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

Abstract

Current pediatric heart valve replacement options are suboptimal because they are incapable of somatic growth. Thus, children typically have multiple surgeries to replace outgrown valves. In this study, we present the in vivo function and growth potential of our tissue-engineered pediatric tubular valve. The valves were fabricated by sewing two decellularized engineered tissue tubes together in a prescribed pattern using degradable sutures and subsequently implanted into the main pulmonary artery of growing lambs. Valve function was monitored using periodic ultrasounds after implantation throughout the duration of the study. The valves functioned well up to eight weeks, four weeks beyond the suture strength half-life, after which their insufficiency index worsened. Histology from the explanted valves revealed extensive host cell invasion occurred within the engineered root and commenced from the leaflet surfaces. These cells expressed multiple phenotypes, including endothelial, and deposited elastin and collagen IV. Although the tubes fused together along the degradable suture line, as designed, the leaflets shortened compared to their original height. This shortening is hypothesized to result from inadequate fusion at the commissures prior to suture degradation. With appropriate commissure reinforcement, this novel heart valve may provide the somatic growth potential desired for a pediatric valve replacement.

Characterization of an Acellular Scaffold for a Tissue Engineering Approach to the Nipple-Areolar Complex Reconstruction

“…Although this reduction in elastin may affect the mechanical parameters of the NAC and will be evaluated in future studies, this was an expected outcome of the detergent-based decellularization process. Elastin has been shown in previous studies to be significantly decreased during decellularization in a variety of tissue types (Petersen, Calle et al 2012, Reimer, Syedain et al 2016). However, it has also been observed that the native environment in vivo can restore levels of elastin and other extracellular proteins, such as collagens, after scaffolds are reincorporated into the body (Ghazanfari, Driessen-Mol et al 2015, Reimer, Syedain et al 2016).…”

Computational modeling guides tissue-engineered heart valve design for long-term in vivo performance in a translational sheep model

“…Several previous preclinical studies have demonstrated that remodeling of TEHVs does not naturally lead to a desired outcome (11,12,15,17,18,(20)(21)(22). Consequently, because of the strong interdependency of mechanics and tissue remodeling, mechanical models that can predict the relevant biological mechanisms are extremely valuable in understanding the adaptation of engineered cardiovascular tissues and proposing solutions for how to improve their performance.…”

“…Accordingly, in situ TE concepts relying on the recipient's body to regenerate the implant in vivo represent the most advanced and clinically relevant methodology. In particular, tissue-engineered extracellular matrices (ECMs) depleted of cells have proven to be a valid off-the-shelf alternative to the initially described in vitro TE approaches in several preclinical investigations (11,12,15,18,22). Furthermore, the principal feasibility of implanting biodegradable polymeric scaffolds in a preclinical animal model, which are transformed into cell-repopulated valves in vivo, has been recently demonstrated (10).…”

“…The functionality of most TEHVs is gradually lost within a few months due to adverse tissue remodeling, which translates into the development of leaflet retraction and valvular incompetence almost universally and independently of the bioengineering methodology used (11,12,15,17,18,(20)(21)(22). Understanding and guiding the mechanisms of functionally adaptive and potentially maladaptive remodeling are therefore of central importance for safe and efficient clinical translation.…”

The Pursuit of Engineering the Ideal Heart Valve Replacement or Repair: A Special Issue of the Annals of Biomedical Engineering

“…Although the work of Kang et al employs a more basic science framework to study cell viability, their optimization of crosslinking conditions during the encapsulation of cells is a necessary step in the assessment of hydrogels as a viable scaffold material for tissue engineered heart valves (TEHVs) The articles by Picard-Deland et al and Reimer et al both focus on tubular heart valves. 11,12 Tissue engineered tubular heart valves are emerging as an attractive approach with potential for growth-a characteristic critical for pediatric applications. These two papers offer contrasting approaches to combat the major hurdle of post-implantation activation of valve cells within the TEHV and subsequent contraction of the engineered tissue.…”