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Table of Contents
Vol. 49, No. 1, 2012
Issue release date: August 2012
Free Access
Eur Surg Res 2012;49:44–52
(DOI:10.1159/000339606)

Tissue-Engineered Devices in Cardiovascular Surgery

Klopsch C.a, b · Steinhoff G.a, b
aReference and Translation Center for Cardiac Stem Cell Therapy, University of Rostock, and bDepartment of Cardiac Surgery, Heart Center Rostock, University of Rostock, Rostock, Germany
email Corresponding Author

Abstract

Manufacturing life-long functional cardiovascular (CV) implants is the ultimate goal for researchers and clinicians in the cardiothoracic field. Tissue engineering (TE) is an opportunity to create ideal prostheses that are vital, growing, adaptive, autologous and functionally optimally performing. Today, initial translation from basic science to first clinical trials has begun. The article depicts the state of the art in TE techniques for CV products and describes milestones in the ongoing development of tissue-engineered myocardial, valvular and vascular devices from an experimental and clinical point of view. Artificial CV implants still reveal remarkable limitations but promising advances regarding optimal structural design, the prevention of intimal hyperplasia and the reduction of antigenicity and thrombogenicity. Where applicable, the implantation of vascularized autografts should still be preferred. Apart from that, decellularized allogen bioprostheses currently represent most promising matrix scaffolds that can be autologously cellularized in vitro prior to or in vivo after implantation. Capable biologic alternatives have been described like the decellularized porcine small intestinal submucosa. Rising evidence suggests that in vitro endothelialization might be the minimal requirement for improved long-term results of biological tissue-engineered CV grafts.


 Outline


 goto top of outline Key Words

  • Decellularized graft
  • In vitro and in vivo cellularization
  • Endothelialization
  • Vascularization
  • Artificial and biological prostheses
  • Antigenicity

 goto top of outline Abstract

Manufacturing life-long functional cardiovascular (CV) implants is the ultimate goal for researchers and clinicians in the cardiothoracic field. Tissue engineering (TE) is an opportunity to create ideal prostheses that are vital, growing, adaptive, autologous and functionally optimally performing. Today, initial translation from basic science to first clinical trials has begun. The article depicts the state of the art in TE techniques for CV products and describes milestones in the ongoing development of tissue-engineered myocardial, valvular and vascular devices from an experimental and clinical point of view. Artificial CV implants still reveal remarkable limitations but promising advances regarding optimal structural design, the prevention of intimal hyperplasia and the reduction of antigenicity and thrombogenicity. Where applicable, the implantation of vascularized autografts should still be preferred. Apart from that, decellularized allogen bioprostheses currently represent most promising matrix scaffolds that can be autologously cellularized in vitro prior to or in vivo after implantation. Capable biologic alternatives have been described like the decellularized porcine small intestinal submucosa. Rising evidence suggests that in vitro endothelialization might be the minimal requirement for improved long-term results of biological tissue-engineered CV grafts.

Copyright © 2012 S. Karger AG, Basel


goto top of outline Introduction

Functional reconstruction and replacement of cardiovascular (CV) structures with the means of tissue engineering (TE) is evolving dynamically. The implantation of ideal prostheses has not been described yet. However, TE could enable the generation of vital, growing, adaptive, autologous and functionally competent CV tissues and organs. Understanding the roles and interactions of parenchymal, stromal and stem cells with highly defined biologic and artificial matrices and scaffolds will smoothen the way to success [1]. Herein, translational approaches facilitate bridging the latest results from laboratory benches to surgical theaters. The article describes current advances in TE of myocardial, valvular and vascular products and estimates their availability and feasibility for the clinical surgeon.

