University of Pennsylvania
Departmental Papers (CBE)
Department of Chemical & Biomolecular
Harry L. Goldsmith, Ph.D.
Scott L. Diamond
University of Pennsylvania, firstname.lastname@example.org
Michael B. Lawrence
University of Virginia
Larry V. McIntyre
Georgia Institute of Technology
State University of New York
Postprint version. Published inAnnals of Biomedical Engineering, Volume 36, Issue 4, April 2008, pages 523-526.
Publisher URL: http://dx.doi.org/10.1007/s10439-008-9479-y
This paper is posted at ScholarlyCommons.http://repository.upenn.edu/cbe_papers/110
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Harry L. Goldsmith, Ph.D.
In honor of Dr. Harry L. Goldsmith's 75th birthday, we present a collection of articles
from his collaborators and colleagues to commemorate Harry's outstanding contributions
to the field of Biorheology. On any particular day, bioengineers around the world may
find themselves fortunate enough to peer through a microscope to observe molecular or
cellular level phenomena manifested before their eyes. Such observations of single
molecule mechanics or blood flows or cellular deformation remind us of the power of
clever experimental design and rigorous theoretical constructs as well as the complex
beauty of dynamical systems in nature. In this spirit, the investigations reported in this
issue of the Annals entitled Cellular Biorheology and Biomechanics have followed down
many of the research paths pioneered by Dr. Harry Goldsmith.
Harry Goldsmith, born May 11, 1928 in Nurnberg Germany, obtained his BA (1950), and
B.Sc. (1951) from Oxford University and his PhD (1961) from McGill University where
he maintained his entire research career for over fifty years. While at McGill, he worked
closely with eminent hydrodynamicists and physiologists such as Stanley G. Mason.
Theo G. M. van de Ven, and Mony M. Frojmovic. Rising to the rank of Full Professor in
the Department of Medicine, Harry also served as the Director of the Division of
Experimental Medicine from 1976 to 1995. Notable awards include the Landis Award of
the American Microcirculatory Society (1984) and the Poiseuille Medal of the
International Society of Biorheology (1984). He served as President of the International
Society of Biorheology (1983-86) and President of the North American Society of
Biorheology (1990-92) and continues to serve as the Editor-in-Chief of Biorheology
The flow of ideas and methodologies at work in the scientific investigations captured in
panoramic view in this issue also is a measure of the breadth of Harry's continuing
impact. When today’s generation of scientists and engineers see certain images in talks
and textbooks, it is easy forget that it was Harry who first obtained the data in the days
before high speed digital cameras and image processing software, off-the-shelf numerical
packages, and lab-on-a-chip microfluidic devices.
Microrheology of Human Blood
Through frame by frame tracking (cinephotomicrographs!) of rigid discs, fluid droplets,
hard spheres, red blood cells (RBC), rouleux, platelets, and red blood cells, Harry helped
define the microrheology of blood flow. RBC rotational dynamics and deformation,
liquid droplet deformation, enhanced radial dispersion, inward migrational drift, blunted
velocity profiles, two-body collisions, and doublet rotation became the tools to
understand the microscopic forces on particles within flow. In a classic example, Harry
investigated the migratory paths of rigid and deformable particles in viscous flow both
when Reynolds numbers was low (negligible inertial effects), and at larger Reynolds
number when inertial effects are significant.1 These studies demonstrated the importance
of RBC fluidity and migratory drift in controlling the radial distribution of both the more-
deformable RBCs and less-deformable white blood cells (WBCs) in blood flow.
In this issue of the Annals, this attention to particle microphysics is reflected in papers on
the hematocrit dependence of blood viscometry from the Takeshi Karino laboratory and
large scale computational simulation of deformable leukocytes from the Michael King
laboratory. Lance Munn also provides a detailed discussion of blood cell interactions and
segregation in flow.
Disturbed Flow and Vascular Disease
By tracking individual cells within complex flows in flow expansions and arterial
bifurcations, the resolution of fluid mechanics on the length scale of single cells was
united with large scale macroscopic hemodynamics. For example, in one of many
publicationswith T. Karino2 on platelet deposition downstream of a sudden expansion, a
stenosis analog, the enhanced accumulation of platelets on collagen within the
recirculation zone was studied as a function of flow pulsatility, Reynold’s number and
hematocrit. In other work, particle trajectories in 30o, 90o and 150 o T-junctions were
visually striking with spiraling vortexes set up opposite the flow divider with well
defined flow separation and reattachment points, a site prone to early plaque formation
(Fig. 1). This dynamical complexity was fully apparent well before its use for chaotic
laminar mixing now exploited in microfluidic devices. In contrast, rather orderly
streamlines were often found at the flow divider in many configurations, a region spared
of early disease in coronary atherosclerosis but susceptible to cerebral aneurysm.
