it has greatly increased our knowledge of the internal structure of tissues, cells, organelles, and macromolecular complexes. Engineering development in this field continues to push the limits of spatial resolution, and tomographic techniques have been developed to allow three-dimensional imaging at cellular and molecular levels (65,66).
The development of atomic force microscopy and related technologies are yielding methods for imaging biological structures with resolution at the atomic level, providing important manipulative capabilities for nanoscience (67,68). Another promising area of development is ultrasound-based microimaging techniques.
For decades, the technologies of x-ray crystallography and nuclear MR spectroscopy have been vital tools in biology research for determining the structure and function of molecules, including nucleic acids and proteins. New developments in these fields, coupled with innovations in computational methods, promise to open up new ways to investigate the dynamic properties of biomolecular systems, with promise to contribute to a better understanding of biological systems.
Other imaging technologies and devices.—Investigators are exploring opportunities offered by combining two or more imaging technologies to produce fused images of biological structures and functions. This concept of "hybrid" imaging is proving highly useful in commercial PET/CT systems, which use radiation absorption information provided by congruent CT images to improve the reconstruction of PET images, followed by superimposition of PET functional images on anatomic maps provided by CT.
Researchers are investigating potential applications of untapped regions of the electromagnetic spectrum in biomedical imaging, including terahertz and microwave radiation. Investigators are developing and studying technologies for imaging the tiny magnetic fields generated by neural activity and by the heart (69–71). Many other physical phenomena have promise as potential targets for quantitative imaging of biological systems. Under the right conditions, for example, some forms of electromagnetic energy interact with tissue to generate acoustic/mechanical energy and vice versa. The nature of the interaction that converts one type of energy to another depends on the physical properties of the tissue. An example of this approach is microwave thermoacoustic imaging. This general notion of energy transduction represents a large class of potentially valuable biomedical imaging technologies that is largely unexplored (72–74).
Imaging Tracers and Probes
Pharmaceutical tracers and contrast agents have long played a critical role in medical imaging. The new imaging technologies described in the previous sections provide many opportunities to develop powerful new tracers and targeted probes, including the labeling of multiple in vivo targets and the combining of diagnostic imaging and therapeutic agents into single "smart" packages (75,76). New developments in these areas have potential to lower the cost of imaging technologies, thereby making them more accessible to patients.
New probe identification methods, labeling strategies, and delivery mechanisms are elements to be explored in developing novel tracers. High-throughput screening of compound libraries, developed by combinatorial chemistry and phage-display techniques, are defining a new chemical space for evolution of tracer compounds (77–79). In situ molecular self-assembly reactions, such as "click chemistry," are being used to generate new classes of target-specific molecules (80–82). Homo- and heteromultimers of probes provide opportunities to produce high-affinity cell-surface tracers that may ultimately yield patient-specific targeted delivery of chemical or radioactive therapeutics (6,83,84).
Many potential advances could improve access to and reduce the cost of PET and SPECT tracers. New accelerators and targets will broaden the availability of PET radiopharmaceuticals, and agents combining the potential of SPECT imaging with radioimmunotherapy will be major advances. Microfluidics may play an important role in the future of radiotracer production (85,86). These small devices will facilitate the preparation of tracers in unit doses. They will permit a facility to produce several different tracers on any given day, thereby increasing productivity while reducing tracer production cost.
Dual-purpose microbubbles can improve the quality of US imaging and can also be used for image-guided therapy. These microbubbles can be targeted by attaching targeting agents to their surface. Agents trapped inside the bubble can be released on activation by the targeting chemistry and/or by spatial focusing of ultrasound beams (87–89).
Advances in nanotechnology could also have a profound effect on probe development and imaging. Nanochips may provide a means to rapidly identify patient-specific targets for radioprobe and therapeutic delivery (90,91). Nanomaterials may facilitate rapid and efficient tracer synthesis, while nanodevices may be applicable to tracer analysis and quality control.
