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Therapeutic Ultrasound and Wound Closure: Lack of Healing Effect on X-Ray Irradiated Wounds in Murine Skin
Andrea S. Lowe, DPhil, Mark D. Walker, DPhil, Roger Cowan, BSc, G. David Baxter, DPhil
ABSTRACT. Lowe AS, Walker MD, Cowan R, Baxter GD. Therapeutic ultrasound and wound closure: lack of healing effect on x-ray irradiated wounds in murine skin. Arch Phys Med Rehabil 2001;82:1507-11. Objective: To evaluate the efcacy of ultrasonography as a therapeutic agent in wound healing. Design: Randomized, controlled trial. Setting: University animal laboratory. Animals: Male BALB/c mice randomly allocated to 5 groups. Interventions: In group 1, mice were left untreated; in groups 2 through 5, a well-dened area on the dorsum was exposed to 20Gy x-ray irradiation. Seventy-two hours postirradiation, all mice were anesthetized by inhalation (isourane anesthetic) and a 7 7mm area wound made on the dorsum. All wounds were videotaped alongside a marker scale 3 times weekly until closure was complete. Mice in groups 4 and 5 were treated with pulsed therapeutic ultrasound for 5 minutes, 3 times weekly at 1 and 3MHz, respectively (intensity, 0.5W/ cm2); mice in group 3 received placebo ultrasound. Subsequently, the area of each wound was measured from video by using an image analysis system. Main Outcome Measure: Wound closure as a fraction of day zero. Results: Irradiation caused a signicant (p .01) delay in the rate of wound closure by day 11. However, neither placebo ultrasound nor treatment at 1 or 3MHz affected the closure rate. Conclusion: These ndings provide little evidence that 1 or 3MHz ultrasound applied to a radiation-impaired wound stimulates wound closure in mice. Key Words: Mice, inbred BALB c; Rehabilitation; Skin; Therapeutic ultrasound; Wound healing. 2001 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation HERAPEUTIC HAS BEEN widely years to treat various conditions, including T over the past 50 ULTRASOUND soft-tissue injuries, used bursitis, Dupuytrens contracture, and
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herpes zoster.4 Reported effects include decreased pain, increased circulation, and increased tissue mobility.5-7 Since the 1960s, the benets and effects of ultrasound in the promotion of wound healing have been investigated by various investigators.8-11 Although several studies12-15 have investigated its ther-

From the Schools of Health Sciences (Lowe, Baxter), and Biomedical Sciences (Walker, Cowan), University of Ulster at Jordanstown, Newtownabbey, Northern Ireland. Accepted October 17, 2000. Supported by the Department of Education of Northern Ireland. The authors have chosen not to select a disclosure statement. Reprint requests to Andrea S. Lowe, DPhil, Rehabilitation Sciences Research Group, Room 50K15, School of Health Sciences, University of Ulster at Jordanstown, Shore Rd, Newtownabbey, Antrim, BT37 0QB, Northern Ireland, e-mail: a.lowe@ ulst.ac.uk. 0003-9993/01/8211-6466$35.00/0 doi:10.1053/apmr.2001.25083

apeutic benets on pressure sores and venous ulcers, the clinical use of ultrasound for wound healing is still under investigation because many investigators report conicting ndings.15,16 In a recent review of the literature, Johannsen et al17 found only 14 studies on the effects of ultrasound in the treatment of chronic leg ulcers, and proposed that further research should be undertaken to determine its effects and to evaluate any dose-response relationship. Current literature presents with conicting ndings. Early experiments reporting positive results included placebo controls, but no randomization.18,19 In a more recent study of chronic venous leg ulcers, Peschen et al20 reported positive results in patients treated with continuous ultrasound therapy at 30kHz and 0.1W/cm2. Weichenthal et al,21 investigating the effects of ultrasound (30kHz, 0.1W/cm2) in the treatment of chronic venous ulcers, found a signicantly greater decrease in ulcer size with ultrasound compared with control groups. However, the report did not indicate whether pulsed or continuous treatment was applied. In contrast, a study by Eriksson et al14 that also incorporated a placebo control and active treatment (1MHz, 1.0W/cm2) found no signicant differences in wound area between groups. Although Weichenthal21 excluded potential patients who had diabetes or arterial disease (because those diseases could impair the rate of healing), no