Every era in medicine has been driven by one particular discipline which recognized an exciting new development occurring outside its own sphere as an opportunity for a quantum leap. Although this initial phase of integrating an unfamiliar dimension into a traditional medical dominion was seldom blessed with clinical success, retrospectively this era is always perceived as the grand epoch of the particular discipline. For instance, the integration of technical achievements into a discipline like surgery, previously considered to be more a skillful art than anything else, made cardiac surgery possible. Those pioneering cardiac surgeons who dared to let a mechanical pump take over the heart's function, thus allowing procedures on the open heart, were initially viewed with suspicion by their peers. Typically, it was not a single technical aspect which was absorbed into this young discipline but rather a basic openness towards the integration of mechanical and electrical contraptions into the circulatory system, a part of the body which was considered to be untouchable since the days of Theodor Billroth. It seems also typical that the enthusiasm of such a pioneering phase eventually draws the newly discovered, unrelated support discipline further into its sphere of influence. It was not a coincidence that Earl Bakken developed the first pacemaker in Minneapolis in the wake of the emerging new discipline of cardiac surgery, which was plagued by postoperative rhythm problems in this early phase. Retrospectively, the quantum leap which this pinnacle of cardiac surgery initiated for other medical professions remains unchallenged.

In vascular surgery, the late 1970s and early 1980s may well, retrospectively, turn out to have been a similarly fateful period for medicine. However, in contrast to cardiac surgery twenty years before, it was not the world of sophisticated mechanical devices and electronics which were integrated into medicine but the amazing world of biology. Symptomatically, naive amateurism and polarization characterize the early days of this era. Amateurism, because the first to test the water were surgeons and not biologists. This is the trademark of all developments of this kind in medicine: Brave and alert medical doctors initially apply discoveries from an alien field to medicine themselves. On the one hand, this effervescent breed with their urge for knowledge has all the ingredients to overcome initial thresholds and obstacles. On the other hand, it is often a surgical discipline within the medical profession, with its desire for clear cut and simple solutions, which drives such initiatives. As a consequence, this surgical mentality may endanger its own achievements when necessary complexity falls victim to impatience. In the case of the awaking biological awareness of the late 1970s, it was indeed surgeons again who were behind it. Almost predictably, they caused their own setback as they had in previous years with heart transplantation by not handing the newborn over to scientists in time. In the case of heart transplantation, immune and drug research rather than the fury of an ongoing surgical push could have saved 10 years. The eventual breakthrough of the cyclosporin era fought an uphill battle against the prejudices arising from the surgical desire for a quick fix during the preceding 13 years. In the case of the incorporation of biology into prosthetic vascular surgery, it was the endless striving of surgeons to succeed with a simple and instantly applicable, single-staged procedure right from the beginning which almost meant the death knell for the entire idea 10 years later. A further tragedy which repeats itself in the early phases of “quantum leap” eras lies in the typical negative feedback amongst the alien partners which soon follows the initial enthusiasm. Surgeons often feel intimidated by the thought of scientific complexity and scientists shy away from the “gung-ho” approach of surgeons. As contradictory as it may sound, in the end it is often the perseverance of a few dedicated surgeons who continue their mission regardless, accepting a higher level of complexity. This perseverance allows an idea to survive long enough for its final breakthrough. In heart transplantation, Norman Shumway fulfilled this role. In the attempt to incorporate biological principles into prosthetic vascular surgery, in vitro endothelialization may, in retrospect, have played a similar role. If the next decade of research succeeds with tissue engineering of physiologically functional vascular prostheses, the credit for opening a new era in medicine will undoubtedly be deserved by the early pioneers of single-staged endothelial cell seeding. However, the role which Norman Shumway played in heart transplantation—to prevent the flickering flame from being extinguished—may well be granted to those who continuously propagated the complex but eventually successful variant of in vitro endothelialization, to clinically prove the benefit of a principle and thus provide sufficient incentive for today's efforts towards a broadly acceptable breakthrough.

