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National Institutes of Health (U.S.). Biomedical E.

Annual report: National Institutes of Health. Division of Research Services. Biomedical Engineering and Instrumentation Branch (Volume 1983) online

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BIOMEDICAL ENGINEERING AND INSTRUMENTATION BRANCH
DIVISION OF RESEARCH SERVICES
NATIONAL INSTITUTES OF HEALTH CUoS. )

ANNUAL REPORT FY 1983



Dr. Murray Eden, Chief



BEIB Research Projects (ZOl RS)



10001-15 Pharmacokinetics

10002-18 Implant Device Development

10015-08 Development of Toposcopic Catheter

10018-08 Particulate Hydrodynamics in Porous Membranes

1003^^-06 Three-Dimensional Histological Reconstruction

10039-06 Biophysical Instrumentation and Methodology

100^^0-06 Physical Chemistry of Biological Macromolecules

100^3-06 Fiber Optic Probes

10050-05 Positron Emission Tomography Scanner

10053-05 Membrane Based Sampling Systems for In Vivo and

In Vitro Kinetic Studies
10062-0'f lEEE-ifSS General Purpose Interface Bus

Program Development
lOOG'^-0'^■ Indirect Blood Pressure Measurements in

Laboratory Animals Using Oscillometry
10065-0^ Transient Response of Micor-Calorimeter

Using R-C Analysis
10066-03 Egyptian Training Project

10073-0't Secondary Emission Mass Spectrometer

10076-0't Elemental Analysis of Microdroplets

10082-03 Protein Sequencer Modificationl

10095-03 Multiple Probe pH Measurement System for

Canine Myocardium
10096-03 Light Scattering Method for Evaluation of Platelets

10097-03 Mechanics of the Left Ventricle and Myocardial

Blood Flow
10098-03 Laser Instrumentation for Vitreous Surgery

10099-03 Cochlear Mechanics and Neural Modeling

10102-03 Osmotic Behavior of Perfused Tissues and Organs

10103-03 Triple Laser - Multi Parameter Flow Cytometer System

for Study of Tumor Cell Kinetics
10105-03 Adaptation of an EPICS II Flow Cytometer for

T. Cruzi Analysis
10106-03 Molecular Uptake in Tumors Using Chronic, Implanted,

Fiber Optic Probes
10109-03 Adjunct Heat Treatment of Cancer

10110-03 A Dual 3-Dimensional Position Monitor For Speech

Analysis: MOD. II
10112-03 Analysis of Microcirculatory Blood Flow by

Laser Doppler Scattering
1011^^-02 Phasic Aortic Pressure Control System for Awake Dogs

101 16-02 Modeling of Arterial Pulse Waves

10117-02 Optimum Cryoprotectant Introduction/Removal for

Blood Components
10122-02 Mini-computer Controlled Fermentation System

10125-02 Automatic Assessment of Cytochrome P^50

10126-02 Trace Analysis and Elemental Microanalysis in Biological

10132-02 Image Processing and Cell Classification

10135-02 The Effects of Fluid Shear on Cultured Endothelial Cells

10136-02 Imaging in Positron-Emission Tomography



R.L. Dedrick


1


3.W. Boretos


6


D.R. Shook


9


P.M. Bungay


11


5.B. Leighton


[li


M.S. Lewis


16


M.S. Lewis


18


J.I. Peterson


21


W.S. Friauf


23


P.M. Bungay


25



T.R. Clem 28



E.C. Walker 30



C.P. Mudd 32



R.



C.P. Mudd


3^


L. Kelner


36


A.F. LeRoy


38


R.3. Lutz


W


D. Markle


kl


R.F. Bonner


kt\


S. Chadwick


k(>


R.F. Bonner


48


,S. Chadwick


51


R.L. Levin


53


W. Schuette


56


T.E. Hall


58



R.L. Levin 60



R.L. Levin
E.C. Walker



62
65



R.F. Bonner 67



S.R. Goldstein


1^


R.S. Chadwick


72


R.L. Levin


Ik


T.R. Clem


76


R.F. Bonner


78


I A.F. LeRoy


80


3.R. Ellis


83


R.J. Lutz


86


J.R. Ellis


89



Table of Contents, (Cont'd)



