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A three-dimensional valve-on-chip microphysiological system implicates cell cycle progression, cholesterol metabolism and protein homeostasis in early calcific aortic valve disease progression.
Tandon, Ishita; Woessner, Alan E; Ferreira, Laίs A; Shamblin, Christine; Vaca-Diez, Gustavo; Walls, Amanda; Kuczwara, Patrick; Applequist, Alexis; Nascimento, Denise F; Tandon, Swastika; Kim, Jin-Woo; Rausch, Manuel; Timek, Tomasz; Padala, Muralidhar; Kinter, Michael T; Province, Dennis; Byrum, Stephanie D; Quinn, Kyle P; Balachandran, Kartik.
Afiliação
  • Tandon I; Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA.
  • Woessner AE; Arkansas Integrative Metabolic Research Center, University of Arkansas, Fayetteville, AR, USA.
  • Ferreira LA; Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA.
  • Shamblin C; Scripps Research Institute, La Jolla, CA, USA.
  • Vaca-Diez G; Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA.
  • Walls A; Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA.
  • Kuczwara P; Department of Biological and Agricultural Engineering, Materials Science & Engineering, University of Arkansas, Fayetteville, AR, USA.
  • Applequist A; Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA.
  • Nascimento DF; Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA.
  • Tandon S; Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA.
  • Kim JW; Department of Biological and Agricultural Engineering, Materials Science & Engineering, University of Arkansas, Fayetteville, AR, USA.
  • Rausch M; Departments of Aerospace Engineering and Engineering Mechanics and Biomedical Engineering, Institute for Computational Engineering and Science, University of Texas at Austin, Austin, TX, USA.
  • Timek T; Meijer Heart and Vascular Institute at Spectrum Health, Grand Rapids, MI, USA.
  • Padala M; Division of Cardiothoracic Surgery, Joseph P. Whitehead Department of Surgery, Emory University, Atlanta, GA, USA.
  • Kinter MT; Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
  • Province D; Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • Byrum SD; Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • Quinn KP; Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA; Arkansas Integrative Metabolic Research Center, University of Arkansas, Fayetteville, AR, USA.
  • Balachandran K; Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA. Electronic address: kbalacha@uark.edu.
Acta Biomater ; 186: 167-184, 2024 Sep 15.
Article em En | MEDLINE | ID: mdl-39084496
ABSTRACT

BACKGROUND:

Calcific aortic valve disease (CAVD) is one of the most common forms of valvulopathy, with a 50 % elevated risk of a fatal cardiovascular event, and greater than 15,000 annual deaths in North America alone. The treatment standard is valve replacement as early diagnostic, mitigation, and drug strategies remain underdeveloped. The development of early diagnostic and therapeutic strategies requires the fabrication of effective in vitro valve mimetic models to elucidate early CAVD mechanisms.

METHODS:

In this study, we developed a multilayered physiologically relevant 3D valve-on-chip (VOC) system that incorporated aortic valve mimetic extracellular matrix (ECM), porcine aortic valve interstitial cell (VIC) and endothelial cell (VEC) co-culture and dynamic mechanical stimuli. Collagen and glycosaminoglycan (GAG) based hydrogels were assembled in a bilayer to mimic healthy or diseased compositions of the native fibrosa and spongiosa. Multiphoton imaging and proteomic analysis of healthy and diseased VOCs were performed.

RESULTS:

Collagen-based bilayered hydrogel maintained the phenotype of the VICs. Proteins related to cellular processes like cell cycle progression, cholesterol biosynthesis, and protein homeostasis were found to be significantly altered and correlated with changes in cell metabolism in diseased VOCs. This study suggested that diseased VOCs may represent an early, adaptive disease initiation stage, which was corroborated by human aortic valve proteomic assessment.

CONCLUSIONS:

In this study, we developed a collagen-based bilayered hydrogel to mimic healthy or diseased compositions of the native fibrosa and spongiosa layers. When the gels were assembled in a VOC with VECs and VICs, the diseased VOCs revealed key insights about the CAVD initiation process. STATEMENT OF

SIGNIFICANCE:

Calcific aortic valve disease (CAVD) elevates the risk of death due to cardiovascular pathophysiology by 50 %, however, prevention and mitigation strategies are lacking, clinically. Developing tools to assess early disease would significantly aid in the prevention of disease and in the development of therapeutics. Previously, studies have utilized collagen and glycosaminoglycan-based hydrogels for valve cell co-cultures, valve cell co-cultures in dynamic environments, and inorganic polymer-based multilayered hydrogels; however, these approaches have not been combined to make a physiologically relevant model for CAVD studies. We fabricated a bi-layered hydrogel that closely mimics the aortic valve and used it for valve cell co-culture in a dynamic platform to gain mechanistic insights into the CAVD initiation process using proteomic and multiphoton imaging assessment.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article