Aliphatic polycarbonates: building blocks for new biodegradable biomaterials

这项提议涉及到先进和创新的聚合物的开发，用于承载、软组织再生和持续和可控的药物输送。为此目的设计的大多数疏水性生物可降解聚合物是使用脂肪族聚酯(如聚(丙交酯-乙交酯)S)制备的。虽然这些聚合物可通过水解在体内降解，但形成的酸性产物会在局部组织中引发不必要的炎症，导致局部细胞死亡，并可降解所含的酸敏感药物。相比之下，脂肪族聚碳酸酯是耐水解的，但通过宿主细胞分泌的酶的作用，以一种依赖于分子量的方式进行生物降解。重要的是，它们的降解不会产生酸性产物，因此它们具有低细胞毒性。拟议的研究计划将建立在我们之前在两个领域的工作的基础上：1)脂肪族聚碳酸酯，具有易于调节的多肽/蛋白质递送降解速率；2)热稳定但可光交联的共聚物，用于添加制造用于肌腱组织工程的坚固和抗蠕变的支架。在研究计划的药物输送重点方面，将采取两种不同的方法。首先，将开发用于长期缓释的多肽微球和可注射液体制剂。我们为实现这些目标而设计的新聚合物策略旨在克服先前检查的配方方法中存在的与多肽稳定性和产品制造相关的复杂问题。在第二个项目中，我们将开发一种植入式聚合物设备，用于将药物输送到眼睛以治疗视神经疾病。这类装置最近已被批准用于人类；然而，药物释放和装置降解是不可控制的，如果出现并发症，移除植入的装置是有问题的。我们解决这些问题的方法将是利用可光裂解的键来形成能够光激活降解的聚合物。由于眼睛是光学可及的，这种方法将提供一种方法，一旦药物释放完成或由于并发症需要取出植入物，就可以快速取出植入物。在该计划的肌腱组织工程重点中，我们将设计和评估新的共聚物，用于一种被称为熔融电写的添加剂制造技术，以制备具有特定结构的支架，该支架模仿跟腱的机械行为。这些新的共聚物将是热稳定的，以允许有效的熔融加工，但光交联性。我们的光交联型设计将在保持细胞兼容性的同时，为支架提供抗蠕变和增加硬度。由该研究计划支持的学员将获得必要的技能并开发创新，为加拿大新兴的生物医学工程行业做出贡献。

This proposal concerns the development of advanced and innovative polymers for load-bearing, soft tissue regeneration and sustained and controllable drug delivery. The majority of hydrophobic biodegradable polymers designed for these purposes are prepared using aliphatic polyesters such as poly(lactide-co-glycolide)s. While these polymers are degradable in vivo via hydrolysis, the acidic products formed elicit undesirable inflammation in the local tissue, cause local cell death, and can degrade incorporated acid-sensitive drugs. Aliphatic polycarbonates, by contrast, are hydrolysis resistant yet biodegrade in a molecular weight-dependent manner through the action of enzymes secreted by host cells. Importantly, their degradation does not result in acidic products and as a result they feature low cytotoxicity. The research program proposed will build on our previous work in two areas: 1) aliphatic polycarbonates with readily adjustable degradation rates for peptide/protein delivery and 2) thermally stable but photo-cross-linkable copolymers for additive manufacturing of strong and creep resistant scaffolds for tendon tissue engineering. In the drug delivery focus of the research program, two different approaches will be pursued. In the first, peptide loaded microspheres and injectable liquid formulations will be developed for long-term sustained release. Our new polymer strategy for these objectives has been designed to overcome complications with respect to peptide stability and product manufacture present in previously examined formulation approaches. In the second, we will develop an implantable polymer device for drug delivery to the eye to treat optic neuropathy. Such devices have recently been approved for use in humans; however, drug release and device degradation are not controllable and if complications arise, removal of the implanted device is problematic. Our approach to solving these issues will be to utilize photo-cleavable linkages to form a polymer capable of photo-activated degradation. As the eye is optically accessible, this approach will provide a means of rapidly eliminating the implant once drug release is complete or should removal be required due to complications. In the tendon tissue engineering focus of the program, we will design and assess new copolymers to be used in an additive manufacturing technique referred to as melt electrowriting to prepare scaffolds with defined architectures that mimic the mechanical behavior of the Achilles tendon. These new copolymers will be thermally stable to allow for effective melt processing yet photo-cross-linkable. Our photo-crosslinking design will provide creep resistance and increased stiffness to the scaffold while maintaining cell compatibility. The trainees supported by this research program will gain the necessary skills and develop innovations to contribute to the emerging biomedical engineering industry in Canada.