Effect of Mechanical Strain on Cells Involved in Fracture Healing

Abstract

Secondary fracture healing is a complex multi-stage process in which the mechanical environment plays a key role. The use of an appropriate mechanical stimulation such as strain is conducive to tissue formation between fracture ends, thus aiding the healing process. However, if the strain is too large or too small, the biological behavior of the cells involved in bone healing will be affected, resulting in non-union or delayed healing. In this review, we summarize the current state of knowledge regarding the effect of strain on cells that play a role in the fracture-healing process. Overall, the related literature suggests that selection of an adequate strain promotes fracture healing through the stimulation of angiogenesis and osteogenesis, along with inhibition of osteoclast differentiation and bone resorption. However, standardized methods for the application of mechanical stimulation are lacking, and a unified consensus on the mechanism by which strain promotes cell differentiation has not yet been reached. These issues, therefore, deserve further investigation.

Keywords: Biomechanics; Fracture healing; Mesenchymal stem cell; Osteoblast; Osteoclast.

Fig. 1

RhoA/ROCK‐1 signaling pathway of mesenchymal stem cells (MSCs). Transmembrane proteins, such as integrins, located on the MSC membrane can sense mechanical stimuli, convert them into mechanical signals, and subsequently transmit them to the G proteins that bind them. The G protein then transmits the signal into the cell to catalyze the transformation of RhoA to an active GTP state. The activation of RhoA triggers the downstream effector molecule ROCK‐1, which mediates the actions of myosin and determines the direction of MSC differentiation.

Fig. 2

Mechanical stimulation‐induced calcium response mechanism of osteoblasts. The mechanical stimulation of osteoblasts causes the activation of mechanosensitive calcium channels (MSCC) on the membrane that allow the entry of extracellular calcium into the cytoplasm. Extracellular adenosine triphosphate (ATP) binds to the P2 purinoceptors on the cell membrane and triggers the G protein‐coupled receptor (GPCR) and phospholipase C (PLC) to produce inositol triphosphate (IP3). IP3 binds to its corresponding receptor on ER and releases calcium ions into the cytoplasm, thereby causing a series of reactions.

Fig. 3

Mechanical stimulation‐induced calcium response mechanism of osteoclasts. When osteoclasts are mechanically stimulated, extracellular calcium can enter the cytoplasm through mechanosensitive calcium channels (MSCC) on the membrane and subsequently evoke phospholipase C (PLC) to produce inositol triphosphate (IP3). IP3 binds to its corresponding receptor on ER, thereby releasing calcium ions into the cytoplasm.