Heart valve replacements with regenerative capacity

\u3cp\u3eThe incidence of severe valvular dysfunctions (e.g., stenosis and insufficiency) is increasing, leading to over 300,000 valves implanted worldwide yearly. Clinically used heart valve replacements lack the capacity to grow, inherently requiring repetitive and high-risk surgical interventions during childhood. The aim of this review is to present how different tissue engineering strategies can overcome these limitations, providing innovative valve replacements that proved to be able to integrate and remodel in pre-clinical experiments and to have promising results in clinical studies. Upon description of the different types of heart valve tissue engineering (e.g., in vitro, in situ, in vivo, and the pre-seeding approach) we focus on the clinical translation of this technology. In particular, we will deepen the many technical, clinical, and regulatory aspects that need to be solved to endure the clinical adaptation and the commercialization of these promising regenerative valves.\u3c/p\u3

Vascular tissue engineering: pathological considerations, mechanisms, and translational implications

Clinical translation of vascular tissue engineering is hampered by inconsistencies in graft outcomes. In this chapter, we argue that variation in graft outcomes is largely due to our lack of fully understanding vascular regeneration and remodeling in response to specific graft properties. In addition, results obtained from animal studies are difficult to translate into patients. This is mainly due to interspecies variation in vascular regeneration, as well as inter-patient variation in factors influencing regeneration, such as gender, age, clinical condition, and use of medication. Following a review of vascular structure as a blueprint for tissue-engineered grafts and vascular pathologies necessitating such grafts, we describe potential mechanisms of host-graft interaction that explain outcome variability. Next, we propose research strategies to carefully move from understanding (variability in) vascular regeneration to robust and personalized graft design and outcomes

Polymer-based scaffold designs for in situ vascular tissue engineering : controlling recruitment and differentiation behavior of endothelial colony forming cells

In situ vascular tissue engineering has been proposed as a promising approach to fulfill the need for small-diameter blood vessel substitutes. The approach comprises the use of a cell-free instructive scaffold to guide and control cell recruitment, differentiation, and tissue formation at the locus of implantation. Here we review the design parameters for such scaffolds, with special emphasis on differentiation of recruited ECFCs into the different lineages that constitute the vessel wall. Next to defining the target properties of the vessel, we concentrate on the target cell source, the ECFCs, and on the environmental control of the fate of these cells within the scaffold. The prospects of the approach are discussed in the light of current technical and biological hurdles

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

\u3cp\u3eValvular heart disease is a major cause of morbidity and mortality worldwide. Current heart valve prostheses have considerable clinical limitations due to their artificial, nonliving nature without regenerative capacity. To overcome these limitations, heart valve tissue engineering (TE) aiming to develop living, native-like heart valves with self-repair, remodeling, and regeneration capacity has been suggested as next-generation technology. A major roadblock to clinically relevant, safe, and robust TE solutions has been the high complexity and variability inherent to bioengineering approaches that rely on cell-driven tissue remodeling. For heart valve TE, this has limited long-term performance in vivo because of uncontrolled tissue remodeling phenomena, such as valve leaflet shortening, which often translates into valve failure regardless of the bioengineering methodology used to develop the implant. We tested the hypothesis that integration of a computationally inspired heart valve design into our TE methodologies could guide tissue remodeling toward long-term functionality in tissue-engineered heart valves (TEHVs). In a clinically and regulatory relevant sheep model, TEHVs implanted as pulmonary valve replacements using minimally invasive techniques were monitored for 1 year via multimodal in vivo imaging and comprehensive tissue remodeling assessments. TEHVs exhibited good preserved long-term in vivo performance and remodeling comparable to native heart valves, as predicted by and consistent with computational modeling. TEHV failure could be predicted for nonphysiological pressure loading. Beyond previous studies, this work suggests the relevance of an integrated in silico, in vitro, and in vivo bioengineering approach as a basis for the safe and efficient clinical translation of TEHVs.\u3c/p\u3

In situ heart valve tissue engineering using a bioresorbable elastomeric implant - From material design to 12 months follow-up in sheep

\u3cp\u3eThe creation of a living heart valve is a much-wanted alternative for current valve prostheses that suffer from limited durability and thromboembolic complications. Current strategies to create such valves, however, require the use of cells for in vitro culture, or decellularized human- or animal-derived donor tissue for in situ engineering. Here, we propose and demonstrate proof-of-concept of in situ heart valve tissue engineering using a synthetic approach, in which a cell-free, slow degrading elastomeric valvular implant is populated by endogenous cells to form new valvular tissue inside the heart. We designed a fibrous valvular scaffold, fabricated from a novel supramolecular elastomer, that enables endogenous cells to enter and produce matrix. Orthotopic implantations as pulmonary valve in sheep demonstrated sustained functionality up to 12 months, while the implant was gradually replaced by a layered collagen and elastic matrix in pace with cell-driven polymer resorption. Our results offer new perspectives for endogenous heart valve replacement starting from a readily-available synthetic graft that is compatible with surgical and transcatheter implantation procedures.\u3c/p\u3