一种 BMP/Activin A 嵌合体在低于 BMP-2 的浓度下即可诱导非人灵长类动物的脊柱后侧融合。

A BMP/Activin A Chimera Induces Posterolateral Spine Fusion in Nonhuman Primates at Lower Concentrations Than BMP-2.

机构信息

Orthopedic Research and Pharmaceutical Development Consultant, Cambridge, Massachusetts.

Bioventus Surgical, Bioventus LLC, Boston, Massachusetts.

出版信息

J Bone Joint Surg Am. 2021 Aug 18;103(16):e64. doi: 10.2106/JBJS.20.02036.

DOI:10.2106/JBJS.20.02036

PMID:33950879

Abstract

BACKGROUND

Supraphysiologic bone morphogenetic protein (BMP)-2 concentrations are required to induce spinal fusion. In this study, a BMP-2/BMP-6/activin A chimera (BV-265), optimized for BMP receptor binding, delivered in a recombinant human collagen:CDHA [calcium-deficient hydroxyapatite] porous composite matrix (CM) or bovine collagen:CDHA granule porous composite matrix (PCM), engineered for optimal BV-265 retention and guided tissue repair, was compared with BMP-2 delivered in a bovine absorbable collagen sponge (ACS) wrapped around a MASTERGRAFT Matrix (MM) ceramic-collagen rod (ACS:MM) in a nonhuman primate noninstrumented posterolateral fusion (PLF) model.

METHODS

In vivo retention of 125I-labeled-BV-265/CM or PCM was compared with 125I-labeled-BMP-2/ACS or BMP-2/buffer in a rat muscle pouch model using scintigraphy. Noninstrumented PLF was performed by implanting CM, BV-265/CM, BV-265/PCM, or BMP-2/ACS:MM across L3-L4 and L5-L6 or L3-L4-L5 decorticated transverse processes in 26 monkeys. Computed tomography (CT) images were acquired at 0, 4, 8, 12, and 24 weeks after surgery, where applicable. Manual palpation, μCT (microcomputed tomography) or nCT (nanocomputed tomography), and histological analysis were performed following euthanasia.

RESULTS

Retention of 125I-labeled-BV-265/CM was greater than BV-265/PCM, followed by BMP-2/ACS and BMP-2/buffer. The CM, 0.43 mg/cm3 BMP-2/ACS:MM, and 0.05 mg/cm3 BV-265/CM failed to generate PLFs. The 0.15-mg/cm3 BV-265/CM or 0.075-mg/cm3 BV-265/PCM combinations were partially effective. The 0.25-mg/cm3 BV-265/CM and 0.15 and 0.3-mg/cm3 BV-265/PCM combinations generated successful 2-level PLFs at 12 and 24 weeks.

CONCLUSIONS

BV-265/CM or PCM can induce fusion in a challenging nonhuman primate noninstrumented PLF model at substantially lower concentrations than BMP-2/ACS:MM.

CLINICAL RELEVANCE

BV-265/CM and PCM represent potential alternatives to induce PLF in humans at substantially lower concentrations than BMP-2/ACS:MM.

摘要

背景

诱导脊柱融合需要超生理浓度的骨形态发生蛋白（BMP）-2。在这项研究中，一种 BMP-2/BMP-6/激活素 A 嵌合体（BV-265）被优化用于 BMP 受体结合，通过重组人胶原蛋白：CDHA[钙缺乏羟基磷灰石]多孔复合基质（CM）或牛胶原蛋白：CDHA 颗粒多孔复合基质（PCM）递送至体内，该基质可优化 BV-265 的保留和引导组织修复，与 BMP-2 包裹在 MASTERGRAFT Matrix（MM）陶瓷胶原棒（ACS：MM）周围的牛可吸收胶原海绵（ACS）在非人类灵长类动物非器械性后路融合（PLF）模型中进行了比较。

方法

使用闪烁照相术比较 125I 标记的 BV-265/CM 或 PCM 与 125I 标记的 BMP-2/ACS 或 BMP-2/缓冲液在大鼠肌肉囊模型中的体内保留情况。通过在 26 只猴子的 L3-L4 和 L5-L6 或 L3-L4-L5 去皮质横突之间植入 CM、BV-265/CM、BV-265/PCM 或 BMP-2/ACS：MM，进行非器械性 PLF。在手术 0、4、8、12 和 24 周时，根据适用情况获取计算机断层扫描（CT）图像。安乐死后进行手动触诊、μCT（微计算机断层扫描）或 nCT（纳米计算机断层扫描）以及组织学分析。

结果

125I 标记的 BV-265/CM 的保留率大于 BV-265/PCM，其次是 BMP-2/ACS 和 BMP-2/缓冲液。0.43mg/cm3 的 BMP-2/ACS：MM 和 0.05mg/cm3 的 BV-265/CM 未能产生 PLF。0.15mg/cm3 的 BV-265/CM 或 0.075mg/cm3 的 BV-265/PCM 组合部分有效。0.25mg/cm3 的 BV-265/CM 和 0.15 和 0.3mg/cm3 的 BV-265/PCM 组合在 12 和 24 周时产生了成功的 2 级 PLF。