Management of Open Lower Extremity Wounds With Concomitant Fracture Using a Porcine Urinary Bladder Matrix

Background. Open wounds of the distal third of the leg and foot with exposed bone, fractures, and hardware are challenging wounds for which to achieve stable coverage. The orthopedic advances in lower extremity fracture management over the last 30 years have allowed a rethinking of the standard operative approach to close these complex wounds. Materials and Methods. The ability of extracellular matrix (ECM) products to facilitate constructive remodeling of a wound seemed a reasonable approach for treatment, especially in patients who are often poor surgical candidates for more advanced reconstructive procedures. Results. The authors reviewed 9 patients with 11 open fractures of the leg, ankle, or foot treated with a newer ECM wound healing device to total closure. The clinical course and patient management are reviewed. Conclusion. The authors conclude that newer ECM products can provide a reasonable method of management for patients who have wounds with exposed hardware, distal leg wounds, and open foot fractures compared to prolonged negative pressure wound therapy or complex reconstructive operative procedures.

The use of microsurgical free flaps in the management of patients with severe lower extremity trauma heralded a new era in limb salvage for countless patients who otherwise faced unpredictable fracture healing, unstable wound healing or possible amputation.¹ The principle of aggressive wound debridement with early free flap wound coverage has dominated the management of wounds involving distal third leg and grade III open tibia fractures for the last 30 years.^2-5 Despite this long-standing principle, referral for wound closure may fall outside ideal time periods for microsurgical flaps, leading to higher postoperative complication and failure rates. Orthopedic fracture management evolution from extensive cortical bone plating to more Ilizarov frame fixation (with or without minimally invasive plate osteosynthesis [MIPO]) adds mechanical challenges for wound access and technical challenges for flap transfer and inset. The complexity of lower extremity reconstruction with wounds involving open fractures is further compounded when applied to elderly and complex polytrauma patients with multiple medical comorbidities. Patients are left with few options and must accept donor site defects to minimize risk of nonhealing open wounds, infected fracture nonunions, or amputation. For a multitude of reasons, those patients deemed to be poor flap candidates would greatly benefit from alternative, reliable methods of wound management and reconstruction were they available.

The ultimate goal of lower extremity limb reconstruction is obtaining stable wound coverage that is durable, free of infection, and facilitates primary bone healing. Ideally the patient’s leg and foot should have a normal appearance, fit into regular footwear, and be pain-free. The reconstruction technique should allow for preservation of as much “salvageable” tissue as possible and accommodate secondary orthopedic procedures when needed to optimize a stable skeletal reconstruction. A greater appreciation of the tissue envelope surrounding the bone has led to the use of smaller periwound access techniques including intramedullary rods, MIPO, and the Ilizarov fixation frames for complex distal extremity fractures. This less invasive orthopedic fracture management compelled the authors to rethink their standard flap approach to managing the associated open leg and foot wounds. 

The use of porcine urinary bladder matrix-extracellular matrix (UBM-ECM) products provides an exciting new approach to managing patients who are considered poor flap candidates or who are reluctant to undergo flap surgery unless absolutely necessary. Initially marketed as MatriStem, and more recently rebranded as Cytal (ACell, Inc, Columbia, MD), these UBM-ECM products are medical devices with 510(k) U.S. Food and Drug Administration clearance.  The authors have found success using these UBM-ECM devices in the management of lower extremity wounds that previously would have only been treated with a regional or free flap. The addition of UBM-ECM products to the authors’ reconstructive armamentarium has altered their overall thinking of lower extremity wound management involving open fractures. Complex wounds previously believed to be incapable of healing can now be closed with the use of these products alone or in conjunction with skin grafting. Over time, authors have found that the use of UBM-ECM products also allows for more simplified wound care, often without negative pressure wound therapy (NPWT). The UBM-ECM products have been found to facilitate healing despite the presence of exposed hardware and positive bacterial cultures — provided all grossly devitalized bone has been removed. This case series highlights the utility of UBM-ECM devices in powder form (MicroMatrix, ACell, Inc.), bilayer sheet (Cytal Burn Matrix, ACell, Inc.), and multilayer sheet (Surgical Matrix PSMX, ACell, Inc.) configurations in managing challenging lower extremity wounds involving open fractures.  

