Enhanced Antimicrobial Effects of Decellularized Extracellular Matrix (CorMatrix) with Added Vancomycin and Gentamicin for Device Implant Protection.

BACKGROUND: The incidence of cardiac implantable electronic device (CIED) infections has risen significantly over the past years. Although several devices are currently available to decrease the incidence of infection, most are made from nonviable synthetic material and are more prone to infection than vascularized tissue. OBJECTIVE: This study was undertaken to assess the resistance to infection of the CorMatrix CanGaroo (CorMatrix Cardiovascular, Roswell, GA, USA), a CIED envelope made of decellularized extracellular matrix (ECM) hydrated in different antibiotic solutions. METHODS: This study was comprised of two in vitro tests and one animal trial. For all the tests, the ECM was hydrated in a mixture of vancomycin (25 mg/mL) and gentamicin (20 mg/mL) or gentamicin alone (40 mg/mL). The drug elution characteristics were assessed followed by the effectiveness of CanGaroo to prevent the bacterial growth of Staphylococcus aureus and Staphylococcus epidermidis in culture. Then, the direct inoculation of pacemaker implant pockets with both Staphylococcus species was performed in rabbits implanted with either a pacemaker alone or a pacemaker with antibiotic-soaked CorMatrix ECM pouches. RESULTS: The hydration of CanGaroo envelopes in both antibiotic mixtures resulted in antimicrobial activity against both Staphylococcus species, with an early bolus release of antibiotics followed by a slow release lasting for up to 6 days. In vivo, there was a substantial decrease in the occurrence of infection. CONCLUSIONS: The hydration of the CanGaroo ECM with an antibiotic solution prevented Staphylococcus species growth in vitro and substantially reduced the incidence of CIED pocket infections in an in vivo rabbit model.

Second-generation extracellular matrix patch for epicardial infarct repair.

Current myocardial infarction treatments focus on improving hemodynamics rather than addressing the problem of lost myocardium impairing left ventricular function. Epicardial infarct repair with a bioactive patch placed on the ischemic area is an emerging approach to promote endogenous myocardial repair. We report the use of a second-generation CorMatrix-extracellular matrix (ECM) patch as an adjunct to surgical revascularization in treating a young patient with diffuse, multivessel coronary artery disease unamenable to PCI and a large anterior myocardial infarction. The progressive myocardial scar shrinkage and increase in left ventricular ejection fraction from 10 to 51% are generally not observed with surgical revascularization therapy alone, suggesting this new patch has adjunctive potential to current revascularization therapy.

Remodeling of extracellular matrix patch used for carotid artery repair.

BACKGROUND: We evaluated the in vitro strength and in vivo arterial-wall response to an extracellular-matrix-based patch material in a sheep model of carotid artery repair. MATERIALS AND METHODS: A six-ply sheet of acellular, porcine extracellular matrix (ECM) was subjected to in vitro material strength testing and implanted in 15 sheep for 30, 90, and 180 d. Bovine pericardium was used as a control in some animals. In vivo graft patency was assessed by angiography. Explanted grafts were evaluated by histopathology and burst-strength testing. RESULTS: Mean (SD) in vitro suture retention force of the ECM sheet was 14.5 (3.06) N; tensile strength was 29.7 (6.11) N; and probe burst strength was 185 (22.6) N. In vivo, mild stenosis was observed at 30 d for all patches; stenosis was absent at 90 d in the ECM-repaired arteries but not bovine pericardium controls. Pseudoaneurysm was not observed in any animal. Histopathology showed progressive graft degradation, collagen deposition, formation of neocapillaries and fibrocellular neointima, and endothelialization, but no calcification. Mean (SD) burst pressure for unrepaired arteries was 2608 (858) mmHg and 1473 (694) mmHg for ECM-repaired vessels. Mean change in diameter from unloaded state to burst pressure was 29% (9.7) for unrepaired vessels and 24% (13.4) for ECM-repaired vessels. CONCLUSIONS: The six-ply ECM sheet can withstand the forces encountered after carotid artery repair. In sheep, it shows evidence of progressive, constructive remodeling as early as 30 d post-implantation with rapid deposition of endothelium. ECM shows promise as a patch material for CEA repair.

Results of Lung Cancer Screening in a Rural Setting: A Retrospective Cohort Study.

