Modular injectable scaffolds for cell therapy and 3D bioprinting

用于细胞治疗和 3D 生物打印的模块化可注射支架

• 批准号: RGPIN-2020-06684
• 负责人: Lerouge, Sophie
• 金额: $ 4.01万
• 依托单位: École de technologie supérieure
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=717761
• 关键词: Modular; injectable; scaffolds; cell; therapy

The present research program aims to develop biomaterials scaffolds as engineering tools to improve the efficacy of cell therapy. Cell therapy consists in the transplantation of cells into patients and can be used to treat many diseases or repair tissues. However injected cells dye rapidly or are flushed from the tissue. Cell encapsulation in hydrogel scaffolds has the potential to improve cell therapy outcomes by enhancing cell viability and retention at the delivery site, but ideal scaffold are still missing. Moreover, the scaffold parameters that influence the survival and ability of cells to migrate towards the targeted tissue are still poorly understood. In the recent years, the candidate has been developing biodegradable in situ gelling hydrogels with enhanced mechanical properties and excellent cytocompatibility. Cells can be mixed to the pre-hydrogel solution when still liquid at room temperature and injected by needle or catheter. A cohesive gel rapidly form in vivo. The present project aims to further improve these injectable cell carriers, namely by improving cell microenvironment, facilitating oxygen diffusion to the cells and increasing their adhesion to the target tissues. The main approaches will consist in 1) the incorporation of extracellular matrix compounds into hydrogels to better reproduce normal cell-tissue interactions 2) the development of void-forming (macroporous) scaffolds using rapidly biodegradable microspheres, and 3) the fabrication of cell-carriers in the form of microspheres that can self-assemble in vivo. We hypothesize that compared to encapsulation in large hydrogel volumes, encapsulation in microspheres will improve oxygen diffusion to the cells, facilitate cell escape and eventually promote formation of blood vessel network that will provide oxygen and nutrients to the cells. We will also optimize the microencapsulation process to allow endothelial cells adhesion on the surface and thus accelerate the formation of a perfusable vascular network. In addition, we will optimize these injectable hydrogels as bioinks for 3D bioprinting. This additive manufacturing process allows to form tissue-like structures with controlled heterogeneity and personalized geometry, which can be used as 3D in vitro models, or as implantable scaffolds. However only a few bioinks are available and most of them are based on the non-biodegradable alginate. In this project, we will propose new bioinks based on chitosan- methacrylated gelatin interpenetrating networks. These new injectable modular cell carriers will offer many opportunities as tools for cell therapy and formation of 3D models and will bring significant knowledge on the factors influencing the success of cell carrier for cell therapy. A final benefit is the training of high-quality, highly qualified personnel (HQP) in this important field at the frontier between biomaterials science, rheology, mechanical engineering and biology.

本研究计划旨在开发生物材料脚手架作为工程工具，以提高细胞疗法的功效。细胞疗法包括将细胞移植到患者中，可用于治疗许多疾病或修复组织。然而，注射的细胞迅速染色或从组织中冲洗。水凝胶支架中的细胞封装有可能通过增强递送部位的细胞活力和保留率来改善细胞治疗结果，但理想的支架仍然缺失。此外，影响细胞向目标组织迁移的生存和能力的脚手架参数仍然很少了解。 近年来，候选人一直在开发具有具有增强机械性能和出色细胞相置性的原位原位胶凝水凝胶。当仍在室温下液体并用针头或导管注入时，可以将细胞混合到前凝胶溶液中。在体内迅速形成粘性凝胶。本项目的目的是通过改善细胞微环境，促进对细胞的氧扩散并增加对靶组织的粘附力来进一步改善这些可注射的细胞载体。 主要方法将包括1）将细胞外基质化合物掺入水凝胶中，以更好地再现正常的细胞 - 组织相互作用2）使用快速生物降解的微球的空隙形成（宏观）支架的发展，以及3）3）在微球形式的形式中，可以自我组成的组合形式的细胞携带者。我们假设，与大型水凝胶体积的封装相比，微球中的封装将改善对细胞的氧扩散，促进细胞逸出，并最终促进血管网络的形成，从而为细胞提供氧气和养分。我们还将优化微囊化过程，以使内皮细胞在表面上粘附，从而加速灌注可灌注的血管网络。 此外，我们将优化这些可注射的水凝胶作为3D生物打印的生物键。这种添加剂制造过程允许形成具有控制的异质性和个性化几何形状的组织样结构，可以用作3D体外模型或可植入的脚手架。但是，只有少数生物界可用，其中大多数基于不可生物降解的藻酸盐。在这个项目中，我们将基于壳聚糖的明胶互穿网络提出新的生物学。 这些新的可注射模块化细胞载体将为细胞疗法和形成3D模型提供许多机会，并将为影响细胞载体成功用于细胞疗法的因素带来重要的知识。最终的好处是在生物材料科学，流变学，机械工程和生物学之间的边界的这一重要领域中培训高质量，高素质的人员（HQP）。