490
IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. BME-25, NO. 6, NOVEMBER 1978
Future Directions for Biomedical Engineering Research: Recommendations of an Evaluation Workshop for the NIGMS Physiology and Biomedical' Engineering Program P. H. ABBRECHT, J. R. COX, AND F. P. FERGUSON Abstract-This report presents the recommendations of participants in a workshop held to evaluate the content of the Physiology and Biomedical Engineering Program of the National Institute of General Medical Sciences (NIGMS). On the basis of a systematic review of the field, a number of promising areas were identified in which further work is needed.
which you anticipate that a significant role will be played by emerging technologies and advanced engineering methods? You should consider areas currently represented in the Program that should receive increased or decreased emphasis, as well as new areas of high potential that should be added to the
Program."
The most challenging aspect of the work proved to be the INTRODUCTION attempt to identify appropriate research areas not included in FOR the past 15 years the National Institute of General the current Program, or, as one participant aptly described it, Medical Sciences has funded research grants for a broad the "search for undiscovered lakes." In the course of this range of investigations in the field of Biomedical Engineering. search, the Committee identified a number of important new In May 1978 a portion of the NIGMS was officially reorganized areas that appear to be promising candidates for further develto form a new Physiology and Biomedical Engineering Pro- opment. gram (PBME), which combined the former Biomedical EnWe believe that the Evaluation Committee's recommendagineering and the Clinical and Physiological Sciences Programs. tions will be of general interest to research workers and eduThis reorganization brought together the Institute's research cators in Biomedical Engineering and related fields. In this support activities in instrumentation, computers, patient moni- report we present a summary of the Committee's major recomtoring, biomaterials, non-invasive tissue characterization, bio- mendations about the different portions of the current NIGMS mathematics, and physiological systems analysis with the Program, along with comments by Institute staff. The report "users" of this technology, the clinical and basic scientists concludes with some examples of additional areas considered working on pathophysiological studies related to trauma, as promising by the Committee. bums, anesthesiology, and general medicine. Institute staff SUMMARY OF THE EVALUATION COMMITTEE'S felt that the impending reorganization made this an especially RECOMMENDATIONS ON THE PRESENT PROGRAM appropriate time to obtain a peer evaluation of program conAND COMMENTS BY INSTITUTE STAFF tent and priorities, and to attempt to define appropriate future directions for the PBME Program. A consultant group' in- Mathematical Methods cluding representatives from universities, industry, and govern1) Support should be increased for research on mathematiment met on December 8 and 9, 1977 in Bethesda, Md., to cal methods with novel and promising applications to biology consider these questions, with particular reference to the Bio- and medicine. medical Engineering content of the Program. 2) Research involving mathematical methods, including The primary charge given the Evaluation Committee was to modeling and simulation, should be strongly tied to important address the question "What are the areas of rapid and impor- biomedical questions. tant scientific development appropriate to the Program for 3) Only that biostatistical research which will contribute to new fundamental knowledge in biology is appropriate for supManuscript received May 17, 1978; revised May 30, 1978. port by the Institute. P. IL Abbrecht is with the National Institute of General Medical SciComment: All three recommendations embody the concept ences, Bethesda, MD 20014, on leave from the Departments of Physiology and Internal Medicine, University of Michigan, Ann Arbor, MI that the research in mathematical methods to be supported by 48101. the Institute should arise from well defined, important biologiJ. R. Cox is with the Department of Computer Science, Washington cal questions that require new analytical methods. DevelopUniversity, St. Louis, MO 63119. F. P. Ferguson is with the National Institute of General Medical Sci- ment of new mathematical techniques in this context will be ences, Bethesda, MD 20014. encouraged. Conversely, applications in the area of biomathe1The members of the Committee were Jerome R. Cox (Chairman), matics or biostatistics that are not clearly related to well idenWilliam B. Blesser, Dean L. Franklin, Kenneth H. Keller, Donald J. Lyman, Robert Plonsey, Michael D. Stern, Jerome J. Tiemann, Robert tified specific biomedical problems will be deemed inappropriL. Bowman, Norman Caplan, Murray Eden, and John T. Watson. ate for support by this Institute. Applications for development
0018-9294/78/1 100-0490$00.75 © 1978 IEEE
ABBRECHT et al.: FUTURE DIRECTIONS FOR BIOMEDICAL ENGINEERING RESEARCH
