Abstract
Retention and survival of transplanted cells are major limitations to the efficacy of regenerative medicine, with short-term paracrine signals being the principal mechanism underlying current cell therapies for heart repair. Consequently, even improvements in short-term durability may have a potential impact on cardiac cell grafting. We have developed a multimodal hydrogel-based platform comprised of a poly(ethylene glycol) network cross-linked with bioactive peptides functionalized with Gd(III) in order to monitor the localization and retention of the hydrogel in vivo by magnetic resonance imaging. In this study, we have tailored the material for cardiac applications through the inclusion of a heparin-binding peptide (HBP) sequence in the cross-linker design and formulated the gel to display mechanical properties resembling those of cardiac tissue. Luciferase-expressing cardiac stem cells (CSC-Luc2) encapsulated within these gels maintained their metabolic activity for up to 14 days in vitro. Encapsulation in the HBP hydrogels improved CSC-Luc2 retention in the mouse myocardium and hind limbs at 3 days by 6.5- and 12- fold, respectively. Thus, this novel heparin-binding based, Gd(III)-tagged hydrogel and CSC-Luc2 platform system demonstrates a tailored, in vivo detectable theranostic cell delivery system that can be implemented to monitor and assess the transplanted material and cell retention.
Highlights
With the advent of stem cell therapy, the regenerative medicine field united around cell transplantation as an immediately workable solution to restore damaged heart tissue
Time sweeps revealed that gel formulations containing 25%, 75%, and 100% heparin-binding peptide (HBP) cross-linking moieties had similar cross-linking times at 40 ± 2, 47 ± 4, and 39 ± 4 min, respectively. 50% HBP cross-linked gels were slightly slower at 52 ± 10 min, whereas 0% HBP cross-linked gels reached the gelation point more rapidly at 20 ± 2 min (Figure 1A)
Substituting HBP for 25−100% of the cross-linkers within the poly(ethylene glycol) (PEG) hydrogels caused no substantive change in the average moduli displayed in the frequency and strain sweeps at physiologically relevant conditions[37−39] (Figure 1B,C)
Summary
With the advent of stem cell therapy, the regenerative medicine field united around cell transplantation as an immediately workable solution to restore damaged heart tissue. In order to improve the efficacy of cell therapy, the field has transitioned toward developing strategies to enhance transplanted cell engraftment. Various methods, including pretreatment of transplanted cell populations and target tissue, have been attempted to achieve a sustained regenerative effect,[7,8] but the principal focus has been on developing biomaterial delivery systems to improve grafted cell viability and retention within the area of injury after myocardial infarction (MI). Numerous combinations of materials and cellular products have been examined for their impact on cardiac regeneration after MI, progression has been limited with only three alginate-based hydrogel designs in clinical application.[18]
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