Bioresorbable 2D and 3D ordered mesoporous phosphate glasses for bone tissue regeneration and drug delivery

Lead Research Organisation: University of Surrey
Department Name: Chemistry

Abstract

Regeneration or repair of hard and soft tissues represents a major challenge of the modern society. The number of patients that require an implant in order to replace damaged tissue is growing due to the increase of life expectancy. Therefore, the development of new and more efficient biomaterials is a great scientific and human challenge as it has an effect on the everyday life of millions of people worldwide. It has been forecasted that the global market for biomaterials will reach about $130B by 2020.

The function of biomaterials has evolved with time. The first generation of biomaterials had a pure mechanical role with no interaction with the physiological environment (e.g. metals). More recently, a second generation of biomaterials, defined as bioactive, based on calcium silicate glasses has been developed. Their key feature is the capability of their surface to spontaneously with physiological fluids in the human body generating a bone-like layer of hydroxyapatite Ca10(PO4)6(OH)2. Human cells grow and proliferate on this layer promoting a tight bond between the implant and the living tissue. As silicate based glasses are non-soluble in physiological fluids, a subsequent surgery is needed to remove the implant with increased risk for the patient and a lengthening of the total recovery time.

This proposal refers to the latest generation of biomaterials also called "third generation". In addition to the bioactivity, they also show bioresorbability as they react and dissolve over time in the physiological fluid and they are replaced by regenerated hard or soft tissue. The use of soluble bioresorbable materials avoids the necessity of a second surgery. Phosphate-based glasses, differently from the commercially used polymers, are ideal bioresorbable materials being totally biocompatible as any of the degradation products can cause inflammation.

The aim of this proposal is to design, for the first time, phosphate-based glasses with highly ordered structure of mesopores (2-50 nm) and high textural properties (large surface area, pore size and volume, narrow pore size distribution) using a combination of supramolecular chemistry and sol-gel. Phosphate based glasses with ordered 2D channels of mesopores aligned in one direction and 3D ordered cubic network of interconnected pores are excellent candidates for multifunctional biomaterials, being able to combining simultaneously anti-bacterial/anti-cancer activity with cell stimulation and vascularisation.

This makes them ideal materials to be used in two major clinical applications: orthopedics (bone pins and anchors, bone platelets, joint replacements, tissue fixation screws) and drug delivery (e.g. anticancer drugs, antimicrobial agents, growth factors, DNA).

I will demonstrate this potentiality through synthesis and textural/structural characterisation of phosphate glasses with composition close to the bone (P2O5-CaO-Na2O) with and without addition of antimicrobial ions (Ag+/Cu2+/Zn2+) followed by dissolution and biocompatibility tests.

Planned Impact

This proposal comprises leading edge physical and materials chemistry/science and aims to manufacture bioresorbable implants with synergic biocompatibility and controlled drug delivery to benefit society and improve the quality of life within the UK.

A direct output of the proposed project in short term (1-2 years window) will be highly skilled researchers (a postdoctoral researcher, a PhD student, MRes students and undergraduates interns) who will have developed multidisciplinary skills and will have experienced a broad range of technological fields that are important to the development of functional biomaterials, from the synthesis to the in-vitro testing for biocompatibility and antimicrobial activity.
Moreover, the research programme will introduce several new collaborations with UK and overseas Universities (UCL, Kent, Warwick, Queen Mary in the UK and Cagliari in Italy). In particular, the collaboration with Eastman Dental Institute, UCL will give me the opportunity to directly translate the novel materials into development of novel treatments and therapies for treating oral disorders. The UK and international partners are committed to supporting aspects of this project within their own research capacity. Further collaborations with leading groups and the development of multidisciplinarity research projects will be fostered during this project.

Commercial beneficiaries of the research (wealth generation in 5-25 years) will be companies in the UK and worldwide in, or part of the supply chain for, bioresorbable implants. In particular, healthcare companies through the design of new materials with antimicrobial properties and localised drug delivery and medical device manufacturers through the design of implants for orthopaedics and dentistry, devices to assist with brain injuries (dissolvable sensors to monitor patients with traumatic brain injuries), neurodegenerative diseases (nerve conduits) and wound repair (resorbable sutures).