Historical Perspective

If the amateurism of the pioneering years of endothelial seeding, with its lack of involvement of basic scientists, contributed to a delay of today's drive towards an integrated approach to cardiovascular tissue engineering, one can at least explain this shortcoming by the fundamental difference between the worlds of surgeons and biologists. This does not apply to the polarization which plagued all of us who were involved in efforts to “biolize” prosthetic grafts from within our own discipline. This polarization was twofold: On the one hand, each different approach to endothelial seeding was almost religiously upheld by the respective groups which stood for it. On the other hand, a fiercely fought confrontation of principal values led to a schism which continues to divide the surgical community today. Both polarizations may be explained in terms of the previous quantum leap era, under whose spell the majority of cardiovascular surgeons still stood. One aspect of the preceding grand era of cardiovascular pioneering was that it created heroes as never before. Each facet of the overall quantum leap was associated with a big name, whether it was Lillihey, Kirklin, De Bakey, Barnard or Cooley. Even if not openly admitted, each champion of a particular approach towards graft endothelialization therefore hoped for comparable fame. Another aspect of those days in the 1960s was that their pioneers demonstrated that almost everything which previously seemed unresolvable became feasible through the application of new materials and mechanically determined technologies. Naturally, the emergence of a new dimension like biology caused friction. As a result, at all conferences in the 1980s, the believers in existing technologies asked angrily after each talk on endothelial seeding whether the speakers were aware that graft patencies depended primarily on surgical skills. Therefore, they recommended that the presenter spend his time improving those skills rather than wasting it in the laboratory. The fact that this latter group of surgeons still represents the majority within our ranks proves how successful the previous quantum leap was in getting its new standards generally accepted. In his book The Structure of Scientific Revolutions, Thomas Kuhn¹ explains the mechanisms involved in such paradigm shifts. Stephen Hawking² brought it to the point by arguing that people are very reluctant to give up a theory in which they have invested a lot of time and effort. This theory defining concepts and procedures is the accepted paradigm, which is recognized by all scientists working in that field. If, however, unexpected developments result in increasing inconsistency with the prevailing paradigm, a tense situation ensues amongst the scientists. At that stage the majority initially questions the accuracy of the observations. If that fails, they try to modify the existing theory in an ad hoc manner. Eventually, the old paradigm becomes creaking and ugly and a new one is accepted which explains all the awkward observations in an elegant and natural manner. Quantum leaps in medicine are certainly not such revolutionary shifts in scientific paradigms, but their principles and their consequences are similar. The angry discussant, for instance, questioning the purpose of merging vascular prosthetic research with biology, is not an isolated phenomenon but rather a typical veteran who may have actively contributed to yesterday's paradigm shift. This again has many parallels in truly revolutionary paradigm shifts in science. Albert Einstein, for instance, who caused a paradigm shift in physics with his special theory of relativity in 1905, was himself, many years later, one of the major antagonists to the next paradigm shift by resisting the acceptance of quantum mechanics. Surgeons are thus in good company with regard to the resistance to paradigm shifts. However, the 13-year delay in achieving this goal in heart transplantation, and the 20-year delay in accepting biology in cardiovascular surgery, makes it clear that we are dealing with a particularly conservative discipline.

Having tried to understand the driving forces behind the two-fold polarization which characterized the past 20 years of attempts to create a biologically functional vascular prosthesis, it seems easier to explain the concrete developments of those two decades as well as today's situation. The internally dividing question, for instance, regarding the principal approach to the endothelialization of a prosthetic surface, namely the acceptance of initial complexity versus apriori simplicity, was not an issue at the beginning when no pressure of expectation was exerted by the surgical community. In the early to mid-1970s, the entire initiative to surface endothelialization was driven by attempts to culture endothelial cells on synthetic surfaces prior to implantation.^3,4 Pioneers of endothelial seeding, like the groups of Jim Stanley and Linda Graham, were among those who first cultured autologous endothelial cells on vascular graft surfaces.^5,6 Only subsequently in the mid-1980s, when surgeons saw the opportunity of implementing their discoveries through main commercial players, did the focus shift almost entirely to single-stage procedures. Ironically, when the greatest enthusiasm for endothelial seeding seized the surgical community at the beginning of the second half of the 1980s, the death sentence was already sealed through both premature clinical trials^7-11 and “commercial kits” for clinical single-staged procedures. What happened after the majority of disappointed vascular surgeons turned away from this idea really resembled the above-mentioned late developments in heart transplantation. With the hype of the early 1980s over, those who continued were prepared to accept both a long and arduous route of homework prior to implementation and the knowledge that their contribution would be a quiet one.