 

goto top of outline Developments in Cell-Plus-Matrix Constructs

At present, TE predominately applies three-dimensional cell-plus-matrix constructs. Biological or artificial matrix structures for CV implants must demonstrate specific biochemical and biomechanical properties for sufficient long-term performance. Decellularized allografts and xenografts seem to be excellent scaffolds for recellularization-based TE and promise optimal postsurgical results after orthotopic implantation [2]. A possible biological alternative is the extracellular matrix from porcine small intestinal submucosa for tissue-engineered CV devices [3,4]. First artificial matrices used for TE were manufactured of nonbiodegradable polytetrafluoroethylene or Dacron [5,6]. Advancing for biodegradable prostheses followed the idea of generating grafts that could primarily replace the function of a diseased tissue and will secondly be replaced completely by autologous and functional reconstructed tissue (fig. 1). Consequently, growing and adaptive grafts could be manufactured preventing reoperations at least in children. Today, various biodegradable scaffold materials are available and can be combined like collagen, fibrin, gelatin, alginate, polyglycolide, polylactide, polyhydroxybutyrate, polydioxanone, polyesteramides, polyurethane and polycaprolactone beside others [7,8]. The fabrication of artificial matrices requires strong regulation regarding elastic modulus, tensile strength and stability according to the widely varying in vivo demands on the final implants. Therefore, textile reinforcement strategies like controlled fiber alignment [9], gamma radiation [10], photo- or thermal-crosslinking [11,12], multipolymer composites [13], fibrils at different size scales [14], multiple interconnected layers [15,16], selective laser sintering [17] or particle leaching [18] represent important techniques for the TE of artificial grafts. However, one must consider that beside biomechanical properties the micro- and nanostructures are particularly important for engraftment. Consequently, reducing the porosity will strengthen the graft but reduce its capacity for engraftment [19].

FIG01
Fig. 1. General principles in cardiovascular TE. The scheme illustrates the processing of vascular, valvular and myocardial grafts generated from biological and artificial scaffolds and cellularized by in vitro bioreactor-driven conditionings, direct tableside coating strategies or in vivo engraftment following implantation. Consequently, these TE products could replace primarily the function of a diseased structure and secondly the complete structure by autologous and functional reconstructed tissue.

The biocompatibility and long-term performance of biological and artificial devices, in particular xenografts and artificial small-diameter tubular grafts, are clearly limited due to complications like degradation, fibrosis, calcification, immunologic rejection, infection and/or thrombogenicity [20,21,22]. As a consequence, special decellularization processing was recommended for biological grafts improving their immunogenicity and engraftment [23,24]. Today, autologous cellularization of TE products is feasible for various multipotent stem and differentiated mature cell types [1]. It was postulated that endothelial cell seeding could eliminate thrombogenicity of tissue-engineered CV implants [25]. For superior endothelial engraftment, different in vitro cellularization techniques were introduced including bioreactor-driven conditionings [26,27,28,29] or direct coating strategies [30]. For the enhancement of the angiogenic microenvironment, autologous biomaterials like fibrin could be used in cell-plus-matrix molded or coated CV devices [30,31]. As an alternative, tissue-engineered CV implants could be cellularized in vivo (i.e. in situ) with possible regulation by cytokines or special surface coating strategies [29,32,33]. The incorporation of local drug delivery systems into the matrix of a graft could remarkably modulate in vivo stem cell recruitment and the recellularization process [32]. Intense investigation is currently ongoing in order to create smart TE products that are stimulus-sensitive and therefore adaptive to multiple microenvironmental situations.

 

goto top of outline Vascular Tissue Engineering

The transplantation of arterial and venous autografts still represents the gold standard for vascular replacement of small-diameter vessels like coronary arteries. Dacron and polytetrafluoroethylene prostheses, xenografts or allograft are commonly used for the reconstruction of larger vessels like the ascending aorta, the pulmonary trunk and arteries, the aortic arch and its branch vessels. However, these artificial or xenogenic vascular grafts show unsatisfactory long-term results with lower prosthetic diameters (below 6 mm) because of intimal hyperplasia and other above-mentioned reasons [20,21,22]. Apart from that, the availability of autografts can be limited due to former surgery or vascular disease and harvesting of autografts will definitely increase the surgical trauma. Consequently, TE concepts aim at the generation of anytime-available, adaptive, immunologically accepted and functionally long-term competent prostheses [34]. Three-dimensional artificial or biologic cell-free matrices could be tissue-engineered employing in vitro or in vivo cellularization reducing long-term complications especially in small-diameter artificial prostheses [26,30,32,35] (table 1). These cellularization technologies demonstrate the potential to promote complete autologous replacement of implanted vascular grafts with cellular organization and structural integrity of a native vessel. First in-man trials are currently ongoing [36,37,38,39].

