Efficacy of Cold Atmospheric Plasma in Chronic Diabetic Foot Ulcer Management: A Case Report

Introduction

Diabetes is a chronic medical condition characterized by elevated blood glucose levels [1,2]. This condition occurs when the body either cannot produce enough insulin or creates resistance to the insulin produced [1,2]. Insulin is a hormone crucial for regulating blood sugar and allowing cells to absorb and utilize glucose for energy [1,2]. There are different types of diabetes, including type 1, type 2, and gestational diabetes, each with its unique causes and risk factors [3,4].

Diabetes has emerged as a significant global public health concern, with type 2 diabetes mellitus posing a rapidly escalating threat [4]. In the United States, the scale of this issue is profound, with over 15 million individuals struggling with diabetes and an additional 20 million facing impaired glucose control [5,6]. The collective impact translates into an annual cost exceeding $100 billion in the United States [7,8].

The intricacies of diabetic foot ulcers further compound the challenge, as these wounds are notorious for their slow healing process [9]. The presence of comorbidities, such as peripheral vascular disease, hypertension, obesity, and venous insufficiency, among patients with diabetes exacerbates the complexity of treating these ulcers [10]. Additionally, inadequate wound and foot care practices contribute significantly to the financial toll, surpassing $8 billion in the United States alone [7,8]. This alarming scenario underscores the urgent need for comprehensive strategies to address the multifaceted aspects of type 2 diabetes and its associated complications, like diabetic ulcers [7,8].

Considering these factors, our study delves into the complex case of a 69-year-old man dealing with a persistent diabetic foot ulcer, a type of wound associated with diabetes. His 1.68-cm2 ulcer wound persisted for 60 weeks on the plantar surface of his left foot - a tangible manifestation of his ongoing struggle with type 2 diabetes mellitus, hypertension, hyperlipidemia (high levels of fats in the blood, including cholesterol and triglycerides [11]), and benign prostate hyperplasia (enlargement of prostate glands [12]).

In response to this multifaceted situation, the patient embarked on a 4-week trial that merged conventional wound care treatment with cold atmospheric plasma (CAP) therapy by the Plasma Care device. Alternatively known as non-thermal or low-temperature plasma therapy, this treatment stands out as an advanced approach to wound healing [13]. This method entails applying plasma, composed of ions (positively charged particles) and free electrons (negatively charged particles), at room temperature, also known as CAP [14]. The mechanism of action involves the interaction of the plasma components with the wound environment [15]. This interaction produces reactive oxygen species, free radicals (atoms or molecules with unpaired electrons, which can react quickly with other substances in the wound), and other charged particles [16], orchestrating a comprehensive response to combat pathogens, including bacteria, viruses, fungi, or parasites, and stimulating wound healing [16]. Within this innovative context, CAP promotes cell proliferation, migration, and differentiation, which is crucial for tissue repair and maintenance [17].

CAP also has the ability to reduce inflammation [18,19] and enhance the synthesis of specific growth factors (proteins that stimulate cell growth and proliferation) by targeting microorganisms that reside in the biofilms of the wound without causing harm to surrounding healthy tissues [20]. A study evaluating bacteria load on wounds revealed a significant (40%, P<0.016) reduction in bacterial load in plasma-treated wounds when treated every day for 2 min, regardless of the species of bacteria present [21]. Its antimicrobial properties can potentially eliminate bacteria [22] and prevent wound infections while promoting tissue regeneration and accelerating the overall healing process [16,23]. In addition, another study showed that the application of CAP can also improve microcirculation in chronic wounds [24]. It is a noninvasive and effective tool in wound care. This makes it a potentially promising option for treating chronic wounds, diabetic ulcers (25], skin graft donor site wounds [26], and other non-healing wounds [27].

Case Report

A case report of a patient with a chronic diabetic foot ulcer highlights several important insights into the potential effectiveness of CAP therapy in managing hard-to-heal wounds. This report showcases a 69-year-old man with a medical history of hypertension, type 2 diabetes mellitus, hyperlipidemia, and benign prostate hyperplasia who sought medical attention at the Wound Care clinic due to a persistent ulcer on the plantar surface of his left foot. Notably, the patient had experienced an ulcer in the exact location 6 months prior, which initially closed but later reopened. Initial physical examination revealed an open wound on the left foot, with abundant callus formation on the peri-wound and without clinical signs or symptoms of infection in the wound or surrounding tissues. The ulcer measured 1.68 cm2 and was categorized as a diabetic foot ulcer Wagner grade 2.

However, despite the patient being retired and having followed every management plan he had been instructed to follow, the standard wound care treatment and several clinical trials, such as hydrolyzed collagen powder (a type 1 bovine hydrolyzed collagen), Dual Layer Amnion-chorion graft, porcine placental tissue graft, and a polyhexamethylene biguanide (PHMB-1) based antibiofilm cleanser and topical gel (Biakos), failed to improve his wound. In addition to every treatment, the patient had been offloading his left leg by wearing a Defender boot, a type of shoe designed with cushioning that prevents the weight from being placed on the limb, allowing better blood flow and promoting faster healing [28].

