A mold for the preparation of an in-body tissue architecture-induced autologous vascular graft, termed "biotube," was prepared by covering a main silicone rod (outer diameter, 3 mm; length, 30 mm) with two pieces of polyurethane sponge tubes (internal diameter, 3 mm; length, 3 mm) at both ends. The molds were embedded into the dorsal subcutaneous pouch of rabbits (weighing ca. 2 kg) for 2 months. After harvesting the rods with the formed surrounding tissues, the rods were removed to create biotubes impregnated with anastomotic reinforcement cuffs at both ends. The biotubes had homogeneous, thin connective tissue wall (thickness, 76 ± 37 μm) that was primarily composed of collagen and fibroblasts. One biotube was loaded with argatroban and autoimplanted in the carotid artery for 26 months. Neither antiplatelet nor anticoagulant agents were administered, except for an intraoperative heparin injection. Follow-up angiography showed no aneurysm formation, rupturing, or stenosis during implantation. At the end of implantation, the wall thickness of biotube (212 ± 24 μm at the anastomosis portion and 150 ± 14 μm at the midportion) was similar to that of native artery (189 ± 23 μm). The luminal surface was completely covered with endothelial cells on the formed lamina elastica interna-like layer. The regenerated vascular walls comprised multilayered smooth muscle cells and dense collagen fibers with regular circumferential orientation. A remarkable multilayered elastin fiber network was observed near the anastomosis portion. Biotubes could thus be used as small-caliber vascular prostheses that greatly facilitate the healing process and exhibit excellent biocompatibility.
Background-We developed autologous prosthetic implants by simple and safe in-body tissue architecture technology. We present the first report on the development of autologous valved conduit with the sinus of Valsalva (BIOVALVE) by using this unique technology and its subsequent implantation in the pulmonary valves in a beagle model. Methods and Results-A mold of BIOVALVE organization was assembled using 2 types of specially designed silicone rods with a small aperture in a trileaflet shape between them. The concave rods had 3 projections that resembled the protrusions of the sinus of Valsalva. The molds were placed in the dorsal subcutaneous spaces of beagle dogs for 4 weeks. The molds were covered with autologous connective tissues. BIOVALVEs with 3 leaflets in the inner side of the conduit with the sinus of Valsalva were obtained after removing the molds. These valves had adequate burst strength, similar to that of native valves. Tight valvular coaptation and sufficient open orifice area were observed in vitro. These BIOVALVEs were implanted to the main pulmonary arteries as allogenic conduit valves (nϭ3). Postoperative echocardiography demonstrated smooth movement of the leaflets with trivial regurgitation. Histological examination of specimens obtained at 84 days showed that the surface of the leaflet was covered by endothelial cells and neointima, including an elastin fiber network, and was formed at the anastomosis sides on the luminal surface of the conduit. Conclusion-We developed the first completely autologous BIOVALVE and successfully implanted these BIOVALVEs in a beagle model in a pilot study. (Circulation. 2010;122[suppl 1]:S100 -S106.)Key Words: prosthesis Ⅲ regenerative medicine Ⅲ tissue Ⅲ Valsalva Ⅲ valves T issue engineering combines the principles of engineering and biological sciences to develop viable structures that can replace diseased or deficient natural structures. Recently, autologous valve prostheses with enhanced maturation characteristics, such as anticoagulation, self-repair, tissue regeneration, and growth adaptability, have been developed using in vitro tissue engineering technology. Some investigators have successfully implanted in vitro engineered heart valves in animals and humans by using either decellularized natural tissues or biodegradable synthetic polymers as scaffolds. [1][2][3] However, these procedures require complicated cellmanagement protocols, including harvesting, seeding on appropriate scaffolds, and development of neotissues, by culturing cells in bioreactors under strictly sterile conditions; all of these procedures are time-consuming and expensive.We developed autologous prosthetic tissues using "in-body tissue architecture" technology, which is a novel and practical approach of regenerative medicine based on the tissue encapsulation phenomenon of foreign materials in living bodies. 4 This technology has the following advantages. The tissue prostheses can be fabricated in a wide range of shapes and sizes to suit the need of individual recipients and, most imp...
In-body tissue architecture-a novel and practical regeneration medicine technology-can be used to prepare a completely autologous heart valve, based on the shape of a mold. In this study, a three-dimensional (3D) printer was used to produce the molds. A 3D printer can easily reproduce the 3D-shape and size of native heart valves within several processing hours. For a tri-leaflet, valved conduit with a sinus of Valsalva (Biovalve type VII), the mold was assembled using two conduit parts and three sinus parts produced by the 3D printer. Biovalves were generated from completely autologous connective tissue, containing collagen and fibroblasts, within 2 months following the subcutaneous embedding of the molds (success rate, 27/30). In vitro evaluation, using a pulsatile circulation circuit, showed excellent valvular function with a durability of at least 10 days. Interposed between two expanded polytetrafluoroethylene grafts, the Biovalves (N 5 3) were implanted in goats through an apicoaortic bypass procedure. Postoperative echocardiography showed smooth movement of the leaflets with minimal regurgitation under systemic circulation. After 1 month of implantation, smooth white leaflets were observed with minimal thrombus formation. Functional, autologous, 3D-shaped heart valves with clinical application potential were formed following in-body embedding of specially designed molds that were created within several hours by 3D printer.
