Cell-synthesized Thread-based Tissue Engineering

描述（由申请人提供）：之前，我们已经报道了使用称为“薄片组织工程”（SBTE）的自组装方法构建的组织工程血管移植物的出色临床结果。然而，这种方法的主要缺点是，由于生产时间长，制造成本高。为了使这项技术在临床上可用，我们需要找到一种更具商业可行性的制造方法。我们假设我们可以构建细胞合成的线程，这些线程可以组装成更复杂的结构。我们技术的新发展建立在SBTE临床成功的基础上（长期强度和耐久性，卓越的生物相容性，抗感染和抗血栓形成性），但现在引入了使用现有医用纺织品技术更快，成本更低的组装策略的可能性。这项资助的首要目标是为这种新型的自组装平台技术奠定基础，我们称之为基于线程的组织工程（TBTE）。在初步的研究中，我们已经证明我们可以生产细胞合成的线，并编织或编织管状导管。重要的是，这将血管移植物的制造时间从7个多月减少到不到3个月。虽然我们的第一个目标是制造用于血管重建的小直径血管，但TBTE将是一种非常通用的平台技术，可以为各种目标组织和器官提供支架。为了开发第二阶段体内研究计划的基本工具和初始原型，该第一阶段项目将实现以下具体目标：1。生成一个人类线程库并确定它们的机械性能。2. 生成犬齿螺纹库并确定其机械性能。3. 建立原型血管和机械里程碑。里程碑：在这项概念验证研究中，我们需要展示一种组装方案，该方案产生的血管符合我们在之前的基于薄片的组织工程血管移植物临床试验中建立的关键机械性能释放标准（破裂压力>1700 mmHg，缝合拉力> 75 gf）。

DESCRIPTION (provided by applicant): Previously, we have reported excellent clinical results with a tissue engineered vascular graft built using a self-assembly approach termed "Sheet-Based Tissue Engineering" (SBTE). The principal drawback of this approach, however, is the high manufacturing costs due to a long production time. In order to make this technology clinically available, we need to find a more commercially viable manufacturing approach. We hypothesized that we could build cell-synthesized threads that could be assembled into more complex constructs. This novel evolution of our technology builds upon the clinical successes demonstrated for SBTE (long-term strength and durability, remarkable biocompatibility, resistance to infection, and anti-thrombogenicity) but now introduces the possibility of a faster and less costly assembly strategy using existing medical textiles technologies. The overarching objective of this grant is to develop the foundation for this novel self-assembly platform technology, which we term Thread-Based Tissue Engineering (TBTE). In preliminary studies we have demonstrated that we can produce cell-synthesized threads and weave or braid tubular conduits. Importantly, this reduces the manufacturing time of the vascular graft from over 7 months to less than 3 months. While our first target is to produce a small diameter blood vessel for vascular reconstruction, TBTE will be a very versatile platform technology that can provide a scaffold for a variety of target tissues and organs. In order to develop the basic tools and initial prototypes for the in vivo studies planned for Phase II, this Phase I project will achieve the following specific aims: 1. Generate a library of human threads and determine their Mechanical properties. 2. Generate a library of canine threads and determine their mechanical properties. 3. Build prototype blood vessels and mechanical milestones. DELIVERABLE AND GO/NO GO MILESTONE: In this proof-of-concept study, we will need to demonstrate an assembly protocol that produces blood vessels that meet the critical mechanical properties release criteria we have established for our previous clinical trials with the sheet-based tissue engineered vascular grafts (burst pressures >1700 mmHg and suture pull-out strength > 75 gf). PUBLIC HEALTH RELEVANCE: Over the last 10 years we have developed a completely biological tissue engineered vascular graft comprised exclusively of human cells, without the need for exogenous biomaterials or synthetic scaffolds. While initial clinical use of this engineered graft represented a landmark achievement in the field, the manufacturing process is time consuming and expensive and thus, we are exploring a new manufacturing process, termed thread based tissue engineering (TBTE), in which cell-synthesized, biological threads can be woven or braided into robust tissues, decreasing the total manufacturing time down from 6-9 months in previous studies to 3-8 weeks. In this grant, we plan to build and characterize a library of threads built from human and animal cells and this library of functional and mechanical characteristics will form the basis for manufacturing more complex tissues, including a vascular graft for in vivo use in Phase II of this SBIR funding mechanism.