Leading OpinionProsthetic vascular grafts: Wrong models, wrong questions and no healing☆
Introduction
For almost half a century synthetic vascular grafts have been an integral tool of vascular surgery. However, while large bore prostheses added an impressive scope to aortic and iliac surgery, smaller diameter grafts became the nemesis of research and a symbol for the limitations of modern biotechnology. The main reasons for the poor performance of small- (⩽4 mm) to medium-sized (⩽7 mm) grafts (SMGs) are anastomotic intimal hyperplasia and ongoing surface thrombogenicity. In spite of these perpetual shortcomings of contemporary vascular prostheses, no alternative concept has yet emerged that promises to replace the current generation of synthetic grafts soon. While a small spearhead of researchers pursues sophisticated tissue engineering approaches [1], [2], [3], [4] the majority of surgeons continue to implant the well-established products of the past decades. Similarly, commercial grafts continue to be manufactured on the basis of material choices, mechanical strength, regulatory compliance and surgical preferences rather than with a view towards biological integration and functional tissue regeneration. Nevertheless, regenerative medicine has made significant inroads in recent years and it seems only a matter of time until synthetic vascular grafts will also benefit from this development. Before embarking on concepts stimulating the in situ generation of functional vascular tissue, however, it seems paramount to understand why such a physiological tissue formation would not spontaneously occur in contemporary grafts. For reasons still incompletely understood, neither transmural ingrowth through the graft wall nor transanastomotic ingrowth from the adjacent artery seem to be capable of endothelializing more than a narrow zone confined to the immediate anastomotic area in humans [5], [6]. Given the high number of annual implants, it is surprising how poorly investigated these limitations have remained throughout the years. While the initial enthusiasm for the availability of polyester grafts prompted several major studies in the 1960s and 1970s [7], [8], [9], [10], relatively little has been added to our understanding since then. Typical for subsequent prosthetic vascular graft research, intensive efforts went into ever new permutations of prostheses without a sound baseline knowledge of pathological events behind the healing impairment of grafts which have been clinically implanted for decades. Furthermore, by choosing inadequate animal models and too short graft lengths, an involuntary emphasis of the majority of these studies was on transanastomotic endothelial ingrowth—a biological phenomenon of utter irrelevance for the clinical set-up.
Section snippets
Transanastomotic endothelialization (TAE): barking up the wrong tree
Given the key role endothelium plays in preventing a blood vessel from occluding, it is understandable that the main focus of vascular graft studies was on endothelialization. It is therefore even more surprising that the majority of investigators chose largely inadequate models for assessing midgraft endothelialization although the clinical background to all these studies has been unambiguous throughout the years. It has been known for more than four decades that in humans, transanastomotic
Anastomotic intimal hyperplasia: clinical villain, experimental void
Intimal hyperplasia occurs in vein grafts throughout their length. In contrast, intimal hyperplasia is confined to the peri-anastomotic region of prosthetic grafts in humans. The simple reason for this lies in the fact that intimal proliferation can only occur on the back of existing tissue and in man, most of the blood surface of a synthetic vascular graft remains uncovered by tissue. This also explains the clinical failure mode of prosthetic grafts: it is either midgraft thrombosis for a lack
Graft-structure-related limitations to tissue regeneration
Initial attempts to replace arteries with solid tubes of synthetic material [78] soon made it clear that porosity is a prerequisite for graft patency [79], [80]. Therefore, ranking structural porosity above material properties emerged as the early creed of synthetic vascular graft research. To date, this dogma is still unchallenged. Efforts to determine porosity requirements for graft healing, however, are complicated by material specific characteristics, structural uniqueness and the
Midgraft tissue response: no healing, no regeneration
Even after prolonged periods of implantation, a persistent foreign body response dominates the interstices of permanent (non-resorbable) synthetic arterial prostheses. Simultaneously, thrombotic appositions build up on the luminal surface. Thus, healing—defined as the end point of a pacified repair process—does not occur. Moreover, since not even traces of vascular tissue are being formed in the interstices or on the surface of these grafts, regeneration remains permanently absent, too. Yet, in
Biological events: adversity rather than facilitation
The complexity of an unabated chronic foreign body reaction at the blood–tissue interface is certainly beyond the scope of a short review. Yet, the two seemingly trivial main components of the tissue incorporation response—fibrin deposition and macrophage infiltration—are sufficiently contentious to offer themselves as potential keys to understanding main mechanisms behind the mitigated tissue incorporation of prosthetic vascular grafts. Almost from the time of implantation, fibrin becomes an
Half a century of vascular graft implantation: the essence
The key to new and emerging concepts for replacement arteries lies in understanding the obstacles of contemporary vascular prostheses. By analyzing studies of the past half century, certain principles emerged which confirm or defy prevailing stereotypes—some of them more than others:
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The vast majority of contemporary synthetic vascular grafts are so impervious that transmural tissue ingrowth is impossible.
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None of the clinically used ePTFE, Dacron or PU prostheses spontaneously develop a
Conclusions for vascular graft research
Many of the experimental concepts for the vascular grafts of tomorrow promise to overcome the main obstacles plaguing those prostheses currently available for clinical implantation. At the same time, resolving one problem may introduce another. By eliminating the underlying cause of the chronic foreign body response by using resorbable materials, for example, the resulting scar tissue may deprive us of that very compliance which we tried to introduce through new elastomers. Similarly, by
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