Single-stage repair of contaminated hernias using a novel antibiotic-impregnated biologic porcine submucosa tissue matrix.

BACKGROUND: Single-stage repair of incisional hernias in contaminated fields has a high rate of surgical site infection (30-42%) when biologic grafts are used for repair. In an attempt to decrease this risk, a novel graft incorporating gentamicin into a biologic extracellular matrix derived from porcine small intestine submucosa was developed. METHODS: This prospective, multicenter, single-arm observational study was designed to determine the incidence of surgical site infection following implantation of the device into surgical fields characterized as CDC Class II, III, or IV. RESULTS: Twenty-four patients were enrolled, with 42% contaminated and 25% dirty surgical fields. After 12 months, 5 patients experienced 6 surgical site infections (21%) with infection involving the graft in 2 patients (8%). No grafts were explanted. CONCLUSIONS: The incorporation of gentamicin into a porcine-derived biologic graft can be achieved with no noted gentamicin toxicity and a low rate of device infection for patients undergoing single-stage repair of ventral hernia in contaminated settings. TRIAL REGISTRATION: The study was registered March 27, 2015 at www.clinicaltrials.gov as NCT02401334.

Characterization of the local wound environment following treatment of chronic leg ulcers with SIS wound matrix.

BACKGROUND: The SIS Wound Matrix (SISWM) has been shown to improve healing of chronic ulcers over standard of care. In this study, we tested the hypothesis that chronic venous ulcers responsive to treatment with SISWM would more closely mimic an acute wound state as opposed to unresponsive ulcers. METHODS: Serum and wound exudate were collected at baseline and then weekly for up to 12 weeks from 12 patients receiving multiple applications of the SISWM. Levels of matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-9, and MMP-12), pro-inflammatory cytokines (IL-1ß, TNF-α, IL-8), and transforming growth factor beta (TGF-ß1) were evaluated. A variety of Th1/Th2 cytokines were also assayed, as were systemic anti-SIS and anti-α-gal antibody titers. RESULTS: Seven of the 12 patients eventually healed their wounds. Results showed significant decreases in MMP-1, MMP-2, MMP-3, MMP-9, TNF-α and IL-8, and significant increases in TGF-ß1 in wounds responding to treatment with the SISWM versus wounds that did not respond to treatment. None of the 12 patients formed a measurable serum antibody response to the SISWM. CONCLUSIONS: These data show that SISWM does not lead to immune system recognition or sensitization to the matrix and that wounds that went on to heal following treatment were characterized by a more acute wound state. The study confirms that the wound environment is important to healing and that turning a wound toward an acute biochemical state is key to the healing process.

The bolster technique utilising small intestinal submucosa wound matrix: A novel approach to wound treatment.

Managing acute wounds with soft tissue loss can be very challenging for both patients and physicians. Successful wound healing depends on several factors including exudate control, prevention of infection, and moisture balance. In this case series, we describe a novel combination treatment method utilising small intestinal submucosa wound matrix (SISWM) with the bolster technique as a way of assisting the integration of collagen-based wound treatment products into the base of complex wounds with the intent of restoring a dysfunctional extracellular matrix. In case 1, a 44-year-old female presented with an acute wound resulting from a spider bite to the posterior aspect of the right knee. In case 2, a 12-year-old male sustained multiple injuries to his right foot from an all-terrain vehicle accident. In case 3, an 80-year-old female on anticoagulants sustained an avulsion injury to her left lower leg. In case 4, a 41-year-old female sustained a severe complex avulsion injury to the dorsal left forearm sustained from a dog bite. All patients were successfully treated with SISWM and the bolster technique, and their wounds healed completely within 6 weeks. The bolster technique, when combined with an SISWM, is a novel method designed to enable the SISWM to impart its wound healing properties to these complex traumatic wounds. This case series presents treating clinicians with a different treatment methodology to assist the patient in achieving a successful outcome.

An extracellular matrix graft (Oasis® wound matrix) for treating full-thickness pressure ulcers: A randomized clinical trial.

