Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, 720 Rutland Ave, 217 Traylor Bldg, Baltimore, MD, 21205, USA.
Angiogenesis. 2024 Feb;27(1):105-119. doi: 10.1007/s10456-023-09899-0. Epub 2023 Nov 30.
The healing of calvarial bone defects is a pressing clinical problem that involves the dynamic interplay between angiogenesis and osteogenesis within the osteogenic niche. Although structural and functional vascular remodeling (i.e., angiogenic evolution) in the osteogenic niche is a crucial modulator of oxygenation, inflammatory and bone precursor cells, most clinical and pre-clinical investigations have been limited to characterizing structural changes in the vasculature and bone. Therefore, we developed a new multimodality imaging approach that for the first time enabled the longitudinal (i.e., over four weeks) and dynamic characterization of multiple in vivo functional parameters in the remodeled vasculature and its effects on de novo osteogenesis, in a preclinical calvarial defect model. We employed multi-wavelength intrinsic optical signal (IOS) imaging to assess microvascular remodeling, intravascular oxygenation (SO), and osteogenesis; laser speckle contrast (LSC) imaging to assess concomitant changes in blood flow and vascular maturity; and micro-computed tomography (μCT) to validate volumetric changes in calvarial bone. We found that angiogenic evolution was tightly coupled with calvarial bone regeneration and corresponded to distinct phases of bone healing, such as injury, hematoma formation, revascularization, and remodeling. The first three phases occurred during the initial two weeks of bone healing and were characterized by significant in vivo changes in vascular morphology, blood flow, oxygenation, and maturity. Overall, angiogenic evolution preceded osteogenesis, which only plateaued toward the end of bone healing (i.e., four weeks). Collectively, these data indicate the crucial role of angiogenic evolution in osteogenesis. We believe that such multimodality imaging approaches have the potential to inform the design of more efficacious tissue-engineering calvarial defect treatments.
颅骨骨缺损的修复是一个紧迫的临床问题，涉及到成骨龛内血管生成和骨生成之间的动态相互作用。尽管成骨龛内的结构和功能血管重塑（即血管生成演变）是氧合、炎症和骨前体细胞的关键调节剂，但大多数临床前和临床研究都局限于描述血管和骨骼的结构变化。因此，我们开发了一种新的多模态成像方法，该方法首次能够在临床前颅骨缺损模型中对重塑血管及其对新骨生成的影响进行长达四周的纵向（即超过四周）和动态多参数功能特征的评估。我们采用多波长固有光学信号（IOS）成像来评估微血管重塑、血管内氧合（SO）和骨生成；激光散斑对比（LSC）成像来评估血流和血管成熟度的伴随变化；和微计算机断层扫描（μCT）来验证颅骨骨的体积变化。我们发现血管生成演变与颅骨骨再生紧密相关，并与骨愈合的不同阶段相对应，如损伤、血肿形成、再血管化和重塑。前三个阶段发生在骨愈合的最初两周内，其特征是血管形态、血流、氧合和成熟度的显著体内变化。总的来说，血管生成演变先于骨生成，仅在骨愈合结束时（即四周）达到平台期。综上所述，这些数据表明血管生成演变在骨生成中起着至关重要的作用。我们相信，这种多模态成像方法有可能为更有效的组织工程颅骨缺损治疗提供信息。
