Injectable thermosensitive hydrogels with enhanced mechanical properties for cell therapy

可注射水凝胶越来越多地用于微创治疗疾病，特别是与细胞播种相结合，因为它们可以确保适当的细胞定位、保留和存活。理想情况下，可注射凝胶在注射前和注射过程中应具有相对较低的粘度，但在输送后应迅速凝胶化并具有较高的机械强度，以确保基质内聚性和对体内应力的耐受性。然而，缺乏将这些特性与优异的细胞相容性结合起来的可注射材料。我们的团队最近开发了一种使用新型凝胶剂制备高强度、快速热凝胶壳聚糖（CH）基水凝胶的方法，可能会解决这个问题。

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.