Date of Award

August 2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical and Chemical Engineering

Advisor(s)

Dacheng Ren

Second Advisor

Liviu Movileanu

Keywords

Antibiotic susceptibility, BIA-ALCL, Biofilm, Biofilm removal, Shape memory polymer, Surface topography

Subject Categories

Engineering

Abstract

Biofilms are multicellular structures with bacterial cells attached to a surface and embedded in an extracellular matrix. With high-level resistance to antimicrobial agents, biofilms are the cause of chronic infections associated with implanted medical devices such as breast implants, orthopedic devices, pace markers, and many others. Besides the prevalence, biofilm infections are associated with high mortality, presenting an urgent need for more effective controls. Several strategies such as coating with antimicrobial agents and changing chemical, physical, and biological properties of biomaterials have been attempted, but bacteria have remarkable capabilities to overcome unfavorable conditions over time and long-term biofilm control remains challenging. In addition, most approaches are based on empirical experiments rather than rational designs, limiting their effects, especially in vivo.

In this study, we engineered surface topography in two ways (static and dynamic) to better understand and control bacterial biofilm formation. For the static surface topography, a high-throughput approach to study bacterial attachment on PDMS surfaces with different textures was developed. By testing bacterial adhesion to samples with square-shaped recessive patterns with varying size and inter-pattern distance, surface features that promote biofilm formation were identified. E. coli attachment did not exhibit a monotonic, linear relationship with surface area, but depended on the 3D topography.

For dynamic surface topography, we used shape memory polymers (SMPs) to obtain on-demand dynamic changes in substratum topography. Our results show that shape recovery of tert-butyl acrylate (tBA) based one-way SMP caused 99.9% detachment of 48 h Pseudomonas aeruginosa PAO1 biofilms. Interestingly, P. aeruginosa PAO1 biofilm cells detached by shape recovery showed 2,479 times higher antibiotic susceptibility compared to the original biofilm cells. The released biofilm cells also presented 4.1 times higher expression of the gene rrnB, encoding ribosomal RNA, and 11.8 times more production of adenosine triphosphate (ATP) than the control biofilm cells.

To further develop this technology for long-term biofilm control, we synthesized reversible SMP with different molecular weights of poly(ɛ-caprolactone) diisocyanatoethyl dimethacrylate (PCLDIMA), with 25 wt.% of butyl acrylate (BA) as a linker, and 1 wt.% of benzoyl peroxide (BPO) as a thermal initiator. Among various combinations of molecular weight, 2:1 wt. ratio mixture of 15,000 g/mol PCLDIMA and 2,000 g/mol PCLDIMA showed a transition temperature of 36.7°C. The created rSMP has repeatable and reversible shape recovery for more than 3 cycles. With 18% stretch, 61.0±6.6% of 48 h P. aeruginosa PAO1 biofilm cells were removed in each shape recovery cycle on average, with a total of 94.3±1.0% biofilm removal after three consecutive shape recovery cycles.

In summary, the results of this study demonstrated that surface topography has potent effects on bacterial adhesion and biofilm formation. We believe that these results not only provide important information for understanding the risk of medical devices but also helps the design of control methods for preventing chronic infections associated with implanted medical devices.

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