Evaluation of the Safety and Efficacy of a Novel Thrombin Containing Combination Hemostatic Powder Using a Historical Control.

This clinical study compares 2 hemostatic agents, a novel combination powder (CP) (HEMOBLAST™ Bellows) and an established polysaccharide starch powder (PP) (Arista™ AH) to assess the usefulness of CP. Retrospective comparative analysis of CP (July 2018 to July 2019, 68 patients) to PP (January 2011 to January 2013, 94 patients) in cardiothoracic patients was performed using linear regression models adjusting for age, sex, and procedure type for the endpoints: blood loss; protamine to skin closure time (hemostasis time); chest tube output and blood products required 48 hours postoperatively; ICU stay; postoperative comorbidities; and 30 day mortality. 162 patients (108 M: 54 F) underwent 162 cardiothoracic surgical procedures including: transplantation (n = 44), placement of ventricular assist device (n = 87), and others (n = 31). Use of CP compared to PP (Estimated Mean Difference [95% CI], P-value) produced significant reductions: blood loss (mL) (-886.51 [-1457.76, -312.26], P = 0.003); protamine to skin closure time (min) (-16.81 [-28.03, -5.59], P = 0.004); chest tube output (48 hrs, mL) (-445.76 [-669.38, -222.14], P < 0.001); packed red blood cell transfusions (units) (-0.98 [-1.56, -0.4], P = 0.001); and postoperative comorbidities (-0.31 [-0.55, -0.07], P = 0.012). There were no differences in the ICU stay (4.07 [-2.01, 10.15], P = 0.188) or 30-day mortality (0.57 [0.20, 1.63], P = 0.291). The use of CP in complex cardiothoracic operations resulted in improved hemostasis and significant clinical benefits in blood loss, transfusion requirements, morbidity, and time in operating room.

SPOT GRADE II: Clinical Validation of a New Method for Reproducibly Quantifying Surgical Wound Bleeding: Prospective, Multicenter, Multispecialty, Single-Arm Study.

The SPOT GRADE (SG), a Surface Bleeding Severity Scale, is a unique visual method for assessing bleeding severity based on quantitative determinations of blood flow. This study assessed the reliability of the SG scale in a clinical setting and collected initial data on the safety and efficacy of HEMOBLAST Bellows (HB), a hemostatic agent, in abdominal and orthopedic operations. Twenty-seven patients were enrolled across 3 centers and received the investigational device. Bleeding severity and hemostasis were independently assessed by 2 surgical investigators at baseline and at 3, 6, and 10 minutes after application of HB and compared for agreement. The mean paired κ statistic for assignment of SG scores was .7754. The mean paired κ statistics for determining eligibility for participation in the trial based on bleeding severity and the mean paired κ statistics determining the presence of hemostasis were .9301 and .9301, respectively. The proportion of patients achieving hemostasis within 3, 6, and 10 minutes of HB application were 50.0%, 79.2%, and 91.7%, respectively. There were no unanticipated adverse device effects and one possible serious adverse device effect, as determined by the Independent Data Monitoring Committee (IDMC). The reliability of the SG scale was validated in a clinical setting. Initial data on the safety and efficacy of HB in abdominal and orthopedic operations were collected, and there were no concerns raised by the investigators or the IDMC.

An immediate access dialysis graft designed to prevent needle-related complications: Results from the initial pre-clinical studies.