of heuristic as well as mathematical methods and research on computer science applied to specific biomedical problems will be encouraged. Physiological Systems Analysis 1) The potential significance of this area is recognized, and it is recommended that the research that is supported should use the best available physiological systems analysis techniques to address important medical and biological problems. Comment: Research in physiological systems analysis that uses classical control theory, simulation, and numerical analysis techniques to study significant biomedical questions will continue to be supported. Research that uses the techniques of modern control theory such as systems identification methods and nonlinear systems approaches will be especially encouraged. Biomaterials, Biomechanics, and Prosthetics 1) Emphasis should be placed on studies of the properties and chemical synthesis of biocompatible materials. 2) Strong support should be provided for research involving fundamental tissue-implant interactions. Comment: Support of biomaterials research has been and will continue to be encouraged. Of especial interest will be studies of the fundamental chemical, physical, and biological mechanisms that determine the interaction of implants with living tissue and body fluids. 3) Additional support should be provided for biomechanics research with emphasis on characteristics of hard and soft tissue behavior. Comment: Research on the biophysical and biochemical properties of normal and diseased tissues and on the biological significance of those properties will be encouraged, as will research at the molecular and biochemical level that is aimed at achieving a better understanding of the determinants of tissue properties. Development of the instrumentation required for such studies is also recognized to be important. Instrumentation 1) Encouragement should be given for the development of instruments needed for doing basic research, as well as those needed for making important clinical measurements. Comment: Support will be continued for research on the development of new concepts in instrumentation for basic biomedical and clinical investigations, where such development is closely tied to specific and significant biomedical questions. Such proposed instrumentation should have the promise of providing information that will contribute to the solution of scientific problems that cannot be attacked successfully by available techniques, or of enhancing the acquisition of new information over that obtainable with present methods. In instrument development, the utilization of new technology and newly discovered physical and chemical principles, as well as new applications of established principles, will be encouraged.
491
Comment: Advances in instrumentation have brought about a continuous increase in the amount of data generated, both in biomedical research and in clinical medicine. In turn, the increased data have created a major problem in sorting out truly relevant information. Thus new data must be managed to produce a timely, rational, widely understood, and coherent organization of knowledge. "Patient Monitoring" might be better replaced by a broader term that encompasses the general concept of "information processing." Under this rubric will be encouraged research that has as its objectives better understanding, interpretation, and utilization of data obtained from patients and biomedical research studies. Such research
might include utilization ofparameter identification techniques to determine the state of the patient, optimal control techniques to permit better management of medical conditions, improved data base management systems for the acquisition, retrieval, and processing of biomedical data, and the use of decision theory and artificial intelligence methods to organize knowledge for greater usefulness in decision making. Research on image analysis that addresses specific biomedical problems is also relevant.
Noninvasive Tissue Characterization (Ultrasonic Methods) 1) Ultrasonic methods show considerable promise for providing quantitative characterization of normal and pathological tissue structures, and thus should be further exploited. Particularly needed is novel work that emphasizes basic aspects of ultrasound. Comment: Fundamental studies on the development of new ultrasonic imaging techniques, basic research on the interpretation of ultrasound data, and research on the biological effects of ultrasonic exposure will be encouraged. Computers 1) There is no need for identification of computers as a separate area since the modern computer is a tool used in practically all biomedical engineering research. Comment: Research involving routine use of computers should be judged and funded on the basis of the biomedical problems being addressed. Research on computer science applied to biomedical problems is an appropriate area for support.
IDENTIFICATION OF APPROPRIATE NEW RESEARCH AREAS There are a number of important biological problems, amenable to attack by the methods and technology of engineering science, that are not now being addressed by research supported by NIGMS, as well as some areas of engineering expertise not being exploited at present. The Committee developed the matrix shown in Table I in order to ensure consideration of the possible roles for biomedical engineering research at all levels of biological organization. In the following paragraphs, Patient Monitoring we cite several examples of new research problems and areas 1) Novel approaches rather than routine data acquisition identified by the analysis of Table I. While the examples are should be fostered. not exhaustive nor intended to be exclusive, they serve to il2) Research on chronic monitoring techniques should be lustrate possible new directions in which the Institute might encouraged. move in improving its balance and effectiveness of support.
492
IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. BME-25, NO. 6, NOVEMBER 1978
TABLE I ROLES FOR BIOMEDICAL ENGINEERING AT DIFFERENT LEVELS OF BIOLOGICAL ORGANIZATION -
esl
for Biomedical
T
'%.ngineering
IMathematical Methods, Modeling and
Instruments and Scientific -Measurement Problem Areas Techniques
Structure, Interaction and Degradation
techniques including: 'Transmission electron microscope,
.
