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Multi-scale osteointegration and neovascularization of biphasic calcium phosphate bone scaffolds.

机译：双相磷酸钙骨支架的多尺度骨整合和新血管形成。

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摘要

Bone grafts are utilized clinically to guide tissue regeneration. Autologous bone and allogeneic bone are the current clinical standards. However, there are significant limitations to their use. To address the need for alternatives to autograft and allograft, researchers have worked to develop synthetic grafts, also referred to as scaffolds. Despite extensive efforts in this area, a gap persists between basic research and clinical application. In particular, solutions for repairing critical size and/or load-bearing defects are lacking. The aim of this thesis work was to address two critical barriers preventing design of successful tissue engineering constructs for bone regeneration within critical size and/or load-bearing defects. Those barriers are insufficient osteointegration and slow neovascularization. In this work, the effects of scaffold microporosity, recombinant human bone morphogenetic protein-2 delivery and endothelial colony forming cell vasculogenesis were evaluated in the context of bone formation in vivo. This was accomplished to better understand the role of these factors in bone regeneration, which may translate to improvements in tissue engineering construct design.;Biphasic calcium phosphate (BCP) scaffolds with controlled macro- and microporosity were implanted in porcine mandibular defects. Evaluation of the BCP scaffolds after in vivo implantation showed, for the first time, osteocytes embedded in bone within scaffold micropores ( 10 microm) as well as the most extensive bone growth into micropores to date with bone penetration throughout rods 394 microm in diameter. The result is the first truly osteointegrated bone scaffolds with integration occurring at both the macro and micro length scales, leaving no "dead space" or discontinuities of bone in the defect site. The scaffold forms a living composite upon integration with regenerating bone and this has significant implications with regard to improved scaffold mechanical properties.;The presence of osteocytes within scaffold micropores is an indication of scaffold osteoinductivity because a chemotactic factor must be present to induce cell migration into pores on the order of the cell diameter. It is likely that the scaffold undergoes in vivo modifications involving formation of a biological apatite layer within scaffold micropores and possibly co-precipitation of endogenous osteoinductive proteins. To further investigate the effects of scaffold osteoinductivity, BCP scaffolds were implanted in porcine mandibular defects with rhBMP-2, which was partially sequestered in the micropores. Cell migration into osteoinductive scaffold micropores can be enhanced through the delivery of exogenous rhBMP-2 further promoting multi-scale osteointegration.;Finally, endothelial colony forming cells (ECFCs) isolated from human umbilical cord blood (UCB) were evaluated in terms of their in vivo vasculogenic potential in the context of bone formation. This work was completed to determine if ECFCs could be utilized in a bone tissue engineering construct to promote neovascularization. ECFCs were combined with a BCP scaffold and rhBMP-2 and implanted subcutaneously on the abdominal wall of NOD/SCID mice. The result was formation of perfused human vessels within BCP scaffold macropores that were present at 4 weeks. The high density and persistence of human vessels at four weeks indicates that human UCB ECFCs exceed their reported in vivo vasculogenic potential when combined with rhBMP-2 and a BCP scaffold. This shows a dual role for BMP-2 in the context of bone regeneration.;Collectively, the thesis demonstrates that (1) the design of synthetic bone scaffolds should include controlled multi-scale porosity to promote multi-scale osteointegration, which may significantly improve scaffold mechanical properties and (2) human umbilical cord blood-derived endothelial colony forming cells have potential for promoting neovascularization in a bone defect when combined with rhBMP-2.
机译：临床上利用骨移植物来指导组织再生。自体骨和同种异体骨是当前的临床标准。但是，它们的使用受到很大限制。为了满足自体移植和同种异体移植替代品的需求，研究人员致力于开发合成移植物，也称为支架。尽管在这一领域做出了巨大努力，但基础研究与临床应用之间仍然存在差距。特别地，缺少用于修复关键尺寸和/或承载缺陷的解决方案。本文工作的目的是解决两个关键的障碍，这些障碍阻碍了成功的组织工程构造体在临界尺寸和/或承重缺陷范围内进行骨再生的设计。这些障碍是骨整合不足和新血管形成缓慢。在这项工作中，在体内骨骼形成的背景下，评估了支架微孔，重组人骨形态发生蛋白2递送和内皮集落形成细胞血管生成的作用。这样做是为了更好地了解这些因素在骨骼再生中的作用，这可能会改善组织工程构造的设计。将具有可控的大孔和微孔度的双相磷酸钙（BCP）支架植入猪下颌骨缺损。体内植入后对BCP支架的评估首次显示，埋在支架微孔（<10微米）内的骨中的骨细胞以及迄今为止最广泛的骨生长为微孔，直至骨穿透直径394微米的整个杆。结果是第一个真正的骨整合骨支架在宏观和微观尺度上都发生了整合，在缺损部位没有留下“死角”或骨骼的不连续性。支架与再生骨整合后形成活动的复合材料，这对于改善支架的机械性能具有重要意义。支架微孔内存在骨细胞，表明支架具有骨诱导性，因为必须存在趋化因子才能诱导细胞迁移至孔的数量大约是细胞直径。支架可能会经历体内修饰，包括在支架微孔内形成生物磷灰石层，并可能共沉淀内源性骨诱导蛋白。为了进一步研究支架骨诱导性的作用，将BCP支架植入具有部分隔离在微孔中的rhBMP-2的猪下颌骨缺损中。可通过递送外源性rhBMP-2进一步促进多尺度骨整合来增强细胞向骨诱导支架微孔中的迁移。最后，从人脐带血（UCB）分离的内皮集落形成细胞（ECFC）的评估骨形成背景下的体内血管生成潜力。这项工作已完成，以确定ECFC是否可用于骨组织工程构造中以促进新血管形成。 ECFC与BCP支架和rhBMP-2结合，并皮下植入NOD / SCID小鼠的腹壁。结果是在4周时出现的BCP支架大孔内形成了灌注的人血管。四周时人类血管的高密度和持久性表明，当与rhBMP-2和BCP支架组合使用时，人类UCB ECFC超过了其报道的体内血管生成潜力。这表明BMP-2在骨骼再生中起着双重作用。总体而言，本文证明（1）合成骨支架的设计应包括受控的多尺度孔隙度，以促进多尺度的骨整合，这可能会显着改善支架的机械性能和（2）人脐带血来源的内皮集落形成细胞与rhBMP-2结合后，具有促进骨缺损中新血管形成的潜力。

著录项

  • 作者

    Lan, Sheeny K.;

  • 作者单位

    University of Illinois at Urbana-Champaign.;

  • 授予单位 University of Illinois at Urbana-Champaign.;
  • 学科 Engineering Biomedical.;Engineering Materials Science.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 165 p.
  • 总页数 165
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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