Vascular tissue engineering: rational design using modeling

血管组织工程：利用建模进行合理设计

• 批准号: 8292082
• 负责人: Monica T Hinds
• 金额: $ 59.29万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-05 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8292082
• 关键词: Affect; Animal Model; Autologous; Beds; Biochemical; Biological; Biological Assay; Blood; Blood Platelets; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular system; Cell Proliferation; Cell surface; Cells; Coagulation Process; Collagen; Communities; Development; Device Designs; Drug Industry; Elastin; Endothelial Cells; Epoprostenol; Fibrin; Fibrinolysis; Gene Proteins; Goals; Harvest; Healed; Hemostatic Agents; Hemostatic function; Histologic; Human; Hyperplasia; Image; Implant; In Vitro; Inflammatory; Inflammatory Response; Measurable; Measurement; Measures; Mechanics; Mediating; Medical Device; Modeling; Molecular; Operative Surgical Procedures; Outcome; Papio; Pathway interactions; Performance; Physiological; Plasminogen Activator Inhibitor 1; Pre-Clinical Model; Primates; Property; Prosthesis; Protein C; Proteins; Radioisotopes; Reaction; Reporting; Research; Shunt Device; Simulate; Smooth Muscle Myocytes; Stem cells; Surface; TFPI; Technology; Testing; Thrombomodulin; Thromboplastin; Thrombosis; Thrombus; Time; Tissue Engineering; Vascular Graft; Whole Blood; base; cell type; clinical application; clinically relevant; design; design and construction; experience; healing; hemodynamics; improved; in vitro Assay; in vitro activity; in vivo; man; monolayer; novel therapeutics; pre-clinical; preconditioning; public health relevance; receptor; response; success; vascular tissue engineering

DESCRIPTION (provided by applicant): Tissue engineering holds promise for the treatment of cardiovascular disease. For tissue-engineered cardiovascular constructs it is widely believed that a nonthrombogenic endothelial cell (EC) surface will be advantageous. Many studies have therefore attempted to characterize the reactivity of EC with blood, i.e., EC "thrombogenicity". Unfortunately, most in vitro studies with EC have employed anticoagulated blood, static or nonphysiologic blood flow conditions, and relatively short blood exposure times. Consequently, the relevance of these results for in vivo applications remains uncertain. Similarly, in the development of tissue-engineered constructs there have been few studies of EC reactivity in vivo, and no systematic studies have been reported that correlate the properties of ECs that are measurable in vitro with in vivo responses. Nonetheless, it is now recognized within the tissue engineering community (and medical device and drug industries in general) that a key impediment to further progress is the lack of predictive animal models that will enable the rational design of constructs, i.e., preclinical models that will enable optimization of construct performance in vivo based on the identification and selective manipulation of key cellular activities in vitro. Our goal is therefore to establish, for blood-contacting EC surfaces, relationships between pro- and anti- hemostatic properties of ECs that can be preconditioned in vitro, and physiologic responses of thrombosis and vascular healing in vivo. To achieve this goal, the hemostatic properties of constructs variably preconditioned in vitro will be correlated with in vivo outcomes, thereby documenting the utility of rational design. The proposed studies will employ baboon endothelial progenitor cells (EPCs) that are readily isolated from whole blood in vitro, and relevant in vivo baboon models of thrombosis and vascular graft intimal hyperplasia. To specifically enhance or inhibit EPC properties that regulate coagulation, platelets, and other hemostatic functions, EPCs will be grown on conventional ePTFE coated with different matrix proteins (collagen or elastin) and subjected to variable hemodynamic preconditioning (static vs. normal shear). Important hemostatic, inflammatory, and mitogenic activities that are orchestrated by EPCs will be assessed using functional, biochemical, molecular, and histologic assays. We will then assess how EPC properties affect: 1) thrombus formation in native, non-anticoagulated blood under physiologic flow conditions (AV shunt model), and 2) healing of EPC-constructs following surgical placement (aorto-iliac graft model). Although the results may suggest new therapeutic strategies, it is not our primary goal to develop an improved vascular graft or to justify the use of EPCs. Rather, by documenting that cellular preconditioning in vitro can predictably improve outcomes in vivo - a principle that can be extended to other cell types and animal models - these results will validate rational design in general, and encourage studies with other constructs and test beds. Ultimately, these technologies will enable the development of biological constructs for use in man. Public Health Relevance Statement (provided by applicant): Tissue-engineered substitutes are being developed for the treatment of cardiovascular disease. A key advancement that must now be realized is to establish in preclinical animal models that predictive relationships exist between important properties of constructs - properties that can be identified, measured, and optimized in vitro - and in vivo physiological responses including thrombosis and vascular healing. The present studies, to be performed using clinically relevant primate models, will establish such correlations for blood-contacting vascular conduits, thereby validating rational design for these devices and encouraging the development of other predictive test beds. These technologies are critical for the development and clinical application of safe and effective biological prostheses.

