Ultrasound Therapy for Wound Healing

Number: 0746


Aetna considers ultrasound therapy (including high-frequency ultrasound, non-contact low-frequency ultrasound devices) for wound healing and reduction of chronic wound pain experimental and investigational because its effectiveness for these indications has not been established. 

Note: Examples of ultrasound therapy are the Focused Aspiration of Soft Tissue "FAST" procedure, the MIST Therapy System, the Qoustic Wound Therapy System, and the Sonoca 180/185 Wound Care System.

See also CPB 0372 - Noncontact Normothermic/Nonthermal Wound Therapy.


Chronic wounds (e.g., diabetic ulcers, pressure ulcers, and venous ulcers) are common in both acute as well as community healthcare settings.  The management of these chronic wounds entail many approaches.  Cushions, mattresses, and pressure-relieving supporting surfaces/beds are often used as measures for the prevention and treatment of pressure sores; compression therapy in a variety of forms is frequently employed for venous leg ulcer prevention and treatment; and a wide range of therapies including ultrasound is also used in managing chronic wounds.  In August 2004, the MIST Therapy System 5.0 (Celleration, Inc., Eden Prairie, MN), a low-frequency, non-contact ultrasound device, was cleared for marketing by the United States Food and Drug Administration.  It is indicated for wound cleaning and maintenance debridement of wounds containing yellow slough, fibrin, tissue exudate, or bacteria.

Although therapeutic ultrasound has been used clinically to enhance healing of chronic wounds, no consensus exists regarding its effectiveness.

In a placebo-controlled, single-blinded, clinical study, Peschen and associates (1997) examined the effect of low-frequency (30 kHz) low-dose ultrasound in the treatment of chronic venous leg ulcers, when added to conventional therapy of outpatients.  Patients (n = 24) were randomized to conventional therapy with topical application of hydrocolloid dressings and compression therapy or conventional therapy with additional ultrasound treatment for 12 weeks.  The ultrasound treatment consisted of 10-min of foot-bathing, with application of continuous ultrasound 100 mW/cm2 thrice-weekly.  The ulcer area was measured by planimetry, using a millimeter grid before treatment and after 2, 4, 6, 8, 10 and 12 weeks of therapy.  The ulcer radius and the daily ulcer radius reduction were calculated.  Color photographs of the ulcers were taken under standard conditions at the same time.  After each treatment, local findings and side effects were recorded.  After 12 weeks of treatment the control group showed a mean decrease of 16.5 % in the ulcerated area.  In contrast, the mean ulcerated area decreased by 55.4 % in the ultrasound group (p < 0.007).  The daily ulcer reduction in the ultrasound-treated patients was 0.08 mm +/- 0.04 mm and in the placebo patients 0.03 mm +/- 0.03 mm.  Patients recorded only minor side effects (e.g., a tingling feeling and occasionally pinhead-sized bleeding in the ulcer area).  The authors concluded that the application of low-frequency and low-dose ultrasound is a helpful treatment option in chronic venous leg ulcers, especially if they do not respond to conventional ulcer treatment.

In a randomized, double-blinded, controlled, multi-center study, Ennis and colleagues (2005) examined the safety and effectiveness of MIST ultrasound therapy for the healing of recalcitrant diabetic foot ulcers.  Patients (n = 55) received standard of care, which included products that provide a moist environment, off-loading diabetic shoes and socks, debridement, as well as wound evaluation and measurement.  The "therapy" was either active 40 kHz ultrasound delivered by a saline mist or a "sham device" that delivered a saline mist without the use of ultrasound.  After 12 weeks of care, the proportion of wounds healed (defined as complete epithelialization without drainage) in the active ultrasound therapy device group was significantly higher than that in the sham control group (40.7 % versus 14.3 %, p = 0.0366, Fisher's exact test).  The ultrasound treatment was easy to use and no difference in the number and type of adverse events between the two treatment groups was noted.  The authors concluded that compared to control, MIST ultrasound therapy was found to increase the healing rate of recalcitrant, diabetic foot ulcers.  They noted that the findings of this study suggest the need for further research, including assessing the impact of quantitative biopsy results at enrollment, debridement depth and impact on healing, as well as the potential anti-microbial action of MIST ultrasound therapy.

In a non-comparative study, Ennis et al (2006) ascertained the incidence of wound closure for chronic non-healing lower extremity wounds of various etiologies using MIST ultrasound therapy.  These investigators also determined the optimal treatment duration with this device, quantified end points that correlated with a maximal clinical response and identified potential synergistic therapies that could be used in conjunction with this therapy.  Furthermore, they analyzed the impact of MIST ultrasound therapy on the microcirculatory flow patterns within the wound bed.  A total of 23 patients were included in this study.  Control data were obtained from a previously published, prospectively collected database.  During an 8-month period, a total of 29 lower extremity wounds in the 23 subjects who met criteria for inclusion were treated with MIST ultrasound therapy.  Standard of care was provided for 2 weeks for all wounds screened for the study.  A failure to achieve an area reduction greater than 15 % qualified the patient for enrollment to the trial and the addition of MIST ultrasound therapy to the current treatment regimen.  Main outcome measures were wound healing, area and volume reduction, and laser Doppler-derived mean voltage (a marker for microcirculatory flow).  Overall, 69 % of the wounds in the study were healed using an intent-to-treat model.  When MIST ultrasound was used as a stand-alone therapy, median time to healing was 7 weeks.  Historic controls were healed with a median time to healing of 10 weeks; however, a statistically significant number of these patients required wound-related hospitalization and surgical procedures to achieve closure compared with the wounds in the present study.  The authors concluded that treatment with MIST ultrasound achieved healing in chronic wounds when used as a stand-alone therapy or in combination with moist wound care in 69 % of cases.  Response to low-frequency, non-contact ultrasound was evident within 4 weeks of therapy.  Earlier transition to secondary procedures and decreased utilization of inpatient care might result in more cost-effective wound healing than the current standard of care.  These researchers noted that a well-designed health economic-based clinical trial is needed to evaluate this technology.

In a prospective, randomized, controlled study, Kavros and co-workers (2007) assessed the clinical role of MIST ultrasound therapy in the treatment of non-healing leg and foot ulcers associated with chronic critical limb ischemia.  Subjects included 35 patients who received MIST ultrasound therapy plus the standard of wound care (treatment group) and 35 patients who received the standard of wound care alone (control group).  Standard of wound care alone or standard of wound care plus MIST ultrasound therapy were provided for 12 weeks or until wounds were fully healed.  MIST ultrasound therapy was administered thrice-weekly for 5 minutes per treatment.  Main outcome measure was percentage of patients with greater than 50 % reduction in wound size from the index measurement after 12 weeks of treatment.  The relationship of transcutaneous oximetry pressure in the supine and dependent position was evaluated as a factor in assessing the potential to heal ischemic ulcerations of the foot and leg.  A significantly higher percentage of patients treated with the standard of care plus MIST ultrasound therapy achieved greater than 50 % wound healing at 12 weeks than those treated with the standard of care alone (63 % versus 29 %; p < 0.001).  Thus, failure to achieve the minimum wound healing requirement occurred in 37 % of patients in the treatment group and 71 % of patients in the control group.  The predictive value of baseline transcutaneous oxygen pressure may benefit the clinician when assessing the potential to heal ischemic wounds.  The authors concluded that the rate of healing of cutaneous foot and leg ulcerations in patients with chronic critical limb ischemia improved significantly when MIST ultrasound therapy was combined with the standard of wound care.  It should be noted that although the study reported on the importance of baseline transcutaneous oxygen pressure on wound healing, patients with low (1 to 20 mm Hg) and high (21 to 40 mm Hg) transcutaneous oxygen pressure levels do not appear to be equally distributed between the groups. 

