Arterial reconstruction with human bioengineered acellular blood vessels in patients with peripheral arterial disease.

OBJECTIVE: Vascular conduit is essential for arterial reconstruction for a number of conditions, including trauma and atherosclerotic occlusive disease. We have developed a tissue-engineered human acellular vessel (HAV) that can be manufactured, stored on site at hospitals, and be immediately available for arterial vascular reconstruction. Although the HAV is acellular when implanted, extensive preclinical and clinical testing has demonstrated that the HAV subsequently repopulates with the recipient's own vascular cells. We report a first-in-man clinical experience using the HAV for arterial reconstruction in patients with symptomatic peripheral arterial disease. METHODS: HAVs were manufactured using human vascular smooth muscle cells grown on a biodegradable scaffold. After the establishment of adequate cell growth and extracellular matrix deposition, the vessels were decellularized to remove human cellular antigens. Manufactured vessels were implanted in 20 patients with symptomatic peripheral arterial disease as above-knee, femoral-to-popliteal arterial bypass conduits. After HAV implantation, all patients were assessed for safety, HAV durability, freedom from conduit infection, and bypass patency for 2 years. RESULTS: Twenty HAVs were placed in the arterial, above-knee, femoral-to-popliteal position in patients with rest pain (n = 3) or symptomatic claudication (n = 17). All HAVs functioned as intended and had no evidence of structural failure or rejection by the recipient. No acute HAV infections were reported, but three surgical site infections were documented during the study period. Three non-HAV-related deaths were reported. One vessel developed a pseudoaneurysm after suspected iatrogenic injury during a balloon thrombectomy. No amputations of the HAV implanted limb occurred over the 2-year period, and no HAV infections were reported in approximately 34 patient-years of continuous patient follow-up. CONCLUSIONS: Human tissue engineered blood vessels can be manufactured and readily available for peripheral arterial bypass surgery. Early clinical experience with these vessels, in the arterial position, suggest that they are safe, have acceptable patency, a low incidence of infection, and do not require the harvest of autologous vein or any cells from the recipient. Histologic examination of tissue biopsies revealed vascular remodeling and repopulation by host cells. This first-in-man arterial bypass study supports the continued development of human tissue engineered blood vessels for arterial reconstruction, and potential future expansion to clinical indications including vascular trauma and repair of other size-appropriate peripheral arteries.

Treatment of Arm Swelling in Hemodialysis Patients with Ipsilateral Arteriovenous Access and Central Vein Stenosis: Conversion to the Hemodialysis Reliable Outflow Graft versus Stent Deployment.

PURPOSE: To compare outcomes after conversion of arteriovenous (AV) access to Hemodialysis Reliable Outflow (HeRO) graft vs stent deployment in patients with arm swelling owing to ipsilateral central vein stenosis. MATERIALS AND METHODS: This single-center retrospective study comprised 48 patients (19 men, mean age 58 y) with arm swelling ipsilateral to AV access and central vein stenosis over a 13-year period who had clinical follow-up and without prior central stents. Twenty-one patients underwent placement of a HeRO graft with anastomosis of the HeRO graft to the existing graft or fistula, and 27 patients underwent central venous stent deployment. Symptomatic improvement in arm swelling and access patency rates after intervention were ascertained from medical records. RESULTS: Improvement in swelling within 1 month after HeRO conversion and stent deployment was found in 95% and 89%, respectively (P = .62). Swelling eventually recurred in 16 patients (59%) treated with stents compared with 1 patient (5%) who underwent HeRO conversion (P < .001). Primary access patency was statistically significantly longer after HeRO conversions than stent deployments, with 6- and 12-month primary patency rates of 89% and 72% vs 47% and 11% (P < .001). HeRO conversions also resulted in longer 6- and 12-month secondary access patency rates (95% and 95% vs 79% and 58%, P = .006). Mean number of interventions per 1,000 access days to maintain secondary patency was 2.7 for the HeRO group vs 6.3 for the stent group. CONCLUSIONS: Although stent deployment and HeRO graft conversion are effective for alleviating arm swelling in the short term in patients receiving hemodialysis with clinically significant arm swelling and functioning AV access, the HeRO graft has more durable results.

