Noncontact Normothermic/Nonthermal Wound Therapy

Number: 0372

Policy

Aetna considers Warm-Up Active Wound Therapy, also known as noncontact normothermic wound therapy (NNWT) and warming therapy, experimental and investigational because there is insufficient evidence in the peer-reviewed medical literature that Warm-Up Active Wound Therapy/NNWT is effective for the treatment of wounds.

Aetna considers noncontact, nonthermal, low-frequency ultrasound therapy experimental and investigational for the treatment of wounds and all other indications (e.g., bacterial infections, deep tissue pressure injury, and femoral artery thrombosis) because its effectiveness has not been established.

Background

Warm-Up Active Wound Therapy (Augustine Medical, Inc., Eden Prairie, MN), also known as noncontact normothermic wound therapy (NNWT) uses a non-contact radiant-heat bandage to treat chronic venous ulcers when conventional wound-healing therapy has failed.  The device consists of a noncontact, domed wound cover into which a flexible infrared heating card is inserted.  A battery pack powers the device and warms the wound to a pre-determined temperature.  The inside of the wound cover contains a foam ring, which acts as a wick to drain away exudate.

In a Decision Memorandum, the Center for Medicare and Medicaid Services (CMS) reviewed the evidence of the effectiveness of noncontact normothermic wound therapy.  The CMS concluded that “the medical literature does not support a finding that NNWT heals any wound type better than conventional treatment.”  CMS concluded, therefore, that there is insufficient evidence in the peer-reviewed medical literature to consider this device as reasonable and necessary for the treatment of wounds.

An assessment of treatments for chronic pressure ulcers by the Ontario Ministry of Health and Long-Term Care (2009) concluded that "thermal dressings such as noncontact normothermic dressings or radiant heat dressings were associated with greater improvement in stage III and IV pressure ulcers; however, this did not translate into more wound closure. There is no evidence at present to conclude that thermal dressings will result in more complete healing in stage III or IV pressure ulcers."

Several recent studies have evaluated the effectiveness of NNWT for the treatment of chronic wounds.  However, there are drawbacks from these studies -- small sample sizes and lack of long-term follow-up.  McCulloch and Knight (2002) examined the effect of a noncontact, radiant warming device in the treatment of neuropathic foot wounds secondary to diabetes.  Patients (n = 36) were assigned to management with off-loading and warming (treatment) or off-loading therapy only (control) for a period of 8 weeks or until healing.  Wounds of subjects in the treatment group healed at a rate of 0.019 +/- 0.019 cm2/day compared with that of 0.008 +/- 0.009 cm2/day in the control group (p = 0.049).  The difference between treatment and control groups barely reached statistical significance.

The authors of a small (13 patients) preliminary study on Warm-Up® Active Wound Therapy concluded that Warm-Up® Active Wound Therapy is a safe treatment modality for chronic venous stasis ulcers; however, further investigation using a larger prospective study is needed to demonstrate effectiveness

Kloth and associates (2002) studied the effect of NNWT versus standard wound care on patients (n = 40) with 43 stage III and IV pressure ulcers.  A sterile noncontact wound dressing was applied to 21 wounds for 24 hours per day, 7 days per week.  Each day after the wound was irrigated and the noncontact dressing was changed, a heating element in the dressing was activated for 3 1-hour periods for 12 weeks or until wound closure.  Twenty-two control wounds were treated with standard, moisture-retentive dressings 24 hours per day, 7 days per week for 12 weeks or until wound closure.  The healing rate for the treatment group was significantly greater than that for the control group (0.52 cm2 per week and 0.23 cm2 per week, respectively; p < 0.02).  However, the difference in the incidence of closure among wounds that completed the entire 12-week protocol between treatment and control groups were not significant (11 of 14 or 78.5 % for the treatment group and 8 of 16 or 50 % for the control group).

