Venous Ulcers and Hyaluronic Acid Phonophoresis

Enhancing Venous Ulcer Healing Via Hyaluronic Acid Phonophoresis: A Randomized Controlled Clinical Trial

Venous leg ulcers are severe manifestations of chronic venous insufficiency and account for a large proportion of lower limb ulcers. They typically occur below the knee, persist for more than six weeks, and are associated with significant impairment in quality of life and substantial socioeconomic burden. A major clinical challenge is their high recurrence rate, which can reach 50-70% within six months, making treatment resource-intensive and requiring multidisciplinary care. Therapeutic ultrasound and phonophoresis have been proposed to enhance wound healing by promoting tissue repair and improving transdermal drug delivery, including hyaluronic acid, which supports extracellular matrix restoration and wound healing. However, despite the theoretical advantages of combining ultrasound with hyaluronic acid, robust clinical evidence for its effectiveness in venous leg ulcers remains limited.

The study aimed to assess the effect of ultrasound-enhanced hyaluronic acid delivery on venous ulcer healing compared to ultrasound followed by topical application of hyaluronic acid.

Study Overview

• Status: Completed
• Conditions: Venous Ulcer; Venous Ulcer of Leg
• Intervention / Treatment: Other: Phonophoresis group (A); Other: Ultrasound-preceded gel (hyaluronic acid gel) group (B):

Detailed Description

This study aimed to evaluate the efficacy of ultrasound-enhanced hyaluronic acid delivery (phonophoresis) on venous leg ulcer healing. The intervention group (Group A) received hyaluronic acid gel phonophoresis, whereas the comparator group (Group B) received ultrasound followed by topical application of hyaluronic acid gel. Outcomes were assessed after four weeks of treatment. The primary outcome was Percentage Wound Area Reduction (PWAR), defined as the change in wound area over the study period divided by time. The secondary outcomes were epithelialization rate and time-based healing rate.

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Egypt
  • Giza, Egypt
    • Outpatient Clinics of Faculty of Physical Therapy ,Cairo University.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients of both genders whose ages were between 30 - 70 years.

  • Patients with active venous ulcers (C6) according to CEAP (Clinical manifestations- Etiology- Anatomic distribution-Pathophysiology) classification.
  • clinically proved to be non-infected venous ulcers.
  • Patients receive the traditional physical therapy management for venous ulcers which includes compression therapy and active exercise plus frequent dressing change.
  • Patients suffering from recurrent or failed to heal venous ulcers.

Exclusion Criteria:

• Individuals who were confined to bed with life-threatening conditions that could interfere with the study's objectives, such as myocardial infarction, renal failure or autoimmune diseases.
• Patients who had hyaluronic acid hypersensitivity.
• Presence of skin disorders or conditions that considered contraindicated for therapeutic US (e.g., cellulitis).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Study Group A; This group included 32 patients with venous ulcers who received combined treatment of topical hyaluronic acid gel and therapeutic ultrasound therapy, three sessions weekly for four weeks, in addition to the traditional physical therapy management including compression therapy and active ankle exercises.	Other: Phonophoresis group (A); For Study Group (A): A layer of 0.2% topical hyaluronic acid gel was applied to cover and fill the wound cavity . A sterile glove filled with ultrasound gel was, then secured to the wound with surgical plaster, and ultrasound therapy was applied concurrently. The ultrasound was delivered for 1 minute per 1 cm² of the wound. The parameters used were 0.5 W/cm², low intensity, 1 MHz frequency, and pulsed mode with a 20% duty cycle, adjusted based on the ulcer size. The gel was removed, and the wound was dried and cleaned with saline and the US head with alcohol after each session. The treatment period lasted 4 weeks, with three sessions per week.
Experimental: Study Group B; This group included 32 patients with venous ulcers who received ultrasound first then followed by topical hyaluronic acid, three sessions weekly for four weeks in addition to the traditional physical therapy management including compression therapy and active ankle exercises.	Other: Ultrasound-preceded gel (hyaluronic acid gel) group (B): Pulsed TUS was applied to the wound area at identical parameters to Group A (0.5 W/cm², 1 MHz, 20% duty cycle, one minute per cm²). Immediately following the TUS session, 0.2% HA gel was applied topically to the wound surface. Standard wound care was delivered as described for Group A. Treatment frequency and duration were identical to Group A.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Wound Area Reduction (PWAR)	It is calculated as: [(baseline wound area - post-treatment wound area) ÷ baseline wound area] × 100. Digital wound measurements were obtained at baseline and at week four using the validated imitoMeasure smartphone application (imito AG, Zurich, Switzerland). Standardized image acquisition procedures were followed, with the smartphone camera positioned 20-30 cm from the wound and maintained parallel to the wound surface. A calibration marker (QR code) was placed adjacent to the wound on the same plane before image capture, and a photo was taken once the app recognized the QR code. The operator delineated the wound borders on the photo using their finger then the app generated measurements of area, width, length, and circumference.	After 3 sessions per week for 4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Healing	The healing rate to assess the reduction in wound surface area (WSA) over a specified time interval. The formula used was: Healing Rate = Change in Wound Surface Area/ Time Period. *(Change in WSA= Initial WSA - Final WSA). For this study, the healing rate was calculated over a 4-week period. Healing Rate per 4 Weeks = (WSA at Baseline - WSA at 4 Weeks) / 4. Digital wound measurements were obtained at baseline and at week four using the validated imitoMeasure smartphone application (imito AG, Zurich, Switzerland). Standardized image acquisition procedures were followed, with the smartphone camera positioned 20-30 cm from the wound and maintained parallel to the wound surface. A calibration marker (QR code) was placed adjacent to the wound on the same plane before image capture, and a photo was taken once the app recognized the QR code. The operator delineated the wound borders on the photo using their finger then the app generated measurements of area, width, length, and circumference	After 3 sessions per week for 4 weeks

