Regenerative Engineering of Complex Musculoskeletal Tissues and Joints

描述（由申请人提供）：在过去的20年里，P.I.在开发用于肌肉骨骼组织再生的工程系统方面进行了大量工作。受他在骨和软组织领域的工作启发的系统现在已经被植入人体。现在我将利用我所获得的集体专业知识和洞察力来测试一个大胆的新假设，即复杂的组织和关节可以被创造出来，并同样找到它们在人类临床应用的方式。为此，我将使用再生工程的原理，最近发表在《科学》杂志上的概念，转化医学是指利用材料科学、干细胞科学的新进展以及对发育生物学线索的理解，以启发式方法实现复杂的组织再生。我将探索整合通过再生工程方法开发的单个组件组织，使用开发工程组织的基质和细胞基质结构的专业知识。下一步，我们将开发我所称的整合移植系统（IGS），如骨软骨、骨韧带、肌肉/肌腱和血管化组织。随后的步骤将检查周围神经到组织系统中的整合，并开发额外的组成组织。线索很重要我将利用药物输送的经验，并研究使用生物效应分子，如骨形态发生蛋白作为分化的线索。我们最近描述了一组分子，我们称之为诱导剂-小分子分化诱导剂，可能特别适合于肌肉骨骼再生。与我们的合作者合作，我们将利用发育生物学的线索，特别是肢体再生作为我们工作的重要组成部分。最后，我们在组织再生的电/生物力学线索方面获得了大量的专业知识。我相信我们可以利用这些线索来产生新的功能性关节组织，

DESCRIPTION (provided by applicant): Over the past 20 years, the P.I. has performed substantial work in the development of engineered systems for the regeneration of musculoskeletal tissues. Systems inspired by his work in the area of bone and soft tissue have now been implanted in man. Now I will use the collective expertise and insight I have obtained to test a bold, new hypothesis that complex tissues and joints can be created and similarly find their way to clinical use in man. For this I will use principles of Regenerative Engineering, concepts recently published in Science, Translational Medicine that refer to the use of new advances in materials science, stem cell science and the understanding of cues from developmental biology in heuristic approaches toward complex tissue regeneration. I will explore integrating the individual component tissues developed via the regenerative engineering approach using expertise in developing matrix and cell-matrix constructs for engineering tissues. As the next step we will develop what I term integrated graft systems (IGS) such as osteochondral, osteoligamentous, muscle/tendon and vascularized tissues. Subsequent steps will examine the integration of peripheral nerve into the tissue systems and to develop additional component tissues. Cues are important. I will use experience in drug delivery and investigate the use of biological effector molecules such as the bone morphogenetic proteins as cues for differentiation. We have recently described a group of molecules we term inducerons-small molecule inducers of differentiation that may be particularly suited for musculoskeletal regeneration. Working with our collaborator, we will utilize cues from developmental biology, particularly limb regeneration as an important part of our work. Finally, we have gained substantial expertise in electrical/biomechanical cues for tissue regeneration. I believe we can utilize these cues for the generation of new functional joint tissues as well as integrate