Aliphatic polycarbonates: building blocks for new biodegradable biomaterials

脂肪族聚碳酸酯：新型可生物降解生物材料的基础材料

• 批准号: RGPIN-2020-05598
• 负责人: Amsden, Brian
• 金额: $ 4.66万
• 依托单位: Queen's University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=740674
• 关键词: Aliphatic; polycarbonates; building; blocks; new

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.

该提案涉及开发用于承载、软组织再生以及持续可控药物输送的先进创新聚合物。大多数为这些目的而设计的疏水性可生物降解聚合物是使用脂肪族聚酯制备的，例如聚(丙交酯-共-乙交酯)。虽然这些聚合物在体内可通过水解降解，但形成的酸性产物会在局部组织中引起不良炎症，导致局部细胞死亡，并可以降解掺入的酸敏感药物。相比之下，脂肪族聚碳酸酯具有抗水解性，但可以通过宿主细胞分泌的酶的作用以分子量依赖性方式进行生物降解。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，其降解率易于调节，用于肽/蛋白质输送；2）热稳定但可光交联的共聚物，用于增材制造坚固且抗蠕变的支架肌腱组织工程。在该研究计划的药物输送重点中，将采用两种不同的方法。首先，将开发用于长期持续释放的肽负载微球和注射液体制剂。我们针对这些目标的新聚合物策略旨在克服先前研究的配方方法中存在的肽稳定性和产品制造方面的复杂性。第二，我们将开发一种可植入聚合物装置，用于将药物输送到眼睛以治疗视神经病变。此类设备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的，如果出现并发症，移除植入装置就会出现问题。我们解决这些问题的方法是利用光可裂解键形成能够光活化降解的聚合物。由于眼睛是光学可及的，这种方法将提供一种在药物释放完成后或因并发症需要移除植入物时快速移除植入物的方法。在该计划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（称为熔融电写入）的新型共聚物，以制备具有模仿跟腱机械行为的明确架构的支架。这些新型共聚物具有热稳定性，可进行有效的熔融加工，同时可进行光交联。我们的光交联设计将为支架提供抗蠕变性和增加的刚度，同时保持细胞兼容性。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。