such exclusion criteria were used by Erikssons group. Similarly negative results were also reported by ter Riet et al16 from a randomized, blinded study of ultrasound (3MHz, 0.1W/cm2 spatial average, temporal average) for the treatment of pressure ulcers. Because treatment methods vary and some studies are poorly controlled or provide little detail on their protocol, attempts to determine efcacy are confounded. Nevertheless, much of the laboratory research conducted to date is positive, showing a range of ultrasound-mediated effects that support clinical use of ultrasound for promoting wound healing. An in vitro study22 has shown a signicant uptake of calcium ions by using an ultrasound intensity of 0.5W/cm2 at a frequency of 1MHz, which suggests changes in cell membrane permeability with subsequent effects on intracellular communication. It has also been shown23 that insonation (.75MHz, 0.5W/cm2) can effectively stimulate broblasts, possibly by inuencing macrophage activity. From animal studies in rats,24,25 researchers found that ultrasound at an intensity of 0.1W/cm2 (at .75 and 3.0MHz24) accelerates the inammatory phase of repair. Several investigators25,26 have reported signicant increases in rates of wound healing in rats and rabbits at intensities of 0.1 and 0.5W/cm2, respectively; however, these groups did not specify the ultrasound frequency, making comparison with other studies difcult. Nevertheless, this reported accelerated repair is in agreement with ndings from several other studies23,26,27 suggesting that low-dose ultrasound of approximately 0.5W/cm2 pulsed with a frequency of 1 or 3MHz promotes wound healing. Although current animal research suggests that ultrasound therapy may accelerate wound healing, evidence regarding optimal insonation parameters is limited, and selecting them remains a matter of personal choice in the clinical eld. A clear rationale for treatment parameter selection is required. A series
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of experiments using a chronic wound model in animals would permit more rigorous examination of therapeutic ultrasound applied under controlled conditions. A wound that models impaired healing can be induced by (1) inoculating a bacterium or virus into the wound, (2) creating a diabetic state, or (3) irradiating the wound with x-rays.28-31 X-ray irradiation impairs healing by decreasing new collagen formation and contraction.30 The resultant delay in the healing process provides a suitable model for testing new wound healing agents in an impaired healing environment.30,31 In work conducted at the present studys institution, Lowe et al32 reported that a single dose of 20Gy x-ray irradiation before wounding delays wound healing by approximately 7 days. Radiation has both acute and delayed effects on an organisms ability to heal.33 It induces acute degenerative changes in basement membranes and increases vascular permeability.33 Changes in vasculature may include stasis and occlusion, edema of vascular walls, and thrombosis; radiation may also reduce neovascularization.33,34 Progressive loss of vessels and brous tissue replacement may eventually occur, whereas broblasts may be altered permanently either the broblasts do not produce sufcient collagen to keep up the demands of the wound, or the collagen that is produced does not mature quickly enough.35,36 Late radiation effects attributable to broblast injury include atrophy, contraction, and brosis.35-38 The delayed healing allows procedures such as ultrasound therapy to be tested. Our aim in the present study was to investigate the effects on wound closure of pulsed ultrasound at 1 and 3MHz at an intensity of 0.5W/cm2 in a murine model to provide quantitative data to guide further research and use of therapeutic ultrasound in the clinical setting. METHODS The current investigation, which adhered to the University of Ulsters regulations on animal experimentation, included male BALB/c mice, age-matched at 12 weeks old (n 60; mean weight, 28.31g). Animals were supplied with food and water ad libitum, and housed individually to prevent cross-tampering with wounds. The animals were randomly assigned to 1 of 5 experimental groups (n 12, each group). Group 1 was the nonirradiated control; group 2, the irradiated control. Groups 3, 4, and 5 all received x-ray irradiation and ultrasound treatment: group 3, placebo ultrasound; group 4, ultrasound at 1MHz; and group 5, ultrasound at 3MHz.

