180
7.5 Current VEGF-Based Therapeutic Approach
Interestingly, studies with therapeutic VEGF application revealed quite different
effects, depending on the timing of administration and the route of growth factor
delivery. The systemic or intracerebral administration of VEGF, within the first 48 h
after stroke onset, was associated with an increased blood-brain barrier opening and
subsequent edema and promoted the formation of disorganized and immature vasculature [39]. Likewise, the early administration of an antagonist for endogenous
VEGF reduced the ischemia−/reperfusion-related brain edema and injury [35].
Similarly, infusing VEGF into the lateral ventricles stimulated angiogenesis and
decreased infarct volume in rodent models of cerebral ischemia [33]. In transgenic
mice overexpressing human VEGF 165, brain microvessel density was significantly
increased, compared to wild-type before and after ischemia [36]. In addition, VEGF
is associated with a reduced infarct volume when topically applied on the surface of
the reperfusion site in a transient model of cerebral ischemia [15]. A completely
different picture resulted from studies where VEGF was administered repeatedly
[33], in delayed delivery (after day 3) [16] or when the growth factor was encapsulated in a hydrogel [11]. These studies consistently found improvement in neurological deficits following VEGF therapy, along with a reduction in ischemic injury,
brain edema, and blood-brain barrier permeability for serum proteins, with an overall better effect when administered locally rather than systemically [21]. This suggests that maintaining elevated tissue levels of VEGF in the stroke site, for prolonged
periods of time along with controllable spatial distribution, dosage, and duration of
exposure, satisfies many of the characteristics of an ideal delivery system, by overcoming the main limitations of poor penetration across the blood-brain barrier, the
clinically unviable option of repeated local injections, and the short VEGF half-life
time.
7.6 Tissue Engineering Approach to Promote Brain
Angiogenesis
Recent advances in our understanding of the central nervous system and the development of sophisticated biomaterials have significantly changed the landscape for
developing strategies to repair the damaged brain. Tissue engineering approaches
now offer the potential to design biomaterials tailored for particular applications
such as hydrogels to fill out the stroke site, where necrotic tissue gives place to an
empty compartmentalized cavity. These biomaterials offer a physical support for
cell infiltration in a highly inflamed and damaged tissue, and present the ability to
protect and enhance the beneficial effect of provascular growth factors, known to
have a short half-life time and severe side effects due to its ability to promote vascular permeability [39]. Developing engineered pro-repair approaches is a scientific
challenge on many levels, since (1) therapeutic agents must remain alive/active
L. R. Nih et al.
7.5 Current VEGF-Based Therapeutic Approach
Interestingly, studies with therapeutic VEGF application revealed quite different
effects, depending on the timing of administration and the route of growth factor
delivery. The systemic or intracerebral administration of VEGF, within the first 48 h
after stroke onset, was associated with an increased blood-brain barrier opening and
subsequent edema and promoted the formation of disorganized and immature vasculature [39]. Likewise, the early administration of an antagonist for endogenous
VEGF reduced the ischemia−/reperfusion-related brain edema and injury [35].
Similarly, infusing VEGF into the lateral ventricles stimulated angiogenesis and
decreased infarct volume in rodent models of cerebral ischemia [33]. In transgenic
mice overexpressing human VEGF 165, brain microvessel density was significantly
increased, compared to wild-type before and after ischemia [36]. In addition, VEGF
is associated with a reduced infarct volume when topically applied on the surface of
the reperfusion site in a transient model of cerebral ischemia [15]. A completely
different picture resulted from studies where VEGF was administered repeatedly
[33], in delayed delivery (after day 3) [16] or when the growth factor was encapsulated in a hydrogel [11]. These studies consistently found improvement in neurological deficits following VEGF therapy, along with a reduction in ischemic injury,
brain edema, and blood-brain barrier permeability for serum proteins, with an overall better effect when administered locally rather than systemically [21]. This suggests that maintaining elevated tissue levels of VEGF in the stroke site, for prolonged
periods of time along with controllable spatial distribution, dosage, and duration of
exposure, satisfies many of the characteristics of an ideal delivery system, by overcoming the main limitations of poor penetration across the blood-brain barrier, the
clinically unviable option of repeated local injections, and the short VEGF half-life
time.
7.6 Tissue Engineering Approach to Promote Brain
Angiogenesis
Recent advances in our understanding of the central nervous system and the development of sophisticated biomaterials have significantly changed the landscape for
developing strategies to repair the damaged brain. Tissue engineering approaches
now offer the potential to design biomaterials tailored for particular applications
such as hydrogels to fill out the stroke site, where necrotic tissue gives place to an
empty compartmentalized cavity. These biomaterials offer a physical support for
cell infiltration in a highly inflamed and damaged tissue, and present the ability to
protect and enhance the beneficial effect of provascular growth factors, known to
have a short half-life time and severe side effects due to its ability to promote vascular permeability [39]. Developing engineered pro-repair approaches is a scientific
challenge on many levels, since (1) therapeutic agents must remain alive/active
L. R. Nih et al.