Publications by authors named "Martijn Cox"

23 Publications

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Supramolecular Biomaterials in the Netherlands.

Tissue Eng Part A 2022 Mar 22. Epub 2022 Mar 22.

Leiden University, 4496, Leiden, Zuid-Holland, 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 non-covalent 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 will briefly recount the state of supramolecular biomaterials in the Dutch academic and industrial research and development context. This review will provide 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.
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http://dx.doi.org/10.1089/ten.TEA.2022.0010DOI Listing
March 2022

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

Eur J Cardiothorac Surg 2022 Jan 12. Epub 2022 Jan 12.

Department of Cardiology, National University of Ireland Galway (NUIG), Galway, Ireland.

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.
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http://dx.doi.org/10.1093/ejcts/ezab554DOI Listing
January 2022

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

J Biomed Mater Res A 2022 02 29;110(2):245-256. Epub 2021 Jul 29.

Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

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.
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http://dx.doi.org/10.1002/jbm.a.37280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8678182PMC
February 2022

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

EuroIntervention 2021 Dec 17;17(12):e1009-e1018. Epub 2021 Dec 17.

Department of Cardiology, National University of Ireland, Galway (NUIG) and CORRIB Corelab and Center for Research and Imaging, Galway, Ireland.

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.
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http://dx.doi.org/10.4244/EIJ-D-21-00386DOI Listing
December 2021

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

JACC Cardiovasc Interv 2021 07 30;14(14):1523-1534. Epub 2021 Jun 30.

Department of Cardiology, National University of Ireland, Galway (NUIG) and CORRIB Corelab and Center for Research and Imaging, Galway, Ireland.

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.
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http://dx.doi.org/10.1016/j.jcin.2021.04.046DOI Listing
July 2021

Initial Clinical Trial of a Novel Pulmonary Valved Conduit.

Semin Thorac Cardiovasc Surg 2021 May 11. Epub 2021 May 11.

Heart Center, University Hospital of Cologne, Cologne, Germany.

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.
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http://dx.doi.org/10.1053/j.semtcvs.2021.03.036DOI Listing
May 2021

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

Front Cardiovasc Med 2020 4;7:583360. Epub 2021 Mar 4.

Cardiovascular Core Laboratories, MedStar Health Research Institute, Washington, DC, United States.

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. 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 ( = 5), and 18 mm ( = 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. 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 ( = 1), and peripheral stenosis of the branch pulmonary arteries ( = 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. 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. www.ClinicalTrials.gov, identifier: NCT02700100 and NCT03022708.
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http://dx.doi.org/10.3389/fcvm.2020.583360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969645PMC
March 2021

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

J Thorac Dis 2020 Aug;12(8):4168-4173

Xeltis BV, Eindhoven, The Netherlands.

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.
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http://dx.doi.org/10.21037/jtd-19-739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475567PMC
August 2020

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

Cardiovasc Pathol 2019 Jan - Feb;38:31-38. Epub 2018 Oct 25.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.carpath.2018.10.008DOI Listing
March 2019

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

J Thorac Cardiovasc Surg 2018 06 21;155(6):2591-2601.e3. Epub 2017 Dec 21.

CVPath Institute, Gaithersburg, Md.

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.
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http://dx.doi.org/10.1016/j.jtcvs.2017.12.046DOI Listing
June 2018

Acute performance of a novel restorative transcatheter aortic valve: preclinical results.

EuroIntervention 2017 12 8;13(12):e1410-e1417. Epub 2017 Dec 8.

Department of Cardiology, Thoraxcenter, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands.

Aims: The Xeltis aortic valve leaflets are made from a bioabsorbable supramolecular polymer that guides the tissue to restoring itself. It is mounted on a self-expanding nitinol frame that includes three feelers and a native leaflet clipping mechanism. We sought to investigate the acute valve performance in a preclinical setting.