Gehling and Samies (2007) noted that pain associated with chronic wounds and related wound care modalities presents a persistent clinical challenge in patient care, yet evidence supporting the effects of interventions on wound pain remains sparse.  In response to initial clinical observations that several patients with painful chronic lower-extremity wounds reported a reduction in wound pain shortly after ultrasound therapy was initiated, a retrospective chart review and analysis of reported pain scores was conducted.  The records of 15 consecutive patients (7 men and 8 women, age range of 28 to 88 years) with painful, non-healing, lower-extremity wounds treated for 2 to 4 weeks with MIST ultrasound therapy were reviewed and recorded pain scores abstracted.  Mean pain scores decreased from 8.07 (+/- 1.91) pre-treatment to 1.67 (+/- 1.76) post-treatment (p = 0.0003).  No patients reported worsening pain after treatment commenced.  The authors concluded that this preliminary evidence suggests that prospective, controlled clinical studies to evaluate the effect of this treatment on wound-related pain are warranted.

In an open-label, non-randomized, baseline-controlled clinical case series, Kavros and Schenck (2007) conducted a feasibility study to characterize the effects of non-contact low-frequency ultrasound therapy for chronic, recalcitrant lower-leg and foot ulcerations.  Patients were initially treated with the Mayo Clinic standard of care before the addition of or the switch to non-contact low-frequency ultrasound therapy.  These researchers analyzed the medical records of 51 patients (median +/- SD age, 72 +/- 15 years) with one or more of the following conditions: diabetes mellitus, neuropathy, limb ischemia, chronic renal insufficiency, venous disease, and inflammatory connective tissue disease.  All patients had lower-extremity ulcers, 20 % had a history of amputation, and 65 % had diabetes.  Of all the wounds, 63 % had a multi-factorial etiology, and 65 % had associated transcutaneous oximetry levels below 30 mm Hg.  The mean +/- SD treatment time of wounds during the baseline standard of care control period versus the non-contact low-frequency ultrasound therapy period was 9.8 +/- 5.5 weeks versus 5.5 +/- 2.8 weeks (p < 0.0001).  Initial and end measurements were recorded, and percent volume reduction of the wound was calculated.  The mean +/- SD percent volume reduction in the baseline standard of care control period versus the non-contact low-frequency ultrasound therapy period was 37.3 % +/- 18.6 % versus 94.9 % +/- 9.8 % (p < 0.0001).  The authors concluded that the use of non-contact low-frequency ultrasound improved the rate of healing and closure in recalcitrant lower-extremity ulcerations.  They also stated that further clinical and basic science investigations using this technology are warranted.

As stated earlier, there is no consensus regarding the effectiveness of ultrasound therapy in the management of chronic wounds.  There exists randomized, controlled studies, meta-analysis, as well as clinical practice guidelines that question the value of this approach.

In a randomized, controlled trial, Lundeberg et al (1990) studied the effects of pulsed ultrasound in conjunction with a standard treatment for healing chronic leg ulcers on 44 patients.  All patients received standard treatment (paste impregnated bandage and a self-adhesive elastic bandage) plus placebo-ultrasound or pulsed ultrasound (1:9, 0.5 Watt/cm2 at 1 mHz, for 10 min) thrice-weekly for 4 weeks, thereafter twice-weekly for 4 weeks and once-weekly for the following 4 weeks.  Percentage healed ulcer area and comparison of percentage healed ulcers were examined after 4, 8 and 12 weeks.  There were no significant differences in the proportion of healed ulcers or ulcer area in the pulsed ultrasound group as compared with the placebo group.

In another randomized, controlled study, Eriksson et al (1991) examined the effects of ultrasound in conjunction with standard treatment on healing chronic leg ulcers.  A total of 38 patients were divided into two groups.  All patients received standard treatment (paste impregnated bandage and a self-adhesive elastic bandage plus placebo ultrasound or ultrasound (1.0 Watt/cm2 at 1 mHz, for 10 mins) twice-weekly for 8 weeks.  Percentage healed ulcer area and number of healed ulcers were compared after 2, 4, 6 and 8 weeks.  There were no significant differences in the proportion of healed ulcers or ulcer area in the ultrasound group as compared with the placebo group.

In a meta-analysis on ultrasound therapy in the treatment of chronic leg ulceration, Johannsen et al (1998) concluded that available evidence would suggest that ultrasound has the best effect when delivered in low doses around the edge of the ulcer, but further studies are needed to confirm this possible effect and to assess a possible dose-response relationship.

In a Health Technology Assessment on wound care management, Cullum et al (2001) concluded that there is generally insufficient reliable evidence to draw conclusions regarding the contribution of laser therapy, therapeutic ultrasound, electrotherapy and electromagnetic therapy to chronic wound healing.

In a Cochrane review on therapeutic ultrasound for pressure ulcers, Baba-Akbari Sari and colleagues (2006) concluded that there is no evidence of benefit of ultrasound therapy in the treatment of pressure ulcers.  However, the possibility of beneficial or harmful effect cannot be ruled out due to the small number of trials, some with methodological limitations and small numbers of participants.  The authors noted that further research is needed.

Systematic evidence reviews of therapeutic ultrasound in BMJ Clinical Evidence have concluded that therapeutic ultrasound of pressure ulcers and venous leg ulcers are of "unknown effectiveness" (Nelson and Jones, 2007; Cullum and Petherick, 2007).

The American College of Foot and Ankle Surgeons' clinical practice guideline on diabetic foot disorders (Frykberg et al, 2006) noted that low-intensity pulsed ultrasound has been suggested as a useful adjunct in promoting healing of Charcot fractures.  Although promising in theory, this approach has yet been conclusively proven effective through large, prospective, multi-center, randomized trials.  Additionally, the American Society of Plastic Surgeons' evidence-based clinical practice guideline on chronic wounds of the lower extremity (2007) did not mention the use of ultrasound therapy as an option of treatment.

In a retrospective analysis, Kavros and colleagues (2008) assessed the clinical role of non-contact, low-frequency MIST ultrasound therapy in the treatment of chronic lower-extremity wounds.  A total of 163 patients who received MIST therapy plus standard of care (treatment group) and 47 patients who received the standard of care alone (control group) were examined.  All wounds in the control and treatment groups received the standard of wound care and were followed for 6 months.  In the treatment group, MIST therapy was administered to wounds 3 times per week for 90 days or until healed.  Main outcome measures included proportion of wounds healed and wound volume reduction.  Rate of healing was also quantified using 1-way analysis of variance to determine the slope of the regression line from starting volume to ending volume, where a steeper slope indicates a faster healing rate.  Outcomes were evaluated in all wounds and etiology-specific subgroups.  A significantly greater percentage of wounds treated with MIST therapy and standard of care healed as compared with those treated with the standard of care alone (53 % versus 32 %; p = 0.009).  The slope of the regression line in the MIST arm (1.4) was steeper than the slope in the control arm (0.22; p = 0.002), indicating a faster rate of healing in the MIST-treated wounds.  The authors concluded that the rate of healing and complete closure of chronic wounds in patients improved significantly when MIST therapy was combined with standard wound care.  They stated that the addition of MIST therapy to standard wound care appears to expedite healing of chronic wounds in the lower extremities; and further research on the healing impact of MIST therapy in specific wound type will provide additional clinical insight into the use of this non-contact, low-frequency ultrasound therapy.

