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Directions in Engineering Research: An Assessment of Opportunities and Needs (1987)

Chapter: 2. Bioengineering Systems Research in the United States: An Overview

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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Page 85
Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Page 86
Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Page 88
Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Page 90
Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Page 106
Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Page 111
Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Suggested Citation:"2. Bioengineering Systems Research in the United States: An Overview." National Research Council. 1987. Directions in Engineering Research: An Assessment of Opportunities and Needs. Washington, DC: The National Academies Press. doi: 10.17226/1035.
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Bioengineering Systems Research in the United States: An Overview Executive Summary There is no more exciting and challenging field of science and engineering today than the study of living organisms from the entire body through its subsystems down to cells and subcellular processes, and the application of this knowledge to the develop- ment of products and technologies for the benefit of mankind. Already, bioengineering is using the advances made by molecular biologists, geneticists, and biochemists to generate products rang- ing from simple molecules to complex proteins. Advances in our understanding of human physiological systems have led to entirely new technologies for diagnosing disease and repairing or replacing damaged systems. The potential of these technologies for enhanc- ing human health, food production, and environmental quality is enormous. Bioengineering encompasses those disciplines that seek to ap- ply engineering knowledge to (1) the development of new and improved devices for health care, (2) the advancement of our un- derstanding of living systems, and (3) the scale-up and production of new products derived from advances in biology. It includes the fields of biomedical and biochemical engineering. (The latter encompasses the engineering aspects of biotechnology, including 77

78 DIRECTIONS IN ENGINEERING RESEARCH genetic engineering.) By its very nature, bioengineering is inter- disciplinary. It makes use of virtually every traditional engineering discipline as well as those sciences related to agriculture, biology, biochemistry, medicine, and public health. The uses of bioengineering research represent potentially sig- nificant economic opportunities for the United States. An esti- mated $4~$100 billion worth (in 1984 constant dollars) of bio- Togically derived products annually could be created by the year 2000 through biochemical engineering alone (National Academy of Sciences, 1984~. The overall market for biomedical engineer- ing devices and systems is estimated to be $11 billion for 1987. Because most engineering-intensive segments of that market have been growing at annual rates ranging from 10 to 25 percent, the potential size of the market by the end of the century is on the same order as that for biochemical engineering. To achieve the poten- tial that both fields offer, however, mere science and engineering research is required. American researchers have clearly established the United States as the world leader in the fundamental fields related to bio- engineering. Nevertheless, several European countries and Japan are currently devoting a significantly higher proportion of their na- tional resources to important elements of bioengineering research than is the United States. The economic stakes alone are consider- able. To assure U.S. leadership in this economically vital field, and to realize bioengineering's full potential for improving the quality of human life, more government support for research is needed. Support for bioengineering research is relatively small and scattered throughout the federal government. The National Sci- ence Foundation (NSF) and the National Institutes of Health (NTH) are the two principal agencies of the U.S. government that fund bioengineering research. Yet the National Bureau of Stan- dards (NBS), the National Aeronautics and Space Administration (NASA), and the Veterans Administration, among other agencies, also have programs or an interest in various aspects of bioengi- neering research. There is currently no interagency mechanism by which the programs of these various agencies are coordinated. Moreover, bioengineering research projects are typically spread among a va- riety of offices and programs within an agency. The NSF, for example, funds bioengineering research through its programs on biochemical and biomass engineering, biotechnology, and aid to

BIOENGINEERING SYSTEMS 79 the handicapped. Other NSF programs also support bioengineer- ing as a part of larger research studies. As a result, it is difficult to determine with certainty how much NSF spends on bioengineering research alone; however, the research budgets of the NSF divisions that support bioengineering total more than $12 million, of which $2.2 million is earmarked for the newly established bioengineer- ing research center at the Massachusetts Institute of Technology (MIT). The lack of a specific focus on bioengineering is particularly evident at NTH, where only an estimated $11 million out of a $660 million intramural research budget currently supports projects with a significant bioengineering component. Whereas NSF has recently created an Office of Biotechnology Coordination, no such mechanism exists within NTH. As the principal agency of the U.S. government for biomedical research, NTH emphasizes projects that focus on fundamental biological or medical science. Although it is estimated that about one-fifth of NTH's extramural grants include bioengineering studies, usually as a minor component of larger projects, those studies account for only about 3 percent of the extramural research budget. Few engineers sit on the committees that rank and fund research proposals. More generally, there has been a shift in government policy in recent years with respect to research funding. As a result of budgetary restrictions, the philosophy has changed from one that viewed research as an investment in the future to one in which it is considered explicitly as a means to product development. Whereas this approach is beneficial in many ways, it tends to overlook imaginative but speculative research proposals that could achieve significant long-term results. Industry involvement in bioengineering has become consider- able, particularly in the burgeoning field of biotechnology. How- ever, the activity is mostly limited in scope and focused on near- term product development. Sponsorship of fundamental research at universities has not been either substantial or consistent, nor is this situation likely to change soon. In the biomedical field, the market for many devices (e.g., prostheses) is small, and fails within an area in which government has traditionally held responsibility. (The situation in this respect is analogous to that for "orphan drugs." ~ Consequently, federal support of both basic research and the fundamental engineering research needed to realize the useful

80 DIRECTIONS IN ENGINEERING RESEARCH potential of basic discoveries in bioengineering will continue to be essential. This report identifies 11 areas within the field of bioengi- neering that could produce important research results in the years ahead. Eight areas involve biomedical engineering research. These are systems physiology and modeling, human rehabilita- tion and neural prostheses, biomechanics, biomaterials, biosensors, metabolic imaging, minimally invasive diagnostic procedures, and artificial organs. Three areas of biochemical engineering were also selected bioreactors and biocatalysis, separation and purifica- tion, and bioprocess instrumentation and control. These research areas illustrate the potential for bioengineer- ing research and point out where financial support is urgently needed to achieve significant results. They are not, however, the only research areas worthy of government support. In addition, the listing of eight biomedical engineering and three biochemical engineering topics does not signify any relative priority between the two subfields of bioengineering. Both subfields are essential. Although each of the research areas presents its own spe- cific needs and opportunities, certain ones are common to more than one area. For example, more research is needed to extend our knowledge of the physical and chemical properties of living tissues, cells, and subcellular components as well as their relationship to each other. Such research is of particular importance to our under- standing of systems physiology, but could also be applied to neural prostheses, biosensors, biomaterials, and artificial organs. More also needs to be known about the characteristics of materials used in biomedicine and how those materials interact with living tis- sue. This information would be important in developing both new prostheses for disabled persons and new minimally invasive tech- niques for diagnosis and treatment. In this regard, mathematical modeling is important for learning how to represent the properties and behavior of tissues, cells, and subcellular components so as to simulate the response of a living system. Certain topics hold special importance. Improved biosensors, for example, could convert biological signals more quickly and re- liably into electronic responses that can be processed and used for medical diagnoses, as well as providing the input needed for the control and optimization of industrial bioprocesses. Research on biosensors could also help scientists and physicians to better

BIOENGINEERINrG SYSTEMS 81 understand the body's natural sensors. To be useful, however, biosensors must be compatible with the human body and its signal processing systems. Similarly, advances in metabolic imaging could also aid diag- nosis. This field has already produced positron emission tomog- raphy and nuclear magnetic resonance imaging, among other new technologies. Further developments, however, may depend on ba- sic research on tissue properties, both physical and biochemical, and on integrative systems analysis. A third area in which bioengineering research can make par- ticularly significant contributions is the development of artificial organs. Organ replacement is still in its infancy, and great strides can be expected in the future. At present, air-driven artificial hearts are the focus of attention; work is also progressing on elec- trically powered devices that would be implanted to assist the heart for several years rather than replace it. However, many of the body's organs besides the heart are potential candidates for replacement or assistance by engineered devices. Multidisciplinary efforts combining biochemical and biomedical engineering should eventually lead to synthetic systems able to replace a range of human organs and all the functions a single organ performs. In the expansion of biomedical technology, there is a promise of vastly improved health care delivery, possibly even at reduced costs (as illustrated in this report in connection with percuta- neous transTuminal angioplasty). Greater attention needs to be paid to the costs and benefits associated with the introduction of new technologies and new devices to encourage their elective and efficient use and to discourage costly and wasteful practices. To carry out these research programs and projects, more trained bioengineers will be needed. Although the total number of bioengineering students in U.S. graduate schools has increased significantly during the last decade, the number relative to all engi- neering graduate students has remained about the same (roughly 2 percent). Greater support for university programs from NSF and NTH would encourage more engineering graduate and post- graduate students to go into bioengineering. Studies indicate that there are not enough biochemical en- gineers in the United States today to meet existing needs. In addition, there is a shortage of the qualified faculty members needed to expand graduate enrollments and courses in the future.

