IN BRIEF

From What-if to Widely Available – A Proposed Path for Tissue Engineered Vascular Grafts

April 24, 2018
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What if you could utilize tissue engineering, imaging and 3D printing technologies to bring the benefits of a tissue engineered vascular graft to every child who needs one?

Children born with a single ventricle heart defect undergo a series of surgeries and procedures to reroute the blood flow through their heart. The Fontan operation is the final palliative step. Tissue engineered vascular grafts (TEVGs) offer many benefits over traditional synthetic materials for the Fontan conduit – the prosthetic vessel inserted surgically to route blood from the inferior vena cava to the pulmonary arteries.

At Nationwide Children’s Hospital, Christopher Breuer, MD, and Toshiharu Shinoka, MD, PhD, are leading a clinical trial of TEVG for use in Fontan patients. Their work over the last two decades has taken TEVG from the bench to bedside and back several times over.

The TEVG is already near the epitome of personalized medicine. A vessel, made from the patient’s own cells, is created during surgery and implanted in the patient where it will grow, with no risk of rejection, for the patient’s lifetime. But for now, the vessel is limited by the dimensions of the scaffold upon which cells are seeded. For patients with complex anatomies, TEVGs, as they are currently produced, may not be an option.

Inspired by a patient excluded from the trial because of his complex anatomy, Drs. Breuer and Shinoka and their team of tissue engineers and imaging and design specialists began a project to test the feasibility of using 3D printing to create a custom graft with a nonconstant diameter, greater length and a doubly meandering compound curve. Additionally, they wanted to see if they could do it without the labor-intensive, clean room-dependent seeding process, instead using a closed disposable filtration/elution system.

“To take advantage of patient-specific modeling and customized regenerative implants to yield an optimized patient-specific TEVG is a natural extension of the progress in both fields,” says Dr. Breuer, director of the Center for Regenerative Medicine in The Research Institute at Nationwide Children’s. “The implementation of the closed disposable system takes the concept a step further and would increase the accessibility of TEVG.”

The team utilized computer aided drafting (CAD) and the patient’s reconstructed cardiac magnetic resonance (CMR) imaging to design a custom TEVG scaffold and seeding device. The scaffolds were co-electrospun from polyglycolic acid (PGA) and L-lactide-ϵ-caprolactone (PLCL) onto custom 3D printed mandrels.

The researchers also utilized CAD to recapitulate a previously proposed closed seeding apparatus, which was then 3D-printed from PLA using a fused deposition modeler and sterilized with ethylene oxide gas. The seeding chamber held the volume of the scaffold, mandrel and 120 mL of enriched bone marrow mononuclear cells (BM-MNCs) used for seeding. Upon use, the 3D-printed seeding apparatus performed equivalently to the traditional open seeding setup.

“The success of the 3D-closed system supports the vision for future applications of TEVG that are not limited by access to a clean room or the requirement for linear grafts,” says Cameron Best, a PhD student in the Center for Regenerative Medicine at Nationwide Children’s and lead author of the study. “Notably, the concentration of BM-MNCs in this scenario was a fourfold higher dose than the current clinical protocol. Our work to date shows that increasing the number of cells seeded improves the quality of the graft, and we suggest that the next generation of TEVGs use high dose seeding protocols.”

CAD drawing of the custom graft assembly.

The researchers suggest that future iterations of this approach should incorporate fluid dynamic computational modeling and other predictive techniques to model the optimal graft geometry across scales. A well-powered animal study to assess the long-term performance of custom BM-MNC seeded TEVGs would also be required before advocating translation to the clinic.

“While this workflow and test case are speculative, translation of the approach would result in readily available, patient-specific TEVG for point of care treatment of congenital heart disease. This aim remains the focus of our ongoing translational efforts,” Dr. Breuer says.

 

Reference:

Best C, Strouse R, Hor K, Pepper V, Tipton A, Kelly J, Shinoka T, Breuer C. Toward a patient-specific tissue engineered vascular graft. Journal of Tissue Engineering. 2018;9:1-9.

Image credit: Nationwide Children’s Hospital