Protocol-driven Therapy for Lower Extremity Ulcers: A Case Series Supporting the Use of Porcine Intestine Extracellular Matrix

Chronic wounds pose both professional and health system challenges due to their complexity and economic burden. The global social impact of chronic wounds is a consequence of their high occurrence and the increased frequency of chronic wounds in adults 65 years and older. As many as 4.5 million people in the United States have chronic wounds, which have many causes, including arterial or venous insufficiency and diabetes.^1,2

Venous leg ulcers are the most common type of chronic leg injury. These wounds account for the majority of lower extremity ulcerations,^3,4 with an estimated lifetime prevalence of 1% in adults⁵ and even higher rates among older adults.⁶ The prevalence of any open lower extremity ulceration ranges from 1.2 to 11 per 1000 inhabitants in developing countries.⁷ These injuries represent a significant financial burden on US taxpayers, with an estimated annual medical cost of up to $18 billion.⁸

A number of products and dressings for use in the management of chronic wounds are available worldwide.⁹ However, this variety of options, combined with a general lack of high-quality evidence that justifies their use, adds to the challenge of treatment selection.^10-12 In chronic wounds, ECM serves as a scaffold for rapid vascularization and cellular invasion. Both processes provide nutrients and signals to support dermal regeneration and epithelial cell proliferation. The presence of multiple growth factors, each of which plays an important role in the stimulation and regulation of tissue regeneration, is important to wound healing.¹³

These growth factors create a temporary granulation tissue matrix and scaffold, which aids in the repair process, providing structural integrity during each stage of healing.^14-16 This explains the utility and suitability of ECM. Also, it serves as a modulator of cytokines and growth factor actions, thereby regulating the repair activity of the wounds. Thus, the ideal treatment matrix is biocompatible, is nontoxic, promotes regeneration and cellular incorporation, and completely integrates at the recipient tissue site.¹⁷

There is limited evidence on the beneficial effects of ECM in chronic wound healing. Lack of diagnosis and proper treatment have been reported as key factors in delayed healing of such wounds.¹⁸ Initiatives aimed at improving chronic wound treatment significantly influence the total cost of these treatments.¹⁹ The present study aimed to evaluate the evidence of chronic wound management through a new protocol, local and systemic, that includes the application of an ECM.

Study design

This randomized 16-week clinical study included a maximum of 12 weeks of ambulatory treatment. The study was conducted in the chronic wound unit at San Juan de Girón Hospital in Girón, Colombia. Participants were selected and assigned to the treatment group after the protocol was explained to them and written informed consent was obtained from each participant.

Study population

Inclusion criteria were as follows: a history of some degree of vascular disease evidenced by venous Doppler ultrasound, a chronic wound between 0.5 cm² and 10 cm² in size in any anatomic area, no clinical signs or symptoms of ulcer infection and with optimal management of underlying pathology, attendance in an outpatient program, and aged 18 years and older.

Exclusion criteria included exposed bone, tendon, or fascia; severe rheumatoid arthritis; uncontrolled congestive heart failure; history of radiation therapy to the wound site, immunosuppressed status, or disease vascular collagen; malnutrition; immune response to pork derivatives; controlled nondiabetic status with HA_1c level greater than 7; transplant; cultural or religious objections to the use of products derived from swine; ankle-brachial index greater than 0.8; sickle cell anemia; or cognitive disability that prevented the patient from adhering to the protocol.

Ethics

This research was carried out in accordance with Resolution Number 08430 of 1993 of the Colombia Ministry of Health, which establishes scientific, technical, and administrative standards for health research. This study was considered “greater than minimal risk” and was reviewed and approved by the ethics committees of the institutions involved. Written informed consent was obtained from all participants.

Intervention

The healing protocol included 2 phases. The initial phase consisted of wound disinfection with an antibiofilm agent used specifically for wounds and mucous membranes (Octenisept; Schülke & Mayr GmbH), regardless of the clinical appearance of the wound. The antiseptic was applied 3 times a day for 1 week. The wound was thoroughly washed with saline solution and subsequently dried before application of the antibiofilm agent. Patients with ulcers with necrotic tissue on initial presentation or who required ultrasonic or enzymatic collagenase wound debridement under anesthesia in week 1 underwent this protocol at the end of week 2. At this time, an initial wound measurement of all patients’ wounds was taken. This phase was the same for all patients.

In the second phase, the ECM membrane (Regenesis; Osteophoenix) (Figure 1A and 1B) was applied once a week after cleaning the wound with sterile saline and applying antiseptic for treatment of biofilm. The membrane was sized to achieve an approximately 1 cm overlap at the wound edge. The membrane was moistened with saline solution and covered with a nonadherent dressing and a compression bandage. This process was repeated once per week using a new membrane, after the previous one had absorbed. The patients were instructed to keep the bandage dry and covered unless warning signs appeared, such as pain in the extremity, itching, or fever.

At 12-week follow-up, the ulcer was evaluated and measured, any AEs were noted, and the wound area was assessed to determine whether a debridement and/or assigned protocol or standard of care treatment was necessary. Follow-up evaluation continued for 4 weeks after completion of the protocol or total wound healing to assess the durability and note any additional conditions or events. For wounds that did not exhibit tissue regeneration, medical follow-up was performed to ensure patients received adequate treatment. The complete protocol is described in Figure 2.

An initial descriptive analysis was conducted for patients who completed the protocol. The sociodemographic and clinical characteristics of the study population are presented in the Table. A gradual decrease in wound size (in centimeters) was observed, as shown in Figures 3 and 4.

