Harnessing mechanical cues in the cellular microenvironment for bone regeneration

Abstract

At the macroscale, bones experience a variety of compressive and tensile loads, and these loads cause deformations of the cortical and trabecular microstructure. These deformations produce a variety of stimuli in the cellular microenvironment that can influence the differentiation of marrow stromal cells (MSCs) and the activity of cells of the MSC lineage, including osteoblasts, osteocytes, and chondrocytes. Mechanotransduction, or conversion of mechanical stimuli to biochemical and biological signals, is thus part of a multiscale mechanobiological process that drives bone modeling, remodeling, fracture healing, and implant osseointegration. Despite strong evidence of the influence of a variety of mechanical cues, and multiple paradigms proposed to explain the influence of these cues on tissue growth and differentiation, even a working understanding of how skeletal cells respond to the complex combinations of stimuli in their microenvironments remains elusive. This review covers the current understanding of what types of microenvironmental mechanical cues MSCs respond to and what is known about how they respond in the presence of multiple such cues. We argue that in order to realize the vast potential for harnessing the cellular microenvironment for the enhancement of bone regeneration, additional investigations of how combinations of mechanical cues influence bone regeneration are needed.

Keywords: bone; marrow stromal cells (MSCs); mechanical microenvironment; mechanobiology; osteogenesis.

FIGURE 1

Two regions of trabecular bone from the same mouse vertebra, each subjected to the same simulated macroscale stimulus (uniaxial compression of 2,500 μϵ) experience different distributions of microscale stimuli, such as octahedral shear strain (A,D) induced by the applied compression and fluid shear stress (B,E) due to the flow of marrow induced by the compression. 2D histograms (C,F) illustrate the difference in distributions of shear strain and fluid shear stress between the two regions of bone. The most prevalent combination of the two micro-stimuli in each region is denoted by an orange circle at (0.75 mPa, 0.035%) (C) and (2.75 mPa, 0.265%) (F).