1-Year Patency of Biorestorative Polymeric Coronary Artery Bypass Grafts in an Ovine Model.

Many attempts have been made to inhibit or counteract saphenous vein graft (SVG) failure modes; however, only external support for SVGs has gained momentum in clinical utility. This study revealed the feasibility of implantation, and showed good patency out to 12 months of the novel biorestorative graft, in a challenging ovine coronary artery bypass graft model. This finding could trigger the first-in-man trial of using the novel material instead of SVG. We believe that, eventually, this novel biorestorative bypass graft can be one of the options for coronary artery bypass graft patients who have difficulty harvesting SVG.

An optical coherence tomography and endothelial shear stress study of a novel bioresorbable bypass graft.

Endothelial shear stress (ESS) plays a key role in the clinical outcomes in native and stented segments; however, their implications in bypass grafts and especially in a synthetic biorestorative coronary artery bypass graft are yet unclear. This report aims to examine the interplay between ESS and the morphological alterations of a biorestorative coronary bypass graft in an animal model. Computational fluid dynamics (CFD) simulation derived from the fusion of angiography and optical coherence tomography (OCT) imaging was used to reconstruct data on the luminal anatomy of a bioresorbable coronary bypass graft with an endoluminal "flap" identified during OCT acquisition. The "flap" compromised the smooth lumen surface and considerably disturbed the local flow, leading to abnormally low ESS and high oscillatory shear stress (OSI) in the vicinity of the "flap". In the presence of the catheter, the flow is more stable (median OSI 0.02384 versus 0.02635, p < 0.0001; maximum OSI 0.4612 versus 0.4837). Conversely, OSI increased as the catheter was withdrawn which can potentially cause back-and-forth motions of the "flap", triggering tissue fatigue failure. CFD analysis in this report provided sophisticated physiological information that complements the anatomic assessment from imaging enabling a complete understanding of biorestorative graft pathophysiology.

The effect of chronic kidney disease on tissue formation of in situ tissue-engineered vascular grafts.

Vascular in situ tissue engineering encompasses a single-step approach with a wide adaptive potential and true off-the-shelf availability for vascular grafts. However, a synchronized balance between breakdown of the scaffold material and neo-tissue formation is essential. Chronic kidney disease (CKD) may influence this balance, lowering the usability of these grafts for vascular access in end-stage CKD patients on dialysis. We aimed to investigate the effects of CKD on in vivo scaffold breakdown and tissue formation in grafts made of electrospun, modular, supramolecular polycarbonate with ureido-pyrimidinone moieties (PC-UPy). We implanted PC-UPy aortic interposition grafts (n = 40) in a rat 5/6th nephrectomy model that mimics systemic conditions in human CKD patients. We studied patency, mechanical stability, extracellular matrix (ECM) components, total cellularity, vascular tissue formation, and vascular calcification in CKD and healthy rats at 2, 4, 8, and 12 weeks post-implantation. Our study shows successful in vivo application of a slow-degrading small-diameter vascular graft that supports adequate in situ vascular tissue formation. Despite systemic inflammation associated with CKD, no influence of CKD on patency (Sham: 95% vs CKD: 100%), mechanical stability, ECM formation (Sirius red+, Sham 16.5% vs CKD 25.0%-p:0.83), tissue composition, and immune cell infiltration was found. We did find a limited increase in vascular calcification at 12 weeks (Sham 0.08% vs CKD 0.80%-p:0.02) in grafts implanted in CKD animals. However, this was not associated with increased stiffness in the explants. Our findings suggest that disease-specific graft design may not be necessary for use in CKD patients on dialysis.

Quantitative aortography for assessment of aortic regurgitation in the era of percutaneous aortic valve replacement.

Paravalvular leak (PVL) is a shortcoming that can erode the clinical benefits of transcatheter valve replacement (TAVR) and therefore a readily applicable method (aortography) to quantitate PVL objectively and accurately in the interventional suite is appealing to all operators. The ratio between the areas of the time-density curves in the aorta and left ventricular outflow tract (LVOT-AR) defines the regurgitation fraction (RF). This technique has been validated in a mock circulation; a single injection in diastole was further tested in porcine and ovine models. In the clinical setting, LVOT-AR was compared with trans-thoracic and trans-oesophageal echocardiography and cardiac magnetic resonance imaging. LVOT-AR > 17% discriminates mild from moderate aortic regurgitation on echocardiography and confers a poor prognosis in multiple registries, and justifies balloon post-dilatation. The LVOT-AR differentiates the individual performances of many old and novel devices and is being used in ongoing randomized trials and registries.

