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Most current solutions address only a subset of this triad and equate mechanical matching with compliance alone, which can lead to disturbed hemodynamics, maladaptive mechanobiology, and adverse graft-host biochemical interactions that frequently culminate in clinical complications and graft failure. This study presents polyurethane-based heparin-functionalized elastomeric nanofibrillar grafts (H-ENGs) that integrate all three prerequisites while allowing multi-parameter mechanical mimicry. To address the principal failure mode of early thrombosis, a small fraction of polyethyleneimine (PEI) is added to the ENG electrospinning solution to form P-ENGs, enabling one-step covalent heparin conjugation to form H-ENGs. The decoupled design of the ENG platform preserves the biomimetic microstructure and mechanics following PEI incorporation and heparinization, enabling adaptable, indication-specific optimization. In vitro, H-ENGs exhibit good cytocompatibility with minimal hemolysis, platelet adhesion, and whole blood clotting. Pilot porcine abdominal aorta interposition studies demonstrate feasibility: H-ENGs exhibit favorable surgical handling, intact suture-line integrity, and anastomotic hemostasis under dynamic flow, and retain artery-tuned mechanics and surface heparin at two weeks. While further testing is warranted, these results indicate that H-ENGs satisfy the three prerequisites for vascular graft clinical success.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"701857v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.26.701857","type":"posted-content","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T21:10:18Z","timestamp":1769548218000},"source":"Crossref","is-referenced-by-count":0,"title":["Heparinized Elastomeric Nanofibrillar Grafts: A Novel Approach for Mechanically Tunable, Cell-Supportive, and Thromboresistant Vascular Substitutes"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3433-3382","authenticated-orcid":false,"given":"Elizabeth C.","family":"Zermeno","sequence":"first","affiliation":[{"name":"Department of Biomechanics, University of Nebraska at Omaha, Omaha, NE 68182 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John M.","family":"Kapitan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander D.","family":"Sandquist","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda","family":"Reke","sequence":"additional","affiliation":[{"name":"Department of Biomechanics, University of Nebraska at Omaha, Omaha, NE 68182 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Apurbo Kumar","family":"Paul","sequence":"additional","affiliation":[{"name":"Department of Biomechanics, University of Nebraska at Omaha, Omaha, NE 68182 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason N.","family":"MacTaggart","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen A.","family":"Morin","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588 USA"},{"name":"The Nebraska Center for Materials and Nanoscience, University of Nebraska-Lincoln, Lincoln, NE 68588 USA"},{"name":"The Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, NE 68588 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaspars","family":"Maleckis","sequence":"additional","affiliation":[{"name":"Department of Biomechanics, University of Nebraska at Omaha, Omaha, NE 68182 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026020503280738000_2026.01.26.701857v1.1","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000001209"},{"key":"2026020503280738000_2026.01.26.701857v1.2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.123.318239"},{"key":"2026020503280738000_2026.01.26.701857v1.3","doi-asserted-by":"publisher","DOI":"10.1067\/mva.1987.avs0050376"},{"key":"2026020503280738000_2026.01.26.701857v1.4","doi-asserted-by":"publisher","DOI":"10.1007\/s12013-008-9023-6"},{"key":"2026020503280738000_2026.01.26.701857v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/S1078-5884(98)80136-6"},{"key":"2026020503280738000_2026.01.26.701857v1.6","doi-asserted-by":"publisher","DOI":"10.1007\/s10237-014-0576-6"},{"key":"2026020503280738000_2026.01.26.701857v1.7","doi-asserted-by":"publisher","DOI":"10.12336\/biomatertransl.2022.01.008"},{"key":"2026020503280738000_2026.01.26.701857v1.8","unstructured":"Vascular Grafts Market Size, Share & Growth Report, 2030; 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