Extracellular Wound Matrix (OASIS®): Exploring the Contraindications. Results of Its Use in 32 Consecutive Outpatient Clinic

Wound healing occurs in 3 overlapping phases: the inflammatory phase (“lag phase”), the proliferative phase (tissue formation), and the remodeling phase. In the proliferative phase, aside from angiogenesis, granulation tissue is formed and the wound is re-epithelialized.¹ In the authors’ wound clinic, re-epithelialization after successful debridement and granulation is sometimes the most difficult part of the wound closureprocess. Sometimes the wounds are very large and are preferably closed by split-thickness skin grafting. However, most of the clinic patients have high anesthetic risks. In the present study, 64.5% of the treated patients are of American Society of Anesthesiologists (ASA) class III/IV, in whom admittance to the hospital and subsequent surgery might not only lead to a high morbidity, but also possible death.² Therefore, there is a constant search for wound treatments that will lead to full epithelialization of wounds without the need for anesthesia. Other important factors are that the method should be painless and the treatment should preferably be performed on an outpatient basis.
Extracellular matrix (ECM) products seem to be a possible solution in which split skin grafting might not be necessary.³ However, in studies discussing the effectiveness of ECMs (porcine-derived small intestine submucosa [SIS]; OASIS^® Wound Matrix, Healthpoint Ltd, Fort Worth,Tex), a long list of exclusion criteria has been presented, such as 1) infection; 2) deep wounds exposing tendon, bone, or fascia; 3) uncontrolled diabetes; 4) chronic limb ischemia; 5) ABI < 0.80; 6) signs of cellulites and osteomyelitis; 7) undergoing hemodialysis, and more.^4,5 Only 23% of the patients in this study could have been treated with the ECM according to these exclusion criteria.
The present study was designed to explore the contraindications of OASIS Wound Matrix. All patients in whom the wounds were fully debrided and granulated were treated with OASIS Wound Matrix. The exclusion criteria formulated in the reported literature were not followed in order to see if more patients could be successfully treated with OASIS Wound Matrix. The results, complications, and possible directives for further research are reported.

Methods

Study characteristics. Patients. In the period between April 22, 2006 (when the product was available to the authors’ hospital) and March 1, 2007, 32 patients with chronic wounds were recruited into the study. All wounds were granulating and needed to complete the final phase of wound healing—epithelialization. The wounds were already fully debrided and granulating.This was achieved with several techniques, including maggot debridement therapy (MDT) and Vacuum-assisted Closure (V.A.C.^® Therapy^™, KCI, San Antonio, Tex). All patients were treated with extracellular wound matrix (OASIS^®, Healthpoint Ltd, Fort Worth,Tex) at the outpatient surgical department of the Rijnland Hospital, Leiderdorp, The Netherlands. The exclusion criteria formulated in literature were not followed.^4,5 If the exclusion criteria as presented in the medical literature was followed, only 23% of the herein reported patients could have been treated.
One patient, after open abdomen treatment, was excluded after pathological examination revealed normal bowel instead of a chronic wound. This patient, therefore, did not have a chronic wound, but an exposed bowel.
Protocol. Standard protocol prescribed patients to be treated in the outpatient department. All patients gave informed consent to be treated with an ECM. Antibiotic treatment was not considered a contraindication. Indications for antibiotic therapy were based on those formulated by the international consensus on diagnosing and treating the infected diabetic foot.⁶
Application technique. Before applying the ECM to the wound bed,wounds were cleaned with sterile saline, the ECM was cut to the size slightly larger than the wound,placed upon the wound bed,and moistened with sterile saline. As a secondary dressing at first Adaptic^® (Johnson & Johnson, Somerville, NJ), and in a later stage of the study (after 5 patients), Mepitel^® (Mölnlycke Health Care, Göteborg, Sweden) were applied after placement of the ECM to protect the healing environment and to maintain direct contact of the ECM with the wound bed. Repeat applications were applied weekly during a clinic visit, or in the home care setting. In cases of edema or chronic venous insufficiency, treatment of the ECM was combined with compression therapy. In case of infections, patients were also treated with antibiotics during treatment.
Outcome. Seven different outcomes for the ECM treatment were defined based on outcome definitions in the literature^7–11 and the authors’ experience with the technique— effect of ECM observed (beneficial outcome):

1. Wound fully closed by second intervention (eg, split-thickness skin graft)
2. Wound spontaneous fully closed
3. Wound free from infection and < one-third of original wound size. No effect of ECM observed (unsuccessful outcome):
4. No difference observed between the pre- and post- ECM treated wound
5. The wound is worse
6. Minor amputation (eg, partial toe amputation)
7. Major amputation (eg, below knee amputation).