AIM: The purpose of the study was to evaluate clinical safety and effectiveness of Oasis® Wound Matrix as a treatment for full-thickness pressure ulcers and compare it to Standard Care. METHODS: A total of 130 adults with Stage III or Stage IV pressure ulcers were randomly assigned, received either multiple topical treatments of SIS plus standard care (n = 67), or standard care alone (n = 63), and were subsequently evaluated. Ulcer size was determined at enrollment and weekly throughout treatment. Healing was assessed at each visit for a period of up to 12 weeks, with incidence of complete healing and 90% reduction in ulcer area being the primary outcome measures. RESULTS: The proportion of complete healing in the SIS group was 40% as compared to 29% in the standard of care group (p = 0.111); the percentage of patients having a 90% reduction in ulcer surface area was 55% in the SIS group versus 38% in the standard of care group (p = 0.037). CONCLUSIONS: The results of this study suggest that within the setting of a comprehensive wound care program, weekly treatment of chronic pressure ulcers with SIS wound matrix increases the incidence of 90% reduction in wound size versus standard of care alone.

Nipple Reconstruction with the Biodesign Nipple Reconstruction Cylinder: A Prospective Clinical Study.

BACKGROUND: Nipple reconstruction is the last stage in cosmetic reconstruction of the breast after mastectomy, but no method produces reliable and consistent aesthetic results. This study examined the use of the Biodesign Nipple Reconstruction Cylinder (NRC) during reconstruction of the nipple after mastectomy. METHODS: Patients with a history of breast cancer and mastectomy desiring nipple reconstruction were invited to participate. After obtaining consent, unilateral or bilateral nipple reconstruction was performed. Skin flaps were raised, the NRC was placed beneath the flaps as a stent, and the site was protected for up to 4 weeks with a nipple shield. Nipple projection was measured for 12 months after surgery. Patient satisfaction was measured and adverse events were recorded. Follow-up examinations were performed at 1 week, and then at 1, 3, 6, and 12 months after surgery. RESULTS: Eighty-two nipple reconstructions were performed in 50 patients. Related postoperative adverse events were minor, but reported in 8 reconstructions (9.8%) representing 7 patients (14.0%). Average projection at 6 and 12 months was 4.1 ± 1.6 mm and 3.8 ± 1.5 mm, respectively, compared with 10.5 ± 2.2 mm 1 week after surgery. Of patients completing the satisfaction questionnaire at 12 months, 70/75 (93.3%) of reconstructions were rated "pleased" or "very pleased" with the overall outcome. Overall, 45/46 (97.8%) patients would recommend nipple reconstruction to other women. CONCLUSIONS: The Biodesign NRC offers a safe alternative to nipple reconstruction, resulting in stable projection and a high level of patient satisfaction for 12 months after placement.

Transforming surgery through biomaterial template technology.

Templates inserted into surgical wounds strongly influence the healing responses in humans. The science of these templates, in the form of extracellular matrix biomaterials, is rapidly evolving and improving as the natural interactions with the body become better understood.

A prospective, randomized, multicenter trial of Surgisis Gold, a biologic prosthetic, as a sublay reinforcement of the fascial closure after open bariatric surgery.

PURPOSE: This prospective, multicenter, randomized clinical trial was performed to compare the effectiveness of the bioprosthesis Surgisis Gold (Cook Biotech, Inc, West Lafayette, IN) to suture closure alone in reinforcing the abdominal wall after open Roux-en-Y gastric bypass (RYGB). METHODS: A total of 402 adult patients (body mass index ≥35 kg/m(2)) scheduled to undergo open RYGB procedures were randomized to receive either Surgisis Gold placed as a sublay directly under and opposed to the posterior rectus fascia without intervening preperitoneal fat or suture closure alone. Peri- and postoperative complications were tracked. Incisional hernia formation in each group was examined at 6 weeks, 3, 6, and 9 months, and 1 and 2 years after RYGB. RESULTS: A total of 380 (78 male; 302 female) patients with a mean age of 45 years (range 18-69) and a mean BMI of 48 (range 35-79) underwent RYGB. There were no differences in patient demographics or comorbidities between groups. Placement of the Surgisis Gold increased operating time by an average of 14 minutes. Complications were more common in the Surgisis Gold group with significantly more wound events and seroma formation compared with the suture closure alone group. At final follow-up, 32 of 185 (17%) of patients in the reinforced arm and 38 of 195 (20%) in the suture alone arm developed an incisional hernia (P = .6). CONCLUSION: In this challenging patient population, the use of Surgisis Gold for reinforcing the abdominal wall after open RYGB was not shown to be greatly different from a primary suture repair.