There are also case studies as well as case-series studies on the use non-contact, low-frequency ultrasound in the management of various types of chronic wounds such as burns, digital ulcers, infected surgical wounds, and sacral pressure ulcers (Serena, 2008; Samies and Gehling, 2008; Fleming, 2008; Waldrop and Serfass, 2008; Liguori et al, 2008; Schmuckler, 2008; Howell-Taylor et al, 2008).  Moreover, the majority of the authors concluded that additional studies (large, prospective, randomized trials) are needed to elucidate the role of non-contact, low-frequency ultrasound in the management of chronic wounds.

In a systematic review of the effectiveness of interventions to enhance the healing of chronic ulcers of the foot in diabetes, Hinchliffe and associates (2008) identified interventions for which there is evidence of effectiveness.  A search was made for reports of the effectiveness of interventions assessed in terms of healing, ulcer area or amputation in controlled clinical studies published prior to December 2006.  Methodological quality of selected studies was independently assessed by 2 reviewers using Scottish Intercollegiate Guidelines Network (SIGN) criteria.  Selected studies fell into the following categories: sharp debridement and larvae; antiseptics and dressings; chronic wound resection; hyperbaric oxygen therapy (HBOT); reduction of tissue edema; skin grafts; electrical and magnetic stimulation and ultrasound.  Heterogeneity of studies prevented pooled analysis of results.  Of the 2,251 papers identified, 60 were selected for grading following full text review.  Some evidence was found to support hydrogels as desloughing agents and to suggest that a systemic HBOT may be effective.  Topical negative pressure may promote healing of post-operative wounds, and resection of neuropathic plantar ulcers may be beneficial.  These researchers stated that more information was needed to confirm the effectiveness and cost-effectiveness of these and other interventions.  No data were found to justify the use of any other topically applied product or dressing, including those with antiseptic properties.  They noted that further evidence to substantiate the effect of interventions designed to enhance the healing of chronic ulcers is urgently needed.  Until such evidence is available from robust trials, there is limited justification for the use of more expensive treatments and dressings.

In a systematic review on treatment of pressure ulcers, Reddy et al (2008) concluded that there is little evidence to support routine nutritional supplementation or adjunctive therapies including ultrasound compared with standard care.  The review of randomized controlled clinical trials found no clear evidence for the effectivness of ultrasound in healing of pressure ulcers.

Busse et al (2009) determined the effectiveness of low-intensity pulsed ultrasonography (LIPUS) for healing of fractures.  Electronic literature search without language restrictions of CINAHL, Embase, Medline, HealthSTAR, and the Cochrane Central Registry of Controlled Trials, from inception of the database to 10 September 2008 was carried out.  Eligible studies were randomized controlled trials (RCTs) that enrolled patients with any kind of fracture and randomly assigned them to low intensity pulsed ultrasonography or to a control group.  Two reviewers independently agreed on eligibility; 3 reviewers independently assessed methodological quality and extracted outcome data.  All outcomes were included and meta-analyses done when possible.  A total of 13 RCTs, of which 5 assessed outcomes of importance to patients, were included.  Moderate quality evidence from 1 trial found no effect of LIPUS on functional recovery from conservatively managed fresh clavicle fractures; whereas low quality evidence from 3 trials suggested benefit in non-operatively managed fresh fractures (faster radiographic healing time mean 36.9 %, 95 % confidence interval [CI]: 25.6 % to 46.0 %).  A single trial provided moderate quality evidence suggesting no effect of LIPUS on return to function among non-operatively treated stress fractures.  Three trials provided very low quality evidence for accelerated functional improvement after distraction osteogenesis.  One trial provided low quality evidence for a benefit of LIPUS in accelerating healing of established non-unions managed with bone graft.  Four trials provided low quality evidence for acceleration of healing of operatively managed fresh fractures.  The authors concluded that evidence for the effect of LIPUS on healing of fractures is moderate to very low in quality and provides conflicting results.  Although overall results are promising, establishing the role of LIPUS in the management of fractures requires large, blinded trials, directly addressing patient important outcomes such as return to function.

An assessment by the Ontario Ministry of Health and Long Term Care, Medical Advisory Secretariat (MAS, 2009) concluded that the efficacy of ultrasound in improving complete closure of pressure ulcers has not been established.  The review stated that there is no evidence of a benefit of using ultrasound therapy in the treatment of pressure ulcers and the possibility of a beneficial or harmful effect cannot be ruled out due to the very small number of trials.

In a Cochrane review, Cullum et al (2010) examined if ultrasound increases the healing of venous leg ulcers.  These investigators searched the Cochrane Wounds Group Specialised Register (searched 24 February 2010); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2010); Ovid MEDLINE (1950 to February Week 2 2010); In-Process & Other Non-Indexed Citations (searched 24 February 2010); Ovid EMBASE 1980 to 2010 Week 07; EBSCO CINAHL 1982 to 24 February 2010.  Randomized controlled trials comparing ultrasound with no ultrasound were selected.  Two authors independently assessed the search results and selected eligible studies.  Details from included studies were summarized using a data extraction sheet, and double-checked.  They tried to contact trial authors for missing data.  A total of 8 trials were included; all had unclear, or high risks of bias, with differences in duration of follow-up, and ultrasound regimens.  Six trials evaluated high-frequency ultrasound and 5 of these reported healing at 7 to 8 weeks.  Significantly more patients healed with ultrasound than without it at 7 to 8 weeks (pooled risk ratio [RR] 1.4, 95 % CI: 1.0 to 1.96), but later assessments at 12 weeks showed the increased risk of healing with ultrasound was no longer statistically significant (pooled RR 1.47, 95 % CI: 0.99 to 2.20).  One poor-quality study of high-frequency ultrasound found no evidence of an effect on healing after 3 weeks' of treatment.  Two trials evaluated low-frequency ultrasound and reported healing at different time points.  Both trials reported no evidence of a difference in the proportion of ulcers healed with ultrasound compared with no ultrasound: both were significantly under-powered.  The authors concluded that trials evaluating ultrasound for venous leg ulcers are small, poor-quality and heterogeneous.  There is no reliable evidence that ultrasound hastens healing of venous ulcers.  There is a small amount of weak evidence of increased healing with ultrasound, but this requires confirmation in larger, high-quality RCTs.  There is no evidence of a benefit associated with low-frequency ultrasound.

An assessment of the MIST therapy system for the promotion of wound healing in chronic and acute wounds prepared for the National Institute for Clinical Excellence (NICE) (Batki et al, 2010) found "the manufacturer, Celleration, has on file over 200 publications on the MIST Therapy, which includes 104 unpublished single case studies held on Celleration patient registry and eight published case series in magazine "Thoughts on Therapy" funded by Celleration.  The remainder of the publications consist of case series, posters and abstracts, and educational assessment of clinical uses on various wound etiology which the NICE assessment found to be not large enough to provide statistical outcome data".   The assessment prepared for NICE found that a meta-analysis submitted by Celleration acknowledges limitations of the data, and noted that the Celleration meta-analysis stated that “first, all studies were either prospective or retrospective observational studies and are subject to the limitations inherent with non-randomised designs”.  The NICE assessment stated, "however, the analysis is largely based on changes within patients, rather than comparison between groups, and is therefore of very little value".  The assessment also found: "the main limitation is that there are only two small RCTs comparing MIST Therapy with no MIST Therapy.  Moreover, duration of follow-up is generally inadequate with few reports on outcome beyond 9 weeks post treatment.  Less serious issues consist of the limited range of ulcer types in the studies and failure to consider other promising new treatments apart from MIST .... ".

