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.

该阶段I SBIR应用的总体目标是开发一种抑制基于非细胞的方法 工程的血管移植物上的凝血和血小板激活，因此可能是小直径的动脉移植物 可用“架子”。该动脉移植将由脱细胞和的人类工程组织组成 涂有一个新型的共价结合层，该层模仿内皮细胞糖蛋白的各个方面。通过提供 通过抑制固有的凝血途径和血小板的抗栓性功能，这种涂层将 解决当前小直径的血管移植物的主要问题，该血管移植物是早期的严重凝结。如果 功能和成功，这种设计的，涂覆的动脉移植将为缺乏的患者提供一个选择 可用于旁路导管的可用静脉，并可能消除了收集患者自身静脉组织的需求 作为血管旁路手术中的替代导管。 心血管疾病是美国和西部大部分的最昂贵和致命的疾病 世界。周围血管疾病（PAD）影响65岁以上的12-20％。有症状但稳定 疾病通常接受保守疗法（例如饮食变化，运动和药理）治疗 疗法。但是，有20％至30％的PAD患者患有lau不平或严重的肢体缺血，并且 在这些患者中，肢体血运重建可缓解症状和预防截肢。导管- 基于基于的疗法用于恢复PAD患者的动脉通畅，但这些技术经常提供 只有暂时的缓解，许多患者最终需要手术。目前，大约有130个外围 每年每100,000名Medicare受益人每年执行的动脉旁路程序，对应于 在美国，每年约有61,000个外围旁路操作。使这种情况复杂化，几乎 需要旁路的患者中有三分之一没有合适的自体静脉用于旁路 由于先前的静脉收获，静脉疾病或为预期冠状动脉保存静脉的愿望而引起的程序 其他旁路程序。 PTFE堆肥的合成移植物已代替天然静脉，但是 3年时，外周流通中PTFE移植物的通畅仅为50-60％。 PTFE移植物的肝素涂层 为了试图通过血栓形成减少衰竭，如Gore propaten（R）移植物中，并未导致 大量改进，这些肝素涂层的PTFE移植物仍然显示出比 自体静脉。因此，对小直径的“架子上”动脉移植物有很大的医疗需求 这消除了对静脉收获的需求，但比PTFE更好地发挥作用 周围循环无凝结。这样的产品可以大大改善患者的预后 带有严重的垫子。 Humacyte开发了从人类平滑的人类生长工程的血管组织的方法 种子的肌肉细胞在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 来自此过程的收件人。然后将这些组织脱细胞，形成一个细胞的管状组织 具有出色的机械特性。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脉移植物，它们的功能很好。临床试验 Humacyte移植物是目前正在曼联进行血液透析通道的动静脉导管 国家和欧洲。在此I阶段I SBIR应用程序中，这种小说的嫁接将通过创意进一步增强 新的，共价结合的腔内涂层模仿了内皮糖脂的各个方面，从而增加 移植物的血栓抗性，并允许移植物保持专利，即使在小直径中 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 承受外周循环中存在的剪切应力，并测试此的稳定性和功能 一段时间的盐水储存后涂层，以确定涂层是否具有可接受的保质期。 最后，我们将在短期（2周）颈动脉中确定涂层移植物的体内功效 旁路模型。如果这种涂料策略成功，那么本文开发的化学反应不仅可以创造 第一个在小直径垫旁路中运作良好的移植物，但它可以为使用Humacyte铺平道路 冠状动脉旁路中的HAVG。此外，可以对化学反应进行适当的修改以共价覆盖其他 血液接触装置，从而降低血栓形成并改善各种结果 心血管植入物和设备。因此，这种新颖的方法可能会对现场产生重大影响 血管手术。