10137-02 Processing of Electron Microscope Images 3.R. Ellis 92

10143-02 Interaction of Body Temperature and Sleep Rhythms T.L. Talbot 95

10145-01 Opthalmodynamometry: Correlation with C5F Pressure S.B. Leighton 97

10146-01 Prosthetic Urethral Sphincter S.B. Leighton 99

10147-01 Viscoelastic Properties of the Erythrocyte Membrane A. Tozeren 101

10148-01 Analysis of the coupling between left ventricle and R.S. Chadwick 103

10149-01 Mechanics of Muscle Contraction A. Tozeren 105

10150-01 Cardio-vascular Instrumentation System G.M. Maxwell 107

10151-01 Nuclear Magneti Resonance Image D.I. Hoult 109

10152-01 Measurement and Imaging of Magnesium in G. Hook 111

Lymphocytes by Electron Beam X-ray 112

10153-01 A Position Sensor for Computer Modeling H.E. Cascio 112

10154-01 Photo-Irradiation of Cancer Cells P.D.Smith 114

10155-01 Vidicon Detection for Fluorescence Microscopy H.E. Cascio 117

10156-01 Differential Scanning Calorimeter C.P. Mudd 119

10157-01 Temperature Controlled Chamber for C.P. Mudd 121

X-ray Diffraction

10158-01 Isolate Heart Perfusion M.A. MacCollum 123

10159-01 Pathophysiology of Cachexia in Sarcoma Patients R. Corsey 125

10160-01 Heat Treatment Apparatus for Treatment of Leishmaniasis R. Corsey 126

10161-01 Clinical Engineering Program for Hospital R. Corsey 127

Patient Care Areas

10162-01 Wound Healing: Biology and Rheology T. Talbot 128

10163-01 Magnetoencephalography for Localization of Foci of R.F. Bonner 129

Neurologic Activity

10164-01 Distribution of Phosphorus and Calcium in R.D. Leapman 131

Newly Formed Bone

10165-01 EELS Study of Invasion of Red Blood Cells by R.D. Leapman 132

Malaria Parasites

10166-01 Detection of Foreign Particles in Lung Tissue R.D. Leapman 133

10167-01 Low Z Imaging of Chromaffin Cells by EELS R.D. Leapman 134

10168-01 Software for Quantitation of EELS C.R. Swyt 136

10169-01 Software for Electron Energy Loss Imaging C.R. Swyt 138

10170-01 Biological Applications of a Computer Controlled R.D. Leapman 140

Analytical Electron Microscope

10171-01 Electro-optic Element for Projection of 3D Movies P.D. Smith 142

10172-01 Portable Programmable Drug Delivery System C. Wooten 144

10173-01 Computer Control of Electron Beam X-ray Microanalysis C. Fiori 146

10174-01 Display and Response Tester for Amnesic Patients C. Wooten 147,

10175-01 Semi-Automated Electrophoresis Cell Reader C.C. Gibson 149

10176-01 Laboratory Studies of the Biology of Malignant T Cells C.C. Gibson 150

10177-01 Computerized Cell Counting and Morphology C.C. Gibson 151

10178-01 Exocytosis Modelling: Kinetics of Membrane Aggregation C.C.Gibson 152

10179-01 Controller for Rapid Freezing of Tissue C.C. Gibson 153

10180-01 Imaging Calcium and Aluminum Deposits in the G. Hook 154

Brain by Electron Beam X-ray Microanalysis

10181-01 Imaging and Quantifying Platinum Distribution in G. Hook 155

Tissue By Electron Beam X-ray Microanalysis



Page 1



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE

NOTICE OF INTRAMURAL RESEARCH PROJECT



PROJECT NUMBER



ZOl RS 10001-15 BEI



'ectofe'er"!°1982 to September 30, 1983



TITLE OF PROJECT (80 characters or leB8. Title must fit on one line between the borders.)

Pharmacokinetics



PRINCIPAL INVESTIGATOR (List other professional personnel on subsequent pages.)
(Name, title, laboratory, and institute affiliation)

R.L. Dedrick, Chief, ChES, BEIB, DRS



COOPERATING UNITS (if any)



CPB-NCI NTP-NIEHS
North Dakota State University SNB-NINCDS
Howard University CP-CC



LAB/BRANCH

Biomedical Engineering and Instrumentation Branch



SECTION

Chemical Engineering Section



INSTITUTE AND LOCATION „ _ «„-,^^

National Institutes of Health, Bethesda, MD 20205



TOTAL MANYEARS:



2.5



PROFESSIONAL;

2.5



CHECK APPROPRIATE BOX(ES)

IS (a) Human subjects

□ (a1) Minors

□ (a2) Interviews



□ (b) Human tissues



□ (c) Neither



SUMMARY OF WORK (Use standard unreduced type. Do not exceed the $p ace provided.)

