A Non-Inferiority Study to Compare the Effect of Silica Gel Fiber Dressing With Alginate Dressing on Healing of Venous Leg Ulcers

BACKGROUND: Silica gel fiber (SGF) dressing is a novel patch for wound healing. OBJECTIVE: To compare the efficacy and safety of SGF dressing with alginate dressing in local treatment of venous leg ulcers. METHODS: Patients with venous leg ulcers who had undergone effective treatment of venous hypertension and debridement were randomized to receive wound care with either SGF dressing or alginate dressing for 4 weeks. Wounds were assessed weekly during the first 4 weeks and then every 2 weeks until the 8th week. The primary endpoint was the efficacy rate. Secondary endpoints included ulcer area reduction rate, healing rate, frequency of dressing changes, pain score, patient satisfaction, and treatment-related adverse events. RESULTS: A total of 130 patients were enrolled, 67 treated with SGF and 63 with alginate dressing, and the efficacy rates were 89.6% (SGF group) and 84.1% (alginate group). SGF induced a higher “no pain” rate than alginate at week 2 (61.4% vs 43.5%) and week 3 (67.6% vs 53.1%), and a higher “highly satisfied” rate at week 4 (83.3% vs 78.8%) and week 8 (75% vs 59.1%). Markedly fewer dressing changes were required in the SGF group. CONCLUSIONS: SGF dressing is non-inferior to alginate dressing in treating venous leg ulcers. It even substantially decreased the frequency of dressing changes when compared with alginate dressing.

Venous leg ulcers (VLUs) are a worldwide problem, and the prevalence of VLU comprises up to 2% of the population.^1,2 Despite recent advances in wound care, these ulcers may take months to heal, often result in complications (eg, infection, cellulitis) and recurrence, and are costly to treat.³

The pathologic process of venous ulceration is primarily caused by genetic factors that lead to the destruction of normal vein wall architecture and venous hypertension.³ Venous hypertension causes a chronic inflammatory response that over time can cause venous ulceration. Wounds frequently fail to heal in a timely manner owing to the lack of oxygen and nutrient supply coupled with local diffusion dysfunction—a consequence of venous hypertension-induced massive extravasation. Additionally, parasitic bacteria on the body surface tend to grow and multiply, producing toxins and causing local infections. Infections consume a large amount of growth factors as well as various vitamins and other nutrients, which further inhibits the growth of fibroblasts and delays the repair of damaged tissues.⁴

Therapies for venous ulcers are primarily directed at eliminating venous hypertension and promoting ulcer wound healing.³ The standard of care consists of local wound management and compression bandaging to reduce edema and facilitate venous return.⁵ Moist wound healing coupled with graduated compression bandaging has become the cornerstone of treatment for lower extremity ulcers.⁵ Various kinds of dressings have been developed, primarily aiming at infection control and growth factor supplementation, and a variety of regenerative medicine techniques as well. Nonetheless, wound healing remains far from satisfactory. Thus, it is necessary to develop a dressing that not only provides a protective covering and a moist wound environment, but also more effectively enhances cell growth.

Silica gel fiber (SGF; Jiangsu Synecoun Medical Technology Co., Ltd.) dressing is a bioresorbable, inorganic silica gel fiber patch. It is a mesh composed of hydroxy ethoxysiloxane polymer, whose molecular structure is H[Si₈O₁₂O(OH)x(OC₂H₅)6-x]nOH. The role of SGF dressing in wound healing is somewhat akin to that of extracellular matrix (ECM).

An essential component in all human tissues, ECM is composed of various proteins, including collagens, elastin, and smaller quantities of structural proteins.⁶ It provides structural support and tensile strength, provides attachment sites for cell surface receptors, and serves as a reservoir for signaling factors that regulate cell migration, proliferation, and angiogenesis. Extracellular matrix has a complex three-dimensional architecture of fibrous proteins, polysaccharides, and proteoglycans secreted by fibroblast and epidermal cells. It plays a significant and dynamic role in wound healing,^7,8 and it is used as a bioscaffold for the reconstruction of many tissues in human preclinical and clinical studies.⁸

 In addition to providing the wound with a protective covering and a moist environment, SGF dressing also acts as a scaffold that contributes to cell migration and growth as well as capillary growth, and it stimulates cell proliferation. Additionally, because of its absorbability during the wound healing process, it is eventually replaced by new tissue. Once applied, the dressing gradually degrades without irritating either the skin or the wound.

