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, and substrate stimuli, 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.

Lay Summary

Bone and cartilage regenerative engineering aims to create stable, bioactive, and native tissue-like scaffolds which can repair bone and cartilage damages. These scaffolds are often combined with chondrogenic/osteogenic cells or stem cells to create replacement tissue grafts with enhanced regenerative capability. In this approach, physical stimulations such as ultrasound, mechanical force, electrical charge, and magnetic field have significant impacts on cell fate and behavior through regulating various intracellular signaling pathways. The review provides a comprehensive understanding and broad overview of literature on effects of different physical stimulations on cellular behaviors and signaling pathways, which have been reported to induce growth of bone and cartilage. The knowledge lay a strong foundation for the development of future “smart” tissue grafts that can effectively repair bone and cartilage under physical stimulations. Other future works will focus on combining different physical stimulations and fine-tuning parameters of such stimulations to obtain optimal cartilage and bone regeneration.

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Abbreviations

GBR:

guided bone regeneration

ACI:

autologous chondrocyte implantation

hMSCs:

human mesenchymal stem cells

ECM:

extracellular matrix

ASCs:

mouse adipose-derived mesenchymal stem cells

PFF:

pulsating fluid flow

OPN:

osteopontin

SSAT:

spermidine/spermine-N(1)-acetyltransferase

FAK:

focal adhesion kinase

RhoA:

Ras homolog gene family member A

VSCC:

voltage-sensitive calcium channels

ES:

electrical stimulation

EF:

electric field

DC:

direct current

CCEF:

capacitive coupling electric field

EMF:

electromagnetic field

AC:

alternating current

PI3K:

phosphatidylinositol-3-kinase

mTOR:

mammalian target of rapamycin

TGF-β:

transforming growth factor-β

A2AR:

adenosine A2A receptors

GAGs:

glycosaminoglycans

PEMFs:

pulsed electromagnetic fields

ELF-PEMF:

extremely low-frequency pulsed electromagnetic field

ROS:

reactive oxygen species

Col I:

collagen type I

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

US:

ultrasound

LIPUS:

low-intensity pulsed ultrasound

BSP:

bone sialoprotein

MCP:

monocyte-chemoattractant protein

MIP:

macrophage-inflammatory protein

RANKL:

receptor activator of nuclear factor kappa-Β ligand

ATI:

angiotensin II type I receptor

NO:

nitric oxide

PGE2:

prostaglandin E2

VEGF:

vascular endothelial growth factor

GPCRs:

G protein-coupled receptors

BMSCs:

bone marrow-derived mesenchymal stem cells

ESWT:

extracorporeal shock wave therapy

CBFA1:

core-binding factor alpha1

ROCK:

RhoA and Rho-associated protein kinase

PG:

proteoglycan

ACAN:

aggrecan

PRG4:

proteoglycan 4

SZP:

superficial zone protein

PCM:

pericellular matrix

TRPV4:

transient receptor potential vanilloid 4

CC:

capacitive coupling

EPAC:

exchange proteins activated directly by cyclic AMP

TNF-α:

tumor necrosis factor-α

NF-AT:

nuclear factor of activated T cells

SMFs:

static magnetic fields

WOMAC:

Western Ontario and McMaster University Osteoarthritis Index

LLLT:

low-level laser therapy

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The authors thank NIH for the research support (1R21EB024787).

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Huang, X., Das, R., Patel, A. et al. Physical Stimulations for Bone and Cartilage Regeneration. Regen. Eng. Transl. Med. 4, 216–237 (2018). https://doi.org/10.1007/s40883-018-0064-0

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Keywords

  • Bone and cartilage regeneration
  • Fracture repair
  • Physical stimulation
  • Electrical and magnetic fields
  • Mechanical forces
  • Ultrasound
  • Shock waves