Engineering soft/hard tissue interfaces
Lead Research Organisation:
University of Birmingham
Department Name: Chemical Engineering
Abstract
Ligament and tendon injuries are relatively commonplace in patients of all age groups. These connective tissues enable joint locomotion and their injury can result in a debilitating loss of joint function and consequently a significant reduction in a patient's quality of life. Currently, ligament damage is repaired either by using a synthetic material to replace ligament function or by using tissue that is often harvested from elsewhere in the patients body (often from the hamstring or the quadriceps tendon). Failure of these repairs usually occur as a consequence of tensile stress concentrations at the interface with bone (enthesis) that can result in ligament detachment. In normally functioning ligaments, the interface with bone is specially structured with four continuous and yet distinct regions which protect the attachment point by ensuring that it is subject principally to compressive loads. In this work, we will seek to reproduce this structure by interfacing a tissue engineered ligament with a calcium phosphate based anchor material in a bioreactor system. The adhesion of the ligament to the ceramic structure will allow the mechanical conditioning of the tissue outside the body. By providing the necessary mechanical and chemical stimuli to a population of mesenchymal stem cells within the ligament, it may be possible to recreate the specialised enthesis structure in vitro. Ultimately, it is hoped that this multi-component tissue engineered structure will form an intimate bond with bone, resulting in the eventual regeneration of the ligament and enthesis in vivo leading to a better long term clinical outcome for the patient.
Technical Summary
Although many approaches have been applied clinically in the repair and augmentation of diseased and damaged bone, there are currently major issues associated with the repair of the soft/hard tissue interface. Such interfaces are essential for joint articulation and hence locomotion and a loss of their integrity can result in a significant reduction in the patient's quality of life. The anterior cruciate ligament, for example, may be repaired by mechanical fixation, the clinical success of this approach, however, is limited by poor fixation at the graft-bone junction the friability of which is the primary cause of graft failure. Failure typically occurs at the graft-bone junction as a result of localised stress concentrations at the interface between the tendon/ligament and bone, which are caused by a mismatch in modulus between the tissues of several orders of magnitude. In vivo, these stress concentrations are avoided by a complex fibrocartilaginous interfacial region (enthesis) that effectively transfers the load between the more and less compliant tissues. The proposed work will seek to produce a multi-tissue construct using a novel method for engineering a ligament-like structure in vitro, which will interface with a calcium phosphate based bracket of defined morphology. Ultimately, it is anticipated that this approach will allow us to engineer replacement ligaments and tendons in vitro for eventual implantation and clinical treatment of ligament/tendon damage.
People |
ORCID iD |
Liam Grover (Principal Investigator) | |
Keith Baar (Co-Investigator) |
Publications
Wudebwe UN
(2015)
Exploiting cell-mediated contraction and adhesion to structure tissues in vitro.
in Philosophical transactions of the Royal Society of London. Series B, Biological sciences
Wang A
(2016)
Development of tissue engineered ligaments with titanium spring reinforcement
in RSC Advances
Smith AM
(2015)
Nanoscale crystallinity modulates cell proliferation on plasma sprayed surfaces.
in Materials science & engineering. C, Materials for biological applications
Paxton JZ
(2012)
Monitoring sinew contraction during formation of tissue-engineered fibrin-based ligament constructs.
in Tissue engineering. Part A
Paxton JZ
(2010)
Factors affecting the longevity and strength in an in vitro model of the bone-ligament interface.
in Annals of biomedical engineering
Paxton JZ
(2010)
Engineering an in vitro model of a functional ligament from bone to bone.
in Tissue engineering. Part A
Mehrban Nazia
(2011)
Tissue engineering a ligamentous construct
Mehrban N
(2013)
Comparing physicochemical properties of printed and hand cast biocements designed for ligament replacement
in Advances in Applied Ceramics
Lebled C
(2014)
Combined decellularisation and dehydration improves the mechanical properties of tissue-engineered sinews.
in Journal of tissue engineering
Koburger S
(2014)
A novel method for monitoring mineralisation in hydrogels at the engineered hard-soft tissue interface.
in Biomaterials science
Jennifer Paxton (Speaker)
(2012)
Anabolic agents to increase collagen content in tissue-engineered ligaments
Jahromi SH
(2011)
Degradation of polysaccharide hydrogels seeded with bone marrow stromal cells.
