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J Thorac Cardiovasc Surg 2006;132:735-737
© 2006 The American Association for Thoracic Surgery

Letter to the Editor

When less is more: Go slowly when repopulating a decellularized valve in vivo!

Christof Stamm, MDa, Gustav Steinhoff, MDb

a Dept. of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Berlin, Germany
b Dept. of Cardiac Surgery, Universität Rostock, Rostock, Germany

To the Editor:

We read with interest the recent article by Juthier and colleagues1Go describing the effects of granulocyte colony-stimulating factor (GCSF) on decellularized xenogenic heart valves implanted in systemic circulation in sheep. The hypothesis was tested that bone marrow cell mobilization by GCSF would facilitate in vivo repopulation with endothelial and smooth muscle progenitor cells; however, it was found that the valves actually deteriorated sooner than the same scaffolds in untreated animals. Juthier and colleagues1Go concluded quite appropriately that GCSF accelerated valve deterioration through increased inflammatory reaction, and they suggested searching for alternative strategies to improve scaffold recolonization. Our group has been tackling this very problem in the past, and we believe we have found a promising solution. In 2004, we reported on the biologic and mechanical properties of biomatrix/polymer composite material for heart valve tissue engineering.2Go In essence, porcine aortic valves were enzymatically decellularized and coated or penetrated with a slowly biodegradable polymer with known favorable biocompatibility and hemocompatibility. By doing so, we produced valve scaffold tissue that induces less coagulation and complement activation in vitro, displayed favorable behavior in a rabbit aorta in vivo model, and, most importantly, gave superior results in terms of endothelialization and clot deposition on implantation in both pulmonary and aortic positions in sheep. Moreover, polymer impregnation can also help improve the mechanical properties of the valve leaflet, which may be particularly important when enzymatic processes are used for decellularization.3Go The polymer impregnation process does not involve glutaraldehyde- or formaldehyde-based fixation steps, so both the biologic and structural properties of the extracellular matrix (ECM) components are left intact, and repopulation with host cells is not hampered (Figure 1). It also masks platelet-activating moieties on ECM components, thereby reducing the risk of collagen-induced platelet aggregation during the early postimplantation phase.


Figure 1
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  		Figure 1. A, Decellularized porcine heart valve impregnated with biodegradable poly(hydroxy)butyrate to reduce xenoreactivity and improve hemocompatibility and mechanical performance for a limited time. B, Note that polymer impregnation process preserves porosity of decellularized ECM scaffold, so that repopulation with host cells is not disturbed.

 
Juthier and colleagues1Go convincingly showed that removal of all xenogenic cells without altering the biologic characteristics of the ECM components reduces the inflammatory response in sheep and improves in vivo repopulation with host cells. However, as they themselves pointed out, some immunogenicity of xenogenic ECM inevitably persists.4–6Go Even the smallest amount of residual cell detritus can trigger cellular immune response, with macrophage invasion and subsequent blood vessel ingrowth, and the various ECM components possess an inherent immunogenic potential when exposed in a xenogenic setting. We were therefore not surprised to read that massive inflammatory stimulation by GCSF accelerated inflammatory valve matrix infiltration and structural deterioration. After all, the mobilization of (theoretically) beneficial bone marrow stem cells and endothelial progenitor cells by GCSF is secondary to the release of mature leukocytes, and Juthier and colleagues1Go elegantly demonstrated the substantial increase in white blood cell count even in the sheep model. Taken together, we believe that any proinflammatory action should be avoided soon after in vivo implantation of decellularized ECM conduits. The rapid failure of Synergrafts in children (with their pronounced inflammatory response to extracorporeal circulation) adds to the evidence.7Go On the contrary, measures that help reduce the susceptibility of decellularized ECM conduits to cellular and humoral inflammatory are needed. Coating with biodegradable polymer is one such approach, masking proinflammatory components during the early postimplantation phase and thus buying time for vascular host cell repopulation with re-endothelialization and matrix turnover.


   References
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 References
 

  1. Juthier F, Vincentelli A, Gaudric J, Corseaux D, Fouquet O, Calet C, et al. Decellularized heart valve as a scaffold for in vivo recellularization. deleterious effects of granulocyte colony-stimulating factor. J Thorac Cardiovasc Surg 2006;131:843-852.[Abstract/Free Full Text]
  2. Stamm C, Khosravi A, Grabow N, Schmohl K, Treckmann N, Drechsel A, et al. Biomatrix/polymer composite material for heart valve tissue engineering. Ann Thorac Surg 2004;78:2084-2093.[Abstract/Free Full Text]
  3. Grabow N, Schmohl K, Khosravi A, Philipp M, Scharfschwerdt M, Graf B, et al. Mechanical and structural properties of a novel hybrid heart valve scaffold for tissue engineering. Artif Organs 2004;28:971-979.[Medline]
  4. Allaire E, Bruneval P, Mandet C, Becquemin JP, Michel JB. The immunogenicity of the extracellular matrix in arterial xenografts. Surgery 1997;122:73-81.[Medline]
  5. Lynn AK, Yannas IV, Bonfield W. Antigenicity and immunogenicity of collagen. J Biomed Mater Res B Appl Biomater 2004;71:343-354.[Medline]
  6. Kasimir MT, Rieder E, Seebacher G, Nigisch A, Dekan B, Wolner E, et al. Decellularization does not eliminate thrombogenicity and inflammatory stimulation in tissue-engineered porcine heart valves. J Heart Valve Dis 2006;15:278-286.[Medline]
  7. Simon P, Kasimir MT, Seebacher G, Weigel G, Ullrich R, Salzer-Muhar U, et al. Early failure of the tissue engineered porcine heart valve SYNERGRAFT in pediatric patients. Eur J Cardiothorac Surg 2003;23:1002-1006.[Abstract/Free Full Text]

Related Article

Reply to the Editor
André Vincentelli, Francis Juthier, and Brigitte Jude
J. Thorac. Cardiovasc. Surg. 2006 132: 737. [Extract] [Full Text] [PDF]



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J. Thorac. Cardiovasc. Surg., May 1, 2008; 135(5): 1189 - 1190.
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