The final NICE's report on MIST therapy (2011) noted that the committee considered that the MIST Therapy system showed promise in the treatment of chronic wounds and its use was supported by expert opinion.  The potential cost savings claimed for its use depend primarily on evidence of comparative effectiveness.  The low-quality of that evidence and consequent uncertainty about its relative effectiveness in healing wounds compared with standard care alone meant that the case for routine adoption in the NHS could not be supported at the time of writing.

Gottrup and Apelqvist (2012) stated that management of foot ulcer in individuals with diabetes remains a major therapeutic challenge throughout the world.  These investigators performed a critical review of evidence of present and new techniques and devices in the treatment of diabetic foot ulcer.  The golden standard for optimal evidence in the Cochrane system is level I -- RCTs, and meta-analyses of several RCTs.  Available evidence on different types of wound debridement; use of anti-microbials; use of dressings in wounds; topical negative pressure; hyperbaric oxygen treatment; electrical, electromagnetic, laser, shockwave, and ultrasound therapies; growth and cell biology factors; cell products and tissue engineering; bioengineered skin and skin grafts; and adjuvant therapies were evaluated.  The results of this review showed that there is limited evidence on the highest level to justify a change in routine clinical practice.  There is a paucity of high-quality evidence, because the studies were often based on inadequate sample size, short follow-up, non-random allocation to treatment arms, non-blinded assessment of outcomes, poor description of control, and concurrent intervention.  The heterogeneity of the population (of both people and ulcers), with multiple factors contributing to both ulcer onset and failure to heal, makes the trial design difficult in this field.  Another fundamental reason for the lack of evidence is the general use of the outcome measure “complete healing”.  The authors concluded that when the results of this updated review were taken together with those of the earlier reports, they provided limited evidence to justify a change in routine clinical practice.  For this reason, there is an urgent need to increase the quality of clinical studies.  A re-evaluation of which type of research is acceptable for producing evidence in the wound area may be important in the future.

Game et al (2012) noted that the outcome of management of diabetic foot ulcers is poor, and there is continuing uncertainty concerning optimal approaches to management.  It was for these reasons that in 2006 the International Working Group of the Diabetic Foot (IWGDF) working group on wound healing undertook a systematic review of the evidence to inform protocols for routine care and to highlight areas which should be considered for further study.  The same working group has now updated this review by considering papers on the interventions to improve the healing of chronic ulcers published between December 2006 and June 2010.  Methodological quality of selected studies was independently assessed by 2 reviewers using Scottish Intercollegiate Guidelines Network criteria.  Selected studies fell into the following 10 categories: (i) sharp debridement and wound bed preparation with larvae and hydrotherapy; (ii) wound bed preparation using antiseptics, applications and dressing products; (iii) resection of the chronic wound; (iv) HBOT; (v) compression or negative pressure therapy; (vi) products designed to correct aspects of wound biochemistry and cell biology associated with impaired wound healing; (vii) application of cells, including platelets and stem cells; (viii) bioengineered skin and skin grafts; (ix) electrical, electromagnetic, lasers, shockwaves and ultrasound; and (x) other systemic therapies that did not fit in the above categories.  Heterogeneity of studies prevented pooled analysis of results.  Of the 1,322 papers identified, 43 were selected for grading following full text review.  The present report was an update of the earlier IWGDF systematic review, but the conclusion was similar: that with the exception of HBOT and, possibly, negative pressure wound therapy, there is little published evidence to justify the use of newer therapies.  This echoed the conclusion of a recent Cochrane review and the systematic review undertaken by the NICE Guidelines Committee in the United Kingdom.  Analysis of evidence presented considerable difficulties in this field particularly as controlled studies are few and the majority are of poor methodological quality.

Madhok et al (2013) stated that debridement is a crucial component of wound management.  Traditionally, several types of wound debridement techniques have been used in clinical practice such as autolytic, enzymatic, bio-debridement, mechanical, conservative sharp and surgical.  Various factors determine the method of choice for debridement for a particular wound such as suitability to the patient, the type of wound, its anatomical location and the extent of debridement required.  Recently developed products are beginning to challenge traditional techniques that are currently used in wound bed preparation.  These investigators evaluated the current evidence behind the use of these newer techniques in clinical practice.  The authors stated that there is some evidence to suggest that low frequency US therapy may improve healing rates in patients with venous ulcers and diabetic foot ulcers.

Kwan et al (2013) systematically assessed published reports on the effectiveness of electro-physical therapy in the treatment of diabetic foot ulcers, including electrical stimulation (ESTIM), low-level laser therapy, therapeutic US and electromagnetic therapy.  Databases searched included MEDLINE, CINAHL, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) from 1966 to 2011.  Studies reviewed included only RCTs on treatment with electro-physical modalities compared with sham, conventional treatment or other electro-physical modalities.  Information extracted were objective measures of healing and data useful for the calculation of effect size.  A total of 8 RCTs were eventually included in the critical appraisal, with a combined total of 325 participants; 5 studies were conducted on ESTIM, 2 on phototherapy and 1 on US.  All studies reported that the experimental group was significantly more favorable than the control or sham group.  The pooled estimate of the number of healed ulcers of the 3 studies on ESTIM compared to the control or sham-ESTIM showed statistical significance [mean difference of 2.8 (95 % CI: 1.5 to 5.5, p = 0.002] in favor of ESTIM.  The authors concluded that the results indicated potential benefit of using electro-physical therapy for managing diabetic foot ulcers.  However, they stated that due to the small number of trials conducted, the possibility of any harmful effects cannot be ruled out, and high-quality trials with larger sample sizes are needed.

Ebrahim et al (2014) performed a network meta-analysis to indirectly compare LIPUS with ESTIM for fracture healing.  These investigators searched the reference lists of recent reviews evaluating LIPUS and ESTIM that included studies published up to 2011 from 4 electronic databases.  They updated the searches of all electronic databases up to April 2012.  Eligible trials were those that included patients with a fresh fracture or an existing delayed union or nonunion who were randomized to LIPUS or ESTIM as well as a control group.  Two pairs of reviewers, independently and in duplicate, screened titles and abstracts, reviewed the full text of potentially eligible articles, extracted data and assessed study quality.  These researchers used standard and network meta-analytic techniques to synthesize the data.  Of the 27 eligible trials, 15 provided data for the analyses.  In patients with a fresh fracture, there was a suggested benefit of LIPUS at 6 months (RR 1.17, 95 % CI: 0.97 to 1.41).  In patients with an existing nonunion or delayed union, ESTIM had a suggested benefit over standard care on union rates at 3 months (RR 2.05, 95 % CI: 0.99 to 4.24).  These investigators found very low-quality evidence suggesting a potential benefit of LIPUS versus ESTIM in improving union rates at 6 months (RR 0.76, 95 % CI: 0.58 to 1.01) in fresh fracture populations.  The authors concluded that to support these findings, direct comparative trials with safeguards against bias assessing outcomes important to patients, such as functional recovery, are needed.

