Aliphatic polycarbonates: building blocks for new biodegradable biomaterials

该提案涉及用于承载，软组织再生和持续可控药物输送的先进和创新聚合物的开发。大多数为这些目的而设计的疏水可生物降解聚合物都是用脂肪族聚酯如聚丙交酯-羟基乙酸酯制备的。虽然这些聚合物在体内可以通过水解降解，但形成的酸性产物会在局部组织中引起不希望的炎症，导致局部细胞死亡，并且可以降解合并的酸敏感药物。相比之下，脂肪族聚碳酸酯耐水解，但通过宿主细胞分泌的酶的作用，以分子量依赖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。提出的研究计划将建立在我们之前在两个领域的工作基础上：1)脂肪族聚碳酸酯，易于调节肽/蛋白质递送的降解率；2)热稳定但光交联的共聚物，用于肌腱组织工程中坚固和抗蠕变支架的增材制造。在研究项目的药物输送重点中，将采用两种不同的方法。首先，多肽负载微球和可注射液体制剂将被开发为长期缓释。我们针对这些目标的新聚合物策略旨在克服先前检查的配方方法中存在的肽稳定性和产品制造方面的并发症。其次，我们将开发一种植入式聚合物装置，用于将药物输送到眼睛以治疗视神经病变。这种装置最近已被批准用于人类；然而，药物释放和设备降解是不可控的，如果出现并发症，植入设备的移除是有问题的。我们解决这些问题的方法将是利用光可切割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，一旦药物完全释放或由于并发症需要移除，这种方法将提供一种快速消除植入物的方法。在该项目的肌腱组织工程重点中，我们将设计和评估用于增材制造技术的新型共聚物，即熔体电书写，以制备具有模拟跟腱机械行为的定义结构的支架。这些新的共聚物将是热稳定的，允许有效的熔融加工，但光交联。我们的光交联设计将提供抗蠕变和增加支架的刚度，同时保持细胞相容性。这项研究计划支持的学员将获得必要的技能和发展创新，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.