in Journal of the mechanical behavior of biomedical materials
Bannerman A
(2014)
Imaging the hard/soft tissue interface.
in Biotechnology letters
Title | Ligament image |
Description | Image presented at the 'images of research' exhibition, University of Birmingham, 15th March 2012 |
Type Of Art | Artwork |
Year Produced | 2012 |
Impact | no actual impacts realised to date |
Description | 1. We were able to engineer a multi-component structure with potential for ligament replacement using a cell-seeded fibrin gel with bone cement anchors at either end. It was anticipated that using bone cement would allow for the formation of an in tact hard/soft tissue interface that would improve the chance of clinical success of these implants. A hard/soft tissue interface was successfully produced that could last over 18 weeks in culture. 2. We have shown the propensity of several different bone replacement materials to form in vitro hard/soft tissue interfaces. 3. We developed an imaging methodology that can be used to study the formation of a hard/soft tissue interface in vitro. 4. We were able to identify several methods that could be used to increase the mechanical strength of the bone-to-bone ligament constructs to levels that were more appropriate for clinical use. These included chemical stimulation, mechanical stimulation and reinforcement. 5. We were able to develop bioreactor systems to enable mechanical stimulation of the bone-to-bone ligament constructs. 6. We showed that mechanical stimulation above 5% strain lead to matrix destruction, and used this knowledge to identify a stretch regime to increase the collagen content, and also the mechanical strength of the bone-to-bone ligament constructs. 7. We have used the findings of this work to allow us to lever almost £4m from MRC and Wellcome trust on scarring. This work was seen as important to scarring since ultimately the 3D model replicated the wound environment and has allowed us to screen dosages etc. |
Exploitation Route | The bone-to-bone ligament composite produced here may have a significant role in the future treatment of ligament repair. In addition, we also believe that the constructs can be used as a model of hard/soft tissue interface formation and maturation, and in the study of a variety of musculoskeletal disorders. |
Sectors | Healthcare Pharmaceuticals and Medical Biotechnology |
Description | We have identified a molecule that prevents pathological ossification, we are now seeking funding to take this clinic. |
First Year Of Impact | 2016 |
Sector | Healthcare |
Impact Types | Economic |
Description | An organotypic model of the bone remodelling process |
Amount | £98,031 (GBP) |
Funding ID | NC/S001646/1 |
Organisation | National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) |
Sector | Public |
Country | United Kingdom |
Start | 09/2019 |
End | 09/2023 |
Description | Developing a model of pathological ossification |
Amount | £90,000 (GBP) |
Funding ID | NC/L001403/1 |
Organisation | National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) |
Sector | Public |
Country | United Kingdom |
Start | 07/2014 |
End | 07/2017 |
Description | Development of tissue engineered ligaments with titanium spring reinforcement |
Amount | £79,815 (GBP) |
Funding ID | 472 |
Organisation | Orthopaedic Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2011 |
End | 01/2013 |
Description | Development of tissue engineered ligaments with titanium spring reinforcement |
Amount | £79,815 (GBP) |
Funding ID | 472 |
Organisation | Orthopaedic Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2011 |
End | 01/2013 |
Description | From ageing to space travel: Developing an organotypic model of skeletal tissue disuse for understanding degeneration in altered environments |
Amount | £121,762 (GBP) |
Funding ID | NC/S001859/1 |
Organisation | National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) |
Sector | Public |
Country | United Kingdom |
Start | 03/2019 |
End | 12/2021 |
Description | Imaging of hard/soft tissue interfaces |
Amount | £1,000 (GBP) |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2011 |
End | 08/2011 |
Description | Imaging of tissue-engineered ligaments using MRI |
Amount | £1,000 (GBP) |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2012 |
End | 08/2012 |
Description | Research on ossification |
Organisation | University of Oxford |
Department | Botnar Research Centre |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have some high-end chemical imaging techniques at Birmingham, which we have employed to shed light on pathological bone formation. We also developed (through a BBSRC project) a way to align extracellular matrix, such that it can resemble cortical bone. Mineralisation of this has allowed us to develop a model of bone formation (funded by NC3Rs). |
Collaborator Contribution | Biological expertise, particularly around the identification of osteocytes. |
Impact | We have developed a model under the NC3Rs project which has the structural and biological characteristics of bone. This has allowed us to screen for chemicals that might allow dispersion of the mineral phase and identify possible treatment methods. Grover has secured funding from the military to develop this into a therapy and from ORUK to biologically evaluate it. |