In a meta-analysis, Driver et al (2011) summarized the effects of a noncontact low-frequency ultrasound (NLFU) therapy on healing of chronic wounds. These investigators performed a meta-analysis of 8 published studies reporting effects of NLFU on wound size and healing rate of chronic wounds in 444 NLFU-treated patients. A search of the PubMed database was conducted in January 2010 and updated in October 2010. They used random-effects linear regression models to estimate the proportional reductions in wound area and volume and the proportion of wounds healed from baseline to last follow-up. In 4 studies (n = 188) reporting change in wound area from baseline, NLFU was associated with 85.2 % area reduction (95 % confidence interval [CI]: 64.7 % to 97.6 %) over a mean 7 weeks. In 4 studies (n = 278) reporting reduction in wound volume, NLFU was associated with 79.7 % volume reduction (95 % CI: 46.1 % to 98.8 %) over a mean 12 weeks. In 7 studies (n = 429) reporting proportion of wounds healing by study end (mean time to healing 8.2 weeks; median of 6.8 weeks), meta-analyzed healing rates over time suggested 32.7 % of wounds healed on average by 6 weeks (95 % CI: 23.3 % to 42.1 %) and 41.7 % by 12 weeks. The authors concluded that NLFU for treatment of chronic wounds was associated with consistent and substantial wound size reductions, as well as favorable rates of healing. Moreover, they stated that future research on this noncontact, low-frequency ultrasound therapy should focus on larger, randomized clinical trials.

In a randomized, controlled study, Olyaie et al (2013) compared the effectiveness of standard treatment and standard treatment plus either high-frequency ultrasound (HFU) or noncontact low-frequency ultrasound (NCLFU) on VLU outcomes. A total of 90 outpatients (47 men, 43 women, average age of 38.3 [SD 11.5] years) were randomized into the standard care (n = 30), HFU (n = 30), or NCLFU group (n = 30). Standard care included multi-layered compression bandaging (40 mm Hg of pressure at the ankle graduated to 17 mm Hg to 20 mm Hg below the knee), non-adherent dressing, and regular debridement. Standard care dressing changes and ultrasound therapy were provided 3 times per week for 3 months or until healed. HFU delivers high-intensity (0.5 to 1 W/cm2), high-frequency (1 to 3 MHz) ultrasound for 5 to 10 minutes; and NCLFU delivers low-intensity (0.1 to 0.8 W/cm2); low-frequency (40 kHz) ultrasound for 4 to 10 minutes. After 3 months, patients continued to be followed until healed. Wound size, wound pain, and lower leg edema were assessed at baseline and after 2 and 4 months. Data were analyzed using Student's t-test, ANOVA, chi-square, or Fisher's exact test; p < 0.05 was considered significant. Initial wound measurements were 9.60 cm2 (SD 5.54), 9.86 cm2 (SD 3.95), and 10.01 cm2 (SD 4.58) for the standard treatment, HFU, and NCLFU groups, respectively; after 4 months, measurements were 4.28 cm2 (SD 2.80), 3.23 cm2 (SD 2.39), and 2.72 cm2 (SD 2.16), a statically significant difference (p = 0.04). All wounds were healed after an average of 8.50 (SD 2.17), 6.86 (SD 2.04), and 6.65 (SD 1.59) months in the standard treatment, HFU, and NCLFU groups, respectively (p = 0.001). Differences in the amount of edema and pain rating scores were also significant at the 4-month, follow-up visit (p <0.05). Outcomes of both methods of ultrasound therapy were better than standard care alone, and some differences between the 2 ultrasound therapy groups were observed, but they were not statistically significant. The main drawback of this study was its small sample size.   Furthermore, the authors stated that wound surface in this study was measured by tracing the margins of the open wound and measuring the 2 maximum perpendicular axes. Although this method is scientifically valid and reliable, use of more precise imaging and histopathological assessment methods may have enhanced study accuracy.

Beheshti et al (2014) analyzed the effect of standard ulcer care alone with HFU and MIST ultrasound therapy on VLUs. A total of 90 patients with VLUs were assigned into the standard care (SC), HFU and MIST ultrasound groups. All groups received the standard wound care. In the ultrasound groups, HFU and MIST ultrasound therapy was administered to wounds 3 times per week until the wound healed. Time of complete wound healing was recorded. Wound size, pain, and edema were assessed at baseline and after 2 and 4 months. Also, patients were instructed to contact our clinic monthly, and recurrence of VLUs was recorded for 6 months after complete wound healing. The data were analyzed using a Student's t-test, ANOVA, c2, or Fisher's exact test; p < 0.05 was considered significant. Mean time duration of complete wound healing in the first, second and third groups was 8.13 (SD 1.40), 6.10 (SD 1.47) and 5.70 (SD 1.57) months, respectively (p < 0.0001). Size of ulcer, mean degree of pain and edema in ultrasound therapy was decreased after the 4-month visit in comparison to the standard-treatment group (p = 0.01, p < 0.0001 and p < 0.0001, respectively). Also, these results did not show any significant differences between groups in the recurrence of VLUs during a 6-month follow up after complete wound healing (p = 0.37). The authors concluded that the findings of this study showed the significant effectiveness of ultrasound therapy in wound healing. Differences between the 2 ultrasound therapy groups were not statistically significant. These researchers believed that the 6-month follow-up was very short to truly decide about the potential of prevention of recurrence in patients treated with ultrasound therapy. They stated that according to the very limited effects identified in individuals in the MIST therapy group, which showed earlier response to therapy based on wound area and volume reductions, it could give us a cost savings through a prominent reduction in therapeutic times. They noted that additional work on cost-effective outcomes and planning are greatly needed for the future.

In a pilot study, Yao et al (2014) evaluated the relationship between dose and duration of treatment for subjects with non-healing diabetic foot ulcers (DFUs) and explored the correlation between wound healing and change of cytokine/proteinase/growth factor profile. This was a prospective randomized clinical study designed to evaluate subjects with non-healing DFUs for 5 weeks receiving standard of care and/or NCLF-US treatment. Subjects were randomly assigned to 1 of the 3 groups: (i) application of NCLF-US thrice per week (Group 1), (ii) NCLF-US once per week (Group 2) and (iii) the control (Group 3) that received no NCLF-US. All subjects received standard wound care plus offloading for a total of 4 weeks. Percent area reduction (PAR) of each wound compared with baseline was evaluated weekly. Profiles of cytokines/proteinase/growth factors in wound fluid and biopsied tissue were quantified to explore the correlation between wound healing and cytokines/growth factor expression. A total of 12 DFU patients, 2 (16.7 %) type 1 and 10 (83.3 %) type 2 diabetics, with an average age of 58 ± 10 years and a total of 12 foot ulcers were enrolled. Average ulcer duration was 36.44 ± 24.78 weeks and the average ABI was 0.91 ± 0.06. Group 1 showed significant wound area reduction at weeks 3, 4 and 5 compared with baseline, with the greatest PAR, 86 % (p < 0.05); Groups 2 and 3 showed 25 % PAR and 39 % PAR, respectively, but there were no statistically significant differences between Groups 2 and 3 over time. Biochemical and histological analyses indicated a trend towards reduction of pro-inflammatory cytokines (IL-6, IL-8, IL-1β, TNF-α and GM-CSF), matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF) and macrophages in response to NCLF-US consistent with wound reduction, when compared with control group subjects. The authors concluded that this proof-of-concept pilot study demonstrated that NCLF-US is effective in treating neuropathic diabetic foot ulcers through, at least in part, inhibiting pro-inflammatory cytokines in chronic wound and improving tissue regeneration. Therapeutic application of NFLU, 3 times per week, renders the best wound area reduction. Moreover, these researchers stated that “Further research is needed to demonstrate effects of NCLF-US treatment, especially in the area of combined effects of ultrasound therapy with skin grafts, skin substitutes or platelets gels with particular focus on the effects of NCLF-US on angiogenesis and bio-burden control”.