________________________
Cell
Spectroscopy,
_
Cell Material Molecules
Structure, Interaction
l
Biochemical measurements including the use of:
-Cells,
Tagging
Organi
Measurements in man or animal models that are:
F allure
Modes, Differentiation and Regeneration
-Biochemical, 'Biomechanical, 'Chronic, Continuous
Nitural History of Growth,
Chronic Disease and Aging
Data base collection particularly in long timeconstant systems or high data volume
_systems
Each area's location in the matrix of Table I is indicated by the appropriate cell number. (This report does not make specific reference to cell la, since the topics included therein were considered separately at a subsequent workshop.) 1) Experimental and mathematical modeling of tissue perfusion, transport, and reaction. Mass transfer between the microcirculation and tissues has been interpreted largely in terms of lumped parameter models or the single capillary cylinder geometry introduced by Krogh. Continuum models are needed to describe the interactive effects of tissue perfusion, bloodtissue solute transfer, interstitial and intracellular transport, and solute metabolism in tissue regions of macroscopic size. Models developed in analogous situations to describe packed columns, chemical reactors, and flow through porous media are only a starting point for these extensions; serious challenges remain. This area has important applications to such problems as understanding the relation between chemotactic response of white blood cells and the dynamics of tissue infection; establishing optimal chemotherapeutic protocols; understanding transcutaneous gas exchange as a requisite for development of noninvasive blood gas monitoring techniques; and establishing the parameters for pharmacokinetic modeling (cell 2c). 2) Integrated detection, feedback, and control systems as an application of physiological systems analysis. Past efforts in the monitoring of acutely ill patients have been limited largely to tabulation and display of standard medical variables. There has been little effort to apply engineering methods of systems identification to the estimation of less accessible parameters, such as myocardial contractility or autonomic nervous system gain, and to track the physiologic state of the patient. This is a topic in the area of physiological systems analysis that deserves further exploration. The eventual extension of this ap-
2A
Sensors
Fundamental to the introduction of all foreign material into body plus a rational basis for biomedical -
Models of tissue perfusion, fluid transport and interactions of tissue fluids and materials
Chemical synthesis of
Models and analysis based on data bases: v
|
-Drugs, -Prosthetics,
Metabolic pathways and structural changes upon interaction
-
Total Man or Animal
Fundamental to the introduction of all Foreign material into body as in:
-Kinetics, -Binding,
-I
__nie lBn 2
Prosthetic Material
Molecular conformation and interaction models including studies of: -Active sites
-Crystallography
and Degradation
Tissue
Simulation
Chamical and physical
molecule - Molecule
Applications of Measurements and Models
'Statistical 'Pattern recognition Physiological systems
I
oA
biocomipatible materials.
C
Development of synthetic organs (Also target for other institutes and agencies) l 3C
Large scale clinical trials, the establishment of standards and
the dissemination of information. (Largely by other institutes) j3D
proach is the development of closed loop control for therapy of the acutely ill patient (cell 2d). 3) Non-invasive measurements. Instrumentation utilizing noninvasive methods to follow normal variations or pathological changes in humans is essential to minimize the risk, increase the acceptability, and reduce the artifacts of diagnostic procedures. The ability to measure local blood flow or perfusion in various organs is one example of a particularly important kind of measurement for which a non-invasive technique would be quite valuable. For example, using zeugmatography, a method of flow measurement based on nuclear magnetic resonance, it might be possible to measure cerebral blood flow without interference from the skull and integumentary structures, and without exposing the patient to hazardous procedures (cell Ic). 4) Biological-synthetic hybrid organs and instruments. A number of natural organ functions involve complicated and highly specific enzyme-mediated systems for which substitutes are unlikely to be achievable with present or forseeable technologies. The development of prosthetic organs based on tissue cultures or other biological material appropriately protected from rejection phenomena but capable of exchange with body fluids offers an important new approach to replacing the function of organs such as the pancreas and the liver. The development of all of these organs involves work in the area of transport phenomena, materials development, chemical kinetics, and control (cell 3b). While it is recognized that a number of the NIH categorical institutes have responsibility in these areas, the PBME Program is an appropriate place for some of this research. 5) Development of instrumentation and analytical techniques for fundamental physicochemical investigations in cell
ABBRECHT et al.: FUTURE DIRECTIONS FOR BIOMEDICAL ENGINEERING RESEARCH
