Efficacy of a New Flowable Wound Matrix in Tunneled and Cavity Ulcers: A Preliminary Report

Introduction. In chronic wounds the healing is stagnant, and regenerative surgery is often needed. Many engineered tissues with a conventional bidimensional sheet are ineffective for tunneling wounds, because adherence to the wound bed is not complete. An advanced wound matrix for treating wounds with irregular geometries has been developed (Integra Flowable Wound Matrix, Integra LifeScience Corp, Plainsboro, NJ).   Methods and Materials. Between March 2013 and December 2013 the authors treated 18 patients (11 female) with tunneled or cavity ulcers with the advanced wound matrix at the Unit of General and Geriatric Surgery of the Second University of Naples, Naples, Italy. Two patients (11.1%) had postsurgical wounds, two (11.1%) had post-traumatic wounds, and 14 (77.8%) had neuropathic ulcers. After debridement and antibiotic therapy, the lesions were filled with the wound matrix product. Surgical wound edges were either approximated with stitches or left to heal by secondary intention and covered with wet gauze. During the first week, follow-up visits were carried out every 3 days, then once a week until complete healing was achieved. All patients underwent preoperative and postoperative ultrasonography scans and plain radiograph controls. Results. Twenty-one applications were performed. Engraftment was complete in all but 1 patient who had diabetes and graft failure. Three patients needed repeated applications to complete the filling of the lesions. Median (range) pain Visual Analog Scores—on a scale of 0 to 10, where 0 = no pain, and 10 = intolerable pain—were 6.3 (range 3-8) preoperatively and 0.5 (range 0-2) at first follow-up (P ≤ 0.001). All but 2 patients showed a progressive remodeling of the tissue gap at scheduled radiographic controls. Conclusions. To the author’s knowledge, the advanced wound matrix used in this study is the only available biomaterial for the treatment of tunneled lesions. It stimulates tissue regeneration by filling surfaces which cannot be repaired spontaneously or by using conventional biomaterials in the form of sheets. Its application is atraumatic, painless, and safe.

Chronic skin wounds are characterized by a persistent state of inflammation due to a complex pattern of interactions between enzymes, growth factors, and inflammatory cytokines. Chronic inflammation destroys the extracellular matrix (ECM), inhibits growth factors, and apoptosis of fibroblasts and keratinocytes.¹ In vitro studies show that fibroblasts obtained from chronic wounds are less responsive to exogenous growth factors.^2,3 This may be justified by the aged state of these cells, making growth factors ineffective in the treatment of chronic wounds.

Tissue engineering and biomimetic materials can provide innovative biomaterials to develop bioactive tissue substitutes, which can act as a scaffold for in situ formation of new tissue as well as a vehicle for biochemical stimulus favoring regeneration.^4-6 Alongside the biomaterial used to cover or fill the loss of substance,⁷ newer biomimetic products can interact with the injured tissues, leading to active repair.⁸

However, tunneled lesions and those involving bone structures are difficult to treat with conventional sheet-shaped products. Conventional treatment consists of repeated saline lavage followed by a temporary dressing. The clinical result is generally limited to ineffective tissue repair leading to a continued chronic open wound, infection, or scarring. Non-biomatrix flowable hydrogel wound filler achieved faster healing compared to traditional saline gauze dressings⁹ for diabetic foot ulcers, which are often small in area with damage involving deeper structures.

This raises the possibility that an advanced wound matrix (Integra Flowable Wound Matrix, Integra LifeScience Corp, Plainsboro, NJ) flowable biomatrix⁶ may enhance outcomes of deep or tunnelling wounds even more than simple flowable hydrogels. In an effort to lay the foundation for exploring this hypothesis in a prospective randomized controlled trial, the authors explored the feasibility and safety of the advanced wound matrix in patients with cavity or tunnel lesions involving deep structures that are difficult to treat with traditional topical therapy.

All patients with chronic wounds observed at the Unit of General and Geriatric Surgery of the Second University of Naples, Naples, Italy between March 2013 and December 2013 were evaluated for inclusion in the present study. All enrolled patients gave written consent to receive treatment with the advanced wound matrix. Institutional Review Board approval of the Second University of Naples was obtained before starting the study.

