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EDITORIAL |
National University Hospital, Singapore
A/Professor Theo Kofidis, MD, PhD, FAHA, FAMS, Tel: +(65) 6772 2065; (65) 6772 5214, Fax: +(65) 6776 6475, Email: surtk{at}nus.edu.sg; Cardiothoracic Surgeon, Department of Cardiac, Thoracic and Vascular Surgery, National University Hospital/National University of Singapore, 5 Lower Kent Ridge Road, level 2, Singapore 119074.
The demand for vascular grafts in modern medicine and surgery is vast. Vascular grafts are required in a plethora of vascular surgical procedures for obstructed native vessels or dialysis purposes. As many as 1,500,000 angioplasties are performed annually in the USA, along with 500,000 coronary artery bypass procedures and 150,000 carotid endarterectomies, and 300,000 patients are receiving dialysis. It is estimated that the sum of such procedures worldwide reaches billions of dollars every year. This does not include the millions of procedures for implantation of interposition grafts to replace obstructed arteries in peripheral vascular disease. Almost invariably (except for the latter), surgeons use autologous grafts to carry out these procedures. Saphenous veins, internal thoracic arteries, epigastric arteries, homografts, and radial arteries are being sacrificed to treat the consequences of vascular disease, altogether a major health-related socioeconomic plague.
Yet the body’s own generosity is not inexhaustible. The availability of grafts, particularly in procedures that involve multiple utilizations, such as coronary artery bypass, is limited and also associated with significant surgical trauma and infection rates. Moreover, venous grafts tend to degenerate and fail after some period of time, estimated to reach a rate of more than 50% at 10 years after a coronary artery bypass procedure. Science is therefore seeking alternative ways to fill the gap and provide patients with a limitless source of grafts. Robert Eckel, president of the American Heart Association and Professor of Medicine at the University of Colorado at Denver and the Health Sciences Center stated: "There is great need. This is an important area of bioengineering. The applications are broad and could benefit the quality of life of a great number of people". An emerging new science, vascular tissue engineering, offers the prospect of living, inert, and biological vessels to cover the needs of millions of patients if the fabricated grafts can fulfill some crucial biological and functional requirements.
There have been impressive efforts and a growing body of experience with various bioartificial or synthetic grafts, which deserve mention at this point. It is equally relevant to identify the culprit responsible for sabotaging the success and survival of most of these concepts. One of the substances used so far is polyurethane. Gulbins and colleagues1 investigated cell seeding on polyurethane vascular prostheses. Polyurethane prostheses were seeded with a mixed culture of fibroblasts and endothelial cells, followed by endothelial cell seeding and exposure to pulsatile flow. Perfusion conditions were optimized in such a way that confluent and solid endothelial layers resulted. Furthermore, the endothelial cells expressed CD31, factor VIII, and endothelial nitric oxide synthase. The information extracted by this series of experiments regarding the sterilization and perfusion procedures is noteworthy for further investigation. No reports are available yet on the in-vivo performance of these grafts. Stitzel and colleagues2 used electrospinning technology to control composition, structure, and mechanical properties of biomaterials to manufacture a biological vascular substitute. In this innovative approach, polymer blends of type I collagen, elastin from ligamentum nuchae, and poly(D,L-lactide-co-glycotide) compound were used in the electrospinning process. The scaffolds displayed tissue composition and mechanical properties similar to native vessels. Briefly, these are defined as burst pressure, flow characteristics, and suturing capacity, usually compared to native arteries and veins of the same caliber. Furthermore, Sambanis and colleagues3 developed viscoelastic testing methodologies for tissue-engineered blood vessels, based on the principle that tissue-engineered blood vessels must endure pulsatile blood flow and withstand hemodynamic pressures for long periods of time.
The authors used 3- and 4-parameter linear viscoelastic mathematical representations and compared them to porcine carotid arteries. The intergroup comparison between various graft compositions indicated the importance of the described testing methodologies. Wick and colleagues4 established a scaleable perfusion bioreactor for tissue engineering small-diameter arterial constructs. This bioreactor improved sequential seeding and the graft response to dynamic perfusion conditions in terms of functionality and matrix composition.
Stem cells have evolved as the panacea for many cardiovascular diseases. They did not escape the vascular researcher’s watchful eye in the context of generating bioartificial vessels. The following concept stands out as very promising. Schmidt and colleagues5 engineered living blood vessels using functional endothelia derived from human umbilical cord-derived progenitors. The concept involved multilayer sequential seeding of cord-derived myofibroblasts on biodegradable scaffolds, followed by endothelialization with differentiated cord blood-derived endothelial progenitor cells. Histological, biochemical, and biomechanical testing revealed functional organization of the layers, with functional endothelium that was further enhanced by stimulation with tumor necrosis factor alpha (down regulated thrombomodulin expression). Cho and colleagues6 implanted bioartificial vessels in dogs that subsequently received granulocyte colony-stimulating factor. The treated animals had implanted grafts with more extensive endothelial formation and less intimal hyperplasia, a crucial factor in vessel obstruction.
Potentially, the two most clinically advanced approaches involve the use of a heparin- and paclitaxel-coated PTFE graft (HollyGraft, Minneapolis, MN, USA) and the Cytograft human-tissue engineered blood vessel (Cytograft Tissue Engineering, Novato, CA, USA); both of whom we had the privilege to work with in Minneapolis, Hannover (Germany), and Stanford, California. In the former case, we operated on 30 patients using the coated PTFE graft, and performed 1 or 2 sequential anastomoses during coronary bypass procedures. Sadly, the rate of occlusion at the site of insertion of a small metal connector into the obtuse marginal branch of the circumflex artery was too high to allow continuation of the study. A second generation improved graft is under testing in the company’s laboratories, and we will report on the success to the international community. In the latter concept, skin cells and endothelial cells from future recipients of the grafts were harvested, grown into sheets, wrapped around a tube, and fused together to form a vessel. The endothelial layer was added just before implantation into patients, to serve as dialysis shunts. The great advantages of these vessels are due to the fact that they consist solely of the patient’s own cells (no foreign cells or bioartificial materials) as well as the low thrombogenicity. The first 4 patients did not display any occlusion.
Obviously, the major factor that limits and directs bioartificial vessel production is thrombogenicity, which has to resemble or be superior to that of a native vessel. Undoubtedly, the culprit to be addressed in all the above efforts is the endothelium, which not only needs to be seeded functionally, but the tendency for thrombogenicity to shift towards clotting whenever endothelial cells come into contact with bioprosthetic surfaces must be circumvented. Therefore, it is essential to stress the properties we clinicians expect scientists to address when manufacturing bioprosthetic grafts of the future. Endothelial cells, although simple in appearance and culture conditions, have many complex roles. Under normal circumstances, they secrete substances that prevent blood clotting and maintain the tone of vascular smooth muscle. They can be activated by cytokines to express cell adhesion molecules to allow white blood cells to interact. They produce prostacyclin, nitric oxide, tissue plasminogen activator, thrombomodulin, thromboplastin, platelet activating factor, and von Willebrand factor. They also express heparin receptors on their surface, whereupon heparin exerts its function.
Looking at the impressive developments above, one recognizes that the tools are in place: the cell sources have been identified, and the evaluation mechanisms are available. The extent of the diseases that can be addressed as well as the incisions, pain, and complications that can be avoided are so vast that the prospect of having such grafts at hand as soon as possible appears messianic—at the least, a blessing for both surgeon and patient.
REFERENCES
Asian Cardiovasc Thorac Ann 2009;
17:238-239
© 2009 by SAGE Publications
DOI: 10.1177/0218492309104760
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