Start Year | 2014 |
Description | Calcium Phosphate Cements |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | international |
Primary Audience | Participants in your research or patient groups |
Results and Impact | Talk given at University of Wuerzburg, Germany, 8th July 2011. This talk reported the use of calcium phosphate cements in the formation of a hard/soft tissue interface. no actual impacts realised to date |
Year(s) Of Engagement Activity | 2011 |
Description | Engineering the hard/soft tissue interface |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Talk given at 2nd Biomaterials Symposium, Queen Mary Westfield, 30th November 2009 describing the work on the formation of an in vitro hard/soft tissue interface. no actual impacts realised to date |
Year(s) Of Engagement Activity | 2009 |
Description | Healthy Living: Helping you hold yourself together through ligament and tendon engineering. |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Poster presented at the Universitas 21 Healthy Living Poster Conference, 20th November 2011. This poster described the work undertaken in generating functional tissues from bone-to-bone for potential implantation. Poster no actual impacts realised to date |
Year(s) Of Engagement Activity | 2011 |
Description | Inorganic/organic composites for regenerating tissue structures |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Participants in your research or patient groups |
Results and Impact | Talk given at the University of Huddersfield, 8th February 2012 describing the creation of a hard/soft tissue interface from inorganic and organic materials. no actual impacts realised to date |
Year(s) Of Engagement Activity | 2012 |
Description | Pint of science presentation |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | I gave a talk at one of the Birmingham pint of science events in which I talked about how materials could be used to replace parts of the body and how we can make better models of tissue formation. |
Year(s) Of Engagement Activity | 2018 |
URL | https://pintofscience.co.uk/event/healing-with-materials |
Description | Presentation at the British Science Festival |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | The talk received a lot of questions from the general public. I have since been asked to talk on the importance of multidisciplinary science at a local school. A journalist in the crowd wrote up the research that I presented as an article in the Telegraph. |
Year(s) Of Engagement Activity | 2014 |
URL | http://www.britishscienceassociation.org/british-science-festival/making-body-parts |
Description | Regenerating hard/soft tissue interfaces |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Participants in your research or patient groups |
Results and Impact | Seminar given at the Institut des NanoSciences de Paris 12th Septmeber 2011. no actual impacts realised to date |
Year(s) Of Engagement Activity | 2011 |
Description | Repairing tissues: Taking cues from biology |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Talk given at BPC Conference September 2009 stating the importance of forming in vitro hard/soft tissue interfaces for tissue repair. no actual impacts realised to date |
Year(s) Of Engagement Activity | 2009 |
Description | Snot and concrete: a tail of two convergent research areas |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Participants in your research or patient groups |
Results and Impact | Talk given at University of California, Davis, June 2010 reporting the formation of hard/soft tissue interfaces in vitro. no actual impacts realised to date |
Year(s) Of Engagement Activity | 2010 |
URL | http://www.reading.ac.uk:8081/news-and-events/releases/PR443893.aspx |
Description | Tissue engineering tendons and ligaments |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Schools |
Results and Impact | 6x15min talks on tissue engineering tendons and ligaments as part of a STEM (science, technology, engineering and maths) event for GCSE pupils. no actual impacts realised to date |
Year(s) Of Engagement Activity | 2010 |
Description | Tissue repair: exploiting biological cues |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Participants in your research or patient groups |
Results and Impact | Talk given at Central South University, China, June 2010 describing the tissue engineered ligament system and the importance of formation of a hard/soft tissue interface. no actual impacts realised to date |
Year(s) Of Engagement Activity | 2010 |
Description | Tissue repair: exploiting biological cues |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Participants in your research or patient groups |
Results and Impact | Talk given at the Italian Institute of Technology, April 2010. This talk described the importance of forming hard/soft tissue interfaces for repair of soft tissues. no actual impacts realised to date |
Year(s) Of Engagement Activity | 2010 |