Injectable hydrogels from segmented PEG-bisurea copolymers.

We describe the preparation of an injectable, biocompatible, and elastic segmented copolymer hydrogel for biomedical applications, with segmented hydrophobic bisurea hard segments and hydrophilic PEG segments. The segmented copolymers were obtained by the step growth polymerization of amino-terminated PEG and aliphatic diisocyanate. Due to their capacity for multiple hydrogen bonding within the hydrophobic segments, these copolymers can form highly stable gels in water at low concentrations. Moreover, the gels show shear thinning by a factor of 40 at large strain, which allows injection through narrow gauge needles. Hydrogel moduli are highly tunable via the physical cross-link density and the length of the hydrophilic segments. In particular, the mechanical properties can be optimized to match the properties of biological host tissues such as muscle tissue and the extracellular matrix.

Tissue response, macrophage phenotype, and intrinsic calcification induced by cardiovascular biomaterials: Can clinical regenerative potential be predicted in a rat subcutaneous implant model?

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.

Supramolecular Biomaterials in the Netherlands.

Synthetically designed biomaterials strive to recapitulate and mimic the complex environment of natural systems. Using natural materials as a guide, the ability to create high-performance biomaterials that control cell fate, and support the next generation of cell- and tissue-based therapeutics, is starting to emerge. Supramolecular chemistry takes inspiration from the wealth of noncovalent interactions found in natural materials that are inherently complex, and using the skills of synthetic and polymer chemistry, recreates simple systems to imitate their features. Within the past decade, supramolecular biomaterials have shown utility in tissue engineering and the progress predicts a bright future. On this 30th anniversary of the Netherlands Biomaterials and Tissue Engineering society, we briefly recount the state of supramolecular biomaterials in the Dutch academic and industrial research and development context. This review provides the background, recent advances, industrial successes and challenges, as well as future directions of the field, as we see it. Throughout this work, we notice the intricate interplay between simplicity and complexity in creating more advanced solutions. We hope that the interplay and juxtaposition between these two forces can propel the field forward. Impact statement Supramolecular biomaterials based on noncovalent interactions hold the ability to rebuild some of the complexity of natural biomaterials in synthetic systems. While still in its infancy, the field is currently vigorously moving from fundamental experiments toward applications and products in the tissue engineering and regenerative medicine arena. Herein, we review the current state of the field in the Netherlands. While supramolecular biomaterials have incredible potential, systematic studies, balancing complexity and simplicity, efficient translation, and enhanced performance are all required for success of these strategies. As we move the field toward commercial solutions for clinical patients, we must also pay homage and remember the fundamental studies that allow these jumps in innovation.

Initial Clinical Trial of a Novel Pulmonary Valved Conduit.

Valved allografts and xenografts for reconstruction of the right ventricular outflow tract (RVOT) lack durability and do not grow. We report the first clinical use of a completely bioabsorbable valved conduit (Xeltis pulmonary valve - XPV) in children. Twelve children (six male), median age five (two to twelve) years and median weight 17 (10 to 43) kg, underwent RVOT reconstruction with the XPV. Diagnoses were: pulmonary atresia with ventricular septal defect (VSD) (n = 4), tetralogy of Fallot (n = 4), common arterial trunk (n = 3), and transposition of the great arteries with VSD and pulmonary stenosis (n = 1). All had had previous surgery, including prior RVOT conduit implantation in six. Two diameters of conduit 16mm (n = 5) and 18mm (n = 7) were used. At 24 months none of the patients has required surgical re-intervention, 9 of the 12 are in NYHA functional class I and three patients in NYHA class II. None of the conduits has shown evidence of progressive stenosis, dilation or aneurysm formation. Residual peak gradient of >40 mm Hg was observed in three patients, caused by kinking of the conduit at implantation in 1 and distal stenosis in the peripheral pulmonary arteries in 2 patients. Five patients developed severe pulmonary valve insufficiency (PI); the most common mechanism was prolapse of at least one of the valve leaflets. The XPV conduit is a promising innovation for RVOT reconstruction. Progressive PI requires however an improved design (geometry, thickness) of the valve leaflets.

