Clinical implementation of the Humacyte human acellular vessel: Implications for military and civilian trauma care
The incidence of wartime vascular injury has increased and is a leading cause of mortality and morbidity. While ligation remains an option, current resuscitation and damage control techniques have resulted in vascular repair being pursued in more than half of wartime injuries. Options for vascular reconstruction are currently limited to autologous vein or synthetic conduits, choices which have not changed in decades, both of which have problems. Autologous vein is preferable but requires time to harvest and may not be available. Synthetic grafts are poorly resistant to infection and associated with thrombotic complications. Recognizing this capability gap, the US Combat Casualty Care Research Program has partnered with academia and industry to support the development and clinical introduction of a bioengineered human acellular vessel. This human acellular vessel has the potential to be an off-the-shelf conduit that is resistant to infection and incorporates well into native tissues. This report reviews the rationale of this military-civilian partnership in medical innovation and provides an update on the clinical use and ongoing study of this new vascular technology. (J Trauma Acute Care Surg. 2019;87: S44–S47. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)
Vascular trauma; vascular conduit; trauma surgery.
Vascular injury is a significant contributor to loss of life and limb in the civilian and military setting.1 The incidence of vascular trauma in combat has increased from a rate of 2% to 3% during the Vietnam War to more than 15% in the wars in Iraq and Afghanistan.2,3 The increased rate is multifactorial and partly due to force protection measures that reduce the incidence of lethal torso and head injuries, and the use of modern extremity tourniquets to control extremity hemorrhage. More effective damage control resuscitation strategies used within a data-driven, military trauma system also means that more injured service members are surviving to have vascular injury treated.
The operative approach to vascular injury has been transformed since World War II when ligation (and often amputation) was the dictum.5 Reports from the recent wars show that some type of revascularization is now pursued in more than half of cases, and that early limb salvage is nearly 90%.2,3,6,7 While the principles of vessel ligation and of “life over limb” are still important, modern damage control resuscitation and use of temporary vascular shunts have allowed pursuit of life and limb in a greater number of complex cases.8–10 At the same time, research has shown that the ischemic threshold of the limb is less than the traditional “6-hour” rule and that reperfusion should be restored within 3 hours or less if quality or functional limb salvage is to be expected.
This transformation has occurred in an era in which training opportunities in open vascular surgery have decreased significantly. Subspecialization and reliance on endovascular approaches have meant that today's surgeon has less experience exposing, preparing, and sewing saphenous vein conduit. Now more than ever, there is a need for an “off the shelf,” infectionresistant vascular conduit that can be quickly used by nonspecialized surgeons to treat vascular injury. This report reviews one such technology resulting from a military-civilian partnership in medical innovation.
Existing Conduit Options
Autologous vein—most frequently the great saphenous— is the preferred and most often used conduit in the management of wartime vascular injury. In the setting of extremity trauma this most commonly involves interposition graft replacement of the injured artery. Studies from the military trauma system and the Combat Casualty Care Research program show that saphenous vein is an effective conduit in this setting with good patency rates and tissue incorporation, although thrombosis and infection occur in 10% to 20% of cases.
Despite favorable outcomes associated with vein, its use is precluded in a number of cases. For example, saphenous vein may be damaged and unusable in situations where both lower extremities are injured (i.e., complex blast or penetrating injuries). In austere environments, where quick, damage control operations are the rule, the time and resources required to surgically identify, remove, and prepare the saphenous vein may be a limiting factor. The time needed to harvest and prepare the saphenous vein is particularly problematic in multiple casualty situations in which a number of operations need occur in a short period.20 Finally, the surgical wound created to remove the vein is not insignificant and itself becomes infected in 5% to 10% of cases.
When saphenous vein is not available, synthetic grafts including expanded Polytetrafluoroethylene (ePTFE) (i.e., Gortex) and Dacron are common alternatives. Synthetics are used in 6% to 7% of military cases and have been found to be less durable and resistent to infection than autologous vein. Registry data and anecdotal observations have shown that synthetic conduit is poorly incoproprated in large soft tissue wounds in which surrounding tissue viability is questionable, and in which a greater degree of contamination exists. Poor incorporation and susceptibility to contamination can lead to long-term graft infection, with or without anascomotic disruption, and thrombosis. In the military experience, synthetic conduit has been shown to have lower patency than saphenous vein, with studies showing thrombotic complications in nearly 50% of the cases.
Other less-common conduit options include xenogeneic tissues, such as bovine carotid artery and cyropreserved cadaveric vessels. Although interesting and useful in some situations, large scale availability and use of these conduits—especially for the acute phase of injuy management—have been limited by the ability to efficiently and reproducably procure, ship, and safely store these products. The experience of these xenogenic conduits is almost entirely in the realm of elective or semielective chronic vascular disease conditions, and there are no reports of their use in the acute management of wartime vascular injury. The clinical data available for these types of conduits comes from small studies which suggest lower patency than autologous vein and higher risk of structural complications, such as stenoses and or aneurysm formation. Postimplantation immune response has also been reported in patients in whom cryopreserved vessels have been used, possibly leading to graft durability issues.
The Ideal Vascular Conduit
The ideal material for vascular reconstruction would combine the favorable safety, efficacy, and durability profiles of autologous vein, with the expediency and predictable sizing (i.e., diameter and length) of an “off-the-shelf ” product. Such a conduit would eliminate the technical expertise and time required for vein harvest as well as associated wound complications. A perfect conduit would also have physical characteristics that make it easy to handle and sew, and biologic properties allowing it to become incorporated by the host patient. The military's medical research program has responded to this requirement in vascular injury management and made this type of enhanced conduit a top priority. As with other research and innovation efforts, the military has partnered with civilian academia and private industry to develop a new product with many of the features of an ideal vascular conduit. Leveraging scientific breakthroughs in the field of regenerative medicine and the enterprising nature of private industry, this effort has resulted in the growth of novel human acellular vessels (HAV) that hold promise in addressing this high-priority gap in combat casualty care.
Humacyte is developing the HAV, which is a bioengineered, sterile, nonpyrogenic acellular tubular vessel composed primarily of human collagen and other extracellular matrix components. The HAV has “off-the-shelf ” availability and reproducable sizing of synthetic grafts and studies have shown it to have favorable resistance to infection.24 Findings also show that the HAV is extensively remodeled by the host or receipent patient when the conduit is used for arteriovenous access creation. In these studies, HAV sections were taken during routine procedures and subjected to histological analysis which revealed the HAV is permissive to infiltration of host cells, modifying into a multi-layered living structure mimicking the native vasculature. This evolution of HAV into a living tissue lends the capacity to heal and respond to changes in the host, notably without invoking an overt immune response.
The HAV is being studied in Phase II and Phase III clinical trials for use in arteriovenous access creation for hemodialysis, and vascular repair and reconstruction (including perpheral arterial disease and vascular trauma). In hemodialysis the HAV has received regenerative medicine, advanced therapy designation, an expedited approval pathway designated by the Food and Drug Administration for exceptionally promising medical advances that treat serious conditions under the 21st Century Cures Act. The HAV is being developed in close collaboration between the Department of Defense (DoD) and Humacyte for its use in vascular repair and reconstruction.
Figures 1 to 3 demonstrate the use of an HAV in the setting of a civilian gun-shot wound to the superficial femoral artery. The patient had sustained multiple injuries and a temporary vascular shunt inserted to sustain flow to his extremity as a damage control maneouver. The HAV was used as a conduit for definitive repair, sutured in place using a standard vascular technique.