Bioactive polysaccharide-based hydrogels for growth factors delivery during tissue repair.

由于人口老龄化，癌症发展过程中的病理条件，包括骨不愈合缺陷、皮肤病变、神经系统疾病和炎症过程正在增加。这些问题使人衰弱，代价高昂，目前的办法在减轻痛苦方面收效有限。生物分子的受控递送，如生长因子（GFs）——一种协调我们发育的蛋白质，具有刺激细胞生长和分化的能力，从而可以推动再生——可以提供有效的组织工程策略来促进组织发育和修复。然而，这些蛋白质的可溶性给药通常意味着它们以高剂量给药，这会产生不希望的，潜在的严重/致命的全身效应，限制了它们的临床应用。在这个提议中，我们将开发一种新的水凝胶，基于芦荟内叶的主要生物活性成分——葡甘露聚糖多糖，它将作为生物活性载体，用于组织工程应用中高效和局部递送gf。作为一种水凝胶，这种天然载体将增加GFs在愈合部位的保留时间，使细胞能够迁移、增殖和分化。此外，载体固有的生物活性（例如抗炎特性、防腐功能和促进血管化、刺激成骨分化的潜力），与释放的GF一起，将提供协同效应，从而允许超低剂量的GF递送，比目前临床技术中使用的低几个数量级。因此，这一战略将通过增加再生潜力，同时减少与使用高剂量GF相关的危及生命的问题和高成本，显著改善社会健康。同时，通过微创手术将产生易于注入体内的微载体。为此，一种新型的微流体技术将被用作一种有效的工具，以比传统技术更高的通量产生微载体，这将使我们能够轻松地扩展技术以满足临床实践中的高需求水平。虽然该提案将重点关注骨再生过程中的GF递送，但这种新的生物活性载体将为GF递送提供一个多功能平台，具有广泛应用于不同生物医学应用的潜力。

Pathological conditions, including non-union bone defects, skin lesions, neurological disorders and inflammatory processes during cancer development are growing in occurrence due to an aging population. These problems are debilitating, costly and current approaches have limited success in alleviating suffering. The controlled delivery of biological molecules, such as growth factors (GFs) - proteins that orchestrate our development and hold the capacity to stimulate cellular growth and differentiation and that could thus drive regeneration - could provide potent tissue engineering strategies to promote tissue development and repair. However, the soluble administration of these proteins usually implies their delivery at high doses, which produces undesired, potentially serious/fatal systemic effects limiting their clinical use. In this proposal we will develop a new hydrogel, based on the acemannan polysaccharide - main bioactive component from the inner leaves of Aloe Vera - that will act as a bioactive carrier for the efficient and local delivery of GFs for tissue engineering applications. As a hydrogel, this natural carrier will increase the retention of the GFs within the healing site for a sufficient period to allow cells to migrate, proliferate and differentiate. Moreover, the inherent biological activity of the carrier (e.g. anti-inflammatory properties, antiseptic functions and potential to promote vascularisation, stimulate osteogenic differentiation), together with the released GFs, will provide a synergistic effect that will allow ultra-low dose GF delivery, several orders of magnitude lower than the ones used in current clinical technologies. Thus, this strategy will significantly improve societal health by increasing regenerative potential while reducing the life-threatening issues and high cost associated with the use of high GF doses. Also, microcarriers will be generated for their easy injection into the body through minimally invasive surgery. To do so, a novel microfluidics technology will be used as an efficient tool to generate microcarriers at higher throughput than conventional technologies, which will allow us to easily scale the technology to meet high demand levels in clinical practice. Although this proposal will focus on GF delivery during processes of bone regeneration, this new bioactive carrier will provide a versatile platform of GFs delivery with the potential to be widely used for different biomedical applications.