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Dense collagen-based tubular tissue constructs for airway tissue engineering

Authors
Publisher
McGill University
Publication Date
Keywords
  • Engineering - Biomedical
Disciplines
  • Biology
  • Engineering
  • Mathematics
  • Medicine
  • Physics

Abstract

To date, only engineered tissues of planar geometry, such as epidermal and dermal layer substitutes, have successfully reached the market, mainly due to their relative low complexity and simple geometry. In contrast, the mechanical and functional requirements of tubular tissues are more stringent compared to planar tissues. Tubular tissues, which are the main components of several biological systems (e.g. circulatory, urinary or respiratory), not only present an increased complexity in geometry and tissue architecture, they are also populated by mixed cell types. In addition, these are continuously exposed to cyclic mechanical stimuli, which modulate cellular responses and ultimately the functionality of the tissues. Therefore, the understanding and the ability to reproduce physiologically equivalent environments are critical to generate mechanically and biologically functional neo-tissues or tissue models. The aim of this doctoral research was to produce and characterize 3D DC-based tubular constructs as tissue models for airway tissue engineering in physiologically relevant culture conditions. The first objective was to develop DC-based constructs and evaluate, in real-time, the responses of seeded fibroblasts to PC and to culturing with the DC environment; the fabrication and characterization of mesenchymal stem cell (MSC) seeded multilayered DC-SF-DC hybrids; and to evaluate the differentiation of MSCs cultured within multilayered DC-SF-DC hybrids.The second objective was to develop and characterize cell-seeded tubular dense collagen constructs (TDCCs) with bioinspired mechanical properties.The third objective was to implement tubular dense collagen-based constructs as an airway tissue model through the evaluation of airway smooth muscle cell (ASMC) responses within TDCC under physiological mechanical stimuli, and the development of a multilayered tubular dense collagen-silk fibroin construct (TDC-SFC) that mimicked airway tract architecture in order to study MSC responses under physiological mechanical stimulation.By providing ASMCs with a physiologically equivalent niche, and through pulsatile flow stimulation, in vitro, ASMCs exhibited their native orientation, maintained their contractile phenotype and enhanced the mechanical properties of the TDCC through matrix remodelling. The ability of TDC-SFC to transfer physiological pulsatile stimulation to resident MSCs resulted in native-like cell orientation (i.e. parallel to circumferential strain), and induced MSC contractile phenotype expression.In conclusion, the tubular dense collagen-based constructs developed and implemented, in this doctoral dissertation, effectively provided an in vitro airway tissue model for potential preclinical studies to mimic physiological and pathological conditions (e.g. inflammatory and degenerative diseases) in a relevant biomechanical environment, as alternatives to simple tissue culture techniques or complex animal models.

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