Patient and wound characteristics. Patient characteristics. The following patient characteristics were recorded: age, sex,body mass index (BMI) > 25, presence of diabetes mellitus, smoking behavior, the presence of chronic limb ischemia, interventions for chronic limb ischemia within the last 6 months, ASA class, and other relevant medical history.
A BMI between 25 and 30 indicates that the person is overweight, while a BMI of 30 or more is classified as obese.¹¹ Patients were recorded as overweight accordingly. Smoking behavior was recorded as “yes” or “no.” A patient was considered a nonsmoker if he/she avoided smoking for more than 3 months.The diagnosis of lower chronic limb ischemia (CLI) was made if both pedal pulses of the involved foot were absent and/or the ABI was less than 0.6 and/or the absolute ankle pressure was below 50 mmHg.¹³ The ASA classification of all patients was recorded. Postoperative morbidity is seen in 3.9% of ASA Class I patients, whereas in 33.7% of ASA Class IV patients. Mortality varies from 0% in ASA Class I to 7.3% in ASA Class IV.²
Wound characteristics. The following characteristics related to the wounds were recorded: ulcer site, ulcer size (> 2 cm), wound depth, presence of chronic venous insufficiency, presence of edema, whether trauma was the cause of the wound,whether a fracture accompanied the trauma, whether there was decubitus, presence of septic arthritis, signs of osteomyelitis,presence of wound infection, as well as the duration of the wound before treatment with ECM was started.
Depth of the wound was recorded as following: containing only epidermis (1); containing dermal layers (2); or deeper containing tendon (3); bone (4); or joint (5).
Chronic venous insufficiency was recorded on clinical grounds and standard treatment consisted of 3- or 4-layer compression treatment. In case of infection near a joint, it was recorded if septic arthritis was present. A diagnosis of wound infection was made if there was purulent discharge and/or 2 local signs present (warmth, erythema, lymphangitis, lymphadenopathy, edema or pain).

Statistical Analysis

Univariate analyses using Chi-square and Fisher’s exact statistics were performed. Multivariate analyses were not possible because of the many variables in a relatively small group.

Results

The study population consisted of 32 patients. The patient characteristics are discussed first, followed bywound characteristics, and therapy results.
Patient characteristics. From April 2006 to January 2007 32 patients with chronic wounds were treated with ECM. One patient was excluded after pathological examination of the chronic wound revealed the patient had no chronic wound, but an exposed small bowel. The remaining patient group consisted of 17 men (54.8%) and 14 women (45.2%) with a mean age of 63.7 years (range: 19–90 years, SD ± 17.7) (Table 1).
Outcome was negatively influenced by diabetes mellitus (58.3% versus 94.7%, P = 0.012), chronic limb ischemia (44.4% versus 95.5%,P = 0.04) and an ABI below 0.8 mmHg (16.7% versus 96%, P < 0.001) (Table 1).
Wound characteristics. Most wounds (N = 31, 80.7%) were located on the lower extremity (Table 2). The wounds existed on average 4.0 months (range: 0.5–24 months, SD ± 5.5) before starting ECM. Wound duration of 3 months or more had a negative impact on successful outcome (50% versus 90.5%,P = 0.033) (Table 2).Wounds with a diameter more than 2 cm (n = 26) had a better outcome than smaller wounds (n = 4) (88.5% versus 25%, P = 0.018). However, because of the small sample size no definitive conclusions can be drawn. Wound depth had no significant influence on outcome (P = 1.000), as well as osteomyelitis (P = 0.557) and septic arthritis (P = 0.366). However, this sample size is too small to draw definitive conclusions whether septic arthritis and osteomyelitis are exclusion criteria for ECM.
Therapy results. Beneficial outcomes were seen in 80.6% of the patients (n = 25) treated with ECM (Table 3). Twenty-three chronic wounds (74.2%) were completely closed after treatment with ECM. One wound (3.2%) was closed with a split-thickness skin graft. This was a very large wound; of which was thought would take a long time to close with an ECM.
Of the 6 wounds with an unsuccessful outcome (19.4%), only 1 (3.2%) had become worse than before starting ECM (Table 3). One minor and one major amputation were done after treatment with ECM. The latter concerned the first patient, whose leg was already in a very bad condition, suffering from chronic limb ischemia with a therapy-resistant infection. Extracellular matrixapplication was a last attempt at limb salvage, which unfortunately did not work. In 9.7% of the patients (n = 3), no difference was seen before and after treatment.
The 2 main complications seen with ECM are infection and hypergranulation tissue. Infection was seen in 7 patients (22.6%). Four patients (57.1%) had unsuccessful outcomes.Hypergranulation tissue occurred in another 7 patients (22.6%) after ECM application (varied between 2 and 4 applications). Applications were discontinued, another treatment for the wound was chosen, and the hypergranulation tissue was treated with AgNO₃. All 7 had a beneficial outcome.

