Manufacturing bespoke human organs; 3D printed nanocomposite trachea

Lead Research Organisation: University College London
Department Name: Surgery

Abstract

Organ failure and tissue loss are challenging health issues due to widespread aging population, injury, the lack of organs for transplantation and limitations of conventional artificial implants. There is a fast growing need in surgery to replace and repair soft tissues such as blood vessels, stent, trachea, skin, or even entire organs, such as bladder, kidney, heart, facial organs etc. The high demand for new artificial implants for long-term repair and substantially improved clinical outcome still remains .Our well-publicised successes in using tissue-engineering to replace hollow organs in cases of compassionate need have shown the world that an engineering approach to hollow organ replacement is feasible, as well as serving to highlight those areas where more work is required to provide bespoke manufactured tissue scaffolds for routine clinical use Being able to replicate a functional part of one's body as an exact match and therefore to be able to replace it 'as good as before' is familiar in science fiction. Most implants will share limitations that are associated with either the materials used or the traditional way in which they have been made. With the advancement of additive manufacturing technology, 3D printing, biomaterials and cell production, printing an artificial organs is becoming a science and engineering fact and understandably can save lives and enhance quality of life through surgical transplantation of such printed organs produced on-demand, specifically for the individual of interest.

The project seeks to addresses the unmet need in traditional implants by exploiting our proprietary polymer nanocomposites developed at UCL and advanced digital additive manufacturing with surgical practice. we aim to develop a 3D advanced digital bio-printing system for polymer nanocomposites in order to manufacture a new-generation of synthetic soft organs 'on-demand' and bespoke to the patient's particular needs. Our extensive preclinical and on-going preclinical study on the nanocomposite-based organs will ensure the construct is able to induce angiogenesis and to perform function of an epithelium. Here we take these experiences in the compassionate case, and take trachea as an exemplar to develop a manufacturing method of producing bespoke tubular organs for transplantation with nanocomposite material.

This proposal will allow us to develop; a) a customer made 3D bioprinter with multi-printing heads and an environmental chamber which can print 'live' soft organs/scaffolds with seeded cells to meet the individual patients needs; b) a series of polymer nanocomposites suitable for 3D printingorgan constructs/host scaffolds; c) a formulations of bio-inks for printing cells, proteins and biomolecules. d) a printed artificial tracheal constructs using their radiographic images with optimised biochemical, biophysical and mechanical properties. e) Establishment of in-vivo feasibility data through observation of restoration of respiratory function and normal tissue integration of pig models which will be surgically transplanted

Planned Impact

Clinical Impact
Live organ harvesting and transport, as well as the intensive care of critically ill patients and the loss of useful and healthy lives costs the UK and worldwide an inestimable amount in active resources. The successful outcome of this research proposal will enable manufacturing of tailor made organs for those require critical clinical attention and can potentially change the NHS surgical protocols for organ transplantation. This will shorten waiting times, allow early effective treatment, shorter hospital stay, and reduce or eliminate costs for direct hospital and palliative care costs, costs to the patient and loss of productivity e.g. employment (indirect costs). Therefore if this clinical need was to be successfully met, at a cost that was acceptable to society, not only will patient's benefit (reduced mortality/morbidity) but also national resources. Once we have established the exemplar protocol with this project it will catalyse the progress of a number of other tubular organ manufacturing to potentially have a greater impact.

3D printing/Rapid prototyping
Organ replacement is one of the supreme applications of 3D printing, which can really establish rapid prototyping as a key technology requirement not only in major surgical centres, but the spin of interest in what is possible with these techniques will rapidly establish this new technology as a norm. This will certainly have a significant impact on the manufacturers of this technology.