Early animal studies confirmed the safety of SGF dressing and showed that it outperformed all other scaffold types with respect to the positive role in cell growth and long-term cell viability.⁹ In principle, these findings indicate that SGF dressing is a safe and cost-effective alternative to conventional dressings.

       To determine the efficacy and safety of SGF dressing in venous leg ulcer wound healing, the present study compared it with alginate dressing (Kaltostat; ConvaTec Inc), a widely used dressing that provides a moist, warm wound healing environment without scaffolds.

This prospective, multicenter, randomized, parallel controlled clinical trial was conducted in 6 Chinese medical centers from December 2017 to October 2019.

Ethics. The study protocol was submitted to local ethics committees for approval, and the clinical trial was conducted in compliance with Good Clinical Practice guidance and the principles of the Declaration of Helsinki. Written informed consent was obtained from each patient prior to the study.

Patient population. Included in this study were patients with simple venous ulcers of the lower extremity, an ankle to brachial pressure index (ABPI) greater than or equal to 0.9 but less than 1.3, and with ulcer duration between 1 month and 2 years and ulcer size less than or equal to 40 cm (measured using acetate tracing method). Participants also had to meet all the following criteria: Complete debridement had been performed, and venous hypertension had been controlled; body temperature was less than 38℃, without systemic symptoms such as fatigue; the wound was at the granulation tissue growth phase, with a clean wound surface, and without foul odor and high levels of exudate.

 The main exclusion criteria were as follows: lower extremity ulcer caused by other than pure venous etiology (eg, diabetic foot ulcer, or ulcers resulting from electrical, chemical, or radiation insults), bedsores, eczema, or lower limb arterial ulcers, mixed arteriovenous (venous and arterial) lower extremity ulcers; severe systemic disease, including uncontrolled congestive heart failure or severe arrhythmia, severe respiratory dysfunction, uncontrolled diabetes or vascular disease, hematologic disease, malignant tumors or immunodeficiency, or severe malnutrition; and hepatitis C virus, HIV, or syphilis.

Sample size. This study was designed as a non-inferiority study. Sample size was based on power analysis, which ensured 80% power to detect the non-inferiority of SGF to the control dressing. Non-inferiority testing was performed based on 2.5% (unilateral) alpha level, 80% testing power, with a non-inferiority margin of 10%. Comparison between the groups adopted a 1:1 design. According to sample size calculation software PASS 13.0, a total of 106 subjects was needed. Considering a 20% dropout rate, the sample size needed per group was 65, and hence a total of 130 subjects was required.

Study process. Patients who met the inclusion criteria were randomly allocated to receive wound care with either SGF dressing or alginate dressing for 4 weeks. Patient demographics, baseline characteristics, ulcer history, and local assessments at baseline were recorded. At baseline, the size of each ulcer was measured using the acetate tracing method and a photograph was taken. The ulcer was fully covered with either SGF dressing or alginate dressing (cut to an appropriate size), with a sterile cotton gauze pad placed over it.

Venous hypertension was controlled by leg elevation, ankle pump exercise, compression, and medication prior to enrollment into the study. Compression therapy was administered with the use of an elastic bandage that provides a compression force of approximately 25 mm Hg. Oral medication included diosmin and horse chestnut seed extracts. Ongoing compression therapy was provided for each patient during the study.

For the study arm, the frequency of SGF dressing changes was decided by investigators as needed. For the control arm, alginate dressing changes were done based on wound condition and exudate volume.

The study was expected to last 8 weeks, including a 4-week treatment period and a 4-week follow-up period. Wounds were assessed weekly during the first 4 weeks and biweekly during the second 4 weeks. Wound status as well as ulcer size and condition (presence or absence of predefined local signs) were recorded at each clinic visit. The nature and frequency of all adverse events (AEs) were recorded and a safety profile generated. Wound assessments were performed with the help of a uniform assessment tool. All individuals responsible for patient assessments were properly trained before the study.

Outcomes/endpoints. The primary endpoint—that is, efficacy (healing + improvement) rate—was measured at week 4, based on the results of full analysis set (FAS) and per protocol (PP) set analyses. The secondary endpoints were healing rate, ulcer area reduction rate, wound condition assessment, dressing change frequency, pain score, patient satisfaction, and safety.

Data analysis. Data analysis was performed using SAS software (version 9.2; SAS Institute Inc).

The FAS, PP set, and safety set were analyzed. The FAS population consisted of all patients who received at least 1 assigned treatment. The PP population consisted of all enrolled patients who satisfied the inclusion criteria of this study and completed the treatment defined in the protocol, without any major protocol violation. The safety population consisted of all patients who received at least 1 treatment with either SGF dressing or alginate dressing and had at least 1 safety-related follow-up visit or observation.