The hair on the dorsum of the mice was shaved; all animals were then placed individually into custom-made lead jigs, which allowed a 4cm2 area of dorsal skin to be exposed. The area was marked with indelible ink and the mice exposed to 20Gy x-ray irradiation by using a Siemens Stabilipan x-ray machine.a Seventy-two hours after irradiation, hair on the dorsal surface was reshaved (where required) and the skin cleaned with 70% alcohol. Mice in all groups were then anesthetized by inhalation by using isourane anesthetic,b and a 7 7mm area of skin was removed from within the area previously exposed to x-rays. An equivalent area was removed from mice in group 1. In groups 4 and 5, mice received ultrasound therapy 3 times weekly by using a stationary head, Sonoplus 590 device.c The parameters of this unit were: group 4, 1MHz, pulsed 1:4, pulse duration 4ms at 48Hz, 0.5W/cm2 intensity; and group 5, 3MHz, pulsed 1:4, pulse duration 4ms at 48Hz, 0.5W/cm2 intensity. Group 3 received sham ultrasound therapy at equivalent time periods. During each treatment session, ultrasound therapy was administered for 5 minutes by using a stationary head and standard coupling gel.d All wounds were videotaped adjacent to a marker scale 3 times weekly until closure was complete. Wound areas were then calculated31,32 by means of an image analysis system.e To allow for variation between the initial size of the wound on each animal, data were expressed as the fractional change in wound area for each mouse. The results were then analyzed blind by using repeated-measures and 1-factor analysis of variance at 95% condence levels, with post hoc Fisher tests where appropriate.31,32 RESULTS In the present murine model, the overall rate of wound closure was not accelerated after therapeutic ultrasound treatment. Figure 1 shows wound closure (areas expressed as a fraction-of-day-0 values) for the nonirradiated controls (group 1) and the irradiated controls (group 2). Although both groups had a similar pattern of wound closure, by day 11 postwounding group 2 had a statistically signicant (p .01) delay in wound closure when compared with group 1. Such statistically signicant differences continued until day 23. After day 23, the effects of x-ray irradiation on wound closure were statistically nonsignicant; however, the wounds in group 1 reached com-

Fig 1. Wound closure as a fraction of day 0 for irradiated 12) and nonirradiated (n 12) controls. NOTE. (n Points are mean standarderror of the mean (SEM). *Signicant (p < .01) difference between group 1 and group 2. Legend: s, group 1, nonirradiated; }, group 2, irradiated.

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Fig 2. Wound closure as a fraction of day 0 for irradiated 12) and ultracontrols (n sound treatment groups (n 12). NOTE. Points are mean SEM. Legend: }, group 2, irradiated control; s, group 3, irradiated ultrasound placebo; , group 4, irradiated 1MHz, ultrasound; F, group 5, irradiated 3MHz ultrasound.

