Thromboresistant Small Diameter Tissue-Engineered Vascular Grafts

抗血栓小直径组织工程血管移植物

• 批准号: 8713858
• 负责人: Robert David Kirkton
• 金额: $ 21.73万
• 依托单位: HUMACYTE, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2014-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8713858
• 关键词: Acute; Address; Affect; Amputation; Antithrombins; Arteries; Autologous; Binding; Bioreactors; Blood; Blood Circulation; Blood Platelets; Blood Vessels; Blood flow; Bypass; Caliber; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Catheters; Cell Culture Techniques; Cells; Characteristics; Chemistry; Clinical; Clinical Trials; Coagulation Process; Collagen; Compost; Coronary; Coronary Artery Bypass; Development; Devices; Diet; Disease; Distal; Elderly; Endothelial Cells; Endothelium; Engineering; Europe; Exercise; Exposure to; Extracellular Matrix; Factor IXa; Failure; Family suidae; Glycocalyx; Glycoproteins; Glycosaminoglycans; Goals; Harvest; Hemodialysis; Heparin; High temperature of physical object; Human; Human Engineering; Hyaluronic Acid; Hyperplasia; Implant; In Vitro; Ischemia; Laboratories; Legal patent; Life; Limb structure; Marketing; Masks; Mechanics; Medical; Medicare; Methods; Modeling; Nature; Operative Surgical Procedures; Outcome; Pacemakers; Pathway interactions; Patients; Peripheral; Peripheral Vascular Diseases; Peripheral arterial disease; Phase; Phase I Clinical Trials; Platelet Activation; Polytetrafluoroethylene; Prevention; Primates; Procedures; Process; Running; Saline; Small Business Innovation Research Grant; Smooth Muscle Myocytes; Stable Disease; Staging; Surface; Symptoms; System; Techniques; Technology; Testing; Thrombosis; Time; Tissue Banking; Tissue Banks; Tissue Engineering; Tissues; Transplanted tissue; Tubular formation; United States; Vascular Graft; Veins; Venous; Western World; Work; base; beneficiary; claudication; clinically relevant; crosslink; high risk; implantable device; implantation; improved; in vivo; novel; novel strategies; operation; phase 2 study; public health relevance; scaffold; shear stress; stability testing; success; vascular tissue engineering; ventricular assist device

The overall goal of this Phase I SBIR application is to develop a non-cell-based means of inhibiting coagulation and platelet activation on engineered vascular grafts, so that small-diameter arterial grafts may be available "off the shelf." This arterial graft will consist of human engineered tissue that is decellularized and coated with a novel, covalently-bound layer that mimics aspects of the endothelial cell glycocalyx. By providing an anti-thrombotic function through inhibition of the intrinsic clotting pathway and platelets, this coating will address the main problem with current small diameter vascular grafts, which is early, severe clotting. If functional and successful, this engineered, coated arterial graft will provide an option for patients who lack available vein for bypass conduit, and possibly eliminate the need to harvest a patient's own vein tissue for use as a replacement conduit in vascular bypass surgeries. Cardiovascular disease is the most costly and deadly disease in the US and in much of the Western world. Peripheral vascular disease (PAD) affects 12-20% of people over age 65. Symptomatic but stable disease is usually treated with conservative therapies such as dietary changes, exercise and pharmacological therapies. However, 20-30% of PAD patients suffer from debilitating claudication or critical limb ischemia, and in these patients, limb revascularization offers relief of symptoms and prevention of amputation. Catheter- based therapies are being used to restore arterial patency in PAD patients, but these techniques often offer only temporary relief, and many patients eventually require surgery. Currently, there are roughly 130 peripheral arterial bypass procedures performed annually for every 100,000 Medicare beneficiaries, corresponding to approximately 61,000 peripheral bypass operations each year in the US. Complicating this situation, almost one-third of patients requiring bypass do not possess suitable autologous vein for use in their bypass procedure due to prior vein harvest, venous disease, or the desire to preserve vein for anticipated coronary or other bypass procedures. Synthetic grafts composted of PTFE have been used in place of native vein, but the patency of PTFE grafts in the peripheral circulation is only 50-60% at 3 years. Heparin-coating of PTFE grafts in order to attempt to reduce failure through thrombosis, as in the Gore Propaten(R) graft, has not resulted in substantial improvement, and these heparin coated PTFE grafts still display lower patency rates than autologous vein. Hence, there is a significant medical need for a small-diameter, "off the shelf" arterial graft that eliminates the need for vein harvest yet functions better than PTFE, and ideally as well as native vein, in the peripheral circulation without clotting. Such a product could substantially improve outcomes for patients with severe PAD. Humacyte has developed methods to grow engineered vascular tissues from banked human smooth muscle cells that are seeded onto a biodegradable scaffold and cultured in bioreactors. No cells are harvested from the recipient for this process. These tissues are then decellularized, creating an acellular tubular tissue that has excellent mechanical characteristics. We have tested these tubular engineered tissues as arteriovenous grafts in a primate model, and they have shown excellent function. Clinical trials of the Humacyte graft as an arteriovenous conduit for hemodialysis access are currently underway in the United States and Europe. In this Phase I SBIR application, this novel graft will be further enhanced with a creative new, covalently-bound luminal coating that mimics aspects of the endothelial glycocalyx, thereby increasing the graft's thromboresistance and allowing the graft to remain patent even when used in small-diameter settings, such as bypass procedures for PAD. In this application, we will test the ability of the coating to withstand the shear stress present in the peripheral circulation and test the stability and functionality of this coating after a period of storage in saline in order to ascertain whether the coating has an acceptable shelf-life. Finally, we will determine the in vivo efficacy of coated grafts in a short-term (2-week) porcine carotid artery bypass model. If this coating strategy is successful, then the chemistry developed herein could not only create the first graft to function well in small-diameter PAD bypass, but it could pave the way for using the Humacyte HAVG in coronary artery bypass. In addition, the chemistry could be suitably modified to covalently coat other blood-contacting devices, thereby decreasing thrombogenicity and improving outcomes for a variety of cardiovascular implants and devices. Thus, this novel approach could have a significant impact on the field of vascular surgery.