Pharmacokinetic models are developed for the distribution and disposition of drugs,
environmental contaminants , and endogenous metabolites in animals and man. They
provide a plausible set of equations that can be used to extrapolate data from animals to
man and thereby improve chemotherapy , and risk assessment . Increased emphasis has
been placed on regional drug administration, in particular intrathecal, intraperitoneal and
intra-arterial. The former two modes have required the development of spatially
distributed models of the tissue adjacent to the cerebrospinal fluid (CSF) or peritoneal
fluid. These analyses have provided considerable insight into the penetration depths of
drugs administered by these routes and the interpretation of CSF kinetics in terms of
brain concentration profiles. The penetration of cis-dichlorodiam mine-platinum (II) (DDP)
into peritoneal and subperitoneal tissue is being examined experimentally with an electron
probe and the results compared with a reaction-diffusion equation of the process. A
lumped model of DDP pharmacokinetics is also being developed to include both
metabolism to a mobile species and covalent binding to macromolecules
Pharmacokinetic theory has been developed for intra-arterial drug administration
combined with hemoperfusion of vascular drainage, and the concepts have been validated
experimentally in monkeys. A clinical trial is in progress.



PHS6040 (Rev. 1/83)



GPO 895-100



DEPARTMENT OF HEALTH AND HUMAN SERVICES- PUBLIC HEALTH SERVICE
NOTICE OF INTRAMURAL RESEARCH PROJECT



Page 6

PROJECT NUMBER

ZOl RS 10002-18 BEl]



PERIOD COVERED ,„„^ ^ , ,„„,

October I, 1982 to September 1983



TITLE OF PROJECT (80 characten or lets. Title must fit on one line between the borders.)

Implant Device Development



PRINCIPAL INVESTIGATOR (List other professional personnel on subsenuent pages.)
(Name, title, laboratory, and institute affiliation)

John W. Boretos, Physical Scientist, BEIB, DRS



COOPERATING UNITS (if any)

CR-CC; RO-NCI, Penn State Univ.



LAB/BRANCH . , ,

Biomedical Engineering and Instrumentation



SECTION

Chemical Engineering Section



INSTITUTE AND LOCATION

National Institutes of Health, Bethesda, MD 20205



TOTAL MANYEARS:



1.0



CHECK APPROPRIATE BOX(ES)

^ (a) Human subjects

□ (a1) Minors

□ (a2) Interviews



PROFESSIONAL:

.7



.3



□ (b) Human tissues



□ (c) Neither



SUMMARY OF WORK (Use standard unreduced type. Do not exceed the tpaee provided.)

The purpose of the project is to elucidate the interaction of biomaterials used for specific
implants with the physiological environment and to explore specially prepared
biomaterials and design features with respect to their suitability and performance in a
variety of contexts. For catheters designed to be used in the vascular system,
thrombogenic events have been reduced by incorporating an anticoagulent at various
levels within hydrogel layers which are attached to the surface. Slow release of the
anticoagulant has significantly reduced the amount of clot generated on the surfaces as
compared with untreated polyurethane catheters. Specific hydrogel formulations have
been shown to reduce drag and eliminate sticking of catheters in the vascular system. A
multi-lumen micro-catheter which is propelled and directed through small diameter blood
vessels via jets of fluid emanating from its distal end has shown promise for negotiating
heretofore difficult to reach areas. The catheter is controlled by an adjustable
pressurized manifold operated by a joy stick. A transparent model of the vascular
network simulating blood flow of a pulsatile nature was designed to evaluate the
efficiency of the jet catheter system and its behavior in administering embolizing agents
and chemotheropeutic drugs. Ex vivo studies of the polyurethane insulation of stimulating
and pacing electrodes, along with long-term in vitro coupon studies have indicated reliable
stability for segmented polyurethane for a number of surgical applications. Good
correlation exists between in vivo and in vitro data for ultimate tensile strength and
elongation over short-and long terms. Minor changes in physical properties when stored
wet appear to be the result of a plasticizing effect which is reversible on drying.
Segmented polyurethane stored in water with high bacteria counts over a 13 year period
show up to 30% decrease in strength although the same material implanted in a sterile
subcutaneous pocket for 3 years showed no appreciable changes. Our studies and that of
others confirm that particles shed from the surfaces of in vivo and in vitro devices are not
totally avoidable but can be minimized by careful control of the materials used for
catheters, heart assist devices, injection sets, etc..



