Introduction

Approximately 50 000 years ago, during an age called upper paleolithic revolution [1], mankind began to develop finer tactile senses and greater perceptional capabilities than ever before. This great mystery of human evolution endowed our ancestors with the tools and the intellectual prowess to investigate the origins of pain and disease. The tools they probably used-auscultation, palpation, and sight-are still valuable tools for diagnostic routine in modern clinical practice. The knowledge that ancient physicians had accumulated by observing their patients and the precision with which they drew their conclusions is exemplified in the Ebers Papyrus, one of the oldest and most beautiful medical books of humanity, which was written during the reign of pharaoh Ahmose I (1560-1525 BCE). As shown in Figure 1, Ahmose's doctors paid significant attention to palpation: manually deforming and shifting soft tissue layers and carefully sensing the resistance of tissue against that deformation provided them with an incredibly rich source of diagnostic information. The wealth of information attainable through palpation is still being explored today. On the one hand, physicists have developed mechanical models of soft biological tissues that describe how structures on several length scales, from the cellular level to larger fibers or vascular trees, translate to the macroscopic level, affecting the haptic sensation that we perceive with our fingers. On the other hand, modern biological and biophysical research has revealed that altered mechanical properties play a key role in the progression of numerous diseases, from fibrosis to tumors. It has even been suggested that these mechanical cues can precede other signs or symptoms of diseases (see Figure 2).

Figure 1 Papyrus Ebers, Columns 107 (right) and 108 (left). Demarcated sections highlight descriptions of palpation examinations. Ebers 872: If a swelling presents spherical and stiff and recedes pressure of the fingers, then it originates from the vessel and should be treated with a heated knife. Ebers 873: If a swelling at internal layers of the skin appears nodular and feels compliant, like air-filled cavities, then it is a tumor of the vessels and you should not treat it (with a knife), but rather use remedies or incantations to improve the condition of the vessel in all affected areas of the human body. Ebers 867: If a swelling in any part of the body feels elastic under the fingers and comes apart under constant pressure, it is of fat and should be treated with the knife. Ebers 868: If a swelling has the property of a son (or daughter, metastasis?) and it can be found isolated or spread and feels moderately solid, then it should be treated with the knife. (Nonliteral translation by the authors, based on the German text of Wolfhart Westendorf, Handbuch der ägyptischen Medizin, 1999, volume 2, pg. 547, kindly provided by Marko Stuhr, Mayen, Germany.

Reproduced with permission of Universität Leipzig.)

Figure 2 Example of the importance of mechanical tissue properties in disease: Stiffness (storage modulus ) measured by shear oscillatory rheometry in fibrosis-induced rat livers. Fibrosis is characterized by the accumulation of excess and abnormal extracellular matrix material. Samples were stained for the presence of collagen by sirius red, which detects primarily type I collagen. The time axis indicates time since initiation of fibrosis. Significant changes relative to day 0 are demarcated by asterisks (, ). The data suggest that an increase in liver stiffness precedes fibrosis and that increased liver stiffness may play an important role in initiating early fibrosis.

(Georges 2007 [2]. Reproduced with permission of American Journal of Physiology.)

Viscoelastic properties are one of the three main determinants of haptic sensation, the other two being temperature and surface texture. Viscoelasticity provides a framework to classify the response of a material when a force is applied to it. On the coarsest scale, viscoelasticity is comprised of the complementary concepts of elasticity and viscosity. Elastic materials can be deformed when a force is applied, but they will immediately return to their original shape when the force is removed. Objects such as a steel spring and gelatin dessert ("jelly," "jello") are typical examples exhibiting elastic behavior. Viscous materials, on the other hand, also deform when a force is applied; however, they will remain in their deformed shape after removal of the force. Honey and other thick liquids are examples of such material properties. However, most materials possess both elasticity and viscosity at the same time. For example, according to the above classification, a rubber ball and metal ball would both be classified as elastic, since they both tend to return to their original shape after deformation. Yet, when a rubber ball and a metal ball bounce up from a hard surface after being dropped from the same height, the metal ball will reach a greater height than the rubber ball.1 The reason is that the rubber ball converts a portion of the energy that was used to deform it into heat, whereas the metal ball restores almost all of the deformation energy back into kinetic energy, and therefore bounces back with higher velocity. Viscosity is also a measure of how much of the deformation energy is converted into heat. Therefore, in addition to being elastic, the rubber ball is characterized by a much higher viscosity than the metal ball. We can therefore define what we call a "square of viscoelasticity," shown in Figure 3, that allows us to compare viscoelastic properties of different materials. The four corners are characterized by the extreme cases found in solid bodies (excluding liquids): "highly viscous/highly elastic2" (rubber), "purely elastic" (spring), "low elasticity/high viscosity" (marshmallow), and "low elasticity/low viscosity" (jelly). Different materials-including different types of organic tissue-can be characterized in terms of their elasticity and viscosity and thus be represented by a point within the square of viscoelasticity. If a disease alters the viscoelastic properties of a specific type of tissue, for example, the liver, healthy and diseased tissue would therefore appear as two different points in the diagram.

Figure 3 The "square of viscoelasticity:" viscoelastic properties can be characterized in a two-dimensional plot in terms of viscosity and elasticity. The arrows indicate how viscoelasticity of human organs is affected when the liver becomes fibrotic, when a muscle contracts or when the brain undergoes degradation.

(Sack 2013 [3]. Reproduced with the permission of Royal Society of Chemistry.)

Diagnosis of disease can therefore be performed by comparing the viscoelastic properties of a potentially diseased organ to those of a healthy one. This is the foundation of manual palpation. Through years of experience, physicians develop a sense of the "correct" properties of different organs, and they can detect deviations based on the haptic feedback that they receive when manually deforming the tissue. While this method is very powerful, it has two major drawbacks:

• Assessment of tissue elasticity through a physician is qualitativerather than quantitative, and hence subjective. For a widely applicable clinical instrument, a quantitative method that also allows less experienced examiners to detect disease based on numbers rather than sensation is desirable.
• Noninvasive assessment of tissue viscoelasticity is only feasible for a few organs that can be palpated through the skin. This excludes most deeper organs as well as those shielded by bones, such as the brain.

Both limitations can be overcome when medical imaging is employed to replace palpation, leading to "elastography." Elastography can be separated into two independent steps: application of a force that causes tissue deformation and detection of the response of the tissue to that force. Ultrasound (US) imaging or magnetic resonance imaging (MRI) are capable of performing the latter, since they are both sensitive to tissue motion on the order of micrometers. For achieving tissue deformation, various approaches exist. Most of them rely on the application of an external force that is transmitted through skin and bones into the organ of interest. In magnetic resonance elastography (MRE), the most common type of applied force is harmonic vibration, which stimulates mechanical waves that propagate through the body. By detecting the displacement induced by these waves, viscosity and elasticity of tissue can be retrieved quantitatively through wave inversion algorithms.

Mechanical testing and MRE experiments performed on phantoms3 has revealed that minute structural changes can lead to huge differences in viscoelastic properties. For example, the addition of less than one mass percent of agarose, a gelling agent extracted from seaweed, turns liquid water into a solid block, thus increasing its elasticity by many orders of magnitude. Furthermore, Guo and Posnansky demonstrated that adding a small amount of structured elements, such as paper strips, to a homogeneous gel induces viscous properties [4, 5]. In the context of clinical diagnosis, this means that small structural modifications on the cellular level can translate into well-measurable changes in the viscoelastic parameters of the whole organ. The same applies to...