Effectiveness of Type I Collagen Matrix Plus Polyhexamethylene Biguanide Antimicrobial for the Treatment of Pressure Injuries

Normal wound healing involves a series of phases that includes hemostasis, inflammation, proliferation, and remodeling. In chronic wounds, the healing process is often arrested in the inflammatory phase. This phase is characterized by increased levels of inflammatory mediators and matrix metalloproteinases (MMPs), which damage growth factors and the extracellular matrix (ECM) that are required for wound healing. These wounds are superficially colonized with high levels of bacteria that stimulate the immune cells to release proteolytic enzymes that damage the ECM. The formation of a polymicrobial biofilm supports the excessive bacterial bioburden, which is considered the primary cause of a prolonged inflammatory response and delayed healing.^1,2 Microbes associated with the biofilm produce an extracellular polymeric substance composed of a very dense collection of proteins, sugars, and other factors that acts as a protective layer to impair diffusion of inflammatory cells (eg, neutrophils and macrophages) as well as antibodies and antibiotics.³

Pressure injuries (PIs) are chronic cutaneous wounds localized to the skin or underlying tissues over a bony prominence. They are the result of sustained pressure or pressure in combination with shear and/or tissue deformation and affect more than 2.5 million individuals in the United States annually.^4,5 Populations at highest risk for the development of PIs include elderly people; those in critical care, palliative care, community care, or rehabilitation settings; those with spinal cord injury or obesity; and neonates and children. In general, these individuals are sedentary and have multiple comorbidities. Overall, the highest rates of PIs are reported in critically ill patients in hospitals.⁴ The prevalence of PI varies from approximately 9% to 32% in long-term care facilities and from 3% to 19% in patients in home care, with most of these lesions categorized as stage 1 and stage 2.^6-9 The National Pressure Injury Advisory Panel (NPIAP) staging criteria were applied in the study. Briefly, stage 1 is defined by intact skin with a localized area of nonblanchable erythema. Stage 2 is defined by partial-thickness loss of skin with exposed dermis. Stage 3 is characterized by full-thickness loss of skin, in which adipose (fat) is visible in the ulcer and granulation tissue and epibole (rolled wound edges) are often present. Stage 4 shows full-thickness skin and tissue loss with exposed or directly palpable fascia, muscle, tendon, ligament, cartilage, or bone.¹⁰

Like most chronic wounds, PIs are associated with the formation of a biofilm.⁴ In general, management of the biofilm is considered essential in wound management. Two approaches are surface debridement and antimicrobial therapies. Although surface debridement effectively removes the biofilm, a new biofilm can rapidly re-form within 24 hours and mature in 3 days.^11-14 Thus, current guidelines for biofilm-based wound care recommend debridement in combination with topical antiseptic agents to reduce the bacterial counts and prevent biofilm reformation.

Topical or systematic antibiotics, or a combination of both, may be effective antimicrobial agents, but they primarily work against metabolically active bacteria and do not work against the many microbes within a biofilm that are metabolically inactive.¹ Some antimicrobial agents may be effective at controlling the bioburden, but they may be deleterious to normal cells. Polyhexamethylene biguanide (PHMB) is a positively charged broad-spectrum antimicrobial agent capable of binding to the bacterial cell walls and membranes; it has broad antimicrobial activity without microbial resistance, with low microbial tolerance, and with no cytotoxic effects.^15,16 Additionally, topically applied PHMB is not systemically absorbed through the skin or wounds.

Native collagen dressings are used as a skin substitute in wound care to mimic the natural environment for tissue remodeling by allowing for the migration of fibroblasts and keratinocytes to encourage new collagen growth at the wound bed.^17,18 Collagen dressings can also bind and reduce the activity of excess MMPs present in the ECM that prohibit wound healing.¹⁹ PuraPly AM (Organogenesis, Inc) is a construct of a purified native type I collagen ECM plus PHMB antimicrobial (referred to as PCMP hereafter) that is intended for wound management.²⁰ This is a US Food and Drug Administration class II medical device that has received 510(k) clearance (#K051647).^20,21 The postmarket, open-label, prospective, observational, multicenter registry study, Real-World Effectiveness Study of PuraPly AM on Wounds (RESPOND), was conducted to examine the use of PCMP in wound treatment in the clinical setting.^22,23 This study included 307 patients with venous leg ulcers (VLUs), diabetic foot ulcers (DFUs), PIs, postoperative wounds, and other wounds.²³ Most of the wounds in this study were classified as chronic. The results demonstrated PCMP to be clinically beneficial in the treatment of various types of cutaneous wounds and showed favorable overall wound closure rates associated with substantial reductions in wound area (81%), depth (71%), and volume (85%).