We developed autologous vascular grafts, called "biotubes," by simple and safe in-body tissue architecture technology, which is a practical concept of regenerative medicine, without using special sterile conditions or complicated in vitro cell treatment processes. In this study, biotubes of extremely small caliber were first auto-implanted to rat abdominal aortas. Biotubes were prepared by placing silicone rods (outer diameter 1.5 mm, length 30 mm) used as a mold into dorsal subcutaneous pouches in rats for 4 weeks. After argatroban coating, the obtained biotubes were auto-implanted to abdominal aortas (n = 6) by end-to-end anastomosis using a custom-designed sutureless vascular connecting system under microscopic guidance. Graft status was evaluated by contrast-free time-of-flight magnetic resonance angiography (TOF-MRA). All grafts were harvested at 12 weeks after implantation. The patency rate was 66.7 % (4/6). MRA showed little stenosis and no aneurysmal dilation in all biotubes. The original biotube had wall thickness of about 56.2 ± 26.5 μm at the middle portion and mainly random and sparse collagen fibers and fibroblasts. After implantation, the wall thickness was 235.8 ± 24.8 μm. In addition, native-like vascular structure was regenerated, which included (1) a completely endothelialized luminal surface, (2) a mesh-like elastin fiber network, and (3) regular circumferential orientation of collagen fibers and α-SMA positive cells. Biotubes could be used as small-caliber vascular prostheses that greatly facilitate the healing process and exhibit excellent biocompatibility in vascular regenerative medicine.
The safety and feasibility of Biotubes for pediatric PA patch augmentation are described. Because Biotubes are completely autologous, they may be ideal material for pediatric PA augmentation.
In this study, we aimed to describe the development of tissue-engineered self-expandable aortic stent grafts (Bio stent graft) using in-body tissue architecture technology in beagles and to determine its mechanical and histological properties. The preparation mold was assembled by insertion of an acryl rod (outer diameter, 8.6 mm; length, 40 mm) into a self-expanding nitinol stent (internal diameter, 9.0 mm; length, 35 mm). The molds (n = 6) were embedded into the subcutaneous pouches of three beagles for 4 weeks. After harvesting and removing each rod, the excessive fragile tissue connected around the molds was trimmed, and thus tubular autologous connective tissues with the stent were obtained for use as Bio stent grafts (outer diameter, approximately 9.3 mm in all molds). The stent strut was completely surrounded by the dense collagenous membrane (thickness, ∼150 µm). The Bio stent graft luminal surface was extremely flat and smooth. The graft wall of the Bio stent graft possessed an elastic modulus that was almost two times higher than that of the native beagle abdominal aorta. This Bio stent graft is expected to exhibit excellent biocompatibility after being implanted in the aorta, which may reduce the risk of type 1 endoleaks or migration.
Using simple, safe, and economical in-body tissue engineering, autologous valved conduits (biovalves) with the sinus of Valsalva and without any artificial support materials were developed in animal recipients' bodies. In this study, the feasibility of the biovalve as an aortic valve was evaluated in a goat model. Biovalves were prepared by 2-month embedding of the molds, assembled using two types of specially designed plastic rods, in the dorsal subcutaneous spaces of goats. One rod had three projections, resembling the protrusions of the sinus of Valsalva. Completely autologous connective tissue biovalves (type VI) with three leaflets in the inner side of the conduit with the sinus of Valsalva were obtained after removing the molds from both terminals of the harvested implants with complete encapsulation. The biovalve leaflets had appropriate strength and elastic characteristics similar to those of native aortic valves; thus, a robust conduit was formed. Tight valvular coaptation and a sufficient open orifice area were observed in vitro. Biovalves (n = 3) were implanted in the specially designed apico-aortic bypass for 2 months as a pilot study. Postoperative echocardiography showed smooth movement of the leaflets with little regurgitation under systemic circulation (2.6 ± 1.1 l/min). α-SMA-positive cells appeared significantly with rich angiogenesis in the conduit and expanded toward the leaflet tip. At the sinus portions, marked elastic fibers were formed. The luminal surface was covered with thin pseudointima without thrombus formation. Completely autologous biovalves with robust and elastic characteristics satisfied the higher requirements of the systemic circulation in goats for 2 months with the potential for valvular tissue regeneration.
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