Vascular Mechanobiology: Towards Control of In Situ Regeneration

Abstract

The paradigm of regenerative medicine has recently shifted from in vitro to in situ tissue engineering: implanting a cell-free, biodegradable, off-the-shelf available scaffold and inducing the development of functional tissue by utilizing the regenerative potential of the body itself. This approach offers a prospect of not only alleviating the clinical demand for autologous vessels but also circumventing the current challenges with synthetic grafts. In order to move towards a hypothesis-driven engineering approach, we review three crucial aspects that need to be taken into account when regenerating vessels: (1) the structure-function relation for attaining mechanical homeostasis of vascular tissues, (2) the environmental cues governing cell function, and (3) the available experimental platforms to test instructive scaffolds for in situ tissue engineering. The understanding of cellular responses to environmental cues leads to the development of computational models to predict tissue formation and maturation, which are validated using experimental platforms recapitulating the (patho)physiological micro-environment. With the current advances, a progressive shift is anticipated towards a rational and effective approach of building instructive scaffolds for in situ vascular tissue regeneration.

Keywords: growth and remodeling; in situ tissue engineering; mechanosensing; mechanotransduction; regeneration; scaffolds; tissue homeostasis; vessels.

Figure 1

Collagen microstructure of the three different layers of the aortic wall visualized with second harmonic generation microscopy (reproduced with permission from [33]). Mimicking the native collagen organization in fibrous scaffolds should be one of the strategies in the design of instructive scaffolds. Scalebar = 100 $\mathsf{\mu }$m.

Figure 2

Interrelationships between structure and function: functionality (in terms of mechanical properties) follows directly from structure, which is regulated by cell-mediated growth and remodeling in response to mechanical loading (in terms of stress and strain).

Figure 3

Mechanical homeostasis is a delicate balance between tissue growth, degradation, and remodeling. A perturbation of the equilibrium will result in a relative upregulation of one of these processes (indicated in red), in an attempt to restore the balance.

Figure 4

Passive and active cues in the context of scaffold design parameters and cardiovascular systems. Passive cues define the physical environment in which the cells reside, such as fibre diameter (nano-fibres vs. micro-fibres), topography (isotropic vs. anisotropic), and substrate stiffness. Active cues directly impose mechanical stimulations to the cell, such as shear stress (${\tau }_w$), cyclic strain (${\epsilon }_{\theta }$), and residual stress (${\sigma }_{r,i}$).

Figure 5

A rational design of a scaffold should provide the right passive cues and transmit the right active cues to guide cells towards a mechanical homeostasis via growth and remodeling. The process of growth and remodeling is both active (cell-mediated) and passive (e.g., dilatation of the vessel wall and micro-structure dictated by degree of axial pre-stress). Following this approach results in controlled in situ regeneration.