PHS 6040 (Rev. 1/83)



GPO 895-100



DEPARTMENT OF HEALTH AND HUMAN SERVICES- PUBLIC HEALTH SERVICE
NOTICE OF INTRAMURAL RESEARCH PROJECT



Page 9

PROJECT NUMBER

ZOl RS 10015-08 BEl



PERIOD COVERED

October 1, 1982 to September 30, 1983



TITLE OF PROJECT (80 characte)r8 or less. Title must fit on one line between the borders.)

Development of Toposcopic Catheter



PRINCIPAL INVESTIGATOR (List other professional personnel on subsequent pages.)
(Name, title, laboratory, and institute affiliation)

D.R. Shook, Biomedical Engineer, BEIB, DRS



COOPERATING UNITS (if any)

Diagnostic Radiology, CC



LAB/BRANCH

Biomedical Engineering and Instrumentation Branch



SECTION

Mechanical Engineering Section



INSTITUTE AND LOCATION -„-,/, ^

Division of Research Services, NIH, Bethesda, MD 20205



TOTAL MANYEARS:



1.8



PROFESSIONAL:
1



CHECK APPROPRIATE BOX(ES)

K] (a) Human subjects
ISl (a1) Minors
□ (a2) Interviews



CZl (b) Human tissues



□ (c) Neither



SUMMARY OF WORK (Use standard unreduced type. Do not exceed the tpace provided.)

Toposcopy has been shown to be a viable means to catheterize small, tortuous vascular
and gastrointestinal vessels. These regions have been inaccessable by existing techniques.
Continuing developmental work will optimize catheter material properties, desigr
parameters, and system configuration for diverse clinical applications.

The toposcopic element everts from the tip of a conventional catheter. This extremely
flexible polyurethane element has been fabricated in 3, k, and 5 French sizes mated with
5, 6, and 7 French catheters, respectively, and is capable of eversion lengths in excess oi
30 cm. The present system design facilitates sterilization and maximizes safety,
reliability, and reconfigurability for clinical investigations. The design of a completely
automated system is underway.

Human use has continued from May <*, 1983 with the local delivery of a chemotherapy
agent to brain tumors. Treatment is provided by positioning the conventional catheter ir
the internal carotid artery from a femoral entry, everting the toposcopic element through
the carotid sinus and beyond the opthalmic artery to avert retinal toxicity, and perfusing
the tumor through the middle and/or anterior cerebral arteries. Note that a conventiona
catheter cannot safely negotiate the tortuosity of the carotid sinus. Localizec
chemotherapy of other tumor locations, delivery of embolizing agents, and treatment o]
other vascular lesions are contemplated.

The toposcopic catheter is also under modification for gastrointestinal placement through
the fiber optic endoscope. The toposcopic element has successfully negotiated the
convoluted cystic duct, aspirating pure bile from a catheter entry at the exposed canine
papilla of Vater. Envisioned uses for the catheter are sampling of pancreatic, gal
bladder, and hepatic secretions for clinical research and infusions for dissolving gal.
stones in situ.



PHS 6040 (Rev. 1/83)



GPO 895-100



Page 11



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE
NOTICE OF INTRAMURAL RESEARCH PROJECT



PROJECT NUMBER

ZOl RS 10018-08 BEl



PERIOD COVERED

October 1, 1982 to September 30, 1983



TITLE OF PROJECT (80 charactert or lesB. Title muit fit on one line between the borders.)

