Distinct Long-term Effects of Precision X-Radiation on Reflex Saliva Flow Rate and Tissue Integrity in a Preclinical Model of Chronic Hyposalivation

Abstract

32Chronic salivary hypofunction and xerostomia are common side effects of radiation therapy 33 which is an essential component in the curative management in patients with head & neck 34 cancers. Over the years, improvements in delivery techniques such as image-guided intensity 35 modulated radiation therapy have led to improvement in cancer management but chronic 36 hyposalivation continues to be a challenge that causes long-term health implications resulting in 37 compromised quality of life. Recent advances in salivary stem cell research promise new 38 frontier in the treatment of radiation-induced hyposalivation by initiating regeneration of 39 radiation-damaged salivary parenchymal cells. Lack of a standard preclinical immunodeficient 40 model to assess radiation-induced changes objectively and quantitatively in salivary flow rates 41 will impede rapid progress towards the development of cellular therapies for chronic salivary 42 dysfunction and attendant xerostomia. Herein, we report the first fully characterized novel cone-43 beam computed tomography (CBCT)-guided precision ionizing radiation (IR) induced chronic 44 hyposalivation model in radiosensitive, immunodeficient transgenic NSG-SGM3 mice 45 expressing three human cytokines including c-KIT ligand/stem cell factor. Additionally, we also 46 report a novel and instantaneous method to objectively assess the kinetics of pilocarpine-47 stimulated salivary flowrate. Comprehensive structural and functional characterization of 48 salivary glands revealed previously unknown and highly complex gender, age, IR dose and 49 salivary gland subtype-specific effects of salivary-ablative precision IR. 50 Aalam et al. Preclinical Model of Chronic Hyposalivation Preprint