Inclusion criteria were patients ≥ 18 years of age; tunneled or cavity wounds with or without involvement of deep structures, diagnosed at least 3 months before the start of the study; body mass index (BMI) ≤ 30 kg/m²; and ankle brachial pressure index (ABPI) ≥ 0.8. Exclusion criteria included an ABPI ≤ 0.8; coagulopathies; and autoimmune diseases.

Wound dimensions were assessed by means of a wound measurement system (VISITRAK digital and VISITRAK depth, Smith & Nephew, Hull, UK). All patients were requested to grade their wound-related pain with a Visual Analogue Scale (VAS) where 0 = no pain and 10 = unbearable pain. All patients received a wound biopsy, cultured exam, and antibiogram. An antibiotic treatment was administered accordingly, and dressings were placed on the wound.

Ultrasonography scan and plain radiograph of the wound site were performed to assess the involvement of deep structures. Before the advanced wound matrix application, all patients underwent surgical curettage and debridement of the wounds.

The advanced wound matrix comes in a kit containing a sterile disposable syringe of dry particles of collagen (6 mL), an empty syringe for saline solution, a luer lock connector, and a flexible tip to extrude through a cannula directly inside the wound after surgical debridement. The advanced wound matrix is sufficiently flowable such that the composition can be placed in a syringe and extruded through a cannula if desired. Saline (3 mL) is dispensed into a collagen syringe before plungers are depressed back and forth between the syringes at least 15 times. The mixture is ready when product appearance is consistent and homogeneous. An angiocath tip is attached to the syringe to dispense the material, thereby filling defects or minimizing dead space. After application, a secondary dressing (wet gauze) can be applied to maintain dressing adherence and protect the wound area. In the series described here, surgical wound edges were either approximated with stitches or left open to allow healing by secondary intention. The wounds were then covered with wet gauze.

During the first week, follow-up visits were carried out every 3 days. Then, outpatient postoperative follow-up was scheduled once a week until complete healing was achieved. During every follow-up visit, the binary presence or absence of each inflammation marker (eg, edema, erythema, increased local temperature, presence of abscesses) was recorded. A complete clinical exam was always performed and snapshots were taken. Wound dimension was recorded at the first visit; for each subsequent visit, wound dimension and discharge were annotated. Engraftment of the dermal implant was checked by assessing the binary presence or absence of peri-implant erythema, graft colliquation, or displacement. Adverse events were recorded. All patients received ultrasonographic and/or radiographic control, as required, 30 and 60 days after treatment.

A total of 21 applications of the advanced wound matrix were performed on 18 patients (11 female [61.1%], 7 male [38.9%]), with a median age of 54.3 years (range, 51-63 years). One wound was treated per patient. Two patients (11.1%) had post-surgical ulcers, two (11.1%) had post-traumatic ulcers, and 14 (77.8%) had neuropathic ulcers. Neuropathic ulcers (n = 14) were due to diabetes in 11 patients (11 out of 14, 78.6%), spina bifida in 2 (14.3%), and congenital neuropathy in 1 (7.1%). 

Three patients required 2 applications of the advanced wound matrix; engraftment was not achieved for 2 of the patients. Preoperative median time from ulcer diagnosis was 81 months (range, 4-132 months). Median ulcer width and median depth were 16.2 cm (range, 3-33 cm) and 7.8 cm (range, 2-14 cm), respectively. Staphylococcus aureus and Pseudomonas aeruginosa were the most common microorganisms identified in wound biopsies.

Ten patients (55.5%) underwent abscess drainage and curettage, and 5 patients (27.8%) received curettage of the cavity/track. Residual cavities and/or tracks were filled with the advanced wound matrix. Wounds were left open to allow healing by secondary intention in 7 patients (38.9%), and in 11 patients (61.1%) edges were approximated by means of stitches. The surgical wounds were covered with wet gauze. Wound discharge gradually decreased in all patients. The advanced wound matrix was well tolerated and no local edema or hyperthermia was observed. Only 2 patients (11.1%) had colliquation of the dermal implant. One of these 2 patients had a neuropathic ulcer of the fifth metatarsal bone, and had insulin-dependent diabetes and chronic kidney insufficiency needing dialysis beginning 5 years before treatment. The other patient had a post-traumatic calcaneal lesion 7 years prior to treatment. No clinical signs of inflammation or infection were observed in these 2 patients. In the remaining 16 patients (88.9%) the engraftment was complete. Median time to heal according to type of wound closure was 45 days (range, 35-60 days) for patients healing by secondary intention, and 17.3 days (range, 15-21 days) for patients for whom wound edges were approximated by stitches (P = 0.04).

