Building a Functional Salivary Gland for Cell-Based Therapy: More than Secretory Epithelial Acini.

A few treatment options exist for patients experiencing xerostomia due to hyposalivation that occurs as a result of disease or injury to the gland. An opportunity for a permanent solution lies in the field of salivary gland replacement through tissue engineering. Recent success emboldens in the vision of producing a tissue-engineered salivary gland composed of differentiated salivary epithelial cells that are able to differentiate to form functional units that produce and deliver saliva to the oral cavity. This vision is augmented by advances in understanding cellular mechanisms that guide branching morphogenesis and salivary epithelial cell polarization in both acinar and ductal structures. Growth factors and other guidance cues introduced into engineered constructs help to develop a more complex glandular structure that seeks to mimic native salivary gland tissue. This review describes the separate epithelial phenotypes that make up the gland, and it describes their relationship with the other cell types such as nerve and vasculature that surround them. The review is organized around the links between the native components that form and contribute to various aspects of salivary gland development, structure, and function and how this information can drive the design of functional tissue-engineered constructs. In addition, we discuss the attributes of various biomaterials commonly used to drive function and form in engineered constructs. The review also contains a current description of the state-of-the-art of the field, including successes and challenges in creating materials for preclinical testing in animal models. The ability to integrate biomolecular cues in combination with a range of materials opens the door to the design of increasingly complex salivary gland structures that, once accomplished, can lead to breakthroughs in other fields of tissue engineering of epithelial-based exocrine glands or oral tissues. Impact statement Millions of people worldwide suffer from xerostomia/dry mouth owing to hyposalivation from disease, injury, or aging. Loss of saliva impairs eating, swallowing and leads to oral disease. Tissue engineering of salivary glands using primary adult stem/progenitor cell populations encapsulated in customized hydrogels offers a permanent solution. New materials are being developed to provide cues to encourage salivary cells to organize into functional structures that resemble acini connected to functional, branched ductal networks. Once formed, it is envisioned that these salivary neotissues can be implanted to restore salivation and improve the quality of life for xerostomic patients.