Various types of nanoparticles are showing promise as imaging agents. Monocrystalline iron oxide nanoparticles, or MIONs, are showing promise for several MR imaging applications, both as particles and as particles with targeting molecules attached to the surface. When the surface of these particles is altered, they can remain in the circulation for times varying from tens of minutes to hours. A rapid-clearing agent allows contrast-enhanced MR imaging of the arteries and veins, while the targeted slower-clearing agents are being developed for tumor imaging (92–94). Other nanoparticles with radionuclides attached are being developed for PET and SPECT imaging. These nanoparticles can be functionalized with cell-permeable peptides, as well as with therapeutic drugs. They have high promise for both diagnosis and therapy through multimodality imaging. New probes may also be developed that are useful for both imaging and therapy. One approach is to attach a diagnostic radionuclide that also has therapeutic properties. The same functionalized molecule could also bind a diagnostic radionuclide and a therapeutic radionuclide to be used consecutively (95,96). The diagnostic radionuclide would be used to perform dosimetric measurements, and the therapeutic radionuclide would be used for tumor killing. Another example is the use of nanoparticles, including quantum dots, to identify a tumor, to determine the type of cancer, and to release a toxin to kill the tumor (97–101).
Development of new reporter molecules will make it easier to target and visualize diseased areas. Development of more specific imaging probes to target diseased areas could improve the quality of imaging while reducing the time needed to collect the imaging data. It is also possible that optical imaging with multiple probes of different wave lengths could be used to measure different cellular processes (102,103).
Innovative Imaging Strategies
It has been observed that medical imaging has, until recently, been mainly concerned with demonstrating the structure of biological systems rather than exploring function. To some extent this is a misperception. It is in the nature of biological structures for form to follow function. While many medical imaging technologies are considered anatomic imaging techniques, their rich data streams permit them to routinely provide important functional information (eg, the biological aggressiveness of a tumor) (104).
Multiple advances in imaging technology offer many new opportunities to directly and sensitively assess functional aspects of biological systems at many levels. The existence of all of these options is leading to a broader view of imaging strategies in clinical applications and in biomedical research.
Structural imaging at multiple scales.—It is useful to study the organization of biological systems across multiple scales, ranging from the whole organism to the organ, tissue, cellular, organelle, macromolecular, and molecular levels. Advances in imaging technologies such as CT, MR imaging, and US provide an unprecedented capability to assess and understand the integrated structure of the entire body and to evaluate the normal and pathologic morphology of organs and organ systems.
The organization and composition of tissues can also be assessed noninvasively through use of existing and rapidly evolving imaging methods based on MR imaging, US (often in combination with contrast materials), and nuclear methods. For instance, advanced MR imaging techniques have been developed to detect the presence of microscopic vascular changes in adjacent tissues that allow a small cluster of previously dormant tumor cells to transform into invasive cancer (105,106).
Until recently, structural imaging at the cellular level in the living body was not considered feasible. Now, a host of methods are becoming available to make this goal achievable. Optical coherence tomography can provide cellular imaging in any part of the body that is accessible by a fine light fiber. Similarly, high-frequency ultrasound devices show promise for providing near-cellular level imaging in accessible locations of the body, such as within blood vessels (107,108). A growing class of MR imaging techniques based on measuring water proton diffusion is permitting noninvasive assessment of the size, shape, orientation, and organization of cells in tissue (109,110).
Another expanding group of imaging technologies—employing molecular probes using optical, PET/SPECT, MR, and US imaging technologies—is demonstrating the capability to noninvasively assess the spatial distribution of specific types of cells in the body. These technologies promise to extend the capability of in vivo morphologic imaging to the molecular level by developing probes that target specific structural changes in proteins (111).
Functional, metabolic, and molecular imaging.—Due to its high temporal resolution and its inclusion of the Doppler phenomenon, US imaging is a powerful technology for noninvasive assessment of heart and vascular function. MR imaging and CT also offer many opportunities to measure cardiovascular functions that were previously accessible only with invasive angiographic procedures. Researchers are developing imaging technologies that reliably measure tissue perfusion and oxygenation (112), with important implications for research on and treatment of common diseases such as hypertension and cancer.
