The Use of Urinary Bladder Matrix in the Treatment of Complicated Open Wounds

Background. Management of complicated open wounds represents a challenge when reconstructive options are not applicable. Urinary bladder matrix (UBM) provides a biocompatible material that allows inductive tissue remodeling. Methods. The use of urinary bladder matrix in the treatment of 5 patients with complicated open wounds that failed to heal with conventional therapy is presented. Results. A 3-year old male sustained a second-degree oil burn measuring 8 cm x 4 cm to his dorsal forearm; UBM was applied weekly and the wound epithelialized in 3 weeks. A 52-year old male sustained massive second and third degree burns to his leg after a fire; UBM was applied weekly and the wound epithelialized in 28 weeks. A 61-year old female sustained a severe crushing injury to her right knee. A gastrocnemius muscle transfer and rectus abdominus muscle free flap transfer both failed, then UBM and vacuum-assisted closure therapy were applied and the wound epithelialized in 24 weeks. A 54-year old female underwent a breast mastectomy and immediate reconstruction with pedicled transverse rectus abdominus flap. The patient developed partial necrosis and the wound was managed with UBM and vacuum-assisted closure therapy. The wound epithelialized in 12 weeks. A 36-year old female sustained severe degloving injuries to both hands with exposed metacarpals. Weekly application of UBM provided tissue remodeling over the bones, which allowed successful skin grafting and closure. Conclusions. These experiences show UBM to be an effective method in management of complicated open wounds in select cases. Further studies need to be implemented to confirm this conclusion.

  Annual wound care cost to the US health care system exceeds 20 billion dollars.¹ This estimate is largely inflated by the costs of wound complications including infection, extended physician care, repeat surgical intervention, and prolonged hospital stay. A chronic dermal ulceration can cost up to $40,000 to heal, and costs often increase as recurrence rates exceed 50% within 18 months of healing.² Beyond financial costs, the loss of integrity of large portions of the skin due to injury or illness can result in significant morbidity and mortality.

  The principal goal of wound management is to achieve rapid wound closure and a functional, aesthetically acceptable scar. Extraordinary advances in cellular and molecular biology have expanded our understanding of basic molecular processes underlying wound repair and tissue regeneration.³ However, translating this understanding into improved management of complicated open wounds continues to be a challenge, particularly when reconstructive options are not applicable. This paper presents a case series of the use of urinary bladder matrix (UBM) scaffold for treatment of complicated open wounds.

Extracellular matrix (ECM) scaffolds are structural and functional proteins that act as a tissue-specific template for constructive tissue remodeling. The molecular composition of the ECM varies depending on the donor organ and processing methods used to create the biologic product. Urinary bladder matrix is a type of ECM derived from porcine bladder that provides structural support and biologic signals for cell adhesion, migration, and proliferation.⁴

  The ideal matrix scaffold is amenable to cell growth and proliferation. A study conducted by Brown et al⁵ evaluated the presence and integrity of basement membrane complex in processed ECM derived from urinary bladder, small intestine, and liver. Of the 3 donor organs, the ECM derived from urinary bladder was the only intact basement membrane complex that survived processing and modulated in vivo growth patterns. Cellular and molecular research conducted by Badylak et al⁶ demonstrated that ECM scaffolds derived from xenogenic UBM provide a biocompatible material that allows inductive tissue remodeling and wound closure.⁶

  During preparation, UBM undergoes a process of decellularization, lyophilization, disinfection, and terminal sterilization.⁷ Decellularization removes or masks antigenic epitopes, DNA, and damage-associated molecular pattern molecules. Urothelial cells are removed from the luminal side of the bladder while the tunica serosa, tunica muscularis externa, tunica submucosa, and muscularis mucosa are mechanically delaminated.⁸ Physical treatments, including sonication and mechanical massage, disrupt the cell membrane and release cell contents. This processes is often combined with chemical detergents with inter- and extra-cellular connections, yielding an acellular scaffold with intact structural and functional ECM. Studies by Gilbert et al⁹ have shown that the mildest decellularization protocol that minimizes cell disruption is optimal to yield an acellular material with native mechanical and biologic properties. The remaining UBM components include collagen, fibronectin, laminin, glycosaminoglycans, and growth factors.¹⁰

  Once prepared, UBM induces bioactive growth factors that support angiogenesis and facilitate proliferation of connective tissues. The intact basement membrane is conductive to epithelial and endothelial cell proliferation, while the opposing lamina propria is composed of connective tissue that induces wound bed neovascularization. Molecular signaling patterns between the scaffold and host cells are complex and continue to be studied.¹⁰

