Delivery of Osteogenic Regulatory Growth Factors - Engineered Bone: Tissue Engineering Intelligence Unit - page 111

prolong exposure of the proteins to stem cells and may allow their interaction with other growth
and differentiating factors, setting the stage for synergistic activity. However, in many studies,
authors point out the difficulty in maintaining growth factor release over the rather long dura-
tion of bone regeneration. It seems essential that the delivery system provides a prolonged
release of the active growth factor over the full duration of wound healing.
The observations made on in vitro studies as well as on retrieved implants in the rat ectopic
model indicate that pharmacokinetic profiles of rhBMP could be influenced by the chemical
properties of the carrier system. 36,38 The typical in vivo release profile consists of an initial burst
release within the first few hours of implantation, which appears to be carrier dependent, fol-
lowed by a secondary release characterised by a half-life of 1 to 10 days (Fig. 1). The differences
in the initial rhBMP-2 release between carriers (range 75-10%) are presumably due to differ-
ences in their available surface areas and/or differences in binding affinities with the growth
factor. Collagen based carriers demonstrate a sustained release which parallels the gradual deg-
radation of the material. Conversely, mineral based carriers show a burst in initial release, but
thereafter, seem to irreversibly bind a fraction of rhBMP-2 within the implants. 36 The reason
for this behaviour is not clearly understood and would need a more precise understanding of
the interaction between the carrier surface and the growth factors. Recently, Ziegler et al ob-
served an alteration of the molecular structure of released growth factors in vitro from various
biodegradable carriers (TCP, PLG/ceramic glass, ceramic glass and dehydrated bone). 38 This
observation emphasises the need to check the biological activity of the released growth factor
after its association with the carrier. To impede the potential degradation of the protein, some
authors protect the growth factor molecule with material comprising similar properties to those
of heparin. 33
It has been suggested that the initial burst release of growth factor from the implants might
serve as a chemotactic signal for the local recruitment of stem cells. Thereafter, the slow release
of residual BMP retained in the implant might serve to differentiate recruited stem cells to-
wards an osteoblast phenotype. 36 This is important in the treatment of large defects, where
undifferentiated cells have to migrate long distances for proliferation and differentiation into
hypovascularized tissues.
Interestingly, different in vivo pharmacokinetics have demonstrated a positive correlation
between the retention of rhBMP upon implantation and the osteoinductive activity, i.e., a
higher growth factor retention within a scaffold resulted in significantly higher bone scores.
For instance, despite similar in vitro specific activities, rhBMP-2 has been shown to be more
effectively retained at the implant site and more osteoinductive than rhBMP-4. This phenom-
enon was observed for both collagen and lactide/glycolide-based delivery systems 37 (Fig. 2). A
high local BMP concentration in the implant might allow a larger proportion of uncommitted
cells to differentiate into osteoblasts.
In conclusion, all these investigations demonstrate that pharmacokinetics of BMP-release is
a key factor for good bone regeneration. However several important questions remain:
Do the rhBMP pharmacokinetics obtained at a heterotopic site correspond to the ones
obtained in an intraosseous site?
What are the local needs for various growth factors and their doses during human bone
regeneration?
What is the optimal time period for the most effective growth factor delivery?
Carrier Matrices
This chapter gives an overview of the major organic, inorganic, and composite carriers that
have been used in preclinical experiments, or promising ones, which are still at an experimental
stage. It summarises the relevant experiments with these materials as growth factor delivery
systems and highlights the advantages and drawbacks of these materials (see Table 1).
However, the comparison of these scaffolds as BMPs delivery systems is a difficult task due
to variations in either preclinical models (differences in animal species, age and anatomical sites
of implantation, etc.) or BMP sources (especially for purified BMP preparations).