Accordion-Like Honeycombs for Tissue Engineering of Cardiac Anisotropy

Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, E25-330 Cambridge, Massachusetts 02139, USA.
Nature Material (Impact Factor: 36.5). 12/2008; 7(12):1003-10. DOI: 10.1038/nmat2316
Source: PubMed

ABSTRACT Tissue-engineered grafts may be useful in myocardial repair; however, previous scaffolds have been structurally incompatible with recapitulating cardiac anisotropy. Here, we use microfabrication techniques to create an accordion-like honeycomb microstructure in poly(glycerol sebacate), which yields porous, elastomeric three-dimensional (3D) scaffolds with controllable stiffness and anisotropy. Accordion-like honeycomb scaffolds with cultured neonatal rat heart cells demonstrated utility through: (1) closely matched mechanical properties compared to native adult rat right ventricular myocardium, with stiffnesses controlled by polymer curing time; (2) heart cell contractility inducible by electric field stimulation with directionally dependent electrical excitation thresholds (p<0.05); and (3) greater heart cell alignment (p<0.0001) than isotropic control scaffolds. Prototype bilaminar scaffolds with 3D interconnected pore networks yielded electrically excitable grafts with multi-layered neonatal rat heart cells. Accordion-like honeycombs can thus overcome principal structural-mechanical limitations of previous scaffolds, promoting the formation of grafts with aligned heart cells and mechanical properties more closely resembling native myocardium.

