The long-term objective of this research is to develop new insights into the pathogenic processes responsible for the progressive intimal fibromuscular hyperplasia and atherosclerosis that cause the ultimate failure of prosthetic grafts. Study of this problem will require in vivo and in vitro studies which will run concurrently.
The aims of the in vivo studies will be to develop and define the pathobiology of polytetrafluoroethylene (PTFE) implants in the Sinclair Research Farm minipig model under normal and hypercholesterolemic conditions. PTFE implants will be installed in the thoracic aorta and aorto-iliac system using different types of anastomotic geometries. The associated changes in conduit geometry will be evaluated angiographically; hemodynamics will be evaluated by doppler profiles and doppler spectral distributions. The vascular pathologic responses will be studied by light microscopy, electron microscopy, and morphometric analysis. When possible, these data will be compared to like data from human surgical patients to assess the validity of the model. These studies will provide a foundation of less equivocal data than now exists for design of research to probe more deeply the fundamental mechanisms underlying the observed pathobiology.
The aims of the in vitro studies are to examine some of the basic biological mechanisms that appear to be related to the pathobiology observed in the above in vivo studies. Normal vessels, as well as excised implant vessel systems, will be studied in a specially designed in vitro arterial organ support system (OSS) in which alterations in the metabolic, structural, rheologic, mass transport, and cellular response parameters can be analyzed under rigorously controlled conditions of pressure, flow (direction and magnitude), chemical milieu, controlled injury, and preexisting atherosclerosis. The measured parameters will include: tissue chemistries (e.g., lactate, nucleotides, etc.) serum reagent chemistries (PH, pCO2, pO2, electrolytes, etc.), ultrastructure, tissue elastic moduli, transmural water flux, and transmural transport (e.g., diffusivities, solute convective velocity, etc., of 125-1-albumin and 125-1-LDL) all as functions of the aforementioned experimental conditions of pressure, etc. Analysis of these data by statistical and mathematical modeling techniques will provide new information regarding the metabolic, structural, and mass transport parameters of normal and mildly atherosclerotic vessels and of vessel implant systems. In addition, studies of changes in these parameters under conditions of controlled changes in flow direction and magnitude and under conditions of controlled injury should provide new insights into the mechanisms of early tissue responses to aberrant hemodynamic conditions and injury. It is likely that these mechanisms are among the initiating factors leading to the chronic intimal changes that are associated with the ultimate failure of many vascular reconstructions. The understanding of these underlying mechanisms is essential for the design of improved more enduring therapeutic procedures and materials.
