Advanced acrylate based hybrid materials for osteochondral regeneration

Lead Research Organisation: Imperial College London
Department Name: Materials

Abstract

The world's population is increasing and ageing so incidences of degenerative diseases (e.g. osteoporosis and osteoarthritis), bone cancer, and trauma are also increasing. Bone is currently the second most transplanted tissue after blood and without enough natural graft material available for transplantation, focus has shifted towards recruiting the body's natural regenerative properties by using temporary scaffolds to stimulate and support the healing process. Regenerative materials currently used in the clinic include bioceramics and degradable polyesters. However, bioceramics have serious limitations, such as a highly brittle nature, that exclude their use in cyclically loaded bone repair applications. Despite having regulatory approval, conventional polyesters degrade via autocatalysis making their degradation occur suddenly. It is essential that bespoke materials are synthesised that combine the strength and bioactivity of bioceramics with the toughness of polymers whilst also maintaining stringent control over the degradation rates, so that the material degrades concurrently with new tissue growth. In order to achieve this, the field of structural biomaterials must shift from focussing on conventional bioceramics and polyesters and instead embrace the opportunities available from bottom-up design and synthesis.
New hybrid materials, with nanoscale interactions and bonding between co-networks of carefully designed tough degradable polymers and silica, will create a step change in biomaterials research and lead the way towards better osteochondral regeneration. Crucial to this step change is the design of new polymers with well-defined molecular size, architectures, chemical composition and degradability. This requires a synergy between materials engineering, polymer chemistry and cell culture. Acrylate based polymers synthesised with techniques that will enable control of molecular weight and composition will be used. These polymers will contain important functional groups. Key aspects are controlling the hydrophilicity of the hybrid and type of bonding between the polymer and the silica. The degree of hydrophilicity dictates the degree of swelling and to obtain optimal cell attachment. While acrylates are not inherently degradable, chains that are small enough to pass through the kidneys can be linked by biodegradable crosslinks, hence the need for control of size of the acrylate chains. The type of bonding (covalent or dynamic or combinations of) will determine the mechanical properties and rate of degradation. The hybrid materials will be fabricated into 3D porous structures, by developing a novel 3-D printing approach, where the hybrid sol will be directly printed. Due to the complexity of the materials and the interdependence of processing variables, it is essential that the structure of materials are understood at multiple length scales. State of the art techniques will be employed to probe and optimise the materials' structures from the nano- to macro-scale with respect to cellular response.
An essential component for clinical success is that all stakeholders (clinicians and medical device companies) play an early role in scaffold development and technology transfer. The success of this interdisciplinary and complementary team, spanning polymer and inorganic chemistry; materials processing; hierarchical characterisation; cell biology; orthopaedic surgery; and technology transfer, will encourage internationally renowned researchers to move to and stay in the UK.
Within 20-50 years, the UK will experience significant impact, speeding up return to work and maintaining the population's activity into older age. This exciting and innovative project bringing together international and UK collaborators will focus on developing a dynamic and supportive research environment. This project will produce leaders of new fields created by this project and ensures that the UK remains at the forefront of Biomaterials research.

Planned Impact

This project will positively impact end users such as orthopaedic surgeons, patients and health services (e.g. the NHS) in a 20-50 year timeframe. It addresses at least two of the government's Eight Great Technologies (Advanced Materials and Regenerative Medicine). Patients will benefit from improved regeneration and accelerated recovery, which will benefit the UK economy by reducing the time it takes for patients to return to work and keeps the population active for longer. The step change in biomaterials created by this project will create market leading products which will benefit medical device companies.

Degenerating cartilage results in 180 000 hip and knee replacements (>1M worldwide) performed annually by the NHS. These implants typically last only 15-25 years and as life expectancy increases, more must be revised. The NHS needs to make £4 billion of savings, in its £10 billion musculoskeletal disease budget, by 2015. This project will reduce spending in the longer term through new devices that can regenerate damaged cartilage rather than replace it. Bone is the second most transplanted tissue after blood. 25 000 bone graft operations are carried out in the UK every year (in excess of 1M worldwide) and this number is expected to increase. 1 in 4 patients suffer from complications from harvesting bone from a donor site in autograft operations, which may result in revision operations. We are in need of synthetic grafts that can regenerate the damaged bone. The NHS could save ~£100M pa if the procedure was a single operation, the length of recovery time and the number of revision operations would also be reduced. The improvement of the quality of life of the UK's aging population with enable people to be active for longer and reduce the burden on a heavily overloaded social care system.

These bone regeneration devices could fill 10-15% of the £700M global market. With the addition of successful cartilage regeneration capabilities, the market would be considerably higher. For success, medical device companies must invest in these materials in order to gain regulatory approval. Imperial Innovations will file intellectual property generated by this research and the collaborating companies (e.g. JRI Orthopaedics, TheraGlass) will license it, contributing to the growth of the UK's biosciences sector. Critical to the success of this project will be dissemination to clinicians and a high level of take-up after obtaining regulatory approval. To achieve this, and to ensure that the materials meet the needs of the patients, leading surgeons from Imperial College NHS trust will be involved in the project from concept to clinic, identifying current limitations and need, and providing guidance and feedback along the way. A wider market will be reached by bringing together clinicians and academics at a Showcase for Clinicians event and the International Network on Aging (led by Prof. Maria Vallet-Regi in Madrid).