The technologies of functional MR imaging, radionuclide imaging, and optical imaging have revolutionized the study of brain function. Major progress is being made in the effort to integrate structure and function in order to understand cognition, learning, and memory development (113). Although substantive challenges remain, these technologies promise to provide critical new knowledge in areas such as childhood development and the neurobiological bases of psychiatric, cognitive, and neurodegenerative disorders. By increasing the basic understanding of normal and abnormal brain function, imaging science is critical to the development of effective therapies for major mental disorders, such as attention deficit disorder, depression, schizophrenia, obsessive-compulsive behavior, and dementia (including Alzheimer disease) (114).
Rapid developments in molecular and metabolic imaging are providing new methods for noninvasive, high-resolution imaging of molecular pathways in vivo (115,116). These imaging advances support and are supported by developments in the basic research of molecular and cell biology and will directly effect patient care by depicting predisease states through identified biomarkers. Biomarkers at the molecular level could allow physicians to tailor therapy to the unique molecular profile of a patient or a disease, such as cancer (117–119).
Molecular imaging contributes to biomedical research and development in many ways. Its techniques provide powerful tools for revealing the normal function of molecules, cells, organ systems, and whole organisms. They can be used for diverse purposes, from tracking cell migration to assessing gene expression. They also can be used to assess changes over time in living organisms that are caused by progressive developmental degenerative or other disease processes (120). Molecular imaging technologies are likely to have an important and expanding role in the field of drug development.
In clinical practice, molecular imaging offers extraordinary promise. Molecular imaging technologies may allow detection of some disease processes years before they cause symptoms or before they would have been detected by means of conventional diagnostic tests. They may be used to rapidly determine an appropriate and highly targeted therapy for that disease. Finally, during treatment, molecular imaging techniques are expected to play an important role in rapidly and precisely measuring the effectiveness of a prescribed therapy.
Imaging Informatics and Computation
The dramatic expansion of biomedical imaging over the final 3 decades of the past century and the 1st decade of this century has been due in large measure to the rapid evolution of computational capacity, driven by ever-faster and less expensive signal generation and image-processing hardware and software. In the previous century, discovery of new knowledge about biological systems and human disease was constrained principally by the limited amount of data that could be acquired about the systems. Today, the constraint often is an overabundance of data; the challenge is to extract meaningful information from the data to move forward the frontiers of research and clinical care (121,122). Genetic profiling of patients is one example of an emerging discipline burdened with the problem of an overabundance of data. Another example is biomedical imaging.
Imaging technologies such as multi–detector row CT, MR imaging, and PET create vast amounts of data in time spans of a few seconds to a few minutes. These data require many computational steps to produce useful images. One of the most important and active areas of progress in imaging science has been the development of more powerful algorithms for extracting image information from the raw data provided by imaging systems. These complex inversion algorithms, which are based on advanced mathematical techniques, are continually being refined through research and require ever more powerful computation systems (123,124).
The quantity of multidimensional data that can be obtained by imaging a single patient, animal, or molecular organism is expected to continue to increase exponentially, with improvements in spatial and temporal resolution of imaging systems and with the expanding ability to integrate a variety of structural, biochemical, and genetic information within images (125,126). These large image data sets are challenging to use with existing technology; they require development of new approaches for information visualization and extraction. They demand improved computational models of biological systems at all levels and development of methods for computer-aided detection and diagnosis of abnormal conditions, hidden within huge multidimensional compilations of imaging data.
Repeated medical imaging over brief intervals of time is increasingly being used to guide treatment, whether that treatment is by means of drug or radiation therapy or by means of surgery (127,128). This approach places extreme demands on computational and image-processing hardware and software. It stimulates the development of new algorithms, as well as adoption of image processing techniques from other disciplines, in order to keep up with the demands.
A growing need to investigators is availability of open-access libraries of imaging data at the human, animal, and molecular levels. These libraries will accelerate development of computational models of biological structure, and they are needed at various levels, ranging from the molecular to the whole animal, to evaluate experimental therapies in silico. They will also expedite the development of imaging standards, data-sharing protocols, and quality control measures to ensure that data entering the libraries are compatible. Improved network grids will be useful in outsourcing computational problems to groups that are best suited to address them.
Biomedical imaging, combined with computational models and computer simulations, has the potential to accelerate clinical trials and to focus them more narrowly on subpopulations of patients. Advances in data analysis and management will aid in the assessment of biomedical imaging technologies and their specific contributions to biomedical research and to patient care.
