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Hexagonal scaffolds induce iPSC-CM contractile properties and maturation. iPSC-CM characterization before combination with scaffold, showing A) proliferating cells, B) sarcomeric structures, C) Connexin 43 (Cx43), and D) mitochondrial localization. iPSC-CMs localize to both E) hexagonal and F) rectangular fiber scaffolds, and confocal microscopy shows G,H) Cx43 expression, and increased sarcomere density, I,J) alignment, and K) length in hexagonal scaffolds compared to rectangular scaffolds. L) Beating rate at days 2, 7, 10, 11, and 14. M) Cardiac marker and maturation-related gene expression in hexagonal and rectangular scaffolds at day 7 and day 14.

After a person suffers a heart attack, they lose about half the cells in their heart, greatly weakening the organ and increasing the odds that further attacks will occur. Doctors have begun injecting cells into the heart to grow into muscle and help contractions, but 99% of those cells get washed away. But there are alternative approaches – like 3D printing. Scientists have developed 3D printed cardiac patches that can be used to repair hearts damaged by heart attacks, but only about five have been produced worldwide.

Injectability and in vivo placement of cardiac patch with hexagonal geometry. A) In vitro culture of cardiac patch consisting of iPSC-CMs in cardiac-like ECM on large hexagonal scaffolds. B) In vitro injectability, shape recovery, and C) macro image of cardiac patch after injection. D) Application and shape recovery of cardiac patch on beating porcine heart. E) Cell viability of in vitro F,G) noninjected and H,I) injected cardiac patches. J) Spontaneous beating rate of in vitro noninjected and injected cardiac patches 30 min and 2 d after injection.

In a new study entitled “Melt Electrowriting Allows Tailored Microstructural and Mechanical Design of Scaffolds to Advance Functional Human Myocardial Tissue Formation,” a group of researchers 3D printed a world-first stretchable microfiber scaffold with a hexagonal design. They then added specialized stem cells called iPS-Cardiomyocytes, which began to contract unstimulated on the scaffold. The work was then demonstrated on the actual hearts of pigs.

We spoke with the authors of the paper to learn more about the technology used by the scientists and its implications for the future.

What are the advantages of MEW relative to other technologies? 

“Melt Electrospin Writing (MEW) has distinct advantages over other 3D Printing technologies for tissue engineering applications. MEW utilises common thermoplastics used in biomedical engineering, including Polycaprolactone (PCL). The advantage of this approach is that we are able to create microfibres with diameters often in the 10 micron range, but nano-fibres also also achievable. To put this into perspective, a single strand of hair is about 50-100 microns. Printing at such resolutions allows us to mimic the native extracellular matrix (ECM) components, and allows cells to bind onto the small fibres that at similar to collagen fibrils. Additionally, MEW allows for the control over scaffold architecture, creating scaffolds with aligned fibres and controlled fibre diameters. This specific control over architecture, allows us to tailor the mechanical properties, direct cells growth and  control the movement of nutrients. Because we can modify the scaffolds properties so well, they are often used to reinforce hydrogels (as a backbone), which are typically much weaker and less tailorable.”

What is the significance of your paper?

Representation of the workflow and fabricated microfiber scaffolds. A) Schematic illustration of the in house-built MEW device used. B) Designed hexagonal microstructure. C) 3D fiber scaffold combined with iPSC-CMs and further application in vivo through minimally invasive delivery. D) Optical images of the fabricated scaffolds: detail of microstructure with hexagonal cells (with a side length of 400 µm) composed of multiple stacked aligned microfibers. Images acquired from top and lateral perspective.

“We developed patches with controlled hexagonal micro-fibre structures that had unique flexibility and shape-recovery properties, meaning that the patch can be highly deformed without sustaining damage to its structure or cells. Moreover, such novel paths allowed the maturation of contractile human iPSC-derived cardiomyocytes, which is a breakthrough in creating a functional patch that could match an adult heart. Finally, due to the patch’s flexibility, it can be compressed and pushed through a catheter for delivery in vivo with minimally invasive laparoscopic surgery.”

Why are collagen-based hydrogels so important?

“Collagen is the most abundant protein in the human myocardial tissue and for that reason an ideal biomaterial for use in myocardial tissue engineering.”

How close are we to using 3D printing in a clinical setting?

“There are already reports of 3D printed implants used in clinics, mostly metallic or ceramic based for bone repair. However, in what concerns to our heart patch’s that include biological derived components (new cell therapies, iPSC) we believe a few more years will be required. We need first to demonstrate the efficacy and safety of such approach in animal models, which we are currently planning. Also, important challenges like integration with surrounding tissue will need to be solved: for example, currently the patches can contract autonomously, but we don’t know if they will sync with the beating of the heart once implanted.”

What work will you be doing next?

“We want to concentrate our efforts in conducting more extensive animal studies to assess feasibility and show functional effects, such as improved cardiac function. We also intend to make the patches more complex, by integrating other cell types in the patch.”

Authors of the paper include Miguel Castilho, Alain van Mil, Malachy Maher, Corina H.G. Metz, Gernot Hochleitner, Jürgen Groll, Pieter A. Doevendans, Keita Ito, Joost P.G. Sluijter, and Jos Malda.

Discuss this and other 3D printing topics at 3DPrintBoard.com or share your thoughts below.

[Images: Castilho et al, “Melt Electrowriting Allows Tailored Microstructural and Mechanical Design of Scaffolds to Advance Functional Human Myocardial Tissue Formation,” Advanced Functional Materials, 2018. Copyright Wiley – VCH Verlag GmbH & Co. KGaA. Reproduced with permission.]

 

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