Injectable thermosensitive hydrogels with enhanced mechanical properties for cell therapy

可注射水凝胶越来越多地用于疾病的微创治疗，特别是与细胞接种相结合，因为它们可以确保适当的细胞定位，保留和存活。理想地，可注射凝胶在注射之前和期间应具有相对低的粘度，但在递送之后快速胶凝并表现出高机械强度，以确保基质内聚性和对体内应力的耐受性。然而，缺乏将这些品质与优异的细胞相容性相结合的可注射材料。我们的团队最近开发了一种使用新的胶凝剂制备高强度，快速热凝胶化壳聚糖（CH）基水凝胶的方法，可以解决这个问题。** 这项为期5年的研究计划的目标是设计，优化和表征这些热敏性水凝胶作为可注射支架，特别是在细胞治疗中，并探索它们使用3D生物打印进行组织增材制造的潜力。* 我们将首先研究凝胶组成如何影响凝胶化动力学、机械性能和孔隙率，以更好地理解为什么含有碳酸氢钠（SHC）的CH凝胶具有更高的机械性能，并能够根据具体应用的需要定制凝胶的性能。然后，我们将评估它们是否适合封装人类间充质干细胞（MSC）和T淋巴细胞，这两者在细胞治疗中都有很大的希望。MSC存活和治疗效率将通过两种不同的方法优化：a）在包封之前对细胞进行药理学预处理和B）设计含有硫酸软骨素和生长因子的生物活性支架。最后，我们将利用这些可定制的水凝胶用于生物打印，这使得创建模拟活组织的复杂和异质的3D结构成为可能，具有组织工程，药物筛选和毒理学的潜在应用。** 本研究计划将有12名学生参与，其中包括2名博士生，3名硕士生和2名博士后。虽然我们不针对任何特定的临床应用，但我们的工作将为开发具有更高疗效和更低风险的微创治疗提供知识和数据（由于更多的本地交付），从而降低成本和发病率。因此，从长远来看，我们的研究成果和在这一战略领域培训高质量的HQP也将为加拿大的健康和工业带来好处。

Injectable hydrogels are increasingly used for minimally invasive treatment of diseases, especially in combination with cell seeding, because they can ensure appropriate cell localization, retention and survival. Ideally, an injectable gel should have relatively low viscosity before and during injection but gel rapidly and exhibit high mechanical strength after being delivered, to ensure matrix cohesion and tolerance to in vivo stresses. However, there is a lack of injectable material that combines these qualities with excellent cell compatibility. Our team recently developed a method for preparing high-strength, fast-thermogelling chitosan (CH)-based hydrogels using new gelation agents that may solve this issue. ******The objectives of this 5-year research program are to design, optimize and characterize these thermosensitive hydrogels for use as injectable scaffolds, especially in cell therapy, and to explore their potential for additive manufacturing of tissue using 3D bioprinting. ***We will first study how the gelation kinetic, mechanical properties and porosity are influenced by gel composition, to better understand why CH gels containing sodium hydrogen carbonate (SHC) present much higher mechanical properties and to be able to tailor a gel's properties as needed for a specific application. We will then evaluate their suitability for encapsulation of human mesenchymal stem cells (MSCs) and T lymphocytes, both of which hold great promise in cell therapy. MSC survival and therapeutic efficiency will be optimized by two different approaches: a) pharmacological preconditioning of cells before encapsulation and b) design of bioactive scaffolds containing chondroitin sulfate and growth factors. Finally we will leverage these customizable hydrogels for use in bioprinting, which makes it possible to create complex and heterogeneous 3D structures mimicking living tissues, with potential applications for tissue engineering, drug screening and toxicology. ******A dozen students will be involved in this research program, including 2 PhDs, 3 Masters and 2 post-doctoral students. While we do not target any specific clinical application for this grant, our work will contribute knowledge and data toward the development of minimally invasive treatments with increased efficacy and reduced risk (thanks to more local delivery), thereby reducing costs and morbidity rates. Thus, in the long term, benefits for Canadian health and industry are also expected from our research results and the training of high-quality HQP in this strategic field.