Development of tuneable microgels for controlled protein delivery in tissue regeneration

蛋白质（如生长因子）的受控递送是治疗病理状况（包括骨缺损和皮肤病变）的非常有前途的策略。有效的蛋白质治疗剂的主要障碍是缺乏生物相容性、生物活性和可注射的载体，其在损伤部位以高生物活性和合适的释放速率局部递送蛋白质。水凝胶，高度水合的交联聚合物网络，已被研究作为有前途的蛋白质载体，可以模拟天然组织中的细胞外基质的性质。水凝胶内生物活性分子的包封将允许靶向和持续递送到缺损或损伤部位，为组织愈合提供足够的时间并刺激组织生长和细胞分化。可以开发具有高度受控的生物力学特性和蛋白质释放机制的可注射微凝胶，从而允许在损伤部位进行微创给药。微凝胶可以通过使用微流体方法生产，其允许高通量生产球形和单分散微粒，其中可以高精度控制目标尺寸。拟议的研究项目将专注于开发新的微凝胶平台，用于有效和可控地输送生长因子和间充质干细胞（MSC），以促进组织修复。我们将开发具有可调物理化学性质的生物活性微凝胶，在降解性和粘弹性方面，使用具有免疫调节性质和促进细胞增殖、迁移和分化潜力的不同天然和合成水凝胶制剂，目的是减少GF剂量，这将导致更安全的方法。将对微凝胶的物理化学和机械性能进行表征，并在体外评估其生物活性。最后，最成功的微凝胶制剂将使用根据本申请的相关动物模型（例如，用于软骨的皮下模型和用于伤口愈合的糖尿病小鼠模型）。

Controlled delivery of proteins, such as growth factors, is a highly promising strategy to treat pathological conditions, including bone defects and skin lesions. A major roadblock to effective protein therapeutics is the lack of biocompatible, bioactive, and injectable carriers that deliver proteins locally with high bioactivity and suitable release rates in the site of injury. Hydrogels, highly hydrated cross-linked polymer networks, have been studied as promising protein carriers that can mimic the properties of the extracellular matrix in native tissues. The encapsulation of bioactive molecules within the hydrogels would allow for the targeted and sustained delivery to the site of defect or injury, providing enough time for the tissue to heal and stimulating the tissue growth and cell differentiation. Injectable microgels with highly controlled biomechanical properties and protein release mechanisms can be developed, allowing a minimally invasive administration in the site of injury. Microgels can be produced by using microfluidics approaches, that allow the high-throughput production of spherical and monodisperse microparticles, where the targeted size can be controlled with high precision. The proposed research project will focus on the development of new microgels platforms for the efficient and controlled delivery of growth factors and mesenchymal stem cells (MSCs) to promote tissue repair. We will develop bioactive microgels with tuneable physicochemical properties, in terms of degradability and viscoelastic properties, using different natural- and synthetic- based hydrogel formulations with immunomodulatory properties and potential to promote cell proliferation, migration and differentiation, with the aim of reducing the GF doses, which will result in a safer approach. The physicochemical and mechanical properties of the microgels will be characterised and their bioactivity evaluated in vitro. Finally, the most successful microgel formulation will be tested in vivo using the relevant animal model according to the application (e.g., subcutaneous model for cartilage and diabetic mouse model for wound healing).