INTRODUCTION: No technology has been specifically developed with the intent to reduce needle-related vascular access injuries; a significant source of complications and abandonment. We present the initial pre-clinical study results of a novel, self-sealing, immediate cannulation dialysis graft that aims to prevent needle-related complications; to promote safe, reliable needle access; to reduce catheter use; and could facilitate home hemodialyisis. METHODS: The innovative graft design consists of two cannulation chambers with self-sealing properties and materials that prevent side and back wall needle puncture. Study and control grafts (expanded polytetrafluoroethylene) were implanted in one pig and 10 sheep in two studies over the course of 1 year. First cannulation occurred immediately post implant for all study grafts. Post-cannulation time to hemostasis, hematoma and seroma formation, infection, and patency were recorded. RESULTS: The two studies account for nearly 60 weeks (average 6.4 weeks/graft) of study graft follow-up. In the ovine study, average study graft time to hemostasis was 27.3 s (standard deviation = 26.3, range = 0-120), and the control averaged 177.2 s (standard deviation = 113.4, range = 60-600), p < 0.0001. Secondary patency was 75% and 67% for the study and control grafts, respectively. Neither study nor control groups experienced seroma, graft infections, or deaths. DISCUSSION: All novel grafts in the studies were implanted successfully and functioned as intended. There were no complications related to tunneling of the study graft and the chamber prevented back/side wall needle injury. This novel technology may help to mitigate these needle-related complications, while allowing for early/immediate cannulation which could also reduce catheter contact time.

Prospective, multicenter, randomized, controlled trial evaluating the performance of a novel combination powder vs hemostatic matrix in cardiothoracic operations.

AIM: This trial compared the hemostatic performance of a novel combination powder (CP) to a control hemostatic matrix (HM) in cardiothoracic operations. METHODS: Patients meeting eligibility criteria were enrolled after providing informed consent. Subjects were randomized intraoperatively to receive CP (HEMOBLAST Bellows; Biom'up, France) or HM (FLOSEAL Hemostatic Matrix; Baxter Healthcare Corporation, Hayward, CA). Bleeding was assessed using a clinically validated, quantitative bleeding severity scale. The primary endpoint was total time to hemostasis (TTTH), from the start of device preparation, as an indicator of when a surgeon asks for a surgical hemostat until hemostasis was achieved. TTTH at 3 minutes was utilized for the primary analysis, while TTTH at 5 minutes was considered as a secondary endpoint. RESULTS: A total of 105 subjects were enrolled across four institutions. The primary efficacy endpoint for the superiority of CP relative to HM for success at achieving hemostasis within 3 minutes was met, with 64.2% of the CP group achieving hemostasis compared with 9.6% of the HM group, a difference of 54.54% (37.4%-71.6%; P < .001 for superiority). The secondary efficacy endpoint was also met, with 92.5% of the CP group achieving hemostasis at 5 minutes versus 44.2% in the HM group, a difference of 48.2% (31.1%-65.4%; P < .001 for noninferiority). There were no device-related adverse events. CONCLUSIONS: In this multicenter, randomized, controlled trial, comparison of CP to HM revealed CP superiority and noninferiority for TTTH at 3 and 5 minutes, respectively.

Objective Assessment of the Early Stages of the Learning Curve for the Senhance Surgical Robotic System.

OBJECTIVE: The purpose of this research is to study the early stages of the Senhance learning curve to report how force feedback impacts learning rate. This serves as an exploratory investigation into assumptions that fellows and faculty will adjust faster to the Senhance in comparison with residents, and that force feedback will not hinder skill acquisition. DESIGN: In this study, participants completed the peg transfer and precision cutting task from the Fundamentals of Laparoscopic Surgery (FLS) manual skills assessment five times each using the Senhance while instrument motion was tracked. SETTING: This study took place in the Surgical Education and Activities Laboratory at Duke University Medical Center. PARTICIPANTS: Participants for this study were residents, fellows, and faculty from Duke University Medical Center in general surgery and gynecology specialties (N = 16). RESULTS: Postulated linear mixed effects models with participant level random effects showed significant improvement with additional attempts for the peg transfer task after adjusting for surgical experience and force feedback respectively for the primary FLS score metric. The secondary metric of total instrument path length also showed improvement (significant decreases) in path length with additional attempts after respectively adjusting for surgical experience and force feedback. CONCLUSIONS: This study investigates the early stages of the learning curve of the Senhance. Exploratory modeling indicates that residents, fellows, and faculty surgeons rapidly adapt to the controls of the Senhance regardless of experience level and force feedback engagement. The results from this study may serve as motivation for future prospective studies that achieve sufficient statistical power with a larger sample size and strict experimental design.