82 DIRECTIONS IN ENGINEERING RESEARCH Fewer than 20 U.S. colleges and universities now have meaning- ful biochemical engineering programs. In part, this is because biotechnology is still a relatively new field of study, and one that is highly interdisciplinary. In order to realize the vast potential of this field for improving the quality of life, and to meet the strong competitive challenge that other nations are mounting to capture the large market for products of biotechnology, it is imperative that we provide the incentives and the research programs needed to increase the cadre of research talent. RECOMMENDATIONS The following recommendations of the panel are excerpted from the section "Conclusions and Recommendations" at the end of this chapter. See that section for accompanying conclusions and rationale, which are in turn based on the report itself. 1. The panel recommends that the coordination of research programs in bioengineering throughout the federal government be improved and that the coordination include the relevant work of NTH, NSF, NBS, and other agencies interested or involved in bioengineering research. To ensure its effectiveness, it is essential that this interagency coordinating effort receive the full recognition and support of upper management in each of the participating agencies. 2. The coordination of bioengineering research within sup- porting agencies should also be improved. For example, NTH could create an "office of bioengineering research" to review and coordinate its investigations. Such an office would be one way of focusing attention on the careful development of this important field. 3. NIH should give careful attention to the need for large- scale, focused research in biomedical engineering. To achieve the required scale, NTH should consider creating a center for such research, comparable in concept and size to the Engineering Re- search Centers being created by NSF. Any such NTH center should encourage links between acadern~c research and clinical practice. 4. Both NTH and NSF should devote a greater share of their research budgets to supporting bioengineering programs at U.S. universities and colleges. NIH in particular should expand its pro- grarns that encourage medical students to go into research so as

BIOENGINEERING SYSTEMS 83 to include bioengineers as well. Stipends awarded for postdoctoral study should be sufficiently high to offset the attractiveness of salaries offered by industry. 5. Those who rank and award grant proposals within NIH and NSF should consider funding research projects that have a great potential for significant results, but also a high risk of failure. The pane] applauds the strong current trend in this direction at NSF. 6. Bioengineering in all its aspects is advancing rapidly. To ensure the Tong-term health of this commercially important field, a permanent advisory body should be created within the Executive Branch. This body would assess bioengineering research opportu- nities and needs, review the relevant research programs of NIH, NSF, and other government agencies, and identify needs for new programs or changes in directions. Introduction RATIONALE FOR A STUDY Bioengineering is associated with questions that have gener- ated some of the most intense interest, excitement, apprehension, and debate ever seen in the context of American science and technology. Within the last decade, some of its newer and more revolutionary elements have captured the attention of the public fully as much as they have the interest of the research community. From heart transplants and reproductive technology to genetic engineering, these are topics that fascinate people because they deal so intimately with life itself. Apart from (or perhaps partly because of) its intrinsic interest to researchers and the public, bioengineering also has tremendous economic potential. It Is one of the fields on which our most forrn~dable international industrial rivals are placing great em- phasis; it is also a field that holds the promise of providing the new technologies needed to supply our increasingly sophisticated medical care at minimum costs for benefits received. Thus, the Engineering Research Board considered it to be essential to iden- tify research needs in this field and to assess the health of the environment within which it is conducted.

84 DIRECTIONS IN ENGINEERING RESEARCH SCOPE OF THE STUDY The Pane] on Bioengineering Systems Research was formed to address the status of research in the bioengineering field.* In particular, it was charged with identifying new or emerging areas of research. To establish boundaries, the pane] defined three broad areas of research as falling within the scope of its study. These are . the application of engineering knowledge and concepts to understanding the human body and other biological systems and the interaction of humans, machines, and the environment; . new and improved biomedical devices for use in maintain- ing health and treating disease; and . the manufacture of products using the techniques of the so-called "new biology," including molecular and cellular biology. Because of the need to set boundaries, certain significant areas could not be addressed; agriculture and food processing and mili- tary bioengineering are examples of such areas. In addition, those areas falling primarily within the purview of other panels of the Engineering Research Board were not specifically addressed. It is worth noting that considerable confusion exists over the terms used to describe the field of engineering that seeks to apply the biological and medical sciences. ~Bioengineering,n Genetic engineering,n ~biotechnology," and ~biomedical" or ~biochemical" engineering all have their adherents; often the terms are used almost interchangeably. This report uses ~bioengineering" to encompass those disci- plines that seek to apply our understanding of living systems to the engineering of useful products. Bioengineering uses the knowI- edge gained through research to develop new and improved devices for use in maintaining health and treating disease as well as for the manufacture of products using the processes of modern biol- ogy. Thus, bioengineering can be said to include both biomedical and biochemical engineering. The latter terms are used, where appropriate, when referring to those specific areas. In the three areas listed previously as being within the scope of bioengineer- ing research, the second refers to biomedical engineering and the *The word "systems" is used here to denote, not "systems engineering," but the organismic, physiological, and hardware systems on which this research focuses. For a more detailed definition of this concept, see the report of the Engineering Research Board.

BIOENGINEERING SYSTEMS 85 third refers to biochemical engineering. The first item on the list is relevant to both disciplines. Biomedical engineering research investigates (1) the structure and properties of cells, tissues, organs, and whole bodies; (2) the growth and repair of living tissues; (3) strength and tolerance; (4) the behavior of electrically excitable tissues; and (5) relevant surface and flow phenomena. All of these topics apply to the diagnosis and treatment of disease, as well as to rehabilitation, prostheses, artificial organs, aging, and trauma-related injuries. Biochemical engineering includes the engineering aspects of biotechnology. Biotechnology was cleaned in a recent study (Office of Technology Assessment, 1984) as the ruse of living organisms (or parts of organisms) to make or modify products, to improve plants or animals, or to develop microorganisms for specific uses." Thus, there is clearly a substantial overlap with the "new biology." By its nature, Bioengineering research is broadly interdisci- plinary in scope. It relies heavily on the life sciences: biochem- istry, biophysics, biology, medicine, public health, and agriculture. It makes use of virtually every branch of engineering, as well as subdisciplines within the various engineering fields, such as struc- tures, fluid mechanics, thermodynamics, circuit and field theory, and signal processing. Bioengineering also draws from mathemat- ics, chemistry, and physics. Probably no other field of engineering embraces so many spheres of human inquiry. BACKGROUND Bioengineering depends heavily on information gained from the biological and biomedical sciences. It differs from them by focusing on living organisms as systems that can be used for the benefit of mankind. Bioengineering research seeks to discover and organize the information needed to develop new products and processes. In this sense, Bioengineering is concerned with applying basic advances in our knowledge about the human body and other biological systems. To achieve its potential, more engineering research as well as scientific research is required. Processes in biology and medicine, however complicated, ul- timately obey the same basic principles as all the other natural sciences. Thus, an essential step in the engineering of biological processes is the development of mathematical models that describe

86 DIRECTIONS IN ENGINEERING SEARCH and predict biological behavior. Historically, many important ad- vances in the natural sciences have been founded on models based on experimental data. The structure of DNA is perhaps the best known example. Others include cardiovascular flow, the tribology of synovial joints, and musculoskeletal modeling. Together these models have clarified understanding and led to practical develop- ments in diagnosis and therapy. Bioengineering seeks not only to make new devices, but also to understand them more fully. For example, the first artificial heart valve required engineering research. The development of heart valves designed to last a lifetime must be based solidly on the prin- ciples of fluid mechanics, physiology, and biomaterials research. Correspondingly, anatomy, physiology, and pathophysiology in- terpreted by bioengineers at the system and cellular level are being illuminated in new and important ways that lead to novel and less invasive diagnostic methods, replacement joints and or- gans, and other processes and products that improve medical care and enhance human health. Advances in basic science drive the engine of invention and improvement. Breakthroughs in computer science and information science, for example, with their attendant engineering advances in hardware and software, have many poten- tial applications in bioengineering. (See the report of the Pane} on Information, Communications, Computation, and Control Sys- tems Research for a discussion of breakthrough research areas in these fields.) These technologies oilier solutions to long-standing problems in biology, medicine, and health care delivery, as well as improvements to current practices. In addition to the basic capa- bility for computer modeling, promising examples would include the availability of Smart microprocessor-based analytic instru- ments in biology, expert systems in support of medical diagnosis, new imaging diagnostic technologies, and various clinical and med- ical information systems to enable effective and economical health care delivery. Similarly, there have been tremendous advances in the basic sciences relating to gene manipulation. Genetic engineering uses recombinant DNA and cell fusion techniques built on a strong science base in molecular and cellular biology, biochemistry, and microbiology to construct biocatalysts that can produce, under controlled conditions, seemingly limitless numbers of potentially useful products. The ability to make biological products has cre- ated many research needs in the area of bioprocess engineering.