Clinical Outcomes of Arteriovenous Access in Incident Hemodialysis Patients with Medicare Coverage, 2012-2014.

BACKGROUND: Chronic hemodialysis requires a mode of vascular access through an arteriovenous fistula (AVF), a prosthetic arteriovenous graft (AVG), or a central venous catheter (CVC). AVF is recommended over AVG or CVC due to increased patency and decreased intervention rates for those that mature. AVG are preferred over CVC due to decreased infection and mortality risk. The aims of this study were to evaluate the lifespan of AVF and AVG in maturation, sustained access use, and abandonment. METHODS: The United States Renal Data System (USRDS), Medicare claims, and CROWNWeb were used to identify access placements. Patients with a first end-stage renal disease (ESRD) service from January 1, 2012 to June 30, 2014 with continuous coverage with Medicare as primary payer and ≥1 AVF or AVG placed after ESRD onset were included. Maturation was defined as the first use of the access for hemodialysis recorded in CROWNWeb. Sustained access use was defined as 3 consecutive months of use without catheter placement or replacement. Accesses that were never used at any time post-placement were considered abandoned. RESULTS: The cohort included 38,035 AVF placements and 12,789 AVG placements. Sixty-nine percent of AVF and 72% of AVG matured. Fifty-two percent of AVF and 51% of AVG achieved sustained access use. One quarter of AVF and 14% of AVG were abandoned without use as recorded in CROWNWeb. CONCLUSION: Although considered the gold standard for vascular access, only half of AVF and AVG placements achieved sustained access use. The USRDS database has inherent limitations but provides useful clinical insight into maturation, sustained use, and abandonment.

Susceptibility of ePTFE vascular grafts and bioengineered human acellular vessels to infection.

BACKGROUND: Synthetic expanded polytetrafluorethylene (ePTFE) grafts are routinely used for vascular repair and reconstruction but prone to sustained bacterial infections. Investigational bioengineered human acellular vessels (HAVs) have shown clinical success and may confer lower susceptibility to infection. Here we directly compared the susceptibility of ePTFE grafts and HAV to bacterial contamination in a preclinical model of infection. MATERIALS AND METHODS: Sections (1 cm2) of ePTFE (n = 42) or HAV (n = 42) were inserted within bilateral subcutaneous pockets on the dorsum of rats and inoculated with Staphylococcus aureus (107 CFU/0.25 mL) or Escherichia coli (108 CFU/0.25 mL) before wound closure. Two weeks later, the implant sites were scored for abscess formation and explanted materials were halved for quantification of microbial recovery and histological analyses. RESULTS: The ePTFE implants had significantly higher abscess formation scores for both S. aureus and E. coli inoculations compared to that of HAV. In addition, significantly more bacteria were recovered from explanted ePTFE compared to HAV. Gram staining of explanted tissue sections revealed interstitial bacterial contamination within ePTFE, whereas no bacteria were identified in HAV tissue sections. Numerous CD45+ leukocytes, predominantly neutrophils, were found surrounding the ePTFE implants but minimal intact neutrophils were observed within the ePTFE matrix. The host cells surrounding and infiltrating the HAV explants were primarily nonleukocytes (CD45-). CONCLUSIONS: In an established animal model of infection, HAV was significantly less susceptible to bacterial colonization and abscess formation than ePTFE. The preclinical findings presented in this manuscript, combined with previously published clinical observations, suggest that bioengineered HAV may exhibit low rates of infection.

Bioengineered human acellular vessels for dialysis access in patients with end-stage renal disease: two phase 2 single-arm trials.

