Hybrid approaches to tissue engineering

Lead Research Organisation: Imperial College London
Department Name: Materials

Abstract

Our life expectancy is increasing and we are outliving our skeletal tissues. There is a need for orthopaedic surgery to move from replacement of tissues to regeneration. To do this medical devices are required that can stimulate the body's own healing mechanisms. Over the last 10-15 years, tissue engineering has promised that combining engineering principles with cells will lead to regeneration of tissues, however skin is the only tissue engineered product used clinically. The reasons skeletal tissue engineering has not been successful is that materials have not been developed that fulfill all the engineering design criteria for regenerative device (scaffold) and how materials interact with cells is not fully understood. A new hybrid approach is proposed where hybrid refers to an integrated interdisciplinary approach and the innovation in materials engineering that is needed. New materials must be developed that mimic the mechanical properties and structure of natural tissues. The aim is to build an interdisciplinary research team that can deliver high impact step changes in the way tissue engineering research is carried out to make skeletal tissue engineering a clinical reality. Team members will have expertise in materials chemistry and processing, multi-scale characterisation, materials modelling, cell biology, orthopaedic surgery and technology transfer. The adventurous programme will benefit the UK by improving the quality of life of patients, increasing the efficiency of orthopaedic surgery, reducing surgical costs and boosting the UK economy by ensuring patients recover and return to work more rapidly.The core platform technology will be novel nanostructured (hybrid) materials that can be designed to stimulate bone growth or cartilage regeneration before they are remodelled in the body and replaced by natural healthy tissue. To make these complex materials a clinical reality they must be understood from the atomic through the nano to the macro level and optimised with respect to cellular response. Computer models and improved characterisation methods are needed. Bone scaffolds must stimulate stem cells to produce bone and new ways of growing cells in devices may be necessary in order for blood vessels to grow throughout bone scaffolds and for cartilage regeneration to become a reality. If new devices are to reach the clinic, technology transfer must be considered. My vision is to build and lead a world renowned research group successful in musculoskeletal tissue engineering with a new field of inorganic/ organic hybrid materials engineering at its core. The research group will attract best, internationally leading researchers to the UK (or to stay in the UK). It will involve international and UK collaborators, with the UK at the focus, placing it at the forefront of biomaterials and tissue engineering. There will be focus on developing a dynamic and supportive research environment and on developing the career of group members so they will become the next leaders of the new fields that will evolve from the group's work.

Planned Impact

There are several target groups that will benefit directly from this research. Orthopaedic, neurological and plastic surgeons, patients and health services (e.g. the NHS) will benefit as end users. Patients and UK economy will benefit as patients recover more rapidly and to a fuller extend, allowing them to return to work more rapidly. Medical device companies will benefit from potentially market leading products and new tools for their quality assurance. Currently, the NHS performs 60 000 hip (600 000 worldwide) and 70 000 knee replacements (>1M wordwide) annually due to degenerating cartilage. Unfortunately the implants eventually fail (usually after 15-25 years) and revision operations are common, causing patients intense pain and lack of mobility. Revision operations cost the NHS 2-3 times that of the initial operation. This research programme has the potential to create devices that can regenerate diseased cartilage so that the number of joint replacements and therefore revision operations are drastically reduced. 25 000 bone graft operations are carried out in the UK annually (>1M worldwide). Current best practice for surgeons is to take bone from the pelvis and move it to the defect (autograft). Problems are that the supply of bone is limited and there is donor site morbidity. After the operation, the pelvis is extremely painful, recovery time is long (4 weeks to 6 months) and 46% of people have complications that require further treatment, many needing revision operations. Autograft procedures also require two clinicians in theatre. There is therefore a clinical need for synthetic grafts that regenerate bone defects to healthy natural bone. Orthopaedic surgeons require a new device that is a porous construct that stimulates bone growth but is tough and has some flexibility. Surgeons also want to be able to cut the device to shape during the operation and be press-fit into bone defects.These devices will reduce recovery time by stimulating the regenerative process, thereby improving healing rate and removing the need to harvest the bone before implantation, reducing operation time, which will save the NHS 100M per year alone. A reduction in associated secondary disease treatment is particularly pertinent in the context of the UK's aging population, who will benefit from improved the quality of life, reducing the burden on a heavily overloaded social care system. The devices for bone regeneration have the potential to fill 10-15% of the $500M global market. If successful cartilage regeneration to be achieved, the market would be significantly higher. Companies must invest in the materials and take them through regulatory approval. The intellectual property generated will be filed by Imperial Innovations and licensed by the collaborating companies, e.g. RepRegen Ltd., (London), contributing to the growth of the UK's strategically important biosciences industry. They will also form partnerships with larger medical device companies (e.g. NovaBone and Stryker), increasing the adoption rate of the new materials. To ensure that the materials are designed to meet the end user's needs, I have collaborations with leading surgeons within the Imperial College Medical School with whom I meet regularly to discuss their needs and latest results. Progress will be communicated to other surgeons via presentation sessions and through high impact publications. Progress will be communicated to the general public by building on my current media contacts, having recently given interviews to BBC Radio and the Daily Mail. The Victoria and Albert Museum will benefit as they have included a scaffold in their new permanent exhibition of ceramics. Outreach activities, in conjunction with Lord Robert Winston's Outreach Laboratory, will encourage more high quality students to join the fields of materials science and engineering and tissue engineering and aim to increase the number of female scientists.