Outreach to the general public will be achieved by the researchers using current media contacts. Jones and Stevens are regular speakers for a "Pint of Science". Jones has featured on BBC radio. Stevens has appeared in Vogue Magazine, in the BBC shows "How it Works", "The Life Scientific", and "Science Club" and gave a TED talk in 2013. The work that this project builds upon has frequently been featured in the press (e.g. Daily Express, Daily Mail) and on television (e.g. This Morning, ITV). Our Bioglass scaffolds feature in the permanent exhibition of ceramics in The Victoria and Albert Museum and in the Materials Library at the Institute of Making.

Publications

10 25 50
 
Description Bespoke synthetic polymers can be made with controlled architecture and containing silica based functional groups to enable them to be used in hybrid synthesis, producing biomaterials with unprecedented properties

A functional polymer 3-(trimethoxysilyl)propyl methacrylate (TMSPMA) was synthesised by group transfer polymerization (GTP) for the first time. This gave very tight control of the molecular weight and allowed us to produce polymers of different architectures and topologies.

Linear, randomly branched, and star shaped methacrylate based copolymers were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization method. These copolymers were then used to fabricate hybrids. The 3-D polymer structure had a significant effect on mechanical properties, providing higher strain to failure while maintaining a compressive strength similar to sol-gel glass. Star copolymer-SiO2 hybrids had a modulus of toughness 9.6-fold greater and Young's modulus 4.5-fold lower than a sol-gel derived bioactive glass. Bone cells adhered on the surface regardless of the polymer structure.

In similar hybrids, we substituted methyl methacrylate (MMA) with more flexible monomers; butyl methacrylate (BMA), and methyl acrylate (MA). Unlike MMA based hybrids, BMA and MA based hybrids did not show plastic deformation. Ultimate failure stress for both of these hybrids occurred at ~18 MPa while BMA based hybrids had strain to failures of 33%, almost 2 fold higher than the MA based hybrids. However, although the new hybrids were more flexible, MC3T3-E1 osteoblast precursor cells were not able to adhere to either the BMA or MA based hybrids during in vitro cell culture, due to the hydrophobic nature of the polymers.

To make the above hybrids biodegradable, branched and star shaped poly(methyl methacrylate-co-3-(trimethoxysilyl)propyl methacrylate) (poly(MMA-co-TMSPMA)) were synthesized with disulphide based dimethacrylate (DSDMA) as a biodegradable branching agent. Biodegradability was confirmed by exposing the copolymers to the enzyme glutathione, a tripeptide which is known to cleave disulphide bonds. The MM of the copolymers were reduced 1.7 and 2.9 fold for branched and star shaped copolymers respectively within 48 h. Cleaved parts of the star polymer from the hybrid system were detected after 2 weeks of immersion in glutathione solvent, and MM was under threshold of kidney filtration. The presence of the branching agent did not reduce the mechanical properties of the hybrids and bone progenitor cells attached on the hybrids in vitro. Incorporation of the DSDMA branching agent has opened more possibilities to design biodegradable methacrylate polymer based hybrids for regenerative medicine.

the above hybrids can be 3D printed
Exploitation Route Academics: Polymers with bespoke architectures and biodegradable linkers can be synthesised and be used in hybrid biomaterials. The polymers can be used as components in hybrid materials. Industry: new application for methacrylate based polymers is of use of raw material manufacturers.
Sectors Healthcare,Manufacturing, including Industrial Biotechology

 
Description Partnership with Makevale, a producer of polymethylmethacrylate to medical device companies. They carried out an assessment of the potential for up scale of our polymer synthesis processes with a view to mass production of our polymers for manufacture of our hybrid materials as medical devices. Led to a successful new EPSRC application for the production of ACL screws.
First Year Of Impact 2018
Sector Healthcare,Manufacturing, including Industrial Biotechology
Impact Types Economic

 
Description Biodegradable hybrid screws for ligament-bone interface regeneration
Amount £1,119,981 (GBP)
Funding ID EP/S025782/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 05/2019 
End 05/2022
 
Description NIHR Global Health Research Global Health Research Group on POsT Conflict Trauma; PrOTeCT
Amount £1,880,000 (GBP)
Funding ID 1613745 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 11/2017 
End 10/2020
 
Description Methacrylates for regenerative medicine 
Organisation Makevale Ltd
Country United Kingdom 
Sector Private 
PI Contribution Discussions on how methacrylate polymers are used in our hybrid materials for 3D printing and our synthesis methods for controlled polymerisation of new methacrylate based polymers
Collaborator Contribution Makevale are a producer of polymethylmethacrylate to medical device companies. Assessment of the potential for up scale of our polymer synthesis processes with a view to mass production of our hybrid materials
Impact Synthetic chemistry and manufacturing. Planning of a manufacturing process for our new polymers for medical device manufacturing.
Start Year 2018
 
Description Children's BBC Operation Ouch! episode 
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 CBBC Operation Ouch! Hospital Takeover Series 5, Episode 9
A child was featured in the programme who had had an operation involving a bone graft. The presenter came to my lab to film the making of bioglass and to film an interview explaining how it works and our future developments in the area, such as 3D printing
Year(s) Of Engagement Activity 2016,2017
 
Description Daily Mail article featuring our work on hybrid biomaterials 
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 Public/other audiences
Results and Impact Daily Mail article featuring our work on hybrid biomaterials
Year(s) Of Engagement Activity 2016
 
Description Segment on BBC Radio 
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 Media (as a channel to the public)
Results and Impact BBC Radio 4's In Business, talking about 3D printing of biomaterials with presenter Peter Day.
Year(s) Of Engagement Activity 2016