Capacity Building
This project will require training of RAs in multidisciplinary activities unique to this project and thus at the completion of the project will be great assets to the UK as well as internationally in terms of source of knowledge and experience. This manufacturing protocols developed in this research will interest many polymer manufacturing industry as well as instrument manufacturing industry (3D printing industry) who could use these developments to potentially establish a unique industry of tubular organ manufacturing for clinical applications, down the line and therefore should bring in a great deal of income to the country and create jobs for highly skilled individuals. Global medical implant industry such as Boston scientific has expressed their interest in being a partner in taking the end products to clinic and for commercialisation.

World leading research to meet national strategic needs
The applicants contribute to the national policies in applied regenerative science and technology through their representation in relevant select committee at the House of Lords (eg, Nov 2012) and the applicants continue to contribute to national policy making and the proposed developments should be of interest to be considered in the future development and encouraged for wider applications in regenerative medicine. Furthermore, the developments for bespoke manufacturing of implants should also bring solutions to those issues raised at the WHO, such as organ trafficking, transplantation tourism of organ and commercialism as highlighted in 'Declaration of Istanbul, 2008, WHO'
 
Description The first breakthrough of the on-going project is a novel 3D manufacturing technique for solution based materials. We have developed an indirect 3D printing technique, 3D-PPPS, which permits manufacture of wide range of printable and unprintable polymers and their nanocomposites at low cost and with a short lead time. Also novel is that a wide range of polyurethane constructs, for example, from the same solution were produced through thermally controlled phase separation at different scales. Each produced scaffolds with distinctly different structure, mechanical and cell-guiding properties. We provide an early insight into potential cell responses to the stiffness and nanoporous structure of our fabricated scaffolds in real 3D.
Exploitation Route 3D-PPPS technique presents a new and highly versatile approach to the manufacture of bespoke implants/scaffolds for tissue engineering with fundamental understanding of polymer structure, properties and cellular response in 3D. Finally, we create an exciting paradigm for future studies of 3D tissue engineering scaffolds based on otherwise 'unprintable' liquid polymers.
Sectors Chemicals,Education,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description The outcomes and potential impact achieved so far are promising and encouraging. Three new industrial partners have participated the project, contributing both in cash and in-kind, including two PhD studentships and two 3D control systems for bio-printers. One quality journal article and one grant application based on the 3D-PPPS technique developed is under review, and more publications and impact will be following up in the near future.
Sector Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic

 
Description BBSRC Industrial CASE & GSK: 3D Bioprinting Engineering Artificial Respiratory Tract Tissue
Amount £169,522 (GBP)
Funding ID BB/R505985/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2017 
End 09/2021
 
Title 3D-printed preform phase separation 
Description We have developed a novel indirect 3D printing technique, 3D-PPPS, which permits manufacture 3D scaffolds or implant from a wide range of printable and unprintable polymers and their nanocomposites at low cost and with a short lead time. Also novel is that a wide range of polyurethane constructs, for example, from the same solution were produced through thermally controlled phase separation at different scales. Each produced scaffolds with distinctly different structure, mechanical and cell-guiding properties. We provide an early insight into potential cell responses to the stiffness and nanoporous structure of our fabricated scaffolds in real 3D. Both degradable and non-degradable POSS-polyurethane nanocomposites based tracheas, ears and noses have been designed and fabricated. The on-going and near-future in vivo work will provide preclinical validation of the trachea implants designed and optimised in vitro. 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2016 
Provided To Others? Yes  
Impact Three new industrial partners have recently participated the project, contributing both in cash and in-kind, including two PhD studentships and two 3D control systems for bio-printers. One quality journal article and one grant application based on the 3D-PPPS technique developed is under review, and more publications and impact will be following up in the near future. 
 