In a prospective, randomized, controlled, multi-center trial, Gibbons et al (2015) compared percent wound size reduction, proportions healed, pain, and quality-of-life (QOL) outcomes in patients randomized to standard care (SC) alone or SC and 40 kHz NLFU treatments 3 times per week for 4 weeks. A total of 112 eligible participants with documented venous stasis, a VLU greater than 30 days' duration, measuring 4 cm2 to 50 cm2, and demonstrated arterial flow were enrolled. Of these, 81 reduced less than 30 % in size during the 2-week run-in study phase and were randomized (SC, n = 40; NLFU+SC, n = 41). Median age of participants was 59 years; 83 % had multiple complex co-morbidities. Index ulcers were 56 % recurrent, with a median duration of 10.3 months (range of 1 month to 204.5 months) and median ulcer area of 11.0 cm2 (range of 3.7 cm2 to 41.3 cm2). All participants received protocol-defined SC compression (30 to 40 mm Hg), dressings to promote a moist wound environment, and sharp debridement at the bedside for a minimum of 1 time per week. Ulcer measurements were obtained weekly using digital planimetry. Pain and QOL scores were assessed at baseline and after 4 weeks of treatment using the visual analog scale and the Short Form-36 Health Survey. After 4 weeks of treatment, average wound size reduction was 61.6 % ± 28.9 in the NLFU+SC compared to 45 % ± 32.5 in the SC group (p = 0.02). Reductions in median (65.7 % versus 44.4 %, p = 0.02) and absolute wound area (9.0 cm2 versus 4.1 cm2, p = 0.003) as well as pain scores (from 3.0 to 0.6 versus 3.0 to 2.4, p = 0.01) were also significant. The authors concluded that NLFU therapy with guideline-defined standard VLU care should be considered for healing VLUs not responding to SC alone. They stated that the results of this study warrant further research on barriers to healing and the changes occurring in the tissue of the wound to explore theories that the microenvironment impacts wounds that do not heal despite provision of guideline-defined care. Also, limitations of this study included: (i) the investigators and participants were not blinded to treatment group assignment. This was limited to participant-reported measures such as QOL and VAS pain scores, and (ii) the treatment groups did not have the same required frequency of treatment visits.

In a prospective, randomized controlled trial, Prather et al (2015) compared the effects of 40-kHz NLFU in addition to SC with SC alone in subjects with split-thickness donor sites of 20 to 200 cm(2). Standard care consisted of cleansing and moist wound dressings. Outcomes measured were time to healing, defined as absence of drainage and full epithelialization; pain and itching scores; and recidivism rates. Of 33 patients enrolled; 27 were randomized and received a minimum of 4 study treatments. Median age was 49 years, 69 % were male, and 84 % were burn patients. Co-morbidities included hypertension (31 %), coronary artery disease (22 %), pulmonary disease (38 %), anemia (31 %), and diabetes (16 %). Median donor site area was 136.0 cm(2). Noncontact low-frequency ultrasound and SC compared with SC demonstrated a mean time to heal of 12.1 days versus 21.3 days (p = 0.04). All NLFU+SC subjects had epithelialized by 4 weeks compared with only 71 % in SC. Recidivism rates were 8 % for NLFU+SC compared with 45 % for SC. Pain scores were reduced and significant differences in itching were observed. The authors concluded that NLFU and SC compared with SC alone in the treatment of split-thickness donor sites demonstrated significant accelerated healing and reduced pain and itching; NLFU subjects experienced a better quality of healing with less incidence of infection and recidivism. The main drawbacks of this study were: (i) small sample size (n = 27), (ii) subjects were not “blinded”, (iii) the level of drainage was reported by the subject after discharge on non-clinic visit days, (iv) subjects were not evenly distributed among the institutions, and (v) the number of patients with a history of anxiety and depression in the SC group was much greater than in the group treated with NLFU. This could impact the results, particularly with respect to quality of life assessments, such as pain and itching. The authors stated that these results suggested that NLFU should be considered for treatment of acute surgical skin graft donor sites, particularly in subjects who are at higher risk for surgical site infections or delayed healing.

In a prospective RCT, Polak et al (2014) evaluated the effectiveness of high-frequency ultrasound (HFUS) in the treatment of Stage II and Stage III pressure ulcers in geriatric patients. Participants (age range of 71 to 95 years,) all with wounds that did not respond to previous treatment for at least 4 weeks, were randomly assigned to the treatment group (TG) (20 with 21 pressure ulcers, mean age of 83.60 ± 5.04 years) or control group (CG) (22 with 23 pressure ulcers, mean age of 82.59 ± 6.65 years). All patients received standard wound care (SWC); the TG additionally was provided HFUS (1 MHz, 0.5 W/cm2, duty cycle of 20 %, 1 to 3 minutes/cm2; 1 session per day, 5 days a week). Patients were monitored for 6 weeks or until wounds closed. Percent change in wound surface area (WSA), the Gilman's parameter, the weekly rate of change in WSA, and the percentage of pressure ulcers that improved (i.e., decreased in size by at least 50 % or closed) were used to compare differences. Data were analyzed using Fisher's exact test, the Wilcoxon matched pairs test, and the Mann-Whitney U test (p < 0.05). Mean baseline WSA and the pre-treatment duration of pressure ulcers were 15.38 ± 12.92 cm2 and 1.64 ± 0.73 months and 11.08 ± 7.52 cm2 and 2.26 ± 1.42 months in the TG and CG groups, respectively. After 6 weeks of treatment, the WSA of pressure ulcers decreased significantly in both groups (p = 0.000069 in the TG and p = 0.0062 in the CG) with significantly greater improvement in the TG (an average of 68.80 % ± 37.23 % compared with 37.24 % ± 57.84 %; p = 0.047). The value of the Gilman's parameter was greater in the TG than in the CG (0.88 ± 0.62 and 0.43 ± 0.50, respectively; p = 0.018). The mean weekly change of WSA was greater in the TG than in the CG, but only for Stage II pressure ulcers (3.09 ± 2.93 cm2/week and 1.08 ± 1.43 cm2/week; p = 0.045). More Stage II pressure ulcers in the TG decreased by at least 50 % (11 of 14 = 78.57 %) than in the CG (7 of 18 = 38.89 %) (p = 0.035). In the TG, 7 of 14 (50 %) Stage II pressure ulcers closed, 4 of 7 (42.86 %) Stage III pressure ulcers decreased by at least 50 %, and 1 of 7 (14.29 %) Stage III pressure ulcers closed; respective values for the CG are 3 of 18 (16.67 %), 3 of 5 (60 %) and 0 of 5 (0 %) (p = 0.062, p = 0.999, and p = 0.999, respectively). The authors concluded that the findings of this study showed HFUS therapy can reduce the WSA of pressure ulcers regardless of their shape, but further research is needed to establish how ultrasound influences the healing of Stage III and Stage IV pressure ulcers.

