by Samuel Lasinski

Graphic design by Nichole Zhou

When most people think of tissue engineering, they envision the creation of solid organs; sci-fi scenes of ethereal lungs languidly pulsating in neon suspension readily spring to mind. While engineered solid organs remain a distant goal, a more immediate target is of critical clinical and scientific relevance: small diameter vascular grafts. Although these apparently simple structures may not capture the imagination like more complex tissues, they could drastically improve the care of thousands and represent a crucial stepping stone towards engineered solid organs.

Blood vessels are classified as a type of connective tissue that, along with the heart, make up the structural components of the circulatory system. Small arteries—those with outer diameter between one and six millimeters—play a critical role in this system. Their primary function is to transport blood from the large arteries to smaller arterioles and capillaries, ensuring sufficient perfusion of vital organs and peripheral tissues. They also help regulate blood pressure by adjusting their diameter through processes known as vasodilation (widening) and vasoconstriction (narrowing).

Given their role as conduits, it should come as no surprise that the most critical diseases affecting small arteries impede blood flow. Chief among these flow-limiting conditions are coronary artery disease, peripheral artery disease, and cerebrovascular disease.¹ All are characterized by a progressive narrowing of vessels by deposited plaques, risking oxygen deprivation and death of downstream tissues. In the case of coronary artery disease, this results in a myocardial infarction or heart attack.¹ When pharmacological treatment is insufficient to address these conditions, alternative interventional methods are required. One such example is the use of a vascular graft to bypass the occluded region and restore blood flow to the tissues.

Autologous grafts are the current standard of care for bypassing diseased small arteries.^{2, 3} These grafts are harvested from elsewhere on the patient’s body depending on the treatment site. For example, vessels for coronary artery bypass grafting (CABG) may be harvested from the internal thoracic artery in the chest, radial artery in the arm, or the saphenous vein in the leg.¹ These grafts can be effective multiple years post-implantation, helping to alleviate symptoms of vessel occlusion and offering significant improvements to patients’ quality of life.⁴

However, the use of autologous grafts is not without its drawbacks. The secondary procedure to harvest the graft introduces risks of scarring, infection, nerve damage, and reduced blood flow which can result in permanent damage to the donor region. In rare cases, these complications may necessitate the amputation of the limb altogether.⁵ The act of harvesting itself may compromise the graft resulting in later occlusion and failure.⁶ Moreover, prior harvesting or widespread damage to the cardiovascular system due to systemic disease can render potential donor sites unviable and limit the amount of material available for harvest; this is especially true in severe cases requiring multiple bypasses where greater amounts of vascular material are necessary. In contrast to the repair and replacement of large arteries, no alternative grafts—synthetic or otherwise—have been found to be clinically viable for small vessel applications.³ It is here that the promise of tissue engineered vascular grafts comes into play.

Tissue-engineered vascular grafts (TEVGs) are biological constructs intended for the repair or replacement of damaged vascular tissue. They are typically composed of endothelial, smooth muscle, and fibroblast cells seeded within synthetic or biological scaffolds which provide structural organization, mechanical strength, and sites for cell adhesion. These living and non-living components are carefully selected and assembled to replicate the properties of native tissues, aiming to integrate seamlessly into the cardiovascular system. By mimicking natural vascular structures, TEVGs seek to promote tissue regeneration and improve upon existing synthetic grafts.

An understanding of the mechanical and biological characteristics of small diameter grafts best highlights the unique suitability of tissue-engineered constructs for this application. Grafts must have sufficient burst pressure, elasticity, and resilience to withstand the cyclical pressurization of the cardiovascular system driven by the heart’s pulse.³ They must also possess sufficient strength to hold a suture and ensure proper implantation.³ To further complicate matters, properties exceeding those of the native vessels are not suitable as the mismatch of mechanical properties has been found to contribute to disturbed blood flow at the site of anastomosis (vessel joining). This causes excess growth of endothelial cells lining the vessels (intimal hyperplasia) and eventual graft failure.⁷ Simply implanting an exceedingly strong tube is not a viable approach. Graft materials must also be chosen to minimize the risk of immune rejection; biological building blocks like collagen are preferable to synthetic polymeric materials which have been shown to provoke an elevated immune response, and biological materials of human origin are preferred to those of another species.³ Moreover, the graft’s materials should allow for progressive invasion of cells from native tissues and remodeling of the structure to facilitate complete integration into the native architecture.³ Evidently, any cells included within the graft should be of human origin as well.³ Finally, properties of the inner surface of the graft should be carefully selected to minimize the risk of blood-interactions resulting in thrombosis (blood clots).³

Taken together, these design considerations help reveal why previous attempts at synthetic small diameter grafts have largely failed and how tissue engineered grafts are uniquely suited to fill the gap. Where synthetic materials provoke immune response and rejection, a biologically engineered graft may facilitate complete integration. Where differences in mechanical properties induce pathological cell growth and vessel occlusion, a construct made from native materials allows remodeling and even growth. Most insightfully, an overview of these criteria highlights the absolute necessity of an interdisciplinary, collaborative approach between the engineering, health, and biological sciences to the successful generation of such a graft.