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Available from: Christopher J Bettinger, Sep 25, 2015
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    • "Aligned scaffolds exhibited highest anisotropy under tensile loading with an anisotropy ratio T (V, 10) /T (H, 10) of 7.4. This ratio is at least two-fold higher than the anisotropy ratio reported previously for porous accordion-like honeycomb scaffolds (Engelmayr et al., 2008). A parallel to this behavior can also be drawn with aligned and random electrospun fibers. "
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    ABSTRACT: Scaffolds with aligned pores are being explored in musculoskeletal tissue engineering due to their inherent structural anisotropy. However, influence of their structure on mechanical behavior remains poorly understood. In this work, we elucidate this dependence using chitosan-gelatin based random and aligned scaffolds. For this, scaffolds with horizontally or vertically aligned pores were fabricated using unidirectional freezing technique. Random, horizontal and vertical scaffolds were characterized for their mechanical behavior under compressive, tensile and shear loading regimes. The results revealed conserved trends in compressive, tensile and shear moduli, with horizontal scaffolds showing the least moduli, vertical showing the highest and random showing intermediate. Further, these scaffolds demonstrated a highly viscoelastic behavior under cyclic compressive loading, with a pore orientation dependent relative energy dissipation. These results established that mechanical behavior of porous scaffolds can be modulated by varying pore orientation alone. This finding paved the way to recreate the structural and consequent mechanical anisotropy of articular cartilage tissue using zonally varied pore orientation in scaffolds. To this end, monolithic multizonal scaffolds were fabricated using a novel sequential unidirectional freezing technique. The superficial zone of this scaffold had horizontally aligned pores while the deep zone consisted of vertically aligned pores, with a transition zone between the two having randomly oriented pores. This depth-dependent pore architecture closely mimicked the collagen alignment of native articular cartilage which translated into similar depth-dependent mechanical anisotropy as well. A facile fabrication technique, biomimetic pore architecture and associated mechanical anisotropy make this multizonal scaffold a promising candidate for cartilage tissue engineering. Copyright © 2015 Elsevier Ltd. All rights reserved.
    07/2015; 51:169–183. DOI:10.1016/j.jmbbm.2015.06.033
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    • "However, the availability of decellularized human allografts is restricted due to the lack of donors. Although attempts have been made to manufacture and repair various components of the heart such as using nanocomposite polymers for bioartificial heart valves (Kidane et al., 2009), injectable hydrogels that deliver therapeutic payloads to the heart (Chiu & Radisic, 2011), scaffold-free constructs to deliver cardiac cells (Miyahara et al., 2006), conventional cell-scaffold constructs to mimic the anisotropy of the native heart (Engelmayr et al., 2008), these techniques all require the existence of a functioning myocardium and does not take into account the need of ''whole heart engineering''. Thus, decellularized xenogeneic tissues have emerged as an attractive scaffold material for whole-heart cardiac tissue engineering (Zhou et al., 2013). "
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    ABSTRACT: Abstract Whole-organ decellularization and tissue engineering approaches have made significant inroads during recent years. If proven to be successful and clinically viable, it is highly likely that this field would be poised to revolutionize organ transplantation surgery. In particular, whole-heart decellularization has captured the attention and imagination of the scientific community. This technique allows for the generation of a complex three-dimensional (3D) extracellular matrix scaffold, with the preservation of the intrinsic 3D basket-weave macroarchitecture of the heart itself. The decellularized scaffold can then be recellularized by seeding it with cells and incubating it in perfusion bioreactors in order to create functional organ constructs for transplantation. Indeed, research into this strategy of whole-heart tissue engineering has consequently emerged from the pages of science fiction into a proof-of-concept laboratory undertaking. This review presents current trends and advances, and critically appraises the concepts involved in various approaches to whole-heart decellularization and tissue engineering.
    Critical Reviews in Biotechnology 03/2015; DOI:10.3109/07388551.2015.1007495 · 7.18 Impact Factor
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    • "For example, Gonnermann and colleagues described a series of geometrically anisotropic collagen-GAG (CG) scaffolds with aligned tracks of ellipsoidal pores, fabricated via directional solidification and freeze-drying technique [17]. Engelmayr and colleagues used micro-ablation of polyglycerol sebacate (PGS) to manufacture accordion-like honeycomb scaffolds, which matched the anisotropy and mechanical properties of native myocardium and guided the alignment of cultured neonatal rat heart cells and C2C12 myoblasts without any external stimuli [15]. However, while elegant, these techniques are tedious, time-consuming and costly in terms of manufacturing [18] and entail potential thermal degradation of bioresorbable polymers and biomaterials [19]. "
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    ABSTRACT: For patients with end-stage heart disease, the access to heart transplantation is limited due to the shortage of donor organs and to the potential for rejection of the donated organ. Therefore, current studies focus on bioengineering approaches for creating biomimetic cardiac patches that will assist in restoring cardiac function, by repairing and/or regenerating the intrinsically anisotropic myocardium. In this paper we present a simplified, straightforward approach for creating bioactive anisotropic cardiac patches, based on a combination of bioengineering and textile-manufacturing techniques in concert with nano-biotechnology based tissue-engineering stratagems. Using knitted conventional textiles, made of cotton or polyester yarns as template targets, we successfully electrospun anisotropic three-dimensional scaffolds from poly(lactic-co-glycolic) acid (PLGA), and thermoplastic polycarbonate-urethane (PCU, Bionate®). The surface topography and mechanical properties of textile-templated anisotropic scaffolds significantly differed from those of scaffolds electrospun from the same materials onto conventional 2-D flat-target electrospun scaffolds. Anisotropic textile-templated scaffolds electrospun from both PLGA and PCU, supported the adhesion and proliferation of H9C2 cardiac myoblasts cell line, and guided the cardiac tissue-like anisotropic organization of these cells in vitro. All cell-seeded PCU scaffolds exhibited mechanical properties comparable to those of a human heart, but only the cells on the polyester-templated scaffolds exhibited prolonged spontaneous synchronous contractility on the entire engineered construct for 10 days in vitro at a near physiologic frequency of ∼120 bpm. Taken together, the methods described here take advantage of straightforward established textile manufacturing strategies as an efficient and cost-effective approach to engineering 3D anisotropic, elastomeric PCU scaffolds that can serve as a cardiac patch.
    Biomaterials 10/2014; 35(30):8540-8552. DOI:10.1016/j.biomaterials.2014.06.029 · 8.56 Impact Factor
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