BACKGROUND: For patients with end-stage renal disease who are not candidates for fistula, dialysis access grafts are the best option for chronic haemodialysis. However, polytetrafluoroethylene arteriovenous grafts are prone to thrombosis, infection, and intimal hyperplasia at the venous anastomosis. We developed and tested a bioengineered human acellular vessel as a potential solution to these limitations in dialysis access. METHODS: We did two single-arm phase 2 trials at six centres in the USA and Poland. We enrolled adults with end-stage renal disease. A novel bioengineered human acellular vessel was implanted into the arms of patients for haemodialysis access. Primary endpoints were safety (freedom from immune response or infection, aneurysm, or mechanical failure, and incidence of adverse events), and efficacy as assessed by primary, primary assisted, and secondary patencies at 6 months. All patients were followed up for at least 1 year, or had a censoring event. These trials are registered with ClinicalTrials.gov, NCT01744418 and NCT01840956. FINDINGS: Human acellular vessels were implanted into 60 patients. Mean follow-up was 16 months (SD 7·6). One vessel became infected during 82 patient-years of follow-up. The vessels had no dilatation and rarely had post-cannulation bleeding. At 6 months, 63% (95% CI 47-72) of patients had primary patency, 73% (57-81) had primary assisted patency, and 97% (85-98) had secondary patency, with most loss of primary patency because of thrombosis. At 12 months, 28% (17-40) had primary patency, 38% (26-51) had primary assisted patency, and 89% (74-93) had secondary patency. INTERPRETATION: Bioengineered human acellular vessels seem to provide safe and functional haemodialysis access, and warrant further study in randomised controlled trials. FUNDING: Humacyte and US National Institutes of Health.

Early infection risk with primary versus staged Hemodialysis Reliable Outflow (HeRO) graft implantation.

OBJECTIVE: This study evaluated whether the use of a staged Hemodialysis Reliable Outflow (HeRO; Merit Medical, South Jordan, Utah) implantation strategy incurs increased early infection risk compared with conventional primary HeRO implantation. METHODS: A retrospective review was performed of 192 hemodialysis patients who underwent HeRO graft implantation: 105 patients underwent primary HeRO implantation in the operating room, and 87 underwent a staged implantation where a previously inserted tunneled central venous catheter was used for guidewire access for the venous outflow component. Within the staged implantation group, 32 were performed via an existing tunneled hemodialysis catheter (incidentally staged), and 55 were performed via a tunneled catheter inserted across a central venous occlusion in an interventional radiology suite specifically for HeRO implantation (intentionally staged). Early infection was defined as episodes of bacteremia or HeRO infection requiring resection ≤30 days of HeRO implantation. RESULTS: For staged HeRO implantations, the median interval between tunneled catheter insertion and conversion to a HeRO graft was 42 days. The overall HeRO-related infection rate ≤30 days of implantation was 8.6% for primary HeRO implantation and 2.3% for staged implantations (P = .12). The rates of early bacteremia and HeRO resection requiring surgical resection were not significantly different between groups (P = .19 and P = .065, respectively), nor were age, gender, laterality, anastomosis to an existing arteriovenous access, human immunodeficiency virus status, diabetes, steroids, chemotherapy, body mass index, or graft location. None of the patient variables, techniques, or graft-related variables correlated significantly with the early infection rate. CONCLUSIONS: The staged HeRO implantation strategy did not result in an increased early infection risk compared with conventional primary implantation and is thus a reasonable strategy for HeRO insertion in hemodialysis patients with complex central venous disease.

Establishing patient-specific criteria for selecting the optimal upper extremity vascular access procedure.

