Designing In Vivo Bioreactors for Soft Tissue Engineering

Tissue engineering emerged in the early 1990s to address limitations in organ transplantation and synthetic tissue replacements, focusing on coupling cells and a biocompatible matrix known as a scaffold. Some clinical success has been achieved to date; primarily with hard or avascular tissue replacements (e.g., bone and cartilage replacements) and two-dimensional soft tissues (e.g., skin and cornea). The reconstruction of more complicated three-dimensional soft tissues (e.g., cardiovascular, adipose tissues) is far more challenging. Here the commonly taken route of seeding a scaffold with an appropriate progenitor cell type and culturing in a bioreactor in vitro followed by in vivo implantation often results in construct failure due to diffusion limitations causing substantial cell death in the interior of the scaffold. A lack of nutrients and oxygen and the accumulation of waste due to normal cell metabolism contribute to this phenomenon, which is one reason why the repair of large soft tissue defects through tissue engineering has so far eluded successful clinical translation. One emerging trend to circumvent this problem is to utilize in vivo bioreactors that provide intrinsic vascularization or induce in situ vascularization during tissue development. However, the design of in vivobioreactors needs not only to consider ways to improve in situ vascularization, but also needs to include considerations familiar to many tissue engineering approaches such as biocompatibility of the construct material, biodegradability, and biochemical and biomechanical signaling. This review discusses the important design parameters for in vivo bioreactors for tissue engineering with a particular focus on engineering of soft tissues such as adipose, cardiovascular and muscle tissue. Specific examples of in vivo bioreactors currently under investigation clinically or pre-clinically are discussed with respect to their fundamental working principles, past and present developments, and proximity to clinic.