Elsevier

Biomaterials

Volume 28, Issue 34, December 2007, Pages 5009-5027
Biomaterials

Leading Opinion
Prosthetic vascular grafts: Wrong models, wrong questions and no healing

https://doi.org/10.1016/j.biomaterials.2007.07.017Get rights and content

Abstract

In humans, prosthetic vascular grafts remain largely without an endothelium, even after decades of implantation. While this shortcoming does not affect the clinical performance of large bore prostheses in aortic or iliac position, it contributes significantly to the high failure rate of small- to medium-sized grafts (SMGs). For decades intensive but largely futile research efforts have been under way to address this issue. In spite of the abundance of previous studies, a broad analysis of biological events dominating the incorporation of vascular grafts was hitherto lacking. By focusing on the three main contemporary graft types, expanded polytetrafluoroethylene (ePTFE), Dacron and Polyurethane (PU), accumulated clinical and experimental experience of almost half a century was available. The main outcome of this broad analysis—supported by our own experience in a senescent non-human primate model—was twofold: Firstly, inappropriate animal models, which addressed scientific questions that missed the point of clinical relevance, were largely used. This led to a situation where the vast majority of investigators unintentionally studied transanastomotic rather than transmural or blood-borne endothelialization. Given the fact that in patients transanastomotic endothelialization (TAE) covers only the immediate perianastomotic region of sometimes very long prostheses, TAE is rather irrelevant in the clinical context. Secondly, transmural endothelialization seems to have a time window of opportunity before a build-up of an adverse microenvironment. In selecting animal models that prematurely terminate this build-up through the early presence of an endothelium, the most significant ‘impairment factor’ for physiological tissue regeneration in vascular grafts remained ignored.

By providing insight into mechanisms and experimental designs which obscured the purpose and scope of several decades of vascular graft studies, future research may better address clinical relevance.

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:

  • The vast majority of contemporary synthetic vascular grafts are so impervious that transmural tissue ingrowth is impossible.

  • 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

References (192)

  • M. Heise et al.

    PEG-hirudin/iloprost coating of small diameter ePTFE grafts effectively prevents pseudointima and intimal hyperplasia development

    Eur J Vasc Endovasc Surg

    (2006)
  • L. Hollier et al.

    Are seeded endothelial cells the origin of neointima on prosthetic vascular grafts?

    J Vasc Surg

    (1986)
  • J. Zamora et al.

    Seeding of arteriovenous prostheses with homologous endothelium

    A preliminary report. J Vasc Surg

    (1986)
  • G. Koveker et al.

    Endothelial cell seeding of expanded polytetrafluoroethylene vena cava conduits: effects on luminal production of prostacyclin, platelet adherence, and fibrinogen accumulation

    J Vasc Surg

    (1988)
  • M. Ombrellaro et al.

    Healing characteristics of intra-arterial stented grafts: effect of intra-luminal position on prosthetic graft healing

    Surgery

    (1996)
  • J. Christenson et al.

    Forskolin impregnation of small calibre PTFE grafts lowers early platelet graft sequestration and improves patency in a sheep model

    Eur J Vasc Surg

    (1991)
  • P. Fleser et al.

    Nitric oxide-releasing biopolymers inhibit thrombus formation in a sheep model of arterio-venous bridge grafts

    J Vasc Surg

    (2004)
  • M. DeBakey et al.

    Basic biologic reactions to vascular grafts and prostheses

    Surg Clin North Am

    (1965)
  • M. Herring et al.

    Patency in canine inferior vena cava grafting: effects of graft material, size, and endothelial seeding

    J Vasc Surg

    (1984)
  • J. Stronck et al.

    J Thorac Cardiovasc Surg

    (1992)
  • E. Friedman et al.

    Polytetrafluoroethylene grafts in the peripheral venous circulation of rabbits

    Am J Surg

    (1983)
  • R. Binns et al.

    Optimal graft diameter: effect of wall shear stress on vascular healing

    J Vasc Surg

    (1989)
  • A. Clowes et al.

    Mechanisms of arterial graft failure. II. Chronic endothelial and smooth muscle cell proliferation in healing polytetrafluoroethylene prostheses

    J Vasc Surg

    (1986)
  • E. Sho et al.

    Arterial enlargement, tortuosity, and intimal thickening in response to sequential exposure to high and low wall shear stress

    J Vasc Surg

    (2004)
  • R. Zacharias et al.

