History and future of hemorheology: From Reykjavik to Lisboa

Abstract

The word “Biorheology” was introduced in 1948 during the first international congress on Rheology but “hemorheology” was first employed in 1951 during a meeting of the American Institute of Physics. Basically this science is related to physics and mechanics. The first international conference devoted to hemorheology was organized by AL Copley in Reykjavik (Iceland) in July 1969 and an International Society on Hemorheology was created. But after Reykjavik this society was named “International Society of Biorheology”. The term “Clinical Hemorheology” was proposed in Nancy in 1979 which was named “First European Symposium on Clinical Hemorheology” and an European Coordinating Committee on Clinical Hemorheology (ECCCH) was created. The European Society on Clinical Hemorheology and Microcirculation was in fact created in Frankfurt in 1990 initiated by Albrecht Ehrly. In Nancy it was also decided to create a European Award named “Fahraeus Medal”. After Nancy, the ECCCH and the European Society organized symposia in London, Baden Baden, Sienna, Frankfurt, Bordeaux, ... , Sofia ... and now Lisboa. Now it is necessary to give new directions for the development of Hemorheology and Clinical Hemorheology. Different ways can be considered:

Development of new theoretical models which take into account the heterogeneity of blood and blood vessel

Research on cell mechanobiology and mechanotransduction (leucocyte, endothelial and smooth muscle cells)

Study of cellular interactions (aggregation, adhesion, ...) and intracellular transport

Membrane rheology and concept of molecular fluidity

Dynamic blood coagulation in relation with molecular reactions

Development of metrology for clinical hemorheology

Keywords

Hemorheology history mechanobiology cellular interactions

1 Introduction

What is hemorheology? And when was the field of hemorheology elaborated? This paper will be limited to a historical sketch with the main milestones of this approach to blood flow (Table 1). In the second part of this paper, without being exhaustive, some of research orientations in Hemorheology and Clinical Hemorheology will be proposed, the development of which appears essential [16].

In fact modern studies in hemorheology began with William Harvey in the 17th century [33, 47] and the hypothesis that blood circulating from heart through arteries and returning to heart by veins. These first observations were certainly the first important discoveries for hemorheology. After Harvey, Malpighi described the microcirculation and proved the connection between arterial and venous circulation. A major discovery was from Van Leeuvenhoek [67] who described in 1674 the red blood cells. After Harvey’s discovery physicians considered the determining parameters of blood flow in organs and a particular mention is to be noted for the work of Jean-Marie Léonard Poiseuille [46] and the derived relationship between pressure and flow in a cyclindrical tube by Hagenbach [32] named Hagen-Poiseuille’s law (Q = ΠR⁴/8ηl) .

As definition, Rheology is the science which concerns the flow of the matter under strain [50]. Rheology defined as science was founded in 1929 but it is only in 1948 in Schwenningen at the first international congress on Rheology that the role of rheology in biology and medicine was stressed and the word “Biorheology” introduced. In 1951 at a meeting of the American Institute of Physics the term “Hemorheology” was employed. Basically this science is related to physic and mechanics and can be defined as “the study of the flow of blood in relation with the blood vessel and vessel wall” [15 , 49].

The first international conference devoted only to hemorheology was organized by AL Copley in Reykjavik (Iceland) from 10 to 16 July 1966 [13]. Copley chose Reykjavik for this first International Congress, because Iceland is situated geographically between Western Europe and North America (Fig. 1). At this first conference, more than 100 researchers from 13 countries participed and all the 86 conferences where published by Pergamon Press in 1968.

During the meeting it was announce the creation of an international society with a congress every 3 years and that the second conference with be organize in France in 1969 for the 100 anniversary of the death of Jean-Leonard-Marie Poiseuille who can be considered as the first modern hemorheologist. However, we can note that at the end of the 19th century the German physiologist Roux proposed the concept of functional adaptation, which underlined the important role of mechanical stimuli on cell and tissue? Roux definition can be considered as the first definition of mechanobiology. “Many cells are influenced by functional stimuli, the nerve, muscle, gland cells and connective tissue cells by pressure and tension ... . It is plausible that, if this influence is disadvantageous for some cells of a tissue of some parts of it, then these cells will disappear during the process of physiological regeneration ... ”).

