In vivo monitoring of function of autologous engineered pulmonary valve

Gottlieb, Danielle; Tandon, Kunal; Emani, Sitaram M.; Aikawa, Elena; Brown, David W.; Powell, A.; Nedder, Arthur; Engelmayr, George C.; Melero‐Martin, Juan M.; Sacks, Michael S.; Mayer, John E.

doi:10.1016/j.jtcvs.2009.11.006

Cited by 131 publications

(135 citation statements)

References 18 publications

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“…Proper valve closure remains a challenge for heart valve tissue engineering, as regurgitation has been reported in several studies (Flanagan et al, 2009;Gottlieb et al, 2010). Regurgitation is mainly caused by cell-mediated retraction of the leaflets (Dijkman et al, 2012;van Vlimmeren et al, 2011van Vlimmeren et al, , 2012, and to ensure valve closure, these contractile cellular forces should be counteracted by the pressure applied to the valve during diastole.…”

Section: Discussionmentioning

confidence: 99%

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Effects of Valve Geometry and Tissue Anisotropy on the Radial Stretch and Coaptation Area of Tissue-Engineered Heart Valves

Loerakker

Argento

Oomens

et al. 2013

Volume 1A: Abdominal Aortic Aneurysms; Active and Reactive Soft Matter; Atherosclerosis; BioFluid Mechanics; Education; Biotran

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Tissue engineering represents a promising technique to overcome the limitations of the current valve replacements, since it allows for creating living autologous heart valves that have the potential to grow and remodel. However, also this approach still faces a number of challenges. One particular problem is regurgitation, caused by cell-mediated tissue retraction or the mismatch in geometrical and material properties between tissue-engineered heart valves (TEHVs) and their native counterparts. The goal of the present study was to assess the influence of valve geometry and tissue anisotropy on the deformation profile and closed configuration of TEHVs. To achieve this aim, a range of finite element models incorporating different valve shapes was developed, and the constitutive behavior of the tissue was modeled using an established computational framework, where the degree of anisotropy was varied between values representative of TEHVs and native valves. The results of this study suggest that valve geometry and tissue anisotropy are both important to maximize the radial strains and thereby the coaptation area. Additionally, the minimum degree of anisotropy that is required to obtain positive radial strains was shown to depend on the valve shape and the pressure to which the valves are exposed. Exposure to pulmonary diastolic pressure only yielded positive radial strains if the anisotropy was comparable to the native situation, whereas considerably less anisotropy was required if the valves were exposed to aortic diastolic pressure. AbstractTissue engineering represents a promising technique to overcome the limitations of the current valve replacements, since it allows for creating living autologous heart valves that have the potential to grow and remodel. However, also this approach still faces a number of challenges. One particular problem is regurgitation, caused by cell-mediated tissue retraction or the mismatch in geometrical and material properties between tissue-engineered heart valves (TEHVs) and their native counterparts. The goal of the present study was to assess the influence of valve geometry and tissue anisotropy on the deformation profile and closed configuration of TEHVs. To achieve this aim, a range of finite element models incorporating different valve shapes was developed, and the constitutive behavior of the tissue was modeled using an established computational framework, where the degree of anisotropy was varied between values representative of TEHVs and native valves. The results of this study suggest that valve geometry and tissue anisotropy are both important to maximize the radial strains and thereby the coaptation area. Additionally, the minimum degree of anisotropy that is required to obtain positive radial strains was shown to depend on the valve shape and the pressure to which the valves are exposed. Exposure to pulmonary diastolic pressure only yielded positive radial strains if the anisotropy was comparable to the native situation, whereas considerably less anisotropy was ...

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Section: Discussionmentioning

confidence: 99%

“…Indeed, previous studies have demonstrated the in vivo functionality of tissue-engineered heart valves (TEHVs) in animal models (Hoerstrup et al, 2000;Flanagan et al, 2009;Gottlieb et al, 2010;Schmidt et al, 2010). However, also this approach faces a number of challenges.…”

Section: Introductionmentioning

confidence: 99%

Effects of Valve Geometry and Tissue Anisotropy on the Radial Stretch and Coaptation Area of Tissue-Engineered Heart Valves

Loerakker

Argento

Oomens

et al. 2013

Volume 1A: Abdominal Aortic Aneurysms; Active and Reactive Soft Matter; Atherosclerosis; BioFluid Mechanics; Education; Biotran

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“…Over the last decade, bioreactor systems inducing mechanical conditioning and flow profiles have improved in vitro tissue formation (Flanagan et al 2007;Mol et al 2005;Kortsmit et al 2009;Ruel and Lachance 2009;Syedain and Tranquillo 2009). Moreover, in vivo animal studies have demonstrated the feasibility of heart valve tissue engineering, showing remodeling into native-like structures Sodian et al 2000;Stock et al 2000;Sutherland et al 2005;Gottlieb et al 2010;Schmidt et al 2010;Flanagan et al 2009). However, there are still some challenges that need to be overcome.…”