BIOENGINEERING SYSTEMS 87 However, in contrast to the long-standing relationship between chemistry and chemical engineering, no comparable association yet exists between biology and biochemical engineering. Such a relationship is absolutely necessary to extend the practical imple- mentation of genetic engineering. There are many potential uses for the products of biotech- nology. In the health field, new pharmaceuticals for humans and animals are being developed from naturally occurring molecules that are more effective and safer than the drugs they will replace. Monoclonal antibodies and genetically engineered enzymes are now being used to diagnose various diseases. In the area of food production, growth promoters can be used as a food supplement to improve animal nutrition. New crop varieties can be made that will be more resistant to adverse environmental conditions or disease. In addition, crop production will be more effectively controlled by the use of growth regulators. In the area of environ- mental quality, new and more effective ways can be designed to detoxify waste. Similarly, biocatalysis can be used to produce a wide range of chemicals now made from conventional feedstocks. Apart from their obvious benefit to mankind, the applica- tion of these concepts through bioengineering also presents sig- nificant economic opportunities for the United States. Biochemi- cal engineering could create an estunated $4~$100 billion worth of biologically derived products annually by the year 2000 (Na- tional Academy of Sciences, 1984~. The market for biomedical engineering devices (including diagnostic imaging, therapeutic de- vices, medical laboratory instruments, and medical information and other communication systems) is estimated at $11 billion for 1987 (Attinger, 1984), and is growing at an annual rate of 10-25 percent, so that the potential size of this market in the year 2000 is similarly large. However, considerable research is still needed in a variety of areas to take advantage of these vast opportunities. Especially Important or Emerging Areas of Bioengineering Systems Research The Pane! on Bioengineering Systems Research has identified 11 subjects, divided into two broad categories, that represent es-

88 DIRECTIONS IN ENGINEERING RESEARCH pecially important or emerging areas of bioengineering research. The areas selected emphasize the potential usefulness of the results of engineering research in this dynamic field. They are not, how- ever, the only areas worthy of research or likely to yield important results; space limitations preclude a more complete listing. These 11 subjects include 8 areas of biomedical engineering re- search and 3 areas of biochemical engineering research that require priority attention if advances in this field are to proceed rapidly and in a balanced fashion. The areas in biomedical engineering are 1. systems physiology and modeling; 2. neural prostheses for human rehabilitation; 3. biomechanics; 4. biomaterials; 5. biosensors; 6. metabolic imaging; 7. minimally invasive medical procedures; and 8. artificial organs. The areas in biochemical engineering are 1. biocatalysis/bioreactors; 2. separation and purification; and 3. bioprocess instrumentation and control / It is important to emphasize that no priority is implied by the ordering of either the major sections or the topics within sections. The pane! stresses that biomedical and biochemical engineering research are both of vital importance for the health, well-being, and economic fortunes of the nation. BIOMEDICAL ENGINEERING Biomedical research leading to new technology offers the promise of vastly improved health care delivery, possibly even at lower cost per patient (for example, through the automation and centralization of some aspects of health care). Yet with the continued growth of demand for health care services, the increas- ingly greater sophistication of biomedical technology, and an aging U.S. population, there is also the risk that costs can become exor- bitant. As we introduce the biomedical engineering research topics identified as having high priority, the pane! emphasizes that care- ful attention needs to be paid to the costs and benefits associated

BIOENGINEERING SYSTEMS 89 with the introduction of new technologies and new devices to en- courage their effective and efficient use and to discourage costly and wasteful practices. SYSTEMS PHYSIOLOGY AND MODELING I,iving organisms are immensely complex systems. A "mere" subcomponent such as the human brain cannot be rivaled by the largest currently imaginable supercomputer. Neither has even a small system, such as a single red blood cell, ever been fully under- stood in terms of its physical, chemical, and material properties or behavior. In addition, a red blood cell, with some 2,000 metabolic reactions, is less complex than growing, dividing cells or cells with excretory or contracting functions. We now know enough basic facts~in cell biology, biochemistry, and physiology, however, so that an integration of this knowledge is practicable. More information is needed to improve such in- tegration and to translate the results into effective therapies. In particular, more data are needed on anatomy (tissue components and their relationships); on physical properties of tissues, cells, and subcellular components; on chemical and biochemical prop- erties; and on regulatory, transport, and communication mecha- nisms (hormones, agonists and antagonists, receptors, and neural stimuli). The integration of information, expressed quantitatively, can be tested for overall validity by formulating a mathematical model of the system. Such models can serve as repositories for and summaries of vast amounts of information. They can also be used to determine what is missing from our knowledge, because every assumption requires proof by evidence from observation. Mathematical modeling of larger physiological systems will provide a basis for identifying their abnormalities and the rami- fications for cellular, organ, or whole organism behavior, or even for ecology and economics. Mathematical modeling is also appli- cable to studies of plant cells and microorganisms. Some aspects of modeling may also give rise to spin-ofEs in other engineering sci- ences, as is already happening with certain numerical methods for solving partial differential equations and algorithms for parameter optimization.

go DIRECTION'S IN ENGINEERING RESEARCH Physiological knowledge, especially as expressed in models, has a wide range of potential applications in bioengineering. Con- sidering the influence on biological function of mechanical factors such as force, pressure, and strain, or of kinetic and potential energy, entropy, or temperature (to take but a handful of exam- ples) provides many opportunities for bioengineering advances in medicine. For example, the interaction between fluid mechanical forces and the endothelial cells that line the walls of arteries ap- pears to play an important role in the development and spread of atherosclerosis. In another area, the study of load-bearing joints has revealed that friction-induced temperature increases produce direct mechanical effects on, and biological changes in, the bones and tissues of joints. This finding has opened research "windows" on the question of how arthritis occurs. NEURAL PROSTHESES FOR HUMAN REHABILITATION Some 12 percent of the U.S. population suffers to some degree from physical disabilities. Many are victims of congenital de- fects, acquired diseases such as cancer, or trauma. The treatment for such chronic disability is technology dominated and systems oriented the realm of the biomedical and rehabilitation engineer. Despite very modest funding for this research, the lives of handi- capped persons have been significantly improved through a variety of technologies. These include computer braille, reading machines, and electronic mobility aids for the visually handicapped; hearing aids for the deaf; postamputation prostheses; and microcomputer- based communication for those who cannot speak. Rehabilitation and prosthetic devices also contribute greatly to the quality of life of those who have suffered serious trauma. Each year, more than 80,000 Americans sustain permanently dis- abling but nonfatal injuries to the brain or spinal column (National Academy of Sciences, 1985~. The direct and indirect costs to so- ciety of these injuries add up to an estimated $75~$100 billion a year. A new class of neural prostheses are being made possible by integrated electronic circuits, together with an improved un- derstanding of stable and biocompatible electrodes. Such circuits connect directly with the central and peripheral nervous systems. Several examples, some now available, illustrate the potential. The first ear implant to bring sound to the neurologically deaf via a simple electrode has recently received approval from the U.S.