I 期 SBIR 应用的总体目标是开发一种非基于细胞的抑制方法 工程血管移植物上的凝血和血小板活化，因此小直径动脉移植物可以 可用“现成的”。这种动脉移植物将由脱细胞的人体工程组织组成 涂有一层模仿内皮细胞糖萼各方面的新型共价结合层。通过提供 通过抑制内在凝血途径和血小板而具有抗血栓形成功能，该涂层将 解决当前小直径血管移植物的主要问题，即早期、严重的凝血。如果 这种经过工程设计的涂层动脉移植物功能强大且成功，将为缺乏动脉粥样硬化的患者提供一种选择。 可用静脉用于旁路导管，并可能消除采集患者自身静脉组织以供使用的需要 作为血管搭桥手术中的替代导管。 心血管疾病是美国和大部分西方国家最昂贵、最致命的疾病 世界。周围血管疾病 (PAD) 影响 12-20% 的 65 岁以上人群。有症状但稳定 疾病通常采用保守疗法治疗，例如改变饮食、运动和药物治疗 疗法。然而，20-30% 的 PAD 患者患有衰弱性跛行或严重肢体缺血，并且 对于这些患者，肢体血运重建可以缓解症状并预防截肢。导管- 基础疗法用于恢复 PAD 患者的动脉通畅，但这些技术通常无法提供 只能暂时缓解，许多患者最终需要手术。目前，大约有130个外围设备 每年每 100,000 名医疗保险受益人进行动脉搭桥手术，相当于 美国每年大约进行 61,000 次外围旁路手术。使情况变得复杂化，几乎 三分之一需要搭桥的患者没有合适的自体静脉用于搭桥 由于先前采集静脉、静脉疾病或希望保留静脉以用于预期的冠状动脉或 其他旁路程序。由聚四氟乙烯制成的合成移植物已被用来代替天然静脉，但 PTFE 移植物在外周循环中的通畅率在 3 年时仅为 50-60%。 PTFE 移植物的肝素涂层 为了尝试减少血栓形成导致的失败，如 Gore Propaten(R) 移植物，并未导致 显着改善，并且这些肝素涂层 PTFE 移植物的通畅率仍然低于 自体静脉。因此，对于小直径、“现成的”动脉移植物存在巨大的医疗需求 消除了采集静脉的需要，但其功能比 PTFE 更好，并且理想情况下与天然静脉一样， 末梢循环无凝血。这样的产品可以大大改善患者的治疗结果 患有严重的 PAD。 Humacyte 开发了从储存的人类平滑肌细胞中培养工程血管组织的方法 将肌肉细胞接种到可生物降解的支架上并在生物反应器中培养。没有收获细胞 来自此过程的接收者。然后这些组织被脱细胞，形成脱细胞管状组织 具有优良的机械特性。我们已经测试了这些管状工程组织 灵长类动物模型中的动静脉移植物，并显示出优异的功能。临床试验 Humacyte 移植物作为血液透析通路的动静脉导管目前正在美国进行 国家和欧洲。在第一阶段 SBIR 应用中，这种新颖的移植物将通过创造性的技术得到进一步增强 新的共价结合的管腔涂层模仿内皮糖萼的各个方面，从而增加 移植物的抗血栓性，使移植物即使在小直径中使用时也能保持通畅 设置，例如 PAD 的旁路程序。在此应用中，我们将测试涂层的能力 承受周围循环中存在的剪切应力并测试其稳定性和功能 在盐水中储存一段时间后对涂层进行测试，以确定涂层是否具有可接受的保质期。 最后，我们将确定涂层移植物在短期（2 周）猪颈动脉中的体内功效 旁路模型。如果这种涂层策略成功，那么本文开发的化学不仅可以创造 第一个在小直径 PAD 旁路中表现良好的移植物，但它可以为使用 Humacyte 铺平道路 HAVG 冠状动脉搭桥术。此外，可以适当修改化学性质以共价包覆其他物质 血液接触装置，从而减少血栓形成并改善各种疾病的结果 心血管植入物和设备。因此，这种新颖的方法可能会对领域产生重大影响 血管手术。