Optimal delivery systems for bone morphogenetic proteins in orthopedic applications should model initial tissue repair structures by using a heparin-incorporated fibrin-fibronectin matrix.

摘要

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.