Tissue Engineering of axially vascularized skeletal muscle tissue using functional nanoscaffolds in the rat animal model

在大鼠动物模型中使用功能性纳米支架进行轴向血管化骨骼肌组织的组织工程

基本信息

项目摘要

The creation of functional skeletal muscle is still a major challenge in the field of tissue engineering. Besides finding the optimal cell source, developing a suitable matrix for parallel and 3D alignment of the seeded cells is crucial step. Furthermore, growth factors play an important role during myogenesis. Growth differentiation factor-11 (GDF-11) as well as IGF-binding proteins 4, 5, and 6 (IGFBP 4, 5, 6) may influence myogenic differentiation via different actions. Since primary myoblasts lose their differentiation capacities after a few passages, the exclusive application of these cells is not suitable for the creation of large muscle tissues. Thus, mesenchymal stem cells are attractive candidates due to their proliferative and differentiation capacities. Bone-marrow derived stem cells (BMSC) in co-culture with primary myoblasts have shown their ability to differentiate into the myogenic line. An even more exciting cell source for regenerative applications are adipose-derived stem cells (ADSC), which can be harvested by minimally invasive procedures in a clinical setting.Electrospun nanoscaffolds with aligned fibers are a promising matrix as they reproduce the mechanical anisotropy and can be combined with ECM polymers, proteins and polysaccharides. An important aspect is the spinning process itself: toxic components should be avoided in light of a later bench-to-bedside application.In the current study the 3D co-culture of primary myoblasts with BMSC on electrospun parallel aligned PCL-collagen I-nanoscaffolds have already been established. Upcoming experiments would be focusing on replacing BMSC by clinically even more attractive ADSC. Most importantly the newly developed spinning process is now being based on the non-toxic solvent acetic acid instead of toxic solvents like HFIP. Development of this new process, including standardized assessment of batch-to-batch inconsistencies, has been a major effort, but now large quantities of nanoscaffolds can be spun for experiments aimed for in this proposal.Since the myogenic impact of differentiation factors investigated so far (in particular HFG) has only been weak, for the currently scheduled and hereby applied part of the proposal, the influence of GDF-11, IGFBP4, 5, and 6 on myogenic differentiation is analyzed as well as the influence of different culture conditions, static vs. dynamic via a bioreactor. Currently, nanoscaffolds are functionalized by integration of fibers containing growth factor aiming at myogenic differentiation. In addition, sacrificial fibers, containing polyethylenoxide, should facilitate the vascularisation of the scaffolds for in vivo application. Finally, the seeded scaffolds will be implanted into the rat EPI-loop-model, established recently by the applicant, containing an arteriovenous loop as well as a motor nerve. This model enables future vascularisation and neurotisation of the engineered neo-muscle tissue.
功能性骨骼肌的构建仍然是组织工程领域的一个主要挑战。除了找到最佳的细胞来源,开发一个合适的矩阵,用于平行和3D对齐的种子细胞是至关重要的一步。此外,生长因子在肌发生过程中起重要作用。生长分化因子-11(GDF-11)以及胰岛素样生长因子结合蛋白4、5和6(IGFBP 4、5、6)可能通过不同的作用影响肌源性分化。由于原代成肌细胞在几次传代后失去其分化能力,因此这些细胞的单独应用不适合于产生大的肌肉组织。因此,间充质干细胞由于其增殖和分化能力而成为有吸引力的候选者。骨髓源性干细胞(BMSC)与原代成肌细胞共培养已显示其分化为肌原细胞系的能力。一个更令人兴奋的再生应用的细胞来源是脂肪来源的干细胞(ADSC),它可以在临床环境中通过微创程序收获。具有排列纤维的静电纺丝纳米支架是一种有前途的基质,因为它们再现了机械各向异性,并且可以与ECM聚合物,蛋白质和多糖结合。一个重要的方面是纺丝过程本身:有毒成分应避免在以后的bench-to-bedside application.In的光在目前的研究中,3D共培养的原代成肌细胞与BMSC上静电纺丝平行排列的PCL-胶原蛋白I-nanoscaffolds已经建立。即将进行的实验将集中在用临床上更有吸引力的ADSC取代BMSC。最重要的是,新开发的纺丝工艺现在基于无毒溶剂乙酸,而不是有毒溶剂,如HFIP。这种新工艺的开发,包括批次间不一致性的标准化评估,一直是一项重大努力,但现在可以旋转大量的纳米支架用于该提案中的实验。(特别是HFG)只是微弱的,对于目前计划的和因此应用的提案部分,GDF-11,IGFBP 4,5,和6对成肌分化的影响以及不同培养条件(静态与动态)的影响。目前,纳米支架通过整合含有生长因子的纤维来功能化,目的是肌源性分化。此外,含有聚环氧乙烷的牺牲纤维应促进支架的血管化以用于体内应用。最后,将接种的支架植入申请人最近建立的大鼠EPI环模型中,该模型含有动静脉环以及运动神经。该模型使得工程化的新肌肉组织能够在未来实现血管化和神经化。

项目成果

期刊论文数量(3)
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Professor Dr. Raymund E. Horch, since 8/2017其他文献

Professor Dr. Raymund E. Horch, since 8/2017的其他文献

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