Thromboembolic Events with Enterprise Versus Pipeline: Porcine In Vivo Experiment.

BACKGROUND: Thromboembolic complications are serious adverse events associated with stenting of intracranial aneurysms. For the development of novel devices, currently no practical model exists to evaluate distal embolic events. The purpose of the current study was 2-fold: 1) assess the feasibility of a porcine carotid bifurcation model for in vivo testing of stent thrombogenicity and 2) compare the thrombogenicity of the Enterprise vascular reconstruction device versus the Pipeline embolization device (PED). METHODS: Six Yorkshire pigs underwent implantation of size-matched devices across the carotid bifurcation. Each animal received 1 Enterprise and 1 PED contralaterally. Baseline and 2-week follow-up angiography were performed. Images were analyzed including detailed measurements of the rete mirabile, a small-vessel conglomerate supplied by branches of the common carotid artery. RESULTS: In the absence of thromboembolic events at 2 weeks (n = 8), the perfused rete area measured 134.4 ± 6.9 mm2. In the presence of thromboembolic events (n = 4), the perfused rete was reduced to an area covering 37.1 ± 8.6 mm2 (P < 0.01). There was no difference in thrombogenicity between Enterprise and PED with a thromboembolic event rate of 33.3% for both devices (P > 0.99). CONCLUSION: The swine carotid stent model allows in vivo analysis of device-related thrombogenicity and distal embolic event rates. Size reduction of the perfused rete mirabile indicates the presence of thromboembolic events. Both Enterprise and PED were associated with similar thrombogenicity in this experiment.

Sample Entropy of Speed Power Spectrum as a Measure of Laparoscopic Surgical Instrument Trajectory Smoothness.

In this study the complexity of the speed power spectrum is assessed as a metric for measuring trajectory smoothness. There are a variety of published methods for analyzing trajectory smoothness but many lack validity. This preliminary study took an information theoretic approach to assess trajectory smoothness by applying the sample entropy measure to the speed power spectrum of simulated and experimental trajectories. The complexity measurements of the speed power spectrum were compared to a traditional jerk-based measure of trajectory smoothness, namely $\log $-dimensionless jerk. The approach was first tested on basic simulated shape tracings with varying locations of sporadic movement, simulated as Gaussian noise. This method was duplicated in an experimental setting with the same shapes and locations of sporadic movement by capturing the trace trajectories using an electromagnetic motion tracking system. Finally, this approach was applied to kinematic data of laparoscopic surgical instrument tips, captured over 105 iterations of a basic surgical task. Analysis from all three testing scenarios showed that there is a statistically significant linear correlation between $\log $-dimensionless jerk and the sample entropy of speed power spectra.

Tissue engineered vascular grafts: Origins, development, and current strategies for clinical application.

Since the development of a dependable and durable synthetic non-autogenous vascular conduit in the mid-twentieth century, the field of vascular surgery has experienced tremendous growth. Concomitant with this growth, development in the field of bioengineering and the development of different tissue engineering techniques have expanded the armamentarium of the surgeon for treating a variety of complex cardiovascular diseases. The recent development of completely tissue engineered vascular conduits that can be implanted for clinical application is a particularly exciting development in this field. With the rapid advances in the field of tissue engineering, the great hope of the surgeon remains that this conduit will function like a true blood vessel with an intact endothelial layer, with the ability to respond to endogenous vasoactive compounds. Eventually, these engineered tissues may have the potential to supplant older organic but not truly biologic technologies, which are used currently.

Arteriovenous fistula creation using the Optiflow vascular anastomosis device: a first in man pilot study.

Although arteriovenous fistulae are the preferred form of dialysis vascular access they continue to have significant problems with maturation failure. The Optiflow device is a sutureless anastomotic conduit which could potentially reduce surgical time and also standardize the surgical procedure. We report herein on the "First in Man" experience with the Optiflow device.

Tissue-engineered vascular grafts: autologous off-the-shelf vascular access?