Methods And Results: In 33 sheep, 26 mm Xeltis aortic valves were transapically implanted in a 23 mm native annulus. Aortography (analysable, n=28) and echocardiography (analysable, n=20) images were acquired immediately after implantation of the Xeltis aortic valve to assess the acute device performance. On echocardiography, transvalvular peak pressure gradient (PG) was 7.4 (IQR: 6.0-8.9) mmHg, mean PG was 4.0 (IQR: 3.0-5.0) mmHg, and effective orifice area was 2.2 (IQR: 1.6-2.5) cm2. Trace (n=6), mild (n=2) and no (n=12) transvalvular aortic regurgitation (AR) were seen. Likewise, no paravalvular AR was detected in 7 cases, whereas trace, mild and moderate were seen in 7, 5 and 1 cases, respectively. On quantitative videodensitometric AR (VD-AR) assessment, a median value of 6% (IQR: 1-12%) of AR was seen. Three cases had a VD-AR superior to 17%, which has a prognostic significance. Out of these three cases, two had echocardiographic assessment available, which showed mild and moderate paravalvular regurgitation due to inadequate leaflet clipping.

Conclusions: In a transapical ovine model, the novel restorative transcatheter aortic valve with bioabsorbable leaflets demonstrated good haemodynamic performance comparable to commercially available devices. The highly porous polymeric leaflets demonstrated good competence immediately after implantation with no cases having >mild transvalvular AR.
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http://dx.doi.org/10.4244/EIJ-D-17-00554DOI Listing
December 2017

Restorative valve therapy by endogenous tissue restoration: tomorrow's world? Reflection on the EuroPCR 2017 session on endogenous tissue restoration.

EuroIntervention 2017 Sep;13(AA):AA68-AA77

Imperial College London, London, United Kingdom.

The current standard of treatment of valvular diseases with severe functional and/or clinical consequences is the repair or replacement of the valve, which is usually surgical or, in specific scenarios, percutaneous. The available prosthetic valves, however, are not a magic bullet in the physicians' arsenal for the management of valvular diseases, since the age-dependent structural valve deterioration (SVD) and the need for prolonged systemic anticoagulation in the case of metallic prosthetic valves are not inconsequential during the lifespan of a patient with an implanted prosthetic valve. Based on decades of research combining the scientific disciplines of supramolecular chemistry, electrospinning and regenerative medicine, endogenous tissue restoration has emerged as a very promising domain to provide this magic bullet, in the form of valves, which enables functional restoration by the body itself. The concept of a restorative material that will set the framework for the creation of a new, endogenous valve is very appealing and, recently, proof of concept studies have been completed at both preclinical and clinical levels. These studies have shown favourable pathologic, anatomic and haemodynamic characteristics compared to currently available prosthetic valves, in sheep and in young children undergoing right ventricular outflow tract reconstruction, and may represent an alternative to the bioprosthesis made of xenopericardial tissue. The present manuscript reviews the rationale, background knowledge and historic development of endogenous tissue restoration and presents preliminary data about the Xeltis valve, which appears to have the potential to make restorative valve therapy a reality in clinical practice.
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http://dx.doi.org/10.4244/EIJ-D-17-00509DOI Listing
September 2017

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

EuroIntervention 2017 12 8;13(12):e1418-e1427. Epub 2017 Dec 8.

Department of Cardiology, Thoraxcenter, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands.

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.
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http://dx.doi.org/10.4244/EIJ-D-17-00553DOI Listing
December 2017

Total cavopulmonary connection with a new bioabsorbable vascular graft: First clinical experience.

J Thorac Cardiovasc Surg 2017 06 7;153(6):1542-1550. Epub 2017 Feb 7.

Department of Cardiovascular Surgery, University of Bern, Bern, Switzerland.

Objectives: To assess safety and clinical performance of a novel bioabsorbable vascular graft in pediatric patients with univentricular cardiac malformation who received surgical correction via an extracardiac cavopulmonary conduit.