Research on new materials and recipes that could facilitate advanced bioresorbable implants could impact these industries in the long term by incorporating these concepts within their product technologies. There is a significant gap in the research relating to bioresorbable materials alternative to polymers. The strategy of this proposal bears significant impact for the bioresorbable materials industry, as I foresee the reshaping of the existing market of polymeric materials, with the potential to facilitate novel applications that in turn could provoke further R&D investments for auxiliary exploitation in emerging products and services. Besides, the spin-off consulting company SPINODE, world leader in taking bioactive glass technology to market is actively supporting this proposal (see letter of support), being particularly interested in the potential of ordered mesoporous phosphate glasses technology, offering expert advice and opportunities for translation. The SPINODE support demonstrates a clear commitment for realising industrial research impact, but also attracting additional investments to capitalize on this technology.

On successful commercialisation, society will ultimately benefit (25-50 year longer term) as breakthroughs in the proposed technology sector will have a huge impact on quality of life of people suffering traumatic injuries preventing bacterial infections and promoting natural healing process.

This proposal aims to realise research impact through academic excellence and a willingness to work in an interdisciplinary environment. Although this proposal is aimed at addressing bioresorbable phosphate glasses synthesis challenges, the culminating impact stems from all research activities planned throughout the project, concurrently providing insights into science's fundamentals.
 
Description Mesoporous phosphate-based glasses in the system P2O5-CaO-Na2O undoped and doped with copper, zinc, gallium cerium and strontium ions have been prepared for the first time. Mesoporosity can be clearly identified in all samples. Ordered arrays of pores have been assessed by SEM imaging and low angle X-ray scattering . All samples show antibacterial activity against E.coli, S. aureus, P aeruginosa, E faecalis. Glasses also show good cytocompatibility tested on MG64, Saos (osteosarcoma cells ) and fibroblasts.
These results show that phosphate based glasses prepared via the in solution techniques sol-gel have great potential in the repair of both hard and soft tissues.
Exploitation Route Mesoporous phosphate-based glasses were prepared for the first time. A synthesis protocol has been established that can be used for preparing mesoporous phosphate glasses doped with different antibacterial ions but also therapeutic molecules and growth factors. The synthesis is highly versatile and composition / porosity can be tailored to the application. Therefore, the new route can be used to prepare porous phosphate glasses not only to be used in biomedicine but also but also in catalysis, electronics ( for fast ions conduction) and energy (glass to metal seals for solid oxide fuel cells).
Sectors Chemicals,Energy,Environment,Healthcare

 
Description Preliminary results performed on ex vivo wound tissues have shown that the phosphate based glasses have impressive wound healing capabilities. ON the basis of this new findings we are now closely working with Hull York Medical School to investigate further. The novel materials proposed will have immediate benefits to the quality of life of people that suffer of extensive skin damage caused by injury (acute wounds) or diseases (chronic wounds). In addition, a metal-based antimicrobial strategy overcomes the global issue of antimicrobial resistance (AMR) providing an alternative to the use of common antibiotics.
First Year Of Impact 2018
Sector Chemicals,Education,Healthcare
Impact Types Cultural,Societal,Economic

 
Description Chemistry Degree MChem course. Final year Advanced Topics inPhysical Chemistry module
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
Impact Result of reserch have been included in the final year module Advanced topics in Physical chemistry, taught at the University of Surrey
 
Description Capital Award Competition
Amount £153,000 (GBP)
Funding ID EP/S017771/1 to University of Surrey 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 09/2018 
End 03/2020
 
Description Doctoral College Studentship Award
Amount £70,000 (GBP)
Organisation Fourth State Medicine Ltd 
Sector Private
Country United Kingdom
Start 09/2018 
End 10/2021
 
Description EPSRC Doctoral Training Partnership DTP-UKRI: PhD studentship: Synthesis and characterisation of mesoporous phosphate-based glasses for biomedical applications
Amount £80,000 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 09/2022 
End 10/2026
 
Description EPSRC Industrial CASE (ICASE) "Effect of mechanical properties and surface nanostructure on phosphate-based coacervates biomedical performance"
Amount £117,000 (GBP)
Funding ID 220023 ICase voucher 
Organisation United Kingdom Research and Innovation 
Sector Public
Country United Kingdom
Start 03/2022 
End 04/2027
 
Description Impact Acceleration Account
Amount £60,000 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 11/2018 
End 07/2019
 
