Establishing the Basis for Mechanobiology-Based Physical Therapy Protocols to Potentiate Cellular Healing and Tissue Regeneration

Abstract

Life is mechanobiological: mechanical stimuli play a pivotal role in the formation of structurally and functionally appropriate body templates through mechanobiologically-driven cellular and tissue re/modeling. The body responds to mechanical stimuli engendered through physical movement in an integrated fashion, internalizing and transferring forces from organ, through tissue and cellular length scales. In the context of rehabilitation and therapeutic outcomes, such mechanical stimuli are referred to as mechanotherapy. Physical therapists use mechanotherapy and mechanical interventions, e.g., exercise therapy and manual mobilizations, to restore function and treat disease and/or injury. While the effect of directed movement, such as in physical therapy, is well documented at the length scale of the body and its organs, a number of recent studies implicate its integral effect in modulating cellular behavior and subsequent tissue adaptation. Yet the link between movement biomechanics, physical therapy, and subsequent cellular and tissue mechanoadaptation is not well established in the literature. Here we review mechanoadaptation in the context of physical therapy, from organ to cell scale mechanotransduction and cell to organ scale extracellular matrix genesis and re/modeling. We suggest that physical therapy can be developed to harness the mechanosensitivity of cells and tissues, enabling prescriptive definition of physical and mechanical interventions to enhance tissue genesis, healing, and rehabilitation.

Keywords: exercise therapy; human health and disease; mechanobiology; mechanotransduction; multiscale adaptation; physical therapy; rehabilitation; tissue regeneration.

Figure 1

Mechanical loading throughout life literally shapes the structure and function of cells inhabiting the human body. Cells sense mechano-chemical stimuli and prototype tissue templates (modulate tissue genesis, an important aspect of re-/modeling) via up and downregulation of structural protein transcription, secretion into the extracellular matrix, and post-translational modification. This figure depicts characteristic magnitudes and time domains of mechanical signals applied in studies of multipotent cell differentiation, with nascent lineage commitment depicted by the shape of the data points. Tissue genesis and adaptation represents a continuum in space and time, over the life cycle of the individual organism, from development of the body template in utero (depicted 11.5 days after fertilization at the first stages of skeletogenesis in the mouse) and in the adult human. Dilatational (volume changing, x-axis, on log scale) and deviatoric (shape changing, y-axis) stresses to which cells are exposed over time (z-axis), modulate lineage commitment (shape of data points indicate fate of stem cells exposed “xyz, stress over time”) and tissue genesis throughout life. Image adapted from Song et al. (2013), Anderson and Knothe Tate (2007), used with permission and available online at https://doi.org/10.1371/journal.pone.0043601.g001.

Figure 2

Rationale for physical therapy protocols for mechanotherapy. Force is transferred across multiple length scales (left) while tissues adapt to the dynamic mechanical environment (right). Together, the transfer of force from the environment, and subsequent structure-function adaptation of the system constitute the dynamic process of functional adaptation, also referred to as mechanoadaptation.

Figure 3

Internalization of forces generated during motion across multi-length scales. (A) A simple segment link model depicting the force vectors and joint torque generated during movement at the systemic level. (B) In this model, limbs are idealized as springs that resist loading from intersegmental forces. (C) The interaction of multiple tissues at the knee joint increases the complexity of the model. Different tissues exhibit varied mechanical properties and stiffness, represented by multi-colored springs. (D) Schematic of the muscle—tendon unit at the tissue level showing the anatomical complexities of biological tissues as well as the natural gradients in structure (e.g., composition and architecture) and function (e.g., mechanical stiffness and gradients in force transfer to prevent stress concentration and associated structural weakness).

Figure 4

Mechanotransduction of forces across multiple length scales. (A) Ground reaction forces and joint moments at the systemic level are (B) internalized into tissue structures. In addition, these forces are supported by muscle co-contractions, which (C) together result in compressive (C) and fluid flow shear (V) forces acting on bone. (D,E) At a tissue level, these forces are transferred to bone via periosteal Sharpey's fibers and muscle attachments. (F,G) At the cellular length scale, fluid shear (deviatoric) forces and hydrostatic forces in the ECM affect the cytoskeletal tension (tensegrity) of the cell. Each subsequent diagram is an enlarged view of the previous; the arrows are indicative of force directionality. Green arrows represent external forces before internalization; orange arrows represent forces imparted from muscle; blue arrows depict shear forces; red arrows show compression forces; and dotted red arrows refer to tensile forces.