In understanding the geometric localization of boundary layer attachment, vortices, and
reversing flows, endothelial function became an interest in the context of atherosclerotic
plaque localization, intimal hyperplasia, and graft distal anastomotic hyperplasia.
Research of flow on endothelial function, in laminar or disturbed flows, as well as large
scale simulation of oscillatory flow through flexible bifurcations is now common. In this
issue, papers from the laboratories of Peter F. Davies, Shu Chien, Scott L. Diamond, and
Larry V. McIntire provide coverage of topics in endothelial mechanobiology.Collisions
of Activated Cells in Sheared Suspensions
In activated blood flow, platelets moving in faster streamlines will have collisions with
platelets in slower streamlines. The rate of single cell consumption into aggregates can
be measured in linear shear fields or parabolic shear fields. On estimating the rate of
collisions, the sticking probability can be determined. For activated platelets undergoing
aggregation in tube flow, Bell et al.3found that activated platelets are fabulously sticking,
with about up to 3 of 10 collisions resulting in adhesion due to GPIIb/IIIa-fibrinogen
Harry contributed to studies of cell and particle interaction under flow by developing two
novel and clever experimental systems. In the first setup called the ‘travelling microtube
apparatus4, cell suspensions were subject to laminar viscous flow through a glass tube
using gravity feed between infusion and collecting reservoirs. The slide and reservoirs
were mounted on a jig and attached to the vertically sliding platform of a hydraulically
driven traveling microtube apparatus. The translational and rotational motion of doublets
could be viewed in this system with a camera attached to a horizontally positioned
microscope by moving the sliding platform upward at a velocity equal to that of the
downward-flowing particles. In another novel experimental setup, Harry and colleagues
developed a rheoscope which consists of a counter-rotating transparent cone and plate
viscometer mounted on the stage of an inverted microscope. In this system, the cone and
plate were rotated with equal angular velocity in opposite directions such that a layer of
zero translational velocity was located in the midplane between the cone and plate. Cell
collisions and doublet could be viewed for extended periods of time at this midplane.
Aggregation kinetics, collision efficiency, doublet lifetime and period of rotation data
could be collected using high-speed videomicrosopy.
To complement these experimental systems, existing hydrodynamic theorywas extended
to derive explicit expressions for the nature and magnitude of normal and shear forces
applied in the above experimental systems. These experiments and theory together
provided some of the first estimates on the magnitude of hydrodynamic forces that
prevail at the cellular level various human vascular pathophysiologies during
inflammation and thrombosis. The continual development of defined flow systems for
blood diagnostic testing relies on controlling the frequency of cellular collisions and the
forces applied upon adherent cells. In the current issue, Mony Frojmovic presents
detailedarguments outlining the rationale supporting the application of flow devices and
biorheology principles in the clinical setting to assess the drug and clinical outcome
Adhesion: Microrheology and Molecular Mechanics
With a long track record in single cell tracking and platelet aggregation, it was a natural
extension of Harry’s interests to begin quantification of the mechanics of receptor
mediated adhesion. A small story helps to capture the precision of Harry’s experimental
approach, the range of his understanding of molecular scale and macroscale phenomenon,
and his attention to important problems. In a 1983 study of fixed sphered RBC
undergoing two-body collision, adhesion, and doublet rotation in the presence of anti-B
antiserum7, Harry estimated the hydrodynamic force to break up a doublet formed at high
antibody dilution to be Fh = 6 x 10-11 N and noted that this was appreciably less force
than necessary to break a C-C bond. The published “Discussion of the Paper” captures a
moment in time some 25 years ago when 60 pN (or 6 μdynes) became a first estimate of
the force to break an antibody-antigen bond holding a doublet together in a flow field:
[R. M. Hochmuth (Duke University)]: I am interested in those forces of separation you had
between your beads. Did they work out to be about 6 x 10-6 dynes? I cannot think in terms
of nanonewtons, though.
[Goldsmith]: They were 6 x 10-11 N. You divide by 105 to get it back to dynes from Newtons.
