Engineering heart valves
Building next-generation heart valves for tissue regeneration
In the late 1950s, clinicians and scientists collaborated to establish the then nascent field of biomedical engineering as a “new intellectual and technical framework” for the development of synthetic or biological prostheses and replace dysfunctional organ components1. In the field of cardiology, biomedical engineering continues to largely contribute to the evolution of prosthetic heart valves, in response to valvular heart disease affecting the lives of over four million people each year1.
The human heart beats ~35 million times each year2 to effectively pump blood into circulation via four different heart valves; the tricuspid, pulmonary, mitral and aortic valves (Fig 1). The flaps of heart valves open and close with each heartbeat to ensure blood flows in the right direction through the heart’s four chambers to the entire body. Dysfunction of one or more heart valves resulting from birth defects (congenital), age-related changes, infection or other conditions can prevent them from opening/closing fully, causing blood to leak back into the heart chambers and result in cardiac valve disease.
Three basic types of problems with heart valves that interrupt normal blood flow include regurgitation, stenosis and atresia1. Regurgitation (or prolapse) occurs when blood flows back into chambers instead of flowing through heart due to unclosed valve flaps - mainly affecting the mitral valves. When flaps of a valve thicken, stiffen or fuse together stenosis occurs by blocking blood flow. Atresia, most often a congenital condition occurs when a heart valve lacks an opening for blood to pass through, due to abnormalities of the fetal heart preventing usual blood flow. Valvuloplasty, a surgical technique established in the 1920s attempted to surgically correct valvular heart disease, but was largely unsuccessful as it destroyed the valve leaflets and resulted in calcification, influencing the evolution of tissue engineering research3. Pioneers of cardiac surgery (C. Walton Lillehei and Henry T. Bahnson) envisioned the possibility of building artificial leaflets with polymers, although results were consistently poor, highlighting the need for new materials4.
PIONEERING EARLY DESIGNS
The first mechanical valve, implanted within a patient in 1952 was a ball valve designed by Charles Hufnagel, proving synthetic materials could be used to create heart valves (Fig 2A)1. By design the ball valve only permitted placement in the descending aorta instead of the heart itself, thus merely alleviating symptoms and not correcting the problem. Thrombosis and embolization of the valve occurred frequently including some reports of noise generated by the valve, reminiscent to a ticking bomb. A design breakthrough was achieved by physician Albert Starr and mechanical-engineer Lowell Edwards thereafter, when they engineered an integrated structure consisting of a stainless steel cage, fixation ring made from knitted Teflon cloth and a heat-cured Silastic ball. Starr performed the first successful orthotropic valve replacement surgery via prosthetic implantation in the mitral position, although the implant necessitated life-long anticoagulant therapy5 (Fig 2B).
The combined outcome of bench engineering, animal studies and clinical trials emphasized the importance of hemodynamics in valve design, with visible advantages of using cadaveric heart valves (allografts/homografts, i.e. biological tissue for transplant) albeit poor durability6. Alain Carpentier used a method to ensure long-term durability of tissue valves via molecular re-engineering with chemical treatment, to reduce the immunologic reaction (Hank’s solution and oxidizing agent) and prevent collagen denaturation (glutaraldehyde). A valve thus pre-treated and mounted to a fabric-covered stent was termed a “bioprosthesis”, a concept advanced by Carpentier combining biological and mechanical structures to create a three dimensional (3D) tissue-based valve with low thrombogenicity reducing the need for anticoagulants (Fig 2C)7.
Understanding the interwoven roles of hemodynamics, mechanical stress and biological response guided further efforts for better design and engineering. Subsequent valve engineering efforts used biocompatible polymeric leaflets mounted on a stent for delivery to the site via a catheter8 and a common theme of stent-mounted bioprosthetic (animal tissue-based) valves, currently in use clinically after FDA approval9 (Fig 3). The two most common valve replacement options include transcatheter aortic valve replacement (TAVR) and mitral valve replacement, conducted with mechanical or tissue-based heart valves.
While pioneering early efforts of implantable bioprosthetic development dramatically altered the course of valvular disease, progressive tissue-engineering efforts are currently underway to efficiently integrate form and function of heart valves to enable tissue regeneration and improve biocompatibility3. Current research efforts combine computer simulations and advanced tissue-engineering methods, to accurately model and then create next generation heart-valve replacements3.