TAB01
Table 1. Milestones in the development of vascular TE devices

The highly precise fabrication of artificial tubular constructs can be accomplished by computer-controlled rapid prototyping or electrospinning beside other methods. Biomechanical, biochemical as well as micro- and nanostructures (e.g. porosity) can be regulated [10,40]. However, biodegradable vascular prostheses are currently not yet commercially available for the clinical surgeon because of long-term insufficiency [34]. Polymers with prolonged in vivo biodegradation time like polycaprolactone demonstrated at least promising results. Six months after experimental in vivo transplantation into the arterial circulation small-diameter vascular polycaprolactone grafts were found still functional and completely engrafted with autologous endothelialization [41]. More recently, advanced approaches even introduced biodegradable polymer-based vascular grafts into the clinical practice by implanting extracardiac cavopulmonary conduits made from polymer sheets in children [42].

 

goto top of outline Valvular Tissue Engineering

Long-term results after heart valve replacement using allogenic and xenogenic biological heart valves are influenced by tissue degeneration, calcification and infection. Unless optimal hemodynamics valvular allografts and xenografts as well as vital autografts in Ross procedures even show limited late postsurgical outcomes [2,43,44]. TE may be used to generate valve tissue undergoing vital regeneration from autologous cell source and tissue adaptation including endothelial recovery and infectious compatibility. In particular, pediatric and younger patients could be treated with vital, growing and adaptive implants preventing reoperations [2]. In accordance with vascular TE, valvular TE requires a three-dimensional biologic or artificial matrix scaffold as well as in vitro or in vivo cellularization [4,26,30,45]. In addition, there are necessities mainly attributed to valvular TE that have not yet been accomplished today. The regional different load conditions at a performing semilunar valve set strong demands to the fabrication of an optimal TE valve [46]. Soft but sufficient valve closure requires a balance of structural stability, tensile strength and elastic modulus for both the three-dimensional scaffold as well as the single polymer fibers. Moreover, the creation of vital TE valves most probably needs a highly dynamic processing with the maintenance of special active signals [47,48]. Apart from that, polymer biodegradation (of implanted biodegradable valves) and in vivo restoration of a long-term functional vital valve must run simultaneously and equally efficient [49].

Decellularized allografts and xenografts seem almost optimal scaffolds for valvular TE [30,50,51] (table 2). However, different decellularization protocols show varying efficiency for decellularization, recellularization capacity and removal of antigenicity [20,23,24]. The cryopreserved decellularized valves show a highly preserved extracellular matrix structure resulting in adequate midterm hemodynamic performance of allografts that is even superior to conventional allografts [50,51]. These cryopreserved decellularized allografts are commercially available anytime [51] but the overall supply is limited due to the donor dependency. Unfortunately, these valves revealed a seemingly low recellularization capacity complicating in vitro and in vivo TE [30,52,53]. Moreover, several studies documented a remarkable number of residing donor cells and immunogenic epitopes like alpha-Gal that had led to strong foreign body reactions in xenografts [20,24,54]. In contrast, detergent-mediated decellularized valves seem less immunogenic and more engraftable while maintaining adequate midterm hemodynamic performance even in aortic valve position [50,51,55,56]. By applying TE, these allografts and possibly xenografts might become optimal substitutes for a diseased native valve [57].

TAB02
Table 2. Milestones in the development of valvular TE devices

However, the feasibility and necessity of in vitro recellularization of decellularized valves is currently in question. In vitro preconditioning in bioreactors requires several weeks of complex laboratory processing with contamination risks and high costs [58]. Direct cell-coating strategies performed tableside during valve replacement surgeries seem more simply applicable, anytime available and adaptive to individual specialties [30]. Apart from that, the availability of autologous cells for valvular in vitro cellularization is critical especially in pediatric cases. The importance of umbilical cord-derived endothelial cells as well as stem cells has to be emphasized for these special patients [1]. Moreover, valvular cells seem highly differentiated. Consequently, the appropriateness of using endothelial and interstitial cells from peripheral vessels for valvular TE is also questioned [59]. Regarding the necessity for in vitro cellularization prior to implantation, the majority of studies support the need for superficial endothelialization of decellularized valves that might improve long-term results of grafts at least in pulmonary valve position [25,60]. On the contrary, the more demanding interstitial in vitro cellularization might be dispensable for the prevention of explained long-term complications [61].