Dialysis grafts have provided reliable access for millions of patients in need of renal replacement therapy. However, regardless of the material used for artificial dialysis grafts their mean patency remains generally poor and infection rates are greater than native arteriovenous fistulas. The need for superior alternatives to conventional synthetic materials used for vascular access has been an area of investigation for more than 25 years and recently there has been a great deal of progress in the field of tissue-engineered vascular grafts. Many of these technologies are either commercially available or are now entering early phases of clinical trials. This review briefly covers the history, potential advantages, and disadvantages of these technologies, which are likely to create an impact in the field of vascular access surgery.

An early study on the mechanisms that allow tissue-engineered vascular grafts to resist intimal hyperplasia.

Intimal hyperplasia is one of the prominent failure mechanisms for arteriovenous fistulas and arteriovenous access grafts. Human tissue-engineered vascular grafts (TEVGs) were implanted as arteriovenous grafts in a novel baboon model. Ultrasound was used to monitor flow rates and vascular diameters throughout the study. Intimal hyperplasia in the outflow vein of TEVGs was assessed at the anastomosis and at juxta-anastomotic regions via histological analysis, and was compared to intimal hyperplasia with polytetrafluoroethylene (PTFE) grafts in the baboon model and in literature reports from other animal models. Less venous intimal hyperplasia was observed in histological sections with arteriovenous TEVGs than with arteriovenous PTFE grafts. TEVGs were associated with a mild, noninflammatory intimal hyperplasia. The extent of intimal tissue that formed with TEVG placement correlated with the rate of blood flow through tissue engineered vascular grafts at 2 weeks postimplant. Outflow vein dilatation was observed with increased flow rate. Both mid-graft flow rates and outflow vein diameters reached a plateau by week 4, which suggested that venous remodeling and intimal hyperplasia largely occurred within the first 4 weeks of implant in the baboon model. Given their compliant and noninflammatory nature, TEVGs appear resistant to triggers for venous intimal hyperplasia that are common for PTFE arteriovenous grafts, including (1) abundant proinflammatory macrophage populations that are associated with PTFE grafts and (2) compliance mismatch between PTFE grafts and the outflow vein. Our findings suggest that arteriovenous TEVGs develop only a mild form of venous intimal hyperplasia, which results from the typical hemodynamic changes that are associated with arteriovenous settings.

Decellularized tissue-engineered blood vessel as an arterial conduit.

Arterial tissue-engineering techniques that have been reported previously typically involve long waiting times of several months while cells from the recipient are cultured to create the engineered vessel. In this study, we developed a different approach to arterial tissue engineering that can substantially reduce the waiting time for a graft. Tissue-engineered vessels (TEVs) were grown from banked porcine smooth muscle cells that were allogeneic to the intended recipient, using a biomimetic perfusion system. The engineered vessels were then decellularized, leaving behind the mechanically robust extracellular matrix of the graft wall. The acellular grafts were then seeded with cells that were derived from the intended recipient--either endothelial progenitor cells (EPC) or endothelial cell (EC)--on the graft lumen. TEV were then implanted as end-to-side grafts in the porcine carotid artery, which is a rigorous testbed due to its tendency for graft occlusion. The EPC- and EC-seeded TEV all remained patent for 30 d in this study, whereas the contralateral control vein grafts were patent in only 3/8 implants. Going along with the improved patency, the cell-seeded TEV demonstrated less neointimal hyperplasia and fewer proliferating cells than did the vein grafts. Proteins in the mammalian target of rapamycin signaling pathway tended to be decreased in TEV compared with vein grafts, implicating this pathway in the TEV's resistance to occlusion from intimal hyperplasia. These results indicate that a readily available, decellularized tissue-engineered vessel can be seeded with autologous endothelial progenitor cells to provide a biological vascular graft that resists both clotting and intimal hyperplasia. In addition, these results show that engineered connective tissues can be grown from banked cells, rendered acellular, and then used for tissue regeneration in vivo.

Readily available tissue-engineered vascular grafts.