Section: Introductionmentioning

confidence: 99%

“…However, there are still some challenges that need to be overcome. One of those challenges is cell-mediated leaflet retraction, causing regurgitation in vivo (Flanagan et al 2009;Gottlieb et al 2010;Syedain et al 2011). In general, this regurgitation has been neglected and reported to be only mild.…”

Section: Introductionmentioning

confidence: 99%

Passive and active contributions to generated force and retraction in heart valve tissue engineering

Vlimmeren

Driessen-Mol

Oomens

et al. 2012

Biomech Model Mechanobiol

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In tissue engineered heart valves, cell-mediated stress development during culture results in leaflet retraction at time of implantation. This tissue retraction is partly active due to traction forces exerted by the cells and partly passive due to release of residual stress in the extracellular matrix and the cells. Within this study, we unraveled the passive and active contributions of cells and matrix to generated force and retraction in engineered heart valve tissues. Tissue engineered rectangular strips, fabricated from PGA/P4HB scaffolds and seeded with human myofibroblasts, were cultured for 4 weeks, after which the cellular contribution was changed at different levels. Elimination of the active cellular traction forces was achieved with Cytochalasin D and inhibition of the Rho-associated kinase pathway. Both active and passive cellular contributions were eliminated by lysation and/or decellularization of the tissue. Maximum cell activity was reached by increasing the fetal bovine serum concentration to 50%. The generated force decreased ∼20% after elimination of the active cellular component, ∼25% when the passive cellular component was removed as well and remained unaffected by increased serum concentrations. Passive retraction accounted for ∼60% of total retraction, of which ∼15% was residual stress in the matrix and ∼45% was passive cell retraction. Cell traction forces accounted for the remainder ∼40% of the retraction. Full activation of the cells increased retraction by ∼45%. These results illustrate the importance of the cells in the process of tissue retraction, not only actively retracting the tissue, but also in a passive manner to a large extent.

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“…In most TEHV implant studies to date, 2,5,8,21,22,26 autologous animal cells were used to fabricate the implant. Since the transition from an animal cell source to human cells in developing a TEHV with comparable properties can be problematic, our approach was to develop the VE with a convenient human cell source and utilize immunosuppression to evaluate the VE performance in an animal model, recognizing that tissue remodeling may be influenced by the drugs.…”

Section: Introductionmentioning

confidence: 99%

Implantation of a Tissue-engineered Heart Valve from Human Fibroblasts Exhibiting Short Term Function in the Sheep Pulmonary Artery

Syedain

Lahti

Johnson

et al. 2011

Cardiovasc Eng Tech

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Abstract-We have previously demonstrated the feasibility of fabricating a fibrin-based tissue-engineered heart valve (TEHV) using neonatal human dermal fibroblasts (nhDF), including leaflets with structural and mechanical anisotropy similar to native leaflets. The aim here was to evaluate the performance of this TEHV in a pilot study using the sheep model. Bi-leaflet TEHV were conditioned in a cyclic stretching bioreactor, then implanted within a polymeric sleeve interpositionally into the pulmonary artery of four sheep, with the pulmonary valve either left intact or rendered incompetent. Heparin and immunosuppression were administered for the duration. Echocardiography was performed at implantation and at 4 and 8 weeks. Explants were examined histologically, biochemically, and mechanically. In all sheep, echocardiography at implantation showed coapting leaflets, with minimal valve regurgitation and no turbulence. Orifice area and pressure gradients at systole approached the native pulmonary valve values. Echocardiography at 4 weeks revealed both leaflets functional with moderate regurgitation and turbulence in three sheep; in one sheep, only one leaflet was evident. Explanted leaflets had thickness and tensile properties comparable to the implanted leaflets. There was extensive endothelialization of the root lumenal surface. In the two sheep continued to 8 weeks, only one shortened leaflet remained in both cases. Immunocytochemistry indicated this was due to sustained tissue contraction caused by the nhDF and not by the invading host cells, which included a subpopulation consistent with bone marrow-derived cells. Short-term success was thus achieved in terms of excellent valve function at implantation and some valve function for at least 4 weeks; however, an apparent progressive tissue contraction needs to be resolved for long-term success.

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In vivo monitoring of function of autologous engineered pulmonary valve

Cited by 131 publications

References 18 publications

Effects of Valve Geometry and Tissue Anisotropy on the Radial Stretch and Coaptation Area of Tissue-Engineered Heart Valves

Effects of Valve Geometry and Tissue Anisotropy on the Radial Stretch and Coaptation Area of Tissue-Engineered Heart Valves

Passive and active contributions to generated force and retraction in heart valve tissue engineering

Implantation of a Tissue-engineered Heart Valve from Human Fibroblasts Exhibiting Short Term Function in the Sheep Pulmonary Artery

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