Formulation of reactive oxygen delivery systems

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Hall, Thomas ORCID: https://orcid.org/0000-0002-4414-1353 (2020). Formulation of reactive oxygen delivery systems. University of Birmingham. Ph.D.

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Abstract

Antibiotics are vital to modern medicine, helping to protect patients from infection. However, antimicrobial resistance (AMR) is growing at an unprecedented rate, with 10 million people predicted to die annually from resistant infections by 2050.

Honey has been used for thousands of years for topical wound care applications. However, delivering natural honey as an antimicrobial can see its effects differ greatly from batch to batch. Herein, a bioengineered antimicrobial honey (SurgihoneyRO - SHRO) with promising antimicrobial activity was used to circumvent such issues and enable consistent dosing. The antimicrobial properties elicited from SHRO are predominantly owed to the production of reactive oxygen species (ROS), such as hydrogen peroxide (\(H_2O_2\)), by means of a water-sensitive enzymatic reaction. Much like honey, SHRO is an adherent, highly viscous product, limiting clinical use and application. This thesis aims to overcome these issues by developing a fundamental understanding of SHRO and engineering novel delivery systems that ease application, allow for in situ activation of ROS and maintain antimicrobial efficacy.

This work demonstrates three systems that are capable of locally delivering efficacious doses of ROS to a wound site. These systems include: 1) the formulation of ROS producing emulsions which have the ability to trigger the therapeutic generation of \(H_2O_2\) (0.7 – 4.2 μmol g\(^{-1}\)), over 24 hour and display viscosities between 1.4 and 60.7 Pa· s at a shear rate of 4.1 s\(^{-1}\) by varying dispersed phase volumes (30-60%) and adding thickening agents. This flexibility allows for the tailoring of specific applicational mechanisms, such as that of a spray or a cream. 2) the formulation of ROS producing superabsorbent powders with a capacity to absorb up to 120.7 mL g\(^{-1}\) of water and generate 3.1-5.2 μmol g\(^{-1}\) of \(H_2O_2\) in a 24 hour period. In addition to tackling topical infections this system also has the potential to simultaneously provide a protective environment and stimulate wound healing. 3) the formulation of an implantable ROS producing calcium sulphate bone cement capable of generating up to 0.7 μmol g\(^{-1}\) of \(H_2O_2\) over 24 hours. In addition, this system demonstrates compressive strengths comparable to trabecular bone (32.2 MPa), highlighting it’s in vivo suitability. Each of these formulations has been tested in vitro against clinically relevant, World Health Organisation priority pathogens, namely Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Overall this thesis demonstrates the potential to reduce reliance on traditional antibiotics by exploiting formulation engineering to aid society in the fight against AMR.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):