Background In this study, we aimed to determine the performance of the lung cancer screening (LCS) program using low-dose computed tomography (LDCT) in a rural community. Methodology We conducted a retrospective cohort study of patients who underwent LCS at a rural healthcare institution from September 1, 2016, through December 31, 2019, to determine the utilization of screening, rate of positivity, rate of cancer detection, and patient compliance. Results A total of 1,474 patients underwent initial LCS, and 1,776 LCS examinations were performed using LDCT. Of 1,776 tests performed, 375 (21.1%) were categorized as positive (Lung CT Screening Reporting and Data System III or higher), with 215 of the 375 (57.6%) being lost to follow-up. A total of 29 malignancies were identified (in 1.6% of all LCS tests) during the study period, with 23 (82.8%) malignancies being low-stage malignancies (stage I or II), 24 (79.3%) malignancies potentially surgical candidates (stage IIIA or less), and five (17.2%) malignancies being non-surgical candidates based on stage (stage IIIB or IV). A total of 28.7% of all patients eligible for repeat screening had at least one repeat annual test. Overall, 9.9% of all patients eligible for two repeat annual tests had a second repeat annual test. Conclusions LCS using LDCT is effective in detecting lung cancer in a rural setting. However, compliance with repeat annual screening and recommendations for further workup is low. This may be exacerbated by healthcare and socioeconomic issues prevalent in rural communities. The use of LCS patient coordinators and dedicated tracking software may improve compliance with repeat annual screening and compliance with recommendations when LCS tests are positive.

Allergic response to medical products in patients with alpha-gal syndrome.

BACKGROUND: Galactose-α-1,3-galactose (alpha-gal) is a carbohydrate that is ubiquitously expressed in all mammals except for primates and humans. Patients can become sensitized to this antigen and develop alpha-gal syndrome (AGS), or a red meat allergy. Symptoms range from generalized gastroenteritis and malaise to anaphylaxis, and in endemic areas, the prevalence can be as high as 20%. Although AGS patients commonly avoid alpha-gal by avoiding meat, patients have also developed symptoms due to animal-derived medical products and devices. With the rise in transcatheter aortic valve replacement, we investigate the immunogenicity of common cardiac materials and valves. OBJECTIVE: To assess the in vitro immunoglobulin E response toward common medical products, including cardiac patch materials and bioprosthetic valves in patients with AGS. METHODS: Immunoblot and immunohistochemistry techniques were applied to assess immunoglobulin E reactivity to various mammalian derived tissues and medical products for patients with AGS. RESULTS: AGS serum showed strong reactivity to all of the commercially available, nonhuman products tested, including various decellularized cardiac patch materials and bioprosthetic aortic valves. AGS serum did not react to tissues prepared using alpha-gal knockout pigs. CONCLUSIONS: Despite commercial decellularization processes, alpha-gal continues to be present in animal-derived medical products, including bioprosthetic valves. Serum from patients with AGS demonstrates a strong affinity for these products in vitro. This may have serious potential implications for sensitized patients undergoing cardiac surgery, including early valve failure and accelerated coronary artery disease.

The CorMatrix Cor™ PATCH for epicardial infarct repair.

Contemporary management of ischemic heart disease lacks strategies to directly access the heart and promote reparative cellular mechanisms to improve postinfarct cardiac remodeling. Epicardial infarct repair (EIR) is an emerging technique whereby bioactive materials are sewn over ischemic areas of the heart at the time of surgical revascularization to promote adaptive cardiac repair. The CorMatrix Cor™ PATCH (CorMatrix Cardiovascular Inc., GA, USA) is an acellular bioactive material compatible with EIR. Herein, we review current preclinical and clinical data for the CorMatrix Cor PATCH and its use in EIR.

Lay abstract Therapies for heart attacks include revascularization and medical therapy, but clinicians lack methods of stimulating cells to improve cardiac repair and reduce cardiac fibrosis. Epicardial infarct repair (EIR) is an emerging technique where biomaterials are sewn over areas of the heart damaged by heart attacks. These materials have properties to stimulate repair at a cellular level. This procedure can be performed by cardiac surgeons during coronary artery bypass surgery. The CorMatrix Cor™ PATCH (CorMatrix Cardiovascular Inc., GA, USA) is a biomaterial compatible with EIR. Herein, we review the CorMatrix Cor PATCH and discuss its use in EIR.

Pericardial reconstruction using an extracellular matrix implant correlates with reduced risk of postoperative atrial fibrillation in coronary artery bypass surgery patients.