Most of the study participants were female homemakers who were dedicated to daily household tasks. Diagnoses of study participants included dyslipidemia and diabetes. Medical history of altered nutrition and sedentary status were identified in all patients. The average body mass index was 22.7. Peripheral vascular disease together with arterial hypertension was the most relevant pathologic antecedent, as corroborated by the medical history in 15 of the 21 participants.

Two of the 21 participants withdrew from the study, 1 because of pathologic exacerbation of the wound base and the other because of nonadherence to home care follow-up. However, changes were recorded through their final follow-up visit. These 2 patients later underwent wound management at the same health care institution.

Weekly follow-up was performed, at which time photographs were taken and wound measurements noted. Wounds were also assessed for signs of infection. The evolution of 3 cases is shown in Figures 5, 6, and 7.

Historically, compression therapy was the standard treatment for pressure ulcers. However, timely healing was not achieved in up to 75% of patients.^20,21 Ulcer healing rates of 68% to 83% at 24 weeks have been reported with compression therapy²²; however, this rate drops dramatically to 34% to 42% at 12-week follow-up.²¹ Healed ulcers have reportedly recurred in approximately 26% to 28% of patients at 12 months.²² A systematic review reported on a wide variety of products that have been evaluated for their efficacy in the management of chronic ulcer, including patches with silver, honey, and aloe vera, with imprecise results.²³ Many of these products have limited use because of their high price; thus, it is necessary to seek a fast, safe, and cost-effective strategy.

Biomaterials have become critical components in the development of new, effective medical therapies for wound care. New and varied applications for different therapies are being evaluated. Skin substitutes are more cost-effective biomaterial derivatives of natural ECM that provide a new option to stimulate wound closure.²⁴ These substitutes promote dermal wound granulation and epithelialization as well as effective regulation of evaporation and exudate, and they protect the wound site from bacterial infection. In the present case series, promotion of granulation and epithelialization occurred in wounds treated with the new wound care protocol wherein ECM was used, and complete wound closure was achieved in all participants in a short time compared with similar treatments reported in the literature.²³ These results demonstrate the efficacy of this protocol even under extreme chronic wound conditions following years of unsuccessful management with conventional methods. Strict adherence to the protocol is important to achieve satisfactory results, in addition to patient communication and education.

Some studies have reported the use of ECM obtained from ovine collagen in the management of chronic wounds. However, studies of the efficacy of such products reported conflicting results. Some studies showed complete wound closure in a total of 20 weeks, whereas others reported worsening of wounds and reopening of new lesions. Reported cases showed total wound closure in 8 weeks, without related AEs.^25,26

Oasis Wound Matrix (Cook Biotech Inc) is one of the protocols that showed greater efficacy in a shorter time. Application of this product resulted in an average wound closure rate of 55% at 12-week follow-up.²²

These previously published results regarding time to wound closure are different from those in the present study, in which the average time to wound closure was 4.5 weeks. Time to closure in the present study is similar to that reported in a study of porcine mesothelium matrix, which generally showed advantages of using this type of membrane (8 weeks).²⁷

In the present study, the most relevant finding was wound healing speed. A similar study in Canada in which ovine stomach matrix was used to heal various wound types reported full closure at 12 weeks without any AEs.²⁸ Romanelli et al²⁹ reported complete closure in 80% of cases in the ECM group compared with 65% in the control group (ie, standard of care). These results reaffirm the benefits of ECM in the management of chronic wounds,³⁰ in which the application protocol and timing play an important role in time to wound closure.

Some studies that reported similar protocols showed efficacy in just 71% of patients.³¹ A multicenter study by Urciuolo et al reported a success rate of 40% at 12 weeks in 67 patients treated with the extracellular matrix for pressure ulcers.³² A similar study by Chandler et al reported a wound closure rate of 42% for patients in the wound conforming matrix cohort at 12 weeks.³³ While these studies' results were not as positive as those in the present study, the data verify the efficacy of the protocol applied in this study using the ECM and support its usefulness for tissue regeneration.³³

Other evaluated strategies, such as that studied by Mostow et al,²² compared SIS therapy plus compression therapy versus compression therapy alone for 12 weeks, with a 6-month follow-up. A recovery rate of 55% with SIS and compression therapy was reported, versus 34% with compression therapy only, with no recurrence at 6 months in the SIS group.²⁷ A prospective randomized controlled study by Cazzell et al¹⁰ compared the effectiveness of SIS versus conventional therapy in 82 patients. It showed similar results, with closure of 55% of injuries in the treatment group at 12 weeks, versus 32% with conventional treatment.³⁴ The protocol evaluated in this study showed marked differences not only in time but also in comparison with other adjuvant therapies.

This study is limited by the small number of cases. Additional studies that include more cases and more extensive wounds are necessary to assess the effect of the protocol presented herein on healing wounds originating from other pathologies as well.

Patients who completed the entire protocol achieved total wound regeneration. The present study demonstrated 98% efficacy of a new wound management protocol using a porcine intestine ECM. This protocol is safe; of less than 8 weeks’ duration, which promotes optimization of resources; and without AEs. Results were maintained 1 year after study completion.

The results of the present study reaffirm the importance of using this protocol in public institutions to provide timely and efficient chronic wound care. This is a great advancement in countries where this development would have an important socioeconomic impact. In addition, the medical cost per episode was evenly distributed throughout the treatment course, which showed that reduced healing time substantially decreased medical care costs and indicated that strategies such as the ECM protocol are a viable and safe treatment option.

Future research should include patients with larger wounds of different pathologic origin, including burns.