PART II: A New Biomaterial Derived from Small Intestine Submucosa and Developed into a Wound Matrix Device

Initial Clinical Experience with the Wound Matrix WMD, developed from SIS biomaterial, was subjected to biocompatibility testing prior to its use in a clinical setting. Following completion of standard in-vitro and in-vivo biocompatibility testing, WMD was cleared by the Food and Drug Administration (FDA) for the intended use of management of partial-thickness wounds. WMD was evaluated in a pilot study for effectiveness in treating partial-thickness skin wounds. The dressings used in this study were supplied as 7cm x 10cm sheets having a thickness of approximately 0.15mm. The sterile dressings, intended for one time use, were stored either at room temperature in a lyophilized (i.e., dry) state or refrigerated in a fully hydrated state. At the time of application, the WMD was cut to size, slightly larger than the wound, and the lyophilized form was hydrated with sterile saline after placement. The lyophilized form had preferred handling characteristics to the fully hydrated form. However, both forms were evaluated to determine if their effects on wound management differed in any way from each other. Wounds presenting with clinical signs of infection were treated with antibiotic therapy prior to or coincident with the initial application of WMD. A secondary absorbent film dressing was applied after placement of the WMD to further protect the healing environment and to maintain good contact with the wound bed, although the WMD, particularly the dry form, was immediately adherent to the wound. Necessity of repeat applications of the WMD was determined for each wound based on the amount of dressing observed on the surface of the wound and the extent of epithelialization at each change of secondary dressing. The simplicity of application of the WMD allowed for patients enrolled in this pilot study to be treated at a variety of clinical sites, including long-term care facilities, a wound care facility treating outpatients, or in home care. Occasionally patients were instructed to reapply the dressing by themselves between visits. Patients were selected based on the following broad inclusion criteria: greater than 18 years of age and presence of at least one partial-thickness wound. Exclusion criteria included life expectancy less than five months, concurrent adjunct treatment modalities, such as whirlpool treatment or electrical stimulation to target wound, uncontrolled diabetes, and known allergy or cultural/religious objections to porcine products. Wound assessments were made at baseline and weekly or more frequent intervals depending upon wound severity, frequency of dressing changes, and stage of healing until wounds were considered healed. Additionally, the patient’s response to treatment and the condition of the WMD were evaluated. A total of 15 patients were evaluated (8 men, 7 women) with an average age of 72 ± 19 years (Table 3). Most patients were nonsmokers and were nondiabetic. Several partial-thickness wound types were present in the evaluation, including pressure ulcers, venous ulcers, trauma wounds, and drug-induced ulcers (hydroxyurea, a chemotherapeutic agent). Wounds were measured, photographed, and traced for accurate surface area determination.63 The average wound area measured 3.96cm2 (range 0.42–15.48) at time of initial treatment. One patient (87-year-old man) expired due to congestive heart failure (CHF) eight days after the initial treatment. This left 14 patients to follow up for wound healing evaluation. The lyophilized (i.e., dry) WMD was easily placed and hydrated without difficulty in all cases and was preferred due to the greater ease of handling. The hydrated form was found to be less useful on highly exudative wounds as it resisted adherence to the wound bed. At various times in the course of healing, the dressing became translucent in appearance on the wound bed or became incorporated into the granulating bed (Figure 4). In most wounds the absorption of the dressing was observed to be primarily in the central region of the wound. Where the dressing had become translucent or absorbed, new dressing was applied directly on top of the region without attempting to remove that portion of the previous dressing which typically presented with attachment to the wound margin. Wounds were epithelialized with minimal to no scar formation (Figure 4). Time to complete epithelialization was evaluated for each wound and divided into three categories: 1) less than four weeks, 2) five to eight weeks, and 3) greater than eight weeks (Table 4). Three wounds (two treated with WMD stored lyophilized and one treated with the stored hydrated form) were completely epithelialized within four weeks. Six more wounds (four with lyophilized and two with hydrated) were observed to be completely epithelialized within the five-to-eight-week duration. One wound (treated with the dressing stored lyophilized) persisted