From February 2012 through May 2014, 9 patients with lower extremity fractures with 11 complex open lower extremity wounds were treated by the Plastic Surgery Service at St. Louis University (St. Louis, MO) utilizing porcine UBM-ECM devices as the primary wound management modality. Of the 9 patients, 4 had open articular ankle fractures and 5 had open tibial fractures. Six patients had Gustillo III fracture/open joint wounds, while the remaining 3 patients were Gustillo II injuries.  Two patients had failed prior Integra Dermal Regeneration Template (Integra LifeSciences, Plainsboro, NJ) placement: 1 treated by the primary referral service and 1 initially treated by the Plastic Surgical Service. Six of these patients (75%) had exposed hardware in the wound bed at the time of the UBM-ECM product placement. Four patients were treated with a later split- or full-thickness skin graft, and no patient had a concomitant flap. Seventy-five percent of patients had referral for reconstruction delayed by > 1 week with the primary reason being serial washouts attempting to obtain a negative wound culture. The medical comorbidities included infection, 88% (7/8); smoking, 63% (5/8); diabetes mellitus, 38% (3/8); significant arterial vascular disease, 38% (3/8); coronary artery disease or prior myocardial infarction, 25% (2/8); leg edema with venous stasis disease, 25% (2/8); age > 70 years, 25% (2/8); and 1 patient had severe congestive heart failure. The minimum follow-up was 10 months with an average follow-up of all living patients of 18 months. The patient clinical data and care are summarized in Table 1 and Table 2.

All living patients completely healed their wounds and have remained healed. The individual clinical case summaries are presented in Table 1, and the wound management outcomes are presented in Table 2.  A female patient who smoked 1–2 packs of cigarettes per day died prior to fully healing her wound from a myocardial infarction. Ninety percent of wounds were cultured positive at the time of the initial UBM-ECM product application, but 1 patient did not have culture data obtained at the time of operative intervention. The majority of wounds (7/10) had multiple treatments with a range of 1–4 (average 1.7, median 2) treatments. Multiple UBM-ECM product applications were more common in larger wounds and with earlier treated patients while clinicians gained experience with the use of the device. 

Complete wound healing after the UBM-ECM product application occurred over a range of 16–42 weeks, an average of 26.5 weeks, and a median of 25 weeks. Seven wounds healed without subsequent skin grafting. The time to skeletal healing from the last orthopedic fixation ranged from 12–40 weeks (average 26.1 weeks, median 30 weeks). The time to ambulation from the last orthopedic manipulation was 9–40 weeks (average 24 weeks, median 20 weeks). All patients achieved normal leg contours, and no patient required later wound revision. Of the 9 patients, 4 required long-term compression stockings for optimal edema control. Figure 1 shows the clinical healing of Case 3, a 91-year-old male with an exposed plate that was well managed until the fracture healed.  For Case 9, a 59-year-old male had bilateral significant ankle wounds that demonstrated significant tissue remodeling (Figures 2 and 3).

A variety of formulations of the UBM-ECM products were used during the course of this study as newer product formulations became available (the specific product used was released February 2014). Earlier patients in the series had the UBM-ECM product in powder form and/or multilayered, vacuum-pressed sheets applied (with the larger wounds all utilizing the 6-layer sheets). Later patients had the powder and the bilayer formulations used at times in place of or along with the multilayer sheet. The ECM device was typically applied in the operating room at the time of initial plastic surgery operative assessment with prior wound care using NPWT. No patient required additional wound debridement after commencing with the UBM-ECM device. 

