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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.

The host immune response to an implanted biomaterial, particularly the phenotype of infiltrating macrophages, is a key determinant of biocompatibility and downstream remodeling outcome. The present study used a subcutaneous rat model to compare the tissue response, including macrophage phenotype, remodeling potential, and calcification propensity of a biologic scaffold composed of glutaraldehyde‐fixed bovine pericardium (GF‐BP), the standard of care for heart valve replacement, with those of an electrospun polycarbonate‐based supramolecular polymer scaffold (ePC‐UPy), urinary bladder extracellular matrix (UBM‐ECM), and a polypropylene mesh (PP). The ePC‐UPy and UBM‐ECM materials induced infiltration of mononuclear cells throughout the thickness of the scaffold within 2 days and neovascularization at 14 days. GF‐BP and PP elicited a balance of pro‐inflammatory (M1‐like) and anti‐inflammatory (M2‐like) macrophages, while UBM‐ECM and ePC‐UPy supported a dominant M2‐like macrophage phenotype at all timepoints. Relative to GF‐BP, ePC‐UPy was markedly less susceptible to calcification for the 180 day duration of the study. UBM‐ECM induced an archetypical constructive remodeling response dominated by M2‐like macrophages and the PP caused a typical foreign body reaction dominated by M1‐like macrophages. The results of this study highlight the divergent macrophage and host remodeling response to biomaterials with distinct physical and chemical properties and suggest that the rat subcutaneous implantation model can be used to predict in vivo biocompatibility and regenerative potential for clinical application of cardiovascular biomaterials. [ABSTRACT FROM AUTHOR]

Background: Arteriovenous grafts (AVGs) are used for patients deemed unsuitable for the creation of an autogenous arteriovenous fistula (AVF) or unable to await maturation of the AVF before starting hemodialysis. However, AVGs are prone to infection and thrombosis resulting in low long-term patency rates. The novel aXess Hemodialysis Graft consists of porous polymeric biomaterial allowing the infiltration by cells and the growth of neotissue, while the graft itself is gradually absorbed, ultimately resulting in a fully functional natural blood vessel. The Pivotal Study will examine the long-term effectiveness and safety of the aXess Hemodialysis Graft., Methods: The Pivotal Study is a prospective, single-arm, multicenter study that will be conducted in 110 subjects with end-stage renal disease who are not deemed suitable for the creation of an autogenous vascular access. The primary efficacy endpoint will be the primary patency rate at 6 months. The primary safety endpoint will be the freedom from device-related serious adverse events at 6 months. The secondary endpoints will include the procedural success rate, time to first cannulation, patency rates, the rate of access-related interventions to maintain patency, the freedom from device-related serious adverse events and the rate of access site infections. Patients will be followed for 60 months. An exploratory Health Economic and Outcomes Research sub-study will determine potential additional benefits of the aXess graft to patients, health care institutions, and reimbursement programs., Discussion: The Pivotal study will examine the long-term performance and safety of the aXess Hemodialysis Graft and compare the outcome measures with historical data obtained with other graft types and autogenous AVFs. Potential advantages may include superior long-term patency rates and lower infection rates versus currently available AVGs and a shorter time to first cannulation compared to an autologous AVF. As such, the aXess Hemodialysis Graft may fulfill an unmet clinical need in the field of hemodialysis access., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Frans Moll is a consultant to Xeltis B.V. All other authors declare no conflict of interest.

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. 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. [Display omitted] [ABSTRACT FROM AUTHOR]

Objectives: We report the first use of a biorestorative valved conduit (Xeltis pulmonary valve–XPV) in children. Based on early follow-up data the valve design was modified; we report on the comparative performance of the two designs at 12 months post-implantation.Methods: Twelve children (six male) median age 5 (2 to 12) years and weight 17 (10 to 43) kg, had implantation of the first XPV valve design (XPV-1, group 1; 16 mm (n = 5), and 18 mm (n = 7). All had had previous surgery. Based on XPV performance at 12 months, the leaflet design was modified and an additional six children (five male) with complex malformations, median age 5 (3 to 9) years, and weight 21 (14 to 29) kg underwent implantation of the new XPV (XPV-2, group 2; 18 mm in all). For both subgroups, the 12 month clinical and echocardiographic outcomes were compared.Results: All patients in both groups have completed 12 months of follow-up. All are in NYHA functional class I. Seventeen of the 18 conduits have shown no evidence of progressive stenosis, dilation or aneurysm formation. Residual gradients of >40 mm Hg were observed in three patients in group 1 due to kinking of the conduit (n = 1), and peripheral stenosis of the branch pulmonary arteries (n = 2). In group 2, one patient developed rapidly progressive stenosis of the proximal conduit anastomosis, requiring conduit replacement. Five patients in group 1 developed severe pulmonary valve regurgitation (PI) due to prolapse of valve leaflet. In contrast, only one patient in group 2 developed more than mild PI at 12 months, which was not related to leaflet prolapse.Conclusions: The XPV, a biorestorative valved conduit, demonstrated promising early clinical outcomes in humans with 17 of 18 patients being free of reintervention at 1 year. Early onset PI seen in the XPV-1 version seems to have been corrected in the XPV-2, which has led to the approval of an FDA clinical trial.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT02700100 and NCT03022708.

