Electronic Bone Growth Stimulators for Augmentation of Osteogenesis in In Vitro and In Vivo Models: A Narrative Review of Electrical Stimulation Mechanisms and Device Specifications

Abstract

Since the piezoelectric quality of bone was discovered in 1957, scientists have applied exogenous electrical stimulation for the purpose of healing. Despite the efforts made over the past 60 years, electronic bone growth stimulators are not in common clinical use. Reasons for this include high cost and lack of faith in the efficacy of bone growth stimulators on behalf of clinicians. The purpose of this narrative review is to examine the preclinical body of literature supporting electrical stimulation and its effect on bone properties and elucidate gaps in clinical translation with an emphasis on device specifications and mechanisms of action. When examining these studies, trends become apparent. In vitro and small animal studies are successful in inducing osteogenesis with all electrical stimulation modalities: direct current, pulsed electromagnetic field, and capacitive coupling. However, large animal studies are largely unsuccessful with the non-invasive modalities. This may be due to issues of scale and thickness of tissue planes with varying levels of resistivity, not present in small animal models. Additionally, it is difficult to draw conclusions from studies due to the varying units of stimulation strength and stimulation protocols and incomplete device specification reporting. To better understand the disconnect between the large and small animal model, the authors recommend increasing scientific rigor for these studies and reporting a novel minimum set of parameters depending on the stimulation modality.

Electrical Stimulation of Acute Fractures: A Narrative Review of Stimulation Protocols and Device Specifications

“…These studies applied a wide range of stimulation currents and were successful in inducing osteogenesis within a range of 20–100 μA, and lower stimulation currents (13 μA) were not successful ( Nerubay et al, 1986 ; Chakkalakal et al, 1990 ; Toth et al, 2000 ). These results are problematic for translation into humans, however, because these studies used custom-built stimulators and did not report cathode material, lead geometry, or measures of current density in all cases ( Nicksic et al, 2022 ). Direct current electrical stimulation remains largely unstudied in humans as it is impractical, requiring operations for lead placement and removal and presenting an unacceptable infection risk ( Jorgensen, 1977 ).…”

“…For example, the thickness of tissue planes (fat, muscle, and bone) and their relative difference in resistivity, as well as even small changes in the placement of the PEMF device with relationship to the fracture, dramatically change the intensity of the electrical field at the fracture site ( Lunt, 1985 ). By contrast to in vitro and small animal studies, large animal studies have largely been unsuccessful in inducing osteogenesis with PEMF therapy ( Nicksic et al, 2022 ). Studies to date have included a range of indications in both canine and sheep models ( Miller et al, 1984 ; Law et al, 1985 ), but the single study that was able to demonstrate benefit for PEMF therapy applied 0.2 mT, 1.5 Hz stimulation to a canine mid-diaphyseal tibial 2 mm gap osteotomy model ( Inoue et al, 2002 ).…”

“…There is a robust body of evidence in support of ES for fracture non-unions, spinal fusions, and acute fractures in small animal models ( Guizzardi et al, 1994 ; France et al, 2001 ; Atalay et al, 2015 ; Liu et al, 2021 ; Nicksic et al, 2022 ). There has also been a resurgence in interest in the field of ES for the purpose of bone healing in in vitro studies ( Li et al, 2019 ; Portan et al, 2019 ; Escobar et al, 2020 ; Stephan et al, 2020 ).…”

“…For the more popular noninvasive stimulation modalities, computer modeling data demonstrates that changing the thickness of skin, subcutaneous fat, muscle, and cortical bone all have significant effects on the energy transmitted to the fracture site ( Lunt, 1985 ; Plonsey and Barr, 1995 ). This is supported by the fact that large animal studies using DCES—where stimulation can be administered reliably regardless of scale—are largely more successful in inducing osteogenesis than noninvasive treatments ( Nicksic et al, 2022 ).…”

Efficacy of Bone Stimulators in Large-Animal Models and Humans may be Limited by Weak Electric Fields Reaching Fracture

“…Fukada and Yusada discovered the piezoelectric property of bone -that bone generates endogenous electrical elds when put under mechanical stress -and its relationship to bone formation in 1953 [2]. Since then, there have been multiple studies in in vitro, small animal, and largeanimal models, as well as clinical studies, to explore the effects of electrical stimulation on an array of osseous injuries [3]. These studies have led to the approval of nine electronic bone growth stimulators (EBGSs) by the Food and Drug Administration (FDA) for use in the treatment of osseous nonunion [4].…”