Janus magnetic cellular spheroids for vascular tissue engineering

Abstract

Cell aggregates, or spheroids, have been used as building blocks to fabricate scaffold-free tissues that can closely mimic the native three-dimensional in vivo environment for broad applications including regenerative medicine and high throughput testing of drugs. The incorporation of magnetic nanoparticles (MNPs) into spheroids permits the manipulation of spheroids into desired shapes, patterns, and tissues using magnetic forces. Current strategies incorporating MNPs often involve cellular uptake, and should therefore be avoided because it induces adverse effects on cell activity, viability, and phenotype. Here, we report a Janus structure of magnetic cellular spheroids (JMCS) with spatial control of MNPs to form two distinct domains: cells and extracellular MNPs. This separation of cells and MNPs within magnetic cellular spheroids was successfully incorporated into cellular spheroids with various cellular and extracellular compositions and contents. The amount of cells that internalized MNPs was quantified and showed that JMCSs resulted in significantly lower internalization (35%) compared to uptake spheroids (83%, p < 0.05). Furthermore, the addition of MNPs to cellular spheroids using the Janus method has no adverse effects on cellular viability up to seven weeks, with spheroids maintaining at least 82% viability over 7 weeks when compared to control spheroids without MNPs. By safely incorporating MNPs into cellular spheroids, results demonstrated that JMCSs were capable of magnetic manipulation, and that magnetic forces used during magnetic force assembly mediate fusion into controlled patterns and complex tissues. Finally, JMCSs were assembled and fused into a vascular tissue construct 5 mm in diameter using magnetic force assembly.

Manipulation of cellular spheroid composition and the effects on vascular tissue fusion

“…By incorporating magnetic nanoparticles (MNPs) into cellular spheroids, these self-assembled tissues can be aligned and patterned using magnetic force assembly [12–18]. Our lab developed the Janus structure of magnetic cellular spheroids (JMCSs), which provides spatial control of iron oxide MNPs to form two distinct domains: cells and extracellular MNPs [19]. Mattix et al reported that iron oxide MNPs do not adversely affect the viability of JMCSs and that magnetic forces accelerated the fusion of JMCSs [19].…”

“…Our lab developed the Janus structure of magnetic cellular spheroids (JMCSs), which provides spatial control of iron oxide MNPs to form two distinct domains: cells and extracellular MNPs [19]. Mattix et al reported that iron oxide MNPs do not adversely affect the viability of JMCSs and that magnetic forces accelerated the fusion of JMCSs [19]. Unlike conventional tissue patterning methods, magnetic fields are physical forces used to promote active cell–cell contacts and interactions that arise from the adhesive and cohesive interactions between cells under the influence of magnetic attraction [19].…”

Cell surface engineering with polyelectrolyte-stabilized magnetic nanoparticles: A facile approach for fabrication of artificial multicellular tissue-mimicking clusters

“…2015, 8(8): 2515-2532 implementation of MNPs-modified cells in fabrication of artificial constructs imitating vascular tissue [4], skeletal muscle tissues [5], and keratinocyte sheets [6]. Magnetic functionalization of cells was also employed in fabrication of cellular spheroids [7], which are regarded as three-dimensional building blocks in tissue engineering and a prospective tool in pharmaceutical applications (i.e., drug screening) [8] and tumor studies [9]. MNPs-modified cells were also employed for fabrication of aortic valve mimics using a magnetic levitation procedure [10].…”

“…However, experimental approaches based on cell-internalized magnetic nanoparticles have raised concerns regarding possible long-term toxic effects. To minimize the potential toxic effects of MNPs, several recent studies have suggested using MNPs isolated from magnetotactic bacteria [17], which are believed to be less toxic than chemically synthesized MNPs, fabrication of magnetoferritin nanoparticles, or construction of Janus magnetic cellular spheroids by concentrating nanoparticles in certain regions of spheroids, thus reducing MNPs-cell interactions [8]. Although effective, these approaches are rather complex and require time-consuming manipulation of cells or sophisticated methods of nanoparticle preparation.…”

Co-self-assembly of cationic microparticles to deliver pEGFP-ZNF580 for promoting the transfection and migration of endothelial cells

“…15 For example, Mattix et al designed and manufactured magnetic vascular nanoparticles for rapid endothelialization to reduce the risk of restenosis. 16 Moreover, after modification with anti-CD34 antibody on the surface of a stent, the attachment of ECs was promoted greatly. 17 As a future therapeutic strategy, gene therapy has been bloomed over years.…”