BIOENGINEERING SYSTEMS 91 Food and Drug Adrn~nistration. Multichannel devices that can process sound promise in the future to enrich the hearing of the profoundly deaf, and ultimately to permit them to understand speech. Farther off are attempts to regain a semblance of vision by electrical stimulation of the occipital cortex. Neural prostheses even offer hope of restoring functional movement and bladder control to those who have suffered a stroke or spinal cord injury. To achieve this potential, more research is needed on the sys- tems physiology of movement, speech perception, and vision. Re- search is also needed on circuit design, transducer and electrode de- velopment, control and microprocessor systems, custom-integrated monolithic chip design, and fabrication packaging designed for the human belly. Work in a variety of mechanical areas would also be useful. These areas include compact and quiet actuators, com- plex drives and linkages, transducers, automatic controls, systems integration and design, and power supplies. BIOMECHANICS Biomechanics deals with the response of living matter to phys- ical forces. Molecules, cells, tissues, organs, and individuals move, deform, grow, or atrophy as a result of these forces. Hence, they are subject to the laws of biomechanics. The objective of biome- chanics research is to explain and reduce both trauma (as occurs in accidents and sports) and long-term deterioration (as seen in low back pain and osteoarthritis). In recent years, research in biomechanics has improved our understanding of the nature of blood flow, joint movements, Im comotion, trauma, and healing. It has guided the development of clinical diagnostic and treatment procedures, the design and manufacturing of prostheses for sick and disabled persons, and the invention of new medical instruments. Biomechanics research has led to the development of devices and methods that have improved human performance in the workplace, in sports, and in space, and has developed ways to improve automobile safety. An important area of biomechanics research is directed to- ward preventing injuries. Injuries are the fourth leading cause of death in the United States. For ages 1-44, they are the leading cause of death, and for ages 5-44, they kill more people than all other causes combined (National Center for Health Statistics, 1983~. More research is needed on the biomechanics of injury and

92 DIRECTIONS IN ENGINEERING RESEARCH disability. How does the human body, for example, respond to me- chanical forces such as those imparted by automobile dashboards, bullets, and knives? In addition, how do different head move- ments cause injury? Research will improve our understanding of how permanent disability occurs. The recent discovery that the use of alcohol significantly decreases the strength of nerve fibers is an example of such research results. In the future, biomechanics research could reduce the inci- dence of heart diseases, atherosclerosis, and stroke—the leading killers of humans through an improved understanding of the in- teraction of blood flow and blood vessel walls. Research on stresses in the lung could be used in treating emphysema. Similarly, re- search on the spinal column could be used to prevent certain types of back pain. Research could also lead to new ways of prevent- ing arthritis and joint degeneration, and to the development of permanent joint replacements. In another area, biomechanics research is an integral part of the development of artificial limbs, heart valves, hearts, and kid- neys. Future research will aim at developing permanent artificial internal organs that ameliorate the problems of biocompatibil- ity. Such research will focus on the mechanics of living cells and biomolecules in order to understand how artificial materials inter- act with the cells of the body (see the next section). It will also focus on the relationship between the growth of cells and the phys- ical stress caused by fluid! flow and tissue deformation. Knowing the correct range of stresses to apply to the cells could provide a key to controlling the growth of living tissues. Through biomechanics we seek a thorough understanding of the neuromuscular control system. Such an understanding is the key to developing artificial limbs and robotics, which could lead to ambulatory systems for the disabled. It is also important to enhancing productivity through workplace design. BIOMATERIALS Many new opportunities to synthesize materials derive from the ability to manufacture and modify polymers and specific macromolecules. These materials can be designed for specific pur- poses. Notable examples include membranes that provide timed drug release by constraining diffusion, implantable pumps for de-

BIOENGINEERING SYSTEMS 93 livering insulin over an extencled time, and glucose sensors now being developed for diabetics. To develop new biomaterials, bioengineering researchers are conducting basic studies on the interactions between different bi- ological molecules and cells in various physicochemical environ- ments. Increased knowledge and improved assays have paralleled the development of new clinical devices and implants. Yet, because of the complexity of the interaction between artificial] biomaterials and living cells, our knowledge is still far from complete. Contin- ued support of basic research is needed. Particularly important biomaterials research needs are to: . elucidate the physicochemical characteristics of materials to be used in cardiovascular devices; . investigate how materials interact with bone, teeth, and other tissues; and pursue the development of encapsulation materials de- signed specifically for implanted devices. BIOSENSORS Biosensors convert biological information into an electronic signal that can be processed and used in diagnosis, treatment, and in viva control. Improved biosensors and instrumentation systems would permit earlier disease detection. They could provide better and more reliable data, allow more medical care to be accom- plished outside traditional hospitals and clinics, make it possible to monitor patients at home, and thus reduce health care costs. Research on biosensors should also help scientists to better understand the body's natural sensors and actuators. This could in turn lead to ways of obtaining signals from the body's natural sensors by using devices that monitor the nervous system. Smaller, more reliable, and more reproducible sensors might be built us- ing micromachining technology adapted from the microelectronics industry. Such sensors could be directly integrated with signal processors or preprocessors to improve reliability. To be useful, biosensors must be compatible with the human body and with signal processing systems. This aspect of the prow lem requires further study. Sirn~larly, research is needed to develop noninvasive or minimally invasive sensors that would permit di- agnostic and therapeutic monitoring of a patient at home (for

94 DIRECTIONS IN ENGINEERING RESEARCH example). The information from the sensor would be sent to a hospital computer, where it could be read by a physician, nurse, or technician. An important emerging area of biosensor research involves chemical sensors for both laboratory and in viva monitoring. A chemical sensor monitoring blood and urine chemistry, for exam- ple, could provide physicians with bedside information, thus mak- ing earlier diagnosis possible. Research is needed in areas such as membranes (allowing controlled charge transfer), adherence to semiconductor surfaces, and the coupling of biological molecules to traditional electronic and optoelectronic circuits. Such research could lead to better control of therapeutic devices, closed-Ioop pharmaceutical administration, artificial organs, and prosthetics. METABOLIC IMAGING Metabolic imaging involves the use of positron emission too mography (PET), nuclear magnetic resonance (NMR), x-ray com- puted tomography, ultrasound, or other technologies to obtain in- formation on how the body chemically alters, uses, and eliminates food, drugs, hormones, and other substances. These techniques are safe and powerful means of seeing inside the body so as to determine remedial action more precisely or to avoid unnecessary · . Invasion. Recent developments in metabolic imaging include (1) rapid improvements in NMR technology, providing better chemical reso- lution and the potential for imaging cell pH, phosphorus in varied forms, sodium, and other atoms as well as protons (hydrogen); (2) higher temporal and spatial resolution by PET; (3) rapid advances in the kinetics of mass transport and transmembrane exchange; and (4) deeper insight into biochemical regulation in intact func- tioning organs. The new technologies provide better data for interpreting high-resolution spatial unages in terms of rates of transport across membranes, intracellular reactions, and cell functions. To better interpret images and understand their limitations, more needs to be known about kinetic modeling of physiological and biochemical events and about the biochemical changes that occur in disease. This field, highly dependent on basic research in tissue properties (both physical and biochemical) and on integrative systems anal- ysis, is one that could lead to important scientific achievements as

BIOENGINEERING SYSTEMS 95 well as substantial industrial activity. High costs are a feature of most of these technologies. Cost reduction in health care is a long- range (5- to Midyear) proposition an initial several-year period of intensive exploration often leads to a state of knowledge wherein the expensive procedures are used more selectively or replaced by specific and cheaper methodologies. MINIMALLY INVASIVE MEDICAL P RO CEDURES Minimally invasive medical procedures either replace or pre- clude the need for major surgery. One example is the treatment of coronary arteries whose interior walls have become covered by plaque. This deposit restricts bloodflow through the arteries, so that less oxygen is available to the heart. Individual cardiac mus- cle ceils die and, in severe cases (i.e., myocardial infarction), death occurs through arrhythmia or a failure of the heart to contract effectively. Treatment today involves open heart surgery and the replacement of obstructed arteries with segments of veins trans- planted from other parts of the body. Such surgery, though no longer much more risky than an appendectomy, is still traumatic and very expensive. Percutaneous transluminal angioplasty is a minimally invasive procedure in which a catheter is threaded into the restricted vessel from an artery in the leg or arm and a small balloon at the end of the catheter is inflated so as to dilate the affected blood vessel. The goal is to reopen the vessel, taking care not to weaken or tear it. Angioplasty not only reduces patient discomfort and recovery time, but also reduces the costs of treatment. At present, some 250,000 cardiac bypasses are performed annually at a cost of about $16,000 each, or more than $4 billion in total. Angioplasty costs about half that much. Other minimally invasive procedures could have similar cost savings. If they were to replace all bypass procedures, a possible savings of $2 billion per year could be achieved. Experiments are currently being conducted on the use of lasers to remove plaque. The development of this new approach will involve analysis of the mechanical stresses borne by the artery, the desired hydrodynamic properties, and how the laser affects both plaque and healthy tissue. It will also require the design of new mechanical, electrical, and optical instruments. These advances will demand broad engineering skills and knowledge.