Discussion

In studies discussing the effectiveness of ECM (OASIS^® Wound Matrix, Healthpoint Ltd, Fort Worth,Tex) a long list of exclusion criteria has been presented.^4,5 Exclusion criteria used in these studies are, 1) infection; 2) deep wounds exposing tendon, bone, or fascia; 3) uncontrolled diabetes; 4) chronic limb ischemia; 5) ABI < 0.80; 6) signs of cellulites and osteomyelitis; 7) undergoing hemodialysis and more. Only 23% of the herein presented patients could have been treated with ECM according to these criteria. This study was designed to explore the contra indications of ECM.
There were no differences in patient and wound characteristics between the patients that met the exclusion criteria (n = 8) and the patients that did not (n = 23), except for age. Patients in the group that according to the exclusion criteria, should not have been treated with ECM, seem to be older than the other group (73.9 years versus 60 years, P = 0.056). The secondary wound dressing was changed after 5 patients from Adaptic^® (Johnson & Johnson,Somerville, NJ) to Mepitel^® (Mölnlycke Health Care, Göteborg, Sweden). It was thought that the latter would stick less to the wound surface. No differences were observed, but it is possible that changing dressing type affected/ influenced the results. Deep wounds exposing bone, tendon, or joint do not have a negative influence on outcome (Table 3). This ultimately means that wound depth should not be an exclusion criterion for ECM. It is known that these conditions impair wound healing: 1) diabetes mellitus; 2) ABI < 0.8 mmHg; and 3) chronic limb ischemia (Table 1).The present study found that 58.3% of the patients with diabetes mellitus (n = 12) had a beneficial outcome, as well as 44.4% of the patients with chronic limb ischemia (n = 9). Therefore, these contraindications are not absolute.
Whether osteomyelitis, septic arthritis, or undergoing hemodialysis should remain exclusion criteria remains unclear. In this study, there were only a few patients suffering from these conditions who were treated with ECM (Table 2).
This study shows, as others have reported previously,^4,5 that infection does have a negative influence on outcome and should remain as a contraindication for ECM use. It is not advisable to use an ECM in case of infection, as 57.1% of the patients who presented with infection (even if the infection was not in the index wound) had an unfavorable result (n = 4). It is still unclear why SIS derived from pig jejunum can be used successfully in cases of dirty or contaminated abdominal wounds.^14,15 The same multilayer, porcine-derived basis has been used successfully in case of perianal fistula where wound contamination seems almost unavoidable.¹⁵ Other nonsterile places where SIS has been successfully used are enterocutaneous fistulas and bile duct repairs.¹⁶ A possible explanation for the difference in efficacy (local wound care compared to other indications) could be the number of layers—the ECM has (1 layer) and, for example, Surgisis^® (Cook Medical, Bloomington, Ind) has 8 layers. Perhaps if OASIS consisted of multiple layers then this product could also be used in case of epithelialization of infected wounds. Another explanation might be the fact that infection has more effect on the intestinal submucosa in the epithelialization phase of wounds than in wounds that are in the debridement or granulation phase. It must be noted that in a study on ventral hernia repair using Surgisis, seroma formation, direct postoperantive pain, and fever was a major problem.This was, in the authors’ opinion, due to acute inflammation at the mesh site from the activation of inflammatory cytokines.¹⁶ This would favor the authors’ theory that the differences in results are due to differences in wound phase (debridement/ granulation versus epithelialization phase).

Conclusion

Much of the exclusion criteria used in previous reports are too strict. Infection should be the only absolute contraindication for starting treatment with ECM, and is a good reason to discontinue treatment with an ECM.^4,5 However, further investigation is needed regarding how multiple-layer SIS works in abdominal infections.^15,16
Wound depth does not have a negative influence on outcome and should not be an exclusion criterion. Patients with conditions that impair wound healing, such as diabetes mellitus and chronic limb ischemia, have a less beneficial outcome than patients who do not have these conditions,yet still seem to benefit from ECM treatment.
Exclusion criteria such as, septic arthritis, osteomyelitis, and undergoing hemodialysis, require extensive additional research before a definitive conclusion can be drawn.
Hypergranulation tissue (22.6%) is a complication that can be treated easily by AgNO₃ application, and has no negative influence on outcome. All together 77.4% of the patients had no complications, or easily treatable complications, without any negative influence on outcomes.