Implantable and Biodegradable Macroporous Iron Oxide Frameworks for Efficient Regeneration and Repair of Infracted Heart

Abstract

The construction, characterization and surgical application of a multilayered iron oxide-based macroporous composite framework were reported in this study. The framework consisted of a highly porous iron oxide core, a gelatin-based hydrogel intermediary layer and a matrigel outer cover, which conferred a multitude of desirable properties including excellent biocompatibility, improved mechanical strength and controlled biodegradability. The large pore sizes and high extent of pore interconnectivity of the framework stimulated robust neovascularization and resulted in substantially better cell viability and proliferation as a result of improved transport efficiency for oxygen and nutrients. In addition, rat models with myocardial infraction showed sustained heart tissue regeneration over the infract region and significant improvement of cardiac functions following the surgical implantation of the framework. These results demonstrated that the current framework might hold great potential for cardiac repair in patients with myocardial infraction.

Keywords: blood iron pool; cardiac repair.; macroporous frameworks; stem cell; vasculature.

Figure 1

Schematic of the construction of macroporous iron oxide frameworks for efficient regeneration and repair of infracted heart.

Figure 2

SEM images showing the naked iron oxide framework (a), the gelatin-coated framework (b), and stem cells adhering to and proliferating around the framework trabeculae (c); demonstrating the surface features of the naked iron oxide framework (d) and the gelatin-coated framework (e). It can be seen that the gelatin layer significantly smoothened the surface of the framework.

Figure 3

Fluorescence microscopic images showing the proliferation of stem cells in one day (a), three days (b) and seven days (c) after seeding onto the framework; Confocal imaging and 3D reconstruction indicating the extensive cell proliferation around and inside the framework at Day 7 (d, e); SEM images acquired at a depth of 1.5 mm to the surface (f), a thick layer of robustly proliferated cells can be seen enveloping the frame of the pore (g). The microchannel is clearly visible at the center of the pore and surrounded but otherwise unhindered by the proliferated cells.

Figure 4

Light microscopic (a) and fluorescent microscopic (b) images of the matrigel-coated framework, demonstrating the continued viability of the cells after the coating; A close-up of the matrigel layer at the surface of the framework, as indicated by the green arrows. Both the light microscopic (c) and fluorescent microscopic (d) images are shown.

Figure 5

MRI scans showing the presence of the framework at the target area (indicated by the yellow arrow) immediately after the implantation (a) and the near-complete degradation of the framework in two months (b); fluorescence imaging of the target area on the heart where the framework was implanted: Significant growth of the implanted cells and regeneration of heart tissues can be seen two months after framework implantation (c) compared with he fluorescent background of the heart control with no framework implant (d); Matrigel-free framework showed low density of green fluorescence (e) compared to matrigel coating framework (f);Representative echocardiograms of a healthy rat (g), a rat with MI in which a framework was implanted (h), and a rat with MI as a control that did not receive any implant (i). Column charts comparing the stroke volume (j), ejection fraction (k) and fraction shortening (l) of the three abovementioned rat models. Bars represent standard error of mean. NS indicates no statistical significance. * P < 0.05.