Description MRC Confidence in Concept (CiC) Round 1 2020/23 - Phosphate-based glasses fibres for wound healing
Amount £149,400 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2021 
End 04/2022
 
Title A novel technique for production of mesoporous phosphate-based glasses 
Description A protocol for the synthesis of mesoporous antibacterial phosphate-based glasses containing silver, copper and zinc ions has been established. A WO patent has been filed 'mesoporous phosphate glass' published as WO2020/260892 
Type Of Material Improvements to research infrastructure 
Year Produced 2018 
Provided To Others? No  
Impact Increased bioactivity of the glasses proved by acceleration of hydroxyapatite formation and fibroblast/osteoblastcell growth/ increase Tetracycline uptake/controlled release 
URL https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020260892
 
Description 4SM_LTD 
Organisation Fourth State Medicine Ltd
Country United Kingdom 
Sector Private 
PI Contribution Expertise in biomaterials/antibacterial synthesis and characterisation
Collaborator Contribution Equipment access and expertise in plasma for wound healing. Plasma box for testing antibacterial efficacy of cold plasma alone and in combination with biomaterial coacervates
Impact 4SM has half funded a PhD studentship (2018-2021) on the effect of plasma treatment on bacteria
Start Year 2018
 
Description Aston Antimicrobial 
Organisation Aston University
Country United Kingdom 
Sector Academic/University 
PI Contribution Give expertise in phosphate glasses made via sol-gel and coacervation. Relationship antimicrobial structure-composition
Collaborator Contribution They performed antimicrobial testing on our samples, provide access to their equipment and staff time
Impact Multidisciplinary research chemistry / microbiologists Joint publication: https://doi.org/10.1039/C9TB02195G
Start Year 2017
 
Description FAU_biomaterials 
Organisation Friedrich-Alexander University Erlangen-Nuremberg
Country Germany 
Sector Academic/University 
PI Contribution Privide expertise in the preparation of phosphate based glasses made via sol-gel and coacervation.
Collaborator Contribution Expertise in biomaterial glasses and controlled delivery of natural molecules. Staff time. testing bioactivity, cellular culture on our glasses
Impact Joint application of an IAA ESPRC grant in January 2021: Phosphate-based glasses for controlled delivery of natural therapeutic molecules. FAU has given an in kind contribution of 7000 GBP. Outcome still to be announced
Start Year 2020
 
Description HYMS_Wound healing 
Organisation Hull York Medical School
Country United Kingdom 
Sector Academic/University 
PI Contribution We are providing fibers scaffolds for wound healing dressings. Expertise in fibres fabrication
Collaborator Contribution Access to medical school facilities, expertise in wound healing, provide contact with clinicians and medical stakeholders
Impact Outcome from collaboration are in progress
Start Year 2020
 
Description Hull York Medical School 
Organisation Hull York Medical School
Country United Kingdom 
Sector Academic/University 
PI Contribution We are in charge of design and optimisation of samples tested at the Hull York medical School for their properties in wound healing.
Collaborator Contribution HYMS has performed advanced and targeted testing of our materials for wound healing applications. In particular, in vitro cytocompatibility, scratch tests and ex vivo studies on a variety of compositions
Impact The collaboration is truly multi disciplinary bringing together an interdisciplinary team of chemists, bioscientists, and clinicians. We have just submitted me as a PI and members of HYMS as Co-I a 1.2m EPSRC grant for the Healthcare technologies: investigator-led research project grant scheme entitled "WEAVE: Wound healing via Electrospun coacerVatE phosphate glass fibres"
Start Year 2020
 
Description Kent_X-ray diffraction and absorption 
Organisation University of Kent
Country United Kingdom 
Sector Academic/University 
PI Contribution input on preparation of sol-gel phosphate glasses
Collaborator Contribution Access to low angle X-ray diffraction facility expertise in amorphous system data analysis Assistance in synchrotron experiments
Impact Joint publication https://doi.org/10.1021/acsbiomaterials.9b01896
Start Year 2017
 
Description NPL_Ultrasound 
Organisation National Physical Laboratory
Country United Kingdom 
Sector Academic/University 
PI Contribution We provided phosphate based glass nanospheres made via electrospraying for use as ultrasound contrast agents, expertise and staff time
Collaborator Contribution NPL provided access to the ultrasound facilities, training of staff and expertise in ultrasound testing
Impact joint manuscript in preparation
Start Year 2018
 
