Use of autologous blood-derived endothelial progenitor cells at point-of-care to protect against implant thrombosis in a large animal model

Jantzen, Alexandra E.; Lane, Whitney O.; Gage, Shawn M.; Jamiolkowski, Ryan M.; Haseltine, Justin M.; Galinat, Lauren J.; Lin, Fu-Hsiung; Lawson, Jeffrey H.; Truskey, George A.; Achneck, Hardean E.

doi:10.1016/j.biomaterials.2011.07.066

Cited by 25 publications

(34 citation statements)

References 24 publications

(26 reference statements)

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“…BOECs are the progeny of bone marrow-derived circulating endothelial progenitor cells and emerging evidence supports their use in cell-based therapies for promoting postnatal vasculogenesis and clinical use in cardiovascular applications [23,24]. Differentiation of these cells may promote the formation of a healthy endothelium on vascular graft surfaces [13,25,26]. This work also investigates whether immobilized heparin will have a negative effect on smooth muscle cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

The blood and vascular cell compatibility of heparin-modified ePTFE vascular grafts

et al. 2013

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Prosthetic vascular grafts do not mimic the antithrombogenic properties of native blood vessels and therefore have higher rates of complications that involve thrombosis and restenosis. We developed an approach for grafting bioactive heparin, a potent anticoagulant glycosaminoglycan, to the lumen of ePTFE vascular grafts to improve their interactions with blood and vascular cells. Heparin was bound to aminated poly(1,8-octanediol-co-citrate) (POC) via its carboxyl functional groups onto POC-modified ePTFE grafts. The bioactivity and stability of the POC-immobilized heparin (POC–Heparin) were characterized via platelet adhesion and clotting assays. The effects of POC–Heparin on the adhesion, viability and phenotype of primary endothelial cells (EC), blood outgrowth endothelial cells (BOECs) obtained from endothelial progenitor cells (EPCs) isolated from human peripheral blood, and smooth muscle cells were also investigated. POC–Heparin grafts maintained bioactivity under physiologically relevant conditions in vitro for at least one month. Specifically, POC–Heparin-coated ePTFE grafts significantly reduced platelet adhesion and inhibited whole blood clotting kinetics. POC–Heparin supported EC and BOEC adhesion, viability, proliferation, NO production, and expression of endothelial cell-specific markers von Willebrand factor (vWF) and vascular endothelial-cadherin (VE-cadherin). Smooth muscle cells cultured on POC–Heparin showed increased expression of α-actin and decreased cell proliferation. This approach can be easily adapted to modify other blood contacting devices such as stents where antithrombogenicity and improved endothelialization are desirable properties.

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Section: Introductionmentioning

confidence: 99%

The blood and vascular cell compatibility of heparin-modified ePTFE vascular grafts

et al. 2013

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“…The cells were fluorescently labeled prior to implantation with PKH26 (Sigma-Aldrich) [17]. Four pigs received IVC implants (grade 2; Tico Titanium, MI, USA, pre-sectioned and reassembled as previously described) [17]. …”

Section: Methodsmentioning

confidence: 99%

“…Ti tubes were directly inserted into the IVCs without use of an artificial graft following our established methods [17,22]. All four Ti tubes were seeded with autologous pBD-ECs (2.4 × 10 6 cells/ml in 4.5 ml of medium) derived with the DWBI method; however, in two of the four implants the cells had additionally been mobilized with AMD3100 (0.5 mg/kg).…”

Section: Methodsmentioning

confidence: 99%

“…We chose pigs for our in vivo study because of the following reasons: they are the preferred large animal model for cardiovascular diseases [15], we have previously characterized pBD-ECs and found them to be phenotypically and functionally analogous to human blood-derived ECs [6,16,17], and pigs enabled us to transplant autologous cells into the pigs’ aortae and inferior vena cavae (IVCs) to test cell functionality under flow in vivo. In vivo studies presented here provide proof-of-concept for utilizing DWBI and AMD3100-mobilized pBD-ECs for autologous cell therapies by demonstrating that pBD-ECs remain functional under flow on the surface of implanted intravascular titanium (Ti) tubes, prevent thrombosis in the IVC locally and also reduce the coagulation response systemically.…”

mentioning

confidence: 99%

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Increased Yield of Endothelial Cells from Peripheral Blood for Cell Therapies and Tissue Engineering

et al. 2015

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Aim Peripheral blood-derived endothelial cells (pBD-ECs) are an attractive tool for cell therapies and tissue engineering, but have been limited by their low isolation yield. We increase pBD-EC yield via administration of the chemokine receptor type 4 antagonist AMD3100, as well as via a diluted whole blood incubation (DWBI). Materials & Methods Porcine pBD-ECs were isolated using AMD3100 and DWBI and tested for EC markers, acetylated LDL uptake, growth kinetics, metabolic activity, flow-mediated nitric oxide production and seeded onto titanium tubes implanted into vessels of pigs. Results DWBI increased the yield of porcine pBD-ECs 6.6-fold, and AMD3100 increased the yield 4.5-fold. AMD3100-mobilized ECs were phenotypically indistinguishable from nonmobilized ECs. In porcine implants, the cells expressed endothelial nitric oxide synthase, reduced thrombin-antithrombin complex systemically and prevented thrombosis. Conclusion Administration of AMD3100 and the DWBI method both increase pBD-EC yield.

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“…18 Our prior work has shown that these cells protect against thrombosis in vivo in a porcine model utilizing smooth Ti implantable devices. 19 …”

Section: Introductionmentioning

confidence: 99%

Point-of-Care Rapid-Seeding Ventricular Assist Device with Blood-Derived Endothelial Cells to Create a Living Antithrombotic Coating

et al. 2016

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The most promising alternatives to heart transplantation are left ventricular assist devices and artificial hearts; however their use has been limited by thrombotic complications. To reduce these, sintered titanium (Ti) surfaces were developed, but thrombosis still occurs in ~7.5% of patients. We have invented a rapid-seeding technology to minimize the risk of thrombosis by rapid endothelialization of sintered Ti with human cord blood-derived endothelial cells (hCB-ECs). hCB-ECs were seeded within minutes onto sintered Ti and exposed to thrombosis-prone low fluid flow shear stresses. The hCB-ECs adhered and formed a confluent endothelial monolayer on sintered Ti. The exposure of sintered Ti to 4.4 dynes/cm2 for 20 hr immediately following rapid-seeding resulted in ~70% cell adherence. The cell adherence was not significantly increased by additional ex vivo static culture of rapid-seeded sintered Ti prior to flow exposure. In addition, adherent hCB-ECs remained functional on sintered Ti, as indicated by flow-induced increase in nitric oxide secretion and reduction in platelet adhesion. After 15-day ex vivo static culture, the adherent hCB-ECs remained metabolically active, expressed EC functional marker thrombomodulin, and reduced platelet adhesion. In conclusion, our results demonstrate the feasibility of rapid-seeding sintered Ti with blood-derived hCB-ECs to generate a living antithrombotic surface.

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Use of autologous blood-derived endothelial progenitor cells at point-of-care to protect against implant thrombosis in a large animal model

Cited by 25 publications

References 24 publications

The blood and vascular cell compatibility of heparin-modified ePTFE vascular grafts

The blood and vascular cell compatibility of heparin-modified ePTFE vascular grafts

Increased Yield of Endothelial Cells from Peripheral Blood for Cell Therapies and Tissue Engineering

Point-of-Care Rapid-Seeding Ventricular Assist Device with Blood-Derived Endothelial Cells to Create a Living Antithrombotic Coating

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