Characterization of the mechanical and structural microenvironment of soft tissues with application to cervix and preterm birth

Ostadi Moghaddam, Amir

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https://hdl.handle.net/2142/117620 Copy

Description

Title

Characterization of the mechanical and structural microenvironment of soft tissues with application to cervix and preterm birth

Author(s)

Ostadi Moghaddam, Amir

Issue Date

2022-08-08

Director of Research (if dissertation) or Advisor (if thesis)

Wagoner Johnson, Amy

Doctoral Committee Chair(s)

Wagoner Johnson, Amy

Committee Member(s)

• Kersh, Mariana
• Dunn, Alison
• Bagchi, Indrani
• Hutchens, Shelby
• Toussaint, Kimani

Department of Study

Mechanical Sci & Engineering

Discipline

Mechanical Engineering

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Collagenous tissue
• Cervix
• Tendon
• Second-harmonic generation
• Nanoindentation
• Preterm birth

Abstract

The tissue microenvironment (TME) is a spatially and temporally dynamic and extremely diverse system that consists of cells, extracellular matrix (ECM) molecules such as collagen and proteoglycans, regulators like collagen crosslinkers, soluble factors, and blood vessels. It plays a significant role in the initiation and progression of many diseases including cancer, arthritis, liver fibrosis, and tendinosis, to name a few. Biophysical properties quantitatively describe the TME and offer valuable insights into the tissue condition. Changes in these properties are often hallmarks of remodeling and disease and affect tissue function. Characterizing and understanding the biophysical properties requires an interdisciplinary approach integrating biology and several fields of engineering. Drawing a detailed picture of the TME points to the root causes of diseases and paves the way for developing new diagnostic techniques and treatment strategies. The overarching goal of this dissertation is to establish new experimental protocols, data analysis techniques, and computational models that allow for probing, quantifying, and modeling the TME. Specifically, this work focuses on two important categories of biophysical properties, 3D collagen microstructure, and micromechanical properties. We use the uterine cervix as the primary model system due to its critical biomechanical function during pregnancy; studying cervical remodeling provides valuable insights into the underlying mechanisms that lead to preterm birth (PTB), a critical issue affecting millions worldwide. Towards this goal, this dissertation has three primary objectives. 1) Establish the required techniques for probing and quantifying the soft tissue: the inherent complexity of TME makes it increasingly challenging to probe the biophysical properties of tissue. Tools and techniques that reveal and quantitatively describe particular aspects of the TME simply do not exist. The first objective of this dissertation was to establish the analytical and experimental techniques that more comprehensively illustrate the TME and the biophysical properties that describe it. Central to this objective was developing the optomechanogram, a combined quantitative and qualitative visualization of spatially co-registered measurements of the microstructural and micromechanical properties. This technique allowed us to identify the direct link between biophysical properties measured by independent platforms. To improve the accuracy of microstructural characterization, we introduced new mathematical tools for quantifying 3D tissue images from second-harmonic generation (SHG) microscopy. 2) Quantify the cervix microenvironment: we capitalized on the techniques introduced in objective one to study the cervix and cervical remodeling. We found that the microstructural and micromechanical properties of cervix are highly correlated and depend on the anatomical region. We showed that microstructural remodeling occurs non-uniformly across the cervix and initially distinct cervical regions converge to a more uniform microstructure at later stages of pregnancy. We also observed a previously unknown cervical remodeling phenomenon; the dominant orientation of the collagen fibers reorients significantly with gestation only in one particular region of the cervix, i.e., the inner cervical zone. Computational simulation showed that this region-specific remodeling phenomenon plays a significant role in pregnancy maintenance by preventing cervical funneling, a major marker for the increased risk of PTB. Together, the results provided a comprehensive description of cervical remodeling and revealed critical microstructural changes that could contribute to PTB. 3) Identify the deformation mechanisms that govern the tissue’s mechanical behavior: the final objective of this dissertation was to evaluate the mechanisms that give rise to the specific mechanical behavior in collagenous tissue. Using cervix and tendon as model systems, we found that crosslinked collagen fibrils accommodate longitudinal compressive forces, while well-established constitutive models do not account for this mechanism. We also demonstrated that glycosaminoglycans (GAGs) modulate the interaction of neighboring fibrils in a strain- and time-dependent manner, but do not function as crosslinks, contrary to several other studies. The results offered new insights into the function of GAGs and collagen crosslinkers in collagenous tissues and, overall, demonstrated the importance of shear-regulated constituent interactions.

Graduation Semester

2022-12

Type of Resource

Thesis

Copyright and License Information

Copyright 2022 Amir Ostadi Moghaddam

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