The ideal small arterial substitute: a search for the Holy Grail?

^a Division of Vascular Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

The increasing age and longevity of the American population, coupled with the prevalence of atherosclerotic cardiovascular disease (ASCVD),¹ ensures that the treatment of ASCVD will remain a major public health priority. Although continued advances in endovascular technology hold promise for less invasive approaches to arterial occlusive diseases, the mainstay of therapy for patients with coronary and peripheral occlusions remains surgical bypass grafting. This is true because surgical bypass is less restrictive in terms of the anatomic nature of lesions that are amenable to treatment and, in general, offers superior long-term patency, albeit at the cost of greater initial risk. Bypass grafts to small-caliber vessels in the coronary or lower extremity circulations are commonly used procedures that offer important benefits to patients and incur significant economic cost on a national level. If one further considers the problem of long-term vascular access in the hemodialysis population, the importance of a durable, versatile, small-caliber vascular graft assumes enormous proportions.

The `ideal' vascular graft would be characterized both by its mechanical attributes and postimplantation healing responses. Mechanical strength is a paramount issue; grafts placed in the arterial circulation must be capable of withstanding long-term hemodynamic stress without material failure, which might be catastrophic. Availability, suturability, and simplicity of handling are desirable for minimizing operating time, risk, and expense. The graft should be resistant to both thrombosis and infection and, optimally, would be completely incorporated by the body to yield a neovessel resembling a native artery in structure and function. Given the economic considerations, low cost and long-term durability are also important issues.

For large-caliber arterial reconstructions, currently available synthetic grafts offer a reasonable approximation of these ideals and proven clinical efficacy. Long-term results of synthetic grafts for replacement of the thoracic and abdominal aorta, arch vessels, iliac, and common femoral arteries for either aneurysmal or occlusive disease are generally excellent when using any of a number of materials and manufacturing processes. While graft infection, occlusion, and dilatation are important clinical problems, the majority of patients can expect durable patency and a low frequency of repeat procedures. Unfortunately, prosthetic grafts have generally proved unfavorable as small-caliber (<6 mm) arterial substitutes. In these demanding, low-flow environments, the primary factor influencing long-term patency is the type and quality of conduit used, with other patient variables (e.g., clinical indication, outflow resistance, site of distal anastomosis, comorbidities) serving as important modifiers.

In the coronary circulation, the internal mammary artery (IMA) and radial artery have been used as bypass conduits, and constitute the closest approximation to this ideal graft yet defined. The long-term function of IMA grafts is excellent, making bypass of the left anterior descending artery with an IMA graft the single most durable intervention for coronary revascularization (1). Free radial artery grafts for coronary bypass are a subject of intense scrutiny at present, and preliminary data is promising. Unfortunately, these arterial conduits are severely limited by availability. Furthermore, it goes without saying that, in the lower extremity, the luxury of a nearby, distinct arterial circulation (e.g., IMA) is not an option as it is in the chest.

Autogenous vein, particularly the greater saphenous, has proved to be a durable and versatile arterial substitute. In the lower extremity, long-term results with saphenous vein bypass (used in either in situ or reversed configurations) to infrapopliteal and even pedal arteries have been excellent. Secondary patency rates at 5 years approach 70–80% in most series, with limb salvage rates of 90% or greater (2). Results with ectopic (i.e., lesser saphenous, arm veins) or composite vein grafts are generally inferior (40–60%/5 years), though still superior to the performance of synthetic grafts in the hands of most surgeons (3, 4). Nonetheless, graft failure and conduit availability are important limitations of the autogenous vein as graft material.

Stenosis or occlusion of vein bypass grafts (coronary or peripheral) is a common clinical occurrence that frequently necessitates another intervention. Vein grafts fail most commonly due to the development of fibrous intimal hyperplasia, which is a flow-restricting lesion that may occur diffusely throughout the graft or, more commonly, at focal sites near anastomoses or in the body of the graft. This process, which is responsible for most mid-late term (3–24 month) failures, is poorly understood and its prevention is a subject of intense investigation. The adaptation of vein grafts to the arterial environment has been studied extensively in animal models and, to a lesser extent, in humans (5, 6). After implantation, vein grafts universally undergo structural changes characterized by intimal hyperplasia and overall wall thickening. The view of vein graft stenosis as merely an exaggerated form of this adaptation process remains to be proved and, by analogy to postangioplasty arterial remodeling, may be an erroneous oversimplification (7). In fact, the critical question of why some grafts remodel favorably whereas others narrow is a difficult one to study, but its answer is likely to be the key to the developent of strategies for prevention and treatment. To date, pharmacologic approaches to prolong vein graft patency have not borne fruit. Genetic approaches to modulate graft healing are actively being studied both experimentally (8) and clinically (V. J. Dzau, principal investigator, current randomized clinical trial at Brigham and Women's Hospital, Boston), and hold significant promise for the future.

