Fiber-reinforced load-bearing soft tissues, including tendon, meniscus, and annulus fibrosus, have hierarchical structure and biochemical composition that enables in vivo mechanical function. These tissues are prone to degeneration and injury, with debilitating consequences, high costs, and limited therapeutic options. Although load-bearing tissues are classically described using idealized schematics showing an ordered prevailing fiber direction, these tissues are in fact highly inhomogeneous, with amorphous proteoglycan-rich structural micro-domains within an otherwise ordered collagen-rich fibrous tissue - they are not simply a schematic. The objective of this proposal is to investigate micro-level structure-function of native and engineered tissue by quantifying and modeling mechanics from the tissue to the cellular level, and evaluating the mechanistic impact of micro-level structure-function on mechanotransduction. This study will also recapitulate these natural and/or potentially diseased micro-environments in engineered tissues in order to develop controlled in vitro systems to evaluate altered mechanotransduction. Quantifying the size, mechanical inhomogeneity, and biological response among tissue micro-domains is important because this is the length scale that governs cell mechanotransduction, and therefore regulation of tissue homeostasis and disease progression. These studies will advance the field of regenerative medicine by addressing micromechanical mechanisms in tissue development, degeneration, and injury. Ultimately, this new understanding will direct therapeutic strategies for rehabilitatio, repair, and replacement to promote and preserve healthy mechanotransduction in fibrous load bearing tissues.

Public Health Relevance

Load-bearing soft tissues, including tendon, meniscus, and annulus fibrosus, have a fiber-reinforced structure that enables mechanical function. These tissues are prone to degeneration and injury, with debilitating consequences, high costs, and limited therapeutic options. This proposal will investigate micro-level structure-function (?S/F) o native and engineered tissue by quantifying and modeling mechanics from the macroscopic to the cellular (micro-domain) level and evaluating the impact of ?S/F on cell mechanotransduction. These relationships are critical, as cell mechanotransduction and regulation of tissue homeostasis and disease progression occurs at this length scale. Ultimately, this new understanding will direct therapeutic strategies for rehabilitation, repair, and replacement to promote and preserve healthy mechanotransduction in fibrous load bearing tissues.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
2R01EB002425-09A1
Application #
8696354
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Hunziker, Rosemarie
Project Start
2003-09-30
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Delaware
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
City
Newark
State
DE
Country
United States
Zip Code
19716
Li, Qing; Qu, Feini; Han, Biao et al. (2017) Micromechanical anisotropy and heterogeneity of the meniscus extracellular matrix. Acta Biomater 54:356-366
Safa, Babak N; Meadows, Kyle D; Szczesny, Spencer E et al. (2017) Exposure to buffer solution alters tendon hydration and mechanics. J Biomech 61:18-25
Heo, Su-Jin; Szczesny, Spencer E; Kim, Dong Hwa et al. (2017) Expansion of mesenchymal stem cells on electrospun scaffolds maintains stemness, mechano-responsivity, and differentiation potential. J Orthop Res :
Szczesny, Spencer E; Fetchko, Kristen L; Dodge, George R et al. (2017) Evidence that interfibrillar load transfer in tendon is supported by small diameter fibrils and not extrafibrillar tissue components. J Orthop Res 35:2127-2134
Szczesny, Spencer E; Mauck, Robert L (2017) The Nuclear Option: Evidence Implicating the Cell Nucleus in Mechanotransduction. J Biomech Eng 139:
Peloquin, John M; Santare, Michael H; Elliott, Dawn M (2016) Advances in Quantification of Meniscus Tensile Mechanics Including Nonlinearity, Yield, and Failure. J Biomech Eng 138:021002
Heo, Su-Jin; Driscoll, Tristan P; Thorpe, Stephen D et al. (2016) Differentiation alters stem cell nuclear architecture, mechanics, and mechano-sensitivity. Elife 5:
Heo, Su-Jin; Han, Woojin M; Szczesny, Spencer E et al. (2016) Mechanically Induced Chromatin Condensation Requires Cellular Contractility in Mesenchymal Stem Cells. Biophys J 111:864-874
Peloquin, John M; Elliott, Dawn M (2016) A comparison of stress in cracked fibrous tissue specimens with varied crack location, loading, and orientation using finite element analysis. J Mech Behav Biomed Mater 57:260-8
Cote, Allison J; McLeod, Claire M; Farrell, Megan J et al. (2016) Single-cell differences in matrix gene expression do not predict matrix deposition. Nat Commun 7:10865

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