Collaborators and Investigators

• Sponsor: Cairo University
• Investigators: Study Director: HESHAM GALAL MAHRAN, Professor of PT, Faculty of Physical Therapy, department of physical therapy for surgery, Cairo University, Egypt; Study Director: SHAIMAA MOHAMED ELSAYEH, Ass. Prof. of PT, Faculty of Physical Therapy, department of physical therapy for surgery, Cairo University, Egypt; Study Director: WALIED MOHAMED KHEREBA, Prof. vascular surgery, Faculty of medicine, department of vascular and endovascular surgery, AL-Azhar University New Damietta, Egypt; Study Director: Rasha S Farag, MSc, Damietta Directorate for Health Affairs

Publications and helpful links

General Publications

• Raffetto JD, Ligi D, Maniscalco R, Khalil RA, Mannello F. Why Venous Leg Ulcers Have Difficulty Healing: Overview on Pathophysiology, Clinical Consequences, and Treatment. J Clin Med. 2020 Dec 24;10(1):29. doi: 10.3390/jcm10010029.
• https://www.mdpi.com/2077-0383/11/3/537
• https://www.mdpi.com/2073-4409/11/15/2439
• Alkahtani SA, Kunwar PS, Jalilifar M, Rashidi S, Yadollahpour A. Ultrasound-based Techniques as Alternative Treatments for Chronic Wounds: A Comprehensive Review of Clinical Applications. Cureus. 2017 Dec 15;9(12):e1952. doi: 10.7759/cureus.1952.
• Biagioni RB, Carvalho BV, Manzioni R, Matielo MF, Brochado Neto FC, Sacilotto R. Smartphone application for wound area measurement in clinical practice. J Vasc Surg Cases Innov Tech. 2021 Feb 26;7(2):258-261. doi: 10.1016/j.jvscit.2021.02.008. eCollection 2021 Jun.

Study record dates

Study Major Dates

• Study Start (Actual): December 12, 2024
• Primary Completion (Actual): February 20, 2025
• Study Completion (Actual): February 26, 2025

Study Registration Dates

• First Submitted: May 31, 2026
• First Submitted That Met QC Criteria: May 31, 2026
• First Posted (Actual): June 4, 2026

Study Record Updates

• Last Update Posted (Actual): June 4, 2026
• Last Update Submitted That Met QC Criteria: May 31, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: ultrasound; phonophoresis; hyaluronic acid; venous ulcer
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Skin Diseases; Skin Ulcer; Varicose Veins; Leg Ulcer; Skin and Connective Tissue Diseases; Varicose Ulcer; Population Characteristics; Demography; Population Groups
• Other Study ID Numbers: Hyaluronic acid phonophoresis

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data (IPD) will not be publicly shared due to privacy and confidentiality considerations, in accordance with institutional and ethical committee regulations governing patient data protection.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No