Pediatric tubular pulmonary heart valve from decellularized engineered tissue tubes

Abstract

Pediatric patients account for a small portion of the heart valve replacements performed, but a pediatric pulmonary valve replacement with growth potential remains an unmet clinical need. Herein we report the first tubular heart valve made from two decellularized, engineered tissue tubes attached with absorbable sutures, which can meet this need, in principle. Engineered tissue tubes were fabricated by allowing ovine dermal fibroblasts to replace a sacrificial fibrin gel with an aligned, cell-produced collagenous matrix, which was subsequently decellularized. Previously, these engineered tubes became extensively recellularized following implantation into the sheep femoral artery. Thus, a tubular valve made from these tubes may be amenable to recellularization and, ideally, somatic growth. The suture line pattern generated three equi-spaced “leaflets” in the inner tube, which collapsed inward when exposed to back pressure, per tubular valve design. Valve testing was performed in a pulse duplicator system equipped with a secondary flow loop to allow for root distention. All tissue-engineered valves exhibited full leaflet opening and closing, minimal regurgitation (< 5%), and low systolic pressure gradients (< 2.5 mmHg) under pulmonary conditions. Valve performance was maintained under various trans-root pressure gradients and no tissue damage was evident after 2 million cycles of fatigue testing.

Implantation of a Tissue-Engineered Tubular Heart Valve in Growing Lambs

“…18 The suture pattern was designed such that there were three commissures and three leaflets that collapse inward and close the valve when exposed to backpressure (Figure 1b), utilizing the principle of tubular heart valve design. 4 The engineered tubes used to make the valve consisted primarily of cell-produced collagen and other extracellular matrix proteins, although a residual fibrin layer remained on the lumenal surface following in vitro culture, as revealed by trichrome staining (Figure 1c).…”

“…18 Briefly, the tubes were sutured together using 7-0 degradable sutures (Covidien Maxon CV) in 2 distinct patterns. The first suture line encompassed the entire circumference of the tubes and defined leaflet and commissure regions.…”

“…18 It is a tubular heart valve, comprised of two tubes of cell-produced matrix grown in vitro held together with degradable sutures. 18 These sutures are reported to maintain 50% of their initial strength after 4 weeks in vivo . 1 We have recently shown that single tubes implanted into young lambs as a pulmonary artery replacement with this suture exhibit somatic growth.…”

Heart Valve Replacements with Regenerative Capacity

“…In addition, it can be efficiently combined with the transcathether approach, without limiting valve functionality and remodeling potential, as demonstrated in sheep [44] and baboons [45]. With a similar approach, others investigated the use of fibrin-based decellularized TEHVs, showing good in vitro [46] and in vivo functionality, with almost complete cell repopulation in the systemic circulation of sheep [36]. Despite the promising pre-clinical results of these decellularized valves, the time and cost associated with scaffold production pushed the researchers to develop new alternatives.…”

In vitro biomechanical and hydrodynamic characterisation of decellularised human pulmonary and aortic roots

“…Therefore, to determine whether decellularised valves are suitable for clinical use, it is important to thoroughly assess functional performance including both the mechanical properties of the decellularised tissue and investigation of the performance of the decellularised valve under physiological flow conditions. Various test methods have been used to assess both the mechanical properties of valve tissue such as flexural (Engelmayr et al, 2005;Sacks et al, 2009b), local indentation (Cox et al, 2006), biaxial tensile (Sacks et al, 2009b;Billiar and Sacks, 2000;Fisher et al, 1986), uniaxial tensile (Luo et al, 2014;Korossis et al, 2002;Anssari-Benam et al, 2011), suture pull-out (Edwards et al, 2005;Walraevens et al, 2008), and dilation (Jennings et al, 2002;Korossis et al, 2005) as well as hydrodynamic performance of the valves under physiological flow conditions (Fisher et al, 1986;Jennings et al, 2002;Syedain et al, 2013;Reimer et al, 2015).…”