plete wound closure by day 25, whereas the wounds in group 2 reached complete wound closure on day 34 postwounding. Figure 2 shows wound closure as a fraction of day 0 for groups 2, 3, 4, and 5; that is, the x-ray irradiated control and the 3 treatment groups, respectively. A similar rate of wound closure was observed for all groups; all achieved complete wound closure by day 34 postwounding. Treatment with ultrasound at both 1 and 3MHz had no effect on the rate of wound closure in this model; similarly, no placebo effect was observed. Irradiation with x-ray doses of 20Gy caused a signicant delay in the rate of wound healing by day 11, when compared with the nonirradiated group. Treatment with ultrasound at frequencies of 1 and 3MHz and an intensity of 0.5W/cm2 had no statistically signicant effect on the rate of wound closure when compared with the irradiated control group or the placebo treatment group. The present ndings are in agreement with other studies using x-ray irradiation as a method for producing a chronic wound model.33,39 DISCUSSION In contrast to normal wound healing, radiation-impaired wound healing is characterized by broblast injury and endothelial cell necrosis, which precipitates microvascular atrophy.39 The overall effect is dermal atrophy, contraction, and a subsequent reduction in wound strength.39 The effect of radiation on the rate of wound healing has also been shown to be dose dependent. Marx et al40 used a dose of 60Gy in rabbits and reported brosis and hypovascularity 6 months postirradiation. Several investigators30,32,41 reported that a wound healing deficit can be caused by a single 18 to 20Gy dose to the skin surface before wounding. Such irradiation lets researchers evaluate in a laboratory the effects of various treatment methods on the rate of compromised or delayed wound healing.30,31 Our present results contrast with most of the previous research on ultrasound. Young and Dyson24 reported that application of ultrasound (.75MHz, 0.1W/cm2) caused an early reduction in wound size. Many investigators23-25,27 agree that the application of ultrasound shortens the inammatory phase of repair, and can affect the onset of the proliferative phase. However, the lack of stimulatory effects in the present investigation supports the ndings of Shamberger et al,42 who reported no increase in wound breaking strength in rats treated with ultrasound at .05 and .15W/cm2 with a frequency of

5MHz. Interestingly, Shambergerwho used a stationary head technique as in the present study, but with a higher frequency suggested that a stationary treatment head is necessary to determine accurately actual energy exposure within the wound. In contrast, Byl et al27 suggested that the movement of the ultrasound head acts as a further mechanical stimulus to collagen deposition. These arguments notwithstanding, the small wound area in the present investigation was completely covered by the treatment head in all ultrasound treatment groups; a moving application would have been impractical and unnecessary. Byl27 proposed that the treatment head should be moved when applying intensities over 1.5W/cm2 and found increased wound breaking strength when ultrasound was applied at an intensity of 0.5W/cm2 and a frequency of 1MHz. It was previously suggested43 that unless the treatment head is moved, standing waves form, arresting the local movement of blood, causing endothelial damage, and releasing free radicals that indicate transient cavitation, all of which may result in a detrimental effect on the rate of wound healing. Although this reaction may explain the present ndings, we found no such inhibition of healing in the present study when we compared irradiated control and placebo groups. In the present study, effects on wound healing were determined by the rate of wound closure. Measuring wound breaking strength may have allowed comparison with the study by Byl,27 in which the investigators used similar parameters, and wound breaking strength is an important area for future research. It may also be benecial in further studies to examine the wounds histologically to detect differences between treatment groups and controls. This approach would allow researchers to investigate cellular content, granulation