96 DIRECTIONS IN ENGINEERING RESEARCH ARTIFICIAL ORGANS Most body organs perform many functions. They typically perform mass transport or mechanical action while separately releasing a substance into the blood that sends a chemical or molecular signal to other organs. Relatively normal physiology and biochemistry is needed for all organs to work in concert and produce a feeling of well-being. A single failed organ can cause disability or death. Recently, medical science has turned to organ transplants and mechanical or synthetic devices to replace diseased organs. Organ replacement is only in its infancy, and great strides can be expected in the future. Current synthetic devices either perform an intermediary metabolic activity or replace a specific mechanical function. The artificial heart is an example of the latter. Air- driven artificial hearts have been implanted in a few patients to replace failed natural ones. Work is progressing on electrically powered devices that would be implanted to assist the heart for several years rather than replace it. These devices are undergoing careful testing to ensure their safety, effectiveness, and reliability. Clinical evaluation is anticipated in the next few years. Whereas the artificial heart program is exceedingly expensive, the development phase will benefit selected individuals. Other organ replacements, such as implanted insulin-producing cells for diabetics, may be less costly. In the future, multidisciplinary efforts combining biochemical and biomedical engineering should eventually lead to synthetic systems capable of replacing a natural, multifunction organ in human beings. BIOCHEMICAL ENGINEERING Biological processes and organisms have been used commer- cially for centuries, but the degree of sophistication and the range of new uses and products have increased significantly in recent years. In fact, the principal limitation on the development of ad- ditional commercial products through biochemical engineering, or biotechnology, is the lack of a technology base that can address the following key challenges: . more experience and better techniques in the use of large- scale cell cultures so that the full range of plant and animal cell

BIOENGINEERING SYSTEMS 97 systems can be used, rather than just simple microorganisms (e.g., bacteria and yeasts); . a broadened understanding of enzymic catalysis in aque- ous, nonaqueous, and mixed-solvent systems so that the chemical process industry can meet selectively and efficiently the increasing challenges posed by environmentalimpact, energy use, and (most important) process chemistry; and . an expanded knowledge base to achieve large-scale process- ing, including the recovery and purification of complex, unstable biological macromolecules (e.g., antibodies and peptide hormones) from product mixtures, as well as the economical and efficient recovery of simple biologically derived organic compounds (e.g., ethanol and amino acids) from highly dilute and impure solutions. The pane} identified three specific areas of research aimed at meeting these challenges: biocatalysis/bioreactors, separation and purification, and bioprocess instrumentation and control. These research needs parallel closely those identified in 1984 by the Pane! on Chemical and Process Engineering for Biotechnology in a briefing to the Office of Science and Technology Policy (National Academy of Sciences, 1984~. BIOCATALYSIS / BIOREACTORS Mechanically agitated reactors currently used for antibiotic fermentations are often poorly or not at all suited to meet the diverse demands of bioprocessing. New techniques are needed for la~ge-scaTe culture of plant and animal cells as well as of the new microorganisms now being engineered for bioproduct synthesis. Fundamental knowledge of how physical and environmental fac- tors influence intracellular biosynthetic pathways is essential to the development of such techniques. Bioreactor research will require joining such sciences as molecular and cellular biology, microbi- ology, and cell physiology with basic engineering skills, chemical kinetics, thermodynamics, fluid dynamics, heat and mass trans- port, and precise bioprocess control a rare combination today in either industrial or academic laboratories. An important parallel direction for bioreactor research is the development of methods for using free or immobilized enzymes, combinations of enzymes, or nongrowing whole cells as catalysts for biosynthesis. The effective use of such diverse forms of bio- catalysts requires exploration of fluid bed, fixed bed, membrane,

98 DIRECTIONS IN ENGINEERING RESEARCH cell recycle, tubular, and other reactor types in which to carry out biosynthesis. The challenge is to translate the existing knowI- edge base for chemical reactors into biosystems in which strict asepsis, complicated biological regulation processes, enzyme and cell fragility, cofactor regeneration of enzyme activity, and main- tenance of cell energy all add to the problem. Fundamental pro- cesses developed in benchtop systems must be tested in large-scale equipment to gain an understanding of the scale sensitivity of biosystems. S EPARAT 10 N AN D P URIF IC ATIO N Once a bioreactor has done its job, the resulting mix must be separated and purified to isolate the desired product. For fragile, high-unit-value products intended for human or animal use, there is a premium on processes that minimize deterioration and max- imize purity. For low-unit-value products, in which competition lies in nonbiological factors, the premium lies in energy-efficient recovery processes with low environmental impact. Biotechnology can benefit from increased research on three aspects of separation and purification. 1. Modification of conventional, large-ecale industrial sepa- ration methods. Ton-exchange chromatography, pressure-driven membrane separation, electrodialysis, and liquid-liquid extraction are now used in industry to recover or purify antibiotics and simple molecules, such as citric acid. These methods are generally too nonselective or too destructive to be used for processing fragile proteins. Refined techniques are needed to make them suitable for recovering the newer products of biotechnology. 2. Adaptation of biochemical laboratory separation methods to large-ecale bioprocess~ng. Life scientists have developed ex- tremely powerful and sophisticated tools, such as electrophoretic and affinity separation, that could be used for large-scale separa- tions. However, much needs to be learned about the molecular mechanisms and kinetics of these processes before they can be used to make products. 3. Novel separation and purification concepts. New separa- tion and purification concepts are needed that combine physical, chemical, and biological processes in unconventional ways. Sev- eral such processes are being studied in Japan and Europe. Some

BIOENGINEERING SYSTEMS 99 concepts, such as aqueous two-phase separations that use water- soluble synthetic polymers and multifield fractionation, are based solely on physicochemical principles. Other processes combine bio- chemistry and cell biology with industrial chemistry and chemical engineering. Examples include separation based on modification of permeability, separation by selective enzymic transformation, and separation by genetically manipulated intracellular processes. BIOPROCESS INSTRUMENTATION AND CONTROL Sophisticated process control is required to successfully oper- ate bioreactors and downstream processing equipment. This, in turn, depends on accurate measurement of critical process vari- ables and the use of advanced estimation algorithms, process mod- els, and control strategies. Current biosensors and control meth- ods often lack the desired reliability or the capability to regulate process conditions with the necessary sensitivity. furthermore, the proper sensors often do not exist to mon- itor complex biological substances on-line. The use of enzymes, monoclonal antibodies, and even whole living cells as components of electrochemical and optical detectors could solve some of these problems. Research on bioprocess models is needed to develop optimal control strategies and to extract the most useful information from measurements. Formulation of these models will require more advanced control algorithms and a greater knowledge of the effects of engineering parameters on cells and complex molecules. Issues Determining the Health of the Field Bioengineering is a diverse field, and many elements of it are very new. Enormous social benefits are anticipated as a result of new knowledge, new procedures, anti new products derived from research in both biochemical and biomedical engineering. However, an important secondary social benefit to be reaped from the explosive growth expected in this field lies in its economic potential. We in the United States can use these technologies to improve our lives; but we can also use them to help strengthen the nation as a whole by creating jobs and a positive balance of trade.

