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In this research, ultrafine fibrous scaffolds with deep cell infiltration and sufficient water stability have been developed from gelatin, aiming to mimic the extracellular matrices (ECMs) as three dimensional (3D) stromas for soft tissue repair. The ultrafine fibrous scaffolds produced from the current technologies of electrospinning and phase separation are either lack of 3D oriented fibrous structure or too compact to be penetrated by cells. Whilst electrospun scaffolds are able to emulate two dimensional (2D) ECMs, they cannot mimic the 3D ECM stroma. In this work, ultralow concentration phase separation (ULCPS) has been developed to fabricate gelatin scaffolds with 3D randomly oriented ultrafine fibers and loose structures. Besides, a non-toxic citric acid crosslinking system has been established for the ULCPS method. This system could endow the scaffolds with sufficient water stability, while maintain the fibrous structures of scaffolds. Comparing with electrospun scaffolds, the ULCPS scaffolds showed improved cytocompatibility and more importantly, cell infiltration. This research has proved the possibility of using gelatin ULCPS scaffolds as the substitutes of 3D ECMs.

In this work, novel electrospun scaffolds with fibers oriented randomly and evenly in three dimensions (3D) including in the thickness direction were developed based on the principle of electrostatic repulsion. This unique structure is different from most electrospun scaffolds with fibers oriented mainly in one direction. The structure of novel 3D scaffolds could more closely mimic the 3D randomly oriented fibrous architectures in many native extracellular matrices (ECMs). The cell culture results of this study indicated that, instead of becoming flattened cells when cultured in conventional electrospun scaffolds, the cells cultured on novel 3D scaffolds could develop into stereoscopic topographies, which highly simulated in vivo 3D cellular morphologies and are believed to be of vital importance for cells to function and differentiate appropriately. Also, due to the randomly oriented fibrous structure, improvement of nearly 5 times in cell proliferation could be observed when comparing our 3D scaffolds with 2D counterparts after 7 days of cell culture, while most currently reported 3D scaffolds only showed 1.5- to 2.5-fold improvement for the similar comparison. One mechanism of this fabrication process has also been proposed and showed that the rapid delivery of electrons on the fibers was the crucial factor for formation of 3D architectures.