OBJECTIVE: The Kidney Disease Outcome Quality Initiative and Fistula First Breakthrough Initiative call for the indiscriminate creation of arteriovenous fistulas (AVFs) over arteriovenous grafts (AVGs) without providing patient-specific criteria for vascular access selection. Although the U.S. AVF rate has increased dramatically, several reports have found that this singular focus on increasing AVFs has resulted in increased AVF nonmaturation/early failure and a high prevalence of catheter dependence. The objective of this study was to determine the appropriateness of vascular access procedures in clinical scenarios constructed with combinations of relevant factors potentially influencing outcomes. METHODS: The RAND/UCLA Appropriateness Method was used. Accordingly, a comprehensive literature search was performed and a synthesis of results compiled. The RAND/UCLA Appropriateness Method was applied to 2088 AVF and 1728 AVG clinical scenarios with varying patient characteristics. Eleven international vascular access experts rated the appropriateness of each scenario in two rounds. On the basis of the distribution of the panelists' scores, each scenario was determined to be appropriate, inappropriate, or indeterminate. RESULTS: Panelists achieved agreement in 2964 (77.7%) scenarios; 860 (41%) AVF and 588 (34%) AVG scenarios were scored appropriate, 686 (33%) AVF and 480 (28%) AVG scenarios were scored inappropriate, and 542 (26%) AVF and 660 (38%) AVG scenarios were indeterminate. Younger age, larger outflow vein diameter, normal or obese body mass index (vs morbidly obese), larger inflow artery diameter, and higher patient functional status were associated with appropriateness of AVF creation. Older age, dialysis dependence, and smaller vein size were associated with appropriateness of AVG creation. Gender, diabetes, and coronary artery disease were not associated with AVF or AVG appropriateness. Dialysis status was not associated with AVF appropriateness. Body mass index and functional status were not associated with AVG appropriateness. To simulate the surgeon's decision-making, scenarios were combined to create situations with the same patient characteristics and both AVF and AVG options for access. Of these 864 clinical situations, 311 (36%) were rated appropriate for AVG but inappropriate or indeterminate for AVF. CONCLUSIONS: The results of this study indicate that patient-specific situations exist wherein AVG is as appropriate as or more appropriate than AVF. These results provide patient-specific recommendations for clinicians to optimize vascular access selection criteria, to standardize care, and to inform payers and policy. Indeterminate scenarios will guide future research.

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.

The impact of femoral arterial thrombosis in paediatric cardiac catheterisation: a national study.

BACKGROUND: Previous studies have identified risk factors for femoral arterial thrombosis after paediatric cardiac catheterisation, but none of them have evaluated the clinical and economic significance of this complication at the population level. Therefore, we examined the national prevalence and economic impact of femoral arterial thrombosis after cardiac catheterisation in children. METHODS: Patients⩽18 years of age who underwent cardiac catheterisation were identified in the 2003-2009 Kids' Inpatient Database. Patients were stratified by age as follows: <1 year of age or 1-18 years of age. The primary outcome was arterial thrombosis of the lower extremity during the same hospitalisation as cardiac catheterisation. Propensity score matching was used to determine the impact of femoral arterial thrombosis on hospital length of stay, cost, and mortality. RESULTS: Among the 11,497 paediatric cardiac catheterisations identified, 4558 catheterisations (39.6%) were performed in children <1 year of age. This age group experienced a higher prevalence of reported femoral arterial thrombosis, compared with children aged 1-18 years (1.3 versus 0.3%, p<0.001). After matching, femoral arterial thrombosis in children <1 year of age was associated with similar mortality (5.4 versus 1.8%, p=0.28), length of stay (8 versus 5 days, p=0.11), and total hospital cost ($27,135 versus $28,311, p=0.61), compared with absence of thrombosis. CONCLUSIONS: Femoral arterial thrombosis is especially prevalent in children <1 year of age undergoing cardiac catheterisation. Clinicians should be vigilant in monitoring femoral arterial patency in neonates and infants after cardiac catheterisation.

A comparison between the HeRO graft and conventional arteriovenous grafts in hemodialysis patients.

Venous stenosis and occlusion are a major cause of vascular access dysfunction and failure. The HeRO Graft bypasses occlusion and traverses stenosis with outflow directly into the central venous circulation. A randomized, multicenter study was conducted to evaluate the efficacy and safety of the HeRO Graft relative to conventional AV grafts. The design was to enroll 143 patients in a 2:1 randomization ratio between HeRO and conventional AV control groups. Data on 72 subjects (52 HeRO Graft and 20 AV graft controls) were obtained. The HeRO Graft and control cohorts were comparable in baseline characteristics. Adequacy of dialysis, bacteremia rates, and adverse events were consistent between groups. Twelve month Kaplan-Meier estimates for primary and secondary patency rates were 34.8% and 67.6% in the HeRO Graft cohort, and 30.6% and 58.4% in the control cohort. There was no statistical difference in terms of patency between groups. The rates of intervention were 2.2/year for HeRO Graft and 1.6/year for the control (p = 0.100). Median days to loss of secondary patency was 238 for HeRO Graft versus 102 for the control (p = 0.032). The HeRO Graft appears to provide similar patency, adequacy of dialysis, and bacteremia rates to those of conventional AV grafts.