biology. Studies of transport, surface phenomena, and population dynamics in cells would complement existing efforts in the understanding of a number of phenomena involving cellcell and cell-surface interaction (cell 2b). These studies would be important in increasing understanding of chemotaxis, cellular differentiation, cell-synthetic surface interaction, and population survival. These, in turn, are important elements in understanding immune response, infection control, rejection phenomena, and tissue ingrowth on prosthetic materials. 6) Sensory organs. The development of replacement organs for sight and hearing represents an exciting new direction in artificial organ development in which a unique set of problems must be addressed (cell 3c). Not only is there a need to develop signal detectors in appropriately miniaturized configurations, but the need to relay those signals to the brain through appropriate connections in the nervous system. Although enormous problems remain in hardware, software, systems analysis, and materials compatibility, progress is being made and the potential for success exists. Moreover, spillover from studies in this area holds promise for advances in the development of nerve prostheses, hormonal control systems, neurological control of hypertension, etc. Research efforts on this kind of problem should be encouraged by the appropriate Institutes. 7) Fluid mechanics and rheology of biofluids. Although rheological investigations of biofluids such as blood and mucus have been conducted in various programs of the NIH and other agencies, the required level of expertise and specialized equipment requirements suggest that there would be significant benefit from coordinated efforts to develop techniques and equipment for the analysis of biofluids. Viscoelastic phenomena, relaxation behavior, and shear induced changes in enzyme activity, molecular configuration, and biochemical kinetics hold promise for providing information on cell properties in normal and disease states (cells lb, lc). 8) Development of instrumentation and methodology for study of synthetic material-biological tissue interaction. A particularly important area of fundamental investigation is that of interactions between synthetic materials and biological tissues (cell 1c), since the limiting factors in the development of prosthetic devices and artificial organs often are problems caused by material incompatibilities. Examples of such problems are tissue erosion or necrosis, inflammation, sepsis, absorption of toxins from synthetic materials, or changes in mechanical properties of synthetic materials due to absorption of biological fluids. These interactions are serious problems not only in artificial organ development, but also in the development of instrumentation that places sensors or control devices in contact with living tissue. The understanding of synthetic material/living system interactions requires continued efforts in: 1) analyzing materials' properties, particularly surface properties; 2) understanding the relationship of these properties to the configuration of molecular and cellular constituents in the vicinity of the surface; and 3) relating this information to the broader questions of trauma and compatibility. Studies of this sort should be encouraged, taking into account support given by other Institutes for specialized endeavors.
493
9) Drug delivery systems. In recent years, there has been a growing interest in the development of systems for drug delivery that would be more selective, effective, and flexible than discrete oral doses or injections, the methods which have been in use for over 100 years (cells 3a, 3b, and 3c). These new delivery systems make use of a number of different approaches to provide constant, continuous drug delivery, including implanted osmotic or vapor driven pumps, saturated drug solutions bounded by membranes of controllable permeability, cylindrical elastomeric reservoirs, etc. These and similar new approaches hold forth the promise of being able to deliver drugs while minimizing side effects, reducing the dosage required for effectiveness, and controlling the dose through on-line patient monitoring. 10) Molecular structure and interaction Computational models of molecules that allow careful study of structure and molecular interaction have become feasible as a result of the continuing increase in computational power available for a reasonable cost. The use of such computational models holds promise of a rational basis for comprehending the mechanisms of drug activity, for drug design, and for basic understanding of the phenomena associated with the introduction of foreign material into the body. The kinetic binding of biologically interesting molecules can be understood in greater depth through the development of more powerful models based on physical structure (cell 2a). 11) Long time constant systems. (Cell Id). In contrast to acute disease processes, the natural history of growth, chronic disease, and aging evolves over long times that are of the same order as those of periods of environmental change that in itself can modify the process under observation. This difficulty with the acquisition of knowledge about long time constant systems complicates the study of many biological problems; for instance, determining the etiology of arteriosclerotic vascular disease. Tools such as clinical trials provide only a snapshot, whereas a continuing view of the evolution of a disease may be more informative in many cases. The feasibility of the collection of data-bases that describe the natural history of such long time constant processes increases with the availability of low-cost computer systems and data acquisition methods that are accurate and timely. Research in the methodology and technology for organizing and accomplishing such natural history studies may be a new opportunity for the PBME Program that could pay dividends throughout the other Institutes.
