Polyethylene glycol Hydrogels for Salivary Gland Regeneration

 描述(申请人提供)：在美国，每年有超过40,000名患者被诊断出患有头颈癌。这些癌症的放射治疗会对唾液腺造成不可修复的损害，导致永久性口干或口干。口干症严重影响口腔卫生，严重影响患者的生活质量，目前尚无再生疗法可恢复正常的唾液分泌。最近的研究表明，将悬浮培养的原代颌下腺(SMG)细胞直接注射到受辐射损伤的腺体中，可以使体内的腺体功能轻微恢复。因此，我们的目标是开发一种生物材料方法，通过支持SMG的存活和功能来增强照射后腺体的恢复。水凝胶具有亲水性和生物惰性，具有与软组织相似的机械性能；然而，关于水凝胶介导的唾液腺再生途径的研究报道很少。该项目试图通过探索使用聚乙二醇水凝胶作为一种移植颌下腺细胞和再生功能性唾液组织的方法来解决这一知识缺口。聚乙二醇水凝胶可以功能化，具有可降解部分和生物活性部分，以增强SMG细胞的再生能力，并可以通过光聚合原位形成。本项目旨在开发可用于原代唾液腺细胞的水凝胶包埋方法，设计水凝胶环境，通过细胞与材料的相互作用促进唾液腺再生，并为唾液腺细胞移植和腺体再生原位形成水凝胶。为了设计细胞相容的包埋方法，将在目标1中评估不同类型的水凝胶聚合对治疗性SMG细胞的影响。在目标2中，将进一步修改细胞相容的聚乙二醇水凝胶化学成分，以包括细胞决定的降解性以及唾液腺细胞外基质(ECM)中发现的重要细胞黏附基序，以提高水凝胶支架的再生潜力。目的：在涎腺损伤的导管结扎和放射损伤模型中，采用原位光聚合的方法移植SMG细胞，以跟踪细胞掺入和腺体功能恢复。这些目标的完成将决定水凝胶胶囊用于SMG治疗的可行性，以及唾液腺组织工程方法的方法。申请书中详细说明了为补充申请者的研究培训而开展的活动。这两个赞助商都致力于申请者作为内科科学家的发展，并将继续培训申请者实验设计、科学写作和演讲。申请人还将与从事癌症治疗工作的医生取得两次纵向临床经验，以更好地了解他的研究的临床背景。 最后，申请者将在他的医学培训期间继续参与未来研究的发展。

 DESCRIPTION (provided by applicant): Over 40,000 patients in the U.S. are diagnosed with head and neck cancers annually. Radiation therapy for these cancers causes irreparable damage to the salivary glands resulting in permanent xerostomia or dry mouth. Xerostomia significantly detracts from patient quality of life by adversely impacting oral hygiene, and currently no regenerative therapy exists to restore proper saliva secretion. Recent work has demonstrated that direct injection of primary submandibular gland (SMG) cells prepared by suspension culture into a radiation damaged glands leads to modest recovery of gland function in vivo. Thus, we aim to develop a biomaterials approach to augment gland recovery after irradiation by supporting SMG survival and function. Hydrogels, which are hydrophilic and bio-inert, have mechanical properties that are similar to those seen in soft tissues; however, few investigations have been reported regarding hydrogel-mediated salivary gland regeneration approaches. This project seeks to address this gap in knowledge by exploring the use of poly(ethylene glycol) (PEG) hydrogels as a means to transplant submandibular gland cells and regenerate functional salivary tissue. PEG hydrogels can be functionalized with both degradable and bioactive moieties to enhance the regenerative potential of SMG cells and can be formed in situ using photopolymerization. This project aims to develop permissive hydrogel encapsulation methods for primary salivary gland cells, design hydrogel milieus to promote salivary gland regeneration through cell-material interactions, and to form hydrogels in situ for salivary gland cell transplantation and gland regeneration. To design cytocompatible encapsulation methods, the effects of different types of hydrogel polymerizations on therapeutic SMG cells will be assessed in Aim 1. Cytocompatible PEG hydrogels chemistries will be further modified in Aim 2 to include cell-dictated degradability as well as vital cell adhesion motifs found in the salivary gland extracellular matrix (ECM) to improve the regenerative potential of the hydrogel scaffold. In Aim 3 SMG cells will be transplanted using in situ photopolymerization in both duct ligation and radiation models of salivary gland injury to track cell incorporation and functional gland recovery. Completion of these aims will determine the feasibility of hydrogel encapsulation for SMG based therapies and approach for tissue engineering approaches for the salivary gland. Detailed within this application are activities to complement the research training of the applicant. Both sponsors are dedicated to the applicant's development as a physician-scientist and will continue to train the applicant in experimental design, scientific writing, and presentation. The applicant will also pursue two longitudinal clinical experiences with physicians working in cancer treatment to gain a better understanding of the clinical context of his research. Finally, the applicant will continue involvement in the development of future studies during his medical training.