Evaluation of next generation nanocomposite polymer coated stents incorporating stem cell capture technology for enhanced in situ endothelialisation.

Lead Research Organisation: University College London
Department Name: Surgery

Abstract

Over 3 million people in the UK suffer from cardiovascular disease causing over 150,000 premature deaths in people under the age of 75. Restriction of blood flow and blockage of blood vessels surrounding the heart leads to interruption of the blood supply to the heart muscle causing heart cells to die. The oxygen shortage, if left untreated can cause damage or death of the heart muscle resulting in heart attack or complete heart failure. Narrowing of the blood vessels in the legs can lead to blockage, amputation and limb loss if left untreated. Patients requiring amputation face a diminished quality of life and severe disability. The primary goal is to restore at least one straight line of blood flow by using a stent depending on the degree of obstruction. The application of stenting is carried out using a minimally invasive approach. A stent is a small mesh tube that is inserted using a catheter, and is deployed at the same time as a balloon is inflated across the diseased vessel wall. The stent acts as a scaffold to hold open the artery to restore blood flow. However, severe healthcare concerns have been raised with current stents, which release drugs through localised allergic reactions, chronic swelling (inflammation) and repeat episodes of thrombosis (or blood clotting), which requires a lifetime prescription of anti-platelet and blood thinning medication causing unwanted side effects followed by repeat surgery. To overcome the current problems with stenting, we plan to build upon our knowledge and expertise to deliver a new generation of stents by developing two products: 1) a novel surface coating with tiny particles embedded in a polymer or plastic coating called nanocomposite polymers, and 2) inclusion of capture antibodies (present on the surface of cells) in to the coating layer to capture stem cells from the circulating blood and converting it to endothelial cells from shear flow, the endothelial is type cells cover entire our cardiovascular system , to protect from blood thrombosis.

The nanocomposite polymers have already undergone extensive testing in the laboratory, and in animals demonstrating that the polymer can be potentially used safely in humans. For example, we developed a range of surgical implants using nanocomposite polymers with a number of successful outcomes, such as the world's first synthetic wind pipe over 2.5 years ago and the patient is doing very well, 6 tubes that drain the tears (lacrimal duct) have been carried out in patients to date, and coronary artery bypass graft using same materials has started at Heart Hospital, heart valves at the preclinical. We have already optimised the polymer coating for stents, and in this study our plan is to carry out a final assessment of coated stents and compare them with currently used stents (as product 1). Pre-clinical animal studies will be used to evaluate their effectiveness application in humans. The development of product 2 is at the proof-of-principle stage. Here, we carry out preliminary tests using antibodies (raised against circulatory stem cells in the blood) incorporated in to the polymer coating for capturing stem cells from the blood, and perform tests to obtain sufficient data to apply for funding towards pre-clinical studies. This proposal will enable us to test polymer coated stents in preparation for first-in-man studies after consultation with the MHRA (UK regulatory agencies) and FDA. We will then be in a strong position to apply for funding towards clinical trials, which can be implanted in humans. The development of a new generation of nanocomposite polymer coated stents, which prevent thrombosis along with the inclusion of stem cell capture technology to enhance endothelisationcells would have a significant impact on the global economy, as individuals affected will be active in the workforce for longer, enjoy a greater quality of life and reduce the strain on vital healthcare resources.

