Please cite this article as: Kitsara, M., Agbulut, O., Kontziampasis, D., Chen, Y., Menasché, P., Fibers for hearts: A critical review on electrospinning for cardiac tissue engineering, Acta Biomaterialia (2016), doi: http://dx.doi.org/ 10. 1016/j.actbio.2016.11.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractCardiac cell therapy holds a real promise for improving heart function and especially of the chronically failing myocardium. Embedding cells into 3D biodegradable scaffolds may better preserve cell survival and enhance cell engraftment after transplantation, consequently improving cardiac cell therapy compared with direct intramyocardial injection of isolated cells.The primary objective of a scaffold used in tissue engineering is the recreation of the natural 3D environment most suitable for an adequate tissue growth. An important aspect of this commitment is to mimic the fibrillar structure of the extracellular matrix, which provides essential guidance for cell organization, survival, and function. Recent advances in nanotechnology have significantly improved our capacities to mimic the extracellular matrix. Among them, electrospinning is well known for being easy to process and cost effective. Consequently, it is becoming increasingly popular for biomedical applications and it is most definitely the cutting edge technique to make scaffolds that mimic the extracellular matrix for industrial applications.Here, the desirable physico-chemical properties of the electrospun scaffolds for cardiac therapy are described, and polymers are categorized to natural and synthetic. Moreover, the methods used for improving functionalities by providing cells with the necessary chemical cues and a more in vivo-like environment are reported.

Electrospinning and plasma post-modification lead to PVDF scaffolds with favorable electromechanical properties and enhanced wettability.

Many works focus on the use of polyesters like poly(lactic acid) (PLA) to produce nanofibrous scaffolds for cardiac tissue engineering. However, such scaffolds are hydrophobic and difficult to functionalize. Here, we show that adding 30% of poly(glycerol sebacate) (PGS) elastomer within PLA leads to PLA:PGS scaffolds with improved biological properties, depending on the processing parameters. Two categories of fibers were produced by blend electrospinning, with diameters of 600 and 1300 nm. The resulting fibers were cured at 90°C or 120°C in order to achieve two different crosslinking densities. The designed scaffolds were considered for cytocompatibility, biocompatibility, biodegradability, chemical and mechanical properties. Our results demonstrated that the presence of PGS increases the hydrophilicity of the material and thus improves surface functionalization by Matrigel and laminin coating, a commonly used cell culture matrix. PLA:PGS scaffolds associated with Matrigel and laminin allow an increased material-cell interaction. Moreover, the cardiomyocytes seeded on such scaffolds acquire a morphology similar to that observed in native tissue, this result being more remarkable on fibers having the smallest diameter and the highest PGS crosslinking density. In addition, these scaffolds induce neovascularization without inflammatory response and foreign body giant cell response after grafting on mice's heart. Hence, the improved biocompatibility and the ability to support cardiomyocytes development suggest that thin PLA:PGS scaffolds could be promising biomaterials for cardiac application.

Limited data are available on the effects of stem cells in non-ischemic dilated cardiomyopathy (DCM). Since the diffuse nature of the disease calls for a broad distribution of cells, this study investigated the scaffold-based delivery of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM) in a mouse model of DCM. Nanofibrous scaffolds were produced using a clinical grade atelocollagen which was electrospun and cross-linked under different conditions. As assessed by scanning electron microscopy and shearwave elastography, the optimum crosslinking conditions for hiPS-CM colonization proved to be a 10% concentration of citric acid crosslinking agent and 150 min of post-electrospinning baking. Acellular collagen scaffolds were first implanted in both healthy mice and those with induced DCM by a cardiac-specific invalidation of serum response factor (SRF). Seven and fourteen days after implantation, the safety of the scaffold was demonstrated by echocardiography and histological assessments. The subsequent step of implantation of the scaffolds seeded with hiPS-CM in DCM induced mice, using cell-free scaffolds as controls, revealed that after fourteen days heart function decreased in controls while it remained stable in the treated mice. This pattern was associated with an increased number of endothelial cells, in line with the greater vascularity of the scaffold. Moreover, a lesser degree of fibrosis consistent with the upregulation of several genes involved in extracellular matrix remodeling was observed. These results support the interest of the proposed hiPS-CM seeded electrospun scaffold for the stabilization of the DCM outcome with potential for its clinical use in the future.

This is a repository copy of Heart on a chip: Micro-nanofabrication and microfluidics steering the future of cardiac tissue engineering.

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International audienceSynergy between micro-nanotechnology and regenerative medicine can lead to new tools for health improvement. In this study, we investigate the efficacy of electrospun scaffolds-fabricated using clinically approved collagen – as supports for cardiomyoblast culture. The scaffolds were prepared using non-toxic solvents and crosslinking agents and characterized by scanning electron microscopy and contact angle measurements. Among different types of collagen samples, we found that atelocollagen can produce better quality of electrospun fibers than acid and basic fibrous collagen. Our results also show that the cell culture performance can be improved by adjusting the crosslinking conditions. Typically, increasing the concentration of citric acid of the cross-link agents from 5% to 10% w/w and the post-crosslink baking time from 1.5 to 2.5 h led to significant increases of the cellular colonization of the scaffold, showing three-dimensional growth of cardiac cells due to the specific morphology of the fibrous scaffolds. Finally, in vivo tests of the biocompatibility of the fabricated scaffolds have been done using a mouse model of dilated cardiomyopathy. As expected, the biocompatibility of the scaffold was found excellent and no visible inflammation was observed after the implantation up to two weeks. However, 5% citric acid electrospun collagen scaffolds was less resistant in vivo, proving again the importance of the processing parameter optimization of the electrospun scaffolds