In vivo assessment of grafted cortical neural progenitor cells and host response to functionalized self-assembling peptide hydrogels and the implications for tissue repair

Rodriguez, Alexandra L.; Wang, Ting‐Yi; Bruggeman, Kiara F.; Horgan, Conor C.; Li, R; Williams, Richard J.; Parish, Clare L.; Nisbet, David R.

doi:10.1039/c4tb01391c

Cited by 67 publications

(79 citation statements)

References 36 publications

(52 reference statements)

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“…This was confirmed when both Fmoc-DDIKVAV and Fmoc-DDIKVAVK formed clear, selfsupporting hydrogels at pH ~7.4 using the pH switch method previously described ( Fig. 1(b)) [34].…”

Section: Materials Characterization Of the Lysinefunctionalized Self-amentioning

confidence: 55%

“…Fmoc-SAPs were synthesized manually by solid-phase peptide synthesis (SPPS) as previously described [34]. SPPS was performed in a rotating glass reactor vessel at 0.4-mmol scale.…”

Section: Solid-phase Peptide Synthesismentioning

confidence: 99%

“…A LaB6 filament at 100 kV was used. Negative stains were performed to image the Fmoc-SAP samples as previously described [34].…”

Section: Transmission Electron Microscopy (Tem)mentioning

confidence: 99%

“…We have shown that the mechanical properties of these Fmoc-SAPs can be easily tailored for tissue-specific applications through adjustment of the rate of assembly as well as the ionic concentration, without disturbing the nanofibrous morphology [31]. The biocompatibility of Fmoc-SAPs has been demonstrated across a range of sequences, and we have shown that optimal biocompatibility and functionality of the Fmoc-SAPs requires the incorporation of bioactive peptide sequences [30,[32][33][34]. Previously, in a demonstration of the utility of these materials in a neural context, we incorporated the laminin-based isoleucine-lysine-valine-alanine-valine (IKVAV) sequence (known to promote neuron survival, neural differentiation, and neurite extension [35]) into an Fmoc-SAP system [36], as we do again here, and have validated its performance in vivo [34].…”

Section: Introductionmentioning

confidence: 96%

“…The biocompatibility of Fmoc-SAPs has been demonstrated across a range of sequences, and we have shown that optimal biocompatibility and functionality of the Fmoc-SAPs requires the incorporation of bioactive peptide sequences [30,[32][33][34]. Previously, in a demonstration of the utility of these materials in a neural context, we incorporated the laminin-based isoleucine-lysine-valine-alanine-valine (IKVAV) sequence (known to promote neuron survival, neural differentiation, and neurite extension [35]) into an Fmoc-SAP system [36], as we do again here, and have validated its performance in vivo [34]. This capacity to concomitantly present a bioactive peptide sequence at high density for directing cell behavior while also providing structural support through the selfassembled matrix makes Fmoc-SAP scaffolds a highly sophisticated class of biomaterials, ideal for tissue engineering in the CNS.…”

Section: Introductionmentioning

confidence: 98%

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Tailoring minimalist self-assembling peptides for localized viral vector gene delivery

et al. 2015

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Viral vector gene delivery is a promising technique for the therapeutic administration of proteins to damaged tissue for the improvement of regeneration outcomes in various disease settings including brain and spinal cord injury, as well as autoimmune diseases. Though promising results have been demonstrated, limitations of viral vectors, including spread of the virus to distant sites, neutralization by the host immune system, and low transduction efficiencies have stimulated the investigation of biomaterials as gene delivery vehicles for improved protein expression at an injury site. Here, we show how Nfluorenylmethyloxycarbonyl (Fmoc) self-assembling peptide (SAP) hydrogels, designed for tissue-specific central nervous system (CNS) applications via incorporation of the laminin peptide sequence isoleucine-lysine-valine-alaninevaline (IKVAV), are effective as biocompatible, localized viral vector gene delivery vehicles in vivo. Through the addition of a C-terminal lysine (K) residue, we show that increased electrostatic interactions, provided by the additional amine side chain, allow effective immobilization of lentiviral vector particles, thereby limiting their activity exclusively to the site of injection and enabling focal gene delivery in vivo in a tissue-specific manner. When the C-terminal lysine was absent, no difference was observed between the number of transfected cells, the volume of tissue transfected, or the transfection efficiency with and without the Fmoc-SAP. Importantly, immobilization of the virus only affected transfection cell number and volume, with no impact observed on transfection efficiency. This hydrogel allows the sustained and targeted delivery of growth factors post injury. We have established Fmoc-SAPs as a versatile platform for enhanced biomaterial design for a range of tissue engineering applications.

