Controlled Tubular Unit Formation from Collagen Film for Modular Tissue Engineering

Bottom-up or modular tissue engineering is one of the emerging approaches to prepare biomimetic constructs <i>in vitro</i>, involving fabrication of small tissue units as building blocks before assembling them into functional tissue constructs. Herein, we reported a microscale tissue engineering approach to generate tubular tissue units through cellular contractile force induced self-folding of cell-laden collagen films in a controllable manner. Self-folding of cell-laden collagen films was driven by film contraction resulted from intrinsic contractile property of adherent mammalian cells seeded in collagen films. We explored in detail independent effects of collagen gel concentration, cell density, and intrinsic cellular contractility on self-folding and tubular structure formation of cell-laden collagen films. Through both experiments and theoretical modeling, we further demonstrated the effectiveness of integrating ridge array structures onto the backside of collagen films in introducing structural anisotropy and thus controlling self-folding directions of collagen films. Our approach of using ridge array structures to introduce mechanical anisotropy and thus promote tubular tissue unit formation can be extended to other biomaterial systems and thus provide a simple yet effective way to prepare tubular tissue units for modular tissue engineering applications.