Marker-Independent Monitoring of in vitro and in vivo Degradation of Supramolecular Polymers Applied in Cardiovascular in situ Tissue Engineering.

The equilibrium between scaffold degradation and neotissue formation, is highly essential for in situ tissue engineering. Herein, biodegradable grafts function as temporal roadmap to guide regeneration. The ability to monitor and understand the dynamics of degradation and tissue deposition in in situ cardiovascular graft materials is therefore of great value to accelerate the implementation of safe and sustainable tissue-engineered vascular grafts (TEVGs) as a substitute for conventional prosthetic grafts. In this study, we investigated the potential of Raman microspectroscopy and Raman imaging to monitor degradation kinetics of supramolecular polymers, which are employed as degradable scaffolds in in situ tissue engineering. Raman imaging was applied on in vitro degraded polymers, investigating two different polymer materials, subjected to oxidative and enzymatically-induced degradation. Furthermore, the method was transferred to analyze in vivo degradation of tissue-engineered carotid grafts after 6 and 12 months in a sheep model. Multivariate data analysis allowed to trace degradation and to compare the data from in vitro and in vivo degradation, indicating similar molecular observations in spectral signatures between implants and oxidative in vitro degradation. In vivo degradation appeared to be dominated by oxidative pathways. Furthermore, information on collagen deposition and composition could simultaneously be obtained from the same image scans. Our results demonstrate the sensitivity of Raman microspectroscopy to determine degradation stages and the assigned molecular changes non-destructively, encouraging future exploration of this techniques for time-resolved quality assessment of in situ tissue engineering processes.

One-year performance of biorestorative polymeric coronary bypass grafts in an ovine model: correlation between early biomechanics and late serial Quantitative Flow Ratio.

OBJECTIVES: This study aimed to investigate the impact of mechanical factors at baseline on the patency of a restorative conduit for coronary bypass grafts in an ovine model at serial follow-up up to 1 year. METHODS: The analyses of 4 mechanical factors [i.e. bending angle, superficial wall strain and minimum and maximum endothelial shear stress (ESS)] were performed in 3D graft models reconstructed on baseline (1-month) angiograms frame by frame by a core laboratory blinded for the late follow-up. The late patency was documented by Quantitative Flow Ratio (QFR®) that reflects the physiological status of the graft. The correlation between 4 mechanical factors and segmental QFR (△QFR) were analysed on 10 equal-length segments of each graft. RESULTS: A total of 69 graft geometries of 7 animals were performed in the study. The highest △QFR at 12 months was colocalized in segments of the grafts with the largest bending angles at baseline. Higher △QFR at 3 months were both at the anastomotic ends and were colocalized with the highest superficial wall strain at baseline. High baseline ESS was topographically associated with higher △QFR at the latest follow-up. Correlations of minimum and maximum ESS with △QFR at 3 months were the strongest among these parameters (ρ = 0.30, 95% CI [-0.05 to 0.56] and ρ = 0.27, 95% CI [-0.05 to 0.54], respectively). CONCLUSIONS: Despite the limited number of grafts, this study suggests an association between early abnormal mechanical factors and late flow metrics of the grafts. The understanding of the mechanical characteristics could help to improve this novel conduit.

Chronic haemodynamic performance of a biorestorative transcatheter heart valve in an ovine model.