Median pain VAS scores were 6.3 (range, 3-8) preoperatively and 0.5 (range, 0-2) at first follow-up (P ≤ 0.001). All but 2 patients showed a progressive remodeling of the tissue gap at scheduled radiographic controls. Figures 1, 2, 3, and 4 show results of application of the advanced wound matrix and outcomes in 3 cases.

In this preliminary report, the advanced wound matrix achieved excellent results in patients with tunneled or cavity ulcers. Permanent tissue regeneration was observed in 16 patients (88.9%) with prompt pain regression in all 18 patients. Deep structures were rapidly covered with regenerated tissue, and the patients experienced fast wound closure.

The aim of treatment of chronic skin wounds is to achieve a natural closure of the defects. The choice of treatment is modified according to wound size, localization, severity, exposure/involvement of visceral or bone structures, patient age, risks, and comorbidities.^5,7 Tissue engineering has recently provided sheet-shaped cellulated and acellulate materials suitable for the regeneration and repair of lesions otherwise needing skin patches or flaps.^10-13 Unfortunately, tunneled or cavity lesions are not suited for treatment with sheet-shaped materials due to the inability of the material to adhere to wound walls.^4,5,7 A fluid matrix could provide the ideal solution to this problem. An advanced wound matrix can be enriched with bioactive molecules which can boost the regenerative capability of the products such as growth factors, coagulation factors, and anti-inflammatory and antimicrobial agents. Hydroxyapatite and/or calcium phosphate can also be added, and are extremely useful when dealing with lesions involving bone structures.⁶

The authors’ experience showed the advanced wound matrix can be easily applied, without the need for donor sites or additional risks for the patient. The advanced wound matrix is a “half-biological implant” that is particularly useful for the treatment of tunneled cutaneous lesions not suited to treatment with sheet-shaped dermal substitutes.⁶ The advanced wound matrix is composed of type I collagen (90%), which acts as a tridimensional scaffold to enhance cells’ access to internal matrix components¹⁴ favoring tissue regeneration, and glycosaminoglycans (10%).  The advanced wound matrix mimics the absence of the defect, eliminating inflammation and related consequences.¹⁵ All patients in this series had a prompt reduction of wound discharge without signs of inflammation—even in the patients experiencing the advanced wound matrix displacement. Concerning alternative options for managing complex wounds, Edwards and Stapley^,9 reviewed 3 randomized controlled trials comparing hydrogel with gauze or standard dress in healing diabetic foot ulcers, and concluded that hydrogel with gauze was significantly more effective (relative risk 1.84, 95% confidence interval 1.3 to 2.61). The authors suggest a goal of future research would be to test healing or scarring or other advantages of this flowable biomatrix compared to non-biomatrix flowable gels with prior proven efficacy.

The advanced wound matrix can expand after application, filling the dead space inside the lesion and absorbing tissue fluids, and may be able to stop inflammation because it does not attract platelets and leukocytes, shifting the host response towards regeneration. However, the present study lacks a detailed histological assessment of changes occurring with use of the advanced wound matrix. While the authors were not able to test it, this possibility merits future research. This may also reflect on understanding and management of wound-related pain, with dramatic regression of the symptoms after treatment with the advanced wound matrix.

This is the first report on a flowable collagen matrix for tunneled or cavity wounds to the authors’ knowledge. An advanced wound matrix is the only biomaterial suitable for difficult lesions and for wounds with an irregular shape not suitable for treatment with sheet-shaped biomaterials. This tridimensional porous matrix is indicated for tunneled and cavity ulcers, irrespective of their etiology.

 An advanced wound matrix is not associated with side effects, is well tolerated, and achieves prompt reduction of wound discharge and size. Wound-related pain is abolished. Patients with lesions involving deep structures may particularly benefit from treatment with this type of biologic matrix.

Ferdinando Campitiello, MD; Angela Della Corte, MD, PhD; Raffaella Guerniero, MD; Gianluca Pellino, MD; Silvestro Canonico, MD are from the Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Naples, Italy

Address correspondence to:
Silvestro Canonico
Unit of General and Geriatric Surgery
Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences
Second University of Naples
Piazza Miraglia 2
80138 Naples
Italy
silvestro.canonico@unina2.it

Disclosure: The authors disclose no financial or other conflicts of interest.