Cell-based approaches to tissue repair suffer from rapid cell death upon implantation, limiting the window for therapeutic intervention. Despite robust lineage-specific differentiation potential in vitro, the function of transplanted mesenchymal stromal cells (MSCs) in vivo is largely attributed to their potent secretome comprising a variety of growth factors (GFs). Furthermore, GF secretion is markedly increased when MSCs are formed into spheroids. Native GFs are sequestered within the extracellular matrix (ECM) via sulfated glycosaminoglycans, increasing the potency of GF signaling compared to their unbound form. To address the critical need to prolong the efficacy of transplanted cells, alginate hydrogels are modified with sulfate groups to sequester endogenous heparin-binding GFs secreted by MSC spheroids. The influence of crosslinking method and alginate modification is assessed on mechanical properties, degradation rate, and degree of sulfate modification. Sulfated alginate hydrogels sequester a mixture of MSC-secreted endogenous biomolecules, thereby prolonging the therapeutic effect of MSC spheroids for tissue regeneration. GFs are sequestered for longer durations within sulfated hydrogels and retain their bioactivity to regulate endothelial cell tubulogenesis and myoblast infiltration. This platform has the potential to prolong the therapeutic benefit of the MSC secretome and serve as a valuable tool for investigating GF sequestration.
Stimulating
angiogenesis during wound healing continues to present
a significant clinical challenge, given the limitations of current
strategies to maintain therapeutic doses of growth factors and endothelial
cell efficacy. Incorporating a balance of specific cues to encourage
endothelial cell engraftment and cytokines to facilitate angiogenesis
is necessary for blood vessel growth in the proinflammatory wound
environment. Here, we incorporate a previously designed peptide (LXW7)
capable of binding to the αvβ3 integrin of endothelial
cells with a dermatan sulfate glycosaminoglycan backbone grafted with
collagen-binding peptides (SILY). By exploiting αvβ3 integrin-mediated
VEGF signaling, we propose an alternative strategy to overcome shortcomings
of traditional growth factor therapy while homing the peptide to the
wound bed. In this study, we describe the synthesis and optimization
of LXW7–DS–SILY (LDS) variants and evaluate their angiogenic
potential in vitro and in vivo. LDS displayed binding to collagen
and endothelial cells. In vitro, the LDS variant
with six LXW7 peptides increased endothelial cell proliferation, migration,
and tubule formation through increased VEGFR2 phosphorylation compared
to nontreated controls. In an in vivo chick chorioallantoic membrane
assay, LDS laden collagen hydrogels increased blood vessel formation
by 43% in comparison to the organism matched blank hydrogels. Overall,
these findings demonstrate the potential of a robust targeted glycan
therapeutic for promoting angiogenesis during wound healing.
Electrically conductive biomaterials direct cell behavior by capitalizing on the effect of bioelectricity in tissue homeostasis and healing. Many studies have leveraged conductive biomaterials to influence cells and improve tissue healing, even in the absence of external stimulation. However, most studies using electroactive materials neglect characterizing how the inclusion of conductive additives affects the material's mechanical properties, and the interplay between substrate electrical and mechanical properties on cell behavior is poorly understood. Furthermore, mechanisms dictating how electrically conductive materials affect cell behavior in the absence of external stimulation are not explicit. In this study, we developed a mechanically and electrically tunable conductive hydrogel using agarose and the conductive polymer PEDOT:PSS. Under certain conditions, we observed that the hydrogel physical and electrical properties were decoupled. We then seeded human mesenchymal stromal cells (MSCs) onto the hydrogels and observed enhanced adhesion and spreading of MSCs on conductive substrates, regardless of the hydrogel mechanical properties, and despite the gels having no cell-binding sites. To explain this observation, we measured protein interaction with the gels and found that charged proteins adsorbed significantly more to conductive hydrogels. These data demonstrate that conductivity promotes cell adhesion, likely by facilitating increased adsorption of proteins associated with cell binding, providing a better understanding of the mechanism of action of electrically conductive materials.
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