The difference and 95% CI of the primary endpoint (ie, efficacy rate) between the study group and the control group were calculated. Non-inferiority was established if the lower limit of the 95% CI for the difference between the 2 groups did not exceed −10% (the clinically significant threshold).

Group t test or rank sum test was used for comparison between the 2 groups, the chi-square test or exact probability method was used for categorical data, and the rank sum test or Cochran-Mantel-Haenszel (CMH) test was used for rank data. The 2-sided test was performed for all statistical tests, and P less than .05 was considered statistically significant. Statistical description was used for safety evaluation.

A total of 130 patients diagnosed with simple venous leg ulcers from 6 Chinese medical centers were enrolled and randomized to receive treatment with SGF dressing (study group) or alginate dressing (control group). Sixty-seven patients were allocated to the study group and 63 to the control group. All of these patients were included in the FAS. Sixty patients in the SGF dressing arm (89.6%) and 52 patients in the alginate dressing arm (82.5%) completed the study. Sixty-one patients in the study arm (91.0%) and 53 patients in the control arm (84.1%) were included in the PP set. All 130 patients were included in the safety set. Patient demographics are shown in Table 1.
 

Baseline characteristics. There was no statistical difference between the groups in general characteristics (age, sex, disease history, etc) or local wound characteristics (ulcer area, depth, duration, etc) at baseline.

Sixty-seven patients in the study group entered the FAS set, including 49 males and 18 females, with an mean age of 61 years (median 63.6 y, range 29-92 y) and a median disease duration of 2 months (range, 1 month - 2 years). Out of the 67, 62 (92.5%) had no major illness other than venous lower extremity ulcers within the past year. ABI was 1.136 ± 0.0963. The baseline ulcer area was 3.265 cm² ± 4.2473 cm².

The FAS covered 63 patients from the control group, including 38 males and 25 females. The mean age was 63 years (median 63.3 years, range 39-85 years), with a median disease duration of 2 months (range, 1 month - 2 years), and 56 (88.8%) of them had no major illness other than venous lower extremity ulcers within the past year. ABI was 1.110 ± 0.1047. The baseline ulcer area was 3.079 cm² ± 3.6475 cm².

According to chi-square analysis, there was no statistical difference between the 2 groups in baseline characteristics (P > .05) for either the FAS or the PP set. These results show that the 2 groups are comparable.

Primary endpoint: efficacy rate. Both dressings were found to be effective according to the results at week 4. In the FAS, the efficacy rates of the study arm and control arm were 89.6% (95% CI=79.7% - 95.7%) and 84.1% (95% CI=72.7% - 92.1%), respectively, a difference of 5.5% (Table 2). In the PP set, the efficacy rates of the study arm and control arm were 98.4% (91.2%, 100.0%) and 96.2% (87.0%, 99.5%), respectively, a difference of 2.2%. As a result, non-inferiority was established based on the predefined non-inferiority margin of −10%.

Ulcer area reduction rate. In the FAS, at week 4 the mean ulcer area of the SGF dressing group was reduced from the baseline of 3.265 cm² ± 4.2473 to 0.658 cm² ± 0.1497, whereas the mean ulcer area of the alginate dressing group was reduced from the baseline of 3.079 cm² ± 3.6475 to 1.259 cm² ± 3.3108. The overall mean ulcer area reduction rate at week 4 was 86.101% ± 23.8272 in the SGF dressing group versus 68.797% ± 56.9700 in the alginate dressing group. At week 8, the overall mean ulcer reduction rate was 93.699% ± 18.0029 in the SGF dressing group versus 88.635% ± 25.3434 in the alginate dressing group. No statistical difference was established between the 2 groups at week 4 (P = .4891) or week 8 (P = .3524).

In the PP set, at week 4 the mean ulcer area of the SGF dressing group was reduced from the baseline of 3.139 cm² ± 4.2347 to 0.658 cm² ± 1.4971, whereas the mean ulcer area of the alginate dressing group was reduced from the baseline of 3.278 cm² ± 3.8704 to 1.284 cm² ± 3.3384. The overall mean ulcer area reduction rate was 86.101% ± 23.8272 in the SGF dressing group versus 68.197% ± 57.3565 in the alginate dressing group. At week 8, the overall mean rate was 93.699% ± 18.0029 in the SGF dressing group versus 88.407% ± 25.5482 in the alginate dressing group. No statistical difference was established between the 2 groups at week 4 (P = .7067) or week 8 (P = .6593).