Planned Impact

CVD remains the most common cause of death worldwide claiming over 17 million lives annually. Blockage of the coronary arteries leads to heart attack and complete heart failure, while narrowing of the vessels that supply the legs result in amputation and limb loss if left untreated. Surgical intervention through percutaneous coronary intervention (PCI) use angioplasty and stenting to restore blood flow by inflation of a balloon catheter. However, recent concerns with DES involving allergic reactions, repeat episodes of stent thrombosis, and a lifetime prescription of dual anti-platelet therapy (DAPT) followed by unwanted side effects have led the search for better alternatives. We have developed a new generation of nanocomposite polymer (POSS-PCU) coated stents with enhanced material properties, which are biostable, durable, biocompatible and possess anti-thrombogenic surface properties similar to the native arteries. We use the same nano-inspired platform technology for conjugation of antibodies to capture EPCs from circulatory blood to enhance endothelial healing via in situ endothelialisation. Such developments will have a significant impact on UK industry and global economy, as affected individuals will not only be active in the workforce for longer, but will enjoy a greater quality of life. The impact on higher education will be achieved by an improved understanding of nanocomposite polymers along with new bioengineering strategies in stent design. The new knowledge acquired will be disseminated in fields ranging from the physical sciences, engineering, materials, cell biology, radiology and surgery to develop strong links with leading institutions of research excellence. Such a new understanding will become an integral part of teaching and learning through specialised lectures and research projects will provide expert training to postgraduate students through publications, conferences and press releases. The PI at UCL has an excellent track record in generating impact through translational research from the laboratory to the clinic (e.g. bypass grafts, tracheal airway replacements, lacrimal duct conduits and many other organs in development), and in training and career progression of postgraduate and early career researchers. We expect these benefits to become evident after the project launch with close cooperation of a diverse team of industrial, scientific and surgical specialists. The impact on public awareness will be achieved through outreach activities such as presentations to schools, patient charities, and stalls at public and scientific festivals and applications to exhibit our research at the Royal Society Summer Exhibition (2014). In February 2014, we are organising the Nanosmat conference at the UCL, which is an international conference in Nanomedicine and Regenerative Medicine with over 250 delegates registered from over 25 different countries. The impact in the commercial sector will be huge as the research will impact on other applications in the human body such as transcatheter heart valves, haemodialysis equipment and cardiac patches. All academic, industrial and clinical project partners are keen to commercialise next generation stents using nanocomposite polymers incorporating stem cell capture technology, and have a purpose built GMP/GLP facility to carry out this research. UCLB with their experience in protecting intellectual property (IP) and established contacts within the specialist healthcare industry and investment sector will drive exploitation of new knowledge that is generated. Impact in the public and healthcare sector will benefit healthcare professionals, who will be able to implement new treatments and therapies in patients with CVD. This will benefit patients in general and improve clinical outcomes, and NHS systems will benefit (through cost and efficiency) from simpler/shorter surgery, recovery and rehabilitation times and will ease the strain on vital healthcare resources.

Publications

10 25 50
 
Description We have found that the nanocomposite stent coatings (product 1) minimises inflammation at the 12 month stage in a large animal model under GLP. We are actively seeking sponsorship to prepare for clinical trials for the nanocomposite coated stent platform. We have also developed a further two base platforms for coating stents, 1) a pro-healing stent coating (product 2), and 2) a drug eluting stent coating (product 3), which are at the in vivo stage of testing, and will be ready for pre-clinical studies in 2018.
Exploitation Route Product 1 - Application for a clinical trial & Product 2-3 - Application for a pre-clinical study. We are ready to take some of the technology developed in this project through a clinical trial and take this study through to full commercialisation.
Sectors Education,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description The persistence of thrombosis and poor endothelialisation of stents in large cohorts of patients highlight unmet clinical needs despite the evolution of new categories of bioabsorbable, biodegradable or drug eluting stents. Cost effective strategies, now in demand, which prevent thrombosis, inflammation and intimal hyperplasia and promote in situ endothelialisation have led the search for suitable alternatives for the next generation of small diameter stents. A non-biodegradable nanocomposite polymer to create platform technology comprised of polyhedral oligomeric silsesquioxane nanoparticles incorporated into poly (carbonate-urea) urethane (PCU) has been developed. Incorporation of nanoparticles into PCU confers unique material properties, which enhances their mechanical strength and results in long-term hydrolytic and oxidative stability in vivo with increased resistance to biodegradation. The nanocomposites have undergone extensive biocompatibility and toxicology tests in vivo in an ovine model over a 3 year period, which demonstrates cytocompatible and anti-thrombogenic properties with no signs of degradation, calcification or inflammation within the host tissue. In this study, we hypothesise that using PCU nanocomposites with mechanical properties similar to the native vessels would represent an ideal platform for next generation coated stent technologies with enhanced biocompatibility and could minimise post-stenting complications such as thrombosis and re-stenosis, and improve the quality of life to patients. We have found that the nanocomposite stent coatings minimise inflammation at the 12 month time period in a large animal model under GLP. We are actively seeking sponsorship to prepare for clinical trials for the nanocomposite coated stent platform. We have also developed two further base platforms for stents, 1) a pro-haling stent coating, and 2) a drug eluting stent coating, which are both as the in vivo stage of testing, and will be ready for pre-clinical studies in 2018.
First Year Of Impact 2014
Sector Education,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Societal

 
Description Department of Science & Technology (India)-UK-India Education and Research Initiative (UKIERI) - DST-UKIERI Fund
Amount £199,714 (GBP)
Funding ID Ref 54/2017 
Organisation British Council 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2017 
End 03/2020
 