Autologous or synthetic vascular grafts are used routinely for providing access in hemodialysis or for arterial bypass in patients with cardiovascular disease. However, some patients either lack suitable autologous tissue or cannot receive synthetic grafts. Such patients could benefit from a vascular graft produced by tissue engineering. Here, we engineer vascular grafts using human allogeneic or canine smooth muscle cells grown on a tubular polyglycolic acid scaffold. Cellular material was removed with detergents to render the grafts nonimmunogenic. Mechanical properties of the human vascular grafts were similar to native human blood vessels, and the grafts could withstand long-term storage at 4 °C. Human engineered grafts were tested in a baboon model of arteriovenous access for hemodialysis. Canine grafts were tested in a dog model of peripheral and coronary artery bypass. Grafts demonstrated excellent patency and resisted dilatation, calcification, and intimal hyperplasia. Such tissue-engineered vascular grafts may provide a readily available option for patients without suitable autologous tissue or for those who are not candidates for synthetic grafts.

Neoadjuvant chemoradiation for rectal cancer reduces lymph node harvest in proctectomy specimens.

PURPOSE: The purpose of this study was to compare the number of lymph nodes retrieved following proctectomy for rectal cancer in patients either receiving no neoadjuvant therapy versus those treated with standard preoperative chemoradiation. METHODS: A retrospective review was performed of all consecutive patients that underwent proctectomy for rectal cancer from 1997-2006. Specimens from patients that received neoadjuvant therapy were compared to patients that did not receive preoperative chemoradiation. RESULTS: Of a total of 286 patients, 188 received neoadjuvant therapy and 88 did not. More patients with stage II or higher cancers received neoadjuvant therapy. Overall, fewer neoadjuvant patients underwent an anastomotic procedure than the no neoadjuvant group (17% vs. 7% APR). Significantly fewer total lymph nodes were retrieved in the neoadjuvant therapy patients compared to those who did not receive preoperatively therapy (Neo 14.6 +/- 0.6 vs. No-Neo 17.2 +/- 1.1, p < 0.029). CONCLUSIONS: Standard neoadjuvant therapy significantly decreases the number of lymph nodes retrieved following proctectomy for patients with rectal cancers. Quality initiatives or performance measures evaluating lymph node harvest following proctectomy should reflect the use of preoperative chemoradiation.

Acute in-vivo evaluation of bleeding with Gelfoam plus saline and Gelfoam plus human thrombin using a liver square lesion model in swine.

BACKGROUND: Management of post-operative bleeding has historically used topical bovine thrombin. However, possible harm through activation of coagulation inhibitors has encouraged investigation with other hemostatic agents. This study utilized a novel ordinal bleeding model to test whether a Gelfoam + human thrombin solution is superior at controlling bleeding when compared to Gelfoam + saline solution at different time intervals. STUDY DESIGN: Four swine underwent open laparotomy after receiving unfractionated heparin. Twenty open liver biopsies were performed in each swine; ten biopsies treated with Gelfoam + human thrombin solution and 10 biopsies treated with Gelfoam + saline solution. Three, 6 min, and 12 min after the procedure, bleeding was objectively graded by a four-point model. RESULTS: There was a significant (P < 0.017), treatment effect on each success/failure outcome (success = bleeding score 1) at 3 (P < 0.001), 6 (P < 0.001), and 12 (P = 0.003) min, based on a 2 x 2 Fisher's exact test. Similarly, there was a significant treatment effect on each success/failure outcome and four-point bleeding score based on a multiple logistic regression analysis controlling for pig, lesion weight, and initial bleeding taking into consideration repeated measures at three time points. CONCLUSIONS: The results demonstrate a superior treatment effect for control of bleeding using human thrombin compared to a saline solution. Future studies should compare bovine thrombin versus human thrombins ability to control bleeding as well as the hazard of each in activating coagulation inhibitors.

Genomic modeling of atherosclerosis in peripheral arterial disease and its variant phenotype in patients with diabetes.