    Mechanisms of healing in synthetic grafts

    J Vasc Surg

    (1987)
  • M. Therrien et al.

    Hydrophobic and fibrillar microporous polyetherurethane urea prosthesis: an ESCA study on the internal and external surfaces of explanted grafts

    Biomaterials

    (1989)
  • A.M. Seifalian et al.

    In vivo biostability of a poly(carbonate–urea)urethane graft

    Biomaterials

    (2003)
  • S. Mathisen et al.

    An experimental study of eight current arterial prostheses

    J Vasc Surg

    (1986)
  • K. Hirschi et al.

    Cell–cell interactions in vessel assembly: a model for the fundamentals of vascular remodelling

    Transpl Immunol

    (1997)
  • D. Cheresh et al.

    Recognition of distinct adhesive sites on fibrinogen by related integrins on platelets and endothelial cells

    Cell

    (1989)
  • E. Wintermantel et al.

    Tissue engineering scaffolds using superstructures

    Biomaterials

    (1996)
  • C. Weinberg et al.

    A blood vessel model constructed from collagen and cultured vascular cells

    Science

    (1986)
  • L. Niklason

    Techview: medical technology. Replacement arteries made to order

    Science

    (1999)
  • K. Berger et al.

    Healing of arterial prostheses in man: its incompleteness

    Ann Surg

    (1972)
  • S. Wesolowski et al.

    Factors contributing to long-term failures in human vascular prosthetic grafts

    Cardiovas Surg

    (1964)
  • J. Ghidoni et al.

    Healing of pseudointimas in velour-lined, impermeable arterial prostheses

    Am J Pathol

    (1968)
  • D. Szilagyi et al.

    Long-term behavior of a Dacron arterial substitute: clinical, roentgenologic and histologic correlations

    Ann Surg

    (1965)
  • L. Davids et al.

    The lack of healing in convenitonal vascular grafts

  • J. Murray-Wijelath et al.

    Vascular graft healing. III. FTIR analysis of ePTFE graft samples from implanted bigrafts

    J Biomed Mater Res B Appl Biomater

    (2004)
  • T. Pfeiffer et al.

    Healing characteristics of small-calibre vascular prostheses coated with plasmin-treated fibrin—an experimental study

    Vasa

    (2000)
  • T. Nishibe et al.

    Enhanced graft healing of high-porosity expanded polytetrafluoroethylene grafts by covalent bonding of fibronectin

    Surg Today

    (2000)
  • D.J. Lyman et al.

    Vascular graft healing. II. FTIR analysis of polyester graft samples from implanted bi-grafts

    J Biomed Mater Res

    (2001)
  • T. Shimada et al.

    Improved healing of small-caliber, long-fibril expanded polytetrafluoroethylene vascular grafts by covalent bonding of fibronectin

    Surg Today

    (2004)
  • T. Ueberrueck et al.

    Healing characteristics of a new silver-coated, gelatine impregnated vascular prosthesis in the porcine model

    Zentralbl Chir

    (2005)
  • R.D. Kenagy et al.

    Accumulation and loss of extracellular matrix during shear stress-mediated intimal growth and regression in baboon vascular grafts

    J Histochem Cytochem

    (2005)
  • Phaneuf MD, Dempsey DJ, Bide MJ, Quist WC, LoGerfo FW. Coating of Dacron vascular grafts with an ionic polyurethane: a...
  • H. Miura et al.

    The influence of node-fibril morphology on healing of high-porosity expanded polytetrafluoroethylene grafts

    Eur Surg Res

    (2002)
  • Begovac PC, Thomson RC, Fisher JL, Hughson A, Gallhagen A. Improvements in GORE-TEX vascular graft performance by...
  • L.B. Sun et al.

    Pretreatment of a Dacron graft with tissue factor pathway inhibitor decreases thrombogenicity and neointimal thickness: a preliminary animal study

    ASAIO J

    (2001)
  • A. Sterpetti et al.

    Healing of high-porosity polytetrafluoroethylene arterial grafts is influenced by the nature of the surrounding tissue

    Surgery

    (1992)
  • Cited by (419)

    View all citing articles on Scopus

    Note: Leading Opinions: This paper provides evidence-based scientific opinions on topical and important issues in biomaterials science. They have some features of an invited editorial but are based on scientific facts, and some features of a review paper, without attempting to be comprehensive. These papers have been reviewed for factual, scientific content.

    View full text