In Reykjavik AL Copley proposed the creation of an Award named “Poiseuille Gold Medal”. The first recipient was Robin Fåhraeus (Figs. 2(a and b)) [14 , 25]. But rapidly after Reykjavik the society was named “International Society of Biorheology” and congresses where organized in Lyon, Baden Baden, Tokyo, San Diego, Nancy, Yokohama ...

It is for this reason that the author propose to organize with AL Copley in Nancy a “Hemorheology and diseases symposium” (Nancy October 1979) (Figs. 3, 4, 5, 6). At the end of the symposium AL Copley, H, Schmidt Schönbein, J Dormandy, S Chien, JF Stoltz decided to organized a second meeting in London in 1981 which was named “Second European Symposium on Clinical Hemorheology” and also to create a European coordinating committee on clinical hemorheology (ECCCH) and an European Clinical Hemorheology Award named ”Fåhraeus Medal” (Fig. 6). The proceeding of the first conference was published by the French editor Doin (Paris) in 1980 (Fig. 7). Since 1981 a Journal is devoted to clinical hemorheology. After London in 1981, the European symposium was organized in relation with the ECCCH in Baden Baden, Sienna, Bordeaux ... and in Lisboa for the 18thsymposium.

However in each Biorheology congress sessions where organized on hemorheology and clinical approaches. Thus in 1989 just after the European Symposium in Frankfort (Fig. 8) the author, organized in Nancy the international Congress of Biorheology with many sessions on Hemorheology and clinical Hemorheology. The 6th recipient of the Poiseuille Award was D. Skalak (Figs. 9 to 10).

The future developments of Biorheology, hemorheology and clinical hemorheology are inherent in the young history of this science and the necessity, more than in any other science, of interdisciplinary researches. It is rightly in this domain that Karl Popper’s thought applies most appropriately when he writes: “bold ideas, unjustified expectations and speculations constitute our only means for comprehending nature”.

2 New developments for hemorheology

2.1 Necessity of models

Everything should be made as simple as possible but not simpler. – A. Einstein

The extremely complex phenomena of biological systems and of their structures involve many types of heterogeneities that require development at the molecular levels. It can, however, be hoped that an adequate choice of models, based on experimental facts, will provide the means of theoretical approaches to understand the phenomena observed and at the same time improve fundamental rheology [29 , 56].

As in every field of physics, there are two major categories of models that can be applied in hemorheology:

Descriptive models that take into account the laws of physics which apply to blood and the blood components,

Mathematical models that disregard the subjacent elementary mechanisms and put forward presumptive equations which will have to be compared with the experimental data.

The descriptive models are obviously more satisfactory as they take into account the physical properties of the different parts of the system. In contrast, these models require comprehensive knowledge of the laws which apply to blood and the blood components. In fact, in a system as complex as blood, the actual facts are much less clear-cut and intermediate rheological laws have been developed [36].

In most cases, the results of experiments, which characterized the in stationary rheological behavior of a tissue led to an interpretation based on viscoelasticity theories, thanks to monophasic structural models, taking into account the nature of the constitutive elements and internal frictions. Such a unique phenomenological characterization does not allow us to link mechanical magnitudes to the geometric and physical magnitudes of the medium (e.g., porosity or permeability). Now, a variation of the porosity or permeability of a tissue entails modifications of the tissue’s rheological properties. For these reasons, recent works stressed the filtration properties of this type of tissue and their biphasic nature linked to the presence of a porous skeleton and interstitial fluid. This consideration led to descriptions of rheological behaviors based on poroelasticity theories requiring the study of the processes of strain transfer between solid phase and liquid phase. In order to develop the acquired knowledge, it is desirable that multidisciplinary research be undertaken in order to tackle the rheological properties of blood and blood vessels [54, 55].