BACKGROUND: Postoperative atrial fibrillation (AF) is a significant complication following open heart surgery, with potentially serious clinical and economic implications. To assess the effect of a novel procedure, pericardial reconstruction using a porcine-derived extracellular matrix (ECM) implant, on the risk of postoperative AF after primary isolated coronary artery bypass grafting (CABG), we performed a retrospective comparison of the incidence of postoperative AF in patients who underwent this procedure versus an untreated control group. METHODS: We performed a retrospective comparison of the incidence of postoperative AF in 111 patients who underwent a pericardial reconstruction procedure with the CorMatrix ECM for Pericardial Closure (CorMatrix Cardiovascular, Atlanta, GA, USA) following primary isolated CABG, versus a control group of 111 patients who did not undergo pericardial reconstruction. RESULTS: Postoperative AF occurred in 43 of 111 control patients (39%; lower control limit [LCL], 30%; upper control limit [UCL], 49%) but in only 20 of 111 treated patients (18%; LCL, 11%; UCL, 27%). This result represents a 54% reduction in relative risk in the treatment group (P < .001). There was a small but statistically insignificant decrease in the hospital length of stay for the treated patients. The 2 treatment groups exhibited similar postoperative complication profiles. CONCLUSIONS: In this retrospective study, pericardial reconstruction with the ECM implant contributed directly to a statistically significant and clinically meaningful reduction in the rate of postoperative AF in patients undergoing primary isolated CABG. A prospective multicenter randomized trial has been planned to further test this approach.

Extracellular matrix scaffold for cardiac repair.

BACKGROUND: Heart failure remains a significant problem. Tissue-engineered cardiac patches offer potential to treat severe heart failure. We studied an extracellular matrix scaffold for repairing the infarcted left ventricle. METHODS AND RESULTS: Pigs (n=42) underwent left ventricular (LV) infarction. At 6 to 8 weeks, either 4-layer multilaminate urinary bladder-derived extracellular matrix or expanded polytetrafluoroethlyene (ePTFE) was implanted as full-thickness LV wall patch replacement. At 1-week, 1-month, or 3-month intervals, pigs were terminated. After macroscopic examination, samples of tissue were prepared for histology, immunocytochemistry, and analysis of cell proportions by flow cytometry. One-week and 1-month patches were intact with thrombus and inflammation; at 1 month, there was also tissue with spindle-shaped cells in proteoglycan-rich and collagenous matrix. More alpha-smooth muscle actin-positive cells were present in urinary bladder matrix (UBM) than in ePTFE (22.2+/-3.3% versus 8.4+/-2.7%; P=0.04). At 3 months, UBM was bioresorbed, and a collagen-rich vascularized tissue with numerous myofibroblasts was present. Isolated regions of alpha-sarcomeric actin-positive, intensely alpha-smooth muscle actin-immunopositive, and striated cells were observed. ePTFE at 3 months had foreign-body response with necrosis and calcification. Flow cytometry showed similarities of cells from UBM to normal myocardium, whereas ePTFE had limited cardiomyocyte markers. CONCLUSIONS: Appearance of a fibrocellular tissue that included contractile cells accompanied biodegradation of UBM when implanted as an LV-free wall infarction patch. UBM appears superior to synthetic material for cardiac patching and trends toward myocardial replacement at 3 months.

Pulmonary Valve Replacement With Small Intestine Submucosa-Extracellular Matrix in a Porcine Model.

BACKGROUND: Prosthetic materials available for pediatric pulmonary valve replacement (PVR) lack growth potential, inevitably leading to a size mismatch. Small intestine submucosa-derived extracellular matrix (SIS-ECM) has been suggested to possess regenerative properties. We aimed to investigate its function and potential to increase in size as a PVR in a piglet. METHODS: An SIS-ECM trileaflet valved conduit was designed. Hanford minipigs, n = 6 (10-34 kg), underwent PVR with an intended survival of six months, with monthly echocardiograms evaluating valve size and function. The conduit was excised for histologic analysis. RESULTS: Of the six, one was sacrificed at three months for midterm analysis, and one at month 3 due to endocarditis. The remaining four constituted the study cohort. The piglet weight increased by 186% (19.56 ± 10.22 kg to 56.00 ± 7.87 kg). Conduit size increased by 30% (1.42 ± 0.14 cm to 1.84 ± 0.14 cm; P < .01). The native right ventricular outflow tract increased by 43% and the native pulmonary artery by 84%, resulting in a peak gradient increase from 10.08 ± 2.47 mm Hg to 36.25 ± 18.80 mm Hg (P = .03). Additionally, all valves developed at least moderate regurgitation. Conduit histology showed advanced remodeling with myofibroblast infiltration, neovascularization, and endothelialization. The leaflets remodeled beginning at the base with the leaflet edge being less cellular. In addition to the known endocarditis, bacterial colonies were discovered within a leaflet in another. CONCLUSIONS: The SIS-ECM valved conduit implanted into a piglet demonstrated cellular infiltration with vascular remodeling and an increase in diameter. Conduit stenosis was a result of slower rates of size increase than native tissue. Suboptimal leaflet performance requires design modifications.