  Following implantation, ECM induces immediate and intense neutrophil and mononuclear cell infiltration, and shifts to mononuclear cells within 72 hours. There is a lack of usual cytotoxic mediators of inflammation and graft rejection, with formation of a polarized type 2 T lymphocyte response.^16,22,24 The ECM scaffolds enzymatically degrade rapidly after implantation, while remodeling continues for weeks.¹¹

  Beattie et al⁴ demonstrated that tissue tested at 14 days represents a mixture of xenogenic scaffold, newly deposited host tissue, and an abundance of host cells. After 14 days, ECM did not appear to provide further positive recruitment of progenitor cells, and the level of cellularity gradually decreased.⁴ The degradation products produce chemotactic and mitogenic properties for multipotential progenitor cells while simultaneously inhibiting chemotaxis and proliferation of differentiated endothelial cells. These multiprogenitor cells differentiate into site-specific tissues.¹²

  Rapid degradation of ECM is followed by replacement with organized site-appropriate functional host tissue. A study conducted by Reddy et al¹³ found no detectable evidence of the UBM scaffold at 3 weeks. Several studies using C-labeled porcine ECM as a scaffold for replacement urinary bladder, laryngeal tissue, and tendinous tissue have shown disappearance of ECM from the graft site, with 90% of implanted scaffold replaced by host tissue 28 days after surgery.^14-16 Once fully resorbed, ECM leaves functional tissue where scar tissue would be presumed to form.⁷

  Additionally, ECM has also been found to possess antibacterial properties against Staphylococcus aureus and Escherichia coli. This property is not of the intact ECM itself, but from the products of ECM degradation.¹⁸ As the bioscaffold is subject to progressive degradation and remodeled by host tissue, antimicrobial peptides may continue to be released, providing sustained antibacterial effects. Additionally, a study by Badylak et al⁶ showed ECM scaffolds resist infection following deliberate bacterial contamination in preclinical studies and spontaneous contamination in the clinical environment.

  Urinary bladder matrix (UBM), specifically Matristem (ACell, Inc, Columbia, MD), was used in the treatment of 5 patients with complicated open wounds (Table 1). All patients provided consent to share their cases for educational and research purposes. Prior to application of the UBM, wounds were debrided to eliminate all necrotic tissues. Patients then had UBM applied to the wound during weekly office visits.

Case 1. A 3-year old male sustained a second-degree oil burn to his dorsal forearm that measured 8 cm x 4 cm. The middle part of the wound, measuring 3 cm x 2 cm, had a deeper burn and did not heal with conventional wound care. The patient underwent weekly applications of UBM and complete epithelialization of his wound was achieved in 3 weeks.

  Case 2. During a fire, a 52-year-old male sustained massive second and third degree burns to his right knee and lower leg that healed with local wound care and skin grafting. Eight years later, the patient sustained trauma to his right knee while walking up stairs and developed a chronic nonhealing ulcer at the initial burn site. He presented to the authors’ office with a nonhealing open wound, measuring 5 cm x 3 cm, over his tibial tuberosity. Biopsy of the wound revealed chronic inflammation with no presence of Marjolin’s ulcer. The ulcer was surrounded by diffuse scar tissue that precluded local reconstructive options. Conventional wound care and multiple skin grafting procedures were unsuccessful. The patient underwent weekly UBM application and his wound healed in 28 weeks.

  Case 3. A 61-year-old female sustained a severe crushing injury to her right knee. The wound was debrided at another institution. Upon debridement, patella was removed. As a result, the patient developed a large open wound of the anterior knee with exposed knee joint. In that same institution, a gastrocnemius muscle transfer and rectus abdominus muscle free flap reconstruction were attempted and both failed. Postoperatively, vacuum-assisted closure therapy alone was attempted and was also unsuccessful. Additionally, the patient developed occlusion of her superficial femoral artery and acute deep venous thrombosis, which precluded further reconstructive surgeries. The patient was informed she might need an above-the-knee amputation (Figure 1a) and was referred to the authors’ institution for consultation and further management. The patient’s wound, which measured 12 cm x 10 cm and had the knee joint exposed, was managed by application of UBM. Initially, UBM was used in combination with vacuum-assisted closure therapy. At 16 weeks, that therapy was discontinued and UBM application was continued on a weekly basis (Figure 1b). At 24 weeks, the wound completely closed and epithelialized, the extremity was salvaged, and the patient began physical therapy (Figure 1c).

  Case 4. A 54-year-old female underwent left breast mastectomy and immediate reconstruction with a pedicle transverse rectus abdominus muscle flap. Postoperatively, the patient developed partial flap necrosis, most probably secondary, to a previous transumbilical tubal ligation surgery. After debridement, the patient’s open wound, which measured 6 cm x 4 cm, was managed with UBM and vacuum-assisted closure therapy (Figure 2a). Vacuum-assisted closure therapy was discontinued at 6 weeks (Figure 2b). Urinary bladder matrix therapy continued to be applied weekly, and the wound completely healed at 12 weeks (Figure 2c).