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.

Percutaneous interventions on the hemodialysis reliable outflow vascular access device.

PURPOSE: To determine the outcomes of percutaneous interventions for prolonging the patency of the Hemodialysis Reliable Outflow (HeRO) device. MATERIALS AND METHODS: Between January 2007 and August 2011, 73 percutaneous interventions were performed on 26 HeRO devices in 25 patients. The graft was implanted in the upper arm with the outflow catheter tip in the superior vena cava or right atrium. Procedural reports, angiographic images, and clinical notes were retrospectively reviewed. The primary and secondary patency rates after intervention were calculated using the Kaplan-Meier method. RESULTS: The mean time from HeRO implantation to initial dysfunction or thrombosis was 171 days. In 60 (82%) procedures, the HeRO device was thrombosed. An intragraft stenosis was the most common lesion identified (59%; n = 43) followed by an arterial anastomosis stenosis identified in 18% (n = 13). In 22% (n = 16) of procedures in which the HeRO device was thrombosed, an underlying cause was not identified after thrombectomy. The 3-, 6-, and 12-month primary patency rates after intervention were 47%, 37%, and 26% for first-time interventions. The secondary patency rates were 80%, 70%, and 64%. The only complication was pulmonary embolism resulting in death 2 days after HeRO thrombectomy. CONCLUSIONS: Percutaneous interventions on thrombosed and failing HeRO devices yielded acceptable primary and secondary patency rates after intervention in these patients with few, if any, alternatives for hemodialysis access.

Six-year outcomes of a phase II study of human-tissue engineered blood vessels for peripheral arterial bypass.

Objective: The human acellular vessel (HAV) was evaluated for surgical bypass in a phase II study. The primary results at 24 months after implantation have been reported, and the patients will be evaluated for ≤10 years. Methods: In the present report, we have described the 6-year results of a prospective, open-label, single-treatment arm, multicenter study. Patients with advanced peripheral artery disease (PAD) requiring above-the-knee femoropopliteal bypass surgery without available autologous graft options had undergone implantation with the HAV, a bioengineered human tissue replacement blood vessel. The patients who completed the 24-month primary portion of the study will be evaluated for ≤10 years after implantation. The present mid-term analysis was performed at the 6-year milestone (72 months) for patients followed up for 24 to 72 months. Results: HAVs were implanted in 20 patients at three sites in Poland. Seven patients had discontinued the study before completing the 2-year portion of the study: four after graft occlusion had occurred and three who had died of causes deemed unrelated to the conduit, with the HAV reported as functional at their last visit. The primary results at 24 months showed primary, primary assisted, and secondary patency rates of 58%, 58%, and 74%, respectively. One vessel had developed a pseudoaneurysm deemed possibly iatrogenic; no other signs of structural failure were reported. No rejections or infections of the HAV occurred, and no patient had required amputation of the implanted limb. Of the 20 patients, 13 had completed the primary portion of the study; however, 1 patient had died shortly after 24 months. Of the remaining 12 patients, 3 died of causes unrelated to the HAV. One patient had required thrombectomy twice, with secondary patency achieved. No other interventions were recorded between 24 and 72 months. At 72 months, five patients had a patent HAV, including four patients with primary patency. For the entire study population from day 1 to month 72, the overall primary, primary assisted, and secondary patency rate estimated using Kaplan-Meier analysis was 44%, 45%, and 60% respectively, with censoring for death. No patient had experienced rejection or infection of the HAV, and no patient had required amputation of the implanted limb. Conclusions: The infection-resistant, off-the-shelf HAV could provide a durable alternative conduit in the arterial circuit setting to restore the lower extremity blood supply in patients with PAD, with remodeling into the recipient's own vessel over time. The HAV is currently being evaluated in seven clinical trials to treat PAD, vascular trauma, and as a hemodialysis access conduit.