100 DIRECTIONS IN ENGINEERING RESEARCH This is one of the main perspectives from which the Engineering Research Board, and in turn this panel, was asked to view the health and the future of engineering research. The nation that leads in research has an edge in commercial- ization. American researchers have clearly established the United States as the world leader in fundamental research in most as- pects of bioengineering, but this position is being challenged. The area of the field with the greatest untapped commercial potential is biochern~cal engineering, or biotechnology. Several European countries and Japan are devoting a significantly higher propor- tion of their national resources to this expanding area than is the United States. In addition, their support is better planned and coordinated. Federal policies toward bioengineering and federal funding for it have a profound effect on its directions and rate of development. Industry involvement, both in the health care field with biomed- ical engineering and in the newly emerging biotechnology field, also affects the health of bioengineering. Finally, the availability of adequate numbers of qualified researchers in biomedical and bio- chemical engineering is critical to the continued development and maintenance of American preeminence in these important areas of · — engineering. IMPACT OF FEDERAL POLICY To maintain U.S. leadership and to realize the full potential of bioengineering for improving the quality of mankind's life and health, more research of the kind discussed in the previous section is needed. Unfortunately, support for such research is at relatively low levels and is scattered throughout the federal government. One reason is the newness of bioengineering. Another reason is its intrinsically interdisciplinary nature. As we pointed out ear- lier, bioengineering encompasses and utilizes elements of several scientific and engineering disciplines. This diversity confounds the delineation of policy issues and research programs. Organizations, both within and outside government, perform best when they deal with well-defined and reasonably restricted bodies of knowledge, competencies, and interests. Because bioengineering defies such constraints, it lacks the organizational focus that biomedical sci- ence research receives, for example, at NIH or that oncology, to use a more specific example, receives at the National Cancer Institute.

BIOENGINEERING SYSTEMS 101 Support for bioengineering research is spread across a number of government agencies, including the NSF, NTH, NBS, the Depart- ment of Energy, and the Veterans Administration, among others. The U.S. Department of Agriculture and the Defense Advanced Research Projects Agency support small programs of engineering research in biotechnology. Besides being spread across agencies, bioengineering research is often spread out among different units and programs within these agencies. Thus, the precise extent of government support for bioengineering research is difficult to determine. N S F SUPPORT Until the NSF recently created an Office of Biotechnology Co- ordination, it was hard to find reliable figures for bioengineering research in the principal agency through which the U.S. govern- ment supports scientific and engineering research. Most bioengi- neering research supported by NSF falls within its Engineering Directorate, which has programs in biochemical and biomass en- gineering, biotechnology, and aid to the handicapped. These three programs had a combined budget of $9.4 million in FY85. The Office of Biotechnology Coordination has now set up a scientific advisory committee and maintains a biotechnology information system for all of NSF. In addition, NSF has created six engineering research centers (ERCs) at major universities in the United States. The ERC pro- gram is designed to promote fundamental engineering knowledge by focusing on cross-clisciplinary research. One center, at MIT, is devoted to biotechnology. It specializes in research on genetics and molecular biology, bioreactor design and operations, product isolation and purification, and biochemical processing. NSF has awarded the center at MIT, known as the Biotechnology Process Engineering Research Center, $20 million for an initial 5 years ($2.2 million in operating funds in 1985~. In addition, NTH has given the center an initial grant of $100,000. NSF also provides funds for biomedical and biochemical en- gineering research through various other engineering divisions, as well as through its Industry-University Cooperative Research Project. Together, these funds make up nearly another $1 million, making NSF's total annual support for bioengineering research more than $12 million.

102 DIRECTIONS IN ENGINEERING RESEARCH NIH SUPPORT NTH is the principal agency of the U.S. government in biomed- ical research. Yet, despite its overall budget of $5.5 billion, NIH provides only limited support for bioengineering research. The groups that rank research proposals (the study sections) have very few engineering representatives; the groups that award grants to non-NTH researchers (the National Institute Councils) contain no engineers. As a result, although one-fifth of the 15,000 outstand- ing extramural grants are thought to have some bioengineering components, those components are estimated to account for about 3 percent of the overall extramural program (or 2 percent of the overall NTH budget), according to NTH internal program docu- mentation. Bioengineers fare no better in NTH's Intramural Research Pro- gram, which funds research by NTH's own in-house investigators. Of the $660 million intramural research budget, the Biomedical Engineering and Instrumentation Branch receives only $11 million. In addition, probably less than 5 percent of the 5,000 advanced- degree personnel who conduct research at NTH are bioengineers or from a related discipline (from NTH program documentation). NIH's support for biochemical engineering per se is roughly equal to that for biomedical engineering. Each is represented by about 400 grants per year and, at a little over $50 million per year apiece, each represents about 1 percent of NIH's overall budget (W. J. Holliman, personal communication). However, according to a recent article in Science (Culliton, 1985), NIH provides an estimated $600 million (or about 15 percent of its overall budget) for basic research and training "directly related" to biotechnology. This work is pursued as a small part of larger research projects in cancer, genetics, clinical immunology and allergy response, vaccine production, and other areas of medical research. Little of the work is applicable to the development of biochemical engineering as an organized discipline. Indeed, the question of whether NIH ought to support biotechnology research in nonmedical fields such as agriculture, thus directing its basic research effort in this area more explicitly toward development of the U.S. biotechnology industry, has recently become a subject of controversy (Culliton, 1985~.

BIOENGINEERING SYSTEMS 103 THE NATIONAL ACADEMIES The controversy with regard to NTH's role in biotechnology is a reflection of the fragmented character of current bioengineering research. This same difficulty in dealing with bioengineering is ev- ident in the national academies. Neither the National Academy of Sciences (NAS) nor the National Academy of Engineering (NAE) has yet identified biophysics or bioengineering, respectively, as fields in their own right. In addition, in the Institute of Medicine (IOM), whose charter mandates that 25 percent of its membership be nonphysicians involved in medically related areas, engineers and non-M.D. scientists. constitute just 2 percent of the membership. Of the 22 regular and senior members of the engineering group, only 5 are non-M.D. biomedical engineers. The sparse representation of bioengineers in the acadern~es does not, however, connote a lack of interest or effort. The Com- mission on Physical Sciences, Mathematics, and Resources of the National Research Council the National Research Council is the principal operating arm of the NAS and NAE and the Board on Health Sciences Policy of the TOM are attempting to promote research collaboration between the engineering and biological sci- ences. The Board of Health Sciences Policy regularly ranks such collaboration at or close to the top of its priorities, including an interest in enhancing the physical underpinnings of a medical education. CHANGING EMPHASIS IN FUNDING Because of the increased competition for limited research re- sources, government agencies involved in supporting bioengineer- ing research have tended to shift from a philosophy in which research grants are seen as instruments for investment to one in which grants are considered a means to procure a product. The losers in such a shift are the imaginative but speculative ideas. Possible remeclial steps include . earmarking funds for basic research Tom which no imme- diate products are expected; . setting aside awards based mainly on an investigator's track record to provide opportunities for more speculative re- search; and *Mathematicians, physicists, and chemists.

104 DIRECTIONS IN ENGINEERING RESEARCH . extending the length of grant awards to 5 or 7 years to en- sure stability and the opportunity to bring a project to a successful conclusion. INDUSTRY INVOLVEMENT BIOTECHNOLOGY The worldwide market for biologically derived products could be as high as $100 billion annually by the year 2000* (or about 15 percent of the estimated total annual market for chemicals) (National Academy of Sciences, 1984~. Since about 1978 there has been a virtual stampede of private investment in new, en- trepreneurial companies entering this field. Venture capital has been an important source of private capital, funding well over 100 biotechnology firms—many of which have not survived in this highly speculative field in which few products have yet come to market. R&D limited partnerships, only one source of funds, to- taled $1.5 billion in 1984 alone (Office of Technology Assessment, 1984~. Many of these small entrepreneurial firms focus on producing one or a handful of products derived from academic research. As such, their challenge is to perform the engineering research necessary to make an idea commercially viable, because this is the type of research that is not often sponsored by federal agencies at universities. Because the work is limited in scope (and highly proprietary), it is not of great use in the overall advancement of the field. Of greater potential value in this regard is the engineering research performed by established industries. The pharmaceutical industry was the first to seek applications of the new biology on a large scale. Biologically engineered prod- ucts have traditionally accounted for roughly 23 percent of annual sales of pharmaceutical products (Drew, 1985~. With domestic expenditures for health care now exceeding 10 percent of the gross national product and the world market for human and animal drugs exceeding $35 billion, this is likely to remain one of the most active areas of research in biotechnology. The key problem for this and other industries involved in *In 1984 constant dollars.