Description Biomer Technology Ltd 
Organisation Biomer Technology
Country United Kingdom 
Sector Private 
PI Contribution Biomer is a manufacturer of biomedical grade polyurethanes. We develop biomedical application using the polymer Biomer produced. This would promote their products in the biomedical market.
Collaborator Contribution Biomer has been involved in the synthesis of POSS reinforced thermoplastic polyurethane (POSS-TPU) using the reactor in the company. The characterisation and 3D printing POSS-TPU is under investigation.
Impact The project is till on-going. The output and impact will be following up in the near future.
Start Year 2014
 
Description GSK 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution We are going to develop synthetic human tissue model which will support the drug discovery and screening at GSK
Collaborator Contribution GSK will contribute 50% of the studentship. GSK will provide expertise in histological, transcriptomic and biomarker based characterisation of tissue and cellular function.
Impact The project will start in Sept 2016
Start Year 2016
 
Description Renishaw partnership for Manufacturing Bespoke human organs 
Organisation Renishaw PLC
Country United Kingdom 
Sector Private 
PI Contribution Provide case study about biomedical application of 3D bioprinting and potential market.
Collaborator Contribution Renishaw provides two 3D control systems for instrumentation of 3D bioprinter
Impact The collaboration just started in April. This is multi-disciplinary collaboration. Renishaw is a global manufacturer of 3D printer. UCL team specialise in development of scaffold for tissue engineering. We will develop a custom-made 3D bioprinter based on Renishaw's 3D control system.
Start Year 2016
 
Title 3D Thermo-induced phase separation (3D-TIPS) Manufacturing of Scaffolds with Hierarchical Porous Structure (3D-CPI), 
Description The invention discloses a generic manufacturing method of producing soft and hard 3D porous implants or scaffolds. the technique permits manufacture of wide range of printable and unprintable polymers and their composites at low cost and with a short lead time. It also permits flexibility in the complex architecture of fabricated constructs, tunability in structure and properties not presently achievable by conventional direct 3D printing techniques or by phase-separation alone. 
IP Reference  
Protection Protection not required
Year Protection Granted 2015
Licensed No
Impact 3D-TIPS is a low-cost, reproducible and versatile fabrication technique, which will be very useful for manufacturing implants, scaffold for tissue engineering. It is envisaged that the technique will be widely adapted by the researchers and developers from both academic and industrial community.
 
Description 10th World Biomaterials Congress, 2016, Canada 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This is the largest international conference in biomaterials. It was an excellent place to disseminate our latest progress on the project.
Year(s) Of Engagement Activity 2016
 
Description Invited talk at 2nd International COnference on 3D Printing Technology and Innovation, 2018, London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited talk to promote the new technology and science of 3D printing for medical application developed from the project at an international conference
Year(s) Of Engagement Activity 2018
URL https://www.haptic.ro/event/2nd-international-conference-3d-printing-technology-innovations/
 
Description Invited talk on KTN HiPerNano2017: 3D printing polymeric nanocomposites for soft human implants. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Presented the advancement of 3D printing nanocomposites for medical applications to industries and policymakers.
Year(s) Of Engagement Activity 2017
URL http://materialschemistry.org.uk/events/hipernano-2017/
 
Description Invited talk presented at: International Conference on Direct Digital Manufacturing and Polymers, 2015, India 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presented our latest progress on 3D printing human organ at the international conference
Year(s) Of Engagement Activity 2015
 
Description Invited talk to Live Meeting across GSK global laboratories and premises 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact The talk was invited by GSK, the major global pharmaceutical industry. A BBSRC-GSK industrial CASE studentship has been awarded later on.
Year(s) Of Engagement Activity 2015
 
Description Presentation at the 28th European Society for Biomaterials, 2017 (ESB2017) Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Poster presentation at the international conference
Year(s) Of Engagement Activity 2017
 
Description Presented at: XXII AISAL Symposium, Innovation in Laboratory Animal Science, The Future is Now, 2015, Italy 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited talk about 3D printing tissue engineering for the scientific community in the area of animal science at this International conference
Year(s) Of Engagement Activity 2015
 
Description TERMIS 2016 - the European Chapter Meeting of the Tissue Engineering and Regenerative Medicin International Society. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Present our latest progress on 3D printing scaffold for tissue engineering in the international conference
Year(s) Of Engagement Activity 2016