Evaluation of tissue-engineered human acellular vessels as a Blalock-Taussig-Thomas shunt in a juvenile primate model.

Objectives: Palliative treatment of cyanotic congenital heart disease (CCHD) uses systemic-to-pulmonary conduits, often a modified Blalock-Taussig-Thomas shunt (mBTTs). Expanded polytetrafluoroethylene (ePTFE) mBTTs have associated risks for thrombosis and infection. The Human Acellular Vessel (HAV) (Humacyte, Inc) is a decellularized tissue-engineered blood vessel currently in clinical trials in adults for vascular trauma, peripheral artery disease, and end-stage renal disease requiring hemodialysis. In addition to restoring blood flow, the engineered HAV demonstrates the capacity for host cellular remodeling into native-like vasculature. Here we report preclinical evaluation of a small-diameter (3.5 mm) HAV as a mBTTs in a non-human primate model. Methods: We implanted 3.5 mm HAVs as right subclavian artery to pulmonary artery mBTTs in non-immunosuppressed juvenile rhesus macaques (n = 5). HAV patency, structure, and blood flow were assessed by postoperative imaging from 1 week to 6 months. Histology of HAVs and surrounding tissues was performed. Results: Surgical procedures were well tolerated, with satisfactory anastomoses, showing feasibility of using the 3.5 mm HAV as a mBTTs. All macaques had some immunological reactivity to the human extracellular matrix, as expected in this xenogeneic model. HAV mBTTs remained patent for up to 6 months in animals, exhibiting mild immunoreactivity. Two macaques displaying more severe immunoreactivity to the human HAV material developed midgraft dilatation without bleeding or rupture. HAV repopulation by host cells expressing smooth muscle and endothelial markers was observed in all animals. Conclusions: These findings may support use of 3.5 mm HAVs as mBTTs in CCHD and potentially other pediatric vascular indications.

Analysis of infection risk following covered stent exclusion of pseudoaneurysms in prosthetic arteriovenous hemodialysis access grafts.

PURPOSE: To determine whether exclusion of pseudoaneurysms with the use of a covered stent in prosthetic arteriovenous (AV) hemodialysis access grafts impacts the incidence of eventual AV graft infection. MATERIALS AND METHODS: Review of an interventional radiology database for prosthetic AV graft interventions involving stent deployment anywhere within the AV graft circuit revealed 235 interventions in 174 patients between November 2004 and December 2008. Incidence of AV graft infection was analyzed based on stent type (bare metal vs covered), location, and indication for stent deployment on a per-stent, per-procedure, and per-graft basis. RESULTS: A total of 16.3% of the stent-implanted AV grafts were eventually surgically excised as a result of graft infection. Covered stents used to treat an intragraft pseudoaneurysm were more commonly associated with subsequent graft infection compared with bare or covered stents deployed within the graft for other reasons: 42.1% versus 18.2% (P = .011). Stents deployed in an intragraft location were also associated with a higher incidence of graft infection compared with those deployed at the venous anastomosis or outflow vein: 26.9% versus 6.9% (P < .001). No significant difference was identified in infection rates between bare and covered stents. CONCLUSIONS: Covered stent exclusion of intragraft pseudoaneurysms demonstrated a significant correlation with eventual prosthetic AV graft infection.

Use of aspirin associates with longer primary patency of hemodialysis grafts.

