Date of Award

Spring 5-2018

Embargo Period

5-8-2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Engineering

Advisor(s)

Keith Cook

Abstract

Inhaled drug delivery is currently the gold standard for treating many respiratory diseases. However, improved treatments are needed for lung diseases like Cystic Fibrosis (CF) and Acute Respiratory Distress Syndrome (ARDS), where mucus or fluid build-up in the lung limits ventilation and, thus, delivery of inhaled drugs. Delivery is most needed in the diseased or damaged regions of the lung, but if an area is not ventilated, inhaled drug will simply not reach it. To overcome this, this research proposes delivering drugs to the lungs within a perfluorocarbon (PFC) liquid. The lungs will be filled with a reverse emulsion containing a disperse phase of aqueous drugs within the bulk PFC and then ventilated. The PFC functions as both a respiratory medium, providing gas exchange, and as a delivery vehicle, providing a more uniform deposition of drugs. After treatment, the highly volatile PFCs are exhaled, returning the patient to normal respiration. This technique improves upon current therapies as follows. First, drugs are delivered directly to where they are needed, yielding higher concentrations in the lung and lower systemic concentrations. Second, PFCs are ideal for washing out lung exudate and mucus. The low surface tension and high density of PFC allows it to easily penetrate plugged or collapsed alveoli, detach infected mucus from the airway walls, and force these fluids to the top of the lungs where they can then be removed via suction. Mucus and exudate removal should allow drugs to penetrate previously plugged airways during emulsion delivery and subsequent treatment with inhaled therapies. Thus, drug delivery via emulsion would be used as a pre-treatment to enhance inhaled or systemic drug therapy. Third, PFC’s anti-inflammatory properties help return to normal lung function. This research examines two applications of this technology: delivery of antibiotics to combat respiratory infections (antibacterial perfluorocarbon ventilation, APV) or delivery of growth factors to enhance alveolar repair (perfluorocarbon emulsions for alveolar repair, PEAR). This work represents an in-depth analysis of the emulsions used during APV and PEAR. Initial efforts evaluated emulsion efficacy under in vitro setting that better simulated lung in vivo antibiotic delivery. The subsequent studies utilized an in vivo rat model of bacterial respiratory infection to validate the effects of emulsion on pharmacokinetics and to assess APVs potential treatment benefits. Lastly, in vitro methods of cellular response assessed the utility of delivering growth factors in PEAR. Significant advancements were made in optimizing the emulsion as a viable means of pulmonary drug delivery. Final efforts resulted in a promising emulsion formulation that overcame the quick transport of tobramycin away from the lung and successfully reduced pulmonary bacterial load in vivo. In vitro applications of PEAR showed the emulsions posed a significant barrier to the availability and, thus, the biological effect of lysophosphatidic acid growth factors. Further in vivo work is required to improve APV’s efficacy over conventional treatments and to determine PEAR’s feasibility and efficacy in promoting lung repair.

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