Feasibility study of particulate extracellular matrix (P-ECM) and left ventricular assist device (HVAD) therapy in chronic ischemic heart failure bovine model.

Myocardial recovery with left ventricular assist device (LVAD) support is uncommon and unpredictable. We tested the hypothesis that injectable particulate extracellular matrix (P-ECM) with LVAD support promotes cell proliferation and improves cardiac function. LVAD, P-ECM, and P-ECM + LVAD therapies were investigated in chronic ischemic heart failure (IHF) calves induced using coronary embolization. Particulate extracellular matrix emulsion (CorMatrix, Roswell, GA) was injected intramyocardially using a 7 needle pneumatic delivery tool. Left ventricular assist devices (HVAD, HeartWare) were implanted in a left ventricle (LV) apex to proximal descending aorta configuration. Cell proliferation was identified using BrdU (5 mg/kg) injections over the last 45 treatment days. Echocardiography was performed weekly. End-organ regional blood flow (RBF) was quantified at study endpoints using fluorescently labeled microspheres. Before treatment, IHF calves had an ejection fraction (EF) of 33 ± 2% and left ventricular end-diastolic volume of 214 ± 18 ml with cardiac cachexia (0.69 ± 0.06 kg/day). Healthy weight gain was restored in all groups (0.89 ± 0.03 kg/day). EF increased with P-ECM + HVAD from 36 ± 5% to 75 ± 2%, HVAD 38 ± 4% to 58 ± 5%, and P-ECM 27 ± 1% to 66 ± 6%. P-ECM + HVAD demonstrated the largest increase in cell proliferation and end-organ RBF. This study demonstrates the feasibility of combined LVAD support with P-ECM injection to stimulate new cell proliferation and improve cardiac function, which warrants further investigation.

Extracellular matrix for myocardial repair.

OBJECTIVE: To evaluate the remodeling characteristics of an extracellular matrix (ECM) scaffold when used as a template for myocardial repair. BACKGROUND: Xenogeneic ECM has been shown to be an effective scaffold for the repair and reconstitution of several tissues, including lower urinary tract structures, dura mater, the esophagus, musculotendinous tissues, and blood vessels. These ECM scaffolds are completely degraded in vivo and induce a host cellular response that supports. Constructive remodeling rather than scar tissue formation. METHODS: Full-thickness circular defects measuring approximately 2.5 cm in diameter were created in the right ventricular anterior walls of 6 adult Yucatán pigs and 4 adult mongrel dogs. The defects were repaired with an ECM sheet 80 m thick that was derived from either the porcine small intestinal submucosa or the porcine urinary bladder matrix. The animals lived for periods of 6 to 24 weeks before sacrifice. RESULTS: There was a complete replacement of the acellular scaffolds by a mixture of tissue types, including well-vascularized fibrous connective tissue, cartilage, adipose connective tissue, and myocardial tissue. The remodeled scaffold tissue showed spontaneous contractility and peak contractile force equivalent to 70% of the contractile force of the adjacent native myocardium. CONCLUSIONS: We conclude that porcine ECM scaffolds alter the typical scar tissue healing response in myocardial tissue and instead support vascularization and the local development of multiple tissue types, including contractile myocardium.

In vivo remodeling potential of a novel bioprosthetic tricuspid valve in an ovine model.