BACKGROUND: The Xeltis biorestorative transcatheter heart valve (BTHV) leaflets are made from an electrospun bioabsorbable supramolecular polycarbonate-urethane and are mounted on a self-expanding nitinol frame. The acute haemodynamic performance of this BTHV was favourable. AIMS: We sought to demonstrate the preclinical feasibility of a novel BTHV by evaluating the haemodynamic performances of five pilot valve designs up to 12 months in a chronic ovine model. METHODS: Five design iterations (A, B, B', C, and D) of the BTHV were transapically implanted in 46 sheep; chronic data were available in 39 animals. Assessments were performed at implantation, 3, 6, and 12 months including quantitative aortography, echocardiography, and histology. RESULTS: At 12 months, greater than or equal to moderate AR on echocardiography was seen in 0%, 100%, 33.3%, 100%, and 0% in the iterations A, B, B', C, and D, respectively. Furthermore, transprosthetic mean gradients on echocardiography were 10.0±2.8 mmHg, 19.0±1.0 mmHg, 8.0±1.7 mmHg, 26.8±2.4 mmHg, and 11.2±4.1 mmHg, and effective orifice area was 0.7±0.3 cm2, 1.1±0.3 cm2, 1.5±1.0 cm2, 1.5±0.6 cm2, and 1.0±0.4 cm2 in the iterations A, B, B', C, and D, respectively. On pathological evaluation, the iteration D demonstrated generally intact leaflets and advanced tissue coverage, while different degrees of structural deterioration were observed in the other design iterations. CONCLUSIONS: Several leaflet material iterations were compared for the potential to demonstrate endogenous tissue restoration in an aortic valve in vivo. The most promising iteration showed intact leaflets and acceptable haemodynamic performance at 12 months, illustrating the potential of the BTHV.

Validation of Prosthetic Mitral Regurgitation Quantification Using Novel Angiographic Platform by Mock Circulation.

OBJECTIVES: This study aimed to validate a dedicated software for quantitative videodensitometric angiographic assessment of mitral regurgitation (QMR). BACKGROUND: Quantitative videodensitometric aortography of aortic regurgitation using the time-density principle is a well-documented technique, but the angiographic assessment of mitral regurgitation (MR) remains at best semi-quantitative and operator dependent. METHODS: Fourteen sheep underwent surgical mitral valve replacement using 2 different prostheses. Pre-sacrifice left ventriculograms were used to assess MR fraction (MRF) using QMR and MR volume (MRV). In an independent core lab, the CAAS QMR 0.1 was used for QMR analysis. In vitro MRF and MRV were assessed in a mock circulation at a comparable cardiac output to the in vivo one by thermodilution. The correlations and agreements of in vitro and in vivo MRF, MRV, and interobserver reproducibility for QMR analysis were assessed using the averaged cardiac cycles (CCs). RESULTS: In vivo derived MRF by QMR strongly correlated with in vitro derived MRF, regardless of the number of the CCs analyzed (best correlation: 3 CCs y = 0.446 + 0.994x; R = 0.784; p =0.002). The mean absolute difference between in vitro derived MRF and in vivo derived MRF from 3 CCs was 0.01 ± 4.2% on Bland-Altman analysis. In vitro MRV and in vivo MRV from 3 CCs were very strongly correlated (y = 0.196 + 1.255x; R = 0.839; p < 0.001). The mean absolute difference between in vitro MRV and in vivo MRV from 3 CCs was -1.4 ± 1.9 ml. There were very strong correlations of in vivo MRF between 2 independent analysts, regardless of the number of the CCs. CONCLUSIONS: In vivo MRF using the novel software is feasible, accurate, and highly reproducible. These promising results have led us to initiate the first human feasibility study comprising patients undergoing percutaneous mitral valve edge-to-edge repair.

Total cavopulmonary connection with a new restorative vascular graft: results at 2 years.

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.

A Novel Restorative Pulmonary Valve Conduit: Early Outcomes of Two Clinical Trials.

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.

Morphology and mechanisms of a novel absorbable polymeric conduit in the pulmonary circulation of sheep.

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.

Mechanical characterization of anisotropic planar biological soft tissues using finite indentation: experimental feasibility.

Heart valve tissue engineering offers a promising alternative for current treatment and replacement strategies, e.g., synthetic or bioprosthetic heart valves. In vitro mechanical conditioning is an important tool for engineering strong, implantable heart valves. Detailed knowledge of the mechanical properties of the native tissue as well as the developing tissue construct is vital for a better understanding and control of the remodeling processes induced by mechanical conditioning. The nonlinear, anisotropic and inhomogeneous mechanical behavior of heart valve tissue necessitates a mechanical characterization method that is capable of dealing with these complexities. In a recent computational study we showed that one single indentation test, combining force and deformation gradient data, provides sufficient information for local characterization of nonlinear soft anisotropic tissue properties. In the current study this approach is validated in two steps. First, indentation tests with varying indenter sizes are performed on linear elastic PDMS rubbers and compared to tensile tests on the same specimen. For the second step, tissue constructs are engineered using uniaxial or equibiaxial static constrained culture conditions. Digital image correlation (DIC) is used to quantify the anisotropy in the tissue constructs. For both validation steps, material parameters are estimated by inverse fitting of a computational model to the experimental results.