Biologic collagen cylinder with skate flap technique for nipple reconstruction.

A surgical technique using local tissue skate flaps combined with cylinders made from a naturally derived biomaterial has been used effectively for nipple reconstruction. A retrospective review of patients who underwent nipple reconstruction using this technique was performed. Comorbidities and type of breast reconstruction were collected. Outcome evaluation included complications, surgical revisions, and nipple projection. There were 115 skate flap reconstructions performed in 83 patients between July 2009 and January 2013. Patients ranged from 32 to 73 years old. Average body mass index was 28.0. The most common comorbidities were hypertension (39.8%) and smoking (16.9%). After breast reconstruction, 68.7% of the patients underwent chemotherapy and 20.5% underwent radiation. Seventy-one patients had immediate breast reconstruction with expanders and 12 had delayed reconstruction. The only reported complications were extrusions (3.5%). Six nipples (5.2%) in 5 patients required surgical revision due to loss of projection; two patients had minor loss of projection but did not require surgical revision. Nipple projection at time of surgery ranged from 6 to 7 mm and average projection at 6 months was 3-5 mm. A surgical technique for nipple reconstruction using a skate flap with a graft material is described. Complications are infrequent and short-term projection measurements are encouraging.

Abdominal wall reconstruction with components separation and mesh reinforcement in complex hernia repair.

BACKGROUND: Abdominal closure in the presence of enterocutaneous fistula, stoma or infection can be challenging. A single-surgeon's experience of performing components separation abdominal reconstruction and reinforcement with mesh in the difficult abdomen is presented. METHODS: Medical records from patients undergoing components separation and reinforcement with hernia mesh at Royal Liverpool Hospital from 2009 to 2012 were reviewed. Patients were classified by the Ventral Hernia Working Group (VHWG) grading system. Co-morbidities, previous surgeries, specific type of reconstruction technique, discharge date, complications and hernia recurrence were recorded. RESULTS: Twenty-three patients' (15 males, 8 females) notes were reviewed. Median age was 57 years (range 20-76 years). Median follow-up at the time of review was 17 months (range 2-48 months). There were 13 grade III hernias and 10 grade IV hernias identified. Synthetic mesh was placed to reinforce the abdomen in 6 patients, cross-linked porcine dermis was used in 3, and a Biodesign® Hernia Graft was placed in 14. Complications included wound infection (13%), superficial wound dehiscence (22%), seroma formation (22%) and stoma complications (9%). To date, hernias have recurred in 3 patients (13%). CONCLUSIONS: Components separation and reinforcement with biological mesh is a successful technique in the grade III and IV abdomen with acceptable rate of recurrence and complications.

First experience with the use of a collagen fistula plug to treat enterocutaneous fistulas.

This report describes the authors' first experiences with the use of the Biodesign Enterocutaneous Fistula Plug (EFP). Six patients presented with intraperitoneal abscess and associated chronic bowel fistulas. The fistulas were treated by delivering an EFP by using radiologic guidance. The EFP placement procedure was successfully performed in all patients. All fistulas were closed within 2 weeks. Fistula recurrence occurred in two patients (33%) at 9 and 12 months after the procedure. One recurrence was associated with an adverse reaction to chemotherapy. The other was associated with the silicone flange migrating out of the bowel lumen. The Biodesign EFP offers a promising new approach for the treatment of enterocutaneous fistulas.

Suppression and activation of the malignant phenotype by extracellular matrix in xenograft models of bladder cancer: a model for tumor cell "dormancy".