Publications

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Fiedler T (2014) A comparative study of oxygen diffusion in tissue engineering scaffolds. in Journal of materials science. Materials in medicine

 
Description Silica/PCL hybrids have unique mechanical properties: the "glass" can bounce and be hit with a hammer. They also have self-healing properties.

When cartilage cells are grown on 3D printed silica/PCL hybrid of defined pore size, type II collagen is produced that is indicative of articular cartilage.

Hybrid scaffolds can be produced by 3D printing directly from the sol. A new 3D printing technique was developed.

Using co-cultures of cells inside silica/ gelatin hybrid foam scaffolds, vascular networks were grown inside scaffolds.

Monodispersed bioactive glass nano particles, with control of particle size, can be synthesised from a modified Stober process, but it is challenging to introduce cations into the nano particles at high concentrations. When the particles are introduced to stem cells, they were internalised but did not trigger differentiation or toxicity.

When macrophage cells are seeded on bioactive glass sol-gel scaffolds, they differentiate into osteoclasts and remodel the scaffolds.

In vivo performance of sol-gel scaffolds is very dependent on calcium ion incorporation and subsequent release.

Cotton-wool like bioactive glass scaffolds can be produced by electrospinning calcium containing sol-gel compositions.

New hybrid biomaterials can be produced with tailored mechanical properties and biodegradation rate by introducing natural polymers in the sol-gel process but only if coupling agents (organosilanes) are used to bond the organic to the inorganic components. The reactions of GPTMS are very dependent on pH of the reaction and are more difficult to control than previously thought.

Calcium can be incorporated into the silicate sol-gel network at room temperature through the use of calcium alkoxides.
Exploitation Route TheraGlass Ltd is assisting with commercialisation of the cotton-wool bioactive glass scaffolds, potentially for wound healing applications.
Sectors Education,Healthcare,Manufacturing, including Industrial Biotechology

 
Description TheraGlass Ltd are assisting with commercialisation of our cotton-wool like bioactive glass scaffolds for wound healing applications. They applied for a grant that enabled them to carry out up-scaling trials of our process using manufacturing facilities of the Electrospinning Company (Harwell). A Healthcare Impact Partnership Grant was successfully obtained from EPSRC to begin translation of the hybrid technology.
First Year Of Impact 2016
Sector Healthcare,Manufacturing, including Industrial Biotechology
Impact Types Economic

 
Description EPSRC Doctoral Award for Louise Connell
Amount £47,000 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 11/2013 
End 11/2014
 
Description EPSRC Responsive Mode
Amount £615,722 (GBP)
Funding ID EP/M019950/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 04/2015 
End 03/2018
 
Description EPSRC Responsive Mode
Amount £136,177 (GBP)
Funding ID EP/M004414/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 10/2014 
End 10/2016
 
Description Healthcare Impact Partnership
Amount £1,072,444 (GBP)
Funding ID EP/N025059/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 07/2016 
End 06/2019
 
Description Marie Curie Individual Fellowship
Amount € 200,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 06/2016 
End 05/2018
 
