Development of tuneable microgels for controlled protein delivery in tissue regeneration

蛋白质的控制输送，如生长因子，是治疗包括骨缺损和皮肤损伤在内的病理疾病的一种非常有前途的策略。有效的蛋白质疗法的一个主要障碍是缺乏生物相容的、生物活性的和可注射的载体，这些载体能够在局部输送具有高生物活性的蛋白质，并且在损伤部位具有适当的释放率。水凝胶是一种高度水化的交联型聚合物网络，是一种很有前途的蛋白质载体，可以模拟天然组织中细胞外基质的性质。将生物活性分子包裹在水凝胶中将允许靶向和持续地输送到缺损处，为组织愈合提供足够的时间，并刺激组织生长和细胞分化。具有高度可控的生物力学性能和蛋白质释放机制的可注射微凝胶可以被开发出来，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来生产，这种方法允许高通量地生产球形和单分散的微粒子，其中目标尺寸可以高精度地控制。拟议的研究项目将侧重于开发新的微凝胶平台，用于高效和受控地输送生长因子和间充质干细胞(MSCs)，以促进组织修复。我们将使用不同的天然和合成水凝胶配方开发具有生物活性的微凝胶，这些微凝胶具有可降解性和粘弹性，具有可调节的物理化学特性，具有免疫调节特性和促进细胞增殖、迁移和分化的潜力，目的是减少GF的剂量，这将导致一种更安全的方法。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，最成功的微凝胶配方将根据应用使用相关的动物模型在体内进行测试(例如，软骨的皮下模型和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).