tissue formation, and collagen deposition for different physical parameters. In a study by Young and Dyson,24 a signicantly higher level of broblasts occurred in rat wounds after sonation of 0.1W/cm2 intensity at .75 and 3MHz. The cells were found to be aligned in a manner conducive to efcient wound contraction, and the overall conclusion was a resultant acceleration in the inammatory phase of repair and an earlier onset of wound contraction. Because histologic examination was not performed in the present investigation, some differences in groups may have been overlooked. In the search for an improved experimental model more relevant to wounds encountered clinically, the use of mice or
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other loose-skinned animals may not be the optimum choice. Because these animals heal by wound contraction, in contrast to humans who heal by reepithelialization, conclusions made from studies on loose-skinned animals may not always be directly relevant to humans.44 Nevertheless, these studies can be useful as precursors to further research, such as those investigating the most benecial physical parameters and mechanisms of action. Pigs were used in a study by Byl, et al11 because porcine skin physiology is similar to that of humans; the investigators reported that wound strength and rate of closure improved after ultrasound therapy (0.5W/cm2 for the rst 2 days; 1.5W/cm2 for the 3 subsequent days). Thus, pig skin may be a more suitable wound healing model for investigating the effects of ultrasound therapy. Results from the present murine model may also be limited by the difculty of extrapolating for application in humans. Considering the relative size of mice compared with the average human patient, dosage and area of treatment used in the present study were higher than would be used in clinical practice. The present ndings are not necessarily indicative of potential effects in humans, particularly in cases of wounds from causes such as diabetic ulceration and infection. Nevertheless, the present protocol provides an animal model of radiation-impaired healing, which is a signicant problem in oncology and radiation medicine.32 Whether a similar porcine model of healing would be more sensitive to the putative effects of therapies such as ultrasound remains to be established. The porcine model is an important area for future investigation, particularly because of its clinical relevance and the ethical constraints of undertaking controlled research in a patient population. CONCLUSION The present murine study provides no evidence to support the claimed stimulatory effects of therapeutic ultrasound on the rate of wound closure at 1 and 3MHz in the irradiationimpaired healing model. Nevertheless, because previous researchers24 proposed that the application of ultrasound therapy leads to an earlier proliferative phase of repair through a stimulatory effect on inammatory mediators, further research is required to determine the effects of different doses of ultrasound therapy when applied for different durations at different stages in the repair process. The chronic wound is a signicant problem for health professionals throughout the world. A careful understanding of the repair process in compromised or delayed wound healing, and the effects of various treatments are required to make a positive intervention in this area. Although the present study does not provide evidence to support the claimed effects of therapeutic ultrasound, further work to establish its efcacy remains a priority.
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8. Paul BJ, Lafrayya CW, Dawson AR, Babb E, Bullock F. Use of ultrasound in the treatment of pressure sores in patients with spinal cord injury. Arch Phys Med Rehabil 1960;41:438-40. 9. Dyson M, Pond JB, Joseph J, Warwick R. The stimulation of tissue regeneration by means of ultrasound. Clin Sci 1968;35:27385. 10. Dyson M, Pond JB. The effect of pulsed ultrasound on tissue regeneration. Physiotherapy 1070;56:136-42. 11. Byl NN, McKenzie AL, West JM, Whitney JD, Hunt TK, Scheuenstuhl HA. Low-dose ultrasound effects on wound healing: a controlled study with Yucatan pigs. Arch Phys Med Rehabil 1992;73:656-64. 