Particulate Hydrodynamics in Porous Membranes



PRINCIPAL INVESTIGATOR (List other professional perionnel on lubseQuent pages.)
(Name, title, laboratory, and institute affiliation)

P.M. Bungay, Chemical Engineer, BEIB, DRS



COOPERATING UNITS (lY any; r- i j

Department of Mathematics, University College, London, England
North Atlantic Treaty Organization, Brussels, Belgium



iLAe.'eRANCH

I Biomedical Engineering and Instrumentation Branch



SECTION

Cremical Engineering Section



INSTITUTE AND LOCATION

National Institutes of Health, Bethesda, MD 20205



TOTAL MANYEARS:



.1



PROFESSIONAL;
.1



CHECK APPROPRIATE BOX(ES)

□ (a) Human subjects

□ (a1) Minors

□ (a2) Interviews



□ (b) Human tissues



Kl (c) Neither



SUMMARY OF WORK (Use standard unreduced type. Do not exceed the gpace provided.)

Mathematical models are being developed to describe passive membrane transport through
pores or intercellular spaces junctions. The Taylor-Aris dispersion analysis is extended tc
treat combined Brownian motion and convection in a single pore. The solute particle
dimension is assumed to be large compared to that of the solvent molecules and also
appreciable in size compared to the lateral pore dimension. The latter condition implies
strong hindered diffusion and related solute-membrane interaction effects. A key aspecl
of the analysis is a generalized Einstein relation for predicting axial and radia
components of the diffusivity tensor from hydrodynamics solutions for resistance
coefficients. Perturbation techniques are used to obtain asymptotic solutions to the
hydrodynamic equations, and the method of moments is employed to analyze the solute
continuity equation. Related hydrodynamic problems are also being considered, such a:
flow through constricted vessels.

The hydrodynamic results in combination with an analysis derived from irreversible



thermodynamics , provide a predictive theory for simultaneous coupled convective anc
diffusive transport across porous membranes - either biological or synthetic.

A review of the theoretical approaches to transport in porous membranes is included ir
the curriculum for the North Atlantic Treaty Organization Advanced Study Institute or
Synthetic Membranes; June 26-3uly 8, 1983, directed by the principal investigator



PHS 6040 (Rev. 1/83)



GPO 895-100



DEPARTMENT OF HEALTH AND HUMAN SERVICES- PUBLIC HEALTH SERVICE
NOTICE OF INTRAMURAL RESEARCH PROJECT



Page 14

PROJECT NUMBER

ZOl RS 1003^-06 BEl



PERIOD COVERED

October 1, 1982 to September 30, 1983



TITLE OF PROJECT (80 characters or less. Title mutt fit on one line between the borders.)

Three-Dimensional Histological Reconstruction



PRINCIPAL INVESTIGATOR (List other professional personnel on subsequent pages.)
(Name, title, laboratory, and institute affiliation)

S. B. Leighton, Mechanical Engineering, BEIB DRS



COOPERATING UNITS (if any)

LB NINCDS



LAB/BRANCH

Biomedical Engineering and Instrumentation Branch



SECTION

Mechanical Engineering Section



INSTITUTE AND LOCATION

National Institutes of Health, Bethesda, MD 20205



TOTAL MANYEARS:



PROFESSIONAL:

A5



.05



CHECK APPROPRIATE BOX{ES)

□ (a) Human subjects

□ (a1) Minors

□ (a2) Interviews



O (b) Human tissues



S (c) Neither



SUMMARY OF WORK (Use standard unreduced type. Do not exceed the space provided.)

A semi-automatic system for acquisition of three-dimensional structural information
about histological material is being developed. The system should have significant speed
and reliability advantages over present techniques using serial sections, although
resolution may be limited. In brief, an embedded tissue block will be fixed relative to a
scanning electron microscope imaging system, the surface of the block will be imaged and
stored, and successive slices will be removed by a built-in microtome . Handling and
registration of thin sections will thus be eliminated. Human and computer pattern
recognition will transform the resulting set of images into a three-dimensional
reconstruction. Oxygen plasma etching has been found to give sufficient topographic
relief that the resolution of the images is now limited by the SEM and not by the
preparation technique. The images of Hermissenda Crassicornis obtained by this
technique correlate well with TEM images of the same tissue, indicating that the lack of
artifact is adequate for the contemplated studies.



PHS 6040 (Rev. 1/83)



GPO 895-100



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE
NOTICE OF INTRAMURAL RESEARCH PROJECT



Page 16

PROJECT NUMBER

ZOl RS 10039-06 BE]



PERIOD COVERED ,„ .„„,

October 1, 1982 to September 30, 1983



TITLE OF PROJE CT {80 characten or lete. Title must fit on one line between the borden.)

