Pulsed ultrasound for bone regeneration – outcomes and hurdles in the clinical application: a systematic review

Abstract

Impaired bone-fracture healing is associated with long-term musculoskeletal disability, pain and psychological distress. Low-intensity pulsed ultrasound (LIPUS) is a non-invasive and side-effect-free treatment option for fresh, delayed- and non-union bone fractures, which has been used in patients since the early 1990s. Several clinical studies, however, have questioned the usefulness of the LIPUS treatment for the regeneration of long bones, including those with a compromised healing. This systematic review addresses the hurdles that the clinical application of LIPUS encounters. Low patient compliance might disguise the effects of the LIPUS therapy, as observed in several studies. Furthermore, large discrepancies in results, showing profound LIPUS effects in regeneration of small-animal bones in comparison to the clinical studies, could be caused by the suboptimal parameters of the clinical set-up. This raises the question of whether the so-called “acoustic dose” requires a thorough characterisation to reveal the mechanisms of the therapy. The adequate definition of the acoustic dose is especially important in the elderly population and patients with underlying medical conditions, where distinct biological signatures lead to a delayed regeneration. Non-industry-funded, randomised, double-blind, placebo-controlled clinical trials of the LIPUS application alone and as an adjuvant treatment for bones with complicated healing, where consistent control of patient compliance is ensured, are required.

Low‐Intensity Pulsed Ultrasound Maintains Bone Mass After Withdrawal of Human Parathyroid Hormone in Ovariectomized Mice

“…When using the same size LIPUS probes commonly used in clinical practice for preclinical studies, the probe-to-human bone ratio and the probe-to-rodent bone size ratio must be considered. 52 Furthermore, the probe area of the device used in this study is approximately twice the area of the probe of a typical LIPUS device for fracture treatment. 53,54 Therefore, the irradiated area to the lower limbs of mice is larger than that of a typical LIPUS probe, which is thought to be more likely to increase bone mass.…”

“…When using the same size LIPUS probes commonly used in clinical practice for preclinical studies, the probe‐to‐human bone ratio and the probe‐to‐rodent bone size ratio must be considered 52 . Furthermore, the probe area of the device used in this study is approximately twice the area of the probe of a typical LIPUS device for fracture treatment 53,54 .…”

Focused Low-Intensity Pulsed Ultrasound (FLIPUS) Mitigates Apoptosis of MLO-Y4 Osteocyte-like Cells

“…Low-Intensity Pulsed Ultrasound, an FDA-approved treatment for fresh, delayed- and non-union bone fractures [ 16 ], has recently been called for its contentious clinical outcomes [ 17 , 18 , 19 ]. The understanding of the LIPUS-associated mechanisms is to this day limited by the untranslatability of the clinical conditions and parameters for the in vitro and small animal models [ 20 ]. This urges a detailed characterization of the clinical acoustic dose and development of the corresponding laboratory set-ups free of undesirable physical artifacts.…”

A Tissue Engineering Acoustophoretic (TEA) Set-up for the Enhanced Osteogenic Differentiation of Murine Mesenchymal Stromal Cells (mMSCs)

“…The application of external physical fields, i.e., magnetic [ 16 , 17 ], electrical [ 18 ], and acoustic forces [ 19 , 20 , 21 ], as novel regenerative medicine strategies for bone healing has been intensively researched by the scientific community. Another TE approach for the fabrication of regenerative constructs is the self-assembly of cells and biomolecules into a functional scaffold.…”