Department of Orthopedics, Balgrist Hospital, University of Zurich, Zurich, Switzerland; Institute for Biomechanics, ETH Zurich, Zurich, Switzerland.
Department of Orthopedics, Balgrist Hospital, University of Zurich, Zurich, Switzerland; Institute for Biomechanics, ETH Zurich, Zurich, Switzerland; Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands.
Acta Biomater. 2018 Apr 15;71:306-317. doi: 10.1016/j.actbio.2018.03.004. Epub 2018 Mar 10.
Healthy tendon tissue features a highly aligned extracellular matrix that becomes disorganized with disease. Recent evidence suggests that inflammation coexists with early degenerative changes in tendon, and that crosstalk between immune-cells and tendon fibroblasts (TFs) can contribute to poor tissue healing. We hypothesized that a disorganized tissue architecture may predispose tendon cells to degenerative extracellular matrix remodeling pathways, particularly within a pro-inflammatory niche. This hypothesis was tested by analyzing human TFs cultured on electrospun polycaprolactone (PCL) mats with either highly aligned or randomly oriented fiber structures. We confirmed that fibroblast morphology, phenotype, and markers of matrix turnover could be significantly affected by matrix topography. More strikingly, the TF response to paracrine signals from polarized macrophages or by stimulation with pro-inflammatory cytokines featured significant downregulation of signaling related to extracellular synthesis, with significant concomitant upregulation of gene and protein expression of matrix degrading enzymes. Critically, this tendency towards degenerative re-regulation was exacerbated on randomly oriented PCL substrates. These novel findings indicate that highly aligned tendon cell scaffolds not only promote tendon matrix synthesis, but also play a previously unappreciated role in mitigating adverse resident fibroblast response within an inflammatory milieu.
Use of biomaterial scaffolds for tendon repair often results in tissue formation characteristic of scar tissue, rather than the highly aligned type-1 collagen matrix of healthy tendons. We hypothesized that non-optimal biomaterial surfaces may play a role in these outcomes, specifically randomly oriented biomaterial surfaces that unintentionally mimic structure of pathological tendon. We observed that disorganized scaffold surfaces do adversely affect early cell attachment and gene expression. We further identified that disorganized fiber surfaces can prime tendon cells toward pro-inflammatory signaling. These findings represent provocative evidence unstructured fiber surfaces may underlie inflammatory responses that drive aberrant collagen matrix turnover. This work could be highly relevant for the design of cell instructive biomaterial therapies that yield positive clinical outcomes.
健康的肌腱组织具有高度有序的细胞外基质，而这种有序性在疾病状态下会被打乱。最近的证据表明，炎症与肌腱的早期退行性变化并存，免疫细胞与肌腱成纤维细胞（TFs）之间的相互作用可能导致组织愈合不良。我们假设，组织结构的紊乱可能使肌腱细胞容易发生退行性细胞外基质重塑途径，尤其是在炎症环境中。我们通过分析在具有高度有序或随机取向纤维结构的电纺聚己内酯（PCL）垫上培养的人 TFs，验证了这一假说。我们证实，成纤维细胞形态、表型和基质转化标志物可以显著受到基质形貌的影响。更引人注目的是，TF 对极化巨噬细胞的旁分泌信号或促炎细胞因子的刺激的反应，表现出与细胞外合成相关的信号显著下调，同时伴有基质降解酶的基因和蛋白表达显著上调。关键是，这种退行性再调节的趋势在随机取向的 PCL 基质上更加明显。这些新发现表明，高度有序的肌腱细胞支架不仅促进肌腱基质的合成，而且在炎症环境中，对减轻固有成纤维细胞的不良反应也起着以前未被认识到的作用。
用于肌腱修复的生物材料支架的使用通常会导致组织形成特征类似于疤痕组织，而不是健康肌腱的高度有序的 1 型胶原基质。我们假设，非最佳生物材料表面可能在这些结果中起作用，特别是随机定向的生物材料表面，它们无意中模仿了病理肌腱的结构。我们观察到，无序的支架表面确实会对早期细胞附着和基因表达产生不利影响。我们进一步确定，无序纤维表面可以使肌腱细胞向促炎信号方向发展。这些发现代表了一个有争议的证据，即无结构纤维表面可能是炎症反应的基础，炎症反应会导致异常的胶原基质周转。这项工作对于设计产生积极临床结果的细胞指令性生物材料疗法可能具有重要意义。
