Search

In situ heart valve tissue engineering is an emerging approach in which resorbable, off-the-shelf available scaffolds are used to induce endogenous heart valve restoration. Such scaffolds are designed to recruit endogenous cells in vivo, which subsequently resorb polymer and produce and remodel new valvular tissue in situ. Recently, preclinical studies using electrospun supramolecular elastomeric valvular grafts have shown that this approach enables in situ regeneration of pulmonary valves with long-term functionality in vivo. However, the evolution and mechanisms of inflammation, polymer absorption and tissue regeneration are largely unknown, and adverse valve remodeling and intra- and inter-valvular variability have been reported. Therefore, the goal of the present study was to gain a mechanistic understanding of the in vivo regenerative processes by combining routine histology and immunohistochemistry, using a comprehensive sheep-specific antibody panel, with Raman microspectroscopy for the spatiotemporal analysis of in situ tissue-engineered pulmonary valves with follow-up to 24 months from a previous preclinical study in sheep. The analyses revealed a strong spatial heterogeneity in the influx of inflammatory cells, graft resorption, and foreign body giant cells. Collagen maturation occurred predominantly between 6 and 12 months after implantation, which was accompanied by a progressive switch to a more quiescent phenotype of infiltrating cells with properties of valvular interstitial cells. Variability among specimens in the extent of tissue remodeling was observed for follow-up times after 6 months. Taken together, these findings advance the understanding of key events and mechanisms in material-driven in situ heart valve tissue engineering. STATEMENT OF SIGNIFICANCE: This study describes for the first time the long-term in vivo inflammatory and regenerative processes that underly in situ heart valve tissue engineering using resorbable synthetic scaffolds. Using a unique combinatorial analysis of immunohistochemistry and Raman microspectroscopy, important spatiotemporal variability in graft resorption and tissue formation was pinpointed in in situ tissue-engineered heart valves, with a follow-up time of up to 24 months in sheep. This variability was correlated to heterogenous regional cellular repopulation, most likely instigated by region-specific differences in surrounding tissue and hemodynamics. The findings of this research contribute to the mechanistic understanding of in situ tissue engineering using resorbable synthetics, which is necessary to enable rational design of improved grafts, and ensure safe and robust clinical translation., Competing Interests: Declaration of Competing Interest The research labs from K. Schenke-Layland and A. Smits performed independent scientific contract work for the company Xeltis and received for this work financial compensation. M. Cox, H. Bauer and A. Serrero are employees of Xeltis, M. Cox and C. Bouten are shareholders of Xeltis and F. Schoen is a financially compensated scientific advisor to Xeltis. All other authors report no competing interests., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: To evaluate the safety and the short-term function of a novel pulmonary valved conduit (Xeltis Pulmonary Valved Conduit; XPV) up to 12 months in a sheep model., Methods: XPV and Hancock bioprosthetic valved conduits (H, used as control) were implanted in adult sheep in the pulmonary artery position. Animals were killed at 2 months (n = 6 XPV), 6 months (n = 6 XPV and n = 3 H), and 12 months (n = 6 XPV) and examined histologically. During follow-up, function of the device as well as diameter of both XPV and H were assessed by transthoracic echocardiography., Results: Of 18 animals that received an XPV, 15 survived until they were killed; 3 animals that received H survived the planned observational interval. XPV showed mild neointimal thickening and degradation beginning at 2 months with an ongoing process until 12 months. Only 1 of the 18 animals with XPV had significant calcification at 6 months. Pathologic specimen did not show any significant narrowing of the conduit whereas neointimal thickness showed a peak at 6 months. Inflammatory process reached a maximum at 6 months and the degradation process at 12 months. Gel permeation chromatography analysis showed molecular weight loss beginning at 2 months with a peak at 12 months for the conduit with slower absorption for the leaflets. The wall of the H conduits showed more neointimal thickening, narrowing, and calcification compared with XPV, but the leaflets demonstrated minimal changes., Conclusions: Both conduits demonstrated an acceptable safety and functionality. Significant calcification was rarely observed in the XPV, whereas the H developed more neointimal thickness with calcification of the porcine aortic root portion of the wall., (Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

The pulmonary valve is the most frequently replaced cardiac valve in congenital heart diseases. Whether the valve alone or part of the right ventricular outflow tract have to be repaired or replaced depends on the specific pathological anatomy of the malformation. Once the decision to replace the pulmonary valve has been made, two options are available: the isolated transcatheter pulmonary valve replacement and the surgical implantation of a prosthetic valve either isolated or in combination with a procedure on the right ventricular outflow tract. In this paper, we will focus on the different past and present surgical options and present a new concept called “endogenous tissue restoration,” a promising alternative to the hitherto existing implants. From a general point of view, neither the transcatheter nor the surgical valvular implants are magic bullets in the arsenal for the management of valvular diseases. Smaller valves have to be frequently replaced because of outgrowth of the patients, larger tissue valves may present late structural valve deterioration, while xenograft and homograft conduits may calcify and therefore become narrowed within unpredictable incidence and interval following implantation. Based on long-term research efforts combining the knowledge of supramolecular chemistry, electrospinning, and regenerative medicine, endogenous tissue restoration has emerged most recently as a promising option to create long-term functioning implants. This technology is appealing because following resorption of the polymer scaffold and timely replacement through autologous tissue, no foreign material remain at all in the cardiovascular system. Proof-of-concept studies as well as small first-in-man series have been completed and have demonstrated favorable anatomic and hemodynamic results, comparable to currently available implants in the short term. Based on the initial experience, important modifications to improve the pulmonary valve function have been initiated.