Microarrays can be used to discover candidate genes associated with peripheral arterial disease (PAD) and develop models that predict patient clinical status. We hypothesize that multiple phenotypes of PAD with distinct patterns of gene expression exist. We histologically characterized and extracted ribonucleic acid from 31 arterial samples collected from the lower extremities of patients undergoing amputation or free fibular grafting. Analysis using the Affymetrix U133A microarray identified 335 genes with twofold or greater differences in expression between normal and diseased arteries (p< .01) and 104 genes with twofold or greater differences between diabetic and nondiabetic atherosclerotic arteries (p< .1). Many genes identified have known roles in inflammatory and lipid uptake pathways. Predictive models were developed that could predict PAD and the associated diabetic phenotype with an accuracy of 71 to 90%. Developing distinct genomic models of PAD will serve as the first step toward understanding the molecular and genetic basis of PAD and subsequent application of novel therapeutics to this condition.

Bipolar sealing increases mesenteric reach during bowel transection compared with stapled division: clinical evidence and laboratory support in a porcine model.

BACKGROUND: The ideal technique for mesenteric division to create tension-free anastomoses has not been defined. For patients undergoing Roux-en-Y gastric bypass (RYGB), the mesenteric division technique was changed from stapler to bipolar sealing using LigaSure for cost reasons. This study aimed objectively to assess the impact of the mesenteric division method on mobilization length of the Roux limb in an animal model. Clinical complications related to Roux limb tension also were analyzed in the authors' population of RYGB patients. METHODS: Bowel and mesenteric divisions were performed in a porcine model. Four pigs received six to eight mesenteric divisions each. Steady force was applied for 1 min. The distances between the divided limbs of bowel were compared. To assess the clinical impact with RYGB patients, anastomotic complications were analyzed before and after incorporation of bipolar sealing in the authors' practice. RESULTS: In the porcine model, the length of mesenteric stretch averaged 93.7 mm with stapled division and 109 mm with bipolar sealing (p = 0.021). From a laparoscopic RYGB population, 160 patients with stapled division were included, all of whom were at least 1 year beyond their surgery. The study analyzed 792 patients with bipolar sealing for leak or bleeding and included 479 bipolar sealed patients more than 1 year beyond their surgery for analysis of their strictures. No difference in bleeding or leaks was found between these groups. The stricture rate was significantly different, with seven strictures after stapled division (4.37%) compared with one stricture after bipolar sealing (0.2%; p = 0.001). CONCLUSIONS: Bipolar sealing for mesenteric division is superior to stapling for optimization of enteric limb length at constant tension in a laboratory model. Clinical evidence supports this hypothesis with patients undergoing RYGB surgery by a decrease in the complications that can arise from Roux limb tension.

Effectiveness of Glycerol Mono-oleate as a Biosealant.

BACKGROUND: The number of femoral artery catheterizations will increase over the next decade to more than 9 million worldwide. Accordingly, a new era of access site management with vascular closure techniques utilizing biologics are being developed and implemented. Glycerol mono-oleate (GMO) is one such biologic - a biodegradable compound that changes from a solid phase to a bioadhesive swollen semisolid phase when exposed to aqueous solutions and heat. We assessed whether GMO would: 1) achieve hemostasis more effectively than control when injected into a swine liver biopsy tract; and 2) inhibit common percutaneous procedure pathogens. METHODS: During the hemostasis experiment, seven swine anticoagulated with heparin (ACT > 250) underwent 10 open-liver biopsies with a 14 gauge cutting needle; 5 injected with GMO (treatment) and 5 injected with nothing (control). Thirty seconds, 2 minutes, 5 minutes and 10 minutes after the procedure, bleeding was objectively graded; 0 = no bleeding (success) and 1 = bleeding (failure). During the bacteria experiment, GMO was injected into plates containing culture media for 4 common percutaneous pathogens (Enteroccocis faecalis, Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae). When injected, GMO converted to a semisolid phase with definitive margins in the culture media. Each bacterium was then coated over their respective media and GMO. RESULTS: The results showed a significant treatment effect (p < 0.017) on each success/failure bleeding outcome at 30 seconds (p < 0.0001), 2 minutes (p < 0.0001) and 5 minutes (p = 0.0038) based on a multiple logistic regression analysis controlling for initial bleeding, pig and side-of-liver biopsy (medial or lateral lobe). At 10 minutes, the bleeding results were not significant (p = 0.0917), likely explained by a pig's innate ability to clot at this time period. For the bacteria experiment, there was no growth of bacteria on the GMO for any of the plates. Specifically, the Staphylococcus aureus plate displayed a 200 micron halo containing no bacterial growth surrounding the GMO. CONCLUSION: In conclusion, these results illustrate a significant hemostatic effect post liver biopsy at multiple time points using GMO. Furthermore, GMO displays bacterial deterrent properties.