Promising alternatives are exclusively in vitro manufactured autologous cell-plus-matrix molded valves that have already been tested in vivo in a pioneer study [31]. However, bioreactor conditioning is intensely time consuming and the concept is currently not yet applicable for clinical use. Another biologic opportunity might be the construction of valves with the decellularized matrix from small intestinal submucosa. These xenografts would be commercially available anytime and seemingly demonstrate high in vivo recellularization potential [3,4]. Apart from that, coating of conventional glutaraldehyde-fixed xenografts with titanium might accelerate in vivo endothelialization and improve long-term outcomes [62].

 

goto top of outline Myocardial Tissue Engineering

The bioartificial generation of myocardial tissues similarly employs artificial or biologic cell-free matrices that will be cellularized in vitro or in vivo. In contrast to other TE products, myocardial prostheses demonstrate special requirements like a synchronized activation and contraction of its cardiomyocytes, adequate mechanical strength, elastic modulus and force development as well as electrophysiological integration after in vivo implantation. Apart from that, cell-plus-matrix myocardial TE grafts (thicker than 100 µm) need vascularization for the survival of cardiac myocytes [63].

Various biological substrates like the urinary bladder, the small intestinal submucosa or the pericardium have been tested (table 3). These cell-free matrices were vascularized and recellularized in vivo with cardiomyocytes, myofibroblasts and smooth muscle cells beside others. Some of the in vivo tissue-engineered prostheses even demonstrated remarkable contractility [3,64,65]. The addition of growth factors and/or stem cells could further accelerate the recellularization process [66,67]. In our group, we found that precisely directed cell seeding on artificial matrices with the use of laser cell printing (‘endothelial network printing’) could faster facilitate a functional connection of the grafts’ preformed microvasculature to the host’s microvasculature [68]. Apart from that, the use of vascularized autotransplants from small intestinal or gastric submucosa, peritoneum or omentum enables the application of transplants with immediate sufficient vascularization. At present, they have been predominately tested experimentally as epicardial patches for the repair of ischemic myocardium [69,70,71]. Prostheses from skeletal muscle seemingly still demonstrate the greatest potency for myocardial support or replacement [72]. However, the transdifferentiation potential and electrical coupling of myoblasts and myocytes to cardiomyocytes is limited [73]. Clinically, pioneer surgeons have treated severe heart failure patients with combined biological TE products [74].

TAB03
Table 3. Milestones in the development of myocardial TE devices

A decellularized heart muscle logically seems as the most favorable biomatrix for myocardial TE products. The macroscopic and microscopic three-dimensionality is preserved and cell-matrix interactions after autologous recellularization could work optimally [75]. However, the limited availability of allografts, the immunogenicity of xenografts as well as the difficulties in isolation and cultivation of an adequate number of autologous contractile cells currently impede clinical translation. Nevertheless, highly advanced approaches experimentally tested in vitro tissue-engineered myocardial pouches for ventricular assist devices following physical conditioning in bioreactors [76]. This research group even showed efficient electrical coupling of tissue-engineered cardiomyocyte cell sheets after pericardial transplantation to the heart [77]. These encouraging results will hopefully soon find translation into clinical practice for the regeneration and replacement of diseased myocardium.

