Growth and Remodeling of Collagen Tissues

Soft collagenous tissues exhibit a highly organized  structure, where  stiff collagen fibrils embedded in a soft proteoglycan matrix are assembled into  fibers and larger scale tissue-specific  structures. The collagen structure can change in response to mechanical stimuli to produce tissue-level growth and remodeling of tissue-level properties. Growth and remodeling can occur as part of physiological processes, such as from regular exercise and pregnancy.    However, disordered or unchecked growth and remodeling is a defining feature of many diseases, such as cardiac hypertrophy  and  glaucoma.

We seek to understand the micromechanisms through which mechanical stimuli direct collagen growth and remodeling. We hypothesize that the collagen structure is actively maintained or changed through concurrent processes of collagen deposition and degradation, and that the rates of collagen  deposition and degradation can be altered by collagen mechanochemistry and by mechanosensitive collagen production and cellular contraction. Numerous experimental studies have shown that stretch can inhibit  enzymatic degradation of  collagen molecules, fibrils,  and tissues.  However, it is currently unknown if stretch has an analogous mechanochemical effect of enhancing collagen deposition. Mechanical stimulation can cause fibroblasts to contract and produce metalloproteinases (MMPs) and extracellular matrix (ECM) components. Mechanical loading can also induce fibroblasts to  proliferate and differentiate into  myofibroblasts, with increased contractility and ECM production.  For example, myofibroblasts have been shown to develop in the mouse sclera within a week after a chronic increase in the intraocular pressure.

Our research aims to:

  • Measure the effects of global mechanical and chemical stimuli on growth and remodeling
  • Develop a micromechanical model for collagen growth and remodeling
  • Investigate the effects of cell-scale perturbations on growth and remodeling.
Figure 1: (A) The microTug platform developed in the Reich lab to study the mechanics of self assembled tissues has flexible PDMS micro pillars to provide tissue force readouts and magnetic tweezer for testing tissue mechanical properties. (D) Fluorescent images of the microtissues showing that arrangement of the pillars can yield control of collagen anisotropy. Scale bars are 100 micron in (B)  and 300 microns in (C) and 300 microns in (D).
Figure 2 Schematic of micromechanical model for fibril-level growth and remodeling of collagenous tissues.  The collagen tissue is represented as (a) a 3D distribution of wavy fibers, showing (b) the reference, growth, and deformed configurations.  The circles to the right show the fiber cross-sectional area in the reference, growth, and deformed configurations.  (c) The effect of a pressure perturbation on the stress response of a thin spherical tissue membrane, showing recovery of the homeostatic stress state after a sudden increase and decrease in pressure. (d) Effect of uniaxial tension on enzymatic degradation of an initially isotropic collagen tissue. The polar plot shows that the isotropic probability density distribution of collagen fiber orientation remodels to an anisotropic orientation distribution aligned with the loading direction denoted by arrows.

Collaborators

Jeffrey Ruberti, Ph.D., Department of Bioengineering, Northeastern University

Daniel Reich, Ph.D. Department of Physics and Astronomy, Johns Hopkins University

Researchers

Publications