Imaging Assessment
One essential challenge for biomedical imaging is to demonstrate its value to the biomedical research community, to the general medical community, and to society as a whole. Assessment of the value of any particular technology should start with a rigorous examination of the technology itself and of the accuracy with which it can help reveal disease or injury and lead to proper diagnosis. It must then show its value in improving treatment, patient outcomes, and quality of life. As image-guided therapies are developed, they likewise need to demonstrate improvement in patient outcomes. Systematic and suitably powered research is needed to identify the possible bioeffects and to establish the safety parameters of emerging imaging technologies. The need for this research is especially apparent in areas such as high-field MR imaging and high-intensity US imaging.
In imaging, one of the more difficult challenges is the timing of when to assess a particular technology (129,130). Imaging technologies tend to evolve in both sophistication and application. A large-scale study of a new technology in the development stage runs the risk of becoming obsolete before the findings are published, because of changes in the technology or its applications. On the other hand, waiting until a new technology or its applications are mature makes it difficult to influence clinical practice. A challenge for the imaging research community is to develop a layered or adaptive strategy that provides both technology assessment and guidance to clinicians as a technology and its applications are developing. Faster, better, and cheaper methods than the ones currently in use are needed for clinical assessment of devices.
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Basic Research
Imaging allows researchers to monitor properties such as cell migration, tissue inflammation, and malignant processes (9,135,136). Imaging aids understanding of how cells differentiate, and it contributes to predictive models of developmental biology. New knowledge about developmental biology will help to elucidate functional defects related to disease that can be correlated with genetics (137,138). This correlation is a key component in the attainment of a systems-level understanding of human health and in realizing the potential of genomics to prevent and treat disease.
Imaging also provides dynamic information that is essential to understanding signal transduction (139,140). A challenge for imaging research is to develop probes that can measure multiple signaling pathways simultaneously to assess dynamic interactions. Speed, resolution, and automation in image analysis are three areas where major improvements would immediately benefit the field of functional genomics (141). Better electron-based imaging methods are also needed to detect the molecular architecture of complex biological assemblies. New research into three-dimensional optical coherence tomography and tools for electron microscopy, such as cryoelectron microscopy, could create the methods and technologies needed to pursue these questions.
Bridging gaps between molecular, subcellular, and cell biology, as well as between cell and developmental biology, is essential to understanding the complex interactions between different levels of an organism. For researchers to understand these complex interactions, imaging must improve the quantifiable spatial and temporal data that it acquires for cellular components, single cells, cells in organs, and interactions among organ systems (92). These data will enable researchers to understand how temporal and spatial interactions influence cell and tissue function. Advances in imaging may facilitate the temporal monitoring of signaling events inside cells (142).
Molecular imaging enables the visualization of molecular events and improves understanding of drug actions. This knowledge helps scientists to create pharmaceuticals that are targeted more precisely, permitting more efficient, effective, and personalized health care.
Imaging can also play a key role in regenerative medicine. Tissue engineering is moving into the realm of molecularly designed self-assembling materials. Imaging contrast agents that allow noninvasive in vivo imaging will be of the utmost importance in the development of new regenerative treatments (143).
Preclinical (Translational) Research
Imaging has the potential to facilitate major changes in the design and conduct of preclinical and clinical trials. The goal is to introduce imaging early in the drug development process, so that it can be useful in the transition of the development process into humans. To date, the primary focus of research has been on diseases that are either related to a single gene or have a single biochemical control point. In these cases, imaging can individualize the health care process by enabling identification of patients with sufficient levels of target protein to heighten the efficacy of chemotherapy or radiation therapy (144–146). This application of imaging requires rapid identification and validation of an appropriate targeting probe—first in preclinical studies and then in clinical trials. Successful ability to stratify the population will ensure faster and more efficient trials. The most impressive example to date is the use of fluorine 18 fluorodeoxyglucose as a biomarker for determination of the efficacy of the cancer agent imatinib (147,148).
In preclinical trials, imaging can improve the understanding of host response and variability by using animal models, although obtaining relevant models is still problematic for many diseases. Animal models are highly effective in validating new targeted probes. Gene-manipulated mice are important to this process because they can provide efficient proof of targeting while avoiding the large pharmacologic doses required to validate binding to a saturable site in larger animals (149).
