Biomimetic matrices for myocardial stabilization and stem cell transplantation

Department of Bioengineering, University of California at Berkeley, Berkeley, California, USA.
Journal of Biomedical Materials Research Part A (Impact Factor: 3.37). 12/2010; 95(4):1055-66. DOI: 10.1002/jbm.a.32904
Source: PubMed


Although natural biological matrices have demonstrated modest improvement in the survival of cells transplanted into the infarcted myocardium, these materials have not been amenable to systematic optimization and therefore have limited potential to treat postinfarct cardiac injuries. Here we have developed tunable bioactive semi-interpenetrating polymer network (sIPN) hydrogels with matrix metalloproteinase (MMP) labile crosslinkers to be used as an assistive microenvironment for transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) into the infarcted myocardium. Injectable sIPN hydrogels were designed with a range of mechanical and biological properties that yielded material-dependent BMSC proliferation in vitro. Five groups were evaluated to treat myocardial infarction (MI) in adult mice: saline injection; green fluorescent protein (GFP)(+)-BMSCs delivered in saline; a sIPN matrix; a sIPN + GFP(+)-BMSCs; and Matrigel™ + GFP(+)-BMSCs. Injection of cells alone created a transient improvement in LV function that declined over time, and the synthetic hydrogel without cells resulted in the highest LV function at 6 weeks. Donor GFP-positive cells were detected after matrix-enhanced transplantation, but not without matrix support. Biomimetic sIPN hydrogel matrices succeeded both in mechanically supporting the injured myocardium and modestly enhancing donor cell survival. These matrices provide a foundation for systematic development of "pro-survival" microenvironments, and improvement in the long-term results of cardiac stem cell transplantation therapies.

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    • "n.d. 2.0 × 10 1 [131] MMP8 GGYGPVG↓LIGGK 0.08 25.9 3.0 × 10 3 [141] MMP9 GGYGPVG↓LIGGK 2.10 4.3 4.9 × 10 5 [141] QPQG↓LAK 25.4 1223 2.1 × 10 4 [98] GPLG↓MHGK 167.8 727 2.3 × 10 5 [98] GPLG↓LSLGK 46.7 940 5.0 × 10 4 [98] MMP13 QPQG↓LAK 0.82 1128 7.3 × 10 2 [98] GPLG↓LSLGK 14.1 317 4.5 × 10 4 [98] GPLG↓MHGK 73.9 465 1.5 × 10 5 [98] GGYGPVG↓LIGGK 0.58 4.7 1.2 × 10 5 [141] MMP14 GGYGPVG↓LIGGK 1.48 5.8 2.6 × 10 5 [141] Collagenase QPQG↓LAK 0.65 20,403 3.2 × 10 1 [97] Elastase YAAPV↓FGCG 1.32 48 2.7 × 10 5 a [61] YAAPV↓QGCG 1.83 134 1.4 × 10 5 a [61] YAAPV↓LGCG 2.19 106 2.1 × 10 5 a [61] YAAPV↓RGCG 3.13 146 2.1 × 10 5 a [61] YAAPA↓GGCG 0.18 292 6.2 × 10 2 a [61] Plasmin GCYK↓NR↓DCG 319 446 7.2 × 10 5 a [92] "
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    Progress in Polymer Science 07/2014; 39(12). DOI:10.1016/j.progpolymsci.2014.07.003 · 26.93 Impact Factor
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    • "Additionally, a short matrix metalloproteinase-13 (MMP-13) cleavable peptide sequence was used as a crosslinker to tune the mechanical properties and degradation kinetics of the hydrogel. We chose a MMP-13 degradable crosslinker, since this MMP was upregulated in an in vivo bone regeneration injury model [13], [14], [32]. "
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    PLoS ONE 06/2014; 9(6):e98640. DOI:10.1371/journal.pone.0098640 · 3.23 Impact Factor
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    ABSTRACT: Enzymatically degradable semi-interpenetrating polymer networks (edsIPNs) were explored for their biocompatibility and ability to promote new scleral tissue growth, as a means of reinforcing the posterior wall of the eye. The edsIPNs comprised thermoresponsive poly(N-isopropylacrylamide-co-acrylic acid), customizable peptide crosslinkers cleavable by matrix metalloproteinases, and interpenetrating linear poly(acrylic acid)-graft-peptide chains to engage with cell surface receptors. Rheological studies revealed an increase in stiffness at body temperature; the complex shear modulus |G*| was 14.13 +/- 6.13 Pa at 22 degrees C and 63.18 +/- 12.24 Pa at 37 degrees C, compatible with injection at room temperature. Primary chick scleral fibroblasts and chondrocytes cultured on edsIPN increased by 15.1- and 11.1-fold, respectively, over 11 days; both exhibited delayed onset of exponential growth compared with the cells plated on tissue culture polystyrene. The edsIPN was delivered by retrobulbar injection (100 microL) to nine 2-week-old chicks to assess biocompatibility in vivo. Ocular axial dimensions were assessed using A-scan ultrasonography over 28 days, after which eyes were processed for histological analysis. Although edsIPN injections did not affect the rate of ocular elongation, the outer fibrous sclera showed significant thickening. The demonstration that injectable biomimetic edsIPNs stimulate scleral fibrous tissue growth represents proof-of-principle for a novel approach for scleral reinforcement and a potential therapy for high myopia.
    Tissue Engineering Part A 10/2009; 16(3):905-16. DOI:10.1089/ten.TEA.2009.0488 · 4.64 Impact Factor
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