Management of hemostasis in vascular surgery.

The fate of the circulatory system in response to vascular injury is governed by a series of complex biochemical reactions involving cellular elements and plasma proteins. Alteration of this hemostatic balance can result in excessive bleeding or procoagulant complications. In the field of vascular surgery, modulation of this process can have severe implications with respect to the maintenance of vascular conduit patency by avoiding thromboembolic events and the prevention of excess bleeding in the operative setting. The nature of the hemostatic response in the setting of surgical-induced injury and stress is increasingly complex and not fully understood. When faced with the management of bleeding in the operative setting, the vascular surgeon must first understand the theories of hemostatic regulation before adapting these concepts to the surgical milieu. This review addresses the management of blood loss in the setting of vascular surgery. In so doing, insight will be shed on the interdependence and manipulation of hemostatic events as they relate to surgery. Topics related to preoperative evaluation, surgical technique, monitoring, and pharmacologic manipulation will be discussed.

Adventitial endothelial implants reduce matrix metalloproteinase-2 expression and increase luminal diameter in porcine arteriovenous grafts.

OBJECTIVE: Vascular access dysfunction is a major problem in hemodialysis patients. Only 50% of arteriovenous grafts (AVGs) will remain patent 1 year after surgery. AVGs frequently develop stenoses and occlusions at the venous anastomoses in the venous outflow tract. Lumen diameter is not only determined by intimal thickening but is also influenced by remodeling of the vessel wall. Vascular remodeling requires degradation and reorganization of the extracellular matrix by the degradation enzymes, matrix metalloproteinases (MMPs). In this study, we aimed to provide further insight into the mechanism of endothelial regulation of vascular remodeling and luminal narrowing in AVGs. METHODS: End-to-side carotid artery-jugular vein polytetrafluoroethylene grafts were created in 20 domestic swine. The anastomoses and outflow vein were treated with Gelfoam matrices (Pfizer, New York, NY) containing allogeneic porcine aortic endothelial (PAE, n = 10) cells or control matrices without cells (n = 10), and the biologic responses to PAE implants were investigated 3 and 28 days postoperatively. Angiograms before euthanasia were compared with baseline angiograms. Tissue sections were stained with hematoxylin and eosin, Verhoeff elastin, and antibodies specific to MMP-9 and MMP-2 and underwent histopathologic, morphometric and immunohistochemical analysis. RESULTS: Veins treated with PAE cell implants had a 2.8-fold increase in venous lumen diameter compared with baseline (P < .05), a 2.3-fold increase in lumen diameter compared with control, and an 81% decrease in stenosis (P < .05) compared with control at 28 days. The increase in lumen diameter by angiographic analysis correlated with morphometric analysis of tissue sections. PAE implants increased the venous lumen area 2.3-fold (P < .05), decreased venous luminal occlusion 66%, and increased positive venous remodeling 1.9-fold (P < .05) compared with control at 28 days. PAE cell implants reduced MMP-2 expression and neovascularization at 3 and 28 days and adventitial fibrosis at 28 days, suggesting a role of the implants in controlling the affects of medial and adventitial cells in the response to vascular injury. CONCLUSIONS: These results demonstrate that the adventitial application of endothelial implants significantly reduced MMP-2 expression within the venous wall, and increased venous lumen diameter and positive remodeling in a porcine arteriovenous graft model. Adventitial endothelial implants may be useful in decreasing luminal narrowing in a clinical setting.