Failure mechanisms in collagen of heart valves and tissue engineered replacements

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Tissue engineering seeks to replace damaged or diseased tissues with fully natural, regenerated structures. Many of the targets for this enterprise are mechanically critical structures (e.g. heart valves, artery replacements, heart wall) where failure can mean severe illness or death for the patient. Since the heart beats 35 million times a year, there is a strong need to understand the mechanisms by which both native tissues and engineered replacements respond to the mechanical fatigue associated with repeated loading. Moreover, tissue-engineered replacements are often juvenile in structure and function and face real challenges in immediately taking over the duties of mature, adult tissues. In this research program, we are seeking to understand the fundamental structural roots of biomechanical failure, and its prevention, in natural heart valves and tissue engineered replacements. Thereby, we hope to decrease the likelihood of failure of a replacement valve in a patient and bioengineer valves that have a defined safety in their design. Project one will use synchrotron x-ray diffraction and small angle scattering to study the packing of collagen molecules (i) in intact tissues and tissues overloaded to failure, and (ii) in tissues of varying age, from neonatal life to old age. By this means we hope to understand how this molecule-level characteristic of tissue architecture defines the stability of collagen and thereby its resistance to uncoiling and degradation. Project two will use two new confocal laser microscopy techniques (2nd harmonic generation and CNA35 binding) to examine changes in collagen fibre and bundle structure during uniaxial and biaxial loading to failure. This approach will allow direct visualization of the mechanisms by which the collagen architecture is disrupted, and the influence that age, crosslinking, and mechanical fatigue has on those mechanisms. Finally, in Project three, we will use host inflammatory cells (macrophages) to look at how changes in collagen (fatigue damage, enzyme breakdown, and crosslinking) influence the host reaction to implanted tissue devices.