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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 optical engineers. This does not apply to the polarization which plagued all of us who were involved in efforts to promote microscopy and tissue-culture microscopes 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 and microscopy 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 whether using gynecology microscopes or tissue-culture microscopes 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 Kuhn explains the mechanisms involved in such paradigm shifts.

Stephen Hawking 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 whether using gynecology microscopes or tissue-culture microscopes 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 whether using gynecology microscopes or tissue-culture microscopes was driven by attempts to culture endothelial cells on synthetic surfaces prior to implantation.

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 using tissue-engineering microscopes. 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 and “commercial kits” for clinical microscopy employing the newly-introduced obstetric microscopes and procedures at that time. 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 whether using gynecology microscopes or tissue-culture microscopes, the low cellular inoculum mass harvest methods for microvascular cells, as well as mass culture procedures for macrovascular endothelial cells, 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 microscopy, 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 whether using gynecology microscopes or tissue-culture microscopes 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 prior to in vivo experiments ranging from canine implants to primate experiments and preclinical primate studies. The success of those implants was convincing enough to apply the principle to very small diameter grafts as well as to bioprosthetic surfaces and to heart valves. 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.



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Saturday, April 12th, 2008 at 3:17 am
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