Ann Thorac Surg 2005;80:704-707
© 2005 The Society of Thoracic Surgeons
New technology
A Stentless Trileaflet Valve From a Sheet of Decellularized Porcine Small Intestinal Submucosa
Jennifer K. White, MD
*
,
Arvind K. Agnihotri, MD,
James S. Titus,
David F. Torchiana, MD
Division of Cardiac Surgery, Massachusetts General Hospital, Boston, Massachusetts
Accepted for publication August 26, 2004.
* Address reprint requests to Dr White, Division of Cardiac Surgery, Massachusetts General Hospital, Bullfinch 119/50 Fruit St, Boston, MA 02114 (Email: jkwhite{at}partners.org).
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Abstract
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PURPOSE: The purpose of this study was to investigate the function of a trileaflet pulmonary valve constructed from a sheet of porcine small intestinal submucosa.
DESCRIPTION: In four sheep, the native pulmonary valve and a segment of the pulmonary trunk was excised and replaced with a trileaflet valve constructed from decellularized porcine small intestinal submucosa. The valve construct was created from a sheet of the xenograft material by a method of involuting flaps of tissue inside a cylinder of itself. The function of the valve was assessed by echocardiography, catheter pullback across the valve, and observation of an excised valve in a flow simulator.
EVALUATION: The valve constructs exhibited low gradients and symmetrical leaflet movement with good mobility when tested under physiologic conditions in an acute sheep model.
CONCLUSIONS: This method offers a means to create a functional trileaflet valve replacement from a sheet of tissue.
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Introduction
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Various tissue engineered materials have been investigated for their potential use as substrates for prosthetic cardiac valves [1]. In order to reach their full potential as predominantly autologous structures, tissue engineered substances require a period of maturation for cell seeding or remodeling to occur. If this period of maturation is occurring in vivo, the tissue engineered material needs to provide a bridge to support the function of the valve until cellular remodeling confers biomechanical strength necessary for valve function.
Decellularized porcine-derived small intestinal submucosa (SIS) has emerged as a potentially useful tissue engineering material for valve construction, in part due to its biomechanical strength [2], which may enable it to function as a valve until remodeling is complete [3]. The SIS is harvested and supplied as a sheet of tissue. Methods of constructing functional valves from this substance need to be developed. This study is an investigation of the function of a stentless trileaflet valve construct derived from a sheet of SIS and implanted as a pulmonary valve replacement in sheep.
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Material and Methods
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Four valve constructs were created using porcine small intestinal submucosa (SIS) tissue (Fig 1, A–F) obtained from industrial sources (Edwards Lifesciences, Irvine, CA; and Cook, West Lafayette, IN). The SIS was derived from porcine jejunum immediately after slaughter. The intestine was rinsed to remove its contents, and the layers of the tunica mucosa, the tunica muscularis externa, and tunica serosa were removed by mechanical delamination. The SIS was reverted to its original orientation, split open longitudinally, and rinsed in water to lyse any cells. The SIS was treated with dilute peracetic acid and supplied to our laboratory as hydrated sheets of single-ply tissue. An 11-blade scalpel was used to sharply excise a 20 mm wide by 62 mm long rectangular sheet along the longitudinal plane of a sheet of tissue. A cylinder was formed by suturing the sheet along its width using a continuous 7-0 Prolene (Ethicon, Somerville, NJ) suture (Fig 1, B). The smooth submucosal surface of the material was orientated facing the inside of the cylinder. Three symmetrical tissue flaps were generated in the cylinder by creating three longitudinal incisions positioned at equidistant points and extending one quarter the height of the cylinder of tissue (Fig 1, B). The flaps of tissue were involuted inside the cylinder (Fig 1, C and D). Three valve leaflets were formed from the flaps of tissue by securing the edge of each flap to the wall of the cylinder at 120 degrees apart using 6-0 Prolene U sutures (Fig 1, E). A 2.0 cm wide cuff of SIS tissue was sutured along both the superior and inferior aspects of the valve construct to form extensions of tissue at either end of the construct (Fig 1, F).
