Graduation Year

2020

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Biomedical Engineering

Major Professor

Piyush Koria, Ph.D.

Committee Member

William Lee, Ph.D.

Committee Member

Nathan Gallant, Ph.D.

Committee Member

Mark Jaroszeski, Ph.D.

Committee Member

Joseph Walton, Ph.D.

Keywords

Drug-Delivery, Elastin-Like-Peptide, Engineering, Nanomedicine, Protein

Abstract

Chronic wounds are those wounds which are refractory to treatment, often taking years to heal. These wounds are complex and may present with elevated protease levels, resulting in rapid degradation of growth factors, both native and augmented via treatment. This study’s focus was the development of a system to protect growth factors from protease mediated degradation.

The protective system consisted of chimeric fusion proteins developed to contain both a growth factor or known protease inhibitory peptide and an Elastin-Like-Peptide (ELP)component. The unique phase transitioning abilities of the ELP component allowed for the self-assembly of these chimeric fusion proteins into a heterogenous nanoparticle which puts the inhibitory component near the growth factor.

These developed heterogenous nanoparticles showed success in protecting and preserving the growth factor in highly proteolytic environments as well as in human chronic wound fluid. Treatment with these nanoparticles in a protease augmented diabetic mouse model were found to result in enhanced collagen remodeling and resolution of inflammation.

This system is novel as it places the protease inhibitor in close proximity to the growth factor, allowing for inhibition of proteases in the immediate environment surrounding the growth factor. In addition, this system is highly modular, allowing for the protection of multiple growth factors using the same inhibitor, without having to alter the amino acid sequences of each individual growth factor.

Our results suggest that the developed protective system holds tremendous promise and potential in the field of wound healing therapy and may help bridge the translation of growth factor therapies to the clinic. In addition, the modular nature of this nanoparticular system allows for the opportunity to customize protective systems across several fields in research and medicine.

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