12. McDiarmid T, Burns PN, Lewith GT, Machin D. Ultrasound and the treatment of pressure sores. Physiotherapy 1985;71:66-70. 13. Lundeberg T, Nordstrum F, Brodda-Jansen G, Eriksson SV, Kjartanson J, Samuelson UE. Pulsed ultrasound does not improve healing of venous ulcers. Scand J Rehabil Med 1990;22:195-7. 14. Eriksson SV, Lundeberg T, Malm M. A placebo controlled trial of ultrasound therapy in chronic leg ulceration. Scand J Rehabil Med 1991;23:211-3. 15. Nussbaum E, Biemann I, Mustard B. Comparison of ultrasound/ ultraviolet-C and laser for treatment of pressure ulcers in patients with spinal cord injury. Phys Ther 1994;79:812-23. 16. ter Riet G, Kessels AG, Knipschild P. A randomised clinical trial of ultrasound in the treatment of pressure ulcers. Phys Ther 1996;76:1301-12. 17. Johannsen F, Gam AN, Karlsmark T. Ultrasound therapy in chronic leg ulceration: a meta-analysis. Wound Repair Regeneration 1998;6:121-6. 18. Dyson M, Suckling J. Stimulation of tissue repair. Physiotherapy 1978;64:105-8. 19. Roche C, West J. A controlled trial investigating the effect of ultrasound on venous ulcers referred from general practitioners. Physiotherapy 1984;70:475-8. 20. Peschen M, Weichenthal M, Schopf E, Vanscheidt W. Low frequency ultrasound treatment of chronic venous leg ulcers in an outpatient therapy. Acta Derm Venereol 1997;77:311-4. 21. Weichenthal M, Mohr P, Stegmann W, Breitbart EW. Low-frequency ultrasound treatment of chronic venous ulcers. Wound Repair Regeneration 1997;5:18-22. 22. Mortimer AJ, Dyson M. The effects of therapeutic ultrasound on calcium uptake in broblasts. Ultrasound Med Biol 1998;14:499506. 23. Young SR, Dyson M. Macrophage responsiveness to therapeutic ultrasound. Ultrasound Med Biol 1990;16:809-16. 24. Young SR, Dyson M. Effect of therapeutic ultrasound on the healing of full-thickness excised skin lesions. Ultrasonics 1990; 28:175-80. 25. Taskan I, Ozyazgan I, Tercan M, Kardas Y, Balkanli S, Saraymen R, et al. A comparative study of the effect of ultrasound and electrostimulation on wound healing in rats. Plast Reconstr Surg 1997;100:966-72. 26. El-Batouty MF, El-Gindy M, El-Shawaf I, Bassioni N, ElGhaweet A, El-Eman A. Comparative evaluation of the effects of ultrasonic and ultraviolet irradiation on tissue regeneration. Scand J Rheumatol 1986;15:381-6. 27. Byl NN, McKenzie A, Wong T, West J, Hunt TK. Incisional wound healing: a controlled study of low and high dose ultrasound. J Orthop Sports Phys Ther 1993;18:619-28. 28. Rudolph R. Complications of surgery for radiotherapy skin damage. Plast Reconstr Surg 1982;70:179-83. 29. Gorodetsky R, McBride WH, Withers HR. Assay of radiation effects in mouse skin as expressed in wound healing. Radiat Res 1988;116:135-44. 30. Bernstein EF, Harisiadis L, Salomon GD, Harrington F, Mitchell JB, Uitto J, et al. Healing impairment of open wounds by skin irradiation. J Dermatol Surg Oncol 1994;20:757-60. 31. Lowe AS, Walker MD, OByrne M, Baxter GD, Hirst DG. Effect of low intensity monochromatic light therapy (890nm) upon a radiation-impaired, wound-healing model in murine skin. Lasers Surg Med 1998;23:291-8.

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40. Marx RE, Ehler WJ, Tayapongsak P, Pierce LW. Relationship of oxygen dose to angiogenesis induction in irradiated tissue. Am J Surg 1990;160:519-24. 41. Franklin A, Coultas P. Some effects of radiation on the healing of transected mouse ear. Radiat Res 1984;100:55-64. 42. Shamberger RC, Talbot TL, Tipton HW, Thibault LE, Brennan MF. The effect of ultrasound and thermal treatment on wounds. Plast Reconstr Surg 1981;68:860-70. 43. Dyson M. Mechanisms involved in therapeutic ultrasound. Physiotherapy 1987;73:116-9. 44. Basford JR. Low-energy laser therapy: controversies and new research ndings. Lasers Surg Med 1989;9:1-5. Suppliers a. Siemens AG, Medical Group, Henkestr 127, 91052 Erlagen, Germany. b. Abbott Laboratories Ltd, Norden Rd, Maidenhead, Beckshire SL6 4XE, UK. c. Enraf-Nonius BV, Rontgenweg 1, PO Box 810, 2600 AV Delft, The Netherlands. d. Pharmaceutical Innovations Inc, 897 Frelinghuysen Ave, Newark, NJ 07114-2195. e. Fenestr, version 2.1, Kinetic Imaging Ltd, 2 Brunel Rd, Croft Business Park, Bromborough, Wirral, Merseyside, CH62 3NY, UK.

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