JSUR Journal

Introduction

Diabetic Foot Ulcers (DFUs) are among the many complications associated with diabetes over time. Even if the ulcer is relatively shallow (UT1A, Wagner Grade 1), patients are at risk of amputation if Standard of Care (SOC) measures are ineffective [1]. Foot ulcers form and prognosis result from the interaction and joint action of many factors closely related to neurological dysfunction, extravascular lesions, and infectious conditions.[2] Therefore, it is particularly urgent and necessary to study the intrinsic causes of foot ulcer healing, optimize existing treatment protocols further, and actively explore effective early prevention and treatment. Wound healing is a finely tuned process involving various cells, including epidermal, dermal, endothelial, and immune cells, and can be divided into overlapping phases.[3] At the onset of the injury, the wound enters an inflammatory phase, during which immune cells infiltrate the wound site; at the same time, cells from the epidermis and dermis begin to proliferate and migrate to the wound bed to fill the wound defect.[4] This is followed by a proliferative phase in which epidermal and dermal cells proliferate and migrate, further contributing to wound closure.[5] This is followed by the remodeling phase, where dermal cells undergo extracellular matrix deposition and remodeling.[6] Unlike acute wounds, the healing process of Diabetic Foot Ulcers (DFUs) and other chronic wounds is not a step-by-step linear progression from one stage to the next, as is the case with acute wounds.[7] The main characteristic of such chronic wounds is the presence of ongoing chronic inflammation [8].

Various biomaterials, including hydrogels, are used in relevant therapeutic areas and can produce significant therapeutic effects.[9] These biomaterials provide a suitable and supportive environment for the cells, which helps the cells survive and precisely regulates the release of bioactive factors.[10] Through this mechanism of action, the therapeutic efficacy of Mesenchymal Stem Cells（MSCs（can be effectively enhanced.[11] Further, this application can improve the overall wound healing status in all aspects and enhance the healing effect. Alginate dressings have been successfully marketed and used in wound care since the 1980s, when Sorbsan was introduced as a treatment option for diabetic and nutritional ulcers.[12] Since then, many different brands of dressings have been produced and commercialized. Today’s dressings are available in various shapes and sizes, designed to meet multiple needs. Alginate dressings are suitable for the management of superficial wounds and lacerations, as well as for the treatment of cavities that often occur during the development of bedsores [13]. This study aimed to explore the role of alginate gel in diabetic foot healing.

Methods

Study Design

The study was a randomized controlled trial in which participants were randomized (1:1) to either the Alginate Care or the placebo arm. Randomization is done by pre-prepared sealed random envelopes containing a unique three-digit random number, preassigned to one of the treatment groups. Figure 1 provides a flowchart of the recruitment and allocation of study participants. All participants signed an informed consent form, and the Institutional Review Boards of all participating institutions approved the study (2024-013-01).

Subjects

The main inclusion criteria for participation in the study were Diabetic patients aged 18 years or older with unhealed wounds, uninfected DFUs with a Wagner grade <3 (no osteomyelitis), and

0.5-12 cm2. Therefore, chronic diabetic foot wounds with adequate wound pre-treatment and post-surgical amputation wounds below the upper ankle were eligible for inclusion in the study. Exclusion criteria consisted of four components: possible noncompliance with study requirements, presence of necrotic tissue that could not be debrided or required amputation, exposed vessels that could not be covered or bleeding that interfered with hemodynamics (especially posterior tibial and dorsalis pedis arteries), and severely impaired coagulation.

Interventions

The study treatment with Alginate Care or placebo gel started at the baseline visit. The study gel (Alginate Care group) or matrixmatched placebo was applied directly to the wound bed using aseptic technique to form a complete coverage layer and extend a 1-cm coated area to the surrounding healthy skin, and after the gel had cured to form a pliable protective film, an inert standardized dressing was superimposed for secondary coverage, with dressing change intervals adjusted according to the amount of wound exudate to ensure that standardized care procedures were carried out at least 2-3 times per week. In patients with multiple wounds, the largest ulcer≥2 cm from other lesions was selected as the target wound.

Outcomes

The primary outcome was wound closure (100% epithelialization of the wound, no drainage, no suture material, no wound dressing or adjuvant required). The maximum study treatment period was 12 weeks. Secondary endpoints included (1) reduction in wound area. (2) at least 50% and 75% wound closure. (3) pain scores at 12 weeks. (4) Improvement in wound status as assessed by the BWAT score and the Wagner Ulcer Classification. (5) occurrence of adverse events.

Statistical Analysis

Sample Size: Based on previous data, the wound closure rate at week 10 was expected to be 50% in the placebo group and 75% in the Alginate Care group. Thirty patients per arm were needed to rule out the null hypothesis at α = 0.05 and efficacy of 0.80. The dropout rate was 10%, so a total of 80 patients, 40 in each study arm, were needed.

Statistical Methods: Data were reported as the mean ± Standard Deviation (SD). Statistical analyses were performed using SPSS Version 26 (IBM Corp, Armonk, NY, USA). A paired t-test was used to compare the blood glucose levels before and after the intervention. Two independent sample t-tests were used to compare baseline and intervention data between groups. For count data, frequencies and percentages were presented. Two-way ANOVA was used to compare multiple groups. p < 0.05 was considered an indication of statistically significant differences.

Result

Baseline Characteristics of Participants

The flow of participants is illustrated in Figure 1. Initially, 100 individuals were evaluated at baseline, among which 90 fulfilled the inclusion criteria and consented to enroll in the study. These participants were then randomly assigned in a 1:1 ratio to two groups: the Alginate Care group and the placebo group. In the Alginate Care group, two participants refused cooperation and three became unreachable, leading to their withdrawal from the study. Three participants exhibited poor compliance in the placebo group, and two lost interest, resulting in their dropout. In the end, there were 40 participants in each group. As demonstrated in Table 1, all baseline indicators were comparable among the two groups, with no significant differences observed.

Figure 1: Flow diagram of the study participants.

a Self-reported as drinking 3 or more alcoholic drinks (can/bottle) per typical week.

BMI = body mass index; HbA1c = glycosylated hemoglobin;

Table 1: Baseline Characteristics of the Participants.

Primary Outcomes

After 12 weeks of treatment, 7 of 40 wounds (17.5%) healed in the AlginateCare group compared with 2 of 40 (7.5%) in the placebo group (Table 2).

Secondary Outcomes

The Alginate Care group significantly outperformed the placebo group on key wound healing metrics, with a 10% improvement in complete healing (17.5% vs. 7.5%, P=0.021), a 32.5% improvement in healing above 75% (57.5% vs. 25%, P=0.013), and a doubling of wound area reduction (70.2% vs. 34.8%, P= 0.016) (Table 2). The Bates-Jensen score decreased up to three times as much as in the placebo group (-31.1% vs -10.6%, P=0.022), suggesting multidimensional improvement of the wound regarding exudate, necrotic tissue, and margin status (Table 2). Alginate Care has shown significant efficacy in promoting wound healing. This finding has important implications for developing more effective wound care products or treatments that may help reduce wound healing time, minimize the risk of infection, and improve patients’ quality of life (Figure 2).

Table 2: Study outcomes at week 12 for AlginateCare and placebo groups.

Figure 2: Weekly healing rates by treatment group.

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