Spatial Recombinant Human Bone Morphogenetic Protein 2 Delivery from Hydroxyapatite Scaffolds Sustains Bone Regeneration in Rabbit Radius
Spatial Recombinant Human Bone Morphogenetic Protein 2 Delivery from Hydroxyapatite Scaffolds Sustains Bone Regeneration in Rabbit Radius
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DOI：
10.1089/ten.tec.2022.0102
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发表时间：
2022-07-01
影响因子：
3
通讯作者：
Guda, Teja
中科院分区：
文献类型：
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作者：
Ong, Joo L.;Shiels, Stefanie M.;Guda, Teja
再生大的骨缺损需要一个多方面的方法，结合最佳的支架设计和适当的生长因子输送。重组人骨形态发生蛋白2(RhBMP2)的超生理剂量，通常用于临床上用于大型骨缺损的再生，与无细胞胶原海绵(ACS)联合使用，已导致许多并发症。在这项研究中，我们开发了一种羟基磷灰石/I型胶原(HA/COL)支架，以提高HA支架的力学性能，同时保持开放的连通性。然后将不同剂量的rhBMP2从胶原骨膜中植入，并与HA或HA/Col支架配对修复新西兰白兔临界大小(15 Mm)的骨干骨缺损。受试组分别为：ACS+76mU rh BMP2(临床输注剂量)、HA+76mg rh BMP2、HA+15mUg rh BMP2、HA/COL+15mUg rh BMP2、HA/COL+15mUg rh BMP2+骨髓基质细胞(BMSCs)。植入8周后，对所有新生骨进行显微计算机断层扫描、组织学、组织形态计量学和扭转测试。观察到HA/Col+15mUg rhBMP2组再生的骨体积明显高于76mUg组。相同的支架和生长因子组合，再生骨的骨密度最高，在支架表面的骨沉积最多。与76mU/g重组人骨形态发生蛋白2组相比，植入15mU/g重组人骨形态发生蛋白2的HA和HA/Col支架在植入后2周内矿化程度明显增加。在所有组中，观察到缺损处完全桥接，扭转强度、僵硬或失败角度没有显著差异。在任何量化指标上，没有观察到额外的骨髓间充质干细胞种植的好处，而细胞种植组的骨-种植体对位减少。这项研究表明，以显著较低的剂量将重组人骨形态发生蛋白2控制在骨膜上的空间输送可以作为一种策略来促进维持间隙支架周围的骨再生。TweetInside-Out或Outside-In：在一项兔研究中，从多孔矿物-胶原支架外部输送生长因子，保持强度并更好地再生骨骼。资深作者(@Guda_Lab)和赞助机构(@UTSA)影响声明本研究提供了在空间控制输送重组人骨形态发生蛋白2(RhBMP2)存在的情况下骨再生的见解，从覆盖有I型胶原薄膜的多孔羟基磷灰石支架中。利用在骨骼成熟的新西兰大白兔的桡骨骨干造成的临界大小的缺损，微电脑断层扫描和组织形态计量学显示显著更高的骨再生、骨密度和骨-种植体接触，以及较低剂量的rh BMP2骨膜给药持续更长时间的再生。
Regenerating large bone defects requires a multifaceted approach combining optimal scaffold designs with appropriate growth factor delivery. Supraphysiological doses of recombinant human bone morphogenetic protein 2 (rhBMP2), typically used for the regeneration of large bone defects clinically in conjunction with an acellular collagen sponge (ACS), have resulted in many complications. In this study, we develop a hydroxyapatite/collagen I (HA/Col) scaffold to improve the mechanical properties of the HA scaffolds, while maintaining open connected porosity. Varying rhBMP2 dosages were then delivered from a collagenous periosteal membrane and paired with HA or HA/Col scaffolds to treat critical-sized (15 mm) diaphyseal radial defect in New Zealand white rabbits. The groups examined were ACS +76 mu g rhBMP2 (clinically used INFUSE dosage), HA +76 mu g rhBMP2, HA +15 mu g rhBMP2, HA/Col +15 mu g rhBMP2, and HA/Col +15 mu g rhBMP2 + bone marrow-derived stromal cells (bMSCs). After 8 weeks of implantation, all regenerated bones were evaluated using microcomputed tomography, histology, histomorphometry, and torsional testing. It was observed that the bone volume regenerated in the HA/Col +15 mu g rhBMP2 group was significantly higher than that in the groups with 76 mu g rhBMP2. The same scaffold and growth factor combination resulted in the highest bone mineral density of the regenerated bone, and the most bone apposition on the scaffold surface. Both the HA and HA/Col scaffolds paired with 15 mu g rhBMP2 had sustained ingrowth of the mineralization front after 2 weeks compared to the groups with 76 mu g rhBMP2, which had far greater mineralization in the first 2 weeks after implantation. Complete bridging of the defect site and no significant difference in torsional strength, stiffness, or angle at failure were observed across all groups. No benefit of additional bMSC seeding was observed on any of the quantified metrics, while bone-implant apposition was reduced in the cell-seeded group. This study demonstrated that the controlled spatial delivery of rhBMP2 at the periosteum at significantly lower doses can be used as a strategy to improve bone regeneration around space maintaining scaffolds. TweetInside-out or outside-in: growth factors delivered from the outside of porous mineral-collagen scaffolds, maintain strength and regrow bone better in a rabbit study.Twitter handle for senior author (@Guda_Lab) and sponsoring institution (@UTSA) Impact StatementThis study provides insights on bone regeneration in the presence of spatially controlled delivery of recombinant human bone morphogenetic protein 2 (rhBMP2) from porous hydroxyapatite scaffolds coated with collagen I films. Using critical-sized defects created in the radial diaphysis of skeletally mature New Zealand White rabbits, microcomputed tomography and histomorphometry indicated significantly higher bone regeneration, bone mineral density, and bone-implant contact, as well as sustained regeneration over longer durations with lower dosage of rhBMP2 delivered periosteally.