2.2 Deterministic chaos in hemorheology

Deterministic chaos, which was introduced at the end of the 19th century by the French mathematical school of Poincaré and Hadamard, is at the origin of numerous theories and interpretations of phenomena. On the other hand, the introduction by Mandelbrot of the mathematical notion of fractal dimension allowed novel approaches to natural behaviors. However, besides its descriptive character, the “fractal” notion has not found, to date, direct applications in biology and medicine.

Nevertheless, global rheological approaches to physiological systems may constitute promising researches for fractal approaches and applications of, chaos theory. One may also investigate the function-fractal structure relationship and the role of chaotic behavior in organ physiorheological functioning. Indeed, conventional medicine’s postulate that regularity is a sign of good health is not an absolute rule, as shown by studies of the variations of cardiac rhythm.

Other investigations could also be considered, such as the fractal structure of macroscopic biological systems in relation to their architecture, functionality and rheological properties. For example, the random formation of junctions between the cells of lung capillaries generates a passage set of heterogeneous sizes comparable to a fractal object. This model of “disordered geometry” allows, a description of the control of macromolecule exchanges between blood and tissues.

In this context, what could be the interest in knowing the fractal structure of pulmonary circulation? What is the role of the rheological properties of blood and surrounding tissues in such an approach? Obviously, one cannot answer these questions today, but one may think that the application of fractal geometry to the rheology of living systems might be an interesting approach for a dynamic global understanding of these systems.

Another prospective approach of the application of fractal analysis could be considered in the study of complex structures. Is it not possible, for example, to characterize the tridimensional structures formed by the red blood cells upon aggregation? Can we study the formation dynamics and the structure of the aggregates of erythrocytes during different pathological states from simple models, as already done for aggregates of spherical particles controlled by diffusion?

In summary, the applications of fractal theory in Hemorheology may take place in quite different domains. The first one would concern the approach of random phenomena; this would be a set of probabilistic studies. The second group of applications could be the dynamics study of systems (such as erythrocyte aggregates). Finally, the third category of investigations involving fractals could be the study of interfacial physiorheological phenomena such as gas exchanges in ling alveoli and vascular beds structures.

2.3 Hemorheology and cellular interactions

Among the domains in which hemorheology could develop, cell adhesion and aggregation and cell polarization appear particularly worthy [5 , 69].

Many functions are modulated by cellular interactions and it is well known that the proliferation of various cell types requires the adhesion onto the appropriate substrate. Thus, besides the local rheological conditions that favor or counteract the phenomena, cell adhesion or aggregation involves and modifies the rheological properties of the cells. The modifications are particularly reflected by morphological or structural variations, e.g., polarization phenomena, modifications of electric charges, or membrane potential [8, 57].

Many physical or biological events must be considered, such as electrostatic repulsion between charged surfaces, interaction between membrane receptors and proteins, van der Waals attraction between hydrophobic regions of membranes, and displacement of ligand molecules on and in the membrane. For a global understanding of cell adhesion or aggregation, it is essential to take into account the rheological properties of the cell and its components. For example, leukocyte adhesion to the endothelium during inflammation involves both local conditions of cell flow and the interactions with erythrocytes and membrane receptors.

Understanding these phenomena of cell interaction is basic for the development of a clinical hemorheology that aims at being explanatory rather than descriptive. For example, in hemorheology, if platelet-vessel interactions are presently well specified, the understanding of the modifications of pathologic erythrocytes (e.g., red blood cells of diabetic patients, or those of patients with sickle-cell anemia) is much less documented. If the influence of fibrinogen, fibronectin and the von Willebrand factor has been suggested, the nature of the linkages, the role of glycosylated proteins and membrane modifications (fluidity, ultrastructure) of the erythrocyte as well as of the endothelial cell are still poorly investigated.

2.4 Hemorheology, mechanobiology and mechanotransduction

Almost all cells in the human body are subjected to mechanical stresses. These forces can vary from a few Pascals (shear stress on vascular bed) to some Mega Pascal (on hip cartilage). It is now well known that mechanical forces have a decisive effect on cellular physiology. However, although the main biological effects of mechanical forces are well documented, the relation between mechanical forces and physiological phenomena is mainly unknown (mechanotransduction phenomenon) [48].

