Biomedical Engineering Reference
In-Depth Information
radio-labeled growth factors yielded target recovery rates of 0.5%afterintra-
venous injection and 3-5% after injection into the heart [148]. Consequently,
inappropriate local and temporal availability of VEGF, and the lack of interac-
tion with other important growth factors likely account for the disappointing
results of clinical trials. Enhancing the applied dose may improve the desired
outcome at the diseased tissue site; however, this could cause pathologic an-
giogenesis at nontarget sites (e.g., the eye or dormant tumors) (Fig. 1).
Biomimetic polymeric vehicles may represent an ideal approach to deliver
VEGF in a biologically relevant manner. We suggest that appropriately de-
signed systems are capable of regenerating functional blood vessel networks,
and that high drug target levels, prolonged presence of the factor, minimized
systemic exposure, and simultaneous or sequential supply of multiple growth
factors are critical to this end. Specifically, polymeric devices that allow com-
bination therapy of VEGF with vessel stabilizing factors such as PDGF or
Ang-1 may lead to enhanced functionality of regenerated blood vessels.
4.1.2
Polymeric Delivery Systems
Polymeric VEGF delivery systems that can be applied in a minimally invasive
manner are ideal for therapeutic angiogenesis applications. Acute situations
(e.g., infarctions due to occlusion of blood vessels that supply the heart mus-
cle) may require VEGF delivery for weeks, while chronic diseases may require
more prolonged VEGF delivery. The physical characteristics of the circula-
tory system and the heart are amenable to delivery with a vehicle that may
be placed by injection through a syringe or catheter, or implantable systems.
Hydrogels and microspheres may be suitable candidates for injection as their
characteristics can be adjusted according to the local geometry and physi-
cal environment (e.g., delivery to either the apex or the base of the heart
wall [149]), while porous polymer scaffolds may be useful as patches and
wraps.
A variety of different injectable gels and microspheres may be used to en-
hance local angiogenesis. Delivery from glutaraldehyde cross-linked gelatin
microspheres may result in prolonged local presentation of angiogenic fac-
tors, relative to bolus injection [150, 151], although the advantage of this car-
rier over bolus injection has still to be proven [150, 151]. Injectable systems
releasing VEGF upon cellular demand have also been prepared from PEG and
fibrin matrices [31, 35]. Fibrin inherently promotes blood vessel formation.
PEG hydrogel matrices, in contrast, need to be rendered adhesive by polymer
conjugation with cell recognition motifs such as RGD-peptides [35, 91]. The
concentration of incorporated VEGF can regulate proteolytic enzyme pro-
duction by endothelial cells, while incorporation of additional growth factors
(e.g., TGF-beta) may aid in bioactivation of these enzymes [91], and con-
comitantly provides signal necessary for the maturation of neovessels [18, 19].
