Harnessing Mechanobiology for Tissue Engineering

Abstract

A primary challenge in tissue engineering is to recapitulate both the structural and functional features of whole tissues and organs. In vivo, patterning of the body plan and constituent tissues emerges from the carefully orchestrated interactions between the transcriptional programs that give rise to cell types and the mechanical forces that drive the bending, twisting, and extensions critical to morphogenesis. Substantial recent progress in mechanobiology-understanding how mechanics regulate cell behaviors and what cellular machineries are responsible-raises the possibility that one can begin to use these insights to help guide the strategy and design of functional engineered tissues. In this perspective, we review and propose the development of different approaches, from providing appropriate extracellular mechanical cues to interfering with cellular mechanosensing machinery, to aid in controlling cell and tissue structure and function.

Keywords: cytoskeleton and adhesion; mechanical environment; mechanobiology; tissue engineering.

Figure 1.. Top-down approaches: manipulation of the extracellular mechanical environment.

(A) Biophysical properties of synthetic biomaterials including viscoelasticity, ligand type and density, degradability and pore size can be tailored orthogonally to control mechanosensitive cellular responses and functions in engineered tissues. (B) Mechanical properties as well as biochemical ligand presentation can be dynamically tuned with light. (C) Fabrication of biomaterials with defined physical geometries recapitulate native multicellular structures, such as villus- and crypt-like pattern, to better guide functional tissue development. (D) Complex hierarchical structures such as vascular tree-like channel networks can be created with 3D bioprinting. (E-F) Physiological mechanical forces exerting compressive, tensile or shear stress can be employed to activate mechanoregulatory processes essential for tissue organization and function. (E) Tensile stresses by pressurising from an intraluminal space, stretching the cell-seeded membrane, or using the tissue lengthening apparatus such as compressed spring and shear stress by medium perfusion through vascular network or organoid culture chambers can be exploited to emulate corresponding mechanical cellular environments. (F) Local mechanical forces can be applied in non-invasive and dynamic spatiotemporal manners by optical or magnetic actuation of nanoparticles, ferromagnetic or light-deformable hydrogels.

Figure 2.. Bottom up approaches: harnessing mechanotransduction machinery and signaling to build tissues.

Engineering complex folding patterns and sprouts are two main challenges facing tissue engineers. Here we depict in the center, gut microvilli, a tissue which emerges from complex folding patterns, as an example tissue that could perhaps be created from contractility (A-C), adhesions (D-F) and signaling (G-F) based tools. Bends within tissues have been demonstrated to emerge from (A) cell’s contracting, pulling on and locally aligning the matrix as well as (B) increases in intracellular tension from inducible constructs such as RhoA. (C) In contrast, protrusions emerge as actin polymerization and branching are induces from actin remodelers such as RAC, CDC42 or WASP. An analogous is to manipulate cadherin and integrins. (D) Scaffolds integrating specific cadherin and integrin bioactive cues promote formation and stabilization of these tissue structures. (E,F) Finer manipulations of these adhesion can be engineered with inducible synthetic constructs. A third approach is to target key mechanosensitive signaling molecules such as (G) YAP/TAZ or (I) Piezo. (H,J) Optogenetic constructs for Yap or Piezo enable spatiotemporal control of activity. (J) Additionally, Piezo channel can be stimulated with sound or magnetic fields.