A nanopatterned cell-seeded cardiac patch prevents electro-uncoupling and improves the therapeutic efficacy of cardiac repair

Abstract

The heart is an extremely sophisticated organ with nanoscale anisotropic structure, contractility and electro-conductivity; however, few studies have addressed the influence of cardiac anisotropy on cell transplantation for myocardial repair. Here, we hypothesized that a graft's anisotropy of myofiber orientation determines the mechano-electrical characteristics and the therapeutic efficacy. We developed aligned- and random-orientated nanofibrous electrospun patches (aEP and rEP, respectively) with or without seeding of cardiomyocytes (CMs) and endothelial cells (ECs) to test this hypothesis. Atomic force microscopy showed a better beating frequency and amplitude of CMs when cultured on aEP than that from cells cultured on rEP. For the in vivo test, a total of 66 rats were divided into six groups: sham, myocardial infarction (MI), MI + aEP, MI + rEP, MI + CM-EC/aEP and MI + CM-EC/rEP (n ≥ 10 for each group). Implantation of aEP or rEP provided mechanical support and thus retarded functional aggravation at 56 days after MI. Importantly, CM-EC/aEP implantation further improved therapeutic outcomes, while cardiac deterioration occurred on the CM-EC/rEP group. Similar results were shown by hemodynamic and infarct size examination. Another independent in vivo study was performed and electrocardiography and optical mapping demonstrated that there were more ectopic activities and defective electro-coupling after CM-EC/rEP implantation, which worsened cardiac functions. Together these results provide comprehensive functional characterizations and demonstrate the therapeutic efficacy of a nanopatterned anisotropic cardiac patch. Importantly, the study confirms the significance of cardiac anisotropy recapitulation in myocardial tissue engineering, which is valuable for the future development of translational nanomedicine.

Injection of Peptide Nanogels Preserves Postinfarct Diastolic Function and Prolongs Efficacy of Cell Therapy in Pigs

“…It is probably because the benefits of material injection are due to passively providing mechanical support. [35][36][37][38] To truly improve cardiac systolic function and pumping ability, it relies on either directly implanting constructs with actively contractive cells [38][39][40][41] or indirectly reducing loss of host cardiomyocytes by angiogenesis or paracrine effects from biological substance. 42,43 We previously showed angiogenesis was induced by MNC transplantation with/without NFs at 1 month post-MI.…”

Novel insights into cardiomyocytes provided by atomic force microscopy

“…Burridge et al [54] used AFM to verify that interaction of iPSC-CMs with other cell types in a 3D hydrogel did not interfere with the contractile activity. Lin and co-workers [61] investigated the effect of size and orientation of electro-spun fibrous patches of gelatine-coated polyacrylonitrile on the beating frequency and force of neonatal rat myocytes. Authors found that CMs on aligned nanofibres beat faster and stronger than those on randomly oriented ones.…”

Living nano-micro fibrous woven fabric/hydrogel composite scaffolds for heart valve engineering

“…In the present weaving technique, two distinct sets of warps (PAN MY) and wefts (PAN UANY) are interlaced at right angles to form nano-micro fibrous woven fabrics, which can effectively mimic the fiber architecture and physical anisotropy of native ECM of aortic valve leaflet. Although PAN is not a widely-used material, it has been demonstrated by our group and others to be a biocompatible material for both in vitro and in vivo applications [34,56,57]. With the additional capacity for textile processing and cellularization, PAN based scaffolds have unique advantages for fabricating engineered valve conduits.…”