P. H. Abbrecht, photograph and biography not available at the time of publication.
J. R. Cox, photograph and biography not available at the time of publication.
F. P. Ferguson, photograph and biography not available at the time of publication.
IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. BME-25, NO. 6, NOVEMBER 1978
Future Directions for Biomedical Engineering Research: Recommendations of an Evaluation Workshop for the NIGMS Physiology and Biomedical' Engineering Program P. H. ABBRECHT, J. R. COX, AND F. P. FERGUSON Abstract-This report presents the recommendations of participants in a workshop held to evaluate the content of the Physiology and Biomedical Engineering Program of the National Institute of General Medical Sciences (NIGMS). On the basis of a systematic review of the field, a number of promising areas were identified in which further work is needed.
which you anticipate that a significant role will be played by emerging technologies and advanced engineering methods? You should consider areas currently represented in the Program that should receive increased or decreased emphasis, as well as new areas of high potential that should be added to the
Program."
The most challenging aspect of the work proved to be the INTRODUCTION attempt to identify appropriate research areas not included in FOR the past 15 years the National Institute of General the current Program, or, as one participant aptly described it, Medical Sciences has funded research grants for a broad the "search for undiscovered lakes." In the course of this range of investigations in the field of Biomedical Engineering. search, the Committee identified a number of important new In May 1978 a portion of the NIGMS was officially reorganized areas that appear to be promising candidates for further develto form a new Physiology and Biomedical Engineering Pro- opment. gram (PBME), which combined the former Biomedical EnWe believe that the Evaluation Committee's recommendagineering and the Clinical and Physiological Sciences Programs. tions will be of general interest to research workers and eduThis reorganization brought together the Institute's research cators in Biomedical Engineering and related fields. In this support activities in instrumentation, computers, patient moni- report we present a summary of the Committee's major recomtoring, biomaterials, non-invasive tissue characterization, bio- mendations about the different portions of the current NIGMS mathematics, and physiological systems analysis with the Program, along with comments by Institute staff. The report "users" of this technology, the clinical and basic scientists concludes with some examples of additional areas considered working on pathophysiological studies related to trauma, as promising by the Committee. bums, anesthesiology, and general medicine. Institute staff SUMMARY OF THE EVALUATION COMMITTEE'S felt that the impending reorganization made this an especially RECOMMENDATIONS ON THE PRESENT PROGRAM appropriate time to obtain a peer evaluation of program conAND COMMENTS BY INSTITUTE STAFF tent and priorities, and to attempt to define appropriate future directions for the PBME Program. A consultant group' in- Mathematical Methods cluding representatives from universities, industry, and govern1) Support should be increased for research on mathematiment met on December 8 and 9, 1977 in Bethesda, Md., to cal methods with novel and promising applications to biology consider these questions, with particular reference to the Bio- and medicine. medical Engineering content of the Program. 2) Research involving mathematical methods, including The primary charge given the Evaluation Committee was to modeling and simulation, should be strongly tied to important address the question "What are the areas of rapid and impor- biomedical questions. tant scientific development appropriate to the Program for 3) Only that biostatistical research which will contribute to new fundamental knowledge in biology is appropriate for supManuscript received May 17, 1978; revised May 30, 1978. port by the Institute. P. IL Abbrecht is with the National Institute of General Medical SciComment: All three recommendations embody the concept ences, Bethesda, MD 20014, on leave from the Departments of Physiology and Internal Medicine, University of Michigan, Ann Arbor, MI that the research in mathematical methods to be supported by 48101. the Institute should arise from well defined, important biologiJ. R. Cox is with the Department of Computer Science, Washington cal questions that require new analytical methods. DevelopUniversity, St. Louis, MO 63119. F. P. Ferguson is with the National Institute of General Medical Sci- ment of new mathematical techniques in this context will be ences, Bethesda, MD 20014. encouraged. Conversely, applications in the area of biomathe1The members of the Committee were Jerome R. Cox (Chairman), matics or biostatistics that are not clearly related to well idenWilliam B. Blesser, Dean L. Franklin, Kenneth H. Keller, Donald J. Lyman, Robert Plonsey, Michael D. Stern, Jerome J. Tiemann, Robert tified specific biomedical problems will be deemed inappropriL. Bowman, Norman Caplan, Murray Eden, and John T. Watson. ate for support by this Institute. Applications for development
0018-9294/78/1 100-0490$00.75 © 1978 IEEE
ABBRECHT et al.: FUTURE DIRECTIONS FOR BIOMEDICAL ENGINEERING RESEARCH