Vein bypass grafts are also subject to progressive atherosclerotic degeneration after implantation, causing a continued attrition rate of approximately 5% per year beyond 2–3 years. In the lower extremity, in particular, where multiple bypass grafts are generally not feasible as an initial revascularization procedure, vein graft failure almost always leads to a recrudescence of symptoms. With the increasing survival of patients with ASCVD and the frequency of previous coronary or peripheral bypass procedures, lack of available autogenous veins of adequate length and quality becomes an important limitation. In the absence of the suitable autogenous vein, many patients with recurrent coronary disease are considered inoperable, and those with distal lower extremity disease may suffer loss of limb with its attendant consequences on both quality of life and survival.

Prosthetic grafts, primarily made of expanded polytetrafluoroethylene, have been used as small-caliber arterial substitutes with generally inferior results (9). They may fail due to their innate surface thrombogenicity (particularly in low flow applications), the development of focal anastomotic strictures because of intimal hyperplasia, or, most commonly, both. In general, these grafts never completely `heal' in humans, and endothelial coverage is limited to the small area of pannus ingrowth adjacent to anastomoses. To address the lack of functional endothelium and improve long-term performance, attempts have been made to line (`seed') prosthetic grafts with cultured endothelial cells. Despite more than a decade of active investigation of this approach, its ultimate value remains greatly in doubt (10). Critical questions have centered around maximizing the retention of seeded endothelial cells (ECs) to the prosthetic surface, the possible need for prolonged in vitro culture to stabilize EC adhesions to the substrate, the phenotype and function of the cultured, implanted cells, and the technical complexity and cost inherent in this approach. Genetic engineering may ultimately address some of these limitations and/or augment the potential benefits of this strategy.

The search for alternative biologic grafts has been filled with disappointments. Heterografts (bovine carotid artery) and homografts (glutaraldehyde-treated human umbilical cord vein) are both prone to long-term degradation, dilation, and frank aneurysm formation (11). Mechanical fatigue due to lack of stability of collagen cross-links is a likely postulated mechanism. Cryopreserved saphenous vein, which is commercially available, has yielded poor patency rates, likely due to immunologic mechanisms (12). Others have examined the approach of producing a vascular graft in vivo by implantation of a mandril that engenders a surrounding foreign body reaction, yielding a fibrocollagenous tube (Sparks' mandril graft, ref 13). Clinical trials with such grafts have yielded poor results, with high rates of thrombosis and aneurysmal degeneration.

With the development of techniques to reliably harvest and culture human vascular endothelial and smooth muscle cells, investigators have attempted to construct multilayer biologic `grafts' to mimic arterial wall architecture (14). Historically, this concept dates to the seminal efforts of Alexis Carrel, the surgical Nobelist who developed tissue culture and envisioned it as a means for producing replacements for solid organs and vessels. Even though the individual cell types of the arterial wall may be easily cultured and the protein components isolated, the production of a cohesive 3-dimensional structure with mature extracellular matrix and elastic tissue layers has been a major technological obstacle. It is not surprising that the mechanical strength of these constructs has been universally poor. In this issue of The FASEB Journal, a novel approach is reported in which tubular sheets of mesenchymal cells were produced with enhanced mechanical strength (15). Multilayered grafts were constructed of these sheets and subsequently lined with cultured endothelial cells. The unique property of these structures was the de novo generation of a multilayered, organized collagenous matrix that imparted significant physical burst strength as well as suturability. Clearly, much more effort will be required to understand and refine the manufacturing process, as well as to examine the long-term healing properties of these experimental grafts. Of the many significant technical obstacles ahead, the requirement of autologous tissue/cells and the time, cost, and complexity of production loom the largest. Ultimately, genetic manipulation of the vascular cells may provide an alternative strategy to address some of these limitations and to enhance the potential function of these biologic grafts.

The search for the ideal small-caliber arterial substitute may remind us of the Holy Grail metaphor, but the continued refinement of bioengineering and genetic approaches, combined with improved cellular and molecular understanding of the biology of the vessel wall, has dramatically increased the probability of attaining this goal. A maintained, long-term commitment from private and public funding agencies will be needed to bring these concepts to clinical fruition.

FOOTNOTES

¹ Abbreviations: ASCVD, atherosclerotic cardiovascular disease; EC, endothelial cell; IMA, internal mammary artery.

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