Delivery of Osteogenic Regulatory Growth Factors - Engineered Bone: Tissue Engineering Intelligence Unit - page 119

Others
Other synthetic materials that have been tested as BMP carrier include polyanhydrides, 134
poloxamers, 135 polyphosphate, 136 and methacrylate-based polymers. 137
Recently, Uludag and Gao explored a novel way to sequester BMP locally and investigated
synthetic thermoreversible polymers (i.e., polymers that exhibit a temperaturedependent solu-
bility in aqueous medium). 138,139 These polymers, based on N-isopropyl-acrylamide and ethyl
methacrylate, were engineered by incorporating a protein reactive group for controlled drug
delivery. In the soluble phase, an injectable solution is obtained which can conjugate with
BMP through the functional groups. Then, by simple transition of the temperature, the poly-
mer solution turns into insoluble hydrogel at the application site. A local retention of rhBMP-2
was observed using these thermoreversible polymers, although their in vivo osteoinductive
activity has to be demonstrated. Moreover, at this moment the biocompatibility and the
nonresorption of the polymer are critical issues that need to be evaluated for the use of this new
and promising BMP delivery system.
Composites Materials
As most of the carriers did not fulfil all the requirements of the ideal BMP delivery system,
much attention has been focused on the synthesis of composites of different materials combin-
ing the properties of both constituents.
On the one hand, osteoconductive materials with interesting physical characteristics such as
high porosity and large continuous macropores are typically unable to hold a large reservoir of
protein and are not capable of retaining proteins locally for a prolonged period of time. On the
other hand, materials with controllable local retention and release of growth factors usually
have weak mechanical properties as well as uncontrollable porosity. The association of comple-
mentary materials in term of properties will likely lead to materials of the next generation.
Some composite materials have already been tested as BMP delivery systems. For instance,
interesting results were obtained by the association of PLG polymers 140 or TCP and HA ce-
ramics with collagen or gelatin. 59,141-143
Conclusion
As early as 1982, upon isolating BMP, Urist et al realised the necessity of a suitable carrier to
decrease the rate of BMP diffusion and allow the induction process to proceed. 17 Recombinant
technology has enabled the cloning and expression of human BMPs in sufficient quantities for
therapeutic applications in preclinical studies. Many carriers have been tested as growth factor
delivery systems. Some of them have been evaluated more intensively such as collagen sponges
which have been tested in various animal models and in clinical trials for bone repair, 91,144
spine fusion 15,90 as well as in oral applications. 145 However, it seems unlikely that one single
delivery system for BMP will achieve optimal effects to suit all clinical needs. Different ana-
tomical sites do not heal in the same manner, and thus require carriers demonstrating different
features in terms of degradation rate, release kinetics and amount of implanted growth factor.
The challenge for researchers today is to deliver these factors in ways to ensure consistent
and safe success in humans. In the next decade, the delivery system should be improved and
delivery of a therapeutic dose of a drug is pivotal to its success. Thus, the carrier should retain
the optimal dose of the entrapped growth factor within the recipient bed.
Furthermore, we know that the bone repair process requires several growth and differentia-
tion factors, which act in a spacio-temporale manner. Novel carriers will combine various poly-
mers that release each growth factor with suitable kinetics in order to mimic the natural bone
healing process. These manifold delivery systems would improve the osteoinductive potency as
well as decrease the amount of factor within the site. They likely represent carriers of the future.
Acknowledgements
The author thanks Herve Petite and Keisuke Nakagawa for critical readings of the manu-
script.