Description Queen Mary London_Solid state NMR 
Organisation Queen Mary University of London
Department School of Biological and Chemical Science QMUL
Country United Kingdom 
Sector Academic/University 
PI Contribution Expertise on phosphate baseg glasses prepared via sol-gel and coacervation
Collaborator Contribution Access to solid state NMR and technical support for 31P measurements
Impact Multidisciplinary physics/chemistry 2 joint publications: https://doi.org/10.3389/fchem.2020.00249 https://doi.org/10.1021/acsbiomaterials.9b01896
Start Year 2017
 
Description Structural Uni Cagliari 
Organisation University of Cagliari
Country Italy 
Sector Academic/University 
PI Contribution Collaborative discussion on the comparison phosphate glasses and silicate glasses. We have provided phosphate systems for comparison and characterisation
Collaborator Contribution Availability of transmission electron microscope and surface absorption instruments, staff time, technical expertise
Impact manuscript in preparation
Start Year 2017
 
Description UCL_Dissolution Studies 
Organisation University College London
Department Eastman Dental Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Expertise in sol-gel and coacervate phosphate glasses
Collaborator Contribution Access to ion chromatography, academic expertiese and technical support for dissolution studies of phosphate based glasses
Impact multidsciplinary chemistry-biomaterials Joint publications: https://doi.org/10.3389/fchem.2020.00249 https://doi.org/10.1021/acsbiomaterials.9b01896 https://doi.org/10.1021/acsbiomaterials.9b01291
Start Year 2017
 
Description UNIMORE Italy 
Organisation University of Modena and Reggio Emilia
Country Italy 
Sector Academic/University 
PI Contribution We have prepared mesoporous phosphate glasses ceria doped to be tested at UNIMORE for functionalisation and impregnation with antioxidants and antibiotics for controlled release
Collaborator Contribution They made instrumentation and expertise available for functionalisation of mesoporous glasses
Impact Physicists, chemists, materials scientists, bioscientists
Start Year 2021
 
Description Warwick NMR 
Organisation University of Warwick
Country United Kingdom 
Sector Academic/University 
PI Contribution We have provided novel phosphate based materials for a novel structural study based on solid state NMR
Collaborator Contribution They gave access to state of the art NMR facilities (EPSRC hub) and staff time/expertise
Impact This is an interdisciplinary collaboration between Department of Physics (Warwick) and Department of Chemistry (Surrey) We have published a join article https://doi.org/10.1021/acsbiomaterials.9b01291
Start Year 2017
 
Description Warwick University_MAS NMR 
Organisation University of Warwick
Department Department of Physics
Country United Kingdom 
Sector Academic/University 
PI Contribution Expertise in sol-gel and coacervate made phosphate glasses
Collaborator Contribution Access to MAS NMR equipment and technical support
Impact Multidisciplinary chemistry-physics Joint publication https://doi.org/10.1021/acsbiomaterials.9b01291
Start Year 2017
 
Title MESOPOROUS PHOSPHATE BASED GLASS 
Description The disclosure provides a method of producing a mesoporous phosphate-based glass. The method comprises (a) contacting a phosphate with an alcohol and/or a glycol ether to create a reaction mixture; (b) contacting the reaction mixture with alkali metal cations and/or alkaline earth metal cations; (c) contacting the alcohol, the glycol ether or the reaction mixture with a surfactant, wherein the surfactant is configured to provide channel-like pores in the resultant mesoporous phosphate-based glass; (d) allowing the reaction mixture to gel; and (e) calcinating the gel to obtain the mesoporous phosphate-based glass. 
IP Reference WO2020260892 
Protection Patent application published
Year Protection Granted 2020
Licensed No
Impact The publication of the IP has paved the way for further links/collaborations Hull York Medical School (HYWS). We are currently testing more specific molecules for controlled release including natural products and specific antibacterial ions for wound healing. Having observed very promising results, we expect the involvement of industrial partners in the next month.
 
Description Presentation of the research at Queen Mary University, London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Several undergraduates attended the talk entitled: "Antibacterial phosphate-based glasses for biomedical applications" and a discussion has arisen on the topic
Year(s) Of Engagement Activity 2018