Healing rate. In the FAS, at week 4 the mean healing rate was 52.2% for the study group (35 of 67) and 46.0% for the control group (29 of 63). At week 8, the mean healing rate was 71.6% for the study group (48 of 67) and 63.5% for the control group (40 of 63). No statistical difference was observed between the 2 groups at week 4 (P = .1029) or week 8 (P >.99).

Similarly, in the PP set the mean healing rate was 57.4% for the study group (35 of 61) versus 52.8% for the control group (28 of 53) at week 4, and 78.7% for the study group (48 of 61) versus 73.6% for the control group (39 of 53) at week 8. No statistically significant difference was observed between the 2 groups at week 4 (P = .0808) or week 8 (P >.99).

Wound condition and local signs of infection. At each clinic visit, the wound condition was assessed by indicators including color, edge, redness, pain, edema, and exudate. The condition of the wound was assessed at each visit based on color, edge, redness, pain, edema, and exudate using a scale of 0 to 3, in which 0 = “good,” 1 = “moderate,” 2 = “poor,” and 3 = “very poor.” More patients in the study group than in the control group had a score of 0.

The study group seemed to have a greater “score 0” rate than the control group. In the FAS set, at 1 week, the “score 0” rate was 35.7% vs 21.8% for the control; at 2 weeks, it was 36.4% vs 30.4%; at 3 weeks, 45.5% vs 31.3%; and at 4 weeks, 70.8% vs 61.9%, respectively. In the PP set, at 1 week, the rate was 34.6% vs 25.0%; at 2 weeks, 39.0 vs 33.3%; at 3 weeks, 45.5% vs 32.3%; and at 4 weeks, 70.8% vs 61.0%.

According to statistical analysis, however, both in the FAS and in the PP set, there was no significant difference between the two groups at any week (all P >.05).

Frequency of dressing changes. According to the Wilcoxon rank sum test, there was no statistical difference in the nominal frequency of dressing changes between the 2 groups at any week (all P >.05).

In actual fact, however, for most patients treated with SGF dressing, the wound was clean and only the outer layer (the covering cotton gauze pad) needed to be replaced. The inner layer (SGF dressing) did not need to be changed within 1-2 weeks, and no debridement was required. Whereas for patients treated with the control dressing, the inner layers of the alginate dressings needed to be changed every time, and the wound often had to be debrided during the initial weeks. Therefore, the actual frequency of dressing changes was reduced in the SGF group when compared with that in the alginate group.

Pain score. Pain was assessed using the Visual Analogue Scale (VAS) scale each time when the primary wound dressing was removed. The scale consists of a horizontal line. The left end of the line signifies no pain (score 0) while the right end signifies the worst possible pain (score 10). The patients could simply mark a spot on the scale to express their perception of the intensity of their pain.

Pain levels were classified as no pain (score 0), minor pain (scores 1-3), moderate pain (scores 4-6), and marked pain (scores 7-10).

Most patients reported “no pain” or “minor pain,” only a small proportion reported “moderate pain,” and “marked pain” was least reported.

In the FAS set, at weeks 2, 3, and 4, the percentage of “no pain” was 61.4%, 67.6%, and 78.0% in the study group, and 43.5%, 53.1%, and 73.6% in the control group, respectively. In the PP set, the results were similar (65.9%, 67.6%, and 78.0% vs 45.2%, 54.8%, and 73.1%).

With regards to “marked pain” in the FAS set, there was only 1 patient in the study arm who reported “marked pain” at week 1 and 2; whereas in the control arm, 3, 2, 1, and 1 patient(s) reported “marked pain” at 1, 2, 3, and 4 weeks, respectively. In the PP set, no patients in the study arm reported “marked pain,” whereas in the control arm, 2, 1, 1, and 1 subject reported “marked pain” at 1, 2, 3, and 4 weeks, respectively.

There was no significant difference between the 2 groups in overall pain level at each week (all P > .05). However, patients treated with SGF dressing had a higher “no pain” rate than patients treated with alginate dressing at both week 2 (61.4% and 43.5%, respectively) and week 3 (67.6% and 53.1%, respectively).

Patient satisfaction. Patient satisfaction was evaluated at week 4 and week 8 via questionnaires using a scale of 1 to 5: 1, highly dissatisfied; 2, dissatisfied; 3, neutral; 4, satisfied; and 5, highly satisfied.