Attitude-wise back to square one, the remaining groups focused on the main weakness of graft endothelialization, the low cellular inoculum. Mass harvest methods for microvascular cells,^12-16 as well as mass culture procedures for macrovascular endothelial cells,^17-19 were scientifically refined. One of the main reasons for a more relaxed approach in this second half of the 1980s was the conviction that a principle rather than a particular solution needed to be proven. At the onset of the era of vascular biology, nobody challenges that a biologically functional prosthesis would eventually come as a product from the shelf, integrating all encoded signals for spontaneous healing. Nevertheless, such an undertaking needs a critical mass which can more easily be achieved on the basis of at least one proven principle. Although important principles of today like intramural contractility, compliance and cellular quiescence could not yet be tackled, we all focused on the proof that graft endothelialization alone can already dramatically improve synthetic graft performance, even if the old prosthetic scaffolds of yesterday are used. In a step-by-step approach, adherence and shear stress resistance of cultured endothelial cells on various protein matrices were ascertained^20-37 prior to in vivo experiments ranging from canine implants²⁰ to primate experiments^38,39 and preclinical primate studies.⁴⁰ The success of those implants was convincing enough to apply the principle to very small diameter grafts⁴¹ as well as to bioprosthetic surfaces^42-47 and to heart valves.^48-51 Eventually, the step into clinical trials had to be taken. However, in contrast to the clinical studies with single-staged endothelial seeding, the situation regarding clinical trails with in vitro lining was distinctly different: By having accepted the disadvantages of a complex procedure, we had eliminated most of the uncertainties prior to commencing the trials.

Current and Future Perspective

Today's cumulative experience with clinical endothelial cell lining covers almost a decade and comprises more than 200 patients.^52-60It has clearly demonstrated that in vitro endothelialized synthetic prostheses are equal or better than saphenous vein grafts with regard to patency in all anatomical positions and any clinical stage other than stage IV.^52-60

Although ePTFE grafts with 30-mm internodal distance, which are noncompliant and do not allow transmural tissue in-growth, were used for these studies, the autologous surface endothelium alone was not only sufficient to significantly improve patency rates, but also led to the development of a neomedia between an internal elastic membrane underneath the endothelium and the ePTFE surface.⁵⁹ This observation indicates that the previous fear of “contaminating” smooth muscle cells was unfounded. Furthermore, it not only supports the current holistic approach towards tissue engineered prosthetic vascular grafts which aim at fully functional neoarteries, but also removes the last remnants of the previous polarization between mixed microvascular mass seeding and macrovascular in vitro lining.

The tools which biology offers today often seem like a dream to those of us who believed in the idea of integrating biology into prosthetic grafts, long before vascular biology had entered its maturity. At the same time we also see that these tools require a commitment of all parties to a many-fold higher level of complexity than the one from which most of us had shied away in the early days of endothelial seeding. Last but not least, we as surgeons are still the majority shareholders in this venture, although the scientists will soon take over the supervisory board. This is a necessary and correct development which should have happened many years ago. However, even if the scientists do take over the lead, in the end there will still be three partners: the industry, the surgeons and the scientists. The industry will need strongly convincing data to voluntarily accept the replacement of a simple and profitable product by a complex and expensive one. The surgeons will need the final painful push to accept the shift of a paradigm and the biologists will need both the true commitment of the other two parties and a strong motivation with regard to the broad application of their discoveries before they will wholeheartedly join hands. This may well be the last challenge for the veteran surgeons on board. Convincing clinical studies with a method which significantly improves graft performance will eventually break the resistance against a paradigm shift amongst our peers and thus prepare the way for the acceptance of tissue engineering. Acceptance of a complex approach by surgeons will mellow the scientists who still see us as “gung-ho” cowboys. And finally, a joint front of scientists and surgeons will eventually force the industry to see beyond today's profits. Last but not least, one needs to keep in mind that even an “Los Alamos” approach to tissue engineering will take many years for the development and many years for clinical trials. This consideration certainly upgrades clinical in vitro endothelialization to a procedure which could benefit an uncountable number of patients over many years to come.

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