Drug-Eluting Bioresorbable Polymer Scaffolding for Treatment of Aortic Aneurysms

用于治疗主动脉瘤的药物洗脱生物可吸收聚合物支架

• 批准号: 7745928
• 负责人: Jack Cabell Griffis
• 金额: $ 15.91万
• 依托单位: MEDSHAPE SOLUTIONS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-17 至 2010-02-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7745928
• 关键词: Abdomen; Abdominal Aortic Aneurysm; Accounting; Address; Affect; Age; Amines; Anatomy; Aneurysm; Animal Model; Aorta; Aortic Aneurysm; Aortic Segment; Apoptosis; Biodegradation; Biological; Biomechanics; Blood Vessels; Blood flow; Bypass; Cardiovascular system; Cause of Death; Cessation of life; Characteristics; Chemistry; Clinical; Collagen Diseases; Complex; Data; Databases; Deposition; Development; Device or Instrument Development; Devices; Diagnosis; Disease; Disease Progression; Doctor of Philosophy; Drug Delivery Systems; Elderly; Ensure; Environment; Esters; Excision; Extracellular Matrix Degradation; Freedom; Functional disorder; Future; Genes; Grant; Health; In Situ; In Vitro; Inflammation; Injectable; Institutes; Lead; Length; Link; Location; Marketing; Matrix Metalloproteinases; Mechanics; Mediating; Medical Device; Methods; Mus; Operative Surgical Procedures; Organ Culture Techniques; Pathogenesis; Patients; Performance; Pharmaceutical Preparations; Phase; Physiological; Play; Polymer Chemistry; Polymers; Postoperative Period; Preparation; Procedures; Process; Production; Property; Qualifying; Radial; Reporting; Research; Research Personnel; Role; Rupture; Ruptured Aortic Aneurysms; Safety; Sampling; Second Look Surgery; Seeds; Series; Simulate; Site; Smooth Muscle; Smooth Muscle Myocytes; Solutions; Speed; Stents; Structure; Surgeon; System; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Thrombus; Time; Tissue Engineering; Tissues; Treatment Protocols; Tunica Adventitia; United States; Universities; Vascular Diseases; Weight-Bearing state; Work; abdominal aorta; base; biodegradable polymer; biomaterial compatibility; commercialization; cost; design; iliac artery; implantation; in vitro Model; in vivo; interest; medical specialties; meetings; minimally invasive; monomer; polymerization; pressure; prevent; product development; professor; programs; prototype; public health relevance; renal artery; repaired; scaffold; treatment site

DESCRIPTION (provided by applicant): This proposal is focused on the development of a bioabsorbable polymeric scaffold intended to provide both time-release delivery of therapeutic agents as well as structural support in the treatment of aortic aneurysms. An abdominal aortic aneurysm (AAA) is a condition in which the aorta, the main blood vessel in the abdomen, expands like a balloon. The aneurysm weakens the wall of the aorta and can result in rupture. Because the volume of blood flowing through the aorta is under relatively high pressure, a rupture can be catastrophic, resulting in death. Up to 75% of patients are asymptomatic prior rupture. In the United States, approximately one in every 250 people over the age of 50 will die of a ruptured aortic aneurysm. Aortic aneurysms affect as many as eight percent of people over the age of 65 and remains the 13th leading cause of death in the United States, accounting for more than 15,000 deaths each year. Current treatment options for AAA are limited to the surgical removal of the aneurysm and replacement with artificial grafts or intravascular placement of a stent-graft intended to provide a bypass for blood flow through the aneurysmal space. However, both approaches have limitations. Surgical revision rates have been reported as high as 26% and post-operative complications rates as high as 41%. While the use of stent-grafts has been increasing in recent years due to their minimally invasive approach, this procedure is not applicable to all patients. The occurrence of unfavorable anatomy limits the utility of these devices. In 2007, over 60,000 procedures of either surgical revision or endovascular stent-graft placement were performed in the US alone. This does not take into account the nearly 26% revision rates reported for endovascular stent-grafts, nor does it account for the nearly 50% of patients ineligible for endovascular stent-grafts due to unfavorable anatomy. Recent research performed by the collaborators of this proposal from Emory University has shown that in the setting of AAA formation, the smooth muscle component of the arterial wall undergoes apoptosis and ceases to be mechanically relevant. The adventitia becomes thickened and assumes the role as the major load bearing component of the vessel wall. Overall, these results have lead us to suggest that since the adventitia is the vulnerable component of the arterial wall in advanced AAA, that an "outside-in" therapy to mechanically and biologically stabilize the vessel wall may represent a more efficacious approach to aneurysm repair than those currently offered. MedShape Solutions has been working on a series of bioabsorbable polymers capable of carrying various therapeutic agents. The proposed bioabsorbable polymeric scaffold will be developed to provide for the delivery of an agent to treat the aneurysmal tissue as well as provide structural support for the diseased portion of the aorta to prevent further expansion and/or rupture. Neither of the current treatment options discussed above are capable of treating the underlying cause of the disease state, and while the surgical graft removes the diseased aortic segment, neither it nor the endovascular stent-graft are capable of preventing the progression of the disease. In addition, the polymer chemistries proposed are capable of in-situ polymerization which would allow the placement of the scaffold around aortic segments that would normally be classified as having unfavorable anatomy and that might go untreated otherwise. Finally, the delivery system to be developed will be compatible with laparoscopic techniques which would make it significantly less invasive than surgical repair. The aims of the Phase I proposal have been designed to fundamentally investigate the polymeric scaffolding chemistry as it relates to mechanical characteristics as well as biodegradation and drug elution capability. In addition, a prototype delivery system for the drug/device combination will be developed and evaluated ex-vivo to determine ease of use and to trouble shoot some the expected challenges associated with mixing the polymer in a partially polymerized state (oligomer), combined with a therapeutic agent in solution, and polymerized in-situ while being placed over and around the diseased aortic segment. The primary research team will consist of Jack Griffis (PI), who is an expert in cardiovascular device development and testing; Ken Gall PhD, a full professor from Georgia Tech who specializes in specialty polymers; and W. Robert Taylor, MD, a cardiologist from Emory University that specializes in vascular diseases, especially AAA. PUBLIC HEALTH RELEVANCE: Abdominal aortic aneurysms (AAA) affect as many as eight percent of people over the age of 65 and remains the 13th leading cause of death in the United States, accounting for more than 15,000 deaths each year. In addition, for those who receive treatment, surgical revision rates are as high as 26% and up to 50% of those diagnosed are not eligible for the latest, minimally invasive techniques. This project will provide an approach that is both compatible with minimally invasive techniques as well as provide a means to reduce post-operative complications while delivering therapeutic agents directly into the aneurysmal tissue.

