Physical Stimulations for Bone and Cartilage Regeneration

Abstract

A wide range of techniques and methods are actively invented by clinicians and scientists who are dedicated to the field of musculoskeletal tissue regeneration. Biological, chemical, and physiological factors, which play key roles in musculoskeletal tissue development, have been extensively explored. However, physical stimulation is increasingly showing extreme importance in the processes of osteogenic and chondrogenic differentiation, proliferation and maturation through defined dose parameters including mode, frequency, magnitude, and duration of stimuli. Studies have shown manipulation of physical microenvironment is an indispensable strategy for the repair and regeneration of bone and cartilage, and biophysical cues could profoundly promote their regeneration. In this article, we review recent literature on utilization of physical stimulation, such as mechanical forces (cyclic strain, fluid shear stress, etc.), electrical and magnetic fields, ultrasound, shock waves, substrate stimuli, etc., to promote the repair and regeneration of bone and cartilage tissue. Emphasis is placed on the mechanism of cellular response and the potential clinical usage of these stimulations for bone and cartilage regeneration.

Keywords: Bone and cartilage regeneration; electrical and magnetic fields; fracture repair; mechanical forces; physical stimulation; shock waves; ultrasound.

Fig. 1. Schematic of cell-based bone and cartilage regeneration from different physical stimulations.

ES, electrical stimulation; US, ultrasound; MSCs, mesenchymal stem cells.

Fig. 2. Possible pathways involved in the biological response to mechanical stress, ES, US, and shock wave stimulations on bone cells.

Several pathways of MAPK/ERK, Wnt/β-catenin, PI3K/Akt, TGF-β/BMP, NF-κΒ, PKA, PKC, Ca²⁺ signaling could be regulated in response to biophysical stimulations, to enhance the cell proliferation and differentiation and to modulate the inflammatory response by modulating the expressing of bone markers Rux2, BMP2/4, OCM and Osx, etc. or other related regulators. GSK-3β (Glycogen synthase kinase-3 beta), TRK (tyrosine kinase receptor), TCF/LEF (T-cell factor/lymphoid enhancer factor), PI3K (phosphatidylinositide 3-kinases), TGF-β (transforming growth factor beta), BMP (bone morphogenetic proteins), AKT (protein kinase B), mTOR (mechanistic target of rapamycin), NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), PGE2 (Prostaglandin E2), AC (adenylyl cyclase), cAMP (cyclic adenosine monophosphate), PKA (protein kinase A), CREB (cAMP response element-binding protein), PKC (protein kinase C), MAPK (mitogen-activated protein kinase), ERK (extracellular signal-regulated kinases), FAK (focal adhesion kinase), GPCR (G protein-coupled receptor), OCN (osteocalcin), Osx (Osterix), ES (electrical stimulation), US(ultrasound), TRK (tyrosine kinase).

Fig. 3

The biological mechanism of fibrin-mediated osteoconduction on (A) negatively and (B) positively charged surfaces.

Fig. 4. Possible pathways are regulated in response to extra biophysical stimulations on chondrocytes.

Biophysical stimulations could act through one or a combination of MAPK/ERK, PKA/CREB, Wnt/β-catenin, PI3K/Akt, TGF-β/BMP, NF-κB, PKA, PKC, Ca²⁺ signaling pathways to enhance cell proliferation, survival, and differentiation and to modulate the inflammatory response by regulating the expressing of cartilage markers Sox9, TGF-β1, collagen type II, ACAN, etc.