In the FAS, at week 4, 50 of 60 patients in the study group (83.3%) were highly satisfied and 10 of 60 (16.7%) were satisfied; in the control group, 41 of 52 patients (78.8%) were highly satisfied, and 11 of 52 (21.2%) were satisfied (Table 3). At week 8, 75% of patients in the study group were highly satisfied and 25% were satisfied, and in the control group 59.1% of patients were highly satisfied, 27.3% were satisfied, and 13.6% were neutral.

In the PP set, at week 4, 83.3% of patients in the study arm were highly satisfied and 16.7% were satisfied, and in the control arm 78.4% of patients were highly satisfied and 21.6% were satisfied. At week 8, 75.5% of patients in the study group were highly satisfied and 25.5% were satisfied, and in the control group 59.1% of patients were highly satisfied, 27.3% were satisfied, and 13.6% were neutral.

Wilcoxon rank sum test analysis showed no significant difference in overall patient satisfaction between the 2 groups at week 4 or week 8 (all P > .05). However, the study arm had a higher highly satisfied rate than the control arm at both week 4 (83.3% and 78.8%, respectively) and week 8 (75% and 59.1%, respectively).

Treatment-related AEs. A total of 3 patients in the study group experienced 3 cases of treatment-related AEs, including 1 case of wound infection (moderate), 1 case of skin ulcer (mild), and 1 case of skin abrasion (mild). A total of 2 patients in the control group experienced 4 cases of treatment-related AEs, including 2 cases of wound inflammation (1 mild, 1 moderate), 1 case of wound infection (moderate), and 1 case of venous ulcer pain (mild). No serious AEs occurred in either group.

Exact probability analysis showed no significant difference in treatment-related AEs between the 2 groups (P = .4093).

This clinical trial, which was designed as a non-inferiority study, compared the efficacy and safety of SGF dressing versus alginate dressing in the local treatment of venous leg ulcers. The efficacy rate at week 4 was chosen as the primary endpoint. In the FAS, the difference in efficacy rate between the study group and the control group was 5.5% (89.6% and 84.1%, respectively), and in the PP set the difference was 2.2% (98.4% and 96.2%, respectively). Thus, the non-inferiority of SGF dressing to alginate dressing was established based on the prespecified margin of −10%.

Non-inferiority was also supported by secondary endpoints. No statistical difference between the 2 groups was observed in healing rate, ulcer area reduction rate, wound condition, overall pain score, or overall patient satisfaction (all P > .05). Patients treated with SGF dressing had a higher "no pain" rate than those treated with alginate dressing at week 2 (61.4% and 43.5%, respectively) and week 3 (67.6% and 53.1%, respectively), and a higher highly satisfied rate at both week 4 (83.3% and 78.8%, respectively) and week 8 (75% and 59.1%, respectively).

The SGF dressing group had an acceptable healing rate of 52.2% at week 4 and 71.6% at week 8, indicating that it is an effective wound dressing.

The fact that SGF outperformed alginate dressings in dressing change frequency is an unexpected finding.

A reduction in frequency of dressing changes can prevent unnecessary mechanical damage and minimize pain during application and removal, which makes it an important indicator for selecting a wound dressing. 

In the SGF dressing group, although there was no reduction in nominal number of dressing changes, in actual fact only the outer layer (ie, the covering cotton gauze pad) was frequently changed. The inner layer did not need to be changed during the first 1-2 weeks after application. Therefore, the actual frequency of dressing changes was substantially reduced in the SGF group.

A probable explanation for the reduced number of dressing changes may lie in the special scaffold mechanism that enables SGF dressing to promote healthy cell growth and enhance self-humidity regulation and antimicrobial activities, which can lower the infection risk even if the dressing is not changed within 1 to 2 weeks.

Venous ulcers of the lower extremity included in this clinical trial are considered as often difficult-to-heal wounds that are susceptible to microbial invasion and can lead to serious complications. [A] In the present study, during the treatment of venous ulcers, the incidence of spreading infection (according to the 2022 IWII consensus¹⁰) was low, although the SGF was not an infection-resistant material and did not contain special antimicrobial property. Prior to enrollment, only local infection was seen in patients; during the study process, 3% (2/67) of patients suffered spreading infection.

The most reasonable explanation for the low incidence of spreading infection in the SGF dressing arm is that complete debridement had been performed prior to enrollment to ensure that the wounds were not contaminated or infected, and the dressing itself, if properly applied, could act as a physical barrier to outsider contaminants. On the other hand, on the basis of the efforts eliminating venous hypertension, the application of SGF dressing further improved the wound milieu, promoted cell growth, and shortened the duration of healing, thereby decreased the chance of infection.