  Case 5. A 36-year-old female sustained severe crushing and degloving injuries to both hands resulting in large complicated open wounds. Specifically, the patient’s left hand had a wound 8 cm in length that had 2 metacarpal bones completely exposed and devoid of periosteum. All extensor tendons were destroyed. The patient was not a good candidate for a free flap reconstruction due to the extent of the injury (Figure 3a). Serial debridement and subsequent skin grafting were planned. The part of the wound with exposed bones was managed with serial application of UBM in an effort to provide scaffold for skin graft take. One month after initial injury, the 8 cm degloving hand wound with exposed metacarpals was successfully covered with newly formed soft tissue (Figure 3b). The wound underwent minimal contraction, and this allowed successful application of a 6 cm skin graft 9 weeks after the initial injury. After a course of rehabilitation therapy the patient achieved satisfactory functional recovery relative to the severity of the injury (Figure 3c).

Management of complicated open wounds with large areas of exposed bone or tendons is a formidable task when free flap coverage is contraindicated. Those cases include extensive crush or burn injuries, prior flap failures, or patients with significant comorbidities. Alternatives such as pedicle flaps are not always feasible.

  Several authors have reported successful management of wounds with exposed bone, tendon, and orthopedic hardware using vacuum-assisted closure therapy.^19-21 However, vacuum-assisted closure therapy alone was attempted prior to UBM application in some of the cases in this study and was unsuccessful. In this case series, 2 patients were initially treated with a combination of UBM and vacuum-assisted closure therapy, and the latter therapy was discontinued after sufficient granulation tissue developed in the wound. Subsequently, the treatment was continued with UBM alone. The authors believe the use of UBM was the defining factor in successful wound healing in the case series.

  Experimental studies have shown UBM to be promising in the management of complicated open wounds. The composite structure of extracellular matrix molecules, as well as its in vivo degradability, has marked effects upon the host response and remodeling events that determine clinical outcome. The mechanical forces, oxygen requirements, and inherent gene expression patterns of resident cells influence ECM bioactivity.²²

  Research by Hodde et al²³ argues that matrices must either create or induce the host to establish an early and aggressive angiogenic response to develop a blood supply for restoration of structure and function of the diseased tissue. A study conducted by Eweida et al²⁴ supports the role of epidermal keratinocytes in cutaneous wound healing through secretion of factors that promote angiogenesis.²⁴ In that research, UBM scaffolds induced rapid and complete healing of full-thickness wounds in New Zealand rabbits within 3 weeks.

  There are currently few clinical in vivo studies that evaluate the effect of UBM on complex wound healing. A retrospective study conducted by Lechaminant et al¹¹ utilized UBM in 34 patients with diabetic, venous, ischemic, or decubitus ulcerations that failed to close with local wound care including Dermagraft and Apligraf (Organogenesis, Canton, MA), Integra Wound Matrix (Integra LifeSciences, Plainsborough NJ), and Regranex (Smith and Nephew, St, Petersburg, FL). Following initial application, all wounds progressed to full healing with a mean time of 9 weeks.¹¹ However, the authors noted increased healing time in patients with increasing dimensions and depth of the wounds.

  In the current case series, complicated open wounds that healed completely with the chosen UBM product are reported. All patients failed conventional wound care therapy prior to application of the UBM. The average time of healing varied from 3-28 weeks based on the size and depth of the wound, comorbid conditions, and patient cooperation.

  Urinary bladder matrix is not a dermal scaffold. Though it functions as an ECM, its inherent wound properties differ from, and are not comparable to, dermal products on the market.

  Patients who underwent treatment with the UBM did not require multiple dressing changes or visiting nurses for wound care. All wounds demonstrated progressive reepithelialization during weekly visits. Patients were able to resume home activities and present to the authors’ office weekly for dressing changes.

  The authors’ experience shows UBM to be an effective method in management of complicated open wounds in select cases. It is especially useful when conventional methods for wound care fail or when reconstructive options are exhausted. These findings support the use of UBM as a valuable tool in management of complicated open wounds when reconstruction options are not available. The time to wound healing is relatively lengthy. Further studies must be conducted to evaluate the economic aspects of this treatment.

Affiliations: The authors are from Rutgers, The State University of New Jersey, Biomedical and Health Sciences, Newark, NJ.

Address correspondence to:
Alexis Lanteri Parcells, MD
Division of Plastic Surgery
Department of Surgery
Rutgers Biomedical and Health Sciences
140 East Bergen Street
Suite E 1620
Newark, NJ 07103

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