Imaging can also optimize the use of small animal models in a variety of settings by illuminating key physiologic differences and similarities between the animal models and humans (150). The power of animal imaging is in the use of paired statistics to study the effect of a potential drug in the same animal. This approach makes animal models more predictive, leading to improved translation of therapies from preclinical animal studies to clinical trials. Molecular imaging is also expanding the use of exploratory investigational new drug trials ("phase 0" trials) for drugs (151). These trials use microdoses of a compound to identify the most promising drugs for further development and to encourage earlier abandonment of those that lack appropriate pharmacokinetic or pharmacodynamic properties (152).
Clinical Research
Biomedical imaging makes an important contribution today to clinical research. By identifying surrogate endpoints with greater predictive value, it will likely play an even more important role in the future. By combining surrogate endpoints with computational models and simulations, it may well become possible to predict the effectiveness of a therapeutic approach much earlier in a clinical trial, thereby reducing costs and shortening the time to delivery of effective agents into the marketplace.
Imaging, combined with computational models and simulations, will permit identification of subpopulations of patients for whom a therapeutic agent is clearly efficacious and others for whom the agent presents a risk. Clinical trials can then be modified to exclude or include subpopulations during the course of the trial, using an adaptive study design (153–155). This more responsive approach to clinical research may eventually lead to clinical trials and therapies that are personalized to those subpopulations for which the therapies are the most efficacious.
Biomarker development is growing in importance for research on organs and organ systems. Improvements in imaging make the identification of disease and predisease states easier and more systematic. Enhanced knowledge of predisease states will lead to more opportunities for prevention and early treatment.
Imaging can also be used to elucidate how genotypes are expressed in the phenotypes of individuals. A better understanding of phenotypes will create new knowledge about the role of the genome and its interplay with the environment in health and disease. This knowledge may change how clinical trials are conducted by allowing researchers to acquire a clearer understanding of therapeutic effects and how they are influenced by environmental and genomic factors. This dramatic increase in our understanding of the environmental and genetic contexts of health and disease can open up new methods to prevent and monitor disease on the basis of biomedical imaging.
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Recent advances in imaging science have dramatically enhanced the important role of imaging in selecting, guiding, and monitoring treatment. These advances include development of new imaging modalities, targeted tracers and probes, improved visualization tools, and novel treatment technologies (6,53,92,156,157).
As therapies become directed at specific biochemical pathways, there will be a need for tailoring treatments to the biochemical status of individual patients. Increasingly, imaging is able to provide a noninvasive means to determine the type and required dose of drug for successful treatment (158). Imaging can guide targeted therapy by informing selection of the initial treatment regimen, suggesting a change in treatment plan on the basis of tumor or patient response, monitoring side effects during treatment, and mapping drug delivery to diseased and normal tissues on the basis of tumor response and normal tissue toxicity (159).
In the field of traditional surgery, three-dimensional imaging and data visualization technologies are increasingly being used for advance treatment planning, simulation, and education. For guidance during surgery, navigational systems that use three-dimensional image data obtained prior to the surgery are widely used, particularly in neurosurgery (160). A further advance is the use of real-time imaging technology for surgical navigation, using a variety of modalities including US and MR imaging (161,162). Image-guided surgery improves the precision of many surgical procedures by eliminating much of the guesswork, reducing the risk of human error, and minimizing variations among the abilities of individual physicians (163,164). For diseases such as cancer, the precision of surgical intervention is a key factor in determining whether a tumor recurs. With the advent and expanding application of robotics in conventional surgery, image-based navigational approaches are becoming more important and are expected to provide ever better surgical outcomes in patients (165,166).
An implicit connection between imaging and therapy is the creation of novel treatment approaches that combine the function of an imaging probe with that of a therapeutic agent. Radiolabeled antibodies serve as a model of image-guided targeted therapy, in which the same molecule is used for both imaging and treatment. Sequential SPECT or PET imaging of an antibody tagged with a diagnostic radionuclide can inform a patient-specific optimized dosing plan generated for the same antibody linked to a therapeutic nuclide (167). In the future, this two-step approach may become an essential feature of other forms of molecularly targeted radioactive drug treatment. Furthermore, it is envisioned that quantitative imaging will facilitate the preclinical development and clinical application of emerging therapeutic strategies, including protein kinase inhibitors, gene therapies, and immunotoxins (168,169).