A detailed subgroup analysis of the effectiveness of PCMP in the 45 patients with PIs who participated in the RESPOND registry trial is presented in the current study.

Study design and patients

This RESPOND registry was a postapproval, open-label, prospective, multisite registry examining the clinical effectiveness of PCMP on various types of wounds as previously described.²³ The primary objectives of that study were to measure the frequency of and time to wound closure over 32 weeks. The key secondary analyses included the incidence of wounds that demonstrated greater than 60% reduction in wound area and depth from baseline and the incidence of wounds that demonstrated greater than 75% reduction in wound volume from baseline. The study was approved by the institutional review board (IRB), and written informed consent was obtained from all participants prior to any study-related procedures being performed. Unblinded information provided to the IRB included the protocol, investigator’s brochure, and sample advertisement intended for patients to be seen or heard.

Male and female patients 18 years or older, with a target wound (partial- or full-thickness) suitable for the use of PCMP were eligible for participation.²³ A total of 307 patients from 28 sites in the United States were enrolled. Appropriate wounds included pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds, trauma wounds with tissue damage, and draining wounds. Key exclusion criteria included patients with third-degree burns, known sensitivity to PHMB, known sensitivity to porcine materials, and those with target wounds previously treated with PCMP.

All wounds were categorized by the treating physician; this process relied on clinical assessment of signs and symptoms reported by the patient. Categorizing a PI was based on staging of the type of tissue visualized or palpated. The study included stage 2 through stage 4 wounds as defined by involvement of skin layers extending from the papillary and reticular dermis (partial- and full-thickness [stage 2]), to the subcutaneous fat (full-thickness [stage 3]), to the exposed tendon, muscle, or bone (full-thickness [stage 4]).

The physician’s choice of using PCMP for wound treatment was not dependent on the participant’s decision to participate in this study. This study did not include an interventional control group because it was designed as a prospective, noninterventional study to collect information regarding the use of PCMP in a real-world situation. Thus, each patient underwent clinical assessments and received the standard of care for treating their wound as determined by the physician investigator. Target wounds were cleansed and debrided of nonviable tissue. The PCMP was moistened with normal saline, applied, and immobilized using thin adhesive strips. A moisture balance dressing (eg, hydrogels, hydrocolloids, and alginates) and a nonstick layer were used to cover the PCMP. Each treatment application of PCMP remained on the study wound for 1 week. Moisture balance dressings were used as secondary dressings. The mean number of treatment applications was 3.6, and the mean interval of time between applications was 16 days. The PCMP was permitted to be applied weekly or until wound closure. Wound dressings were applied at the clinical sites from study day 1 through to the end of the study.

Eligible enrolled patients were followed approximately weekly for up to 32 weeks. Although multiple wounds may have been managed simultaneously, a single wound was identified as the target wound for evaluation, and characteristics regarding this wound were consistently documented. Participating patients may have had any type of wound other than a third-degree burn. Potential wounds studied included chronic wounds (eg, DFUs and VLUs), acute wounds (eg, wounds following a general surgery or plastic surgery procedure), and traumatic wounds (eg, abrasions, lacerations, or first- or second-degree burns).

Statistical analysis

All data were descriptively analyzed to include mean, standard deviation, median, frequencies, and percentages. Frequency of and median time to wound closure were determined by Kaplan-Meier time-to-event analysis through study end for all wounds and subgroups of wounds.

A forward selection Cox proportional hazards regression model that adjusted for patient demographics (ie, age, race, sex, and BMI) and wound characteristics (ie, area, depth, volume, and age of the ulcer at baseline) was performed to compute the adjusted wound closure rates for all wounds from PCMP treatment application day 0 through to week 32. The Cox analyses were used to estimate the frequency of wound closure at every time point at which patients were evaluated. All analyses were intended to treat and include data from all patients who received PCMP in the registry.

The PCMP registry included 307 patients with a variety of wounds; of these, 45 patients were reported as having PIs.²³ Of the remaining 262 patients, 67 had VLUs, 62 had DFUs, 54 had postoperative wounds, and 79 had other wounds.

The subpopulation of patients with PIs in this registry trial were older adults (mean age, 69 years) and were overweight (mean BMI, 27 kg/m²) (Table 1). A slightly higher proportion of the PI-treated patients were female (56%). Most of these patients were treated for new wounds (n = 32 [71%]) rather than recurring wounds (n = 13 [29%]). The mean duration in clinic before receiving PCMP was 92 days. They also had a larger wound area (mean area, 10.5 cm²; mean depth, 8.0 mm; mean volume, 12.6 cm³) (Table 2). Most wounds were located on the trunk or lower extremities (n = 35 [78%]) and were predominantly categorized as stage 3 or 4 (n = 35 [78%]). Few patients had baseline osteomyelitis (n = 8 [18%]) or infection (n = 3 [7%]).

