Nasal Organ Regeneration using Nanocomposite Material and Adipose Stem Cells

Background: The nose is a vital organ of the face facilitating breathing, smelling and central to a person's facial aesthetics. Each year, worldwide thousands of surgical operations are required to restore nasal defects caused by cancer, inflammatory conditions, trauma and congenital malformations. This devastating facial disfigurement causes significant psychological and physical difficulties for patients. The huge impact on patient's self esteem and confidence affects their social life, interpersonal relationships and ability to work. Children's educational and social development is affected by the multiple hospital admissions and reduced self-confidence. To replace a person's nasal organ, current surgical treatment involves harvesting tissue from elsewhere in the body and using this material to carve a new nose. These techniques cause pain, can fail and has many surgical risks. Artificial materials are currently available to restore nasal organs but with their high levels of infection, unnatural look and feel, they are not considered an acceptable alternative. There is an urgent need to find an alternative synthetic material for nasal regeneration, due the failure of current surgical treatment to repair nasal defects.

The University College London, Laboratory for Nanotechnology & Regenerative Medicine has an international reputation for developing organs and tissues using their unique man-made polymer and patients own stem cells. The synthetic material has already been extensively tested and found to be non-toxic and compatible for human use. Over the last five years our research group has already successfully applied our unique polymer with stem cells to aid the regeneration of several patient's organs. The polymer has been successfully used as the world's first adult windpipe, child's windpipe, adult tear duct and adult lower limb artery.

Aims and Objectives: We believe that our polymer is the ideal material to be used to restore nasal defects due its previous successful patient use and advantageous properties. Through this MRC research fellowship I endeavour to overcome the infection and patient dissatisfaction complications of current materials used for nasal regeneration. To achieve this I aim to match our polymer material to human nasal tissue so it has a natural appearance, feel and physical properties.

Benefits and Outcomes: This innovative technology will provide an alternative surgical treatment for nose reconstruction, which prevents the complications currently associated with this type of surgery. Our new surgical advancement will make a significant difference on patient's social, economic and physical quality of life. This project will be the foundation to understanding how to utilise our polymer as a facial organ creating a platform to develop further facial organs in the future including the ear and lip.

Nasal defects caused by cancer, congenital deformities and trauma give rise to huge psychological distress and physical morbidity. Current surgical restoration of nasal defects involves harvesting patient's own tissue, which causes large donor site morbidity, postoperative pain and restricted by tissue availability. The high levels of extrusion and infection limit alternative synthetic materials. Our nanocomposite polymer POSS-PCU has already replaced patient's organs as the World's First Synthetic Trachea, lacrimal duct and lower limb by-pass graft. This project aims to develop a nasal organ composed of POSS-PCU to overcome complications with current techniques available for nose reconstruction.
Objectives
To design POSS-PCU nasal organs that promote 1) tissue integration and 2) angiogenesis to overcome infection and extrusion.
Methodology:
1. Define the optimal porosity of the polymer for tissue ingrowth and angiogenesis based on the mechanical properties of the human nasal cartilage by implantation in a rat model.
2. Delineate the effect of plasma techniques to modify the surface chemistry of POSS-PCU to enhance fibroblast cell adhesion, survival and proliferation using immunofluorescence, RT-PCR and western blotting.
3. Based on preliminary data examine the role of adipose derived stem cells (ADSCs) for angiogenesis. After co-culture with ADSCs, endothelial cell survival and tube formation will be examined using confocal and scanning electron microscopy.
4. Determine vessel and tissue ingrowth of POSS-PCU after plasma and ADSCs treatment via in vivo implantation.
Scientific and Medical Opportunities
a. Understand how to optimise porosity and surface chemistry of nanomaterials for organ regeneration.
b. Improved understanding of the use of ADSCs to create vascularised tissue engineered organs.
c. Production of a stem cell nanocomposite nasal organ, which provides better clinical outcomes for patients requiring nose reconstruction.

National Health Service (NHS) / Patients
The main beneficiary of this research project, whose aim is to develop a POSS-PCU nasal organ in the long-term is the NHS and similar worldwide health care systems, the patient population and their families who require nasal reconstruction.
POSS-PCU nasal organs will overcome complications with current materials including infections and patient dissatisfaction. Consequentially, the NHS will create financial savings from the prevention of hospital admissions and repeated operations to treat surgical complications, reduced hospital stays and shortened operation times. With a reduction in operations times and treatment of complications, plastic health professional's time and expertise including surgeons, nurses and theatre staff, would be effectively optimised. Other health care systems would be able to initiate the implants, creating similar savings in resources.
The patients with nasal defects will benefit by having an alternative therapeutic surgical treatment, which has significantly better clinical outcomes. Patients will experience decreased postoperative pain and shorter hospital stay, providing a better social and financial outcome following treatment. With better quality of life following surgery, patients will be able to return to work earlier, improving the UK's economic effectiveness. For the paediatric population, generating nasal organs would be hugely significant as it would mean earlier surgery as they would not need to wait till they reached eight or nine years of age when they had sufficient tissue to replace the defect. In addition, using nanocomposite materials rather than patient's own tissue would mean a decreased hospital stay and number of operations, leading to enhanced quality of life for both the child and parent.

Regenerative Medicine
This project will be the foundation of creating other facial POSS-PCU organs including the ear, chin, lip and orbital floor. As highlighted in the regenerative medicine report in 2013, by parliament's Science and Technology Committee, translational research has the capacity to create new innovative therapies or cues when conventional approaches are failing. It was highlighted that despite regenerative medicine being supported in other countries, there is major concern the UK could fall behind in this area and miss opportunities to create new viable treatments using translational science. This project could potentially make UK a leader in facial regenerative research with potential funding from industry and commercial private funding for research funding bodies.

Regenerative/Biomaterial Scientists
This project will examine the role of plasma treatment to modify the surface of POSS-PCU to create chemical and topographical changes to promote cell adhesion. This knowledge is transferable to other medical device scientists such as the delivery of orthopaedic implants that promote new bone formation. By improving the understanding of the use of adipose stem cells for angiogenesis of POSS-PCU implants it is hoped delivering other vacularised medical implants could be developed. This project could subsequently drive forward other regenerative medicine strategies such as the emergence of synthetic vascularised bone grafts.

Commercial Private Sectors/Industry
Commerical private sectors may benefit in the short term if they provide funding for the preclinical trials, to ensure that the nasal implant reaches the clinical market. We are already in collaboration with several commercial companies (Flexicare Medical Ltd, UK, Pharmidex Ltd, UK, Biomaterials at Smith & Nephew, NuMED, USA) providing options for the commercialisation of the nasal organs. Private sectors/ industry will benefit in the long term from funding spin off companies as a result of other medical and engineering applications of POSS-PCU and plasma treatment of materials.