Next-generation transcatheter aortic valve implantation

Abstract

Objective: Transcatheter aortic valve implantation (TAVI) procedures are increasing rapidly, but the durability of tissue valve and periprocedural complications are not satisfactory. Immune reaction to the galactose-α-1,3 galactose β-1,4-N-acetylglucosamine (α-Gal) and conventional processing protocols of cardiac xenografts lead to calcification. Next-generation TAVI needs to be made with α-Gal-free xenografts by multiple anticalcification therapies to avoid immune rejection and enhance durability, and three-dimensional (3D) printing technology to improve the procedural safety.

Methods: Porcine pericardia were decellularized and immunologically modified with α-galactosidase. The pericardia were treated by space filler, crosslinked with glutaraldehyde in organic solvent, and detoxified. The sheep-specific nitinol (nickel-titanium memory alloy) wire backbone was made from a 3D-printed model for ovine aortic root. After it passed the fitting test, we manufactured a self-expandable stented valve with the porcine pericardia mounted on the customized nitinol wire-based stent. After in vitro circulation using customized silicone aortic root, we performed TAVI in 9 sheep and obtained hemodynamic, radiological, immunohistopathological, and biochemical results.

Results: The valve functioned well, with excellent stent fitting and good coronary flow under in vitro circulation. Sheep were sequentially scheduled to be humanely killed until 238 days after TAVI. Echocardiography and cardiac catheterization demonstrated good hemodynamic status and function of the aortic valve. The xenografts were well preserved without α-Gal immune reaction or calcification based on the immunological, radiographic, microscopic, and biochemical examinations.

Conclusions: We proved preclinical safety and efficacy for next-generation α-Gal-free TAVI with multiple anticalcification therapies and 3D-printing technology. A future clinical study is warranted based on these promising preclinical results.

Keywords: 3D, 3-dimensional; BSA, bovine serum albumin; GA, glutaraldehyde; TAVI, transcatheter aortic valve implantation; bioengineering; biomaterials; bioprosthesis; calcification; heart valve; xenograft; α-Gal KO, α1,3-galactosyltransferase knockout; α-Gal, galactose-α-1,3 galactose β-1,4-N-acetylglucosamine.

Graphical abstract

Transcatheter aortic valve from α-Gal–free porcine pericardia on customized nitinol stent.

Figure 1

Three-dimensional (3D) computed tomography images (A-B) and segmented 3D image stored as a stereolithography file (C-D) for ovine aortic root.

Figure 2

Three-dimensional (3D)–printed models (A-B) for ovine aortic root and hollow elastic model with both coronary arteries (C-D) made by painting liquid silicone evenly on the surface of 3D model.

Figure 3

Customized jig made from a 3-dimensional–printed model for ovine aortic root (A), fitting test of sheep-specific nitinol (nickel–titanium memory alloy) wire back bone made from the jig inside the customized silicone aortic root (B), and side view (C) and top view (D) of prototype for self-expandable transcatheter aortic valve made from α-Gal–free porcine pericardium mounted on the customized nitinol wire–based stent.

Figure 4

Photograph (A-B) of in vitro mock circulation. A pulsatile pressure of 120/80 mm Hg was repetitively provided to the transcatheter aortic valve at a constant interval of 60 rpm in one direction to reproduce in vivo circulation, and good valve motion with excellent fitting of valved stent inside customized silicone aortic root was identified. Both coronary arteries were connected into 3-way stopcocks with extension tubing, and good coronary flow was identified to return into in vitro mock circulation (B). Bottom view (C) and top view (D) of gross findings 196 days after transcatheter aortic valve implantation. All aortic valve leaflets were well mobile without degeneration and calcification (C-D), stent was well endothelialized (C), and both coronary arteries (see 2 forceps inserted into both coronary arteries) were patent above aortic valve (D).

Figure 5

Specimen radiographic findings taken from explanted aortic valve after TAVI. Side view: 2 (A), 8 (B), 23 (C), 29 (D), 149 (I), 182 (J), 196 (K), and 238 (L) days after TAVI. Top view: 2 (E), 8 (F), 23 (G), 29 (H), 149 (M), 182 (N), 196 (O), and 238 (P) days after TAVI. TAVI, Transcatheter aortic valve implantation.

Figure 6

Microscopic findings taken from explanted aortic valve leaflet 2 (A, B, C, G, H, I), 29 (D, E, F, J, K, L), 182 (M, N, O, S, T, U), and 196 (P, Q, R, V, W, X) days after TAVI. Hematoxylin–eosin staining (A, D, G, J, M, P, S, V), Masson's trichrome staining (B, E, H, K, N, Q, T, W), von Kossa staining (C, F, I, L, O, R, U, X), ×100 (A-F, M-R), and ×400 (G-L, S-X). Staining showed well-preserved collagen fibers with normally banded structure, no specific matrix derangement, compact array of collagen fibers with preserved structural integrity, and no calcification for 8 months after TAVI.

Figure 7

Immunohistochemistry stainings taken from explanted aortic valve leaflet 2 (A, B, E, F), 29 (C, D, G, H), 182 (I, J, M, N), and 196 (K, L, O, P) days after TAVI. F4/80 (macrophage) staining (A, C, E, G, I, K, M, O), CD4 (T-cell) staining (B, D, F, H, J, L, N, P), ×100 (A∼D,I∼L), and ×400 (E∼H,M∼P). Staining revealed no or rare immune cells for 8 months after TAVI.

Figure 8

Development of next generation α-Gal–free TAVI with multiple anticalcification therapies and 3D printing technology. 3D, 3-dimensional; TAVI, transcatheter aortic valve implantation; α-Gal, galactose-α-1,3 galactose β-1,4-N-acetylglucosamine.