Drug Delivery and Advanced Materials Team, School of Pharmacy, RCSI, Dublin, Ireland.
Tissue Engineering Research Group, Department of Anatomy and Regenerative Medicine, RCSI, Dublin, Ireland.
J Tissue Eng Regen Med. 2019 Oct;13(10):1843-1853. doi: 10.1002/term.2934. Epub 2019 Aug 8.
The healing of large, critically sized bone defects remains an unmet clinical need in modern orthopaedic medicine. The tissue engineering field is increasingly using biomaterial scaffolds as 3D templates to guide the regenerative process, which can be further augmented via the incorporation of recombinant growth factors. Typically, this necessitates supraphysiological doses of growth factor to facilitate an adequate therapeutic response. Herein, we describe a cell-free, biomaterial implant which is functionalised with a low dose, combinatorial growth factor therapy that is capable of rapidly regenerating vascularised bone tissue within a critical-sized rodent calvarial defect. Specifically, we demonstrate that the dual delivery of the growth factors bone morphogenetic protein-2 (osteogenic) and vascular endothelial growth factor (angiogenic) at a low dose (5 μg/scaffold) on an osteoconductive collagen-hydroxyapatite scaffold is highly effective in healing these critical-sized bone defects. The high affinity between the hydroxyapatite component of this biomimetic scaffold and the growth factors functions to sequester them locally at the defect site. Using this growth factor-loaded scaffold, we show complete bridging of a critical-sized calvarial defect in all specimens at a very early time point of 4 weeks, with a 28-fold increase in new bone volume and seven-fold increase in new bone area compared with a growth factor-free scaffold. Overall, this study demonstrates that a collagen-hydroxyapatite scaffold can be used to locally harness the synergistic relationship between osteogenic and angiogenic growth factors to rapidly regenerate bone tissue without the need for more complex controlled delivery vehicles or high total growth factor doses.
治疗大的、临界大小的骨缺损仍然是现代骨科医学中未满足的临床需求。组织工程领域越来越多地使用生物材料支架作为 3D 模板来引导再生过程，通过掺入重组生长因子可以进一步增强。通常，这需要超生理剂量的生长因子来促进足够的治疗反应。在此，我们描述了一种无细胞的生物材料植入物，它具有低剂量的组合生长因子治疗功能，能够在临界大小的啮齿动物颅骨缺损中快速再生血管化骨组织。具体来说，我们证明了在骨诱导性胶原蛋白-羟基磷灰石支架上以低剂量（5μg/支架）双重递送电活性因子骨形态发生蛋白-2（成骨）和血管内皮生长因子（血管生成）非常有效地治疗这些临界大小的骨缺损。这种仿生支架的羟基磷灰石成分与生长因子之间的高亲和力使其能够将它们局部隔离在缺陷部位。使用这种负载生长因子的支架，我们在非常早期的 4 周时间内显示出所有标本中临界大小颅骨缺损的完全桥接，与无生长因子支架相比，新骨体积增加了 28 倍，新骨面积增加了 7 倍。总的来说，这项研究表明，胶原蛋白-羟基磷灰石支架可用于局部利用成骨和血管生成生长因子之间的协同关系，快速再生骨组织，而无需更复杂的控制释放载体或高总生长因子剂量。