Extended-release dipyridamole plus low-dose aspirin (ERDP/ASA) prolongs primary unassisted graft patency of newly created hemodialysis arteriovenous grafts, but the individual contributions of each component are unknown. Here, we analyzed whether use of aspirin at baseline associated with primary unassisted graft patency among participants in a randomized trial that compared ERDP/ASA and placebo in newly created grafts. We used Cox proportional hazards regression, adjusting for prespecified baseline comorbidities and covariates. Of all participants, 43% reported use of aspirin at baseline; of these, 82% remained on nonstudy aspirin (i.e., excluding ERDP/ASA) at 1 year. After 1 year of follow-up, the incidence of primary unassisted patency among participants using aspirin at baseline was 30% (95% CI: 24 to 35%) and among those not using aspirin was 23% (95% CI: 18 to 27%). Use of aspirin at baseline associated with a dose-dependent prolongation of primary unassisted graft patency that approached statistical significance (adjusted HR, 0.83; 95% CI: 0.68 to 1.01; P=0.06). Use of aspirin at baseline did not associate with prolongation of cumulative graft patency or participant survival. In conclusion, use of aspirin associates with a trend toward longer primary unassisted patency of newly placed hemodialysis grafts similar to that observed for ERDP/ASA.

Five Year Outcomes in Patients with End Stage Renal Disease Who Received a Bioengineered Human Acellular Vessel for Dialysis Access.

OBJECTIVE: Patients with end stage renal failure who require haemodialysis suffer morbidity and mortality due to vascular access. Bioengineered human acellular vessels (HAVs) may provide a haemodialysis access option with fewer complications than other grafts. In a prospective phase II trial from 2012 to 2014 (NCT01744418), HAVs were implanted into 40 haemodialysis patients at three sites in Poland. The trial protocol for this "first in man" use of the HAV contemplated only two years of follow up, and the trial results were initially reported in 2016. In light of the retained HAV function seen in many of the patients at the two year time point, follow up for patients who were still alive was extended to a total of 10 years. This interim follow up report, at the long term time point of five years, assessed patient and conduit status in those who continued routine dialysis with the HAV. METHODS: HAVs are bioengineered by culturing human vascular smooth muscle cells on a biodegradable polymer matrix. In this study, patients with patent HAV implants at 24 months were followed every three months, starting at month 27 through to month 60, or at least five years post-implantation. This report contains the follow up functional and histological data on 29 of the original 40 patients who demonstrated HAV function at the 24 month time point. RESULTS: Eleven patients completed at month 60. One patient maintained primary patency, and 10 maintained secondary patency. Secondary patency was estimated at 58.2% (95% confidence interval 39.2-73.1) at five years, after censoring for deaths (n = 8) and withdrawals (n = 1). No HAV conduit infections were reported during the follow up period. CONCLUSION: This phase II long term follow up shows that the human acellular vessel (HAV) may provide durable and functional haemodialysis access for patients with end stage renal disease.

Influence of diabetes and perivascular allogeneic endothelial cell implants on arteriovenous fistula remodeling.

