Designing Biomaterials to Modulate Notch Signaling in Tissue Engineering and Regenerative Medicine

The design of cell-instructive biomaterials for tissue engineering and regenerative medicine is at a crossroads. Although the conventional tissue engineering approach is top-down (cells seeded to macroporous scaffolds and mature to form tissues), bottom-up tissue engineering strategies are becoming appealing. With such developments, we can study cell signaling events, thus enabling functional tissue assembly in physiologic and diseased models. Among many important signaling pathways, the Notch signaling pathway is the most diverse in its influence during tissue morphogenesis and repair following injury. Although Notch signaling is extensively studied in developmental biology and cancer biology, our knowledge of designing biomaterial-based Notch signaling platforms and incorporating Notch signaling components into engineered tissue systems is limited. By incorporating Notch signaling to tissue engineering scaffolds, we can direct cell-specific responses and improve engineered tissue maturation. This review will discuss recent progress in the development of Notch signaling biomaterials as a promising target to control cellular fate decisions, including the influences of ligand identity, biophysical material cues, ligand presentation strategies, and mechanotransduction. Notch signaling is consequently of interest to direct, control, and reprogram cellular behavior on a biomaterial surface. We anticipate that discussions in this article will allow for enhanced knowledge and insight into designing Notch targeted biomaterials for various tissue engineering and cell fate determinations. Notch signaling is recognized as an important pathway in tissue engineering and regenerative medicine; however, there is no systematic review on this topic. The comprehensive review and perspectives presented here provide an in-depth discussion on ligand presentation strategies both in 2D and in 3D cell culture environments involving biomaterials/scaffolds. In addition, this review article provides insight into the challenges in designing cell surrogate biomaterials capable of providing Notch signals. To the best of the authors' knowledge, this is the first review relevant to the fields of tissue engineering.