OBJECTIVES: A novel bioprosthetic tricuspid valve was constructed from an acellular extracellular matrix (ECM) bioscaffold. The valve's mechanical functionality and potential for histologic regeneration was evaluated in an ovine model. METHODS: The native tricuspid valves of 4 domestic sheep were excised and replaced with bioprosthetic valves constructed from the ECM bioscaffold material shaped into the form of a tube. In vivo function was assessed over time by transthoracic echocardiography. Animals were euthanized at 3, 5, 8, and 12 months after valve implantation, and explanted valves were examined for gross morphology and by qualitative histopathologic analysis. RESULTS: All 4 sheep survived until the specified date. Forward flow by echocardiography was normal with trivial to mild regurgitation. Annular morphology and mobility of the leaflets appeared normal with excellent leaflet coaptation. Explanted valves were grossly normal at all time points and showed evidence of progressive tissue remodeling and integration at the host-tissue interface. Histopathologic analysis demonstrated massive host-cell infiltration, structural reorganization of the ECM bioscaffold, elastin generation at the annulus by 3 months, and increased collagen organization and glycosaminoglycan presence in the leaflets by 5 months, with no evidence of foreign body response. CONCLUSIONS: When implanted in the form of a tubular valve, the acellular ECM bioscaffold demonstrates feasibility as a biomechanically sound bioprosthetic tricuspid valve replacement with evidence of progressive endothelialization and constructive tissue remodeling.

Development of an extracellular matrix delivery system for effective intramyocardial injection in ischemic tissue.

Biomaterials with direct intramyocardial injection devices have been developed and are being investigated as a potential cardiac regenerative therapy for end-stage ischemic heart failure. Decellularized extracellular matrix (ECM) has been shown to improve cardiac function and attenuate or reverse pathologic remodeling cascades. CorMatrix Cardiovascular, Inc. has developed a porcine small intestinal submucosa-derived particulate extracellular matrix (P-ECM) and ECM Delivery System to provide uniform and controlled intramyocardial delivery of the injectable P-ECM material into infarcted regions. The CorMatrix ECM Delivery System is composed of a Multi-Needle P-ECM Syringe Assembly, Automated Injection Controller, and Tissue Depth Measurement System (portable ultrasound). Feasibility of the P-ECM delivery system was tested intraoperatively in a chronic ischemic heart failure bovine model (n = 11), and demonstrated the ability to control injection volume (0.1-1.0 ml) and depth of penetration (3-5 mm) under regulated injection pressure (150 psi CO2) into the ischemic region. Targeted intramyocardial delivery of P-ECM may improve efficacy and enable development of novel patient-specific therapy.

Use of a novel acellular xenograft as a patch for aortic annular enlargement during aortic valve replacement.

A patient with a history of aortic valve endocarditis and surgical debridement presented with acute congestive heart failure because of severe aortic stenosis. During valve replacement surgery, an aortic annular enlargement was required to overcome a potential patient-prosthesis mismatch. We describe the use of a novel, bioresorbable, acellular xenograft for the enlargement patch. This material is expected to remodel into native patient tissue over time. This case offers an alternative implant for left heart reconstruction using a regenerative patch.

Improvement in cardiac function with small intestine extracellular matrix is associated with recruitment of C-kit cells, myofibroblasts, and macrophages after myocardial infarction.

OBJECTIVES: This study tested the hypothesis that modulation of angiogenesis and cardiac function by injecting small intestine extracellular matrix emulsion (EMU) into myocardium is associated with recruitment of c-kit cells, myofibroblasts, and macrophages after myocardial infarction. BACKGROUND: Degradation of native extracellular matrix has been associated with adverse cardiac remodeling after infarction. METHODS: Sixty-four rats were subjected to 45 min ischemia followed by 3, 7, 21, and 42 days of reperfusion, respectively. Saline or EMU (30 to 50 microl) was injected into the area at risk myocardium after reperfusion. Histological examination was performed by immunohistochemical staining, and cardiac function was analyzed using echocardiography. RESULTS: The population of c-kit-positive cells in infarcted myocardium with the EMU injection increased significantly relative to the saline control at 7 days of reperfusion. Along with this change, alpha-smooth muscle actin expressing myofibroblasts and macrophages accumulated to a significant extent compared with the saline control. Increased vascular endothelial growth factor protein level and strong immunoreactivity of vascular endothelial growth factor expression were observed. Angiogenesis in the EMU area was significantly enhanced relative to the saline control, evidenced by increased density of alpha-smooth muscle actin positive vessels. Furthermore, echocardiography showed significant improvements in fractional shortening, ejection fraction, and stroke volume in the EMU group. The wall thickness of the infarcted middle anterior septum in the EMU group was significantly increased relative to the saline control. CONCLUSIONS: We show for the first time that injection of EMU into the infarcted myocardium increases neovascularization and preserves cardiac function, potentially mediated by enhanced recruitment of c-kit-positive cells, myofibroblasts, and macrophages.