Abstract Background Right ventricular outflow tract (RVOT) conduits used in children with congenital heart disease often degenerate rapidly or develop other complications, and they do not grow with the patient. This leads to multiple surgeries until adult-sized conduits can be implanted. We report experimental in vivo experience with an entirely synthetic absorbable graft, designed to be replaced by tissue in-vivo by host cells, in a process termed Endogenous Tissue Restoration (ETR), and to grow commensurate with somatic growth. Methods We characterized the structure, mechanical properties, biocompatibility, and in vivo remodelling of a bioabsorbable polyester based on the self-complementary ureido-pyrimidinone (UPy) quadruple hydrogen-bonding motif. Electrospinning was used to process the polymer into a tubular graft with a highly porous wall structure, which was implanted as a pulmonary artery interposition graft in 9 adult sheep with a maximum follow-up of 1 year, followed by pathologic and mechanical analysis. Results All grafts were patent by transthoracic echocardiography. Eight were intact at post-mortem examination. One graft had aneurysmal dilation. Graft polymer resorption in vivo was consistent among specimens. Histologic examination revealed progressive tissue replacement of graft polymer, ongoing at one year, with remodeling to a structure that had some key features of native vascular wall. Burst pressures for all explants at 8 weeks and beyond were higher than those of native pulmonary artery (PA) and largely determined by newly formed tissue. Conclusions Preclinical studies of a new, absorbable polymeric graft for PA replacement showed remodelling by endogenous cells up to one-year follow-up. Our results show that ETR leads to progressive and substantial replacement of an off-the-shelf synthetic bioabsorbable conduit by functional host tissue to one year in sheep. Thus, further development of this novel concept is warranted. Highlights • A tubular graft with a highly porous wall structure, fabricated from bioabsorbable polyester based on the self-complementary ureido-pyrimidinone (UPy) quadruple hydrogen-bonding motif was implanted as a pulmonary artery interposition graft in 9 adult sheep with a maximum follow-up of one year. • The graft was designed to be replaced by tissue in-vivo. • Explanted grafts we analyzed by mechanical testing and histological examination, focusing on biocompatibility and in vivo remodeling. • Eight of 9 grafts were intact at post-mortem examination; one graft had aneurysmal dilation. • Histologic examination revealed progressive tissue replacement of graft polymer, ongoing at one year, with remodeling to a structure that had some key features of native vascular wall. Burst pressures for all explants at 8 weeks and beyond were higher than those of native pulmonary artery (PA) and largely determined by newly formed tissue. [ABSTRACT FROM AUTHOR]

In situ tissue engineering offers an innovative solution for replacement valves and grafts in cardiovascular medicine. In this approach, a scaffold, which can be obtained by polymer electrospinning, is implanted into the human body and then infiltrated by cells, eventually replacing the scaffold with native tissue. In silico simulations of the whole process in patient-specific models, including implantation, growth and degradation, are very attractive to study the factors that might influence the end result. In our research, we focused on the mechanical behaviour of the polymeric scaffold and its short-term response. Following a recently proposed constitutive model for the anisotropic inelastic behaviour of fibrous polymeric materials, we present here its numerical implementation in a finite element framework. The numerical model is developed as user material for commercial finite element software. The verification of the implementation is performed for elementary deformations. Furthermore, a parallel-plate test is proposed as a large-scale representative example, and the model is validated by comparison with experiments.

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., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Carrel.)

Background: To present a 2-year follow-up regarding safety and hemodynamic performance of a new restorative vascular graft used as extracardiac cavo-pulmonary connection in patients with univentricular congenital heart malformations., Methods: The graft was implanted in five patients (aged 4-12 years) as extracardiac connection between the inferior vena cava and the pulmonary artery. The conduit consists of a bioabsorbable polymer-based implant able to generate endogenous tissue restoration leading to a fully functional neo-vessel while the polymer progressively absorbs. All patients have reached more than 24 months following surgery and underwent echocardiography and magnetic resonance imaging., Results: All patients are doing well at 24 months follow-up, with no graft-related serious adverse events. Transthoracic echocardiography demonstrated adequate function of the conduit in all patients while magnetic resonance imaging showed anatomical and functional stability of the restorative grafts., Conclusions: The new restorative conduit has been successfully used for the second step of the Fontan procedure as extracardiac total cavopulmonary connection. The results are promising because they suggest that complete transformation of a bioabsorbable polymer and replacement through endogenous tissue may represent a major advantage in the treatment of congenital heart disease patients. Further monitoring will allow to evaluate the long-term behavior of this new graft, in terms of clinical and hemodynamic performance, thrombogenicity and ability to grow., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-19-739). This clinical study was sponsored by Xeltis, and all payments were made to the hospital. The authors attest that they had full freedom to explore the data and analyze the results independently from the sponsor and that they had sole authority to make the final decision to submit the material for publication. AL, MC and OS are employed by and hold stock options of Xeltis. ATC is a member of the Medical Advisory Board of Xeltis. The other authors have no conflicts of interest to declare., (2020 Journal of Thoracic Disease. All rights reserved.)

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. [ABSTRACT FROM AUTHOR]