A fundamental property of living tissues is their adaptation to the environment and to movement (a property described by Roux at the end of the 19th century). These movements are at the origin of local mechanical stresses and constitute stimuli which can lead to modification of the biological behaviour of cells. These stresses influence the functionality and cellular metabolism and can lead to appropriate tissue remodelling by triggering a cascade of chain reactions or a process of mechanotransduction, which is a signal for the adaptation of cells and tissues. These new approaches (mechanobiology) now make it possible not only to better understand observed tissue remodelling but also to develop in vitro repair tissues (tissue engineering). However, it is important to recall that while the exponential development of research and applications is recent, the first observations on mechanical tissue adaptation and structure/strain relation of tissues were realized many years ago (Meyer 1866, Wolff 1869). During a conference in Zurich in 1866, Meyer suggested that: ⪡ the bone spongiasa showed a well-motivated architecture which is closely connected with the statics and mechanics of bone ⪢. In the same period, Wilhelm Roux (1880) introduced the concept of functional adaptation which he defined as a quantitative autoregulation controlled by functional stimuli. He wrote ⪡many cells are influenced by functional stimuli, the nerve, muscle, gland cells by the related electric pulse, bone cells and connective tissue cells by pressure and tension⪢. He thus described the phenomenon today termed mechanotransduction, which has been the subject of numerous works since the 1980s. Mechanobiology in hemorheology can be considered as essential mainly on endothelial and vascular smooth muscle cells.

In vivo, the vascular endothelial cell (EC) is subjected to three types of mechanical forces whose intensity vary according to the vascular bed: shear stress (τ, some mPa), hydrostatic pressure (p, some Pa) and periodic parietal deformation (ɛ, 0 to 3 Hz). The shear stress (τ) induced by the blood flow acts tangentially on the EC. It is generally determined by the relation of Poiseuille. The hydrostatic pressure acts perpendicular to the surface of the endothelium. It affects the extracellular matrix as well as the endothelium [43 , 70].

The response of the EC to mechanical forces has been widely studied and variations in different cell functions have been reported (electrophysiology, biochemistry, receptors, regulation of gene, etc.). The various responses of EC to mechanical forces can be classified according to reaction time, although they are often simultaneous [9 , 64].

In other respects, the pulsatile nature of blood flow causes cyclic stretching of EC. Stretch deformation has been observed in deformable substrates with cyclic uniaxial and biaxial stretch [19 , 42].

Regulation of gene expression of molecules synthesized by the EC, like ET-1, PAF, PDGF A and B, MCP-1, adhesion molecules (ICAM-1, VCAM-1), is also influenced by the flow. Thus, expression of PDGF-B and FGF is increased in the EC and in the vascular smooth muscle cells when these are subjected to shearing forces. A gene coding for ICAM-1, which is involved in inflammation, increased when EC were subjected to shearing forces. Expression of VCAM-1 and ELAM-1 was not affected under the same conditions. The other transcription factors responsible for the activation of promoters by shear stress are the nuclear factor kappa B, the activating protein-1 (AP-1), the early-1 growth promoter (Egr-1) c-fos, c-jun, c-myc and stable (Sp-1). The variations observed in gene regulation by microarray analysis suggest that two types of gene elements that are sensitive to shear stresses (positive and negative) may exist. For instance, shear stress regulates atherogenic genes (egMCP1) but disturbed flow causes sustained activation of MCP1. This result provides an explanation for the observed localization of atherosclerosis lesions.

The mechano-sensing of EC is multifactorial and the application of shear stress can lead to the activation of various signalling pathways. It was demonstrated that integrins can sense shear stress but other membrane components involved in the sensing of mechanical forces include G protein receptors, ion channels, membrane glycocalyx and lipids. Mechanotransduction phenomena involve numerous sensors and genes. In another respect, if endothelial cells react to various mechanical forces, it should be recalled that the response times vary from a few seconds to 24 hours, depending on the parameters concerned. Thus NO synthesis takes place in seconds (Fig. 7), that of PG in minutes whereas it takes several hours to observe the rearrangement of the cytoskeleton and an alignment of the cells in the flow suggesting that multiple complex mechanisms are involved. Many of these changes appear to involve gene regulation at the transcriptional level and are analogous to EC activation by cytokines and the endothelial lining of the vascular system is a dynamic interface which responds to humoral mechanical factors.