A major problem in cancer research is the lack of a tractable model for delayed metastasis. Herein we show that cancer cells suppressed by SISgel, a gel-forming normal ECM material derived from Small Intestine Submucosa (SIS), in flank xenografts show properties of suppression and re-activation that are very similar to normal delayed metastasis and suggest these suppressed cells can serve as a novel model for developing therapeutics to target micrometastases or suppressed cancer cells. Co-injection with SISgel suppressed the malignant phenotype of highly invasive J82 bladder cancer cells and highly metastatic JB-V bladder cancer cells in nude mouse flank xenografts. Cells could remain viable up to 120 days without forming tumors and appeared much more highly differentiated and less atypical than tumors from cells co-injected with Matrigel. In 40% of SISgel xenografts, growth resumed in the malignant phenotype after a period of suppression or dormancy for at least 30 days and was more likely with implantation of 3 million or more cells. Ordinary Type I collagen did not suppress malignant growth, and tumors developed about as well with collagen as with Matrigel. A clear signal in gene expression over different cell lines was not seen by transcriptome microarray analysis, but in contrast, Reverse Phase Protein Analysis of 250 proteins across 4 cell lines identified Integrin Linked Kinase (ILK) signaling that was functionally confirmed by an ILK inhibitor. We suggest that cancer cells suppressed on SISgel could serve as a model for dormancy and re-awakening to allow for the identification of therapeutic targets for treating micrometastases.

Update on Bioactive Prosthetic Material for the Treatment of Hernias.

The use of mesh in the repair of hernias is commonplace. Synthetic mesh, like polypropylene, has been the workhorse for hernia repairs since the 1980s. Surgisis® mesh (Cook Surgical, Bloomington, IN), a biologic hernia graft material composed of purified porcine small intestinal submucosa (SIS), was first introduced to the United States in 1998 as an alternative to synthetic mesh materials. This mesh, composed of extracellular matrix collagen, fibronectin and associated glycosaminoglycans and growth factors, has been extensively investigated in animal models and used clinically in many types of surgical procedures. SIS acts as a scaffold for natural growth and strength. We reported our initial results in this publication in July 2006. Since then, there have been many more reports and numerous other bioactive prosthetic materials (BPMs) released. The object of this article is to briefly review some of the current literature on the use of BPM for inguinal hernias, sports hernias, and umbilical hernias.

Addition of nimesulide to small intestinal submucosa biomaterial inhibits postsurgical adhesiogenesis in rats.

Adhesion formation is a common complication in abdominal surgery with incidence as high as 93% and small bowel obstruction a common complication. Because the extracellular matrix material, small intestinal submucosa (SIS), is commonly used in various surgical procedures, methods to inhibit adhesiogenesis are of great interest. This study was undertaken to determine if incorporation of nimesulide (NM), a selective cyclooxygenase (COX)-2 inhibitor, could reduce the extent and tenacity of intraabdominal adhesion formation associated with SIS implantation. Female Sprague-Dawley rats underwent a cecal abrasion surgical procedure to induce adhesiogenesis. Rats were either left untreated or treated by direct application over the injured cecum with polypropylene mesh (PPM); SIS; SIS containing a low dose of NM; or SIS containing a high dose of NM. Rats were euthanized 21 days later, and adhesion extent and tenacity were evaluated using standard scales (0 = minimal adhesiogenesis; 4 = severe adhesiogenesis). Addition of NM to SIS resulted in a significant (p < 0.05) reduction in adhesion extent and in a similar reduction in adhesion tenacity for SIS containing a low dose of NM. Adhesions typically extended from the abraded cecal surface to the body wall and were characterized histologically by fibrous tissue adherent to the cecal wall. In conclusion, addition of the nonsteroidal anti-inflammatory, COX-2 selective drug, NM, to SIS attenuates adhesion extent and tenacity when compared with surgical placement of SIS or PPM alone.

Rapid biofabrication of tubular tissue constructs by centrifugal casting in a decellularized natural scaffold with laser-machined micropores.