In a pilot study, Karr (2003) studied the use of NNWT in the treatment of wounds associated with osteomyelitis.  This study consisted of 2 arms:
  1. the control arm (11 patients with 11 ulcers) received standard wound care, and
  2. the treatment arm (5 patients with 6 ulcers) received NNWT.
Standard wound care resulted in complete ulcer healing at an average of 127 days, while NNWT resulted in complete ulcer healing at an average of 59 days, or 54 % faster than in the control arm.  However, the mean wound healing times between the 2 groups were not significantly different (p < 0.33).  Moreover, the median wound healing time for the 2 groups were quite similar (70 days for the control group and 68 days for the treatment group).  The authors concluded that a larger prospective study that evaluates NNWT for ulcers associated with osteomyelitis is warranted.

In a prospective, randomized, controlled study, Alvarez and colleagues (2003) compared diabetic foot ulcer healing in patients being treated with either NNWT applied for 1 hour 3 times daily until healing or 12 weeks, or standard care (saline-moistened gauze applied once-daily).  Surgical debridement and adequate foot off-loading was provided to both groups.  Evaluations were performed weekly and consisted of acetate tracings, wound assessment, and serial photography.  A total of 20 patients completed the study and both treatment groups were distributed evenly (n = 10).  Ulcers treated with NNWT had a greater mean percent wound closure than control-treated ulcers at each evaluation point (weeks 1 to 12).  After 12 weeks, 70 % of the wounds treated with NNWT were healed compared with 40 % for the control group.  However, the differences were not significant (p < 0.069).  The authors concluded that further study in a greater patient population is needed to assess the effectiveness of NNWT in treating neuropathic foot ulcers.

In a randomized controlled study, Thomas et al (2005) examined the effectiveness of radiant heat bandage on the healing of stage 3 or stage 4 pressure ulcers.  A total of 41 subjects with a stage 3 or stage 4 truncal pressure ulcer greater than 1.0 cm2 were recruited from outpatient clinics, long-term care nursing homes, and a rehabilitation center.  The experimental group was randomized to a radiant-heat dressing device and the control group was randomized to a hydrocolloid dressing, with or without a calcium alginate filler.  Subjects were followed until healed or for 12 weeks.  Eight subjects (57 %) in the experimental group had complete healing of their pressure ulcer compared with 7 subjects (44 %) with complete healing in the control group (p = 0.46).  The authors noted that although a 13 % difference in healing rate between the 2 arms of the study was found, this difference was not statistically significant.

In a single center randomized study with 49 patients, Alvarez et al (2006) reported that NNWT improves the healing of diabetic neuropathic foot ulcers.  Moreover, these researchers stated that further study in a greater patient population is needed to fully assess the effectiveness of this device and to provide additional information on whether local warmth can reduce the incidence of infection.

Serena et al (2009) examined if noncontact, nonthermal, low-frequency ultrasound (LFU) therapy is effective in controlling wound bacterial colony counts in a series of 4 related experiments.  First, ultrasound penetration in both wounded and intact skin was assessed in-vitro.  Compared to sham, noncontact ultrasound penetrated farther into both wounded (3.0 to 3.5 mm versus 0.35 to 0.50 mm) and intact (2.0 to 2.5 mm versus 0.05 to 0.07 mm, respectively) pig skin.  Second, using an in-vitro model to stain and count live/dead bacteria, 0 % of sham-treated and 33 % of Pseudomonas aeruginosa, 40 % of Escherichia coli and 27 % of Enterococcus faecalis were dead after 1 ultrasound application.  Minimal effects on methicillin-resistant Staphylococcus aureus (MRSA) and S. aureus were observed.  Third, using an in-vivo model, after 1 week, while differences between different bacterial species were observed, overall bacterial quantity decreased with ultrasound treatment (from 7.2 +/- 0.79 to 6.7 +/- 0.91 colony forming units [CFU] per gram of tissue [CFU/g]) and silver anti-microbial dressings (from 7.2 +/- 0.79 to 5.7 +/- 0.6 CFU/g) but increased to 8.6 +/- 0.15 CFU/g for sham and 8.6 +/- 0.06 CFU/g for water-moistened gauze.  Fourth, 11 patients (average age of 60 years) with pressure ulcers containing bacterial counts greater than 10(5) CFU/g of tissue received 2 weeks of noncontact ultrasound therapy.  The quantities of 7 bacterial organisms were reduced substantially from baseline to 2 weeks post-treatment.  None of the wounds exhibited signs of a clinical infection during the treatment period and no adverse events were observed.  Taken together, these 4 studies indicated that noncontact ultrasound can be used to reduce bacterial quantity.  The authors concluded that controlled clinical studies are needed to determine the effectiveness of this treatment and to further elucidate its effects on various Gram-negative and Gram-positive bacteria.