Methods: The implanted graft material is designed to attract patient's own cells and proteins, which trigger a cascade of physiological events leading to endogenous tissue restoration. As the graft resorbs progressively after implantation, components of native tissue including collagen, endothelial lining, and capillary blood vessels develop and organize into a natural tissue. Five patients (aged 4-12 years) received this new vascular graft as interposition between the inferior vena cava and the pulmonary artery. They were followed up to 12 months after surgery. The conduit was assessed by echocardiography, computed tomography and magnetic resonance imaging, including 4-dimensional flow.

Results: All patients recovered from the procedure without complications. No device-related adverse events were reported. Two patients required interventional occlusion of aortopulmonary collaterals. At 12 months, there was a significant improvement in the patients' general condition. Imaging studies demonstrated anatomical (conduit diameter, length and wall thickness) and functional (blood flow pattern) stability of the bioabsorbable grafts in all patients with no significant changes at 12 months compared with early postoperative data.

Conclusions: Initial clinical experience with a novel absorbable graft underlines the potential of this new material to improve cardiac and vascular surgical procedures. In addition, better biocompatibility may reduce permanent implant-related complications. A longer follow-up is needed to assess the long-term effectiveness of biodegradable vascular grafts, including their ability to grow.
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http://dx.doi.org/10.1016/j.jtcvs.2016.11.071DOI Listing
June 2017

Superior Tissue Evolution in Slow-Degrading Scaffolds for Valvular Tissue Engineering.

Tissue Eng Part A 2016 Jan 1;22(1-2):123-32. Epub 2015 Dec 1.

2 Department of Biomedical Engineering, Eindhoven University of Technology , Eindhoven, The Netherlands .

Synthetic polymers are widely used to fabricate porous scaffolds for the regeneration of cardiovascular tissues. To ensure mechanical integrity, a balance between the rate of scaffold absorption and tissue formation is of high importance. A higher rate of tissue formation is expected in fast-degrading materials than in slow-degrading materials. This could be a result of synthetic cells, which aim to compensate for the fast loss of mechanical integrity of the scaffold by deposition of collagen fibers. Here, we studied the effect of fast-degrading polyglycolic acid scaffolds coated with poly-4-hydroxybutyrate (PGA-P4HB) and slow-degrading poly-ɛ-caprolactone (PCL) scaffolds on amount of tissue, composition, and mechanical characteristics in time, and compared these engineered values with values for native human heart valves. Electrospun PGA-P4HB and PCL scaffolds were either kept unseeded in culture or were seeded with human vascular-derived cells. Tissue formation, extracellular matrix (ECM) composition, remaining scaffold weight, tissue-to-scaffold weight ratio, and mechanical properties were analyzed every week up to 6 weeks. Mass of unseeded PCL scaffolds remained stable during culture, whereas PGA-P4HB scaffolds degraded rapidly. When seeded with cells, both scaffold types demonstrated increasing amounts of tissue with time, which was more pronounced for PGA-P4HB-based tissues during the first 2 weeks; however, PCL-based tissues resulted in the highest amount of tissue after 6 weeks. This study is the first to provide insight into the tissue-to-scaffold weight ratio, therewith allowing for a fair comparison between engineered tissues cultured on scaffolds as well as between native heart valve tissues. Although the absolute amount of ECM components differed between the engineered tissues, the ratio between ECM components was similar after 6 weeks. PCL-based tissues maintained their shape, whereas the PGA-P4HB-based tissues deformed during culture. After 6 weeks, PCL-based engineered tissues showed amounts of cells and ECM that were comparable to the number of human native heart valve leaflets, whereas values were lower in the PGA-P4HB-based tissues. Although increasing in time, the number of collagen crosslinks were below native values in all engineered tissues. In conclusion, this study indicates that slow-degrading scaffold materials are favored over fast-degrading materials to create organized ECM-rich tissues in vitro, which keep their three-dimensional structure before implantation.
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http://dx.doi.org/10.1089/ten.TEA.2015.0203DOI Listing
January 2016

Tailoring the foreign body response for in situ vascular tissue engineering.