Complete wound closure was evident from week 4 (5%), and it was achieved in 39% of patients by week 16, in 49% by week 24, and in 62% by week 32 (Figure 1). The median time to wound closure was 32 weeks. For all 45 PIs treated with PCMP, the incidence of achieving greater than 60% reduction in baseline area and depth were 78% and 64%, respectively, with approximately 82% showing a reduction of greater than 75% in volume (Figure 2).

The PIs in the RESPOND registry demonstrated 20%, 40%, and 50% partial area reduction (PAR) from baseline at median times of 3, 4, and 6 weeks, respectively. Concerning PAR, 96% of PIs demonstrated 20% PAR, 92% demonstrated 40% PAR, and 91% demonstrated 50% PAR. These data and the PI healing rate of 62% are consistent with early and sustained wound closure responses.

No unusual or situational observations were noted in the 45 PIs treated with PCMP. Routine stages of wound healing proceeded in an organized fashion through the 4 phases: hemostasis, inflammation, proliferation, and maturation. Few patients underwent other procedures or received adjunctive wound care other than the standard of care offloading and moisture balance dressings. One patient underwent an endovascular procedure, 1 patient underwent treatment with a muscle flap, and 2 patients received hyperbaric oxygen therapy.

The current study reports data from a prospective clinical trial that included patients with PI. The patients in this registry were primarily elderly, with large, deep wounds of long duration that were representative of wounds in the population of patients with PI and considered to be negative risk factors for healing.^24-26 With a mean depth of 8 mm and a mean area of approximately 11 cm², the pressure-related wounds in this study were complex and larger in size than typical PIs. Although most patients with PIs have stage 1 or 2 skin lesions,^8,9 78% of the patients with PIs in this registry were categorized as having stage 3 or 4 wounds, which are more difficult to heal. Despite these baseline criteria, the use of PCMP was successful in healing a considerable number of PIs in this patient population, with demonstrated reductions in wound area, depth, and volume.

The data analysis from the subpopulation of 45 patients with PIs included in the RESPOND registry indicated that treatment with PCMP resulted in clinically meaningful benefits for patients with pressure-related wounds.²³ Complete wound closure was observed from as early as 4 weeks of treatment, and it was achieved in 39% of patients by week 16, in 49% by week 24, and in 62% by week 32. The median time to complete time to wound closure was 32 weeks. The median times to partial reductions in area and depth (by >60%), and volume (by >75%) were determined to be 12 weeks. A large proportion of wounds demonstrated reductions in wound area, depth, and volume (Figure 2).

The time course of wound closure in the PI subpopulation of 45 patients was similar to that of all 307 patients (including these 45 patients) with various wounds in the complete RESPOND registry.²³ The frequency of wound closure in the subpopulation with PIs was slightly lower than that for all wound types included in the full registry because of the inclusion of fewer chronic wounds (eg, postoperative wounds) in the overall registry.²³

In general, the stage of a pressure-related wound is an indicator of healing success: the lower the stage, the higher the likelihood of improvement.^27,28 Thus, perhaps it is not surprising that most PI wound healing clinical studies have been conducted in patients with stage 1 or 2 wounds or more shallow stage 3 wounds.^27,29 Wound healing data from patients with stage 3 or 4 PIs are predominantly from retrospective cohort studies from which median times to healing cannot be calculated.^27,28 Therefore, results of the current prospective clinical trial are particularly consequential because complete wound closure has been observed in very large stage 3 and 4 PIs.

This was a noninterventional study without a control group, because it was a registry study conducted in a real-world setting.

These PI cohort data share limitations in common with all noninterventional studies. The RESPOND registry was an observational, noninterventional cohort study without an active or placebo control group. Without a comparator, the possibility exists that similar clinical outcomes would have been observed with other skin substitutes or standard-of-care therapies. Randomized controlled trials with larger sample sizes are needed to investigate the comparative effectiveness of PCMP vs other treatment modalities.

In this noninterventional cohort study, the use of PCMP in the management of PIs resulted in a high proportion of 50% PAR from baseline (91%) and a high rate of healing (62%). The product PCMP appears to be a valuable adjunct to the standard of care for the treatment of chronic wounds such as PIs. Future randomized controlled trials with larger sample sizes are needed to investigate comparative effectiveness.