Engineered dual affinity protein fragments to bind collagen and capture growth factors.
Engineered dual affinity protein fragments to bind collagen and capture growth factors.
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DOI：
10.1016/j.mtbio.2023.100641
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发表时间：
2023-06
期刊：
影响因子：
--
通讯作者：
Salmeron-Sanchez M
中科院分区：
文献类型：
--
作者：
Sarrigiannidis SO;Dobre O;Navarro AR;Dalby MJ;Gonzalez-Garcia C;Salmeron-Sanchez M
I型胶原缺乏对生长因子（GFs）的亲和力，但它在临床上用于传递骨形态发生蛋白2 (BMP-2)，这是一种有效的成骨生长因子。为了减轻这种亲和力的缺乏，在胶原海绵中装载了超过生理浓度的BMP-2，导致BMP-2从材料中不受控制地泄漏。这导致了重要的不良副作用，如致癌。在这里，我们设计了在大肠杆菌中产生的重组双亲和蛋白片段，它包含两个区域，一个自发地与胶原蛋白结合，另一个与BMP-2结合。通过将片段添加到胶原海绵中，BMP-2被隔离，使BMP-2的固相呈现。我们证明了超低剂量BMP-2在体内的成骨作用。我们的蛋白质技术提高了胶原蛋白的生物活性，而不使用复杂的化学物质或改变基础材料的制造，因此开辟了临床翻译的途径。一个蛋白质片段被设计成具有结合骨再生生长因子（即rhBMP-2）和胶原蛋白的能力。与目前使用的临床系统相比，该蛋白片段在细菌中表达，并且增加了rhBMP-2与胶原海绵的结合。该技术在体外和体内对临界尺寸骨缺损均显示出良好的成骨潜力。
Collagen type I lacks affinity for growth factors (GFs) and yet it is clinically used to deliver bone morphogenic protein 2 (BMP-2), a potent osteogenic growth factor. To mitigate this lack of affinity, supra-physiological concentrations of BMP-2 are loaded in collagen sponges leading to uncontrolled BMP-2 leakage out of the material. This has led to important adverse side effects such as carcinogenesis. Here, we design recombinant dual affinity protein fragments, produced in E. Coli, which contain two regions, one that spontaneously binds to collagen and a second one that binds BMP-2. By adding the fragment to collagen sponges, BMP-2 is sequestered enabling solid phase presentation of BMP-2. We demonstrate osteogenesis in vivo with ultra-low doses of BMP-2. Our protein technology enhances the biological activity of collagen without using complex chemistries or changing the manufacturing of the base material and so opens a pathway to clinical translation. A protein fragment was engineered with the ability to bind both bone regenerating growth factors (i.e. rhBMP-2) and collagen. The protein fragment was expressed in bacteria and increased rhBMP-2 binding to collagen sponges compared to currently used clinical systems. The proposed technology showed excellent osteogenic potential in vitro and in vivo in critical-sized bone defect.
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DOI：
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