Tissue Eng Part C Methods 2015 May 1;21(5):436-46. Epub 2014 Dec 1.

1 Department of Nephrology, Leiden University Medical Center , Leiden, The Netherlands .

This study describes a screening platform for a guided in situ vascular tissue engineering approach. Polymer rods were developed that upon 3 weeks of subcutaneous implantation evoke a controlled inflammatory response culminating in encapsulation by a tube-shaped autologous fibrocellular tissue capsule, which can form a basis for a tissue-engineered blood vessel. Rods of co-polymer were produced using different ratios of poly(ethylene oxide terephthalate) and poly(butylene terephthalate) to create a range of physicochemical properties. In addition, a set of different physical, chemical, and biological surface modifications were tested on their ability to actively steer this tissue capsule formation using a rat model as testing platform. Tissue capsules were mainly composed of circumferentially aligned collagen and myofibroblasts. Different implant material resulted in distinct differences in tissue capsule formation. Compared to its unmodified counterparts, all surface modifications resulted in increased wall thickness, collagen, and myofibroblasts. Oxygen plasma-treated rods resulted in loose tissue arrangement, collagen, and collagen/TGF-β-coated rods yielded thick, collagen-rich, densely packed tissue capsules, though with a random distribution of myofibroblasts. In contrast, chloroform-etched rods provided homogenous densely packed tissue capsules, completely populated by myofibroblasts. In conclusion, by varying the implant's surface characteristics, tissue capsule composition, cell distribution, and tissue arrangement could be tailored, enabling controlled guidance of the tissue response for in vivo vascular tissue engineering.
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http://dx.doi.org/10.1089/ten.TEC.2014.0264DOI Listing
May 2015

Poly-ε-caprolactone scaffold and reduced in vitro cell culture: beneficial effect on compaction and improved valvular tissue formation.

J Tissue Eng Regen Med 2015 Dec 16;9(12):E289-301. Epub 2013 May 16.

Department of Biomedical Engineering, Eindhoven University of Technology, The Netherlands.

Tissue-engineered heart valves (TEHVs), based on polyglycolic acid (PGA) scaffolds coated with poly-4-hydroxybutyrate (P4HB), have shown promising in vivo results in terms of tissue formation. However, a major drawback of these TEHVs is compaction and retraction of the leaflets, causing regurgitation. To overcome this problem, the aim of this study was to investigate: (a) the use of the slowly degrading poly-ε-caprolactone (PCL) scaffold for prolonged mechanical integrity; and (b) the use of lower passage cells for enhanced tissue formation. Passage 3, 5 and 7 (P3, P5 and P7) human and ovine vascular-derived cells were seeded onto both PGA-P4HB and PCL scaffold strips. After 4 weeks of culture, compaction, tissue formation, mechanical properties and cell phenotypes were compared. TEHVs were cultured to observe retraction of the leaflets in the native-like geometry. After culture, tissues based on PGA-P4HB scaffold showed 50-60% compaction, while PCL-based tissues showed compaction of 0-10%. Tissue formation, stiffness and strength were increased with decreasing passage number; however, this did not influence compaction. Ovine PCL-based tissues did render less strong tissues compared to PGA-P4HB-based tissues. No differences in cell phenotype between the scaffold materials, species or cell passage numbers were observed. This study shows that PCL scaffolds may serve as alternative scaffold materials for human TEHVs with minimal compaction and without compromising tissue composition and properties, while further optimization of ovine TEHVs is needed. Reducing cell expansion time will result in faster generation of TEHVs, providing more rapid treatment for patients.
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http://dx.doi.org/10.1002/term.1753DOI Listing
December 2015

Injectable hydrogels from segmented PEG-bisurea copolymers.

Biomacromolecules 2012 Dec 28;13(12):3966-76. Epub 2012 Nov 28.

Laboratory for Macromolecular and Organic Chemistry, Department of Mechanical Engineering, Institute for Complex Molecular Systems, Eindhoven University of Technology, P.O. Box 513, 5600 MB Eindhoven, The Netherlands.

