O2 Diffusion through Collagen Scaffolds at Defined Densities: Implications for Cell Survival and Angiogenic Signalling in Tissue Models

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The success of any biomaterial for tissue engineering is dominated by its mechanical properties and ability to support nutrient diffusion. Collagen scaffolds are ideal candidates due to their ability to immerse cells in a biomimetic nano-fibrous matrix. We have established O2 diffusion coefficients through native, dense collagen scaffolds at two tissue-like densities, with and without photo-chemical crosslinking, by adapting an optical fibre-based system for real-time core O2 monitoring deep within collagen constructs. The high diffusion coefficients of these collagen scaffolds, as well as their material properties, render them viable tissue engineering matrices for tissue replacement. Due to this O2 diffusion through cell-seeded collagen type I scaffolds, natural gradients of O2 form and cells in different locations are subject to varying levels of O2. These gradients were controlled by varying cell density, as it was found that cell consumption of O2 played a greater role compared to material diffusion in formation of such O2 gradients. Potent angiogenic signaling molecules were upregulated at both the gene and protein level, particularly within the core of 3D scaffolds, where O2 was low, but remained within physiological hypoxia. By incorporating phosphate-based dissolving glass fibres into collagen constructs, as they are produced, it was possible to introduce channels throughout the construct in a gradual manner. Where channeled architecture was introduced to the 3D constructs, thus delivery of sustained O2 to all cells even within the core, this upregulation of angiogenic factors was abolished. We can now engineer collagen type I scaffolds with varying density, varying degrees of crosslinking and various architectural features to control delivery of O2 to all cells embedded within the construct.