of heuristic as well as mathematical methods and research on computer science applied to specific biomedical problems will be encouraged. Physiological Systems Analysis 1) The potential significance of this area is recognized, and it is recommended that the research that is supported should use the best available physiological systems analysis techniques to address important medical and biological problems. Comment: Research in physiological systems analysis that uses classical control theory, simulation, and numerical analysis techniques to study significant biomedical questions will continue to be supported. Research that uses the techniques of modern control theory such as systems identification methods and nonlinear systems approaches will be especially encouraged. Biomaterials, Biomechanics, and Prosthetics 1) Emphasis should be placed on studies of the properties and chemical synthesis of biocompatible materials. 2) Strong support should be provided for research involving fundamental tissue-implant interactions. Comment: Support of biomaterials research has been and will continue to be encouraged. Of especial interest will be studies of the fundamental chemical, physical, and biological mechanisms that determine the interaction of implants with living tissue and body fluids. 3) Additional support should be provided for biomechanics research with emphasis on characteristics of hard and soft tissue behavior. Comment: Research on the biophysical and biochemical properties of normal and diseased tissues and on the biological significance of those properties will be encouraged, as will research at the molecular and biochemical level that is aimed at achieving a better understanding of the determinants of tissue properties. Development of the instrumentation required for such studies is also recognized to be important. Instrumentation 1) Encouragement should be given for the development of instruments needed for doing basic research, as well as those needed for making important clinical measurements. Comment: Support will be continued for research on the development of new concepts in instrumentation for basic biomedical and clinical investigations, where such development is closely tied to specific and significant biomedical questions. Such proposed instrumentation should have the promise of providing information that will contribute to the solution of scientific problems that cannot be attacked successfully by available techniques, or of enhancing the acquisition of new information over that obtainable with present methods. In instrument development, the utilization of new technology and newly discovered physical and chemical principles, as well as new applications of established principles, will be encouraged.
491
Comment: Advances in instrumentation have brought about a continuous increase in the amount of data generated, both in biomedical research and in clinical medicine. In turn, the increased data have created a major problem in sorting out truly relevant information. Thus new data must be managed to produce a timely, rational, widely understood, and coherent organization of knowledge. "Patient Monitoring" might be better replaced by a broader term that encompasses the general concept of "information processing." Under this rubric will be encouraged research that has as its objectives better understanding, interpretation, and utilization of data obtained from patients and biomedical research studies. Such research
might include utilization ofparameter identification techniques to determine the state of the patient, optimal control techniques to permit better management of medical conditions, improved data base management systems for the acquisition, retrieval, and processing of biomedical data, and the use of decision theory and artificial intelligence methods to organize knowledge for greater usefulness in decision making. Research on image analysis that addresses specific biomedical problems is also relevant.
Noninvasive Tissue Characterization (Ultrasonic Methods) 1) Ultrasonic methods show considerable promise for providing quantitative characterization of normal and pathological tissue structures, and thus should be further exploited. Particularly needed is novel work that emphasizes basic aspects of ultrasound. Comment: Fundamental studies on the development of new ultrasonic imaging techniques, basic research on the interpretation of ultrasound data, and research on the biological effects of ultrasonic exposure will be encouraged. Computers 1) There is no need for identification of computers as a separate area since the modern computer is a tool used in practically all biomedical engineering research. Comment: Research involving routine use of computers should be judged and funded on the basis of the biomedical problems being addressed. Research on computer science applied to biomedical problems is an appropriate area for support.
IDENTIFICATION OF APPROPRIATE NEW RESEARCH AREAS There are a number of important biological problems, amenable to attack by the methods and technology of engineering science, that are not now being addressed by research supported by NIGMS, as well as some areas of engineering expertise not being exploited at present. The Committee developed the matrix shown in Table I in order to ensure consideration of the possible roles for biomedical engineering research at all levels of biological organization. In the following paragraphs, Patient Monitoring we cite several examples of new research problems and areas 1) Novel approaches rather than routine data acquisition identified by the analysis of Table I. While the examples are should be fostered. not exhaustive nor intended to be exclusive, they serve to il2) Research on chronic monitoring techniques should be lustrate possible new directions in which the Institute might encouraged. move in improving its balance and effectiveness of support.
492
IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. BME-25, NO. 6, NOVEMBER 1978
TABLE I ROLES FOR BIOMEDICAL ENGINEERING AT DIFFERENT LEVELS OF BIOLOGICAL ORGANIZATION -
esl
for Biomedical
T
'%.ngineering
IMathematical Methods, Modeling and
Instruments and Scientific -Measurement Problem Areas Techniques
Structure, Interaction and Degradation
techniques including: 'Transmission electron microscope,
.