On September 25, 2023, the patient was enrolled in a new trial, A Prospective Case Series Evaluating the Safety and Effectiveness of Cold Atmospheric Plasma (CAP) and Standard of Care in the Treatment of Hard-to-Heal Wounds. CAP is a state of matter created by adding energy to a gas at ambient air temperature, working in combination with reactive oxygen and nitrogen species, such as O3, H2O2, and NO2, as therapeutic components [29]. It produces the inactivation of pathogens, such as fungi [30] and bacteria [31]. It also promotes wound healing by stimulating the release of cytokine that triggers cell growth and angiogenesis [13,32].

At the start of the trial assessment, the ulcer wound had an area of 1.06 cm2, with a depth of 0.3 cm. There were no visible signs of an infection in the wound or the surrounding tissue (Figure 1). Still, after using the MolecuLight, a device that provides precise digital wound measurements and detects bacterial loads [33], it was revealed that there was an area of red fluorescence indicating an elevated concentration of bacteria in the peri-wound (Figure 2). In fluorescence light, fluorophores, molecules that can absorb light and then emit it [34], bind to bacterial structures or their components, causing them to emit red fluorescence when exposed to particular wavelengths of light [35]. However, as elevated bacterial load in fluorescence images does not always correlate with clinical infection, no bacterial wound culture was taken, due to the lack of signs and symptoms of infection in the patient.

During the treatment, the patient received a 2-min session of CAP twice a week. On each visit, the wound was assessed for signs of ulcer healing. The ulcer size was measured using the MolecuLightDX imaging device, with weekly fluorescence images captured to monitor bacterial load, and swabs were employed to collect host proteases. The wound was cleansed with polyhexamethylene biguanide (PHMB-1) bacterial cleanser, and sharp mechanical debridement with a scalpel and a dermal curette was performed as needed to eliminate callus in the peri-wound to expose healthy tissue. Then, a 4×4 gauze soaked with Biakos spray was applied for 10 min to help eliminate microbes from the wound. The wound was then filled with bovine hydrolyzed collagen powder as a dressing and covered with a hydrocellular foam dressing. The patient received instructions to change the wound dressing every 2 days and to offload the left foot using the Defender boot.

After 3 weeks into the treatment, the wound responded with a decrease in its surface area to 0.54 cm2 and depth to 0.2 cm (Figures 3, 4), with a minor reduction in bacteria expression (Figure 5).

After 4 weeks of treatment, the wound continued to heal but was not fully closed. Considering the wound improvements and percentage reduction of 48.11% in the area, the primary investigator, Dr. Serena, extended the treatment protocol to 15 weeks. By the 15th week, the wound went into complete closure (Figure 6). The patient could return to his normal activities and was instructed to continue a diabetic diet and regular foot care.

Discussion

Diabetes mellitus type 2 is increasingly prevalent worldwide, imposing significant healthcare costs due to its complications [8]. In the United States alone, over 15 million individuals are affected by diabetes, with an additional 20 million experiencing impaired glucose control, leading to annual costs exceeding $100 billion [4]. Among the complications associated with diabetes, diabetic foot ulcers pose a particularly challenging problem. These difficult-to-heal ulcers often result from a combination of factors, including peripheral vascular disease, hypertension, obesity, and venous insufficiency [36]. Together, these comorbidities and inadequate foot care contribute to a financial burden exceeding $8 billion in the US alone [8].

The case report highlights the urgent need for comprehensive management strategies for treating diabetic foot ulcers. These chronic ulcers can take months or even years to heal fully, necessitating a multifaceted approach to care. A similar study in Germany found in a randomized clinical trial comparing CAP therapy with standard wound therapy that CAP demonstrated shorter healing times and more complete closures [37].

In this case study utilizing CAP therapy, another remarkable outcome was observed: the patient’s leg wound decreased by over 70% of its area during the first four weeks of treatment. Due to the promising outcomes observed with CAP therapy, the initial 4-week duration of the trial was extended. This extension, sanctioned by a waiver from the principal investigator, Dr. Serena, reflected the CAP potential as an innovative treatment in managing complex conditions, such as diabetic foot ulcers. It also underscored the importance of flexibility and adaptability in clinical trials to maximize patient outcomes and advances in diabetes care.

During treatment, the patient was instructed to adopt a diabetic diet, which may have contributed to improved wound healing, as glycemic control is known to affect recovery [38,39]. Additionally, education on offloading the limb was provided, to reduce pressure on the wound. Risk factors for reopening a closed ulcer included diabetic neuropathy and poor daily foot care by the patient, which could also have slowed the healing progress of the ulcer.

The limitation of the report was that its findings were based on no more than 1 case study. The small sample size made it challenging to draw definitive conclusions about CAP therapy as a treatment for diabetic foot ulcers, chronic ulcers, and ulcers in general. Nonetheless, preliminary results indicate positive outcomes for CAP in managing hard-to-heal wounds in patients with diabetes. Further research is essential to establish more robust evidence. This report aims to foster interest in developing effective treatments for diabetic foot ulcers, a growing concern among the diabetes population that is steadily rising [6].

Conclusions

This report has highlighted the challenges of managing chronic diabetic foot ulcers and has shown that CAP may promote wound healing. CAP appears effective not only in enhancing wound closure but also in inactivating pathogens while preserving surrounding healthy tissue.