OBJECTIVES: Arteriovenous fistula (AVF) is the preferred type of vascular access for hemodialysis to treat end-stage renal disease. A high proportion of AVF are never used for dialysis because the vein fails to mature adequately. We have previously described the safety and feasibility of Vascugel (Genzyme BioSurgery, Cambridge, Mass) (allogeneic aortic endothelial cells in a gelatin matrix) when placed around the anastomotic and venous outflow sites of AVFs (Vascular intimal Hyperplasia: Extending Arterial and venous patency, Limiting vascular Trauma, and inhibiting Hyperplasia while re-establishing vascular health [V-HEALTH] clinical study). In this retrospective analysis, we investigated factors that influenced AVF remodeling in patients from the V-HEALTH study. We hypothesized that providing healthy endothelial cells and their secreted factors immediately after surgery could enhance venous remodeling in the setting of vascular injury. METHODS: Thirty-one AVF patients from the V-HEALTH study were randomized 2:1 to receive either Vascugel or control matrices (placebo) at surgery and were followed for 24 weeks. Venous lumen diameter was measured by ultrasound at 1, 3, and 5 cm from the anastomosis. Vein remodeling (change in lumen diameter at 4, 12, and 24 weeks compared with baseline diameter at 2 weeks) was analyzed using a multiple regression mixed model. RESULTS: The results indicated that diabetes was a significant, negative predictor of venous remodeling over the 24-week study (P = .02). The model-predicted change in lumen diameter from 2 to 24 weeks was -0.7 mm in diabetic patients (n = 11) and +2.4 mm in nondiabetic patients (n = 15), a difference of 3.1 mm, 95% confidence interval [CI] (1.4-4.9), P = .0014. Patient race, baseline vein diameter, and time post-AVF creation were also significant factors that affected remodeling (P < .05). Compared with placebo, there was a strong suggestion that Vascugel treatment improved the rate of venous enlargement in diabetic patients (P = .05). The model-predicted change in lumen diameter at 24 weeks was -1.9 mm for placebo-treated diabetic patients and +0.4 mm for Vascugel-treated diabetic patients, a difference of 2.3 mm, 95% CI (-0.1-4.8), P = .06, suggesting that treatment with Vascugel may mitigate the negative influence of diabetes on AVF remodeling. CONCLUSIONS: Diabetes negatively impacts AVF remodeling and targeted local therapy with perivascular, allogeneic endothelial cells may ameliorate this effect. A phase II trial designed specifically to evaluate AVF remodeling is needed to determine if Vascugel can increase AVF maturation and use and to support larger randomized trials.

Autologous bone marrow mononuclear cell therapy is safe and promotes amputation-free survival in patients with critical limb ischemia.

OBJECTIVE: The purpose of this Phase I open label nonrandomized trial was to assess the safety and efficacy of autologous bone marrow mononuclear cell (ABMNC) therapy in promoting amputation-free survival (AFS) in patients with critical limb ischemia (CLI). METHODS: Between September 2005 and March 2009, 29 patients (30 limbs), with a median age of 66 years (range, 23-84 years; 14 male, 15 female) with CLI were enrolled. Twenty-one limbs presented with rest pain (RP), six with RP and ulceration, and three with ulcer only. All patients were not candidates for surgical bypass due to absence of a patent artery below the knee and/or endovascular approaches to improving perfusion was not possible as determined by an independent vascular surgeon. Patients were treated with an average dose of 1.7 ± 0.7 × 10(9) ABMNC injected intramuscularly in the index limb distal to the anterior tibial tuberosity. The primary safety end point was accumulation of serious adverse events, and the primary efficacy end point was AFS at 1 year. Secondary end points at 12 weeks posttreatment were changes in first toe pressure (FTP), toe-brachial index (TBI), ankle-brachial index (ABI), and transcutaneous oxygen measurements (TcPO(2)). Perfusion of the index limb was measured with positron emission tomography-computed tomography (PET-CT) with intra-arterial infusion of H(2)O(15). RP, using a 10-cm visual analogue scale, quality of life using the VascuQuol questionnaire, and ulcer healing were assessed at each follow-up interval. Subpopulations of endothelial progenitor cells were quantified prior to ABMNC administration using immunocytochemistry and fluorescent-activated cell sorting. RESULTS: There were two serious adverse events; however, there were no procedure-related deaths. Amputation-free survival at 1 year was 86.3%. There was a significant increase in FTP (10.2 ± 6.2 mm Hg; P = .02) and TBI (0.10 ± 0.05;P = .02) and a trend in improvement in ABI (0.08 ± 0.04; P = .73). Perfusion index by PET-CT H(2)O(15) increased by 19.3 ± 3.1, and RP decreased significantly by 2.2 ± 0.6 cm (P = .02). The VascuQol questionnaire demonstrated significant improvement in quality of life, and three of nine ulcers (33%) healed completely. KDR(+) but not CD34(+) or CD133(+) subpopulations of ABMNC were associated with improvement in limb perfusion. CONCLUSION: This Phase I study has demonstrated safety, and the AFS rates suggest efficacy of ABMNC in promoting limb salvage in "no option" CLI. Based on these results, we plan to test the concept that ABMNCs improve AFS at 1 year in a Phase III randomized, double-blinded, multicenter trial.