[Hochmuth]: Yes…so it is 6 x 10-6 dynes.
[Goldsmith]: That is correct.
[Hochmuth]: …What you really need is a force displacement relationship to get the free energy of
adhesion or disaggregation.
[Goldsmith]: …People have obtained equilibrium constants from which they can work out
thermodynamic quantities, but they cannot work out the actual magnitude of the force of
In the above discussion, it is no surprise that Harry knew the unit conversion and that he
anticipated the hard work ahead in relating the dissociation constant measured by
immunologists to the actual strength of a biological adhesion under hydrodynamic force
loading. The “microdynes” of biorheology became the “picoNewtons” of molecular
biophysics. In fact, Harry had first published in 19818 the observation “forces of the order
of 0.1 nN were required to break up these [antibody-antigen] linkages”after completing a
full characterization of the underlying DLVO interactions of latex spheres or fixed RBCs.
The importance of background forces remains very significant because force loading
regimes are often used today that can go down to the low pN ranges.
In the later part of his career, the Goldsmith lab would continue research on fibrinogen-
mediated and von Willebrand factor (vWF)-mediated adhesion of platelets, L-
selectin/PSGL-1 adhesion of neutrophils, as well as E-selectin and P-selectin mechanics.
The exploration of receptor-mediated adhesion under mechanical loading continues to
fascinate and challenge. In this issue, the topics of bond mechanics and adhesion are
presented from the laboratories of: Cheng Dong, Sriram Neelamegham, Scott Simon,
David Tees, and Cheng Zhu.
Overall, Harry Goldsmith advanced the use of many novel techniques in microrheology:
the traveling microscope to image cells in tube flow, the counter-rotation plate flow to
observe doublet collisions in a linear shear field, T-junctions and sudden expansions and
vein valves for particle trajectory tracking. In today’s world of interdisciplinary research,
we can look to his early example of bridging colloidal hydrodynamics with the study of
hemodynamics, platelet and neutrophil biology, and bond mechanics.
In a publication record spanning fifty years, Harry has shown himself to be a dedicated
and meticulous scientist who consistently tackled and elucidated the most fundamental
principle or phenomenon embedded in the study at hand. Throughout his career, he has
been a kind mentor and collaborator to many younger scientists, eager to exchange ideas
and insights. We are enriched by his warmth, his scholarship, and his many long lasting
contributions to the fields of Biorheology, Physiology and Biophysics.
Scott L. Diamond
University of Pennsylvania
Michael B. Lawrence
University of Virginia
Larry V. McIntire
Georgia Institute of Technology
State University of New York at Buffalo
1. Goldsmith HI, Mason SG. Axial migration of particles in Poiseulle flow. Nature.
2. Karino T, Goldsmith HL. Adhesion of human platelets to collagen on the walls
distal to a tubular expansion. Microvasc Res. 17(3 Pt 1):238-262, 1979
3. Bell DN, Goldsmith HL. Platelet aggregation in poiseuille flow: II. Effect of shear
rate. Microvasc Res. 27(3):316-330, 1984
4. Tha SP, Shuster J, Goldsmith HL. Interaction forces between red cells
agglutinated by antibody. II. Measurement of hydrodynamic force of breakup.
Biophys J. 50(6):1117-1126, 1986
5. Arp PA, Mason SG. The kinetics of flowing dispersions VII. Doublets of rigid
spheres (theoretical). J. Coll. Interf. Sci. 61(21-43), 1977
6. Brenner H, O'Neill ME. On the Stokes resistance of multiparticle systems in a
linear shear field. Che. Eng. Sci. 27:1421-1439, 1972
7. Goldsmith HL, Takamura K, Bell D. Shear-induced collisions between human
blood cells. Ann N Y Acad Sci. 416:299-318, 1983
8. Goldsmith HL, Lichtarge O, Tessier-Lavigne M, Spain S. Some model
experiments in hemodynamics: VI. Two-body collisions between blood cells.
Biorheology. 18(3-6):531-555, 1981
Figure 1. Particle paths in the rounded T-junction defining locations of boundary
layer separation (S) and reattachment (R) adjacent to the flow divider. (from Karino
T, Kwong HH, Goldsmith HL. Particle flow behaviour in models of branching vessels: I.
Vortices in 90 degrees T-junctions. Biorheology. 16(3):231-248, 1979, used with