Tricco et al (2015) identified effective interventions to treat complex wounds through an overview of systematic reviews. MEDLINE (OVID interface, 1946 until October 26, 2012), EMBASE (OVID interface, 1947 until October 26, 2012), and the Cochrane Database of Systematic Reviews (Issue 10 of 12, 2012) were searched on October 26, 2012. Systematic reviews that examined adults receiving care for their complex wounds were included. Two reviewers independently screened the literature, abstracted data, and assessed study quality using the Assessment of Multiple Systematic Reviews (AMSTAR) tool. Overall, 99 systematic reviews were included after screening 6,200 titles and abstracts and 422 full-texts; 54 were systematic reviews with a meta-analysis (including data on over 54,000 patients) and 45 were systematic reviews without a meta-analysis. Overall, 4% of included reviews were rated as being of high quality (AMSTAR score greater than or equal to 8). Based on data from systematic reviews including a meta-analysis with an AMSTAR score greater than or equal to 8, promising interventions for complex wounds were identified. These included bandages or stockings (multi-layer, high compression) and wound cleansing for venous leg ulcers; 4-layer bandages for mixed arterial/venous leg ulcers; biologics, ultrasound, and hydrogel dressings for diabetic leg/foot ulcers; hydrocolloid dressings, electrotherapy, air-fluidized beds, and alternate foam mattresses for pressure ulcers; and silver dressings and ultrasound for unspecified mixed complex wounds. For surgical wound infections, topical negative pressure and vacuum-assisted closure were promising interventions, but this was based on evidence from moderate-to-low quality systematic reviews.

Velez-Diaz-Pallares et al (2015) examined the evidence from systematic reviews (SRs) of the primary studies on non-pharmacologic interventions to treat pressure ulcers in older patients. PubMed, Cochrane Database of Systematic Reviews, EMBASE, and CINHAL (from inception to October 2013) were searched. A new search for updates in the Cochrane Database was launched in July 2014. Systematic reviews that included at least 1 comparative study evaluating any non-pharmacologic intervention to treat pressure ulcers in older patients, in any health care setting, were included. Any primary study with experimental design was then identified and included. From each primary study, quality assessment was undertaken as specified by the Cochrane Collaboration and the Grading of Recommendations Assessment, Development and Evaluation working group. Interventions were identified and compared among different studies to explore the possibility of performing a meta-analysis, using complete ulcer healing as the outcome measure. A total of 110 SRs with 45 primary studies satisfied the inclusion criteria. The most frequent interventions explored in these trials were support surfaces (13 studies), nutrition (8 studies), and electrotherapy (6 studies). High or moderate quality of evidence was found in none of the interventions, mainly because of the very serious risk of bias of most studies and imprecision in the treatment effect. Evidence grade is very low or insufficient to support the use of any support surface, nutrition intervention, multi-component interventions, re-positioning or other adjunctive therapy (ultrasound, negative pressure, laser, electromagnetic, light, shock wave, hydrotherapy, radiofrequency, or vibration therapy) to increase the rates of pressure ulcers healing in older patients. Electrotherapy showed some beneficial effect in the treatment of pressure ulcers, although the quality of evidence is low. The authors concluded that in older patients with pressure ulcers, evidence to use any non-pharmacologic therapy to increase the rates of wound healing is inconclusive, except for low quality evidence that supports the use of electrotherapy. This situation is especially alarming for interventions that are usually standard clinical practice (re-positioning, support surfaces).

In a single-site, evaluator-blinded RCT, White et al (2015) compared non-contact low-frequency ultrasound (NLFU) in addition to UK standard of care [SOC: (NLFU + SOC)] 3 times a week, with SOC alone at least once-weekly. Patients with chronic venous leg ulcers were eligible to participate. All 36 randomized patients completed treatment (17 NLFU + SOC, 19 SOC), and baseline demographics were comparable between groups. Non-contact low-frequency ultrasound + SOC patients showed a -47 % (SD: 38 %) change in wound area; SOC, -39 % (38 %) change; and difference, -7.4 % [95 % CI: -33.4 to 18.6; p = 0.565]. The median number of infections per patient was 2 in both arms of the study and change in quality of life (QoL) scores was not significant (p = 0.490). Non-contact low-frequency ultrasound + SOC patients reported a substantial mean (SD) reduction in pain score of -14.4 (14.9) points, SOC patients' pain scores reduced by -5.3 (14.8); the difference was -9.1 (p = 0·078). Results demonstrated the importance of high-quality wound care. The authors concluded that outcome measures favored NLFU + SOC over SOC, but the differences were not statistically significant. They stated that a larger sample size and longer follow-up may reveal NLFU-related improvements not identified in this study.

In summary, there is currently insufficient evidence to support the effectiveness of ultrasound therapy in the management of patients with chronic wounds.

CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
ICD-10 codes will become effective as of October 1, 2015:
CPT codes not covered for indications listed in the CPB (not all-inclusive):
97610 Low frequency, non-contact, non-thermal ultrasound, including topical application(s), when performed, wound assessment, and instruction(s) for ongoing care, per day
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive): :
I70.231 - I70.25 Atherosclerosis of the lower extremities with ulceration
I70.261 - I70.269 Atherosclerosis of the lower extremities with gangrene
I83.001 - I83.029 Varicose veins of lower extremities with ulcer
L02.01, L02.11, L02.211 - L02.219, L02.31, L02.411 - L02.419, L02.511- L02.519, L02.611 - L02.619, L02.811 - L02.818, L02.91, L03.011 - L03.91 Other cellulitis and abscess
L05.01 - L05.02 Pilonidal cyst or sinus with abscess
L05.91 - L05.92 Pilonidal cyst or sinus without mention of abscess
L89.000 - L89.95 Pressure ulcer
Numerous options Open wound
T81.31x+ - T81.32x+ Disruption of external or internal operation (surgical) wound, not elsewhere classified
T81.4xx+ Infection following a procedure
T81.89x+ Other complications of procedures, not elsewhere classified [non-healing surgical wound]

