Delivery of Osteogenic Regulatory Growth Factors - Engineered Bone: Tissue Engineering Intelligence Unit - page 109

authors have demonstrated the effects of these parameters on bone formation. 24,25 Three
dimensional-systems for bone tissue regeneration imply a specific internal microarchitecture of
the materials used. Microarchitecture entails having sufficiently large porosity (> 100 µ m) and
interconnections between the pores for diffusion of nutrients, clearance of wastes, and infiltra-
tion of progenitor cells. In addition to osteoprogenitor cells, endothelial cells must be able to
migrate into or near the matrix and develop vascular beds to nourish the newly formed tissue.
Interestingly, Jin et al have shown that the length and continuity of pores as well as the sur-
rounding spaces controlled the capillary penetration and thus influenced bone formation. 23
They observed that a porous structure such as hydroxyapatite particles or fibrous collagen,
which are favourable for vascularisation, allowed rapid differentiation leading to direct osteo-
genesis without an observable chondrogenesis phase. Early in 1961, Bassett showed that oxy-
gen pressure was one of the reasons vasculature is essential to osteogenesis but not to chondro-
genesis. He reported that high oxygen pressure favours osteogenesis whereas low oxygen pressure
favours chondrogenesis in an in vitro culture system.
The mechanical stability of the scaffold as well as the mechanical load transfer might also
play a significant role in the success of a device. For this reason, osteoconductive biomaterials
can serve as a starting point for the design of BMP carriers.
Degradation of the Carrier
Biodegradable materials are preferred for several reasons: Firstly, they disappear from the
body, leaving space for the newly formed bone. Secondly, they obviate concerns about long-term
biocompatibility. Thirdly, while diffusion-controlled release is an excellent means of achieving
predefined rates of drug delivery, it is limited by the material permeability and the characteris-
tics of the drug. 26 Thus, complete degradation of the scaffold allows a more efficient and com-
plete drug delivery.
A promising scaffold used to deliver osteoinductive growth factor at the defect site should
not only allow an appropriate delivery of the growth factor but also assist local bone formation.
The important point is that the rate of biodegradation must be commensurate to the rate of
bone formation, otherwise bone repair will be delayed, inhibited, or corrupted. 27 When the
rate of carrier degradation is too slow compared to the rate of bone formation at the implant
site, the remaining carrier will physically impede bone growth in the defect. Inversely, when the
rate of the carrier degradation is too fast, it will fail to prolong the in vivo retention of growth
factors and may promote the ingrowth of soft tissues. It is known that the infiltration of fibrous
tissue into a large size defect will interfere with bone regeneration.
Interactions between Carriers and Growth Factors
The primary role of a delivery system is to provide stabilisation and preservation of the
growth factor until in vivo delivery. 28 The interaction between carriers and growth factors
should delay the rapid dispersion of BMPs from the implant site. Without such protection,
BMPs would rapidly degrade due to cellular proteolysis.
Essentially, the interactions between the carrier and the released growth factor depend on
ionic and hydrophobic interactions. Uludag et al demonstrated that rhBMPs differentially
bound to various carriers as a function of their isoelectric point (pI). 29 The protein retention in
the carrier decreased with the protein pI (rhBMP-2 ~ rhBMP-6 > rhBMP-4 > acetylated/
succinylated rhBMP-2) and this phenomenon was observed irrespective of the physicochemi-
cal nature of the carrier (collagen sponge, poly (glycolic acid) mesh, bovine bone mineral, and
human demineralized bone matrix (DBM)) (Fig. 1). Since proteins with a lower pI have a
higher fraction of negatively charged residues, the faster rate of BMP loss might be attributed
to a lower affinity of the protein for the carrier and/or higher solubility of the molecule in the
biological medium. In order to maximise the in vivo osteoinductive potency of BMPs, these
experiments emphasised the necessity to optimise their initial retention resulting from a good
growth factor-carrier affinity.