Adipose tissue engineering: Obesity disease model and soft tissue regeneration.

摘要

The need for physiologically relevant sustainable adipose tissue models is crucial for understanding tissue development and disease progression, in vitro drug and product development as well as for in vivo soft tissue regeneration.;Adipose tissue is a complex organ whose many roles are becoming better understood. Once thought of a static organ for energy storage, adipose tissue has now been discovered to have more dynamic roles, namely those in metabolism and endocrine signaling. Our understanding of its biology is crucial on many levels. Excess adipose tissue is linked to obesity, type II diabetes, increased cardiovascular risk and any associated co-morbidities. On the other hand, a lack of adipose tissue also carries its own metabolic consequences. Currently, adipose tissue biology is mainly studied in the context of monolayer in vitro cultures, or small animal in vivo studies. Both methods offer insight to the system, yet neither approximate the complex nature of human adipose tissue.;Adipose tissue also functions as a protective layer for our organs and maintains body contours. Soft tissue defects, most often are the result of trauma, congenital defects, or tumor removal. These defects have emotional and social consequences associated with the deformity and fear of not being accepted. One treatment for filling these defects is fat grafting. However, fat grafting, as with other fillers, does not retain volume over time, with 20-90% lost over the first few months. Therefore, there is a large unmet clinical need for a soft tissue filler that maintains its volume.;The goal of this research is to create a physiologically relevant adipose tissue construct to be used as an in vitro platform for studying tissue and disease development, as well as a platform for testing potential therapeutics. This adipose tissue construct can serve as a template for in vivo soft tissue regeneration.;In this dissertation the work centers on exploiting our knowledge of adipose tissue engineering and silk biomaterials. Silk biomaterials can be processed to have a range of physical, mechanical and degradation profiles. Our long-term vascular adipose tissue construct served as a foundation for further long term studies in obesity modeling as well as for soft tissue regeneration. The long-term vascular adipose tissue maintained adipose-like outcomes over a 6 month period, and was improved by dynamic culture. From this, we developed a model of diet-induced obesity by challenging this system with free fatty acids and monocytes to generate inflammation. This model is in line with clinical readouts and can be generated from a patient's own cells. We showed we use therapeutics to try and reverse the inflammatory cascade of obesity. Finally, our in vivo 18 month study was the first to show that we can maintain volume while actually regenerating tissue when silk sponges are soaked with lipoaspirate. This model now is being translated into injectable formats to be minimally invasive. Ongoing pre-clinical studies are underway in a horse model for soft tissue regeneration.