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Fig 1. Schematic of method of preparing valved conduit from a sheet of tissue. (A) Flat sheet of tissue (b = width, 20 mm; l = length, 62 mm). (B) Cylinder of tissue created by suturing the flat sheet along its width (a = cylinder diameter; b = height; c = incised portion, 15 mm; d = longitudinal incision, 5 mm). (C) Involution of flaps inside cylinder. (D-E) Creation of valve and leaflets by suturing tissue flaps to inner wall of cylinder. (F) Two-dimensional cuffs of tissue sutured to superior and inferior aspect of valve to create valved conduit.
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In four anesthetized sheep, intubation was carried out after induction of anesthesia by intravenous injection of 2.5% solution thiopental sodium (10 to 15 mg/kg) through the jugular vein. General anesthesia was maintained with 1% to 2% isoflourane delivered by endotracheal tube. A median sternotomy was performed, and cardiopulmonary bypass was instituted. Cold high potassium crystalloid cardioplegia was given by direct ostial cannulation. The pulmonary trunk was transversely transected approximately 0.5 cm above the sinotubular junction and the native pulmonary valve leaflets excised. A 1.0 cm transverse segment of the pulmonary trunk was removed and replaced with the preformed valve construct by suturing the tissue cuff extensions along the superior and inferior aspects using 4-0 Prolene continuous suture.
After separation of the animal from bypass, valve function was assessed using a handheld echocardiography probe. A catheter connected to a high-fidelity pressure transducer was inserted through a pursestring suture into right ventricle and passed beyond the bifurcation of the pulmonary artery. Transvalvular gradients were determined by pull-back of the catheter across the valve construct. One explanted SIS valve construct was positioned in a pulse duplicator and leaflet opening and closure was observed throughout physiologic pressure gradient cycle. Hematoxylin and eosin and trichrome stains were performed on the explanted valves.
All animals received humane care in compliance with the "Guide for Care and Use of Laboratory Animals"[4] prepared by the Institute of Laboratory Resources, National Research Council. No funding agency was involved in data interpretation.
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Results
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A single sheet of tissue formed a trileaflet valve construct using the method described in this study (Fig 2). This construct provided the basis for a valved conduit positioned as a pulmonary valve replacement in sheep (Fig 3). All animals were successfully weaned from bypass. Echocardiography demonstrated symmetrical leaflet opening and closure. Systolic peak-to-peak gradient of the replacement valve was 0.74 ± 0.73 mm Hg (Fig 4). Histology of the explanted valve leaflets indicated full-thickness impregnation of host red blood cells into the leaflets (Fig 5). The explanted valve demonstrated symmetrical leaflet closure and good leaflet mobility throughout physiologic pressure changes in the flow simulator. (Fig 6).
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Fig 2. Photograph of valve construct derived from a sheet of single-ply porcine small intestinal submucosa using involution method.
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Fig 3. Trileaflet valve construct positioned in conduit surgically implanted in sheep pulmonary trunk.
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Fig 4. Catheter pullback across valve construct in sheep pulmonary trunk. (PA = pulmonary artery; RV = right ventricle.)
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Fig 5. Histology of valve leaflet depicting full-thickness impregnation of erythrocytes in porcine small intestinal submucosal tissue. (Hematoxylin & eosin stain, original magnification x200.)
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Comment
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Cardiac surgeons have continued to develop techniques to construct autologous heart valves from a range of tissue sources since the early days of the field. These methods pose significant technical challenges owing to the need to construct the valve leaflets during surgical implantation of the valve [5] or the requirement to use curved suture lines to form symmetrical valve cusps [6]. Most recently, investigators have stressed that new methods of creating valve replacements from sheets of tissues capable of serving as suitable tissue engineered substances need to be developed [7].
