Cardiac Valve Bioreactor for Physiological Conditioning and Hydrodynamic Performance Assessment
Tissue engineered heart valves (TEHV) are being investigated to address the limitations of currently available valve prostheses. In order to advance a wide variety of TEHV approaches, the goal of this study was to develop a cardiac valve bioreactor system capable of conditioning living valves with a range of hydrodynamic conditions as well as capable of assessing hydrodynamic performance to ISO 5840 standards.
A bioreactor system was designed based on the Windkessel approach. Novel features including a purpose-built valve chamber and pressure feedback control were incorporated to maintain asepsis while achieving a range of hydrodynamic conditions. The system was validated by testing hydrodynamic conditions with a bioprosthesis and by operating with cell culture medium for 4 weeks and living cells for 2 weeks.
The bioreactor system was able to produce a range of pressure and flow conditions from static to resting adult left ventricular outflow tract to pathological including hypertension. The system operated aseptically for 4 weeks and cell viability was maintained for 2 weeks. The system was also able to record the pressure and flow data needed to calculate effective orifice area and regurgitant fraction.
We have developed a single bioreactor system that allows for step-wise conditioning protocols to be developed for each unique TEHV design as well as allows for hydrodynamic performance assessment.
KeywordsTissue engineered heart valve Biomechanical stimulation Biochemical stimulation Three-dimensional tissue culture ISO 5840
The authors gratefully acknowledge Dr. Sorin V. Pislaru, M.D., Ph.D. for assistance with echocardiographic imaging and Drs. Robert T. Tranquillo and Zeeshan Syedain for assistance with pulse duplicator validation.
Conflict of interest
The authors disclose that Harvard Apparatus owns intellectual property filings related to this work with JB, HH, and JC listed as co-inventors. BT, JC, MY, RH, DM, DD, RS, and AL declare that they have no conflict of interest.
This work was supported by a generous gift from HH Sheikh Hamed Bin Zayed Al-Nahyan and by the NIH (T32 HL007111, K99 HL129068).
This article does not contain any studies with human participants or animals performed by any of the authors.
Video 1. Valve functioning in bioreactor. Video taken using the boroscope and digital camera on the outflow side of the tissue valve. (MP4 56125 kb)
- 1.Aleksieva, G., T. Hollweck, N. Thierfelder, U. Haas, F. Koenig, C. Fano, M. Dauner, E. Wintermantel, B. Reichart, C. Schmitz, and B. Akra. Use of a special bioreactor for the cultivation of a new flexible polyurethane scaffold for aortic valve tissue engineering. Biomed. Eng. Online 11:92, 2012.CrossRefGoogle Scholar
- 4.Benjamin, E. J., M. J. Blaha, S. E. Chiuve, M. Cushman, S. R. Das, R. Deo, S. D. deFerranti, J. Floyd, M. Fornage, C. Gillespie, C. R. Isasi, M. C. Jimenez, L. C. Jordan, S. E. Judd, D. Lackland, J. H. Lichtman, L. Lisabeth, S. Liu, C. T. Longenecker, R. H. Mackey, K. Matsushita, D. Mozaffarian, M. E. Mussolino, K. Nasir, R. W. Neumar, L. Palaniappan, D. K. Pandey, R. R. Thiagarajan, M. J. Reeves, M. Ritchey, C. J. Rodriguez, G. A. Roth, W. D. Rosamond, C. Sasson, A. Towfighi, C. W. Tsao, M. B. Turner, S. S. Virani, J. H. Voeks, J. Z. Willey, J. T. Wilkins, J. H. Wu, H. M. Alger, S. S. Wong, P. Muntner, C. American Heart Association Statistics, and S. Stroke Statistics. Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation 135:e146–e603, 2017.CrossRefGoogle Scholar
- 14.ISO/TC. 5840-1:2015: cardiovascular implants—cardiac valve prostheses—part 1: general requirements, 2015.Google Scholar
- 19.Lichtenberg, A., I. Tudorache, S. Cebotari, S. Ringes-Lichtenberg, G. Sturz, K. Hoeffler, C. Hurscheler, G. Brandes, A. Hilfiker, and A. Haverich. In vitro re-endothelialization of detergent decellularized heart valves under simulated physiological dynamic conditions. Biomaterials 27:4221–4229, 2006.CrossRefGoogle Scholar
- 26.Ramaswamy, S., D. Gottlieb, G. C. Engelmayr, Jr, E. Aikawa, D. E. Schmidt, D. M. Gaitan-Leon, V. L. Sales, J. E. Mayer, Jr, and M. S. Sacks. The role of organ level conditioning on the promotion of engineered heart valve tissue development in-vitro using mesenchymal stem cells. Biomaterials 31:1114–1125, 2010.CrossRefGoogle Scholar
- 29.Sierad, L. N., A. Simionescu, C. Albers, J. Chen, J. Maivelett, M. E. Tedder, J. Liao, and D. T. Simionescu. Design and testing of a pulsatile conditioning system for dynamic endothelialization of polyphenol-stabilized tissue engineered heart valves. Cardiovasc. Eng. Technol. 1:138–153, 2010.CrossRefGoogle Scholar