Such tissue-engineered grafts may be closer to clinical use than ever before. Humacyte, a biotech company out of Dr. Laura Niklason’s lab at Yale University, recently announced positive phase 2/3 clinical results for its “Human Acellular Vessel (HAV)” for the treatment of vascular trauma and arteriovenous access for hemodialysis.^8,9 In the trauma repair trial, HAV treatment resulted in a patency rate of 90.2% and an amputation rate of only 9.8% 30 days after treatment, compared to 81.1% and 20.6% for existing synthetic alternatives.⁸ Meanwhile, the arteriovenous access trial showed an HAV 12-month patency rate of 68.3%, slightly higher than the 62.2% seen for standard arteriovenous fistula treatment, although the HAV treatment group did experience a higher incidence of adverse events.⁹ Following the promising vascular trauma data, the US FDA accepted Humacyte’s Biologics License Application for review in February 2024.¹⁰ In August 2024, Humacyte revealed that the FDA required additional time to review its application; as of this publication, the FDA’s decision remains under review.¹¹

Even as implantable tissue-engineered vascular grafts remain just out of reach, research in this area is highly significant for the broader field of tissue engineering. Insights gained from developing vascular grafts will directly inform the creation of other tubular structures, such as bile ducts, segments of the gastrointestinal tract, branches of the airway, and components of the urinary and reproductive systems. Additionally, advances in bioreactor design and perfusion techniques derived from vascular graft research will be crucial for developing perfusion systems for engineered solid organs. More broadly, work in vascular engineering will enhance the understanding of all soft load-bearing tissues as well as the interaction of biological and mechanical aspects in engineered constructs. Thus, the impact of tissue-engineered grafts extends beyond their direct clinical benefits to the development of the field as a whole.

The development of small diameter vascular grafts represents a critical area of research in tissue engineering. With implications far beyond the field of cardiovascular health and disease, the complex, even contradictory challenges posed by the project highlight the strength and requirement of interdisciplinary collaboration in biomedical research. While perhaps not as glamorous as ideas of 3D printed kidneys or xenograft hearts, the deceptively simple vascular graft represents both a stepping stone towards complex tissues and a potentially life-saving intervention. For thousands of patients worldwide, their arrival is eagerly awaited.

References

1.          Hernandez-Sanchez D, Comtois-Bona M, Muñoz M, et al. Manufacturing and validation of small-diameter vascular grafts: A mini review. iScience. 2024;27(6):109845.

2.          Naegeli KM, Kural MH, Li Y, et al. Bioengineering Human Tissues and the Future of Vascular Replacement. Circulation Research. 2022;131(1):109-26.

3.          Niklason LE, Lawson JH. Bioengineered human blood vessels. Science. 2020;370(6513):eaaw8682.

4.          Abdallah MS, Wang K, Magnuson EA, et al. Quality of Life After PCI vs CABG Among Patients With Diabetes and Multivessel Coronary Artery Disease: A Randomized Clinical Trial. JAMA. 2013;310(15):1581-90.

5.          Paletta CE, Huang DB, Fiore AC, et al. Major leg wound complications after saphenous vein harvest for coronary revascularization. Ann Thorac Surg. 2000;70(2):492-7.

6.          Schanzer A, Hevelone N, Owens CD, et al. Technical factors affecting autogenous vein graft failure: Observations from a large multicenter trial. Journal of Vascular Surgery. 2007;46(6):1180-90.

7.          Post A, Diaz-Rodriguez P, Balouch B, et al. Elucidating the role of graft compliance mismatch on intimal hyperplasia using an ex vivo organ culture model. Acta Biomater. 2019;89:84-94.

8.          Humacyte Global, Inc [Internet]. Durham: Globe Newswire; 2023 Sept 12. Humacyte Announces Positive Top Line Results from Phase 2/3 Trial of Human Acellular Vessel™ (HAV™) in Treatment of Patients with Vascular Trauma [cited 2024 Aug 26]. Available from: https://investors.humacyte.com/news-releases/news-release-details/humacyte-announces-positive-top-line-results-phase-23-trial-0

9.          Humacyte Global, Inc [Internet]. Durham: Globe Newswire; 2024 July 31. Humacyte Acellular Tissue Engineered Vessel (ATEV™) Meets Primary Endpoints in V007 Phase 3 Clinical Trial in Arteriovenous Access for Hemodialysis [cited 2024 Aug 26]. Available from: https://investors.humacyte.com/news-releases/news-release-details/humacyte-acellular-tissue-engineered-vessel-atevtm-meets-primary

10.       Humacyte Global, Inc [Internet]. Durham: Globe Newswire; 2024 Feb 9. Human Acellular Vessel™ (HAV™) Biologics License Application Granted Priority Review by U.S. FDA for the Treatment of Vascular Trauma [cited 2024 Aug 26]. Available from: https://investors.humacyte.com/news-releases/news-release-details/human-acellular-vesseltm-havtm-biologics-license-application

11.       Humacyte Global, Inc [Internet]. Durham: Globe Newswire; 2024 Aug 9. Humacyte Announces FDA Communication of Additional Time Required to Complete Review of acellular tissue engineered vessel (ATEV™) BLA for the Treatment of Vascular Trauma [cited 2024 Aug 26]. Available from: https://investors.humacyte.com/news-releases/news-release-details/humacyte-announces-fda-communication-additional-time-required