In an in-vitro study, Conner-Kerr and colleagues (2010) examined the effects of LFU delivered at 35 kHz on bacterial viability, cell wall structure, and colony characteristics, including antibiotic resistance on vegetative forms of MRSA.  They concluded that studies to elucidate the observed effects of LFU on MRSA and evaluate its effect in-vivo are needed.  Furthermore, in a Cochrane review on therapeutic ultrasound for venous leg ulcers, Cullum et al (2010) concluded that the studies 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 randomized controlled trials.  There is no evidence of a benefit associated with LFU.

Voigt and colleagues (2011) examined if LFU used as an adjunctive therapy improves the outcomes of complete healing and reduction of size of chronic lower limb wounds.  PubMed, Cochrane/CENTRAL, technical assessment, relevant wound-related journals, and clinical guidelines were searched along with contacting manufacturers and authors of relevant randomized controlled trials (RCTs) were completed.  Searches focused on the use of LFU in RCTs.  Data were collected via a data collection form and was adjudicated independently via coauthors.  Meta-analyses and heterogeneity checks were performed using Mantel-Haenszel and inverse variance (fixed and random effects) statistical methods on studies with similar outcomes (complete healing and percent wound area reduction) over similar time periods.  Single study results were reported via the statistical methods used in the study; 8 RCTs were identified.  Results demonstrated that early healing (at less than or equal to 5 months) in patients with venous stasis and diabetic foot ulcers was favorably influenced by both high- and low-intensity ultrasound delivered at a low frequency -- either via contact or noncontact techniques.  However, the authors noted that the quality of the data may be suspect, especially for low-frequency, low-intensity noncontact ultrasound because of significant biases.

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 reviewed the current evidence behind the use of these newer techniques in clinical practice.  They noted that there is some evidence to suggest that LFU therapy may improve healing rates in patients with venous ulcers and diabetic foot ulcers.

Low-Frequency Ultrasound Therapy Femoral Artery Thrombosis

Zhu and colleagues (2016) studied the thrombolytic effect of LFU combined with targeted urokinase-containing microbubble contrast agents on treatment of thrombosis in rabbit femoral artery; and determined the optimal combination of parameters for achieving thrombolysis in this model.  A biotinylated-avidin method was used to prepare microbubble contrast agents carrying urokinase and Arg-Gly-Asp-Ser (RGDS) peptides.  Following femoral artery thrombosis in New Zealand white rabbits, microbubble contrast agents were injected intravenously, and ultrasonic exposure was applied.  A 3 × 2 × 2 factorial table was applied to categorize the experimental animals based on different levels of combination of ultrasonic frequencies (Factor A: 1.6-MHz, 2.2-MHz, 2.8-MHz), doses of urokinase (Factor B: 90,000 IU/kg, 180,000 IU/kg) and ultrasound exposure time (Factor C: 30-min, 60-min).  A total of 72 experimental animals were randomly divided into 12 groups (n = 6 per group).  Doppler techniques were used to assess blood flow in the distal end of the thrombotic femoral artery during the 120 minutes thrombolysis experiment.  The rate of re-canalization following thrombolysis was calculated, and thrombolytic effectiveness was evaluated and compared.  The thrombolytic re-canalization rate for all experimental subjects after thrombolytic therapy was 68.1 %.  The optimal parameters for thrombolysis were determined to be
  1. an ultrasound frequency of 2.2-MHz, and
  2. a 90,000 IU/kg dose of urokinase.  Ultrasound exposure time (30 minutes versus 60 minutes) had no significant effect on the thrombolytic effects.

The combination of local LFU radiation, targeted microbubbles, and thrombolytic urokinase induced thrombolysis of femoral artery thrombosis in a rabbit model.  The ultrasonic frequency of 2.2-MHz and urokinase dose of 90,000 IU/kg induced optimal thrombolytic effects, while the application of either 30 minutes or 60 minutes of ultrasound exposure had similar effects.

