Biomimetic Tissue Analogs via Micropatterned Deposition of Proteins

ID：MPS/dmr/bmat(7623)1306665 PI：Akkus，Ozan ORG：Case WESTERN研究标题：通过蛋白质微图案化沉积的仿生组织类似物技术：制造机械坚固的生物材料，同时具有足够的孔洞以供细胞和血管穿透仍然是一个重大挑战，特别是在承重肌肉骨骼组织的工程中。拟议的研究将是开创性的，通过使用微图案电极对富含胶原的蛋白质溶液进行电化学压实(ELC)，从而为设计大小和分布可控的孔阵列创造条件。我们将根据肌腱修复支架的制作来评估ELC的实用性。首先，Aim研究将从根本上深入了解基质各向异性和基质模数(在Mpa到Gpa的范围内)对脂肪组织来源的间充质干细胞(AMSCs)分化和基质沉积的影响。通过在基质中加入硫酸皮肤素(DS)，一种丰富存在于肌腱中的糖胺多糖，将补充地形分化线索的成分线索。被确定为最有利于预期细胞响应的材料配方将用于第二阶段研究，在此期间，将共同使用CAD、CAM和有限元等关键技术来设计最佳的晶格微形态，从而产生强大的宏观机械功能。计算上有价值的支架结构将使用计算机控制的制造方法来制造，并被细胞化以在3D环境中筛选细胞响应。非技术性：肌腱退化，特别是与肩膀衰老相关的肌腱退化，是一个广泛存在的健康问题，正在影响数十万人，并给经济带来巨大负担。目前尚缺乏机械强度高的支架来修复肌腱，大多数生物材料被用作肌腱损伤部位的加固补片。建议的模式沉积技术提供了一种可行的替代方案，作为再生肌腱的3D生物活性框架。这有可能改善目前的治疗方式。这项拟议的研究还将开发一种使能技术，可以扩展到其他组织，如骨、韧带、肝脏和血管结构。相互连接的受控孔隙空间的图案化沉积允许增强质量传输，为设计更大的组织体积创造了机会。这项研究的优点之一是了解在缺乏生长因子的情况下，基质各向异性和基质硬度在诱导骨髓来源的干细胞成为肌腱细胞方面的相对作用。通过机械成分线索实现分化是非常重要的，因为生长因子是昂贵的和严格调控的。拟议项目的外展部分将通过跨学科的高级设计团队和研究参与，培养本科生对脚手架设计和制造的兴趣。本科生将通过以下方式接触到新兴的生物制造领域：(A)在项目的每一年容纳一名本科生(全日制暑期)，以及(B)就与拟议活动相对应的主题指导高级设计团队。新兴的生物制造领域在新经济中很重要，拟议的活动旨在激励未来的创新者。

ID: MPS/DMR/BMAT(7623) 1306665 PI: Akkus, Ozan ORG: Case Western ReserveTitle: Biomimetic Tissue Analogs via Micropatterned Deposition of ProteinsTechnical: Fabrication of mechanically robust biomaterials that also possess sufficient porosity for cell and blood vessel penetration remains a major challenge, particularly in engineering of load bearing musculoskeletal tissues. The proposed research will be groundbreaking through electrochemical-compaction (ELC) of collagen-rich protein solution using micropatterned electrodes, thus creating the provision for designing arrays of pores with controlled size and distribution. The utility of ELC will be assessed in terms of fabricating scaffolds for tendon repair. First aim studies will provide fundamental insight on the effects of matrix anisotropy and matrix modulus (in a range of MPa to GPa) on differentiation and matrix deposition by adipose tissue-derived mesenchymal stem cells (aMSCs). The topographical differentiation cues will be supplemented with compositional cues by including dermatan sulfate (DS), a glycosaminoglycan richly present in tendon, in the matrix. That material formulation determined to be the most conducive to desired cell response will be used in second phase studies during which key technologies such as CAD, CAM and FEM will be used collectively to design for optimal lattice micromorphology resulting in robust macroscale mechanical function. Computationally meritorious scaffold structures will be fabricated using computer controlled fabrication methods and cellularized to screen cell response in the 3D environment. Non-Technical: Tendon degeneration, particularly those associated with aging at the shoulder, is a widespread health problem that is affecting hundreds of thousands and imposing a substantial burden on the economy. There is a lack of mechanically robust scaffolds to repair tendon, and most biomaterials are applied as reinforcement patches over the injured tendon. The proposed pattern deposition technology presents a viable alternative as a 3D bioactive framework to regenerate tendons. This carries the potential to improve the current treatment modalities. The proposed research will also develop an enabling technology that can be extended to other tissues such as bone, ligament, liver, and vascular structures. Patterned deposition of interconnected controlled pore space allows for enhanced mass-transport, creating the opportunity for engineering larger tissue volumes. One of the merits of the proposed studies is understanding the relative roles of matrix anisotropy and matrix stiffness in inducing marrow-derived stem cells to become tendon cells in the absence of growth factors. Achievement of differentiation by mechano-compositional cues is highly significant, because growth factors are expensive and heavily regulated. The outreach component of the proposed project will foster undergraduate students' interests in scaffold design and fabrication through interdisciplinary senior design teams and research engagement. Undergraduate students will be exposed to the emerging field of biofabrication by: (a) accommodating one undergraduate student (full-time summer) for each year of the project, and (b) mentoring senior design teams on topics that map to the proposed activities. The emerging field of biofabrication is important in the new economy, and the proposed activities aim to inspire the innovators of the future.