Reason: Final chapter is under review and awaiting publication.
until file(s) become available
Engineering Design and Mathematical Simulation of Mechano-Instructive Collagen Scaffolds for Treatment of Difficult-to-Heal Wounds
thesisposted on 26.04.2021, 17:41 by David O Sohutskay
Wounds of the skin, especially those that are large and breach multiple tissue layers, remain a major burden to those that they affect as well as our healthcare system. Because these tissue defects supersede the body’s natural healing capacity, normal skin anatomy and functional integrity is not restored in an orderly and timely fashion, leading to devastating consequences such as long healing times, pain, infection, scarring, and loss of mobility and function owing to contracture. As a result, there exists a need for better therapies that can rapidly and reliably restore skin cosmesis and function. Given that the collagen extracellular matrix of the dermis is a vital component to skin mechanobiology and wound healing, our skin restoration strategy focused on defining how specific collagen microstructure features contribute to the multi-scale properties and healing response of dermal replacement scaffolds. In this thesis, we first define the history of collagen biomaterials, their biochemistry and biomechanical properties, and engineering techniques for fabrication of scaffolds. We then hypothesize that collagen fibril density and architecture are important design considerations for mechano-instructive dermal regeneration scaffolds. To test this, we used self-assembling type I collagen polymer (oligomer), together with a controlled plastic compression molding technique to create scaffolds with varied microstructural and mechanical features. The dermal replacement scaffolds were then evaluated in full-thickness skin wounds in rats and compared to no-fill control, autograft rat skin, and a commercial collagen dressing. Increasing fibril content of oligomer scaffolds inhibited wound contraction and decreased myofibroblast marker expression. Cellular and vascular infiltration of scaffolds over the 14-day period varied with the graded density and orientation of fibrils. To extend and enhance prototype development and testing we developed a finite element growth model of wound healing, incorporating experimental measures of scaffold structure and mechanical properties and in-vivo healing outcomes. Model constitutive equations were calibrated to our experimental data with a Bayesian fitting. We demonstrated the ability of the model to match experimental findings and create new predictions. A perturbation analysis showed that wound contraction was most sensitive to collagen density and fiber stiffness, suggesting these are important design features of scaffolds. Collectively, these results will forward the multi-scale design and fabrication of mechano-instructive dermal scaffolds that promote skin regeneration while simultaneously reducing wound contraction. This work bridges experimental and computational tools, highlighting the increasing role of mathematical models in engineered tissue replacement design and their potential to contribute to more personalized wound therapies.