________________________
Cell
Spectroscopy,
_
Cell Material Molecules
Structure, Interaction
l
Biochemical measurements including the use of:
-Cells,
Tagging
Organi
Measurements in man or animal models that are:
F allure
Modes, Differentiation and Regeneration
-Biochemical, 'Biomechanical, 'Chronic, Continuous
Nitural History of Growth,
Chronic Disease and Aging
Data base collection particularly in long timeconstant systems or high data volume
_systems
Each area's location in the matrix of Table I is indicated by the appropriate cell number. (This report does not make specific reference to cell la, since the topics included therein were considered separately at a subsequent workshop.) 1) Experimental and mathematical modeling of tissue perfusion, transport, and reaction. Mass transfer between the microcirculation and tissues has been interpreted largely in terms of lumped parameter models or the single capillary cylinder geometry introduced by Krogh. Continuum models are needed to describe the interactive effects of tissue perfusion, bloodtissue solute transfer, interstitial and intracellular transport, and solute metabolism in tissue regions of macroscopic size. Models developed in analogous situations to describe packed columns, chemical reactors, and flow through porous media are only a starting point for these extensions; serious challenges remain. This area has important applications to such problems as understanding the relation between chemotactic response of white blood cells and the dynamics of tissue infection; establishing optimal chemotherapeutic protocols; understanding transcutaneous gas exchange as a requisite for development of noninvasive blood gas monitoring techniques; and establishing the parameters for pharmacokinetic modeling (cell 2c). 2) Integrated detection, feedback, and control systems as an application of physiological systems analysis. Past efforts in the monitoring of acutely ill patients have been limited largely to tabulation and display of standard medical variables. There has been little effort to apply engineering methods of systems identification to the estimation of less accessible parameters, such as myocardial contractility or autonomic nervous system gain, and to track the physiologic state of the patient. This is a topic in the area of physiological systems analysis that deserves further exploration. The eventual extension of this ap-
2A
Sensors
Fundamental to the introduction of all foreign material into body plus a rational basis for biomedical -
Models of tissue perfusion, fluid transport and interactions of tissue fluids and materials
Chemical synthesis of
Models and analysis based on data bases: v
|
-Drugs, -Prosthetics,
Metabolic pathways and structural changes upon interaction
-
Total Man or Animal
Fundamental to the introduction of all Foreign material into body as in:
-Kinetics, -Binding,
-I
__nie lBn 2
Prosthetic Material
Molecular conformation and interaction models including studies of: -Active sites
-Crystallography
and Degradation
Tissue
Simulation
Chamical and physical
molecule - Molecule
Applications of Measurements and Models
'Statistical 'Pattern recognition Physiological systems
I
oA
biocomipatible materials.
C
Development of synthetic organs (Also target for other institutes and agencies) l 3C
Large scale clinical trials, the establishment of standards and
the dissemination of information. (Largely by other institutes) j3D
proach is the development of closed loop control for therapy of the acutely ill patient (cell 2d). 3) Non-invasive measurements. Instrumentation utilizing noninvasive methods to follow normal variations or pathological changes in humans is essential to minimize the risk, increase the acceptability, and reduce the artifacts of diagnostic procedures. The ability to measure local blood flow or perfusion in various organs is one example of a particularly important kind of measurement for which a non-invasive technique would be quite valuable. For example, using zeugmatography, a method of flow measurement based on nuclear magnetic resonance, it might be possible to measure cerebral blood flow without interference from the skull and integumentary structures, and without exposing the patient to hazardous procedures (cell Ic). 4) Biological-synthetic hybrid organs and instruments. A number of natural organ functions involve complicated and highly specific enzyme-mediated systems for which substitutes are unlikely to be achievable with present or forseeable technologies. The development of prosthetic organs based on tissue cultures or other biological material appropriately protected from rejection phenomena but capable of exchange with body fluids offers an important new approach to replacing the function of organs such as the pancreas and the liver. The development of all of these organs involves work in the area of transport phenomena, materials development, chemical kinetics, and control (cell 3b). While it is recognized that a number of the NIH categorical institutes have responsibility in these areas, the PBME Program is an appropriate place for some of this research. 5) Development of instrumentation and analytical techniques for fundamental physicochemical investigations in cell
ABBRECHT et al.: FUTURE DIRECTIONS FOR BIOMEDICAL ENGINEERING RESEARCH
