Cell-synthesized Thread-based Tissue Engineering

描述(申请人提供)：以前，我们已经报道了一种使用自组装方法构建的组织工程化血管移植物的良好临床结果，该方法被称为“基于薄片的组织工程”(SBTE)。然而，这种方法的主要缺点是由于生产时间长而制造成本高。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。我们技术的这一新发展建立在SBTE所展示的临床成功(长期强度和耐用性、卓越的生物兼容性、抗感染和抗血栓形成)的基础上，但现在引入了利用现有医用纺织品技术更快、更低成本组装策略的可能性。这笔赠款的首要目标是为这种新的自组装平台技术开发基础，我们称之为基于线程的组织工程(TBTE)。在初步研究中，我们已经证明，我们可以生产细胞合成线，并编织或编织管状管道。重要的是，这将血管移植物的制造时间从7个月以上减少到不到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将是一个非常通用的平台技术，可以为各种靶组织和器官提供支架。为了为第二阶段计划的活体研究开发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.生成人类线程库并确定其机械性能。2.建立犬牙线文库，并测定其机械性能。3.建立血管原型和机械里程碑。可交付和通过/不通过的里程碑：在这项概念验证研究中，我们将需要演示一种组装方案，该方案可以生产满足关键机械性能释放标准的血管，这些标准是我们为基于片状组织工程的血管移植物进行的先前临床试验建立的(破裂压力和缝合拔出强度分别为1700 mmHg和75gf)。 与公共健康相关：在过去的10年里，我们已经开发出一种完全由人类细胞组成的完全生物组织工程化血管移植物，而不需要外源生物材料或合成支架。虽然这种工程化移植物的初步临床应用是该领域的一项里程碑式的成就，但制造过程既耗时又昂贵，因此，我们正在探索一种新的制造工艺，称为基于线的组织工程(TBTE)，在这种工艺中，细胞合成的生物线可以编织或编织成坚固的组织，将总制造时间从先前研究的6-9个月减少到3-8周。在这笔赠款中，我们计划建立一个由人类和动物细胞构建的线程库并对其进行表征，这个功能和机械特性的库将形成制造更复杂组织的基础，包括在SBIR资助机制的第二阶段中用于活体使用的血管移植物。

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.