Low-Frequency Ultrasound Debridement in Chronic Wound Healing:

Chang and colleagues (2017) stated that ultrasound debridement is a promising technology that functions to disperse bacterial biofilms and stimulate wound healing.  These researchers focused on LFU (20 to 60 kHz) and summarized the findings of 25 recent studies examining ultrasound efficacy.  Ultrasound debridement appears to be most effective when used 3 times a week and has the potential to decrease exudate and slough, decrease patient pain, disperse biofilms, and increase healing in wounds of various etiology.  The authors concluded that although current studies are generally of smaller size, the results are promising and they recommended the testing of LFU therapy in clinical practice on a larger scale.

Low Frequency Ultrasound for the Treatment of Bacterial Infections:

Cai and colleagues (2017) noted that single anti-microbial therapy has been unable to resist the global spread of bacterial resistance.  These researchers reviewed literatures of available in-vitro and in-vivo studies and the results showed that (LFU has a promising synergistic bactericidal effect with antibiotics against both planktonic and biofilm bacteria.  It also can facilitate the release of antibiotics from medical implants.  The authors stated that as a non-invasive and targeted therapy, LFU has great potential in treating bacterial infections.  However, more in-depth and detailed studies are still needed before LFU is officially applied as a combination therapy in the field of anti-infective treatment.  Moreover, these investigators noted that there is still a long way to go before clinical application of combination therapy of LFU with antibiotics.  First of all, the current studies involved a narrow range of susceptible pathogens.  There are very few studies on the most threatening MDR bacteria.  Secondly, frequency, intensity, and pulse cycle varied a lot at present.  The promising frequency and intensity from in-vitro studies are likely to cause local damage in in-vivo studies.  Therefore, LFU parameters appropriate for clinical application need to be further explored.  Thirdly, 1 study indicated that LFU treatment reduced the interface shear strength and initial stability of vancomycin-loaded acrylic bone cement-stem.  So the impact of LFU on the physical properties of the implant materials requires a comprehensive examination.  At last, because bacteria will partially be removed from the biofilm surface when LFU is applied, whether it will bring the risk of spreading the pathogens and forming systemic bloodstream infection also requires more careful evaluation.

Low Frequency Ultrasound for the Treatment of Deep Tissue Pressure Injury:

Honaker and associates (2016) stated that the optimal treatment for deep tissue pressure injuries (DTPI) has not been determined.  Deep tissue pressure injuries represent a more ominous early stage pressure injury that may evolve into full thickness ulceration despite implementing the standard of care for pressure injury.  In a longitudinal, prospective, historical case control study, these researchers examined the effectiveness of noncontact LFU (NLFU) plus standard of care (treatment group) in comparison to standard of care (control group) in reducing DTPI severity, total surface area, and final pressure injury stage.  The Honaker Suspected Deep Tissue Injury Severity Scale (range of 3 to 18 [more severe]) was used to determine DTPI severity at enrollment (time 1) and discharge (time 2).  A total of 60 subjects (treatment = 30; control= 30) were enrolled in the study.  In comparison to the control group mean DTPI total surface area change at Time 2 (0.3 cm2 ), the treatment group had a greater decrease (8.8 cm2 ) that was significant (t = 2.41, p = 0.014, r2  = 0.10).  In regards to the Honaker Suspected Deep Tissue Injury Severity Scale scores, the treatment group had a significantly lower score (7.6) in comparison to the control group (11.9) at time 2, with a mean difference of 4.6 (t = 6.146, p = 0.0001, r2  = 0.39).  When considering the final pressure ulcer stage at time 2, the control group were mostly composed of unstageable pressure ulcer (57 %) and DTPI severity (27 %).  In contrast, the treatment group final pressure ulcer stages were less severe and were mostly composed of stage 2 pressure injury (50 %) and DTPI severity (23 %) were the most common at time 2.  The authors concluded that the results of this study showed that DTPI severity treated with NLFU within 5 days of onset and in conjunction with standard of care may improve outcomes as compared to standard of care only.