Centrifugal casting allows rapid biofabrication of tubular tissue constructs by suspending living cells in an in situ cross-linkable hydrogel. We hypothesize that introduction of laser-machined micropores into a decellularized natural scaffold will facilitate cell seeding by centrifugal casting and increase hydrogel retention, without compromising the biomechanical properties of the scaffold. Micropores with diameters of 50, 100, and 200 mum were machined at different linear densities in decellularized small intestine submucosa (SIS) planar sheets and tubular SIS scaffolds using an argon laser. The ultimate stress and ultimate strain values for SIS sheets with laser-machined micropores with diameter 50 mum and distance between holes as low as 714 mum were not significantly different from unmachined control SIS specimens. Centrifugal casting of GFP-labeled cells suspended in an in situ cross-linkable hyaluronan-based hydrogel resulted in scaffold recellularization with a high density of viable cells inside the laser-machined micropores. Perfusion tests demonstrated the retention of the cells encapsulated within the HA hydrogel in the microholes. Thus, an SIS scaffold with appropriately sized microholes can be loaded with hydrogel encapsulated cells by centrifugal casting to give a mechanically robust construct that retains the cell-seeded hydrogel, permitting rapid biofabrication of tubular tissue construct in a "bioreactor-free" fashion.

Immune response to small intestinal submucosa (surgisis) implant in humans: preliminary observations.

Surgisis IHM is an acellular biomaterial derived from porcine small intestinal submucosa (SIS) that induces site-specific remodeling in the organ or tissue into which it is placed. Previous animal studies have shown that the graft recipient mounts a helper T type 2-restricted immune response to the SIS xenograft without signs of rejection. The aims of this study were to evaluate the immune response to the SIS implant in a small series of humans and to examine the long-term clinical acceptance of the xenograft in these patients. Five consecutive male patients (mean age 56 years, range 34-68) who underwent inguinal hernioplasty with Surgisis IHM were assessed at 2 weeks, 6 weeks, and 6 months after implant for SIS-specific, alpha-1,3-galactose (alpha-gal) epitope and type I collagen specific antibodies. All five patients were also clinically assessed up to 2 years for signs of clinical rejection, hernia recurrence, and other complications. All 5 patients implanted with Surgisis IHM produced antibodies specific for SIS and alpha -gal with a peak between 2 and 6 weeks after implantation. By 6 months, all patients showed decreasing levels of anti-SIS antibodies. Two patients developed a transient, mild local seroma that resolved spontaneously. None of the patients showed any clinical signs of rejection, wound infection, hernia recurrence, or other complications in the follow-up out to 2 years. Thus, this study showed that in a small series of patients the SIS elicits an antibody response without clinical rejection of the xenograft and minimal postoperative complications.

Effects of sterilization on an extracellular matrix scaffold: part I. Composition and matrix architecture.

The impact of peracetic acid (PAA), lyophilization, and ethylene oxide (EO) sterilization on the composition and three dimensional matrix structure of small intestinal submucosa (SIS), a biologic scaffold used to stimulate the repair of damaged tissues and organs, was examined. Fibronectin and glycosaminoglycans are retained in SIS following oxidation by peracetic acid and alkylation using ethylene oxide gas. Significant amounts of FGF-2 are also retained, but VEGF is susceptible to the effects of PAA and is dramatically reduced following processing. Further, matrix oxidation, lyophilization, and sterilization with EO can be performed without irreversibly collapsing the three dimensional structure of the native SIS. These structural features and growth promoting extracellular matrix constituents are likely to be important variables underlying cellular attachment, infiltration and eventual incorporation of SIS into healing host tissues.

Effects of sterilization on an extracellular matrix scaffold: part II. Bioactivity and matrix interaction.

