3D Printed Vascular Patches with Patterned Channels Used to Grow Organized Blood Vessels in Mice

Ischemic cardiovascular disease is the number one cause of death and disability in the US, and growing fast around the rest of the world as well. Ischemic refers to tissue that has been starved of oxygen – when heart disease results in blocked blood vessels, the tissues can die because the blood cells carrying precious oxygen can’t get through.

Many serious conditions, such as peripheral artery disease, strokes, and even heart failure, can occur when the blood circulation to tissues and organs is impaired. While surgery is an option to get rid of blockages in the larger vessels in the legs or heart, it can’t be done in smaller ones, which is unfortunately where most of the damage takes places that causes these conditions in the first place.

An interdisciplinary research group of biologists, engineers, and physicians, funded in part by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), are working together to develop a 3D printed solution to the problem of ischemia caused by damage to small blood vessels.

In this model of an ischemic limb, a section of the femoral artery in the mouse leg is removed, and a vascular patch, lined with endothelial cells, is placed in the resected area.

The team, led by Christopher Chen, MD, PhD, Professor of Biomedical Engineering and Founding Director of the Biological Design Center at Boston University, has designed 3D printed patches that are seeded, in a variety of geometric patterns, with vessel-inducing endothelial cells, which can actually produce tissue-saving vascular networks.

We’ve seen the benefits of 3D printed heart patches before, as the technology continues to benefit potential advances in understanding cardiovascular health issues and advancing treatment options. This team’s research was published in June, and the NIBIB has recently shared another look.

The results were published in an article, titled “3D-printed vascular networks direct therapeutic angiogenesis in ischaemia,” in the Nature Biomedical Engineering journal; co-authors include T. Mirabella, J. W. MacArthur, D. Cheng, C. K. Ozaki, Y. J. Woo, M. T. Yang, and Chen.

The following universities and institutions worked together on this potentially life-saving research:

• Department of Bioengineering and the Biological Design Center, Boston University
• Wyss Institute for Biologically Inspired Engineering, Harvard University
• Department of Surgery, University of Pennsylvania
• Department of Surgery, Brigham and Women’s Hospital and Harvard Medical School
• Department of Cardiothoracic Surgery, Stanford University
• Innolign Biomedical, Boston, Massachusetts

Schematic of VP fabrication; carbohydrate glasses are 3D printed as
parallel filaments. After PDLGA-coating and fibrin bulking, the sacrificial sugar is removed by overnight washing in PBS. Remaining channels are endothelialized by flowing HUVECs and shear-conditioning the confluent monolayer overnight, before implantation. Middle: representation of implantation site within the cauterized femoral artery space. Right: representation of the patches retrieved
5 days after implantation.

“The results of this collaboration are an excellent example of how engineers can take what biologists and physicians know about how our bodies work and use the information to create practical, innovative medical treatments,” said Rosemarie Hunziker, PhD, Director of the NIBIB Program in Tissue Engineering.

As it’s not possible to surgically remove blockages in small blood vessels, other strategies that can induce new ones to grow are being developed. This involves mimicking the natural repair process of the human body at the location where vascular endothelial cells and growth factors work to induce new vessels to grow in a danger response, which is understandably not the easiest thing in the world to do.

Chen said, “We know that when growth factors are injected into a tissue, they do induce the sprouting of new blood vessels, but in a disorganized pattern unable to deliver oxygen to ischemic tissues. Our goal was to use engineering to direct the growth of new vessels into an orderly, functional network.”

The researchers designed and built 3D printed vascular patches (VPs), and added several different patterns of channels to guide the formation of organized blood vessels. These channels are lined with endothelial cells, which induce new blood vessels to sprout up.

The 3D printed patches with different channel patterns were tested in a mouse model with ischemia in the back, left leg. Researchers implanted the patches inside a gap in the leg where a section of the femoral artery had been removed, to see if they would be able to induce new blood vessels to grow and send oxygen to the ischemic foot. Laser Doppler imaging was used to check if any vessels were forming.

A section of the mouse femoral artery was removed and replaced with each of three different vascular patches (VP) in one leg of the mouse (white arrows). The lack of blood in the ischemic foot can be seen post-surgery. Five days after surgery the Par VP patch, engineered with parallel channels of endothelial cells, resulted in complete restoration of blood flow to the ischemic foot (yellow arrow).

Five days post-op, the sites that had patches with straight rows of channels proved to have the best results, as they induced an organized network of vessels to grow and restore oxygen to the foot.

Chen said, “Although we are still at the very early stages of this project, we are encouraged by the initial results.”

The 3D printed patch with no pattern induced hardly any blood vessels to form, while the grid patterned patch restored about 70% oxygenation to the foot. By identifying which patch patterns would induce the most blood vessel growth, the team showed how its novel technology could, according to NIBIB, “address this significant public health problem.”

Chen’s group will continue their work with biologists and clinicians, and attempt to refine the design of the 3D printed patches in order to “optimize their effectiveness.”

“I can’t stress enough how the current and future success of this project is completely dependent on the partnership of engineers, biologists and clinicians. We are all excited about what can be accomplished when there is so much diverse, yet interdependent expertise focused on beating this major public health problem,” said Chen.

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