In a retrospective, descriptive study, Wagner-Cox and colleagues (2017) examined the effect of NLFU on DTPI, both hospital-acquired and those present on admission (POA).  Medical records from 44 adult patients with a DTPI treated with NLFU were reviewed; 22 had a hospital-acquired DTPI (HADTPI) and 22 had DTPI POA.  Age of subjects was 71.3 ± 16.3 years (mean ± SD); 52 % were men.  Data were collected from the medical records including demographic as well as relevant clinical characteristics, DTPI measurements, and DTPI evolution/resolution.  Data were summarized and examined using descriptive statistics (e.g., frequencies and percentages and means and standard deviations).  Differences between groups were examined using paired t-tests or the Mann-Whitney U test and the Chi-square test as appropriate.  In addition, the heel DTPI subgroup (n = 8) was examined separately due to the small sample size.  All patients with HADTPI and DTPI POA treated with NLFU exhibited a statistically significant decrease in injury size from initiation to discontinuation of NLFU therapy (24.6 cm versus 14.4 cm, p = 0.02).  No statistically significant difference in wound resolution was found between HADTPI versus DTPI POA (27 % versus 18 %, p = 0.47).  Mean size of both HADTPI and DTPI POA decreased significantly from 15.9 to 13.4 cm (p = 0.045) by NLFU therapy.  Wounds were classified as resolved at completion of treatment in 23 % (10 out of 44) of all treated patients.  Of all patients with the potential to be resolved (not discharged early or expired), 63 % (10 out of 16) had wounds classified as resolved.  The authors concluded that the findings of this study suggested that NLFU is a viable and promising therapeutic option for both HADTPI and DTPI POA.  Moreover, they stated that future studies are needed to confirm these results and to examine efficacy and feasibility of DTPI across care settings.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

CPT codes not covered for indications listed in the CPB:

97610 Low frequency, non-contact, non-thermal ultrasound, including topical application(s), when performed, wound assessment, and instruction(s) for ongoing care, per day

HCPCS codes not covered for indications listed in the CPB:

A6000 Non-contact wound warming wound cover for use with the non-contact wound warming device and warming card
E0231 Non-contact wound warming device (temperature control unit, AC adaptor and power cord) for use with warming card and wound cover
E0232 Warming card for use with the non-contact wound warming device and non-contact wound warming cover

