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Biological tissues contain a variety of different types of macromolecules that exist in α helices, single and double helices, extended chain structures, β pleated sheets, random coils, and collagen coiled-coils that form supra-molecular structures that maintain cell and tissue shape, resist mechanical forces, act to transmit loads, generate contractile forces, provide a mechanical link between extracellular matrix and the cell cytoskeleton, and act in recognition of foreign cells and macromolecules. The key element needed to understand how these molecules form is: (1) the chemistry of the repeat unit, (2) the nature of the backbone flexibility, (3) the types of hydrogen bonds that form, (4) the nature of the secondary forces other than H-bonds that form between the chains, (5) the manner in which individual chains fold, (6) the way in which folded chains assemble with other chains, and (6) the manner that assembly is limited. Unfortunately, we are only beginning to understand the intricacies of how chain folding and assembly lead to biological form and function. However, the little we know makes this field so very exciting because nature has created some very clear structure-function relationships. At the very least we now know that structural materials that are aimed at reinforcing tissues have many levels of organization that pack molecules into a regular array. For instance, materials that provide tissue integrity (i.e., keratin and collagen) contain linear regions of highly ordered structure and crosslinks within the molecule to prevent extensive molecular slippage. Macromolecules that transmit force to cells such as actin in the cell cytoskeleton, and myosin in skeletal muscle contain more globular regions that are connected by turns and bends.

In this chapter we have attempted to sample the structure of a variety of tissues. Although tissue structure is quite complex, we do know that collagen and elastic fibers as well as smooth muscle are the predominant load-bearing materials in all tissues. We know from our personal experiences that mechanical loading affects the structure of different types of tissues, however, it is difficult to separate these effects from the effects of aging on tissue structure. It is clear that our skin thins and our blood vessel walls thicken as we get older, but are these effects due to increased duration of mechanical loading or due to aging alone? Although studies on athletes show that training increases muscle, tendon, and bone load-bearing ability, it is still unclear how mechanics influence tissue microstructure. The understanding of how training affects tissue microstructure is important in understanding how mechanical loading and physical therapy may positively influence and even modulate the effects of aging.

Transduction of external mechanical forces by ECMs is a challenging problem. Tissues that passively transfer energy from the environment to cells can do it efficiently if they contain macromolecules in an extended conformation such as the collagen triple helix. Although the triple helix must be somewhat rigid in order to transfer the stress between muscle and bone it also must be flexible enough to store elastic energy during locomotion. The larger the shape factor the more stress is required to stretch a helical conformation of a protein as discussed in Chapter 4. In turn this energy can be transferred to cell membrane components. How strong stiff materials such as collagen are able to transfer energy to cells without disrupting cell structure is still unclear, as is the mechanism by which low modulus cells increase the tension in collagen fibers. What is clear is that nature has designed the structural material outside cells to transduce mechanical energy through changes in helical conformation and that these changes can be controlled through specific interactions at the cell surface as we show in Chapter 9.

We have made much progress in the last decade using springs and dashpots to model the physical behavior of simple ECMs such as tendon, however, we are still struggling with developing models of more complex ECMs such as vessel wall. In vessel wall the series connection between collagen and smooth muscle is likely the important link between external loading and up-regulation of mechanochemical transduction. However, we still can only dream of formulating physical models that will help us understand these complex biological processes. Although the Voigt model consisting of a spring in parallel with a dashpot appears to represent a very simple model for the behavior of the collagen fibril, it is less than adequate for representing the behavior of irregular connective tissue with unaligned collagen fibers. More complex assemblies of Voigt elements can be used to approach the behavior of more complex ECMs. We know from studies of hypertensive animals that blockage of fluid flow in the arterial system not only increases blood pressure but leads to vessel dilation and increases in wall thickness. There appears to be a direct relationship between external (increased blood pressure) mechanical stimulation and up-regulation of mechanochemical transduction processes by increasing the tensile loads that are placed on collagen fibers. This increase in external mechanical stimulation is then directly transferred to smooth muscle cells within the vessel wall. Increased tensile forces lead to increased activation of MAPK pathways as discussed in Chapter 9. We now have the beginning information that details how external mechanical loading influences tissue growth and development.

The purpose of this text is to begin to educate the reader about how mechanical forces influence our lives. Although it is difficult to accept that much of our evolution as a species is dependent on living in a gravitational field, the sci-fi writers may have been correct in describing beings evolving on other planets as big bags of water. Our shape and form clearly derives from our need to locomote in a gravitational field. Because of the similarity between the signaling molecules and pathways that are used to respond to a variety of external stimuli we are stuck being mechanochemical machines. There has been recent interest in the processes that can be labeled mechanobiology, however, we need to expand this field until the interfaces with molecular and cell biology are continuous. Until the biologist and the physical scientist speak the same language we will continue to struggle with trial-and-error solutions to healthcare problems.