The above policy is based on the following references:
    1. Lundeberg T, Nordström F, Brodda-Jansen G, et al. Pulsed ultrasound does not improve healing of venous ulcers. Scand J Rehabil Med. 1990;22(4):195-197.
    2. Eriksson SV, Lundeberg T, Malm M. A placebo controlled trial of ultrasound therapy in chronic leg ulceration. Scand J Rehabil Med. 1991;23(4):211-213.
    3. Peschen M, Weichenthal M, Schöpf E, Vanscheidt W. Low-frequency ultrasound treatment of chronic venous leg ulcers in an outpatient therapy. Acta Derm Venereol. 1997;77(4):311-314.
    4. Johannsen F, Gam AN, Karlsmark T. Ultrasound therapy in chronic leg ulceration: A meta-analysis. Wound Repair Regen. 1998;6(2):121-126.
    5. Cullum N, Nelson EA, Flemming K, Sheldon T. Systematic reviews of wound care management: (5) beds; (6) compression; (7) laser therapy, therapeutic ultrasound, electrotherapy and electromagnetic therapy. Health Technol Assess. 2001;5(9):1-221.
    6. Celleration, Inc. Celleration, Inc. receives FDA clearance for MIST Therapy System 5.0 wound treatment device. Press Release. Eden Prarie, MN: Celleration; June 25, 2004. Available at: Accessed November 19, 2007.
    7. Ennis WJ, Foremann P, Mozen N, et al. Ultrasound therapy for recalcitrant diabetic foot ulcers: Results of a randomized, double-blind, controlled, multicenter study. Ostomy Wound Manage. 2005;51(8):24-39.
    8. Ennis WJ, Valdes W, Gainer M, Meneses P. Evaluation of clinical effectiveness of MIST ultrasound therapy for the healing of chronic wounds. Adv Skin Wound Care. 2006;19(8):437-446.
    9. Baba-Akbari Sari A, Flemming K, Cullum NA, Wollina U. Therapeutic ultrasound for pressure ulcers. Cochrane Database Syst Rev. 2006;(3):CD001275.
    10. Frykberg RG, Zgonis T, Armstrong DG, et al. Diabetic foot disorders: A clinical practice guideline. J Foot Ankle Surg 2006;45(5):S2-S66.
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    12. Cullum N, Petherick E. Pressure ulcers. In: Clinical Evidence. London, UK: BMJ Publishing Group; February 2007.
    13. Kavros SJ, Miller JL, Hanna SW. Treatment of ischemic wounds with noncontact, low-frequency ultrasound: The Mayo clinic experience, 2004-2006. Adv Skin Wound Care. 2007;20(4):221-226.
    14. Gehling ML, Samies JH. The effect of noncontact, low-intensity, low-frequency therapeutic ultrasound on lower-extremity chronic wound pain: A retrospective chart review. Ostomy Wound Manage. 2007;53(3):44-50.
    15. American Society of Plastic Surgeons. Evidence-based clinical practice guideline: Chronic wounds of the lower extremity. Arlington Heights, IL: American Society of Plastic Surgeons; May 2007. Available at: Accessed November 19, 2007.
    16. Kavros SJ, Schenck EC. Use of noncontact low-frequency ultrasound in the treatment of chronic foot and leg ulcerations: A 51-patient analysis. J Am Podiatr Med Assoc. 2007;97(2):95-101.
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    18. Serena T. Wound closure and gradual involution of an infantile hemangioma using a noncontact, low-frequency ultrasound therapy. Ostomy Wound Manage. 2008;54(2):68-71.
    19. Samies J, Gehling M. Acoustic pressure wound therapy for management of mixed partial- and full-thickness burns in a rural wound center. Ostomy Wound Manage. 2008;54(3):56-59.
    20. Fleming CP. Acoustic pressure wound therapy in the treatment of a vasculopathy-associated digital ulcer: A case study. Ostomy Wound Manage. 2008;54(4):62-65.
    21. Liguori PA, Peters KL, Bowers JM. Combination of negative pressure wound therapy and acoustic pressure wound therapy for treatment of infected surgical wounds: A case series. Ostomy Wound Manage. 2008;54(5):50-53.
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    24. Howell-Taylor M, Hall MG Jr, Brownlee Iii WJ, Taylor M. Negative pressure wound therapy combined with acoustic pressure wound therapy for infected post surgery wounds: A case series. Ostomy Wound Manage. 2008;54(9):49-52.
    25. Hinchliffe RJ, Valk GD, Apelqvist J, et al. A systematic review of the effectiveness of interventions to enhance the healing of chronic ulcers of the foot in diabetes. Diabetes Metab Res Rev. 2008;24 Suppl 1:S119-S144.
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    27. Ontario Ministry of Health and Long Term Care, Medical Advisory Secretariat (MAS). Management of chronic pressure ulcers: An evidence-based analysis. Ontario Health Technology Assessment Series. Toronto, ON: MAS; July 2009;9(3).
    28. Serena T, Lee SK, Lam K, et al. The impact of noncontact, nonthermal, low-frequency ultrasound on bacterial counts in experimental and chronic wounds. Ostomy Wound Manage. 2009;55(1):22-30.
    29. Busse JW, Kaur J, Mollon B, et al. Low intensity pulsed ultrasonography for fractures: Systematic review of randomised controlled trials. BMJ. 2009;338:b351.
    30. Cullum NA, Al-Kurdi D, Bell-Syer SE. Therapeutic ultrasound for venous leg ulcers. Cochrane Database Syst Rev. 2010;6:CD001180.
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    33. Chuang LH, Soares MO, Watson JM, et al; VenUS III team. Economic evaluation of a randomized controlled trial of ultrasound therapy for hard-to-heal venous leg ulcers. Br J Surg. 2011;98(8):1099-1106.
    34. Gottrup F, Apelqvist J. Present and new techniques and devices in the treatment of DFU: A critical review of evidence. Diabetes Metab Res Rev. 2012;28 Suppl 1:64-71.
    35. Game FL, Hinchliffe RJ, Apelqvist J, et al. A systematic review of interventions to enhance the healing of chronic ulcers of the foot in diabetes. Diabetes Metab Res Rev. 2012;28 Suppl 1:119-1141.
    36. Madhok BM, Vowden K, Vowden P. New techniques for wound debridement. Int Wound J. 2013;10(3):247-251.
    37. Kwan RL, Cheing GL, Vong SK, Lo SK. Electrophysical therapy for managing diabetic foot ulcers: A systematic review. Int Wound J. 2013;10(2):121-131.
    38. Ebrahim S, Mollon B, Bance S, et al. Low-intensity pulsed ultrasonography versus electrical stimulation for fracture healing: A systematic review and network meta-analysis. Can J Surg. 2014;57(3):E105-E118.
    39. Driver VR, Yao M, Miller CJ. Noncontact low-frequency ultrasound therapy in the treatment of chronic wounds: A meta-analysis. Wound Repair Regen. 2011;19(4):475-480.
    40. Olyaie M, Rad FS, Elahifar MA, et al. High-frequency and noncontact low-frequency ultrasound therapy for venous leg ulcer treatment: A randomized, controlled study. Ostomy Wound Manage. 2013;59(8):14-20.
    41. Beheshti A, Shafigh Y, Parsa H, Zangivand AA. Comparison of high-frequency and MIST ultrasound therapy for the healing of venous leg ulcers. Adv Clin Exp Med. 2014;23(6):969-975.
    42. Yao M, Hasturk H, Kantarci A, et al. A pilot study evaluating non-contact low-frequency ultrasound and underlying molecular mechanism on diabetic foot ulcers. Int Wound J. 2014;11(6):586-593.
    43. Gibbons GW, Orgill DP, Serena TE, et al. A prospective, randomized, controlled trial comparing the effects of noncontact, low-frequency ultrasound to standard care in healing venous leg ulcers. Ostomy Wound Manage. 2015;61(1):16-29.
    44. Prather JL, Tummel EK, Patel AB, et al. Prospective randomized controlled trial comparing the effects of noncontact low-frequency ultrasound with standard care in healing split-thickness donor sites. J Am Coll Surg. 2015;221(2):309-318.
    45. Polak A, Franek A, Blaszczak E, et al. A prospective, randomized, controlled, clinical study to evaluate the efficacy of high-frequency ultrasound in the treatment of Stage II and Stage III pressure ulcers in geriatric patients. Ostomy Wound Manage. 2014;60(8):16-28.
    46. Tricco AC, Antony J, Vafaei A, et al. Seeking effective interventions to treat complex wounds: An overview of systematic reviews. BMC Med. 2015;13:89.
    47. Velez-Diaz-Pallares M, Lozano-Montoya I, Abraha I, et al. Nonpharmacologic interventions to heal pressure ulcers in older patients: An overview of systematic reviews (The SENATOR-ONTOP Series). J Am Med Dir Assoc. 2015;16(6):448-469.
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