Description Newton Bhabba Scholarship
Amount £10,000 (GBP)
Organisation British Council 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2016 
End 05/2016
 
Description Royal Free Charity Grant
Amount £26,460 (GBP)
Organisation Royal Free Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2017 
End 06/2017
 
Title A small animal stenting model for testing small diameter stents in vivo 
Description We have developed a small animal model using the aorta as a stenting model for testing small diameter stents in vivo 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2016 
Provided To Others? Yes  
Impact The procedure is reliable and reproducible in accordance with the 3Rs principle. The procedure is simple and easily achievable and less costly compared to conventional methods. 
 
Description Biomer Technology Ltd 
Organisation Biomer Technology
Country United Kingdom 
Sector Private 
PI Contribution Supply materials for GMP polymer synthesis.
Collaborator Contribution Due to meet and discuss the supply of materials for GMP polymer synthesis.
Impact Due to meet and discuss the supply of materials for GMP polymer synthesis.
Start Year 2015
 
Description Boston Scientific 
Organisation Boston Scientific
Country United States 
Sector Private 
PI Contribution Development of novel stent coatings
Collaborator Contribution Provision of stents and supplies to evaluate coated stents and explore the science.
Impact Multi-disciplinary collaboration due to meet and discuss study results.
Start Year 2015
 
Description CSIR - Institute of Minerals and Materials 
Organisation Indian Institute of Technology Indore
PI Contribution CSIR - Institute of Minerals and Materials initiated thorough similar research interests for the environment and healthcare
Collaborator Contribution Initiated projects relating to diagnostics and sensing technologies of toxic heavy metal ions.
Impact Successful Newton Bhabba Award. Successful DST-UKIERI Award for both partners.
Start Year 2016
 
Title Nanocomposite stent coatings 
Description Pre-clinical evaluation of nanocomposite coatings was successful with minimal inflammation and some migration at the 12 month stage of development. Actively seeking support for clinical trials after study documentation complete. 
Type Therapeutic Intervention - Medical Devices
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2017
Development Status Actively seeking support
Impact Pre-clinical evaluation of nanocomposite coatings was successful with minimal inflammation and some migration at the 12 month stage of development. Actively seeking support for clinical trials after study documentation complete. 
 
Title Polymer Nano-island Coating 
Description Evaluation of polymer nano-island stent coating for drug delivery with favourable haemocompatibility and enhanced endothelialisation. At the in vivo stage of testing for a 1 month pilot study. Actively seeking support for pre-clinical trials after study documentation complete. 
Type Therapeutic Intervention - Medical Devices
Current Stage Of Development Initial development
Year Development Stage Completed 2017
Development Status Under active development/distribution
Impact Evaluation of polymer nano-island stent coating for drug delivery with favourable haemocompatibility and enhanced endothelialisation. At the in vivo stage of testing for a 1 month pilot study. Actively seeking support for pre-clinical trials after study documentation complete. 
 
Title Prohealing stent 
Description Evaluation of prohealing stent coatings was successful with haemocompatibility and enhanced endothelialisation. At the in vivo stage of testing for a 1 month pilot study. Actively seeking support for pre-clinical trials after study documentation complete. 
Type Therapeutic Intervention - Cellular and gene therapies
Current Stage Of Development Initial development
Year Development Stage Completed 2017
Development Status Under active development/distribution
Impact Evaluation of prohealing stent coatings was successful with haemocompatibility and enhanced endothelialisation. At the in vivo stage of testing for a 1 month pilot study. Actively seeking support for pre-clinical trials after study documentation complete. 
 
Description Invited Talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Next Generation Biomaterials Inspired By Nanotechnology. Invited Talk: CSIR- Institute of Minerals and Materials Technology & Indian Institute of Chemical Engineers (IIChE) Bhubaneshwar, Odisha, India (Mar 2018).
Year(s) Of Engagement Activity 2017
URL https://twitter.com/Cousins_BrianG
 
Description Next Generation Coronary Artery Stent Devices 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Next Generation Coronary Artery Stent Devices. Invited Talk: Indian Institute of Technology (IIT), Indore, India (Feb 2018).
Year(s) Of Engagement Activity 2017
 
Description Workshop 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Study participants or study members
Results and Impact Discussions in vascular biology and endothelialisation under flowing conditions, and successful ways how to measure and monitor successful outcomes.
Year(s) Of Engagement Activity 2017