 

goto top of outline Conclusion

Clinical translation has begun in cardiac surgery. TE promises the creation of vital, growing, adaptive, autologous and functionally optimally performing CV implants. However, basic technology and clinical translation is still in an initial phase. Small-diameter vascular grafts, life-long functional valvular grafts without the need for anticoagulation and sufficiently force-developing myocardial grafts will not be clinically available in a short-term development. The article cites landmark studies in the evolution of TE in the CV field. Artificial grafts still show several limitations but remarkable improvements in structural design, engraftment and hemocompatibility. Apart from that, techniques for vascularized autograft transplantation have been described. If autografting is not applicable or feasible, decellularized allogen bioprostheses can be applied that are recellularized in vitro or in vivo. Promising biological alternatives have been portrayed like the decellularized small intestinal submucosa. Noteworthy, in vitro endothelialization might be obligatory for the improvement of long-term results of decellularized biological transplants. The importance of regulating in vivo cellularization by active signals via biofunctionalization is under intense investigation.

 

goto top of outline Acknowledgements

This work was supported by the German Ministry of Education (BMBF; Germany, Berlin; funding indicator 0312138 A), the Ministry of Economy (Mecklenburg-West Pommerania, Schwerin; funding indicator RTC V220-630-08-TFMV-F/S-035) as well as the German Research Foundation (DFG; Germany, Berlin; funding indicator SFB TR37, TPA4) and REBIRTH Cluster of Excellence (Exc62/1).

 

goto top of outline Disclosure Statement

None of the authors have a conflict of interest to declare.


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 goto top of outline Author Contacts

Prof. Gustav Steinhoff, MD
Department of Cardiac Surgery, Heart Center Rostock, University of Rostock
Schillingallee 35
DE–18057 Rostock (Germany)
Tel. +49 381 494 6101, E-Mail gustav.steinhoff@med.uni-rostock.de


 goto top of outline Article Information

Received: May 2, 2012
Accepted after revision: May 17, 2012
Published online: July 14, 2012
Number of Print Pages : 9
Number of Figures : 1, Number of Tables : 3, Number of References : 77


 goto top of outline Publication Details

European Surgical Research (Clinical and Experimental Surgery)

Vol. 49, No. 1, Year 2012 (Cover Date: August 2012)

Journal Editor: Vollmar B. (Rostock)
ISSN: 0014-312X (Print), eISSN: 1421-9921 (Online)

For additional information: http://www.karger.com/ESR


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Manufacturing life-long functional cardiovascular (CV) implants is the ultimate goal for researchers and clinicians in the cardiothoracic field. Tissue engineering (TE) is an opportunity to create ideal prostheses that are vital, growing, adaptive, autologous and functionally optimally performing. Today, initial translation from basic science to first clinical trials has begun. The article depicts the state of the art in TE techniques for CV products and describes milestones in the ongoing development of tissue-engineered myocardial, valvular and vascular devices from an experimental and clinical point of view. Artificial CV implants still reveal remarkable limitations but promising advances regarding optimal structural design, the prevention of intimal hyperplasia and the reduction of antigenicity and thrombogenicity. Where applicable, the implantation of vascularized autografts should still be preferred. Apart from that, decellularized allogen bioprostheses currently represent most promising matrix scaffolds that can be autologously cellularized in vitro prior to or in vivo after implantation. Capable biologic alternatives have been described like the decellularized porcine small intestinal submucosa. Rising evidence suggests that in vitro endothelialization might be the minimal requirement for improved long-term results of biological tissue-engineered CV grafts.



 goto top of outline Author Contacts

Prof. Gustav Steinhoff, MD
Department of Cardiac Surgery, Heart Center Rostock, University of Rostock
Schillingallee 35
DE–18057 Rostock (Germany)
Tel. +49 381 494 6101, E-Mail gustav.steinhoff@med.uni-rostock.de


 goto top of outline Article Information

Received: May 2, 2012
Accepted after revision: May 17, 2012
Published online: July 14, 2012
Number of Print Pages : 9
Number of Figures : 1, Number of Tables : 3, Number of References : 77


 goto top of outline Publication Details

European Surgical Research (Clinical and Experimental Surgery)

Vol. 49, No. 1, Year 2012 (Cover Date: August 2012)

Journal Editor: Vollmar B. (Rostock)
ISSN: 0014-312X (Print), eISSN: 1421-9921 (Online)

For additional information: http://www.karger.com/ESR


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

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