Patient-Specific 3-Dimensional-Bioprinted Model for In Vitro Analysis and Treatment Planning of Pulmonary Artery Atresia in Tetralogy of Fallot and Major Aortopulmonary Collateral Arteries

Abstract

Background Tetralogy of Fallot with major aortopulmonary collateral arteries is a heterogeneous form of pulmonary artery (PA) stenosis that requires multiple forms of intervention. We present a patient-specific in vitro platform capable of sustained flow that can be used to train proceduralists and surgical teams in current interventions, as well as in developing novel therapeutic approaches to treat various vascular anomalies. Our objective is to develop an in vitro model of PA stenosis based on patient data that can be used as an in vitro phantom to model cardiovascular disease and explore potential interventions. Methods and Results From patient-specific scans obtained via computer tomography or 3-dimensional (3D) rotational angiography, we generated digital 3D models of the arteries. Subsequently, in vitro models of tetralogy of Fallot with major aortopulmonary collateral arteries were first 3D printed using biocompatible resins and next bioprinted using gelatin methacrylate hydrogel to simulate neonatal vasculature or second-order branches of an older patient with tetralogy of Fallot with major aortopulmonary collateral arteries. Printed models were used to study creation of extraluminal connection between an atretic PA and a major aortopulmonary collateral artery using a catheter-based interventional method. Following the recanalization, engineered PA constructs were perfused and flow was visualized using contrast agents and x-ray angiography. Further, computational fluid dynamics modeling was used to analyze flow in the recanalized model. Conclusions New 3D-printed and computational fluid dynamics models for vascular atresia were successfully created. We demonstrated the unique capability of a printed model to develop a novel technique for establishing blood flow in atretic vessels using clinical imaging, together with 3D bioprinting-based tissue engineering techniques. Additive biomanufacturing technologies can enable fabrication of functional vascular phantoms to model PA stenosis conditions that can help develop novel clinical applications.

Keywords: cardiovascular disease; cardiovascular research; catheterization; pulmonary artery stenosis; tissue engineering.

Figure 1

Patient‐specific in vitro pulmonary artery atresia model. Neonatal and adult vasculature with pulmonary artery atresia pathology were imaged via computed tomography (CT) (A) and 3‐dimensional (3D) rotational angiography (B). The vessel lumens were converted into 3D stereolithography files with 1‐mm thickness for neonatal and adult patients (C and D, respectively). These digital models were subsequently 3D printed (E and F) using different synthetic resins, including Clear Resin (1) and Flexible Resin (2) to pinpoint the most suitable material for the phantom. Validation using x‐ray angiography using iodine‐based contrast agent was performed on each patient model (G and H) without (left) and after (right) contrast addition. Arrows in (H) mark the vascular atresia. A simplified phantom was derived from the adult patient model by isolating the 3D area that included the occluded vessel and a functional vessel (I). Zoomed view of this area (J, 1) and the extrapolated stenotic phantom (J, 2) are shown. Proof‐of‐concept synthetic models of the phantom were created to evaluate its use (K). Untreated model (1), anastomosed vessels model (2), and stented model (3), mimicking the proposed treatment procedure, were 3D printed using Clear Resin for phantom optimization and iteration purposes.

Figure 2

Bioprinted phantom for recanalization of atretic vessels. A commercial 3‐dimensional (3D) bioprinter (CELLINK Bio X) was used to generate the biological model of tetralogy of Fallot with major aortopulmonary collateral arteries (MAPCAs) (A), which were then assembled into the 3D‐printed housings. A second approach, gelatin methacrylate (gelMA) casting directly into a 3D‐printed housing, was used to generate a second batch of phantoms (B). Render of the assembled phantom (C) shows its key parts (I‐VI, C‐1), with a fully assembled example shown below (C‐2). Schematic of the proposed recanalization procedure (D), showing flow in only the open vessel (2), catheter bridge (4), stent introduction (6), and stent deployment with flow restored in both vessels (8). Catheterization laboratory capture of the full procedure (E) shows the major (1–8) steps, starting from device setup and flow test (1–2) through establishment of bridge between the vessels (3–5), stent introduction (6) and deployment (7), and finally restored flow into both vessels (8). Zoom‐in of the deployed stent before flow reestablishment in both vessels is shown in (7*). The procedure was repeated 3 times. F, Computational fluid dynamic modeling of the stented atretic model, demonstrating (I) the computer‐aided design (CAD) model, (II) normalized flow velocity waveform over the cardiac cycle prescribed, and (III, 1–3) the characteristic flow pattern during the downstroke of systole. Arrow in III‐2 designates a turbulent flow region at the entry of the recanalized connection. III‐3 shows one pulse of velocity waveform and the red circle highlights the time point at which the flow data were acquired. PA indicates pulmonary artery.