The powder facilitates the most robust wound healing response, but doesn’t have the persistence of the bilayer or the multilayer sheet. Time is needed for the wound to replace the applied ECM with the body’s own native ECM-forming, site-specific tissues, and a UBM-ECM supply needs to be available at the wound surface during that time. The amount and choice of the UBM-ECM devices applied was approximated by the senior author’s clinical estimate of the time it would take for the wound to ultimately heal. As the spectrum of the UBM-ECM wound device formulations are of the same derivation, there was no discernable difference in the observed healing among the various combinations used other than the persistence of the device over time. 

Wound management
The wound drainage volume determined the postoperative wound dressing utilized after the UBM-ECM device placement. Wounds draining more than 25 cc/day were treated with NPWT (2 patients: 22%), while lesser draining wounds were treated with either Drawtex (SteadMed Medical, Fort Worth, TX) plus Tegaderm (3M, St. Paul, MN) sheet as the secondary dressing, Tegaderm sheet dressing alone (with or without additional daily saline), or hydrogel (various manufacturers) dressings (7 patients: 78%). 

Complications
One male patient with a severely comminuted open distal tibia fracture required readmission for 2 days of intravenous antibiotics to treat superficial cellulitis. The soft tissue wound was nearly closed when redness developed but then progressed after the patient failed to fill his oral antibiotic prescription. He was extensively counseled about stopping his 1 pack per day cigarette smoking habit, and he was discharged home with oral antibiotics. His wounds subsequently healed, and he had a successful secondary bone grafting procedure for solid bony fracture stabilization. Pain medication requirements were commensurate with the complexity of the bony fracture. The deceased patient died from her general overall poor health and failure to properly care for herself.

Reconstructive limb surgery has benefited countless patients as technical advances and a deeper understanding of the optimal healing processes have led to an individualized care of severely traumatized patients. The landmark studies from the 1980s pushed the authors toward early flap coverage of the complex extremity wound before it entered the subacute phase with flap losses approaching 30% or more and poor fracture healing.^1-12 Appreciation of the utilizing vessels outside the zone of injury and aggressive, extensive wound debridement of all doubtfully viable tissue are also established principles of optimal flap management. Newer understandings of and advances in the treatment of distal open orthopedic fractures have allowed the authors to rethink their standard soft tissue reconstructive techniques and consider alternative approaches to a “less (operatively) traumatized” fracture site. A deeper understanding of the biology of wound healing has also provided new alternatives to standard topical and surgical wound healing.

The addition of UBM-ECM wound closure devices to the armamentarium of a reconstructive surgeon has allowed for salvage of tissues that previously would have been sacrificed in the name of debriding the poorly viable tissues from the wound (Figure 3A). They can be utilized in wounds that culture positive (but are not grossly infected) and be utilized in nearly all patients. The authors now believe free flaps are no longer the sole, primary modality for treating all major distal lower extremity wounds but rather another technique used when more rapid closure is needed. All patients in the present series had a fracture healing without bony infection despite the more prolonged open wound management of the wound. The addition of ECM to the wound allows the tissues to recover from the trauma and remodel the wound. The assumed need for rapid early wound closure seems to be not as imperative with the use of the ECM devices that promote a less scarred constructive remodeling wound healing. Indeed, the present series would suggest the earlier the device is used, the better the wound heals, which is evident in that the authors have not seen any deep infections reported by others with delayed wound closure.¹²

The UBM-ECM devices used herein have availability in several formulations that can be used singularly or in conjunction with each other. These devices have multiple 510(k) clearances from the FDA for management of a wide variety of wound types and for soft tissue reinforcement. Compared to other ECM products, the UBM-ECM products have an intact epithelial basement membrane layer, and they are commercially available as a micronized powder, lyophilized sheets, and a multilaminate, vacuum-pressed sheet of varying thickness options. The UBM-ECM contains native tissue components including various collagens, glycosaminoglycans, and growth factors. In addition to the constructive remodeling wound healing response, the degradation products of UBM-ECM have also been demonstrated to have antimicrobial activity in vitro, which may explain its clinical performance in infected wounds.¹³ Additional studies^14-15 have shown UBM-ECM degradation peptides are chemoattractive to appropriate progenitor cells, suggesting a mechanism for the constructive remodeling response seen in clinical application.

