Xerostomia, or 'dry mouth', is the inevitable consequence of the standard radiation treatment for head and neck cancers, and leads to severe dental issues (caries, infections, decay), difficulties in swallowing, speaking, and eating, gradual weight loss, and overall discomfort. Current therapies have not proven effective in long term application, and few tissue engineering strategies have been applied to this problem. In this application, we assemble three PIs with the necessary engineering, biological, and clinical expertise to address salivary regeneration using core biological design principles.
In Aim 1, Xinqiao Jia's laboratory will develop hyaluronic acid (HA) gels as a modular cellular scaffolding material. HA is a compelling material for salivary gland regenerative medicine, as it is naturally derived, biodegradable, and offers flexible tuning of chemical and mechanical properties to match those of native tissue. Microscale HA hydrogel particles (HGP) will be used as growth factor depots to stimulate salivary cell organization, gland morphogenesis, and vascular input to the neotissue.
In Aim 2, Cindy Farach-Carson's laboratory will apply these technologies in vitro, leveraging their ability to reliably isolate and expand acinar, ductal, and myoepithelial cells fro human tissue samples. Bioactive fragments will be incorporated into the HA matrix to facilitate acinar/ductal cell organization, and cell reconstitution will be conducted in a stepwise fashion to insure proper lumen formation, polarity, and function.
In Aim 3, Robert Witt will conduct in vivo implantations of HA matrices in an animal model, to determine the host response to the HGP growth factors, the viability of the neo-salivary glands, and a functional assessment of saliva production, content, and quality. These three Aims combine fresh discoveries from an existing collaboration among the three PIs, and maintain a clear goal of eventual translational application.
Patients with cancers of the head and neck often undergo radiation therapy as a part of their initial treatment. One side-effect of this radiation is atroph of cells in the mouth that produce saliva, which leads to xerostomia or 'dry mouth'. Xerostomia markedly lowers quality of life. We have identified methods for isolating these cells prior to radiation, growing them in the lab, and seeding them within gels that could help the cells reform as functional salivary glands, which could then be returned to the original patient.
|Srinivasan, Padma Pradeepa; Patel, Vaishali N; Liu, Shuang et al. (2017) Primary Salivary Human Stem/Progenitor Cells Undergo Microenvironment-Driven Acinar-Like Differentiation in Hyaluronate Hydrogel Culture. Stem Cells Transl Med 6:110-120|
|Wang, Z; Pradhan-Bhatt, S; Farach-Carson, M C et al. (2017) Artificial Induction of Native Aquaporin-1 Expression in Human Salivary Cells. J Dent Res 96:444-449|
|Ozdemir, Tugba; Srinivasan, Padma Pradeepa; Zakheim, Daniel R et al. (2017) Bottom-up assembly of salivary gland microtissues for assessing myoepithelial cell function. Biomaterials 142:124-135|
|Ravikrishnan, Anitha; Ozdemir, Tugba; Bah, Mohamed et al. (2016) Regulation of Epithelial-to-Mesenchymal Transition Using Biomimetic Fibrous Scaffolds. ACS Appl Mater Interfaces 8:17915-26|
|Srinivasan, Padma Pradeepa; Patel, Vaishali N; Liu, Shuang et al. (2016) Primary Salivary Human Stem/Progenitor Cells Undergo Microenvironment-Driven Acinar-Like Differentiation in Hyaluronate Hydrogel Culture. Stem Cells Transl Med :|
|Ozdemir, Tugba; Fowler, Eric W; Hao, Ying et al. (2016) Biomaterials-based strategies for salivary gland tissue regeneration. Biomater Sci 4:592-604|
|Ozdemir, Tugba; Fowler, Eric W; Liu, Shuang et al. (2016) Tuning Hydrogel Properties to Promote the Assembly of Salivary Gland Spheroids in 3D. ACS Biomater Sci Eng 2:2217-2230|
|Liu, Shuang; Zhang, Han; Remy, Roddel A et al. (2015) Meter-long multiblock copolymer microfibers via interfacial bioorthogonal polymerization. Adv Mater 27:2783-90|
|Liu, Shuang; Dicker, Kevin T; Jia, Xinqiao (2015) Modular and orthogonal synthesis of hybrid polymers and networks. Chem Commun (Camb) 51:5218-37|
|Zhang, Han; Dicker, Kevin T; Xu, Xian et al. (2014) Interfacial Bioorthogonal Cross-Linking. ACS Macro Lett 3:727-731|
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