Han Daqing, Liu Weiqiang, Ao Qiang, Wang Guangzhi
Center for Advanced Materials and Biotechnology, Research Institute of Tsinghua-University in Shenzhen, Shenzhen High-Tech Industrial Estate, Nanshan, Shenzhen, PR China.
Med Hypotheses. 2008 Sep;71(3):374-8. doi: 10.1016/j.mehy.2008.01.035. Epub 2008 Jun 18.
It is well established that to exert their biological effects, bone morphogenetic proteins (BMPs) need be combined with carriers for controlled release. Clinically available delivery devices for recombinant human BMPs (rhBMPs) are far from ideal, despite their successful application in some orthopedic fields. To date, despite the ready availability of rhBMPs for clinical use, the dilemma facing clinicians and the biotechnology industry is how to find delivery systems that can further decrease the dose of BMPs and produce a more sustained release pattern as well as serve as a more effective scaffold for osteoconduction. A deep understanding of tissue-healing processes provides a clue for suitable delivery systems for BMPs. The processes of normal tissue-healing are biologically optimized, in that there are sequential overlapping stages for the transition from immature (provisional) to mature (definite) tissues. Logically, mimicking both the structures and the sequence of the tissue-healing process should be the best option for the design of materials for tissue repair because of their ability to initiate the body's natural tissue-healing cascades at the site of injury. Bone tissue repair begins with the formation of a blood clot. It follows that the structure of blood clots provides an ideal model of de novo repair material design. At the site of injury, not only fibrinogen but also plasma fibronectin and heparin released from mast cells during tissue injury participate in blood clotting and play important roles in initiating tissue repair. In this respect, the fibronectin-heparin complex is considered to serve as a nucleation center for the selective entrapment of molecules involved in wound repair, such as BMPs. Therefore, we hypothesize that an ideal delivery system for BMPs should be a heparin-incorporated fibrin-fibronectin matrix formed by mimicking the blood coagulation process. In the delivery system, fibrin glue serves as a scaffold that accommodates the infiltrating tissue, fibronectin provides adhesion sites for tissue repair cells and constitutes a connector for the fibrin glue and heparin, and heparin acts as a storage depot for BMPs and enhances their bioavailability. By regulating the ratio of heparin to BMP, BMP release can be predominantly by gel network biodegradation rather than by simple diffusion. The characteristics of this biodegradation determine the release of effective trace amounts of BMP, and these low doses of BMP allow sustained effective long-term release. Overall, this delivery device can meet the requirements of a new generation of BMP delivery systems.
众所周知，骨形态发生蛋白（BMPs）要发挥其生物学效应，需要与载体结合以实现控释。尽管重组人BMPs（rhBMPs）在一些骨科领域已成功应用，但临床上现有的rhBMPs递送装置远非理想。迄今为止，尽管rhBMPs已可用于临床，但临床医生和生物技术行业面临的困境是如何找到能够进一步降低BMPs剂量、产生更持续释放模式并作为更有效骨传导支架的递送系统。对组织愈合过程的深入理解为BMPs的合适递送系统提供了线索。正常组织愈合过程在生物学上是优化的，从不成熟（临时）组织到成熟（确定）组织的转变存在连续重叠的阶段。从逻辑上讲，模仿组织愈合过程的结构和顺序应该是组织修复材料设计的最佳选择，因为它们能够在损伤部位启动人体自然的组织愈合级联反应。骨组织修复始于血凝块的形成。因此，血凝块的结构为从头开始的修复材料设计提供了理想模型。在损伤部位，不仅纤维蛋白原，而且组织损伤期间肥大细胞释放的血浆纤连蛋白和肝素都参与血液凝固，并在启动组织修复中发挥重要作用。在这方面，纤连蛋白 - 肝素复合物被认为是伤口修复相关分子（如BMPs）选择性截留的成核中心。因此，我们假设BMPs的理想递送系统应该是通过模仿血液凝固过程形成的含肝素的纤维蛋白 - 纤连蛋白基质。在该递送系统中，纤维蛋白胶作为容纳浸润组织的支架，纤连蛋白为组织修复细胞提供粘附位点，并构成纤维蛋白胶和肝素的连接体，而肝素作为BMPs的储存库并提高其生物利用度。通过调节肝素与BMP的比例，BMP的释放主要通过凝胶网络生物降解而非简单扩散。这种生物降解的特性决定了有效痕量BMP的释放，而这些低剂量的BMP可实现持续有效的长期释放。总体而言，这种递送装置能够满足新一代BMP递送系统的要求。