Description Nanocomposites for bone regeneration 
Organisation Nagoya Institute of Technology
Country Japan 
Sector Academic/University 
PI Contribution Julian Jones was appointed Visiting Professor, giving an annual seminar at Nagoya Institute of Technology. Post doctoral researcher Gowsihan Poologasaundarampillai employed at Nagoya Institute of Technology for 18 months, PhD student Sen Lin appointed as a post doctoral researcher at Nagoya Institute of Technology for 12 months. Hosted Dr Akiko Obata (Assistant Professor) for 1 year , Jin Nakamura (PhD student) for 1 year and Sungho Lee (PhD Student) for 3 months. Maria Nelson and Lizzie Norris (PhD students) visited Nagoya for 3 Months each. Anthony Macon employed from Jones' group as an Assistant Professor. Hosted 4 Masters students from NiTech. Associate Professors Akiko Obata and Toshihisa Mizuno joined Jones' group for 2 months and 1 year respectively.
Collaborator Contribution Exchange Programme funded through JSPS Sent 9 researchers to Julian Jones' research group Employed a post doctoral researcher and a phd student from Julian Jones' research group Employed and Assistant Professor from Julian Jones' group
Impact Maçon, A. L. B., Lee, S., Poologasundarampillai, G., Kasuga, T., Jones, J. R. "Synthesis and dissolution behaviour of CaO/SrO-containing sol-gel-derived 58S glasses" Journal of Materials Science, 2017, DOI: 10.1007/s10853-017-0869-0.Wang, J., Zhou, P., Obata, A., Jones, J. R., Kasuga, T. "Preparation of cotton-wool-like poly(lactic acid)-based composites consisting of core-shell-type fibers", Materials. 2015: 8: 7979-7987, DOI :10.3390/ma8115434 Gao, C. X., Ito, S., Obata, A., Mizuno, T., Jones, J. R., Kasuga, T. "Fabrication and in vitro characterization of electrospun poly (gamma-glutamic acid)-silica hybrid scaffolds for bone regeneration" Polymer, 2016: 91:106-117. DOI: 10.1016/j.polymer.2016.03.056. Wang, J., Zhou, P., Obata, A., Jones, J. R., Kasuga, T. "Preparation of cotton-wool-like poly(lactic acid)-based composites consisting of core-shell-type fibers", Materials. 2015: 8: 7979-7987, DOI :10.3390/ma8115434. Poologasundarampillai, G., Wang, D., Li, S., Nakamura, J., Bradley, R., Lee, P. D., Stevens, M. M., McPhail, D. S., Kasuga, T., Jones, J. R., "Cotton-wool-like bioactive glasses for bone regeneration", Acta Biomaterialia, 2014: 10: 3733-3746. Obata, A., Ito, S., Iwanag, N., Mizuno, T., Jones, J. R., Kasuga, T. "Poly(?-glutamic acid)-silica hybrids with fibrous structure: effect of cation and silica concentration on molecular structure, degradation rate and tensile properties" RSC Advances, 2014: DOI: 10.1039/c4ra08777a. Wang, D., Poologasundarampillai, G., van den Bergh, W., Chater, R., Kasuga, T., Jones, J. R., McPhail, D. S. "Strategies for the chemical analysis of highly porous bone scaffolds using secondary ion mass spectrometry (SIMS)" Biomedical Materials, 2014: 9 (1): 015013. Nakamura, J., Poologasundarampillai, G., Jones, J. R., Kasuga, T. "Tracking the formation of vaterite particles containing aminopropyl-functionalized silsesquioxane and their structure for bone regenerative medicine" Journal of Materials Chemistry B, 2013: 1: 35: 4446-4454. Obata, A. Ozasa, H., Kasuga, T., Jones, J. R. "Cotton wool-like poly(lactic acid)/vaterite composite scaffolds releasing soluble silica for bone tissue engineering" Journal of Materials Science: Materials in Medicine, 2013: 24: 1649-1658. Fujikura, K., Obata, A., Lin, S., Jones, J. R., Law, R. V., Kasuga, T. "Preparation of electrospun poly(lactic acid)-based hybrids containing siloxane-doped vaterite particles for bone regeneration" Journal of Biomaterials Science, Polymer Edition 2012: 23:10, 1369-1380 Obata, A. Hasegawa, D., Nakamura, J., Jones, J. R., Kasuga, T. "Induction of hydroxycarbonate apatite formation on polyethylene or alumina substrates by spherical vaterite particles deposition", Materials Science and Engineering C, 2012: 32: 1976 - 1981. Obata, A., Jones, J. R., Akiyoshi, S., Kasuga, T. "Sintering and crystallization of phosphate glasses by CO2-Laser irradiation on hydroxyapatite ceramics" International Journal of Applied Ceramic Technology, 2012: 9: 541-549. Obata, A., Hashimoto, T., Kasuga, T., Jones, J. R. "Hydroxyapatite coatings incorporating silicon ion releasing system on titanium prepared by using water glass and vaterite" Journal of American Ceramics Society, 2011: 94 (7): 2074-2079. Wakita, T. Obata, A., Poologasundarampillai, G., Jones, J. R., Kasuga, T., "Preparation of siloxane-containing poly(lactic acid)-vaterite hybrid membranes for guided bone regeneration" Composites Science and Technology, 2010: 70: 1889-1893.
Start Year 2009
 