for more than eight weeks, but did completely epithelialize in ten weeks. Of the remaining four wounds, all of which had been treated with WMD stored hydrated, three were switched to calcium alginate and one was switched to the lyophilized form. The wound switched to the lyophilized form of WMD at week two was completely epithelialized at week three. The patient (32-year-old man) that was switched to the lyophilized form of WMD presented with a venous ulcer of the lower leg (Figure 5A). The patient had recurring ulcerations due to congenital venous abnormalities, and the present ulcer had persisted for one month. At the initial visit, the wound was managed with WMD stored hydrated, and a compression bandage was applied and used throughout. At the one-week visit, the wound was evaluated (Figure 5B). After cleansing, the wound area was determined to have decreased in size by more than 50 percent (Figure 5C), and a second application of WMD stored hydrated was made (Figure 5D). At the second visit (14 days) the wound was again evaluated (Figure 5E) and switched to the stored dry form of WMD because of the obvious exudate accumulation beneath the dressing and because of the greater ease of application for the patient. During the evaluation in the third week, the wound was observed to be completely epithelialized (Figure 5F). With respect to clinical events observed during the course of the study, two patients treated with WMD stored hydrated developed infections; one of these required hospitalization. Both of these patients had venous ulcers with a history of recurrent cellulitis. There was no sign of infection in patients treated with WMD stored dry, but a second patient had CHF (in addition to the death due to CHF mentioned above), and one patient had a chemotherapy related drug toxicity which, on further exploration by the oncologist, was determined to be the cause of the initial leg ulceration. However, there was no evidence of dressing-induced toxicity, clinical signs of rejection of the biomaterial-based dressing, or sub-dressing seroma as the wounds progressed to full healing. Discussion This pilot study of the use of a new dermal wound dressing made from SIS biomaterial demonstrated that the WMD was easy to apply (particularly the dry storage form), was nontoxic, and did not induce an adverse immunological reaction even in patients given repeated applications. The results also demonstrated that placement of WMD on various nonhealing skin wounds and ulcers resulted in initiation and complete epithelialization of the wound. The complete epithelialization of wounds treated with dry stored WMD versus the partial epithelialization with the hydrated stored form indicated that, for dermal applications, the dry form was more effective. These observations and initial clinical findings are consistent with the known properties of the biomaterial, derived from the submucosa of porcine small intestine, and from which the dressing was prepared. Results indicate that WMD can be used to successfully manage acute and chronic partial-thickness wounds due to its excellent protective properties and ability to act as a natural template for tissue regrowth. Dressings derived from acellular ECM tissues are likely to provide environments well suited for the body’s wound repair mechanisms. The mechanism of action of this ECM biomaterial appears to be linked to its basic tissue-like composition and architecture.7 SIS biomaterial retains the three-dimensional architecture created by the fibroblasts in vivo. ECM architecture has been demonstrated to be a critical component of tissue development and necessary for regenerative wound healing.64,65 The three-dimensional architecture of the SIS biomaterial is built upon the complex composition of various collagens, proteoglycans, and glycosaminoglycans, which provide the structural integrity, flexibility, and elasticity appropriate for dermal wound covering and subsequent epithelialization. In wound healing studies, the SIS biomaterial served as a scaffold for rapid vascularization and cellular invasion. Both of these processes are necessary to provide nutrients and signals in support of dermal regeneration and epithelial cell proliferation. In addition, the presence of multiple growth factors, each having a significant role on the stimulation and regulation of tissue regeneration, is likely an important component contributing to the wound healing properties of the biomaterial.50 With ECM biomaterials, the structural integrity of the matrix provides a barrier to dehydration and infection, the regulatory factors provide the signals necessary for the propagation of new and healthy tissue, and the native tissue architecture provides a stable structure for cell attachment, proliferation, and differentiation. Together these elements were expected to combine to provide an exceptional environment to apply to dermal wounds. In light of this, the initial clinical results demonstrating