Delivery of Osteogenic Regulatory Growth Factors - Engineered Bone: Tissue Engineering Intelligence Unit - page 116

Hyaluronic Acid
Hyaluronic acid (HA) is a polysaccharide which exists naturally in the ECM and plays an
important role in proteoglycan organisation, cell hydration, cell differentiation, and wound
healing. 98 Hyaluronan is easily derivatized by the introduction of functional groups onto the
glucuronic acid residue and easily crosslinked yielding biocompatible and biodegradable
hydrogels, films, or sponges. Some derivatized hyaluronic acid scaffolds were investigated as
rhBMP-2 delivery vehicles. Kim et al obtained a matrix that demonstrated in vitro a slow and
sustained rhBMP-2 release during one month. This retention level was much greater than that
from collagen gels, which released most of the initial load of BMP within 14 days in same
experience. 99 This result suggested a good rhBMP-2 affinity towards the HA scaffold, probably
due to an electrostatic interaction between the basic growth factor and the acidic, carboxylic
acid residues of the polysaccharide. However, this scaffold has not yet been evaluated in vivo
with BMP. Others have formed high-molecular-weight HA-derived hydrogels that were easily
infiltrated by cells and supported growth factor-induced bone tissue formation and remodeling
in the rat ectopic bone formation model. 100 Recently, HA sponges have been shown to be
suitable rhBMP-2 carrier for the reconstruction of advanced alveolar ridge defects in dogs. 101
Fibrin Matrix
Fibrin matrix derived from human plasma combine numerous properties such as hemo-
static ability, resorbability, angiotropicity, and provides an excellent three-dimensional cell in-
filtration scaffold. They mimic the last step of the physiological coagulation by the mixture of
fibrinogen, factor XIII, thrombin and Ca 2+ ions. However, because of the lack of solid evidence
of safety and efficacy, commercial fibrin sealants were not approved by the FDA in United
States for many years, which might explain the lack of data with this material. Only recently
commercial products have been developed and are now the object of clinical trials in this
country. 102
Very few experiments reported the implantation of human fibrin as delivery vehicles for
BMP. After three weeks of implantation in ectopic sites, correlated microradiographic and
histologic observations showed that a BMP/fibrin composite produced larger volumes of new
bone than the BMP control group. 103 The authors suggested that the fibrin may cause a syner-
gistic effect, stabilising the BMP while enhancing cell proliferation. More recently, fibrin carri-
ers have been used in association with DBM and FGF-1 in a critical-sized defect in rabbit
radius. Interestingly, the combination fibrin/FGF-1 also promoted a significant increase in
bone formation. 104
Sakiyama-Elbert et al developed a novel approach to deliver growth factor from a fibrin
matrix based on a localised release of bound growth factors from the matrix in response to
cellular activity during healing. 34 The fibrin matrix was modified to contain immobilised hep-
arin that served to sequester exogenous heparin-binding growth factors within the scaffold.
The proteins can be released by enzymatic factors such as heparinase or plasmin. These matri-
ces have been tested with FGF-2 as therapeutic materials to enhance nerve regeneration in
vitro. Although this sustained delivery system needs to be validated in vivo, we can hypothesise
that similar matrices might apply for bone regeneration by locally delivering BMPs, which are
also, heparin-binding growth factors.
Synthetic Polymers
Materials that are well characterised, easy to manufacture, cost-efficient, free of potential
contamination and easy to sterilise are synthetic polymers. Over the past two decades, the use
of polymeric materials as biomedical devices has increased dramatically, particularly in the
areas of controlled drug delivery systems. 105 The pioneering studies in the field of controlled
subdermal drug delivery began in 1960s, and used biostable commercial polymers such as
polyethylene and silicon rubber. 106 The release rate of the drug from the polymeric matrix or
reservoir device was determined solely by diffusion.