描述（由申请人提供）：该提案的重点是开发生物吸附的聚合物支架，旨在同时提供治疗剂的时间释放递送以及在主动脉瘤治疗方面的结构支持。腹主动脉瘤（AAA）是一种疾病，主动脉（腹部的主要血管）像气球一样膨胀。动脉瘤会削弱主动脉的壁，并可能导致破裂。由于流经主动脉的血液量相对较高，因此破裂可能是灾难性的，导致死亡。多达75％的患者是无症状的事先破裂。在美国，大约50岁以上每250人中约有1人死于主动脉瘤破裂。主动脉瘤影响65岁以上的人中有多达8％的人，仍然是美国第13个主要死亡原因，每年占15,000多人死亡。 AAA的当前治疗选择仅限于手术去除动脉瘤，并用人工移植物替换或血管内放置支架移植物，旨在提供通过动脉瘤空间的血液流动的旁路。但是，两种方法都有局限性。据报道，手术修订率高达26％，术后并发症率高达41％。尽管由于其微创方法的最低侵入性，近年来的支架移植物的使用一直在增加，但此手术并不适用于所有患者。不利解剖结构的发生限制了这些设备的效用。 2007年，仅在美国就进行了超过60,000种手术修订或血管内支架移植的手术程序。这没有考虑到血管内支架移植物报告的近26％的修订率，也不考虑由于不利的解剖结构而使近50％的患者不符合血管内支架接枝的含量。埃默里大学（Emory University）该提案的合作者进行的最新研究表明，在AAA组的环境中，动脉壁的平滑肌成分经历了凋亡，并停止了机械上的相关性。外膜变稠，并将其作为容器壁的主要负荷轴承成分。总体而言，这些结果使我们暗示，由于Addeditia是高级AAA中动脉壁的脆弱组成部分，因此，一种“外部”疗法对机械和生物学稳定容器壁可能比目前提供的动脉瘤修复更有效。 MEDSHAPE溶液一直在研究一系列能够携带各种治疗剂的可生物吸附聚合物。提出的可生物吸收的聚合物支架将开发出来，以提供用于治疗动脉瘤组织的药物，并为主动脉患病部分提供结构支持，以防止进一步膨胀和/或破裂。上面讨论的当前治疗方案都不能治疗疾病状态的根本原因，尽管手术移植物可以去除患病的主动脉瘤，但它均不能够预防疾病的进展。此外，提出的聚合物化学成分能够在原位聚合中，这将允许在主动脉片段周围放置脚手架，这些脚架通常被归类为不利的解剖结构，否则可能会未经治疗。最后，要开发的输送系统将与腹腔镜技术兼容，这将使其侵入性明显低于手术修复。 I阶段提案的目的旨在从根本上研究与机械特征以及生物降解和药物洗脱能力有关的聚合物脚手架化学。此外，将开发和评估用于药物/设备组合的原型输送系统，以确定易用性，并在部分聚合状态（低聚物）中与混合聚合物相关的一些预期挑战，并与溶液中的治疗剂相结合，并在溶液中且在溶液中和隔离中均置于隔离状态和围绕无效的良好的一部分和周围的良好的nortical andIrtical andIrtical andIrtical andIrtical andIrtical andirict severict。主要研究团队将由杰克·格里菲斯（Jack Griffis）（PI）组成，他是心血管装置开发和测试的专家；佐治亚理工大学的完整教授肯·加尔（Ken Gall Phd）专门研究特种聚合物；以及埃默里大学（Emory University）的心脏病专家W. Robert Taylor，专门研究血管疾病，尤其是AAA。 公共卫生相关性：腹部主动脉瘤（AAA）影响到65岁以上的人中有多达8％的人，仍然是美国第13个主要死亡原因，每年占15,000多人的死亡。此外，对于那些接受治疗的人，手术修订率高达26％，多达50％的被诊断患者没有资格获得最新的最低侵入性技术。该项目将提供一种与微创技术兼容的方法，也提供了一种减少术后并发症的手段，同时将治疗剂直接输送到动脉瘤组织中。

项目成果

Semi-degradable poly(β-amino ester) networks with temporally controlled enhancement of mechanical properties.

• DOI: 10.1016/j.actbio.2014.04.022
• 发表时间: 2014-08
• 期刊: ACTA BIOMATERIALIA
• 影响因子: 9.7
• 作者: Safranski, David L.;Weiss, Daiana;Clark, J. Brian;Taylor, W. Robert;Gall, Ken
• 通讯作者: Gall, Ken