A significant difference in using UBM-ECM product wound therapy is the appearance of the wound bed during treatment as the material breaks down and constructively remodels the wound (Figure 1B). Although classical teaching suggests the appearance of the product building up in the wound is detrimental wound slough that should be removed, the authors found as long as the product is kept hydrated, its salutary effect will continue to facilitate rapid wound healing. Despite keeping the wounds significantly moist, the authors have seen noticeable decrease in periwound edema similar to wounds treated with NPWT alone without the annoyance of being connected to a device.

A major criticism of the present series is the time to achieving wound closure. The healing time of this case series was more prolonged than that possible with traditional flap therapy and more similar to closure times obtained via NPWT. Both of these latter modalities achieved wound healing by traditional M1-macrophage wound healing scenarios, while the authors believe the favorable healing results observed in this UBM-ECM series were due to M2 macrophage phenotype predominance experimentally shown after ECM application.¹⁶ When employed early, the ECM products seem to limit the zone of injury and indeed “treat” the zone so that tissue salvage is optimized. None of these patients required wound revisions, which is not infrequent with flap-based wound management. The patients’ limb contour was excellent and in most cases exceeded that possible with flap management. Patients reported minimal wound discomfort, resulting from their ECM wound treatment. The authors found with time a significant remodeling of the healed wound allowed for increased skin softness and mobility. 

The authors report a positive experience with a group of UBM-ECM devices in managing open lower leg fractures with exposed hardware and open distal lower extremity fracture wounds in nonideal flap patients. The authors believe this method of wound management is reliable, with the best results occurring from earlier product use. Clinical benefits include operations that are short and easy to perform, with little impact on fracture management and healing; tissues are salvaged that might otherwise be sacrificed; postoperative wound care is simplified, cost-effective, and easily managed in the outpatient setting; patients experience less pain as the treatment is confined to the wound without the morbidity of a flap donor site; healing is associated with a more normal native contour and appearance, allowing patients to resume normal footwear; no delay of fracture healing or bone infections after healing was observed; and product is easily applied in the multilevel traumatized limb and in conjunction with the Ilizarov devices. For these 9 patients, any subsequent orthopedic treatments did not require concern about “raising the flap” or injury to the pedicle. Patients were spared flap-associated anticoagulation, arteriograms, dangling protocols, ICU care, frequent monitoring, and need for emergent operating room “take backs.” No wound was too large for ECM treatment, and there was no concern treating single-vessel leg wounds or patients with severe cardiopulmonary compromise. Patient satisfaction was high, and all were readily willing to undergo product placement rather than flap harvest. With experience, the authors have found the UBM-ECM to be a less time-intensive, resource-requiring treatment for managing patients with these complex wounds. They also believe that ECM products have utility whether they are used as the primary reconstructive modality or as an adjunct to standard reconstructive techniques. Further study is indicated to determine its role in lower extremity trauma wound management.

Affiliations: Division of Plastic and Reconstructive Surgery, Saint Louis University School of Medicine; and Department of Orthopedic Surgery, St. Louis University School of Medicine, St. Louis, MO

Correspondence:
Bruce A. Kraemer, MD, FACS
Pandrangi Professor of Plastic Surgery
Chief, Division of Plastic and Reconstructive Surgery
St. Louis University School of Medicine
3635 Vista Avenue
3rd Floor Desloge Towers
St. Louis, MO 63110
kraemerb@slu.edu 

Disclosure: Dr. Kraemer participates in the Key Opinion Leaders Bureau for ACell, Inc, Columbia, MD and has received monies for presenting his clinical experience using the porcine urinary bladder matrix-extracellular matrix products described in this article. Dr. Geiger received travel and hotel expenses from ACell Inc to present a poster, including these clinical cases, at the Orthopaedic Trauma Association 2014 Annual Meeting in Tampa, FL.