BIOENGINEERING SYSTEMS 105 biotechnology is likely to be performing the engineering research necessary to capitalize on the explosive growth in the biological sci- ences. According to Drew (1985), the current focus of engineering research on process development and scale-up to manufacture has kept pace with new product discovery, but the margin of comfort in completing process development before licensure has dwindled. The trend toward more complex product chemistries, higher prod- uct purities, and increased product stability will only worsen the problem and place process economics under greater constraints. BIOMEDICAL ENGINEERING Most of the research in biomedical engineering to date has been carried out within the academic research community through government funding, private philanthropy, and limited industrial cosponsorship. In recent years, as the commercial potential of a line of research has become clear, industrial research in some cases has brought the basic work beyond the proof-of-concept stage to product development. Yet, here again, the fundamental work leading to the proof-of-concept stage is the key. Despite efforts tc, increase industrial sponsorship of such research at universities, little additional support is anticipated. The nature of this industry dictates that investments in R&D are made only after the concept has been proven and the market potential shown to be adequate to provide a return on investment. One drawback to the advancement of this field appears to be a prevailing belief, on the part of the medical community, that in- dustry should be responsible for medical instrumentation R&D. In fact, industry does not support R&D on medical instrumentation or equipment that is used in research per se, but only that which is addressed to the clinical market. These factors will likely combine with a limited market for many types of instrumentation and devices (e.g., prostheses) to keep industry's investment in research small. Because the public health and welfare are traditionally a responsibility of govern- ment, an adequate research base in biomedical engineering should continue to be maintained through federal support of university researchers.

106 DIRECTIONS IN ENGINEERING RESEARCH BIOENGINEERING IN OTHER COUNTRIES As part of its study, the Panel on Bioengineering Systems Research examined bioengineering research and education in the United States, Western Europe, and Japan. In particular, the analysis pointed up major differences in the magnitude and or- ganizationa] structure of government-supported research and de- velopment efforts in biochemical engineering. West Germany, Japan, and Great Britain each have three government institutes that support biotechnology exclusively. These nine institutes bring together academic and industrial investigators, feature cross- disciplinary activities, and have impressive operating budgets. In West Germany, for example, the Gesellschaft fur Biotech- nologische Forschung had an operating budget of $14 million in 1983 and the Institut fur Biotechnologie II in Julich had a budget of $4.3 million for biochemical engineering alone. The last fig- ure nearly equals the NSF's entire annual budget in biochemical engineering. West Germany also has nearly double the amount of space and equipment for bioengineering research found in the United States. In Japan, the Ministry of International Made and Industry 1~ year plans have strong R&D components in biotechnology. Three of the nine areas emphasized are bioreactors, animal cell culture, and membrane separations. The Japanese government budgeted $20 million in support of membrane separation research and devel- opment alone in 1983. NSF, by comparison, contributes less than $1 million for similar research in the United States. Thus, countries such as West Germany and Japan are lay- ing a foundation of research and trained personnel as part of their strategy for meeting the intense international competition in biotechnology. Given the potential size of the worldwide market described earlier, the economic rewards for success are likely to be very great. Getting into these markets first will be critically important in international competition. Major shares will be cam tured by countries that have the needed national capability in research and personnel. AVAILABILITY OF BIOENGINEERING RESEARCH MANPOWER IN THE UNITED STATES Because bioengineering ~ a relatively new field, and one with great potential for research breakthroughs and commercial devel-

BIOENGINEERING SYSTEMS 107 opment, there is a clear need for training young engineers who understand the major principles of biology, medicine, and other relevant scientific disciplines, and who can communicate readily with researchers in those fields. This human resource will develop only with long-term support for bioengineering research. Funding from NIH, NSF, and other government agencies must be stable, continuous, and sufficiently large to train and support an adequate number of new investigators in bioengineering. BIOMEDICAL ENGINEERING Although the total number of biomedical engineering graduate students in U.S. colleges and universities has increased by about 50 percent during the last 10 years, the number relative to all engi- neering graduate students has remained about the same.* Over the past decade, biomedical engineering students have averaged less than 2 percent of all engineering students enrolled in both master's programs and doctoral programs. Recent trends in enrollment of graduate students in biomedical engineering specifically show a relative increase in master's and a decrease in doctoral students. The decline in Ph.D. candidates may reflect a loss of students to medical schools or other engineering disciplines with competitive popularity or better research funding. Although Ph.D. biomedical engineers are the primary resource for future research in this field, they are not the only resource. In- terdisciplinary doctoral programs in biomedical engineering are relatively new. Indeed, most of the current leaders in the field are doctoral-level researchers in another engineering field (e.g., electri- cal, mechanical, chemical, or even civil) or in a medical speciality who became interested in applying their expertise to developing new knowledge, techniques, or equipment in the biomedical field. Often pairs of Ph.D. researchers with complementary, in-depth knowledge of engineering and medicine can offer an especially powerful capability for creative research In biomedical engineering when they work together on research of mutual interest. For this reason, the ability to understand and communicate with investi- gators in related areas of science and engineering is as important as formal interdisciplinary education in producing a pool of highly qualified bioengineering researchers. *According to calculations made by the panel, based on data published by the American Association of Engineering Societies over the period 1975- 1985. (See, for example, Engineering Manpower Commission, 1985.)

108 DIRECTIONS IN ENGINEERING RESEARCH BIOCHEMICAL ENGINEERING Studies indicate that there are not enough biochemical re- search engineers in the United States today to meet existing needs. The Office of Technology Assessment (OTA) and the Committee on National Needs for Biomedical and Behavioral Personnel of the TOM surveyed the biotechnology industry in 1983 (Office of Technology Assessment, 1984~. The OTA-IOM survey found that more than 80 percent of the existing firms began operations in 1978 or later. About one-third reported shortages of Ph.D.s in one or more specialities. In bioprocess engineering, for example, 80 Ph.D.s were employed in the 138 firms reporting. They ex- pected an increase of over 50 percent in the following 18 months. Fewer than 20 departments of chemical engineering at U.S. universities and colleges have meaningful biochemical/biotechnol- ogy programs. Collectively, they are graduating fewer than 60 doc- toral and master's students* annually (National Research Council, 1984~. The annual need for graduate-level biochemical engineers over the next decade will average two or three times that num- ber. Moreover, biochemical engineering students need to have better exposure to the biological sciences to Improve their ability to manipulate and control cellular biosynthesis. They must also be taught the techniques and methods of the life sciences for solv- ing critical, large-scale bioprocess problems. Learning the "new" biology is important to improving the relationship between the life sciences and biotechnology. There are likely also to be shortages in the faculty needed to train biochemical engineers. Given the powerful allure of indus- try research in biotechnology, it cannot be expected that a large percentage of the few new doctoral graduates will join university faculties. Yet these are precisely the people who are needed to train tomorrow's researchers, because older faculty are not as con- versant with the new technologies or as likely to produce new ideas in research. There is little reason to expect that this situation will solve itself. Demographic studies show that the overall number of sci- ence and engineering students will decrease by 25 percent over the next IS years. The loss of tuition that this reduction represents will pose a financial strain on already hard-pressed universities. Many will probably respond by curtailing hiring and laboratory *Few of these students terminate their studies at the master's level. Most go on to obtain the doctorate.

BIOENGINEERING SYSTEMS 109 improvements. Already the proportion of science and engineering faculty who are recent graduates has decreased from 40 percent in 1968 to 20 percent by 1980. An expanding program of research support (particularly for young investigators) is urgently needed to ensure that university bioengineering research continues to keep the United States in the forefront of knowledge in this field. Conclusions and Recommendations Despite significant advances in the biological and biomedical sciences in recent years, much remains to be learned from bioengi- neering research. Our basic understanding of biological systems and our ability to use that knowledge to produce economically products that can enhance the quality of life and permit the deliv- ery of better health care can be greatly furthered by such research. However, the focus of attention and funding for bioengineer- ing as opposed to biomedical science research in the U.S. gov- ernment is scattered among several agencies, as well as among different divisions and programs within those agencies. To date, little effort has been made to coordinate the work of those agencies and programs. One coordinating body established in the past has not been very active and consequently has been relatively ineffec- tive because, in the panel's judgment, it has not received sufficient support and attention from upper-level management in the par- ticipating federal agencies. Thus, the Pane} on Bioengineering Systems Research recommends that: The coordination of research programs in bioengineering throughout the federal government be improved and that the co- ordination include the relevant work of the NIH, NSF, NBS, and other agencies interested or involved in bioengineering research. To ensure its effectiveness, it is essential that this interagency cm ordinating effort receive the full recognition and support of upper management in each of the participating agencies. Similarly, there is little coordination of bioengineering research within those agencies that support most of the relevant research programs within the U.S. government. This is particularly true of

