Traditional vascular grafts constructed from synthetic polymers or cadaveric human or animal tissues support the clinical need for readily available blood vessels, but often come with associated ...risks. Histopathological evaluation of these materials has shown adverse host cellular reactions and/or mechanical degradation due to insufficient or inappropriate matrix remodeling. We developed an investigational bioengineered human acellular vessel (HAV), which is currently being studied as a hemodialysis conduit in patients with end-stage renal disease. In rare cases, small samples of HAV were recovered during routine surgical interventions and used to examine the temporal and spatial pattern of the host cell response to the HAV after implantation, from 16 to 200 weeks. We observed a substantial influx of alpha smooth muscle actin (αSMA)-expressing cells into the HAV that progressively matured and circumferentially aligned in the HAV wall. These cells were supported by microvasculature initially formed by CD34
/CD31
cells in the neoadventitia and later maintained by CD34
/CD31
endothelial cells in the media and lumen of the HAV. Nestin
progenitor cells differentiated into either αSMA
or CD31
cells and may contribute to early recellularization and self-repair of the HAV. A mesenchymal stem cell-like CD90
progenitor cell population increased in number with duration of implantation. Our results suggest that host myogenic, endothelial, and progenitor cell repopulation of HAVs transforms these previously acellular vessels into functional multilayered living tissues that maintain blood transport and exhibit self-healing after cannulation injury, effectively rendering these vessels like the patient's own blood vessel.
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.
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.
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.
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.
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.
Patients with peripheral artery disease who require surgical revascularization need options when autologous grafts are not available. The human acellular vessel (HAV) has been demonstrated to have characteristics similar to those of autologous vessels in terms of resistance to infection, mechanics, and a very low risk of rejection. Safety and performance were evaluated for ≤6 years after implantation of an HAV in a femoropopliteal position. Overall, the secondary patency rate estimated using the Kaplan-Meier method was 60% at 72 months, with 45% primary patency. No infection or rejection episodes had occurred with the HAV conduits. These data have demonstrated the durability of the HAV and suggest the occurrence of cellular remodeling by the host.
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Malaria remains a public health crisis in areas where it has resisted control efforts. In Nchelenge District, a high-transmission area in northern Zambia, malaria accounts for more than one-third of ...pediatric hospitalizations and nearly one-half of hospital deaths in children. To identify risk factors for death due to malaria, we conducted a retrospective, time-matched case-control study of 126 children hospitalized with malaria who died (cases) and 126 children who survived (controls). There were no differences in age, gender, hemoglobin concentration, or prevalence of severe anemia between cases and controls. Children who died were more likely to come from villages located at greater distances from the hospital than children who survived (median 13.5 versus 3.2 km). Each additional kilometer of distance from the hospital increased the odds of death by 4% (odds ratio 1.04, 95% confidence interval 1.01-1.07,
< 0.01). Extent of anemia and admission during periods when blood was unavailable for transfusion were associated with early death (
≤ 0.03). Delays in initiation of treatment of severe malaria contribute to the increased odds of death in children referred from more distant health centers, and might be mitigated by transportation improvements, capacity at rural health posts to administer treatment before transfer, hospital triage systems that minimize time to treatment, and reliable blood product stores at referral hospitals.
Manufacturing processes for murine monoclonal antibodies (mMABs) used in therapeutic applications must address more safety concerns than those used for in vitro diagnostics. Adequate characterization ...helps ensure that the mMAb retains its functional integrity after more extensive processing.
Experience shows that murine monoclonal antibodies used in cell therapy manufacturing can be produced with safety concerns in mind. In such cases, adequate characterization ensures that they retain ...functional integrity.
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