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

A00.0 - A09 Intestinal infectious diseases
A20.0 - A28.9 Certain zoonotic bacterial diseases
A30.0 - A49.9 Other bacterial diseases
E10.40 - E10.49
E11.40 - E11.49
Diabetes with neurological complications
E10.51 - E10.59
E11.51 - E11.59
Diabetes with peripheral circulatory complications
E10.610 - E10.69
E11.610 - E11.69
Diabetes with other specified complications
I70.231 - I70.25 Atherosclerosis of the lower extremities with ulceration
I70.261 - I70.269 Atherosclerosis of the lower extremities with gangrene
I73.9 Peripheral vascular disease, unspecified
I74.3 Embolism and thrombosis of arteries of the lower extremities
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. Robinson C, Santilli SM. Warm-up active wound therapy: A novel approach to the management of chronic venous stasis ulcers. J Vasc Nurs. 1998;16(2):38-42.
  2. Santilli SM, Valusek PA, Robinson C. Use of a noncontact radiant heat bandage for the treatment of chronic venous stasis ulcers. Adv Wound Care. 1999;12(2):89-93.
  3. Whitney JD, Salvadalena G, Higa L, et al. Treatment of pressure ulcers with noncontact normothermic wound therapy: Healing and warming effects. J Wound Ostomy Continence Nurs. 2001;28(5):244-252.
  4. Canadian Coordinating Office for Health Technology Assessment (CCOHTA). Warm-up therapy. Emerging Device List. No. 8. Ottawa, ON: CCOHTA; July 2001. Available at: http://www.ccohta.ca/. Accessed June 14, 2004.
  5. Center for Medicare and Medicaid Services (CMS). Warm-Up Wound Therapy® a/k/a Noncontact Normothermic Wound Therapy. Updated (02/13/02) (#CAG-00114N). Baltimore, MD: CMS; 2002. Available at: http://www.hcfa.gov/coverage/8b3-hhh.htm. Accessed March 8, 2002.
  6. Center for Medicare and Medicaid Services (CMS). Coverage Issues Manual Section 60-25, Noncontact Normothermic Wound Therapy (NNWT). Baltimore, MD: CMS; 2002.
  7. McCulloch J, Knight CA. Noncontact normothermic wound therapy and offloading in the treatment of neuropathic foot ulcers in patients with diabetes. Ostomy Wound Manage. 2002;48(3):38-44.
  8. Macario A, Dexter F. Is noncontact normothermic wound therapy cost effective for the treatment of stages 3 and 4 pressure ulcer? Wounds. 2002;14(3):93-106.
  9. Kloth LC, Berman JE, Nett M, et al. A randomized controlled clinical trial to evaluate the effects of noncontact normothermic wound therapy on chronic full-thickness pressure ulcers. Adv Skin Wound Care. 2002;15(6):270-276.
  10. Karr JC. External thermoregulation of wounds associated with lower-extremity osteomyelitis. A pilot study. J Am Podiatr Med Assoc. 2003;93(1):18-22.
  11. Alvarez OM, Rogers RS, Booker JG, Patel M. Effect of noncontact normothermic wound therapy on the healing of neuropathic (diabetic) foot ulcers: An interim analysis of 20 patients. J Foot Ankle Surg. 2003;42(1):30-35.
  12. Thomas DR, Diebold MR, Eggemeyer LM. A controlled, randomized, comparative study of a radiant heat bandage on the healing of stage 3-4 pressure ulcers: A pilot study. J Am Med Dir Assoc. 2005;6(1):46-49.
  13. Alvarez O, Patel M, Rogers R, Booker J. Effect of non-contact normothermic wound therapy on the healing of diabetic neuropathic foot ulcers. J Tissue Viability. 2006;16(1):8-11.
  14. 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.
  15. Ontario Ministry of Health and Long-Term Care. Management of chronic pressure ulcers. An evidence-based analysis. Ontario Health Technology Assessment Series. Toronto, ON: Ontario Ministry of Health and Long-Term Care; 2009;9(3).
  16. Conner-Kerr T, Alston G, Stovall A, et al. The effects of low-frequency ultrasound (35 kHz) on methicillin-resistant staphylococcus aureus (MRSA) in vitro. Ostomy Wound Manage. 2010;56(5):32-42.
  17. Cullum NA, Al-Kurdi D, Bell-Syer SE. Therapeutic ultrasound for venous leg ulcers. Cochrane Database Syst Rev. 2010;(6):CD001180.
  18. Voigt J, Wendelken M, Driver V, Alvarez OM. Low-frequency ultrasound (20-40 kHz) as an adjunctive therapy for chronic wound healing: A systematic review of the literature and meta-analysis of eight randomized controlled trials. Int J Low Extrem Wounds. 2011;10(4):190-199.
  19. Madhok BM, Vowden K, Vowden P. New techniques for wound debridement. Int Wound J. 2013;10(3):247-251.
  20. Zhu Y, Guan L, Mu Y. Combined low-frequency ultrasound and urokinase-containing microbubbles in treatment of femoral artery thrombosis in a rabbit model. PLoS One. 2016;11(12):e0168909.
  21. Honaker JS, Forston MR, Davis EA, et al. The effect of adjunctive noncontact low frequency ultrasound on deep tissue pressure injury. Wound Repair Regen. 2016;24(6):1081-1088.
  22. Chang YR, Perry J, Cross K. Low-frequency ultrasound debridement in chronic wound healing: A systematic review of current evidence. Plast Surg (Oakv). 2017;25(1):21-26.
  23. Cai Y, Wang J, Liu X, et al. A review of the combination therapy of low frequency ultrasound with antibiotics. Biomed Res Int. 2017;2017:2317846.
  24. Wagner-Cox P, Duhame HM, Jamison CR, et al. Use of noncontact low-frequency ultrasound in deep tissue pressure injury: A retrospective analysis. J Wound Ostomy Continence Nurs. 2017;44(4):336-342.