Description Reactions of organosilanes in the sol-gel process 
Organisation University of Milano-Bicocca
Country Italy 
Sector Academic/University 
PI Contribution PhD students Louise Connell, Oliver Mahony and Francesca Tallia visited Bicocca to understand the reactivity of the organosilane GPTMS Hosted PhD student Laura Russo
Collaborator Contribution Laura Russo developed a new hybrid based on Silica and PEG Hosted Louise Connell and Oliver Mahony and investigated the reaction of GPTMS with water and nucleophiles Tall developed a new hybrid with self-healing properties
Impact EPSRC Healthcare Impact Partnership Grant "Additive manufacturing of advanced medical devices for cartilage regeneration: minimally invasive early intervention" Connell, L. S., Gabrielli, L., Mahony, O., Russo, L., Cipolla, L., Jones, J. R. "Functionalizing natural polymers with alkoxysilane coupling agents: reacting 3-glycidoxypropyl trimethoxysilane with poly(?-glutamic acid) and gelatin" Polymer Chemistry, 2017: 8: 1095-1103, DOI: 10.1039/c6py01425a. Gabrielli, L., Connell, L. S., Russo, L., Jiménez-Barbero, J., Nicotra, F., Cipolla, L., Jones, J. R. Exploring GPTMS reactivity against simple nucleophiles: chemistry beyond hybrid materials fabrication, RSC Advances, 2014: 4: 1841 - 1848. Russo, L., Gabrielli, L., Valliant, E. M., Nicotra, F., Jiménez-Barbero, J., Cipolla, L., Jones, J. R. "Novel silica/bis(3-aminopropyl) polyethylene glycol inorganic/organic hybrids by sol-gel chemistry" Materials Chemistry and Physics, 2013:140: 168-175. Gabrielli, L., Russo, L. Poveda, A., Jones, J. R., Nicotra, F., Jiménez-Barbero, J., Cipolla, L. "Epoxide opening versus silica condensation during sol-gel hybrid biomaterial synthesis", Chemistry, a European Journal, 2013: 19: 7856-7864.
Start Year 2010
 
Description Supramolecular polymers for 3D printing 
Organisation University of Reading
Department School of Chemistry, Food and Pharmacy
Country United Kingdom 
Sector Academic/University 
PI Contribution Cellular response studies to new polymers for ink development
Collaborator Contribution Development of new supramolecular polymers
Impact Hart, L., Li, S., Sturgess, C., Wildman, R., Jones, J. R., Hayes, W. "3D printing of biocompatible supramolecular polymers and their composites" ACS Applied Materials & Interfaces DOI: 10.1021/acsami.5b10471.
Start Year 2014
 
Title Hybrid materials and process for production thereof 
Description An inorganic/organic hybrid composition and synthesis process that yeilded a material with self healing properties and excellent mechanical properties, that could be 3D printed 
IP Reference GB1605446.2 
Protection Patent application published
Year Protection Granted 2016
Licensed No
Impact Healthcare Impact Partnership grant from the EPSRC and partnership with surgeons and industry to begin technology transfer
 
Description Discovery Channel 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Took part in a Discovery Channel film showcasing bioactive glass and regenerative medicine
Year(s) Of Engagement Activity 2015
URL http://www.discoveryuk.com/future-now/
 
Description Inaugural Lecture broadcast 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Inaugural Public Lecture professionally recorded and edited and put on Youtube
Year(s) Of Engagement Activity 2016
URL https://www.youtube.com/watch?v=71RA0VhTC04
 
Description Interview with IScience 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Interview with Imperial college IScience Student Media team which was then on YouTube
Year(s) Of Engagement Activity 2015
URL http://www.isciencemag.co.uk/features/iscientist-julian-jones-interview/
 
Description Pint of Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The audience fully engaged with my presentation, spreading the understanding that glass is an advanced high tech material
Group members also got outreach experience

Members of the public were enthused about Materials Science, when most did not realise it is a discipline
Year(s) Of Engagement Activity 2014
URL http://pintofscience.co.uk/events/london/spoton/
 
Description Pint of Science science festival talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Pint of Science science festival talk
Year(s) Of Engagement Activity 2018
URL https://pintofscience.co.uk/event/fixing-our-body
 
Description YouTube Channel 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact YouTube Channel set up and populated to promote bioactive glass research
Year(s) Of Engagement Activity 2015
URL https://www.youtube.com/channel/UCNKc2if3dCNM1a1ynoFEh1A