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British Medical Bulletin Advance Access published online on November 16, 2008
British Medical Bulletin, doi:10.1093/bmb/ldn040
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© The Author 2008. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

The effects of LIPUS on soft-tissue healing: a review of literature

Anil Khanna{dagger}, Richard T.C. Nelmes, Nikolaos Gougoulias, Nicola Maffulli* and Jim Gray*

Department of Trauma and Orthopaedic Surgery, Keele University School of Medicine, Thornburrow Drive, Hartshill Stoke on Trent ST4 7QB Staffs, UK and Health Protection Agency, Virus Reference Department, London

* Correspondence to: Nicola Maffulli, Department of Trauma and Orthopaedic Surgery, Keele University School of Medicine, Thornburrow Drive, Hartshill Stoke on Trent ST4 7QB Staffs, UK. E-mail: osa14{at}keele.ac.uk


   Abstract
Top
 Abstract
Introduction
 Methods
 Biophysics of ultrasound therapy
 Biological effects of LIPUS
 Effect of LIPUS on...
 Effects of LIPUS on...
 Economical aspects of LIPUS...
 Conclusions
 References
 
Introduction: Ultrasound is widely used for imaging purposes and as an adjunct to physiotherapy. Low-intensity pulsed ultrasound (LIPUS), having removed the thermal component found at higher intensities, is used to improve bone healing. However, its potential role in soft-tissue healing is still under investigation.

Material and methods: We searched on Medline using the keywords: low-intensity pulsed ultrasound, LIPUS and LIPUS and soft-tissue healing. Thirty-two suitable articles were identified.

Results: Research, mainly pre-clinical, so far has shown encouraging result, with LIPUS able to promote healing in various soft tissues such as cartilage, inter-vertebral disc, etc. The effect on the bone-tendon junction, however, is primarily on bone. The role of LIPUS in treating tendinopathies is questionable. Adequately powered human studies with standardisation of intensities and dosages of LIPUS for each target tissue are needed.

Keywords: low intensity pulsed ultrasound • soft tissue healing


   Introduction
Top
 Abstract
 Introduction
Methods
 Biophysics of ultrasound therapy
 Biological effects of LIPUS
 Effect of LIPUS on...
 Effects of LIPUS on...
 Economical aspects of LIPUS...
 Conclusions
 References
 
Ultrasound is widely used for imaging purposes and as an adjunct to physiotherapy. Low-intensity pulsed ultrasound (LIPUS), having removed the thermal component found at higher intensities, is used to improve bone healing. However, its potential role in soft-tissue healing is still under investigation.

Ultrasound is widely used as an imaging modality1 at intensities of 0.05–0.5 W/cm2. At intensities of 0.2–100 W/cm2, the surgical and therapeutic benefits of ultrasound have also been explored.1 In orthopaedic practice, intensities of ≤ 0.1 W/cm2 have been shown to improve bone healing.1,2

For the management of ligament, muscle and tendon injuries high-intensity (>0.1 W/cm2) continuous ultrasound has been used therapeutically for >50 years.3,4 However, studies on the effects of therapeutic ultrasound in muscle and joint healing have been contradictory. Generally, there seem to be insufficient evidence to support the clinical use of ultrasound at these doses.5 Following the success of ultrasonic waves applied at low intensity (≤0.1 W/cm2), in a constant frequency (1–1.5 MHz) and in a pulsatile manner (LIPUS) on osteoid tissue, the potential benefit in soft-tissue healing is being investigated.6–9

We thus review the currently available literature on the role of LIPUS in soft-tissue healing, investigating its effect both at cellular and tissue level, and summarising the evidence available so far.


   Methods
Top
 Abstract
 Introduction
 Methods
Biophysics of ultrasound therapy
 Biological effects of LIPUS
 Effect of LIPUS on...
 Effects of LIPUS on...
 Economical aspects of LIPUS...
 Conclusions
 References
 
For the purposes of this review, scientific articles were identified on Medline using the primary keywords: low-intensity pulsed ultrasound, LIPUS, tendon, soft tissue and healing. We also used the keywords: LIPUS and tendon, LIPUS and tendon healing, LIPUS and soft tissue, LIPUS and soft-tissue healing, low-intensity pulsed ultrasound and tendon, low-intensity pulsed ultrasound and tendon healing, low-intensity pulsed ultrasound and soft tissue and low-intensity pulsed ultrasound and soft-tissue healing. Additional publications were identified searching manually the references sections of each of the articles identified using the above-mentioned keywords.