biology. Studies of transport, surface phenomena, and population dynamics in cells would complement existing efforts in the understanding of a number of phenomena involving cellcell and cell-surface interaction (cell 2b). These studies would be important in increasing understanding of chemotaxis, cellular differentiation, cell-synthetic surface interaction, and population survival. These, in turn, are important elements in understanding immune response, infection control, rejection phenomena, and tissue ingrowth on prosthetic materials. 6) Sensory organs. The development of replacement organs for sight and hearing represents an exciting new direction in artificial organ development in which a unique set of problems must be addressed (cell 3c). Not only is there a need to develop signal detectors in appropriately miniaturized configurations, but the need to relay those signals to the brain through appropriate connections in the nervous system. Although enormous problems remain in hardware, software, systems analysis, and materials compatibility, progress is being made and the potential for success exists. Moreover, spillover from studies in this area holds promise for advances in the development of nerve prostheses, hormonal control systems, neurological control of hypertension, etc. Research efforts on this kind of problem should be encouraged by the appropriate Institutes. 7) Fluid mechanics and rheology of biofluids. Although rheological investigations of biofluids such as blood and mucus have been conducted in various programs of the NIH and other agencies, the required level of expertise and specialized equipment requirements suggest that there would be significant benefit from coordinated efforts to develop techniques and equipment for the analysis of biofluids. Viscoelastic phenomena, relaxation behavior, and shear induced changes in enzyme activity, molecular configuration, and biochemical kinetics hold promise for providing information on cell properties in normal and disease states (cells lb, lc). 8) Development of instrumentation and methodology for study of synthetic material-biological tissue interaction. A particularly important area of fundamental investigation is that of interactions between synthetic materials and biological tissues (cell 1c), since the limiting factors in the development of prosthetic devices and artificial organs often are problems caused by material incompatibilities. Examples of such problems are tissue erosion or necrosis, inflammation, sepsis, absorption of toxins from synthetic materials, or changes in mechanical properties of synthetic materials due to absorption of biological fluids. These interactions are serious problems not only in artificial organ development, but also in the development of instrumentation that places sensors or control devices in contact with living tissue. The understanding of synthetic material/living system interactions requires continued efforts in: 1) analyzing materials' properties, particularly surface properties; 2) understanding the relationship of these properties to the configuration of molecular and cellular constituents in the vicinity of the surface; and 3) relating this information to the broader questions of trauma and compatibility. Studies of this sort should be encouraged, taking into account support given by other Institutes for specialized endeavors.
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9) Drug delivery systems. In recent years, there has been a growing interest in the development of systems for drug delivery that would be more selective, effective, and flexible than discrete oral doses or injections, the methods which have been in use for over 100 years (cells 3a, 3b, and 3c). These new delivery systems make use of a number of different approaches to provide constant, continuous drug delivery, including implanted osmotic or vapor driven pumps, saturated drug solutions bounded by membranes of controllable permeability, cylindrical elastomeric reservoirs, etc. These and similar new approaches hold forth the promise of being able to deliver drugs while minimizing side effects, reducing the dosage required for effectiveness, and controlling the dose through on-line patient monitoring. 10) Molecular structure and interaction Computational models of molecules that allow careful study of structure and molecular interaction have become feasible as a result of the continuing increase in computational power available for a reasonable cost. The use of such computational models holds promise of a rational basis for comprehending the mechanisms of drug activity, for drug design, and for basic understanding of the phenomena associated with the introduction of foreign material into the body. The kinetic binding of biologically interesting molecules can be understood in greater depth through the development of more powerful models based on physical structure (cell 2a). 11) Long time constant systems. (Cell Id). In contrast to acute disease processes, the natural history of growth, chronic disease, and aging evolves over long times that are of the same order as those of periods of environmental change that in itself can modify the process under observation. This difficulty with the acquisition of knowledge about long time constant systems complicates the study of many biological problems; for instance, determining the etiology of arteriosclerotic vascular disease. Tools such as clinical trials provide only a snapshot, whereas a continuing view of the evolution of a disease may be more informative in many cases. The feasibility of the collection of data-bases that describe the natural history of such long time constant processes increases with the availability of low-cost computer systems and data acquisition methods that are accurate and timely. Research in the methodology and technology for organizing and accomplishing such natural history studies may be a new opportunity for the PBME Program that could pay dividends throughout the other Institutes.
P. H. Abbrecht, photograph and biography not available at the time of publication.
J. R. Cox, photograph and biography not available at the time of publication.
F. P. Ferguson, photograph and biography not available at the time of publication.