Creating complex three-dimensional valves from the substances identified as potential tissue engineered materials has been difficult. Prior attempts to construct cardiac valve scaffolds using hand fabrication welding and molding from soluble fibers encountered problems with low precision, poor reproducibility, and insufficient overlap of the leaflets [8]. Sheets of decellularized xenograft tissues have shown promise as tissue engineered scaffolds for single cusp replacements [9], but methods of valve construction often rely upon rigid stents to provide a multileaflet valve [10].
The valve construction method described in this study entails folding a single layer sheet of decellularized porcine small intestinal submucosa inside a cylinder of itself to create leaflets. This method, referred to as the "involution" method, provided a simple means to consistently create a trileaflet valve from a flat sheet of tissue by eliminating the need to use curved suture lines to form the cusps. As leaflet construction is completed before implantation, this method avoids the technical challenge of trying to surgically construct the leaflets during implantation. A stentless trileaflet valve constructed in this manner provided a competent, low gradient pulmonic valve replacement in an acute sheep model.
Current pulmonic valve replacement prostheses are suboptimal, particularly in the pediatric population. Tissue valves tend to degenerate rapidly in pediatric patients, and patients may outgrow stented valve replacements. Homograft valve replacements are associated with a risk for pulmonic stenosis, which has been a particular concern in patients undergoing a Ross procedure. The valve constructed from decellularized xenograft material in this study may offer a longer-term pulmonic valve replacement by providing a competent, low gradient trileaflet valve to act as a functional bridge as the valve construct itself undergoes remodeling and populates with host cells. Longer-term implants are necessary to determine the ability of the scaffold to remodel and provide a permanent functional valve replacement.
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Acknowledgments
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This work was funded by the Center for the Integration of Medicine and Innovative Technology and by the Massachusetts General Hospital Department of Surgery. The tissue used in this study was donated to the hospital.
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References
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- Schoen FJ, Levy RJ. Tissue heart valvescurrent challenges and future research perspectives. J Biomed Mater Res 1999;47:439-465.[Medline]
- Sacks MS, Gloeckner DC. Quantification of the fiber architecture and biaxial mechanical behavior of porcine intestinal submucosa J Biomed Mater Res 1999;46:1-10.[Medline]
- Badylak SF. Small intestinal submucosa (SIS)a biomaterial conducive to smart tissue remodeling. In: Bell E, editor. Tissue engineering. current perspectives. Cambridge, MA: Burkhauser; 1993. pp. 179-189.
- National Research Council Guide for the care and use of laboratory animalsWashington, DC: National Academy Press; 1996.
- Senning A. Fascia lata replacement of aortic valves J Thorac Cardiovasc Surg 1967;54:465-470.[Medline]
- Schlichter AJ, Kreutzer C, Mayorquim RD, et al. Five-to fifteen-year follow-up of fresh autologous pericardial valved conduit J Thorac Cardiovasc Surg 2000;119:869-879.[Abstract/Free Full Text]
- Sutherland FW, Mayer JE. Tissue engineering for cardiac surgeryIn: Cohn LH, Edmunds LH, editors. Cardiac surgery in the adult. New York: MacGraw-Hill; 2003. pp. 1527-1536.
- Hoerstrup SP, Sodian R, Daebritz S, et al. Functional living trileaflet heart valves grown in vitro Circulation 2000;102(Suppl 3):44-49.
- Matheny REG, Hutchison ML, Dryden PE, Hile MD, Shaar CJ. Porcine small intestinal submucosa as a pulmonary valve leaflet substitute J Heart Valve Dis 2000;9:769-775.[Medline]
- Pavcnik D, Machan L, Uchida B, Kaufman J, Keller FS, Rosch J. Percutaneous prosthetic venous valvecurrent state and possible applications. Tech Vasc Intervent Radiol 2003;6:137-142.[Medline]
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Abstract
Introduction
