Digoxin and adenosine triphosphate enhance the functional properties of tissue-engineered cartilage

Eleftherios A. Makris, Brian J. Huang, Jerry C. Hu, Ye Chen-Izu, Kyriacos A. Athanasiou

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Toward developing engineered cartilage for the treatment of cartilage defects, achieving relevant functional properties before implantation remains a significant challenge. Various chemical and mechanical stimuli have been used to enhance the functional properties of engineered musculoskeletal tissues. Recently, Ca2+-modulating agents have been used to enhance matrix synthesis and biomechanical properties of engineered cartilage. The objective of this study was to determine whether other known Ca2+ modulators, digoxin and adenosine triphosphate (ATP), can be employed as novel stimuli to increase collagen synthesis and functional properties of engineered cartilage. Neocartilage constructs were formed by scaffold-free self-assembling of primary bovine articular chondrocytes. Digoxin, ATP, or both agents were added to the culture medium for 1 h/day on days 10-14. After 4 weeks of culture, neocartilage properties were assessed for gross morphology, biochemical composition, and biomechanical properties. Digoxin and ATP were found to increase neocartilage collagen content by 52-110% over untreated controls, while maintaining proteoglycan content near native tissue values. Furthermore, digoxin and ATP increased the tensile modulus by 280% and 180%, respectively, while the application of both agents increased the modulus by 380%. The trends in tensile properties were found to correlate with the amount of collagen cross-linking. Live Ca2+ imaging experiments revealed that both digoxin and ATP were able to increase Ca2+ oscillations in monolayer-cultured chondrocytes. This study provides a novel approach toward directing neocartilage maturation and enhancing its functional properties using novel Ca2+ modulators.

Original languageEnglish (US)
Pages (from-to)884-894
Number of pages11
JournalTissue Engineering - Part A
Volume21
Issue number5-6
DOIs
StatePublished - Mar 1 2015

Fingerprint

Digoxin
Cartilage
Adenosine Triphosphate
Collagen
Tissue
Modulators
Chondrocytes
Tensile properties
Scaffolds
Monolayers
Proteoglycans
Elastic moduli
Culture Media
Imaging techniques
Defects
Joints
Chemical analysis
Experiments

ASJC Scopus subject areas

  • Bioengineering
  • Biochemistry
  • Biomedical Engineering
  • Biomaterials

Cite this

Digoxin and adenosine triphosphate enhance the functional properties of tissue-engineered cartilage. / Makris, Eleftherios A.; Huang, Brian J.; Hu, Jerry C.; Chen-Izu, Ye; Athanasiou, Kyriacos A.

In: Tissue Engineering - Part A, Vol. 21, No. 5-6, 01.03.2015, p. 884-894.

Research output: Contribution to journalArticle

Makris, Eleftherios A. ; Huang, Brian J. ; Hu, Jerry C. ; Chen-Izu, Ye ; Athanasiou, Kyriacos A. / Digoxin and adenosine triphosphate enhance the functional properties of tissue-engineered cartilage. In: Tissue Engineering - Part A. 2015 ; Vol. 21, No. 5-6. pp. 884-894.
@article{927d701f30a245f2b32c67d60f6fef20,
title = "Digoxin and adenosine triphosphate enhance the functional properties of tissue-engineered cartilage",
abstract = "Toward developing engineered cartilage for the treatment of cartilage defects, achieving relevant functional properties before implantation remains a significant challenge. Various chemical and mechanical stimuli have been used to enhance the functional properties of engineered musculoskeletal tissues. Recently, Ca2+-modulating agents have been used to enhance matrix synthesis and biomechanical properties of engineered cartilage. The objective of this study was to determine whether other known Ca2+ modulators, digoxin and adenosine triphosphate (ATP), can be employed as novel stimuli to increase collagen synthesis and functional properties of engineered cartilage. Neocartilage constructs were formed by scaffold-free self-assembling of primary bovine articular chondrocytes. Digoxin, ATP, or both agents were added to the culture medium for 1 h/day on days 10-14. After 4 weeks of culture, neocartilage properties were assessed for gross morphology, biochemical composition, and biomechanical properties. Digoxin and ATP were found to increase neocartilage collagen content by 52-110{\%} over untreated controls, while maintaining proteoglycan content near native tissue values. Furthermore, digoxin and ATP increased the tensile modulus by 280{\%} and 180{\%}, respectively, while the application of both agents increased the modulus by 380{\%}. The trends in tensile properties were found to correlate with the amount of collagen cross-linking. Live Ca2+ imaging experiments revealed that both digoxin and ATP were able to increase Ca2+ oscillations in monolayer-cultured chondrocytes. This study provides a novel approach toward directing neocartilage maturation and enhancing its functional properties using novel Ca2+ modulators.",
author = "Makris, {Eleftherios A.} and Huang, {Brian J.} and Hu, {Jerry C.} and Ye Chen-Izu and Athanasiou, {Kyriacos A.}",
year = "2015",
month = "3",
day = "1",
doi = "10.1089/ten.tea.2014.0360",
language = "English (US)",
volume = "21",
pages = "884--894",
journal = "Tissue Engineering - Part A",
issn = "1937-3341",
publisher = "Mary Ann Liebert Inc.",
number = "5-6",