Exclusion criteria: Publications in language other than English, articles not discussing the subject matter, studies where low-intensity ultrasound was used continuously and studies where intensity of ultrasound was >0.1 W/cm2 were excluded. Also, studies where primary action of LIPUS was on osteoid tissue [e.g. bone-tendon junction (BTJ)] were excluded to specifically focus on the effect of LIPUS in soft-tissue healing.

We thus identified 32 articles fulfilling the inclusion criteria.


   Biophysics of ultrasound therapy
Top
 Abstract
 Introduction
 Methods
 Biophysics of ultrasound therapy
Biological effects of LIPUS
 Effect of LIPUS on...
 Effects of LIPUS on...
 Economical aspects of LIPUS...
 Conclusions
 References
 
Ultrasound, an acoustic radiation, is a form of mechanical energy that can be transmitted into the body as a high-frequency pressure wave. The acoustic energy generated from ultrasound is produced from a piezoelectric crystal within a transducer, which emits high-frequency acoustic pressure waves (1–12 MHz) transmitted through body tissues by molecular vibrations and collisions.10 The micromechanical strains produced by these pressure waves in body tissues can result in biochemical events at the cellular level.11 This ultrasonic energy can be divided into two categories: high-intensity ultrasound with peak intensities from 5000 to 15 000 W/cm2, and low-intensity ultrasound with intensities of 0.5–3000 mW/cm2. This low-intensity ultrasound is used in physical therapy, whereas the high intensities are used in treating tumours by selectively heating tissue and causing necrosis.12


   Biological effects of LIPUS
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 Abstract
 Introduction
 Methods
 Biophysics of ultrasound therapy
 Biological effects of LIPUS
Effect of LIPUS on...
 Effects of LIPUS on...
 Economical aspects of LIPUS...
 Conclusions
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Passing through the tissue, the ultrasonic energy is absorbed at a rate proportional to the density of the tissue. Thus, the radical changes in density inherent in a healing tissue may well establish the gradients of mechanical strain.13 Absorption of the ultrasound signal also results in energy conversion to heat.14 While this heating effect is extremely small for low frequency ultrasonic waves, well below 1°C, some enzymes, such as matrix metalloproteinase-1, or collagenase, are exquisitely sensitive to small variations in temperature.15 Therefore, ultrasound may serve to re-establish or normalize effective metabolic temperatures in tissue-healing regions; this effect, although subtle, may be biologically profound.16 Furthermore, at interfaces of distinct densities, much of the incident radiation energy will be reflected, resulting in complex gradients of acoustic pressure through the tissue.17

Having removed the high thermal component of the higher intensities while maintaining the transmission of acoustic mechanical stress to the target tissue, LIPUS stimulates the union of non-uniting fractures, promotes the healing in a congenital pseudoarthrosis of the tibia, increase the matrix synthesis in chondrocytes, stimulates the differentiation in osteoblast precursor cells and induces the expression of growth factors, proteins and prostaglandins within osteoblasts, chondrocytes and fibroblasts.1,8–27 Furthermore, cartilage healing assisted with LIPUS produces fewer degenerative changes in the long term, as compared with controls.28

In this review, the role of LIPUS in a soft-tissue healing will be discussed at cellular level first, giving a background of laboratory-based evidence before dwelling into various animal and human studies focusing on different soft tissues individually.


   Effect of LIPUS on fibroblasts, myoblasts, epithelial cells and chondrocytes
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In 2004, Zhou et al.29 investigated the effects of daily exposure to LIPUS at an intensity of 0.03 W/cm2 on primary human foreskin fibroblasts. LIPUS activates RhoA (a GTPase protein) which induces the formation of F-actin stress fibres which in turn cause the recruitment of paxillin, a signal transduction adaptor protein—by a Rho-associated coiled—coil-containing protein kinase (ROCK)-dependent pathway. Furthermore, LIPUS exposure promoted a 2-fold increase in extracellular signal-related kinase (ERK) 1/2 activation, triggering DNA synthesis, and thus, cell proliferation. RhoA/ROCK is an upstream regulator of the LIPUS-induced ERK pathway. Similarly, LIPUS triggered Src, a tyrosine kinase, which further regulates the ERK cascade. ERK pathways are typically activated by mechanical stress, although, in this case, LIPUS activated a pathway, with no evidence of epidermal growth factor receptor (EGFR) involvement (EGFR is a tyrosine kinase, usually expressed in ERK pathways, triggered by direct mechanical stress). Thus, LIPUS produced results similar to mechanical stress at cellular level.18

LIPUS involvement in the ERK 1/2 system was also demonstrated by in a mice model. Here, the differentiation pathway of C2C12 (a sub-clone of C2 myoblasts from a C311 mouse) to the lineage of the osteoblast and chondroblast was observed.25