the utility of the ECM based dressing are completely consistent with this expectation. Several additional characteristics of the SIS biomaterial provide an advantage to any wound care product developed from it. First, the biomaterial is prepared from a porcine tissue, which is abundantly available being a by-product of the meat packing industry. Second, the SIS is minimally processed to provide a cell-free, sterile biomaterial, which retains many biological properties. The absence of severe, complicated, or highly technological processing means that production costs will be lower. Development of lower cost wound care alternatives is becoming increasingly important due to projections, which indicate that the patient population over 65 years of age will increase much faster than the general population. These patients require longer treatments for poorly healing wounds. Third, the facilitated epithelialization with the biomaterial results in a tissue that has minimal scarring. This is especially relevant to dermal wounds where cosmetically acceptable appearance is often as important as functional restoration. In fact, in two recent studies in which SIS biomaterial was placed into in-vivo models of growing animals, the SIS biomaterial was able to provide functional tissue replacement even as the tissue was growing with the host animal.38,66 Such preliminary reports suggest that SIS biomaterial based wound care products can have even broader applications to restoring functional tissue. Finally, because the biomaterial is almost completely composed of proteins and carbohydrates, all of which are basic components of the extracellular matrix of all species, there are no anticipated problems with biocompatibility. Therefore, the wound care and other medical products derived from this biomaterial are likely to rapidly become accepted among healthcare professionals. SIS biomaterial has been recently developed into several other medical products, which are sterile biomaterial devices‡ intended for use as soft tissue reinforcements. These products are implanted into low-stress and high-stress body systems, respectively, and provide the additional strength and support necessary to proper functioning of body tissue. Other nondermal applications for the SIS biomaterial, which are already in clinical evaluation, include urological, gynecological, and orthopedic uses. This initial clinical study had several limitations related to it being a pilot study. Progress in wound management was monitored only out to 12 weeks, and none of the wounds were large in surface area. Patients were not defined by any specific pathophysiology (e.g., diabetes), and only partial-thickness wounds were addressed in this study. WMD has recently been cleared by the FDA for full-thickness wounds, and fully controlled clinical studies for partial- and full-thickness wounds are now in progress.67,68 There are few limitations to the WMD produced from SIS biomaterial, one of which is that a patient with known sensitivity or with cultural and religious objections to porcine materials will not be able to be treated with the product. A second limitation is that even though the biomaterial has limited porosity and provides a well-hydrated environment for wound healing, it is not a moisture barrier. Therefore, the wound covered by WMD must be protected by an appropriate secondary dressing to avoid wound dehydration. Conclusion Criteria that define dressings optimal for the treatment of wounds with the goal of facilitating rapid, pain-free, regenerative healing are directing researchers and clinicians towards biological-derived dressings. The development of effective biological-derived dressings previously has been limited by complications of immunologic rejection and risk of disease/infection transfer. Problems of insufficient structural integrity or, in contrast, insufficient elasticity and flexibility have also hampered the use of biomaterials as wound dressings. A new biomaterial derived from the submucosal portion of porcine small intestine is not limited with these complications and has been used successfully in pre-clinical studies of wound healing. This SIS biomaterial now has been developed into WMD. In this pilot clinical study, this new wound matrix was found to have similar outcomes as the biomaterial when applied to partial-thickness wounds in humans. These promising results justify further evaluation of this biological-derived matrix for its effectiveness toward the treatment of full-thickness wounds. *OASIS® Wound Matrix (Cook Biotech, Inc., West Lafayette, Indiana) *Dermagraft® (Smith & Nephew Inc., Largo, Florida) Apligraf® (Novartis Pharmaceuticals Corp., East Hanover, New Jersey) ‡ SURGISIS® and SURGISIS® ES (enhanced strength) (Cook Biotech, Inc., West Lafayette, Indiana) Acknowledgements The authors wish to acknowledge the professional contributions of Marian Punchello, LPN, and Deborah Shields, RN, BSN, CWOCN, in the pilot clinical study.