Small intestinal submucosa (SIS) has been successfully used to treat a variety of damaged or diseased tissues in human patients. As a biologic scaffold, SIS stimulates repair of damaged or diseased tissues and organs with tissue that is similar in structure and function to the material it was meant to replace. To meet clinical safety requirements, biologic materials from animal tissues must undergo processing treatments to minimize host immune response and to eliminate the possibility of disease transmission. The effect of peracetic acid disinfection, lyophilization, and ethylene oxide sterilization on the in vitro bioactivity of the processed SIS was therefore examined in murine fibroblasts and pheochromocytoma (PC12) cells. Specifically, the ability of processed SIS to support fibroblast attachment, to stimulate PC12 cell differentiation, and to upregulate fibroblast VEGF secretion was examined. Fibroblasts attach to the sterilized SIS, remain viable, and more than double their secretion of VEGF as a result of interacting with the SIS matrix components. Additionally, PC12 cells exhibit increased neurite outgrowth following stimulation by SIS matrix proteins versus controls. We conclude that a biologic scaffold can be prepared for human use and still retain significant bioactivity.

Extracellular matrix as a strategy for treating chronic wounds.

The dermis normally directs all phases of skin wound healing following tissue trauma or disease. However, in chronic wounds, the dermal matrix is insufficient to stimulate healing and assistance by external factors is needed for wound closure. Although the concept of the extracellular matrix directing wound healing is not new, ideas about how best to provide the extracellular matrix components required to 'jump-start' the healing process are still evolving. Historically, these strategies have included use of enzyme-inhibiting dressing materials, which bind matrix metalloproteinases and remove them from the chronic wound environment, or direct application of purified growth factors to stimulate fibroblast activity and deposition of neo-matrix. More recently, the application of a structurally intact, biochemically complex extracellular matrix, designed to provide the critical extracellular components of the dermis in a single application, has allowed for the reconstruction of new, healthy tissue and restoration of tissue integrity in the previously chronic wound. This review focuses on this third mechanism as an emerging tactic in effective wound repair. Intact extracellular matrix can quickly, easily, and effectively provide key extracellular components of the dermis necessary to direct the healing response and allow for the proliferation of new, healthy tissue. Its application may promote the healing of wounds that have been refractory to other, more conventional treatment strategies, and may eventually show utility when used earlier in wound healing treatment with the goal of preventing wounds from reaching a truly chronic, nonresponsive state.

Small Intestinal Submucosa Wound Matrix for Chronic Wound Healing.

Chronic wounds represent a state where healing has stagnated. Venous, diabetic, and pressure ulcers are typically difficult to heal and are at high risk of becoming chronic. In an attempt to restart the healing of chronic wounds, many biologically important molecules, such as collagen, hyaluronic acid, and growth factors have been used to treat these wounds with varying degrees of success. Until recently, the idea of replacing the failing extracellular matrix (ECM) with an intact and biologically complex substitute was unknown. Small Intestinal Submucosa Wound Matrix (SISWM) is both a biologically complex and intact ECM, and an effective therapy for treating chronic wounds. A "drop in' replacement for the ECM of difficult to heal or chronic wounds helps to stimulate tissue ingrowth, deposition of new matrix, and rapid epithelialization-potentially leading to improved quality of life for patients.

Bioactive prosthetic material for treatment of hernias.

HYPOTHESIS: Laparoscopic herniorrhaphy using Surgisis (Cook Surgical, Bloomington, IN, USA) mesh is an effective long-term treatment for repair of inguinal hernia. PATIENTS AND INTERVENTION: Between August 1999 and April 2005, 67 patients underwent laparoscopic inguinal hernia repair by the total extraperitoneal (TEP) mesh placement technique using Surgisis mesh. A total of 82 primary direct, indirect, pantaloon, and femoral hernias were repaired using this technique. MAIN OUTCOME MEASURES: Postoperative complications and recurrence as evaluated at two weeks, six weeks, three months, six months, one year, and yearly thereafter for up to five years. RESULTS: The operations were performed successfully on all the patients. One revision was done to an open procedure. Postoperative complications were typical of inguinal hernia surgery. Average follow up was 38 (range: 4-72, median: 35 months. Four non-technical recurrences following repair of direct hernias were reported, which indicates a 4.9% recurrence rate. No recurrences of indirect hernias were noted. CONCLUSIONS: Laparoscopic inguinal herniorrhaphy using Surgisis mesh is effective in treatment of primary inguinal hernias in adults with minimal complications and recurrence up to five years of follow up.