Growth Factor Delivery Systems for the Treatment of Cardiovascular Diseases - Biointerfaces: Where Material Meets Biology - page 77

clinical trial with FGF-2 did not show any difference between the placebo
and treated groups. 23 VEGF has been injected via both the intracoronary and
intravenous routes, showing an improvement in myocardial perfusion and
probing the safety and tolerability of the treatment and a dose-dependent
effect. 24,25 Despite these results Henry et al. did not find any significant
difference between non-treated and VEGF-treated groups using a larger
sample of patients, although they reported an improvement in quality of life.
Another GF that has been administered to patients subcutaneously is G-CSF.
The first trial promoted mononuclear CD34 + cell mobilization, which cor-
related with better ventricular function preservation and less remodeling. 26
The following trials performed by Zohlnh¨fer et al. 27 and Ripa et al. 28 also
observed a significant stem cell mobilization but no impact on infarct size,
left ventricular function or coronary restenosis.
Thenegativeresultsonthesetrialshaveevidencedsomelimitationsto
overcome in future studies. Maintenance of GF half-life at the accurate
concentration in the myocardium and the route of administration are the
main challenges. These are labile molecules that are degraded in a very
short period of time when directly administered to the organism, and
that is why intracoronary injection was thought to be effective but low
protein deposition was seen. Other methods, such as intrapericardial or
intravenous administration, are less attractive in a post-cardiac surgery
patient. 9
Controlled drug delivery systems have been developed to overcome
these limitations, maintaining precise concentrations of active GFs over
days or weeks and drug protection emulating the innate extracellular
matrix, since they can be made of different materials and they can in-
corporate two or more therapeutic proteins with different release profiles.
Currently, these systems are at the preclinical stage of safety and ecacy
evaluation.
In the following section we review the important criteria to design GF
delivery systems, beginning with an overview of biomaterials and GF in order
to deepen in DDS of GF for MI treatment, what has been done so far and the
challenges faced by researchers in this field.

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4.2 Drug Delivery Systems for Growth Factors
Once the GFs are synthesized they are released by cells for immediate sig-
naling or are sequestered in the extracellular matrix (ECM) providing phys-
ical cues for cells through spatial presentation. ECM degradation
coordinates the release of GFs in a controlled manner depending on cell
requirements. 29
Drug delivery systems (DDSs) using biomaterials that emulate natural
ECM behavior might allow temporal distribution of specific GFs, at the right
time and place and also would avoid the rapidly diffusion of these proteins
from the injection site or their degradation by proteases present in in-
flammatory environments like infarcted tissue. 30,31