Calcification in Pulmonary Heart Valve Tissue Engineering: A Systematic Review and Meta-Analysis of Large-Animal Studies

Dewy C. van der Valk, Aleksandra Fomina, Marcelle Uiterwijk, Carlijn R. Hooijmans, Anat Akiva, Jolanda Kluin, Carlijn V.C. Bouten (Corresponding author), Anthal I.P.M. Smits (Corresponding author)

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Tissue-engineered heart valves (TEHVs) are emerging alternatives to current valve prostheses and prospectively a lifelong replacement. Calcification, a pathological complication for biological protheses, has been reported in preclinical TEHV studies. Systematic analysis of its occurrence is missing. This review aims to: 1) systematically review reported calcification of pulmonary TEHVs in large-animal studies; and 2) analyze the influence of engineering methodology (choice of scaffold material, cell preseeding) and animal model (animal species and age) on calcification. Baseline analysis included 80 studies, of which 41 studies containing 108 experimental groups were included in meta-analysis. Inclusion was low because only 55% of studies reported on calcification. Meta-analysis showed an overall average calcification event rate of 35% (95% CI: 28%-43%). Calcification was more prominent (P = 0.023) in the arterial conduit region (34%; 95% CI: 26%-43%) than in the valve leaflets (21%; 95% CI: 17%-27%), and was mostly (42% in leaflets, 60% in conduits) present in a mild form. Time-analysis showed an initial surge within 1 month after implantation, decreased calcification between 1 and 3 months, and then progression over time. There were no significant differences in degree of calcification between TEHV strategy nor animal models. Much variability between individual studies was observed in degree of calcification as well as quality of analysis and reporting thereof, hampering adequate comparisons between studies. These findings underline the need for improved analysis and better reporting standards of calcification in TEHVs. It also necessitates control-based research to further enlighten the risk of calcification for tissue-engineered transplants compared to current options. This can bring the field of heart valve tissue engineering forward toward safe clinical use.

Original languageEnglish
Pages (from-to)572-591
Number of pages20
JournalJACC: Basic to Translational Science
Issue number5
Publication statusPublished - May 2023

Bibliographical note

Funding Information:
The authors would like to thank Dr Fulvia Ortolani, Prof Laura Iop, Dr Michele Gallo, and Dr Jan-Willen van Rijswijk for their quick and informative response to e-mail inquiries, providing added information about their research articles that could be added to the meta-analysis. The authors would like to thank Dr Bente de Kort and Suzanne Koch, MSc, for their discussions on data extraction and meta-analysis. Furthermore, the authors would like to thank Dr Rob de Vries and Dr Judith van Luijk (SYstematic Review Centre for Laboratory animal Experimentation [SYRCLE], Radboudumc, Nijmegen, the Netherlands) for their informative discussions regarding the meta-analysis.

Publisher Copyright:
© 2023 The Authors


  • biomaterials
  • cardiac valve prosthesis
  • mineralization
  • preclinical
  • regeneration
  • scaffold
  • tissue-engineered heart valve


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