Vascular smooth muscles cells (VSMCs) are also influenced by mechanical forces. In vivo, VSMCs are subject to one main force (periodic parietal deformation) in relation with blood pressure. The pressure acts perpendicularly to the wall and induces flow across the matrix. This radial flow transports soluble substances from the blood. In other respects, VSMCs are highly sensitive to mechanical stress. The myogenic response (arterial contraction in response to an increase in blood pressure) was described a century ago by Bayliss, conversely, a reduction in pressure brings about vasodilatation. In both cases, the vascular response occurs in a few seconds. This response is particularly significant in tissues or organs where the speed of perfusion must be as constant as possible (e.g. the brain). The origin of the myogenic response is related to the smooth muscle cells which generate the forces leading to dilation or contraction of the vessels. It has been suggested that the endothelial cells could play the role of “pressure sensor” but this hypothesis has not been confirmed.

Other hypotheses have been proposed:

Smooth muscle cells are directly sensitive to a change in pressure (stretching of the vessel wall). The activation of certain ion channels by stretching has been demonstrated.

The tension T on the vascular wall is thought to be proportional to the pressure and the radius of the vessel and inversely proportional to the thickness of the wall.

The smooth muscle cell is stimulated by flow through the vascular wall linked to changes in intravascular pressure.

In vitro, the impact of the mechanical stresses on smooth muscle cells was and is the subject of many works because these cells are easier to obtain than the cardiac or skeletal muscle cells.

Another important parameter for the analysis of stress – strain in tissue and remodelling, is the zero stress state. This parameter was very few studied for a vascular blood vessel, this state can be experimentally shown by cutting a slice of vessel perpendicular to the axis. The section will open up on its own because of the release of residual strains which can be characterized by the opening angle. The opening angle varies with the location in the vascular tree. If a body is in a zero-stress state, the cut will not cause any deformation. The zero state varies with the location in the vascular bed and is modified in different pathologies (diabetes, hypertension, atherosclerosis, etc.).

If today, the impact of mechanical stresses is accepted to better understand the synthesis of the extracellular matrix, the secretion of specific molecules or the induction of specific functions by intercellular communication, mechanisms still need clarifying and many unknowns remain.

2.5 From concept of molecular fluidity to hemorheology

The development of the biological applications of spectroscopic methods that are relatively easy to handle such as fluorescence polarization and spin labeling, confocal microscopy or atomic force microscopy and that the concept of membranes “fluidity” (or “membrane microviscosity”) have progresses considerably and allowed the integration of these molecular parameters into the understanding of cellular systems. It appeared, therefore, that membrane dynamics and the movements of the different constituents (lipids and proteins) condition many biological and mechanical properties of the cells[1 , 53].

Fluidity properties are linked to the composition of the phospholipid bilayers. For example, cholesterol plays a plastifying role by maintaining high order in the region close to its skeleton, i.e., along the first ten carbons of fatty chains. Modifications may also be observed during cell activation. Thus, blood platelets that are rigid in the resting state become much less ordered as soon as they are activated. These rheological variations at the molecular level are linked to the metabolic pathway of the transformation of phosphatidylinositides, to the liberation of membrane calcium and to the activation of phospholipases.

The variations of the parameters characterizing fluidity in relation to membrane type and physiological conditions are particularly important, constituting the manifestation of a true adaptation that requires rheological, physiochemical and biochemical studies. An example concerns the modifications of EPR spectra of flowing erythrocytes labeled with a nitroxide fatty acid that allow the determination of the orientation rate of cells in relation to their deformability.

The relation between the fluidity and the rheological properties of the membranes are still poorly known, mainly in clinical Hemorheology because the measurements undertaken at the macroscopic level are often too global and mainly concerned with only several molecular parameters. Is there any continuity between the phenomena of the molecular order and the rheological properties ofmembranes?