Biophysical Instrumentation and Methodology



PRINCIPAL INVESTIGATOR (List other professional personnel on subsequent pages.)
(Name, title, laboratory, and institute affiliation) „„„^ i^^..

Marc S. Lewis, Research Chemist, BEIB/DRS



COOPERATING UNITS (if any)



LAB/BRANCH .

Biomedical Engineering and Instrumentation Branch



SECTION

Microanalysis Section



INSTITUTE AND LOCATION „ . . ..^ -«-«r-

National Institutes of Health, Bethesda, MD 20205



TOTAL MANYEARS:



PROFESSIONAL:

.2



CHECK APPROPRIATE BOX(ES)

□ (a) Human subjects

□ (a1) Minors

□ (a2) Interviews



□ (b) Human tissues



S (c) Neither



SUMMARY OF WORK (Use standard unreduced type. Do not exceed the $paee provided.) . • ■

The project is designed to develop new instrumentation and methodology or improve
existing instrumentation and methodology for characterization of biologica
macromolecules. Analytical ultracentrifugation, the techniques ancillary to it, an<
methods of data analysis using mathematical modeling appropriate for these techniques
are the major areas of interest.

Improved precision and optimal efficiency in ultracentrifugal analysis requires improved
methods of data acquisition. A microprocessor controlled data acquisition instrument for
use with the microcomparator used for the measurement of photographic records from th<;
ultracentrifuge has been developed earlier. The methods of data acquisition involved in
the development of this instrument have been extended to the development of a system
for the direct acquisition of data from the photomultiplier tube of the ultraviole :
absorption scanner of the ultracentrifuge. The software requisite for making this system
operational is currently in development. When complete, this system will permit direc :
acquisition of data while the ultracentrifuge is operating and then permit preliminary data
processing followed by transmission of the data to the DEC-10 computer for detailed
analysis. This will effect a marked increase in efficiency, significantly improved
precision, enhanced facility in data analysis and will also more readily permit the
effective modification of some experimental conditions such as rotor speed and
temperature during the course of the experiment if the analysis indicates it to be
desirable.

MLAB, operating on the DEC-10 computer, has been used for mathematical modelinj;
studies for the analysis of various types of protein interactions. These studies have been
applied to ultracentrifugal studies of binding and of protein self -association.



PHS6040 (Rev. 1/83)



GPO 895-100



Page 18



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE
NOTICE OF INTRAMURAL RESEARCH PROJECT



PROJECT NUMBER



ZOl R5 lOO'tO-06 BEI



'"(5cto?>er!fl982 to September 30, 1983



TITLE OF PROJECT (80 characters or lest. Title must fit on one line between the borders.)

Physical Chemistry of Biological Macromolecules



PRINCIPAL INVESTIGATOR (Li$t other professional personnel on subsequent pages.)
(Name, title, laboratory, and institute affiliation)

Marc S. Lewis, Research Chemist, BEIB, DRS



COOPERATING UNITS (if any)



LAB/BRANCH

Biomedical Engineering and Instrumentation Branch



SECTION

Microanalysis Section



INSTITUTE AND LOCATION „ , . ..^__«__

National Institutes of Health, Bethesda, MD 20205



TOTAL MANYEARS:



0.8



PROFESSIONAL;

0.8



CHECK APPROPRIATE BOX(ES)

CZI (a) Human subjects

□ (a1) Minors

□ (a2) Interviews



□ (b) Human tissues



(c) Neither



SUMMARY OF WORK (Use standard unreduced type. Do not exceed the space provided.)

The purpose of this project is to study the physical properties of a wide variety of
biological macromolecules with the goal of correlating these properties to the structure
and function of the macromolecules. The emphasis is on molecular size and shape and the
thermodynamics of molecular interactions. Analytical ultracentrifugation and
mathematical modeling are the principal research techniques used.

Extensive studies on the binding of plasminogen by fibrinogen have been completed. It has
been shown that each fibrinogen molecule can bind four molecules of either the native
glu-plasminogen or lys-plasminogen, a modified form produced by the plasmin or urokinase
removal of a peptide with a molecular weight of kOOO. The equilibrium constants for the


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