描述（由申请人提供）： 组织工程有望治疗心血管疾病。对于组织工程的心血管构建体，人们普遍认为非紧密的内皮细胞（EC）表面将是有利的。因此，许多研究试图表征EC对血液的反应性，即EC“血栓形成性”。不幸的是，大多数对EC的体外研究都采用了抗凝血液，静态或非生理血液流动条件以及相对较短的血液暴露时间。因此，这些结果与体内应用的相关性仍然不确定。同样，在组织工程构建体的发展中，很少有对体内EC反应性的研究，并且没有据报道的系统研究将EC的性质与体外反应相关的EC的性质相关。尽管如此，现在在组织工程社区（以及一般医疗设备和药品行业）中得到认可的是，进一步进步的关键障碍是缺乏预测性动物模型，这些模型将使构造的合理设计，即临时性模型，即可以在体内基于识别和选择性的钥匙蜂窝活动的体内构造性能优化构建体性能。 因此，我们的目标是建立可以在体外预处理的EC和抗止血特性之间的促血液接触的EC表面，以及血栓形成和体内血管愈合的生理反应。为了实现这一目标，体外预处理的构建体的止血特性将与体内结局相关，从而记录了合理设计的实用性。 拟议的研究将采用狒狒内皮祖细胞（EPC），这些细胞很容易在体外从全血中分离出来，并且在血栓形成和血管移植内膜内膜增生的体内狒狒模型中相关。为了特异性增强或抑制调节凝血，血小板和其他止血功能的EPC特性，EPC将在涂有不同基质蛋白（胶原蛋白或弹性蛋白）涂层的常规EPTFE上生长，并受到可变的血液动力学预处理（静态与正常剪切）。 EPC策划的重要止血，炎症和有丝分裂活性将使用功能，生化，分子和组织学测定进行评估。然后，我们将评估EPC特性如何影响：1）在生理流动条件下（AVENUNT模型）和2）手术放置后EPC构造的愈合（主动脉 - 易子移植模型）在生理流动条件下（AVENUNT模型）下的原生，非期权的血液形成。尽管结果可能表明了新的治疗策略，但开发改进的血管移植或证明使用EPC的合理性并不是我们的主要目标。相反，通过记录体外细胞预处理可以预测改善体内的预后 - 这一原理可以扩展到其他细胞类型和动物模型 - 这些结果将一般可以验证合理的设计，并鼓励对其他结构和测试床进行研究。最终，这些技术将使生物结构的开发用于人类。 公共卫生相关性声明（由申请人提供）：正在开发组织工程的替代品用于治疗心血管疾病。现在必须实现的一个关键进步是在临床前动物模型中建立预测关系，即在构建体的重要特性之间存在预测关系 - 可以在体外鉴定，测量和优化的特性以及体内生理反应，包括血栓形成和血管愈合。本研究将使用临床相关的灵长类动物模型进行，将建立与血管作用血管导管的相关性，从而验证这些设备的合理设计并鼓励其他预测性测试床的发展。这些技术对于安全有效的生物假体的开发和临床应用至关重要。

项目成果

Mechanical property characterization of electrospun recombinant human tropoelastin for vascular graft biomaterials.

• DOI: 10.1016/j.actbio.2011.08.001
• 发表时间: 2012-01
• 期刊: Acta biomaterialia
• 影响因子: 9.7
• 作者: McKenna KA;Hinds MT;Sarao RC;Wu PC;Maslen CL;Glanville RW;Babcock D;Gregory KW
• 通讯作者: Gregory KW

Non-destructive label-free monitoring of collagen gel remodeling using optical coherence tomography.

• DOI: 10.1016/j.biomaterials.2010.06.042
• 发表时间: 2010-11
• 期刊: Biomaterials
• 影响因子: 14
• 作者: Levitz D;Hinds MT;Ardeshiri A;Hanson SR;Jacques SL
• 通讯作者: Jacques SL

Endothelial cell micropatterning: methods, effects, and applications.

• DOI: 10.1007/s10439-011-0352-z
• 发表时间: 2011-09
• 期刊: ANNALS OF BIOMEDICAL ENGINEERING
• 影响因子: 3.8
• 作者: Anderson, Deirdre E. J.;Hinds, Monica T.
• 通讯作者: Hinds, Monica T.

Structural and cellular characterization of electrospun recombinant human tropoelastin biomaterials.

• DOI: 10.1177/0885328211399480
• 发表时间: 2012-08
• 期刊: Journal of biomaterials applications
• 影响因子: 2.9
• 作者: McKenna KA;Gregory KW;Sarao RC;Maslen CL;Glanville RW;Hinds MT
• 通讯作者: Hinds MT

Engineering an endothelialized vascular graft: a rational approach to study design in a non-human primate model.

• DOI: 10.1371/journal.pone.0115163
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Anderson DE;Glynn JJ;Song HK;Hinds MT
• 通讯作者: Hinds MT