A number of investigations have been carried out on the erythrocyte. It has been demonstrated that the modifications of lipid composition (cholesterol/phospholipid ratio) and of membrane fluidity (measured by fluorescence polarization) do not appear to influence the overall viscoelastic properties of the membrane significantly [60]. One should notice that to date the studies generally undertaken with probes of low specificity remain too global. However, conversely, protein perturbations (hereditary abnormalities or chemical modifications of the band 4.1, or of spectrin, for example) are accompanied by an increase of the elasticity and viscosity modulus of the membrane. A considerable amount of work remains to be done on order to identify the molecular origin (proteins or lipids) of the parameters characterizing the rheological properties of the membranes. Besides their obvious theoretical interest, these investigations might have numerous applications in clinical biorheology.

Finally, another research perspective pertains to the knowledge of the heterogeneity of the rheological properties and of the fluidity of membrane bilayers to which few works have been devoted so far.

2.6 Other suggestions for rheological studies in hemorheology

The development of Hemorheology, as for all other disciplines in the life sciences, depends on the accumulation of data that may appear of limited interest at the beginning. In addition, it is sometimes difficult to elucidate the relations existing between apparently non-linked phenomena. However, it is important that such rheological investigations be carried out by scientist from various fields in other to develop our knowledge in both theoretical and applied domains, including the clinical and therapeutic fields. I would like to mention in the following sections some domains for which the current rheological implications remain compartmental.

a) Electric phenomena

The term”electrorheology” was proposed [18] by Scott-Blair in his book Introduction to Biorheology (1974). In a plenary lecture presented as an introduction to IVth Congress in Tokyo, E. Fukada [28, 29] has shown that electrical polarization phenomena play an important role in various domains of biorheology. Among the domains relatively well-documented or more hypothetical, one may list the following:

Cell-cell interaction and aggregation;

membrane excitation;

ion permeability;

effect of water polarization and properties of charged lipid membranes;

elastic deformation and electric polarization;

piezoelectricity;

Zeta potential of cells [36, 57] (RBC, platelets and different populations of white blood cells) and streaming potential (blood vessels),

stimulation of cell growth.

b) Blood coagulations and rheological parameters [6]

Many biological fluids are concern, through chemical reactions provoked by exogenous process or endogenous activation, to undergo a liquid-gel transformation (for example, milk or blood coagulation). Relatively few works currently present research in these domains, beyond macroscopic rheological measurements, where structural studies at the molecular level would, without doubt, allow access to basic data on the dynamics of these phenomena. One should point out, the pioneering work of Dintenfass [21] and of the Japanese school demonstrate the role of stress shear on the microscopic structure and clot consistency. Thus, as observed through in vivo analysis of the thrombus, the clot formed at low shear rate has gel properties and is highly viscous with pronounced thixotropic properties, whereas the clot formed at higher shear rate is less viscous. It is certain that the local rheological parameters interfere with the physicochemical mechanism of blood coagulations by:

The increase of the diffusion coefficients of coagulation factors or cofactors and subsequently by the increase of collision frequency;

cell activation (platelets, leukocytes or erythrocytes) which might then release factors in the plasma [4];

direct activation of coagulation factors (conformational change?), and

the orientation of cells and proteins in the flow process which, on the other hand, may affect fibrin polymerization.

One should not forget that for high shear stress, erythrocyte disaggregation takes places as well as a “rheological activation” of the platelets without extraneous agents. All these data about the rheological behavior of blood upon coagulation could be completed by studies through spectroscopic techniques, investigations on the conformational changes of proteins or by rheological studies on fibrin polymerization, as mentioned by Dintenfass.

c) Movement, contraction and intracellular transport [2 , 34]

We have seen that aggregation or cell adhesion triggers polarization phenomena such as the manifestation of an ionic gradient in the cell. Indeed, very few data exist regarding intracellular movements and their rheological controls. What is the particular importance of the properties of cell microtubule systems in the movements undergone by the cytoplasm? More generally, what is the role of contractile and microtubular proteins in muscle cells and in membranes?

