Dr J Chan, Prof Constantin Coussios, Prof A Carr
No more applications being accepted
Competition Funded PhD Project (Students Worldwide)
About the Project
Reference Number: NDORMS 2018/8
Themes;
• Bone & joint
• Infection & Immunology
• Bioengineering
• Drug delivery
Deep bone and joint infections (DBJI) represent a huge unmet clinical need. Most commonly they occur as a complication of joint replacement surgery, open fracture and diabetic foot wounds. They are poorly treated and increasingly prevalent in the ageing population. Bone infection, otherwise known as osteomyelitis (OM), is characterized by progressive inflammatory destruction of bone. Similar to cancer treatment, a multidisciplinary approach combining chemotherapy, in the form of prolonged antibiotic therapy, with surgical excision and reconstruction is critical to achieve infection-free, functional limb salvage. Inadequate treatment is associated with significant recurrence rates of up to 44%. DBJI have a major impact on quality of life as well as life expectancy and incur an enormous socioeconomic burden as its treatment is hugely resource intensive.
Poor drug delivery at the site of infection is a major limiting factor in DBJI treatment. The combination of poor vascularity in chronically inflammed and fibrosed tissues, together with the development of biofilm, are the major barriers to antibiotic penetration. In OM, increased osseous pressure and thrombosed vessels impair blood flow. Antibiotic penetration becomes rapidly compromised and absent in necrotic bone. In addition, the major causative microorganisms including Staphylococcus aureus adhere strongly to bone, cartilage and implants by expressing adhesins, form biofilm, survive intracellularly within osteoblasts and develop antibiotic resistance. Antibiotic concentrations required to penetrate and kill bacteria enclosed in biofilm are 10-100 times the standard bactericidal concentration, often making systemic therapy unsafe and ineffective. Furthermore, as the immunological environment is critical to tissue repair[1-4], the hyperinflammatory microenvironment is destructive to bone healing.
Enhancing target-site penetration of antibiotics would dramatically improve the management of DBJI. This could potentially limit the need for radical surgery, duration and risk of toxic effects of prolonged antibiotic treatment, as well as rates of recurrence. Furthermore, for the significant subset of elderly patients who are not candidates for major surgery due to multiple co-morbidities, this strategy would enable their condition to be safely controlled with antibiotics alone.
There is currently no means to improve drug delivery in a non-invasive manner in DBJI. Various drug-eluting materials including cement for joint prosthesis and bone graft substitutes have become commercially available. However, such treatment requires surgical access and the limited, uncontrolled passive release of a single antibiotic is suboptimal, especially when a significant proportion of cases (29%) are polymicrobial. The local diffusion of antibiotics is limited in time and space and there is currently no controlled study to investigate its efficacy.
A transformative solution is therefore required that can improve drug delivery in a non-invasive manner for DBJI by (i) facilitating the disruption and penetration of high concentrations of the therapeutic in biofilm and (ii) enhancing the transport of the drug away from vasculature throughout the bone.
Many of the challenges encountered in the local delivery of drugs are common to DBJI and cancer, including the hypoxic, hypovascular inflammatory microenvironment with large extravasation distances to reach the cellular targets. The application of focused ultrasound (FUS) and nanoscale inertial cavitation to enhance drug delivery[5], led by Prof Coussios, has already enabled step changes in the delivery, transport, penetration and efficacy of therapeutic antibodies, viruses or small-molecules in the context of oncological drug delivery[6, 7]. Similar advantages have been achieved in transdermal drug delivery[8], demonstrating successful transport across the impenetrable stratum corneum to reach the epidermal and dermal layers. The advantages of ultrasound-mediated cavitational transport include the ability to enhance delivery of any antibiotic present in the bloodstream non-invasively and repeatedly, under real-time imaging guidance. The ultrasound exposure and associated cavitation activity does not cause any alteration in the structure or activity of the transported drugs and does not cause any direct therapeutic effects not related to the mode of action of the drug.
*Our overall mission is to apply FUS-mediated acoustic cavitation to enhance antibiotic delivery in DBJI and improve patient outcomes. The aim for this project is to validate this concept pre-clinically and design a device that is fit for purpose in patients with DBJI in preparation for a first-in-man Phase I clinical trial.*
Training Opportunities
The Botnar Research Centre plays host to the University of Oxford's Institute of Musculoskeletal Sciences, which enables and encourages collaborative research and education into the causes of musculoskeletal disease and their treatment. The Oxford Institute of Biomedical Engineering offers a world-class venue for biomedical engineering research and postgraduate training where engineers and clinicians work together on addressing unmet healthcare needs. There is a strong emphasis on translating new engineering technologies into clinical practice.
The DPhil candidate will be jointly supervised by Dr. James Chan, Prof. Andrew Carr and Prof. Constantin Coussios. Dr. Chan is an academic reconstructive plastic surgeon with expertise in bone biology, immunology and animal models. Prof. Carr is Nuffield Professor of Orthopaedics and Head of NDORMS with extensive experience in bench-to-bedside translational research. Prof. Constantin Coussios is Director of the Oxford Institute of Biomedical Engineering and has successfully taken a number of drug delivery devices to clinical trials.
The project will use a combined in vitro and in vivo approach to maximize translational potential. We will test the disruption and penetration of antibiotic in biofilm using ultrasound-mediated cavitational transport in vitro. The student will learn cell culture techniques and in vivo mouse models of biofilm, OM and prosthetic joint infection to test drug delivery, efficacy and outcomes. He/she will be fully trained in a range of immunological, biomedical engineering and molecular biology techniques and develop expertise across both therapeutic and diagnostic ultrasound. The DPhil programme includes a core curriculum of 20 lectures in the first term of Year 1 to provide a solid foundation in musculoskeletal sciences, immunology and data analysis.
For further information
Contact:
Dr. James Chan
Prof. Constantin Coussios
Email:
[Email Address Removed]
[Email Address Removed]
Webpages:
https://www.ndorms.ox.ac.uk/team/james-chan
http://www.ibme.ox.ac.uk/research/non-invasive-therapy-drug-delivery/people/professor- constantin-c-coussios
https://www.ndorms.ox.ac.uk/team/andrew-carr
References
1. Chan, J.K., et al., Low-dose TNF augments fracture healing in normal and osteoporotic bone by up-regulating the innate immune response. EMBO Mol Med, 2015. 7(5): p. 547-61.
2. Chan, J.K., et al., Alarmins: awaiting a clinical response. J Clin Invest, 2012. 122(8): p. 2711-9.
3. Glass, G.E., et al., TNF-alpha promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells. Proc Natl Acad Sci U S A, 2011. 108(4): p. 1585-90.
4. Chan, J.K., et al., Soft-tissue reconstruction of open fractures of the lower limb: muscle versus fasciocutaneous flaps. Plast Reconstr Surg, 2012. 130(2): p. 284e-295e.
5. Kwan, J.J., et al., Ultrasound-Propelled Nanocups for Drug Delivery. Small, 2015. 11(39): p. 5305-14.
6. Carlisle, R., et al., Enhanced tumor uptake and penetration of virotherapy using polymer stealthing and focused ultrasound. J Natl Cancer Inst, 2013. 105(22): p. 1701-10.
7. Myers, R., et al., Polymeric Cups for Cavitation-mediated Delivery of Oncolytic Vaccinia Virus. Mol Ther, 2016. 24(9): p. 1627-33.
8. Bhatnagar, S., et al., Exploitation of sub-micron cavitation nuclei to enhance ultrasound-mediated transdermal transport and penetration of vaccines. J Control Release, 2016. 238: p. 22-30.
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