The effects of LIPUS appear to not only be limited to the ERK pathways. Ikai et al. noted a locally increased expression of heat shock protein-70 (hsp-70) in LIPUS-exposed canine gingival epithelium. The heat shock protein family is associated with the healing process and, more specifically, with the assembly of molecules utilized for endothelial cell migration and proliferation (Table 1).30–32


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  		Table 1 The effects of LIPUS on fibroblasts, myoblasts, epithelial cells, chondrocytes and inter-vertebral discs

 
Inconsistent effects have been observed in various in vitro studies regarding the exact role of LIPUS in cartilage healing (Table 1). LIPUS stimulates the aggrecan m-RNA expression and proteoglycan synthesis, but it did not influence cell proliferation of rat chondrocytes.33 However, LIPUS influences the cell proliferation in an intensity-dependent manner but did not increase the expression or synthesis of aggrecan and type II collagen of chick embryo chondrocytes.34 In an in vitro atelocollagen gel-embedded culture model, LIPUS exposure promotes the synthesis of chondroitin sulfate, although it does not significantly enhance the cell number of rabbit chondrocytes.35 From these studies, it can be concluded that exposure to LIPUS could significantly affect chondrocytes proliferation, phenotype expression and matrix production. In consistencies in these studies may be attributable to many factors, including culture media, culture models or cell senescence.


   Effects of LIPUS on soft tissues
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 Effect of LIPUS on...
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(1) Inter-vertebral discs (IVDs): Results following the exposure of IVDs to LIPUS appear to feature a distinct LIPUS-activated pathway. In nucleus pulposus (NP) cells, Hiyama et al. reported an increased expression of transforming growth factor-beta type 1 (TGF-BR1) receptor gene on exposure to LIPUS. Transforming growth factor-beta 1 (TGF-B1) promotes IVD cell proliferation and matrix synthesis, as well as playing a part in the regulation of chondrocytes.31 This is attributed to the structural similarities between chondrocytes and the NP and annulous fibrosus cells of the IVDs.36 Exposure of these cells to recombinant TGF-B1 mimicked the effects produced by LIPUS, whereas the exposure of LIPUS-treated cells to anti-TGF-B1 would reverse all the beneficial effects induced by LIPUS.31 Also, a marked increase in proteoglycan synthesis within the NP cells encouraging the uptake of water was observed, resulting in the potential regression of disc herniation.

Also, investigating the effect of LIPUS on NP cells, Omi et al.37 noted not only a 2.06-fold up-regulation of tissue inhibitor of metallo-proteinase-1, but also a 2.3-fold up-regulation in local macrophage monocyte chemotaxis protein-1 compared with controls. Similar findings have been presented by other studies,38 suggesting that LIPUS-induced macrophage migration may play an important role in IVD remodelling and possibly IVD hernia regression, proposing that macrophages could enter IVDs following the increased capillary blood flow and cell-membrane permeability caused by LIPUS stimulation of fine vibrations in local tissue.37 Studies by Miyamoto et al.39 demonstrated increased collagen synthesis by cells isolated from the intervertebral disc by the application of LIPUS (16–19% increase, P < 0.05–0.0001), suggesting that LIPUS may prove useful for tissue engineering of intervertebral disc tissue in future (Table 1).

(2) Ligaments: Several studies investigated the effect of LIPUS in comparison to non-steroidal anti-inflammatory drugs (NSAIDs) in relation to ligamentous healing. They concluded that LIPUS accelerated but did not improve ligament healing, whereas NSAIDs delayed but did not impair healing. When used in combination, the beneficial LIPUS effect was not impaired by the detrimental NSAID effect, suggesting that LIPUS does not influence the cyclo-oxygenase pathway which is normally inhibited by NSAIDs.40,41 Other studies found LIPUS effective in accelerating rat medial collateral ligament injury healing at an intensity of 0.03 W/cm2.42,43 (Table 2).


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  		Table 2 The effects of LIPUS on ligament, tendon and cartilage healing

 
(3) Tendons: Therapeutic ultrasound has been found to have no effect over and above placebo on tendon healing.44 Research focused on the role of LIPUS on tendon healing use BTJ as the main area of investigation. A closer look into the finding of these studies, however, reveals that LIPUS improves BTJ healing mainly by enhancing bony in-growth and osteo-integration.44–48 The study by Warden et al.49 demonstrates no benefit of LIPUS therapy over and above placebo in the management of symptoms associated with patellar tendinopathy. Thus, LIPUS does not seem to have direct effect on healing of tendon tissue itself.