Remodelling of the angular collagen fiber distribution in cardiovascular tissues.

Understanding collagen fiber remodelling is desired to optimize the mechanical conditioning protocols in tissue-engineering of load-bearing cardiovascular structures. Mathematical models offer strong possibilities to gain insight into the mechanisms and mechanical stimuli involved in these remodelling processes. In this study, a framework is proposed to investigate remodelling of angular collagen fiber distribution in cardiovascular tissues. A structurally based model for collagenous cardiovascular tissues is extended with remodelling laws for the collagen architecture, and the model is subsequently applied to the arterial wall and aortic valve. For the arterial wall, the model predicts the presence of two helically arranged families of collagen fibers. A branching, diverging hammock-type fiber architecture is predicted for the aortic valve. It is expected that the proposed model may be of great potential for the design of improved tissue engineering protocols and may give further insight into the pathophysiology of cardiovascular diseases.

The non-linear mechanical properties of soft engineered biological tissues determined by finite spherical indentation.

The mechanical properties of soft biological tissues in general and early stage engineered tissues in particular limit the feasibility of conventional tensile tests for their mechanical characterisation. Furthermore, the most important mode in development of deep tissue injury (DTI) is compression. Therefore, an inverse numerical-experimental approach using a finite spherical indentation test is proposed. To demonstrate the feasibility of the approach indentation tests are applied to bio-artificial muscle (BAM) tissue. BAMs are cultured in vitro with (n = 20) or without (n = 12) myoblast cells to quantify the effect of the cells on the passive transverse mechanical properties. Indentation tests are applied up to 80% of the tissue thickness. A non-linear Neo-Hookean constitutive model is fitted to the experimental results for parameter estimation. BAMs with cells demonstrated both stiffer and more non-linear material behaviour than BAMs without cells.

A novel restorative pulmonary valved conduit in a chronic sheep model: Mid-term hemodynamic function and histologic assessment.

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.

Midterm performance of a novel restorative pulmonary valved conduit: preclinical results.

AIMS: The Xeltis bioabsorbable pulmonary valved conduit (XPV), designed to guide functional restoration of patients' own tissue, is potentially more durable than current pulmonary bioprosthetic valves/valved conduits. The aim of this study was to assess the haemodynamic performance of the novel XPV implanted in an ovine model. METHODS AND RESULTS: The XPV was surgically implanted in adult sheep under general anaesthesia and cardiopulmonary bypass (XPV group, n=20). Sheep that received a Hancock bioprosthetic pulmonary valved conduit served as a control group (HPV group, n=3). Transthoracic echocardiograms from VARC-2 recommended time points at 3, 6, 9, 12, 18 and 24 months (XPV group) and at 3 and 6 months (HPV group) after the procedure were analysed in an independent core laboratory. The primary endpoint was favourable valved conduit performance, defined as peak systolic pressure gradient <40 mmHg, no severe pulmonary regurgitation (PR), and a maximum conduit patency index of -20%. In the latter, negative values denote luminal narrowing and vice versa. The valvular peak systolic pressure gradient (mmHg) was 25.6±9.7 (3 months), 19.6±7.1 (6 months), 10.0±9.2 (24 months) in the XPV group and 18.4±6.6 (3 months), 17.7±4.6 (6 months) in the HPV group. The patency index (%) of the conduit at the valvular level was +30.3±13.6 (6 months) and +64.1±1.4 (24 months) in the XPV group and +2.0±15.9 (6 months) in the HPV group. PR was trace or mild at all visits, except in one animal with persistent moderate PR in the XPV group, up to 24 months. CONCLUSIONS: The XPV showed a favourable and durable haemodynamic performance (up to two years after implantation), without conduit narrowing/obstruction or severe regurgitation.