BUILDING NEXT-GENERATION FIBROUS HEART VALVES
The next-generation of artificial heart valves can be bioengineered with nanofiber-scaffolds that mimic the human extracellular matrix (ECM) and its biological function post-implantation3,10. Three key methods exist to engineer nanofiber-scaffolds including: A) tissue decellularization B) electrospinning and C) rotary jet spinning (Fig 4) (Table 1)11-13.
Although the method of decellularization seen in (A) provides a composite 3D structural scaffold, its constituents cannot be experimentally controlled preventing the method's reproducibility3. Fibrous scaffold production processes (B) and (C) aim to overcome these limitations via bottom-up tissue engineering, where each scaffold component and structure can be experimentally controlled14.
Electrospinning (B) is the most popular synthetic engineering method to fabricate nanofiber scaffolds, where an electrically charged polymer melt or solution is extruded to create a jet that solidifies into nanofibers upon collection on a substrate13,15. The synthetic process allows greater flexibility to control and fine tune the final material. A major limitation is the very low industrial production rate, which hardly reaches a kilogram of fiber per hour3. Additionally, the high voltage based method restricts fabrication of electrospun scaffolds with proteins in its composition3.
ROTARY JET SPINNING
Rotary jet spinning (RJS) introduced above, was developed to overcome the manufacturing limitations of electrospinning when fabricating nanofiber scaffolds16. During RJS, centrifugal forces within a rotary reservoir perforated with micron scale outlets extrude nanofibers after input of solution to create nanofiber scaffolds “like a cotton candy machine” (Video 1). During a single force driven system, the production rates of RJS were two orders of magnitude higher than the preceding system of electrospinning (~100 g/hour)17. The method can overcome production limitations of electrospinning while increasing versatility of spinning materials, from silk to pure protein nanofibers, bringing the fabrication process closer to industrial manufacture and clinical translation.
To achieve specific three-dimensional structure with the bottom-up engineering approach, a variety of geometrical shapes can be used during rotary jet spinning including, electrically grounded plates, heart-valve shaped mandrels or columnar shaped collectors to form the shape of interest. Based on this manufacturing strategy, researchers at the Wyss Institute of Harvard University recently detailed tissue engineering fibrous scaffold heart valves with potential to regenerate biological tissue once implanted. The cell-free, jet spinning method was automated to rapidly produce biomimetic heart valve scaffolds termed JetValves17.
The scaffolds were tailored to mimic native leaflet fibrosa, assembled into 3D structures with initial biocompatibility seen in vitro and functionality within a sheep (ovine) model observed for 15 hours in vivo17. The animal study revealed valves with leaflets remained intact and no observable thrombosis or immune reaction seen via gross histological analyses at explantation. The engineering process was automated with LabVIEW interface for the first time during rapid heart valve manufacture, with 3D printed mandrels of various sizes (simulated with Solidworks software prior to development) used to collect nanofibers giving shape to heart valves of different sizes. The process allowed manufacture of human-sized JetValves in minutes, as customized ready-to-use regenerative heart valves at much lower cost than currently possible, with a displayed shelf life of 1 week when stored in an incubator (370C) (Fig 5).
The present manufacturing process offers remarkable agility and control to simply create a viable, cell-free and biomimetic next-generation heart valve with potential for clinical translation, and possibility to create similarly fibrous organs in the future.
Poster Image: Biomimetic nanofibers generated with RJS technology obtained using a scanning electron microscope, from Engineering heart valves for the many, Wyss Institute at Harvard University.
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- Starr, A. & Edwards, M. L. Mitral Replacement: Clinical Experience with a Ball-Valve Prosthesis. Annals of Surgery 154, 726-740 (1961).
- Binet, J.P. Pioneering in heterografts. The Annals of Thoracic Surgery 48, S71-S72 (1989)
- Carpentier, A. The concept of bioprosthesis. Thoraxchirurgie, vaskulare Chirurgie 19, 379-383 (1971).
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- Luo, J. et al. Development and Characterization of Acellular Porcine Pulmonary Valve Scaffolds for Tissue Engineering. Tissue Engineering. Part A 20, 2963-2974 (2014).
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- Capulli, A. K. et al. JetValve: Rapid manufacturing of biohybrid scaffolds for biomimetic heart valve replacement. Biomaterials 133, 229-241 (2017).