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“…This was confirmed when both Fmoc-DDIKVAV and Fmoc-DDIKVAVK formed clear, selfsupporting hydrogels at pH ~7.4 using the pH switch method previously described ( Fig. 1(b)) [34].…”

Section: Materials Characterization Of the Lysinefunctionalized Self-amentioning

confidence: 55%

“…Fmoc-SAPs were synthesized manually by solid-phase peptide synthesis (SPPS) as previously described [34]. SPPS was performed in a rotating glass reactor vessel at 0.4-mmol scale.…”

Section: Solid-phase Peptide Synthesismentioning

confidence: 99%

“…A LaB6 filament at 100 kV was used. Negative stains were performed to image the Fmoc-SAP samples as previously described [34].…”

Section: Transmission Electron Microscopy (Tem)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 98%

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Tailoring minimalist self-assembling peptides for localized viral vector gene delivery

et al. 2015

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Hydrogel‐Immobilized Supercharged Proteins

et al. 2018

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Shear Containment of BDNF within Molecular Hydrogels Promotes Human Stem Cell Engraftment and Postinfarction Remodeling in Stroke

et al. 2018

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Improved control over spatiotemporal delivery of growth factors is needed to enhance tissue repair. Current methods are limited-requiring invasive procedures, poor tissue targeting, and/or limited control over dosage and duration. Incorporation into implantable biomaterials enables stabilized delivery and avoids burst release/fluctuating doses. Here, the physical forces of fibrils formed by self-assembly of epitope-containing peptides are exploited. This biomimetic hydrogel is loaded with neurotrophic factor BDNF via a shear-induced gel-solution transition, unique to noncovalent hydrogels. This results in a biomaterial with three desirable features: a nanofibrillar scaffold, presentation of a laminin epitope, and slow release of BDNF. In a stroke-injury model, synergistic actions of this trimodal strategy on the integration of transplanted human neural progenitor cells, and protection of peri-infarct tissue are identified. These BDNF-functionalized hydrogels promote the integration of transplanted human embryonic stem cell-derived neural progenitors-resulting in larger grafts with greater cortical differentiation, appropriate for neuronal replacement. Furthermore, BDNF promotes the infiltration of host endothelial cells into the graft to augment vascularization of the graft, and adjacent penumbra tissue. These findings demonstrate the benefits of multifaceted tissue-specific hydrogels to provide biomimetics of the host tissue, while sustain protein delivery, to promote endogenous and graft-derived tissue repair. Self-Assembling PeptidesThe ORCID identification number(s) for the author(s) of this article can be found under https://doi.

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In vivo assessment of grafted cortical neural progenitor cells and host response to functionalized self-assembling peptide hydrogels and the implications for tissue repair

Abstract: Functionalized N-fluorenylmethyloxycarbonyl self-assembling peptides are biocompatible in vivo, demonstrating their utility as a cell delivery vehicle for tissue engineering.

Cited by 67 publications

References 36 publications

Tailoring minimalist self-assembling peptides for localized viral vector gene delivery

Tailoring minimalist self-assembling peptides for localized viral vector gene delivery

Hydrogel‐Immobilized Supercharged Proteins

Shear Containment of BDNF within Molecular Hydrogels Promotes Human Stem Cell Engraftment and Postinfarction Remodeling in Stroke

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