A huge and unmet clinical need is associated with hemodialysis vascular access dysfunction, which is currently considered to be one of the most challenging forms of clinical vascular grafting. The high failure rates associated with all types of dialysis vascular access, including arteriovenous fistulae and arteriovenous graft, result in significant morbidity, mortality and economic cost. Despite the magnitude of this clinic problem, no effective solutions are available. The end-stage renal disease and other health conditions of hemodialysis patients present a hostile milieu, such as uremia, inflammation and flow disturbance caused by small and/or non-compliant vessel, around the vascular access, which account for, at least partially, the access failure. The central hypothesis for this proposal is that precision cell niches, developed under hemodialysis-relevant conditions and when applied to the clinical setting of dialysis vascular access, prevent dialysis access failure. To test this hypothesis, we will introduce cell-protective, regenerative signals in the precision cell niches, which functionalize mesenchymal stem cells (MSCs) to override the hostile milieu impact and orchestrate the arterial regeneration, leading to patent, robust vascular access. This project will use our novel biomaterials platform, which allows both the cell niche and the niche-containing structure to be tailored using clinical inputs such as uremia, blood flow, vessel compliance and diameter, with a goal of optimizing targeted arterial regeneration to reduce access failure. To pursue the research goal, three aims are proposed here.
AIM 1 focuses on incorporating the precision cell niches into a peri-vascular wrap and determining its effect on the arterialization of arteriovenous fistula under simulated hemodialysis conditions.
AIM 2 seeks to establish and spatially integrate distinct precision cell niche designs to promote arteriovenous graft arterialization.
AIM 3 will evaluate how the precision niche design can assist MSC-based arterial regeneration for vascular access in a diseased swine model. If successful, the precision vascular access platforms developed here could transform traditional clinical care paradigms for dialysis vascular access. We envision that in the near future, nephrologists could have the access to a range of vascular access devices derived from precision cell niche designs.

Public Health Relevance

Vascular access is the lifeline of hemodialysis patients. Hemodialysis access dysfunction is considered to be one of the most challenging forms of clinical vascular grafting. This project aims to develop a novel hemodialysis access platform that uses mesenchymal stem cells in precisely defined physical, chemical, structural and biological microenvironments, with the goal of regenerating arterial tissues for successful hemodialysis access.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL119371-07
Application #
10149210
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Lee, Albert
Project Start
2013-08-15
Project End
2024-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Colorado at Boulder
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80303
Patel, Dharmesh; Sharma, Sadhana; Screen, Hazel R C et al. (2018) Effects of cell adhesion motif, fiber stiffness, and cyclic strain on tenocyte gene expression in a tendon mimetic fiber composite hydrogel. Biochem Biophys Res Commun 499:642-647
Yin, Hang; Ding, Yonghui; Zhai, Yao et al. (2018) Orthogonal programming of heterogeneous micro-mechano-environments and geometries in three-dimensional bio-stereolithography. Nat Commun 9:4096
Ding, Yonghui; Xu, Xin; Sharma, Sadhana et al. (2018) Biomimetic soft fibrous hydrogels for contractile and pharmacologically responsive smooth muscle. Acta Biomater 74:121-130
Ding, Yonghui; Floren, Michael; Tan, Wei (2017) High-Throughput Screening of Vascular Endothelium-Destructive or Protective Microenvironments: Cooperative Actions of Extracellular Matrix Composition, Stiffness, and Structure. Adv Healthc Mater 6:
Fan, Yonghong; Pan, Xiaxin; Wang, Ke et al. (2016) Influence of chirality on catalytic generation of nitric oxide and platelet behavior on selenocystine immobilized TiO2 films. Colloids Surf B Biointerfaces 145:122-129
Floren, Michael; Bonani, Walter; Dharmarajan, Anirudh et al. (2016) Human mesenchymal stem cells cultured on silk hydrogels with variable stiffness and growth factor differentiate into mature smooth muscle cell phenotype. Acta Biomater 31:156-166
Ding, Y H; Floren, M; Tan, W (2016) Mussel-inspired polydopamine for bio-surface functionalization. Biosurf Biotribol 2:121-136
Nagiah, Naveen; Johnson, Richard; Anderson, Roy et al. (2015) Highly Compliant Vascular Grafts with Gelatin-Sheathed Coaxially Structured Nanofibers. Langmuir 31:12993-3002
Guo, Dong-Jie; Liu, Rui; Cheng, Yu et al. (2015) Reverse adhesion of a gecko-inspired synthetic adhesive switched by an ion-exchange polymer-metal composite actuator. ACS Appl Mater Interfaces 7:5480-7
Elliott, Winston H; Bonani, Walter; Maniglio, Devid et al. (2015) Silk Hydrogels of Tunable Structure and Viscoelastic Properties Using Different Chronological Orders of Genipin and Physical Cross-Linking. ACS Appl Mater Interfaces 7:12099-108

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