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.
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http://dx.doi.org/10.1021/bm301242vDOI Listing
December 2012

Tissue-engineered heart valves develop native-like collagen fiber architecture.

Tissue Eng Part A 2010 May;16(5):1527-37

Department of Biomedical Engineering, Eindhoven University of Technology, P.O. Box 513, Eindhoven 5600 MB, WH4.107, The Netherlands.

Creating autologous tissues with on-demand and native-like biomechanical properties is the ultimate challenge in functional heart valve tissue engineering. A promising approach toward this goal is to induce development of native-like tissue structure in vitro by mimicking the diastolic loading phase in a bioreactor. Heart valves cultured with this approach showed in vitro sufficient strength to withstand systemic pressures. This study aims to link global functioning of these valves to the development of a native-like fiber architecture induced by in vitro diastolic loading. It is hypothesized that increased loading magnitude during culture will lead to increased collagen fiber alignment. To test this hypothesis, 10 tissue-engineered heart valves were subjected to different loading protocols in vitro. Local fiber distribution and mechanics were determined in an inverse numerical-experimental approach, combining indentation tests with confocal imaging. Indentation tests on native ovine heart valves were used as a comparison. Although the effect of loading magnitude was small within the tested range, results indicated that the local fiber architecture indeed developed toward native structural properties for all loading protocols. However, apparent fiber mechanics were much stiffer compared with native. This confirms that in vitro mechanical conditioning induces development of a native-like tissue architecture, which underlines its importance for functional heart valve tissue engineering.
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http://dx.doi.org/10.1089/ten.TEA.2009.0263DOI Listing
May 2010

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

Comput Methods Biomech Biomed Engin 2008 Oct;11(5):585-92

Department of Biomedical Engineering, Eindhoven University of Technology, PO Box 513, 5600 MB Eindhoven, The Netherlands.

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.
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http://dx.doi.org/10.1080/10255840701771768DOI Listing
October 2008

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

J Biomech 2008 25;41(2):422-9. Epub 2007 Sep 25.

Department of Biomedical Engineering, Eindhoven University of Technology, P.O. Box 513, 5600 MB Eindhoven,The Netherlands.

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.
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http://dx.doi.org/10.1016/j.jbiomech.2007.08.006DOI Listing
April 2008

Remodelling of the angular collagen fiber distribution in cardiovascular tissues.

Biomech Model Mechanobiol 2008 Apr 13;7(2):93-103. Epub 2007 Mar 13.

Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.

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.
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http://dx.doi.org/10.1007/s10237-007-0078-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2792349PMC
April 2008

Mechanical characterization of anisotropic planar biological soft tissues using large indentation: a computational feasibility study.

J Biomech Eng 2006 Jun;128(3):428-36

Department of Biomedical Engineering, Eindhoven University of Technology, PO Box 513, 5600 MB Eindhoven, The Netherlands.

Traditionally, the complex mechanical behavior of planar soft biological tissues is characterized by (multi)axial tensile testing. While uniaxial tests do not provide sufficient information for a full characterization of the material anisotropy, biaxial tensile tests are difficult to perform and tethering effects limit the analyses to a small central portion of the test sample. In both cases, determination of local mechanical properties is not trivial. Local mechanical characterization may be performed by indentation testing. Conventional indentation tests, however, often assume linear elastic and isotropic material properties, and therefore these tests are of limited use in characterizing the nonlinear, anisotropic material behavior typical for planar soft biological tissues. In this study, a spherical indentation experiment assuming large deformations is proposed. A finite element model of the aortic valve leaflet demonstrates that combining force and deformation gradient data, one single indentation test provides sufficient information to characterize the local material behavior. Parameter estimation is used to fit the computational model to simulated experimental data. The aortic valve leaflet is chosen as a typical example. However, the proposed method is expected to apply for the mechanical characterization of planar soft biological materials in general.
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http://dx.doi.org/10.1115/1.2187040DOI Listing
June 2006
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