110 DIRECTIONS IN ENGINEERING RESEARCH NIH, which has primary responsibility for biomedical and related research in the government. Thus, the pane! recommends that: . The coordination of bioengineering research within su p- porting agencies should also be improved. For example, NIH could create an "office of bioengineering research" to review and coordi- nate its investigations. Such an office would be one way to focus attention on the need for careful development of this important field. NSF has recently created six ERCs to promote cros~disciplin- ary studies and to encourage the more rapid implementation of research results into commercial products. One ERC focuses ex- clusively on biotechnology. Although NTH supports that center, it has not established similar centers for biomedical engineering research. Thus, the pane! recommends that: . NTH should give careful attention to the need for large- scale, focused research in biomedical engineering. To achieve the required scale, NTH should consider creating a center for such research, comparable in concept and size to the NSF's ERCs. As is true of the ERCs, any such center created by NIH should encourage links between academic research and clinical practice. There is demand for a wide spectrum of researchers across the different specialties of biomedical and biochern~cal engineer- ing. Certainly the demand for doctoral biochemical engineers in particular is now large and will increase. Because bioengineering is a relatively new field with great potential for research break- throughs and commercial development, there is a clear need for training young research engineers who understand the principles of biology, medicine, and other relevant scientific disciplines, and who can communicate readily with researchers in those fields. Therefore: . NIH and NSF should devote a greater share of their re- search budgets to supporting bioengineering programs at U.S. universities and colleges. NTH, in particular, should expand its programs that encourage medical students to go into research so as to include bioengineers as well. Stipends awarded for postdoc- toral study should be sufficiently high to offset the attractiveness of salaries offered by industry. Although it is understandable, too often government and in- dustry support of research at universities aims at achieving prac- tical results that can be turned into commercial products. This is

BIOENGINEERING SYSTEMS 111 not to be discouraged, because the U.S. economy and competitive- ness in international markets require such efforts. Nevertheless, there is also a need for basic research that does not necessar- iTy lead to commercial products but, in the aggregate, creates the basis for practical results by increasing our understanding of biological systems. Thus, the Pane] on Bioengineering Systems Research recommends that: Those who rank and award grant proposals within NTH and NSF should consider funding research projects that have a great potential for significant results, but also a high risk of failure. The panel applauds the strong current trend in this direction at NSF. The need for a continuing study of bioengineering research programs and issues will not end with this panel's report or the work of the Engineering Research Board. The subject will be with us for many years to come. Thus, the Panel on Bioengineering Systems Research recommends that: . To ensure the long-term health of this commercially impor- tant field, an authoritative and permanent advisory body should be created. This body would assess bioengineering research oh portunities and needs, review the relevant research programs of NIH, NSF, and other government agencies, and identify needs for new programs or changes in direction. References Attinger, E. O. Impacts of the technological revolution on healthcare. IEEE Okay'. Biomcd Eng. BME-31:736~743, 1984. Culliton, B. NIH's role in biotechnology debated. Scicnec 229~4709~: 147-148. Drew, S. Biotechnology and the health care industry. In: Thc Now Engi- necr~ng Research Ccnicr~: Plane, Goals, and Expectations. Washington, DC: National Academy Press, 1985. Engineering Manpower Commission. Engineering and Technology Degrees, 1984. Part III: By Curriculum. Engineering Manpower Commission of the American Association of Engineering Societies, Inc., 1985. Holliman, W. J. Data on NIH research grants, supplied by Chief, Research and Documentation Section, Statistics and Analysis Branch, Division of Research Grants, NIH. March 18, 1985. Institute of Electrical and Electronics Engineers. An IEEE Opinion on Research Needs for Biomedical Engineering Systems. (rev.) Report of an IEEE task force to the Engineering Research Board. IEEE, March 3, 1985.

112 DIRECTIONS IN ENGINEERING RESEARCH National Academy of Sciences. Report of the Research Briefing Panel on Chemical and Process Engineering for Biotechnology. Prepared by the Committee on Science, Engineering, and Public Policy for the Office of Science and Technology Policy. Washington, DC: National Academy Press, 1984. National Academy of Sciences. Injury in America: A Continuing Public Health Problem. Committee on Trauma Research of the Commission on Life Sciences of the National Research Council and the Institute of Medicine. Washington, DC: National Academy Press, 1985. National Center for Health Statistics. Advance report of final mortality statistics, 1980. Monthly Vital Statistics Report (Suppl.) 32~4), 1983. Office of Technology Assessment. Commercial Biotechnology: An Interna- tional Analysis (OTA-BA-219~. Washington, DC: Office of Technology Assessment, January 1984.

BIOENGINEERING SYSTEMS Appendix Responses to the Engineering Research Board's Request for Assistance from Universities, Professional Societies, and Federal Agencies and Laboratories 113 Requests for assistance were sent by the Engineering Research Board to a number of universities, recipients of Presidential Young Investigator Awards, professional societies, and federal agencies and laboratories in order to obtain a broader view of engineering research opportunities, research policy needs, and the health of the research community. Some of the responses included comments on engineering research aspects of bioengineering systems; these responses were reviewed by the panel to aid in its deliberations. The panel found the responses helpful and wishes that it were possible to individually thank all those who took the time to make their views known. Because that is not practical, we hope that this, albeit small, acknowledgment conveys our gratitude. Responses on aspects of bioengineering systems research were received from individuab representing 47 different organizations, which are listed in Table A-1: 28 universities (including 6 rep- resented by recipients of NSF Presidential Young Investigator Awards), 12 professional organizations, and 7 federal agencies or laboratories. Some comments covered specific aspects of the panel's scope of activities, whereas others provided input on a variety of subjects. Although most of the responses addressed priority research needs, several respondents did touch on policy issues. Many of the research needs and policy and health issues addressed by the respondents were similar to those noted by pane! members. The broadened perspective provided by the responses to the survey was most beneficial in the panelts deliberations.

114 DIRECTIONS IN ENGINEERING RESEARCH TABLE A-1 Organizations Responding to Information Requests Relevant to Bioengineering Systems Research UNIVERSITIES California Institute of Technology Case Western Reserve University Cornell University Johns Hopkins University Lehigh University North Carolina State University Northwestern University Oregon State University Purdue University Rensselaer Polytechnic Institute Rutgers University San Diego State University Syracuse University Texas A&M University University of California, Davis University of California, Los Angeles University of Georgia University of Illinois University of Illinois—Urbana/ Champaign University of Kansas University of Michigan University of Minnesota University of Pennsylvania University of Pittsburgh University of Rochester University of Texas at Austin University of Utah Wayne State University PROFESSIONAL ORGANIZATIONS American Chemical Society American Institute of Chemical Engineers American Society of Agricultural Engineers American Society of Civil Engineers American Society of Mechanical Engineers Biomedical Engineering Society Council for Chemical Research Institute of Industrial Engineers Industrial Research Institute Society of Engineering Science, Inc. The Institute of Electrical and Electronic Engineers, Inc. U.S. National Committee for Biomechanics AGENCIES AND LABORATORIES Air Force Office of Scientific Research Army Research Office NASA Goddard Space Flight Center NASA Jet Propulsion Laboratory NASA Langley Research Center Naval Research Laboratory Oak Ridge National Laboratory

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Surveying the dynamic field of engineering research, Directions in Engineering Research first presents an overview of the status of engineering research today. It then examines research and needs in a variety of areas: bioengineering; construction and structural design; energy, mineralogy, and the environment; information science and computers; manufacturing; materials; and transportation.

Specific areas of current research opportunity are discussed in detail, including complex system software, advanced engineered materials, manufacturing systems integration, bioreactors, construction robotics, biomedical engineering, hazardous material control, computer-aided design, and manufacturing modeling and simulation.

The authors' recommendations call for funding stability for engineering research programs; modern equipment and facilities; adequate coordination between researchers; increased support for high-risk, high-return, single-investor projects; recruiting of new talent and fostering of multidisciplinary research; and enhanced industry support. Innovative ways to improve the transfer of discoveries from the laboratory to the factory are also presented.

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