182
et al. developed an implantable porous laminin-based sponge material that immobilizes histidine-tagged VEGF via affinity interactions [27]. The authors report that
the laminin-VEGF transplantation into the injured cortex significantly increased
vessel density in and around the transplant, compared with laminin gel with and
without soluble VEGF. However, this non-injectable material is invasive and would
require further modification to be clinically translatable.
In order to fill the need for an injectable scaffold that provides both structural
support and delivers multiple provascular factors in a sustained manner, we developed a delivery system where VEGF is encapsulated in protease-specific, cleavable
peptides, in which degradation rate controls the VEGF release in the brain [40]. We
showed that the combination of VEGF nanocapsules and HA hydrogel with
fibronectin- derived RGD peptide can be injected directly into the stroke cavity,
which promotes greater vessel formation and pericyte recruitment, in and around
the lesion site, compared with empty HA and HA + soluble VEGF (Fig. 7.3).
Recently, we showed that displaying VEGF in a clustered conformation by
immobilizing covalently the growth factor on nanoparticles of heparin and controlling the discrete distribution on the particle’s surface modulates vascular
sprouting and endothelial proliferation in vitro [4]. In addition, the severe inflammatory response after stroke is widely regarded as the cause that impedes axonal
growth in the damaged central nervous system [3]. Thus, we hypothesized that the
brain administration of a dual-function engineered biomaterial with both immunomodulatory and angiogenic properties, directly to the stroke cavity, can promote tissue formation de novo by modulating poststroke inflammatory response
and vessel growth. For this, male adult mice were subjected to an ischemic stroke
and injected with a hyaluronic acid-based hydrogel containing heparin nanoparticles and different clusterization densities of bound VEGF onto heparin particle’s
surface [25]. We found that the highly clustered VEGF lead to the highest degree
of vascular growth in and around the stroke site (Fig. 7.4). Moreover, the addition
of naked heparin particles generates a vascularized network of regenerated functional axonal connections that leads to recovery and reduces the poststroke inflammation. These results are lost with the absence or reduction of bound VEGF where
only the immunomodulator effect is observed and with the absence or reduction
of heparin particles where angiogenesis is no longer associated with axonal
sprouting.
7.7 Conclusion
The use of pro-angiogenic materials, for focal and controlled delivery of vascular
growth factors to the brain, is an emerging discipline in the field of brain repair.
Although these materials have demonstrated potential in activating endogenous
endothelial cells in and around the damaged tissue, their ability to form vascular
structure de novo in the injected site is limited. Future work in this area needs to
L. R. Nih et al.
et al. developed an implantable porous laminin-based sponge material that immobilizes histidine-tagged VEGF via affinity interactions [27]. The authors report that
the laminin-VEGF transplantation into the injured cortex significantly increased
vessel density in and around the transplant, compared with laminin gel with and
without soluble VEGF. However, this non-injectable material is invasive and would
require further modification to be clinically translatable.
In order to fill the need for an injectable scaffold that provides both structural
support and delivers multiple provascular factors in a sustained manner, we developed a delivery system where VEGF is encapsulated in protease-specific, cleavable
peptides, in which degradation rate controls the VEGF release in the brain [40]. We
showed that the combination of VEGF nanocapsules and HA hydrogel with
fibronectin- derived RGD peptide can be injected directly into the stroke cavity,
which promotes greater vessel formation and pericyte recruitment, in and around
the lesion site, compared with empty HA and HA + soluble VEGF (Fig. 7.3).
Recently, we showed that displaying VEGF in a clustered conformation by
immobilizing covalently the growth factor on nanoparticles of heparin and controlling the discrete distribution on the particle’s surface modulates vascular
sprouting and endothelial proliferation in vitro [4]. In addition, the severe inflammatory response after stroke is widely regarded as the cause that impedes axonal
growth in the damaged central nervous system [3]. Thus, we hypothesized that the
brain administration of a dual-function engineered biomaterial with both immunomodulatory and angiogenic properties, directly to the stroke cavity, can promote tissue formation de novo by modulating poststroke inflammatory response
and vessel growth. For this, male adult mice were subjected to an ischemic stroke
and injected with a hyaluronic acid-based hydrogel containing heparin nanoparticles and different clusterization densities of bound VEGF onto heparin particle’s
surface [25]. We found that the highly clustered VEGF lead to the highest degree
of vascular growth in and around the stroke site (Fig. 7.4). Moreover, the addition
of naked heparin particles generates a vascularized network of regenerated functional axonal connections that leads to recovery and reduces the poststroke inflammation. These results are lost with the absence or reduction of bound VEGF where
only the immunomodulator effect is observed and with the absence or reduction
of heparin particles where angiogenesis is no longer associated with axonal
sprouting.
7.7 Conclusion
The use of pro-angiogenic materials, for focal and controlled delivery of vascular
growth factors to the brain, is an emerging discipline in the field of brain repair.
Although these materials have demonstrated potential in activating endogenous
endothelial cells in and around the damaged tissue, their ability to form vascular
structure de novo in the injected site is limited. Future work in this area needs to
L. R. Nih et al.