Regarding safety, according to the data mentioned above, both dressings were well tolerated, adverse events were rare, and most of them were mild. There were no dressing-related serious adverse events or deaths in either group. Exact probability analysis demonstrated that the 2 dressings were comparable in safety, and there was no significant difference in treatment-related AEs between the two groups (P =.4093). As such, it can be stated that SGF has a reliable safety profile.

The present study was designed as a non-inferiority trial. Therefore, there is a lack of data that directly demonstrate the superiority of the SGF dressing over the control. Further investigation should be conducted based on superiority study design.

For local treatment of venous leg ulcers, SGF dressings are not inferior to alginate dressings. Additionally, use of SGF dressings could substantially reduce the frequency of dressing changes, alleviate pain during dressing application and removal, and improve patient comfort. During the healing process, spreading infections rarely occurred in the study group. These results may prompt research into the use of SGF dressing in the care of other chronic wounds.

Affiliations

¹Department of Interventional Radiology and Vascular Surgery, Wound Healing Center, Peking University Third Hospital, Beijing, China; ²Department of Cardiovascular Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang, China; ³Department of Cardiovascular Surgery, Affiliated Hospital of Qingdao University, Shandong, China; ⁴Wound Diagnosis and Treatment Center, Jinshan Hospital Affiliated to Fudan University, Shanghai, China; ⁵Department of Cardiovascular Surgery, Taizhou Hospital of Zhejiang Province, Zhejiang, China; ⁶Jiangsu Synecoun Medical Technology Co., Ltd, West Side of Chengkou Road, Taizhou City, Jiangsu Province, China; ⁷Professor, Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Address all correspondence to: Xingwu Lu, MD, Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China; luxinwu@shsmu.edu.cn

Conflict of interest

The authors have no conflicts of interest to declare that are relevant to the content of this study.
 

Author contributions

L. Zhang, RP. Dong, and XW. Lu revised/edited the manuscript and accepted the final draft of the manuscript.

Acknowledgments

The authors are thankful to the patients who volunteered to participate in this study. (H.F.W. at the Affiliated Hospital of Qingdao University; W.J.Z. at Taizhou Hospital of Zhejiang Province; J.Y. at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine; and X.C.Z. at Jinshan Hospital of Fudan University)

1. Eberhardt, R.T.; Raffetto, J.D. Chronic venous insufficiency. Circulation. 2014;130:333–346. doi:10.1161/CIRCULATIONAHA.113.006898
    
2. Chi, Y.W.; Raffetto, J.D. Venous leg ulceration pathophysiology and evidence based treatment. Vasc. Med. 2015, 20, 168–181. doi: 10.1177/1358863X14568677
    
3. Finlayson K, Edwards H, Courtney M. Relationships between preventive activities, psychosocial factors and recurrence of venous leg ulcers: a prospective study. J Adv Nurs. 2011;67(1):2180-2190. doi:10.1111/j.1365-2648.2011.05653.x
    
4. Crawford JM, Lal BK, Durán WN, Pappas PJ. Pathophysiology of venous ulceration. J Vasc Surg Venous Lymphat Disord. 2017;5(4):596-605. doi:10.1016/j.jvsv.2017.03.015
    
5. Briggs M, Closs SJ. The prevalence of leg ulceration: a review of the literature. Ewma Journal. 2003;3(2):14-20.
    
6. Robert B Diller, Aaron J Tabor. The role of the extracellular matrix (ECM) in wound healing: a review. Biomimetics (Basel). 2022;7(3):87. doi:10.3390/biomimetics7030087
    
7. Badylak SF. The extracellular matrix as a scaffold for tissue reconstruction. Semin Cell Dev Biol. 2002;13(5):377–383. doi:10.1016/s1084952102000940
    
8. Tracy LE, Minasian RA, Caterson EJ. Extracellular matrix and dermal fibroblast function in the healing wound. Adv Wound Care (New Rochelle). 2016;5(3):119–136. doi:10.1089/wound.2014.0561
    
9. de Oliveira GV, Nunes TA, Magna LA, et al. Silicone versus nonsilicone gel dressings: a controlled trial. Dermatol Surg. 2001;27(8):721-726. doi:10.1046/j.1524-4725.2001.00345.x
    
10. Singer AJ, Clark R. Cutaneous wound healing. N Engl J Med. 1999;341(10):738-746. doi:10.1056/NEJM199909023411006