Over the past decade, investigators have developed minimally invasive image-guided thermal ablation therapies for tumors of the liver, kidney, lung, and bone. These treatments are performed with real-time guidance by means of US, CT, or MR imaging. In patients with appropriate indications, these ablation techniques offer a rate of cure equal to that of conventional radical surgery but without the associated pain, risk, expense, and recuperative time (170–172). Image-guided minimally invasive therapies of the future may also include the delivery of other therapeutics, including proteins, stem cells, gene therapies, chemotherapeutic agents, antibodies, and other payloads.
Investigators are actively pursuing other promising options for minimally invasive image-guided therapy. For example, it is possible to design injectable therapeutic agents that become active only when exposed to focused light, electromagnetic energy, or ultrasound energy (53,173). The therapeutic payload is targeted by focusing the activation energy at appropriate locations in the body.
Another important application in image-guided therapy combines real-time US or MR imaging guidance and high-powered focused ultrasound ablation. This approach allows treatment of lesions deep within the body in a noninvasive fashion (174). The focal spot of the high-powered ultrasound system is positioned electronically with millimeter accuracy and can be visualized relative to normal and abnormal anatomy in real-time with advanced MR imaging techniques. The technology is already in clinical use for some applications, and it shows great promise as a revolutionary treatment for applications as diverse as treating breast or prostate cancer and serving as an alternative to invasive neurosurgical procedures (174,175).
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1. Imaging encompasses more than any one discipline or any one level of analysis. It brings together researchers from many disciplines to address unmet needs and advance discovery.
2. Interdisciplinary research teams that foster pathways for progress across the discovery-development-delivery continuum of biomedical research are crucial.
3. Government support of research in biomedical imaging is critical to the growth of new knowledge in the biomedical sciences.
4. There is a need for scientific societies to collaborate with industry and the different federal agencies to develop standards for quantitative measurements for drug response, by using anatomic, functional, and molecular imaging methods.
5. The ability of imaging technology to interrogate at the cellular level has facilitated investigations about fundamental biological processes, as well as specific disease pathophysiology.
6. The ability of MR imaging techniques to enable identification of areas of increased neuronal activity in the brain has opened the field of functional brain mapping as an important approach to the study of brain function, including cognition.
7. US imaging is a versatile technology that continues to advance in many areas, including the development of novel contrast agents that will offer unique capabilities to probe biological systems.
8. Optical imaging probes that respond to cellular activity and emit near-infrared wave lengths offer the ability to track molecular activity within the cell.
9. Engineering advances in electron microscopy continue to push the limits of spatial resolution. Tomographic techniques have been developed to allow three-dimensional imaging at cellular and molecular levels.
10. Fusion imaging, led by PET/CT scanners, combines the functional properties of radionuclide imaging with the detailed anatomic imaging of CT. Other combinations of imaging modalities promise further enhancements to improve our ability to predict the biologic behavior of tissue.
11. The development of new imaging probes—radiopharmaceuticals, microbubbles, nanoparticles, and reporter molecules—will enhance the scope and specificity of imaging technologies.
12. The dramatic increasing in imaging data generated by imaging technologies has been made possible by improvements in computational capacity. More powerful algorithms for extracting information from the raw data must be developed.
13. In preclinical translational research, imaging can enhance the use of animal models for validating new targeted probes and illuminating key physiologic differences between animal models and humans.
14. Biomedical imaging can identify surrogate endpoints that, when combined with computational simulations, will predict the effectiveness of a therapeutic approach much earlier than traditional clinical trials, thereby reducing the costs and shortening the time to the delivery of effective agents into the marketplace.
15. Imaging has become essential not only for the detection and monitoring of disease but also for intervention. Methods of acquiring, analyzing, and displaying this information in real time during the intervention must be improved.
16. Methods to assess the effect of imaging on patient outcomes are needed.
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