The mechanism of action pertaining LIPUS at the BTJ revolves around the acoustic mechanical stimulation of osteoblasts and fibrocytes, acoustic vibrational aligning of collagen fibres, promoting local influx of calcium and the increased expression of angiogenic factors [i.e. vascular endothelial growth factor (VEGF)].45–47 The increase in VEGF expression of 7% from LIPUS-treated rabbit patellar-tendon samples over control samples (P < 0.05) suggests that a reason for the acceleration in BTJ healing was increased early vascularity and osteoblastic differentiation45 (Table 2).

(4) Cartilage: In vivo studies50,51 in New Zealand rabbit and canine models with full-thickness osteochondral defects have demonstrated that exposure to LIPUS significantly improves the morphologic features and histologic characteristics of repaired cartilage. Jia et al.52 studied the effect of LIPUS on 10 adult New Zealand rabbits with bilateral full-thickness osteochondral defects. The scores of the gross appearance grades, histological grades and the optical density of toluidine blue of the tissues in the experimental group were significantly higher than those of the controls at 8 weeks after injury (P < 0.05), suggesting that LIPUS can accelerate the repair of injured articular cartilage.

Chondrocytes isolated from young children's articular cartilage of ablated polydactylia, showed that LIPUS was found to increase aggrecan synthesis in a time-dependent manner,53 with a maximal response observed at an intensity of 48 mW/cm2. After 14 days of exposure at this intensity, the aggrecan and type II collagen synthesis were significantly higher than control group. However, LIPUS treatment revealed no significant influence on cell proliferation, confirming that the stimulation of aggrecan and type II collagen synthesis by LIPUS was not the result of an increase in chondrocyte cell proliferation. In addition, human chondrocytes harvested from older donors were less responsive to LIPUS.53 Similar studies on human articular chondrocytes isolated from osteoarthritis patients demonstrated an increase in the number and size of glycosaminoglycan-positive lacunae and cellular organelles, appearing as rough endoplasmic reticulum and mitochondria in LIPUS exposed group, suggesting that viability and metabolism of human articular chondrocytes in alginate culture were induced by LIPUS treatment.54 Studies on both animal and human tissues have shown that LIPUS enhance the healing of cartilage defects (Table 2). Whether this acceleration of chondrogenesis in vitro will lead to the maturation of tissue-engineered neo cartilage in a clinical setting has been questioned.55


   Economical aspects of LIPUS therapy
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 Biophysics of ultrasound therapy
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Every fracture or soft-tissue injury is accompanied by direct and indirect implication on the economy of an individual and the establishment for which the individual works. The goal of modern orthopaedic surgery is to minimize this financial strain while maximizing the functional recovery after injury.56,57 Study on potential economical benefit of LIPUS therapy in tibial fractures demonstrated substantial cost savings for third party payers, employers and government agencies after the use of LIPUS therapy, as there was lesser need for secondary procedures after LIPUS treatment thereby substantial reduction of the amount of Workers' Compensation payments.58 The literature, however, is deficient on the economical benefits of LIPUS on soft-tissue healing.


   Conclusions
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 Introduction
 Methods
 Biophysics of ultrasound therapy
 Biological effects of LIPUS
 Effect of LIPUS on...
 Effects of LIPUS on...
 Economical aspects of LIPUS...
 Conclusions
References
 
Research, mainly pre-clinical, so far have shown encouraging result with LIPUS in promoting healing in various soft tissues such as cartilage, inter vertebral disc, etc. The effect on BTJ is primarily on osseous tissue. The role of LIPUS in treating tendinopathies is questionable . These preclinical studies that support the positive effect of LIPUS therapy on soft-tissue healing could be translated into human use. However, poor methodological standards in animal studies mean that positive results rarely translate to the clinical domain59 suggesting that sufficient supporting evidence in the ‘clinically justifiable’ role of LIPUS in soft-tissue healing is lacking. Adequately, powered human studies together with the standardization of intensities and dosages for each target tissue are needed to build a stronger clinical database for routine clinical use. Furthermore, if the aforementioned results with LIPUS concerning IVD's, tendon and cartilage healing are repeatable and consistent in humans, they could change the future of the management of soft-tissue injuries.


   Footnotes
 
{dagger} Mr Khanna is a DePuy International Implant Research Fellow. Back

Accepted for publication October 20, 2008.


   References
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 Abstract
 Introduction
 Methods
 Biophysics of ultrasound therapy
 Biological effects of LIPUS
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 Effects of LIPUS on...
 Economical aspects of LIPUS...
 Conclusions
 References
 

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  51. Cook SD, Salkeld SL, Patron LP, Doughty ES, Jones DG. The effect of low-intensity pulsed ultrasound on autologous osteochondral plugs in a canine model. Am J Sports Med (2008) 36:1733–1741.[Abstract/Free Full Text]
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