Salivary Gland Tissue Engineering to Relieve Xerostomia

Introduction

Xerostomia, or dry mouth, is a product of reduced quality and quantity of saliva. Common causes include physiologic mouth breathing, polypharmacy, autoimmune disease, including Sjogren disease, and radiation. Drug-induced xerostomia can occur in the elderly population treated with medications that include anticholinergics, antidepressants, or sympathomimetics. Radiation-induced xerostomia occurs in 63–93% of head and neck cancer patients who undergo radiotherapy. The resulting alterations in the rate and volume of saliva production, and salivary pH and viscosity lead to dysphagia, dysphonia, dysgeusia, halitosis, and increased oral infections, such as sialadenitis, candidiasis, and dental caries. Collectively, these result in a decline in the overall quality of life. External beam radiation to the salivary glands generates reactive oxygen species, which damage cell membranes and trigger proteolysis and leakage of granules. Irreversible changes to the muscarinic receptors, aquaporins, and parenchyma severely disrupt glandular salivary secretion. Morphologically, the damage to the salivary glands ranges from partial damage to irreversible fibrosis of the entire glandular parenchyma.

Radiation-induced xerostomia is a continuing problem, despite the interventions undertaken to reduce radiation exposure to the salivary gland, which include surgical relocation of salivary glands prior to radiation and/or intensity-modulated radiotherapy (IMRT). First-line pharmacologic treatments, such as systemic cholinergic agents pilocarpine and cevimeline, provide short-term relief if there is residual functional tissue. Patient compliance is impacted by systemic side effects. Other widely used options include topical pilocarpine, enzyme enriched salivary substitute such as Biotene gel and paste, xanthum gum, lozenges, and acupuncture, all of which are largely ineffective. Systemic injections of the chemoprotectant, amifostine and its active metabolite, WR-1065, given prior to radiotherapy, modestly improve post-radiation salivary secretion and function over time in some patients. Further, localized retrograde delivery of amifostine is being investigated with promising cellular radioprotection and fewer potential side effects. The currently available pharmacologic approaches to stimulate saliva production from residual acini and the artificial salivary substitutes remain largely ineffective. Gene therapies have included transduction of aquaporin genes via adenoviral vector, but this failed clinical trials due to immunogenicity. Safer ultrasound-enabled transfer of aquaporin gene is being explored, as well as CRISPR-Cas9-based methods. Reverse engineering a functional and implantable salivary gland has the ability to provide a permanent and promising solution to alleviate xerostomia and its devastating clinical features. This chapter briefly highlights current progress in tissue engineering approaches and salivary gland regeneration.