2.7 Metrology in hemorheology and clinical hemorheology [60 , 71]

No clinical progress can be achieved without reliable experimental investigations for measuring a given parameter. Unfortunately, we have to admit that results obtained with non-specific techniques suffering from a GIRO Syndrome (Garbage In: Rubbish Out) have be used to build hazardous theories. For example, over the past decades, a considerable number of microrheological modifications of red blood cells have been described in numerous clinical fields in hemorheology using filtration methods. Although most of these observations are not doubt related to objective phenomena, some are quite definitely connected with artifacts in the techniques used. One of the problems the experimenter will have to solve is precisely that of detecting which, of the numerous variables observed, are most suitable to be chosen as independent parameters that truly represent the phenomenon investigated. It is for this reason-given the complexity of the phenomena encountered in biorheology- that experimental systems specifically adapted to the parameters that are to be measured will have to be developed [68].

It should be stressed that during the 1990s and 2000s, numerous methods described for rheological investigations have been developed [22 , 62]. Some of these methods are: Measurement of the viscosity and viscoelasticity of blood or; techniques for approaching red blood cell aggregation [62] or deformability [37]. The development of novel approaches to the rheological behavior will necessitate checking into the utilization of physical methods infrequently used at present in hemorheology, such as imaging techniques: NMR, ultrasound and fluorescence, confocal and atomic force microscopy optical tweezers [60].

2.8 Developments in clinical hemorheology

The measurements of blood rheological properties [11 , 59], associated with other biological investigations, has proven interesting for the understanding, diagnosis and, possibly, the treatment of various diseases [23]. It is, however, currently difficult to evaluate the future fields of applications of rheology in clinics. A domain that has undergone particularly rapid development is that of clinical hemorheology [3, 10].

It is extremely satisfying to observe that, in spite of the many problems in clinical hemorheology, the information can help the clinician to decide on hemorheological therapy. For example, the rheological origin of what is known as “hyperviscosity syndrome” and the part played by these syndromes in the occurrence of thrombosis has now been defined according to the microrheological phenomena observed. Numerous investigations in the clinical domains are, however, necessary in order to shift clinical hemorheology from the descriptive stage, which is the case presently, to a more interpretive stage of physiological phenomena [21 , 58].

Other applications of our knowledge concern the characterization of biomaterials for implantation. Few works have so far been realized, although this aim is essential in various domains of surgery, cardiovascular fields. One should mention in this domain the possibilities offered by biotelemeasurement for continuous monitoring of in vivo stress.

Many other biological investigations could be considered, paralleling the more classical works of biocompatibility. For example, what could be the role of the mechanical properties of coronary stents used as vascular endoprostheses? Only more-or-less speculative hypotheses are currently proposed by different authors. Indeed, aside from the mechanical properties of these prostheses, what are the roles of these prostheses in blood outflow and blood-vessel interactions? One may suggest that they prevent distal embolization of large debris by effects on the wall, whether they act as a barrier for migration or cell adhesion, or as a macroscopic sieve which will progressively push out, by a mechanical effect, the neointima plate inside the adventitia. It can be also noted the possible clminical uses of stem cells in vascular pathology [65].

3 Conclusions

The above-mentioned comments are far from being comprehensive concerning the future developments of hemorheology. In addition, as in all domains of medical science and technique, clinical and therapeutic studies are indispensable in order to validate the concepts developed. Finally, one should point out that the originality of the problems posed by the rheology of blood flow could stimulate the development of basic rheology [53 , 64].

But it is the development of harmonious interdisciplinary investigations extending from physics and mechanics to the clinical sciences and pharmacology which will allow hemorheology to become a recognized discipline in the life sciences.

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History and future of hemorheology: From Reykjavik to Lisboa

Abstract

Keywords

1 Introduction

2 New developments for hemorheology

2.1 Necessity of models

2.2 Deterministic chaos in hemorheology

2.3 Hemorheology and cellular interactions

2.4 Hemorheology, mechanobiology and mechanotransduction

2.5 From concept of molecular fluidity to hemorheology

2.6 Other suggestions for rheological studies in hemorheology

2.7 Metrology in hemorheology and clinical hemorheology [60, 71]

2.8 Developments in clinical hemorheology

3 Conclusions

References

2.7 Metrology in hemorheology and clinical hemorheology [60 , 71]