began to degrade, and 30 days after transplantation, the collagen had degraded
completely. Herein, it was concluded that the beneficial effect of the complexes is
mediated by a neuroprotective rather than a regenerative mechanism.
In the same year, Zhong and co-workers carried out a study in a photothrombotic
stroke murine model [38]. The stroke cavity provides an ideal target for transplantation because it is a compartmentalized region of necrosis, can accept a high volume
transplant without tissue damage, and lies directly adjacent to the most plastic brain
area in stroke. However, direct transplantation into the stroke cavity usually causes
massive death in the transplant. To overcome these limitations, the authors tested
stem/progenitor transplants within a specific cross-linked biohydrogel matrix made
of hyaluronan, heparin, and collagen I to create a favorable environment for transplantation into the infarct cavity after stroke, and the results were compared to those
obtained from direct injection of stem cells without hydrogel support. In this study,
both embryonic cortex-derived NPCs and ESC (embryonic stem cell)-derived NPCs
were used. Overall, hyaluronan-heparin-collagen hydrogels were found to promote
the survival of NPCs derived from both the fetal cortex and ESCs, with no effect on
cellular differentiation or migration of the cells from the stroke site. Quantitative
analysis of the transplant and surrounding tissue indicates diminished inflammatory
infiltration of the graft with the hydrogel transplant. In this respect, the beneficial
effect of the hydrogel was found to be at least twofold higher than that obtained with
NSCs in the absence of the gel matrix.
In 2013, Hoban and co-workers provided evidence for collagen I as a
noncytotoxic and self-healing hydrogel in situ [39]. The researchers injected the
striatum of sham rats with glial cell line-derived neurotrophic factor (GDNF)overexpressing rat bone marrow MSCs (GDNF-MSCs) encapsulated in a collagen
hydrogel cross-linked with 4S-StarPEG (PEG ether tetrasuccinimidyl glutarate)
(Fig. 14). In vitro studies confirmed that the collagen I hydrogel was nontoxic to
neural cells or MSCs seeded within it and also permitted diffusion of GDNF from
GDNF-MSCs into the cell culture medium. More importantly, it significantly
reduced the host brain’s response to the cells by reducing the recruitment of both
microglia and astrocytes at the site of delivery. Although the hydrogel prevented
micro- and macrogliosis compared to the medium-injected control group, the scaffold poorly supported MSCs survival and decreased in volume several days post
gelation both in vitro and in vivo.
At the same time, Liang and co-workers developed a set of injectable hydrogels
with variable HA:gelatin:PEG diacrylate ratios and used them to encapsulate C17.2
NSCs (mouse immortalized NSCs), human ReNcells (human immortalized NPCs),
and human GRPs (glial-restricted progenitor cells) [40]. The gelation properties of the
hydrogel were first characterized and optimized for intracerebral injection, resulting in
a 25 min delayed injection after mixing the hydrogel components. To determine the
optimal time for hydrogel delivery into the brain, the authors compared the resulting
morphology of the hydrogel scaffold in vivo following an immediate or delayed
injection. It was found that delayed injection produced optimal results, without leakage
of gelatin into the brain tissue. The authors showed that an increase in gelatin content
extended the gelation time, while HA promoted survival of all cell lines. In contrast,
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R. de la Cruz and D. D. Díaz
completely. Herein, it was concluded that the beneficial effect of the complexes is
mediated by a neuroprotective rather than a regenerative mechanism.
In the same year, Zhong and co-workers carried out a study in a photothrombotic
stroke murine model [38]. The stroke cavity provides an ideal target for transplantation because it is a compartmentalized region of necrosis, can accept a high volume
transplant without tissue damage, and lies directly adjacent to the most plastic brain
area in stroke. However, direct transplantation into the stroke cavity usually causes
massive death in the transplant. To overcome these limitations, the authors tested
stem/progenitor transplants within a specific cross-linked biohydrogel matrix made
of hyaluronan, heparin, and collagen I to create a favorable environment for transplantation into the infarct cavity after stroke, and the results were compared to those
obtained from direct injection of stem cells without hydrogel support. In this study,
both embryonic cortex-derived NPCs and ESC (embryonic stem cell)-derived NPCs
were used. Overall, hyaluronan-heparin-collagen hydrogels were found to promote
the survival of NPCs derived from both the fetal cortex and ESCs, with no effect on
cellular differentiation or migration of the cells from the stroke site. Quantitative
analysis of the transplant and surrounding tissue indicates diminished inflammatory
infiltration of the graft with the hydrogel transplant. In this respect, the beneficial
effect of the hydrogel was found to be at least twofold higher than that obtained with
NSCs in the absence of the gel matrix.
In 2013, Hoban and co-workers provided evidence for collagen I as a
noncytotoxic and self-healing hydrogel in situ [39]. The researchers injected the
striatum of sham rats with glial cell line-derived neurotrophic factor (GDNF)overexpressing rat bone marrow MSCs (GDNF-MSCs) encapsulated in a collagen
hydrogel cross-linked with 4S-StarPEG (PEG ether tetrasuccinimidyl glutarate)
(Fig. 14). In vitro studies confirmed that the collagen I hydrogel was nontoxic to
neural cells or MSCs seeded within it and also permitted diffusion of GDNF from
GDNF-MSCs into the cell culture medium. More importantly, it significantly
reduced the host brain’s response to the cells by reducing the recruitment of both
microglia and astrocytes at the site of delivery. Although the hydrogel prevented
micro- and macrogliosis compared to the medium-injected control group, the scaffold poorly supported MSCs survival and decreased in volume several days post
gelation both in vitro and in vivo.
At the same time, Liang and co-workers developed a set of injectable hydrogels
with variable HA:gelatin:PEG diacrylate ratios and used them to encapsulate C17.2
NSCs (mouse immortalized NSCs), human ReNcells (human immortalized NPCs),
and human GRPs (glial-restricted progenitor cells) [40]. The gelation properties of the
hydrogel were first characterized and optimized for intracerebral injection, resulting in
a 25 min delayed injection after mixing the hydrogel components. To determine the
optimal time for hydrogel delivery into the brain, the authors compared the resulting
morphology of the hydrogel scaffold in vivo following an immediate or delayed
injection. It was found that delayed injection produced optimal results, without leakage
of gelatin into the brain tissue. The authors showed that an increase in gelatin content
extended the gelation time, while HA promoted survival of all cell lines. In contrast,
372
R. de la Cruz and D. D. Díaz