}

TY - JOUR

T1 - Digoxin and adenosine triphosphate enhance the functional properties of tissue-engineered cartilage

AU - Makris, Eleftherios A.

AU - Huang, Brian J.

AU - Hu, Jerry C.

AU - Chen-Izu, Ye

AU - Athanasiou, Kyriacos A.

PY - 2015/3/1

Y1 - 2015/3/1

N2 - Toward developing engineered cartilage for the treatment of cartilage defects, achieving relevant functional properties before implantation remains a significant challenge. Various chemical and mechanical stimuli have been used to enhance the functional properties of engineered musculoskeletal tissues. Recently, Ca2+-modulating agents have been used to enhance matrix synthesis and biomechanical properties of engineered cartilage. The objective of this study was to determine whether other known Ca2+ modulators, digoxin and adenosine triphosphate (ATP), can be employed as novel stimuli to increase collagen synthesis and functional properties of engineered cartilage. Neocartilage constructs were formed by scaffold-free self-assembling of primary bovine articular chondrocytes. Digoxin, ATP, or both agents were added to the culture medium for 1 h/day on days 10-14. After 4 weeks of culture, neocartilage properties were assessed for gross morphology, biochemical composition, and biomechanical properties. Digoxin and ATP were found to increase neocartilage collagen content by 52-110% over untreated controls, while maintaining proteoglycan content near native tissue values. Furthermore, digoxin and ATP increased the tensile modulus by 280% and 180%, respectively, while the application of both agents increased the modulus by 380%. The trends in tensile properties were found to correlate with the amount of collagen cross-linking. Live Ca2+ imaging experiments revealed that both digoxin and ATP were able to increase Ca2+ oscillations in monolayer-cultured chondrocytes. This study provides a novel approach toward directing neocartilage maturation and enhancing its functional properties using novel Ca2+ modulators.

AB - Toward developing engineered cartilage for the treatment of cartilage defects, achieving relevant functional properties before implantation remains a significant challenge. Various chemical and mechanical stimuli have been used to enhance the functional properties of engineered musculoskeletal tissues. Recently, Ca2+-modulating agents have been used to enhance matrix synthesis and biomechanical properties of engineered cartilage. The objective of this study was to determine whether other known Ca2+ modulators, digoxin and adenosine triphosphate (ATP), can be employed as novel stimuli to increase collagen synthesis and functional properties of engineered cartilage. Neocartilage constructs were formed by scaffold-free self-assembling of primary bovine articular chondrocytes. Digoxin, ATP, or both agents were added to the culture medium for 1 h/day on days 10-14. After 4 weeks of culture, neocartilage properties were assessed for gross morphology, biochemical composition, and biomechanical properties. Digoxin and ATP were found to increase neocartilage collagen content by 52-110% over untreated controls, while maintaining proteoglycan content near native tissue values. Furthermore, digoxin and ATP increased the tensile modulus by 280% and 180%, respectively, while the application of both agents increased the modulus by 380%. The trends in tensile properties were found to correlate with the amount of collagen cross-linking. Live Ca2+ imaging experiments revealed that both digoxin and ATP were able to increase Ca2+ oscillations in monolayer-cultured chondrocytes. This study provides a novel approach toward directing neocartilage maturation and enhancing its functional properties using novel Ca2+ modulators.

UR - http://www.scopus.com/inward/record.url?scp=84924419893&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84924419893&partnerID=8YFLogxK

U2 - 10.1089/ten.tea.2014.0360

DO - 10.1089/ten.tea.2014.0360

M3 - Article

C2 - 25473799

AN - SCOPUS:84924419893

VL - 21

SP - 884

EP - 894

JO - Tissue Engineering - Part A

JF - Tissue Engineering - Part A

SN - 1937-3341

IS - 5-6

ER -