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Current research
Photodynamic technologies for antibiotic-free infection control
Chronic wounds fail to progress through the normal stage of wound healing and usually take more than three months to heal. Consequently, they represent a significant economic burden, costing the National Health Service (NHS) over £5 billion annually. Prolonged exposure to exogenous bacteria, and raising trends in antibiotic resistance, contribute increased risks of wound infection, pain, gangrene and amputation. Effective antibiotic-free infection control strategies are therefore urgently needed to support chronic wound healing and correct detrimental biochemical shifts.
We are addressing these challenges by exploring the use of a specific class of dyes, called photosensitisers (PSs), which can release Reactive Oxigen Species (ROSs) following exposure to a specific light under the presence of molecular oxygen (photodynamic therapy, PDT). Our approach aims to integrate PDT in fibre-based wound dressings to achieve a simple route to long-lasting, antiobiotic-free antimicrobial effects with minimal risks of PS diffusion and bacterial resistance.
ROS can react with multiple components of bacteria, while they can be tolerated by mammalian cells. This selective inactivation of bacteria offers a potential route to antibiotic-free infection control with minimal risks of generating bacterial resistance and cytotoxicity. In addition to chronic wound care, this approach can be applied aiming towards localised cancer therapies.
Ultrasound-triggered nanoparticle release for localised cancer therapy
Current clinical cancer treatments predominantly rely on systemic chemotherapy, which is associated with significant side effects and high risks of tumour recurrence. Growing attention has been devoted towards localised therapeutic strategies to achieve precise delivery of anticancer drugs, though challenges persist with respect to the limited tumour accessibility and specificity.
One promising approach to address these challenges involves the integration of magnetically-responsive surgical catheters with smart textiles, aiming towards future cancer therapies with minimal side toxicity and improved patient compliance.
Following cathether access to the tumour site, the integrated mesh can be designed to release drug-loaded particles on-demand, e.g. in response to safe ultrasound stimulation. This approach is particularly appealing aiming to localise therapeutic effects on specific target regions, reduce risks of off-site toxicity and enhance drug efficacy.
Long-lasting resorbable membranes for Guided Bone Regeneration (GBR) therapy
Resorbable membranes are a key component of GBR therapy, where they act to support the regrowth of hard tissue cells and prevent the infiltration of soft tissue cells. However, commercially-available collagen membranes have been documented to suffer from restricted enzymatic stability, raising risks of poor regenerated bone quality, underperforming clinical outcomes, and need of multiple surgeries for patients.
We hypothesised that these challenges could be addressed by building a UV-cured covalent network of atelocollagen via a simple synthetic route free of cells, soluble factors and dispersed polymer phases. Triple helix lysines of atelocollagen were sequentially functionalised with two distinct ethylenically unsaturated monomers, i.e. 4-vinylbenzyl chloride (4VBC) and methacrylic anhydride (MA), to achieve controlled swellability, proteolytic stability and soft tissue cell barrier functionality.
Migration and proliferation of L929 murine fibroblasts in vitro was successfully demonstrated on the surface of, rather than across, the hydrogel in vitro, as indirect evidence of barrier function. UV-cured samples also highlighted significantly increased proteolytic stability with respect to a leading resorbable membrane gold standard, following 14-day incubation in a collagenase-rich medium. Subsequent testing in vivo confirmed the mechanical integrity of the hydrogel following 4-week subcutaneous implantation and 4-week implantation in a two-layer GBR calvarial defect.
Metal-chelating collagen-based molecular networks for inflammation control
Medical devices with matrix metalloproteinase (MMP)-modulating functionality are highly desirable to restore tissue homeostasis in critical inflammation states, such as chronic wounds, osteoarthritis and tumour growth. MMP-modulating functionality is typically achieved via loading of chelating factors, e.g. EDTA, or through the use of MMP-cleavable substrates, raising issues of non-controllable factor release and fast enzymatic degradation, respectively. Aiming towards a device-induced mechanism of inflammation control, this study investigated the chemical modification of type I collagen molecules with metal-chelating residues.
Conjugation of Hydroxamic Acid (HA) residues to type I rat tail collagen (CRT) was successfully demonstrated following methacrylation of collagen lysines. Following 4-day incubation in vitro, HA-conjugated UV-cured networks (HA4*) proved to inhibit the activity of MMP-3 with respect to HA-free network control (MA25*), while presenting enhanced proteolytic stability and no cytotoxic effect with G292 osteosarcoma cells. These results suggest that the presence of HA residues on the collagen network effectively mediates the chelation with active proteolytic zinc sites, yielding a device-induced mechanism of inflammation control.
Photo-active collagen systems with rapid gelation kinetics
Tyep I collagen is the most abundant structural building block of connective tissues and has been widely applied in the design of medical devices, including wound dressings, hemostats and resorbables membranes. However, type I collagen exhibits uncontrollable swelling and poor elasticity in physiological conditions, resulting in challenging processability and material usability. Here, the covalent functionalisation of collagen lysines with photo-active monomers successfully generates UV-cured collagen networks with rapid gelation kinetics, high mechanical competence and retained triple helix architecture.
Resulting hydrogels show appealing mechanical integrity in water, whereby the compressive modulus can be effectively adjusted depending on the molecular architecture of the collagen network. Such systems have widespread potential in e.g. chronic wound care solutions and regenerative medicine.
Earlier research (2005-2015)
Wet-spinning of collagen-derived polypeptides with varied molecular weight
The formation of naturally-derived materials with wet stable fibrous architectures is paramount in order to mimic the features of tissues at the molecular and microscopic scale. Here, we investigated the formation of wet-spun fibres based on collagen-derived polypeptides with comparable chemical composition and varied molecular weight. Gelatin (G) and hydrolysed fish collagen (HFC) were selected as widely-available linear amino-acidic chains of high and low molecular weight, respectively, and functionalised in the wet-spun fibre state in order to preserve the material geometry in physiological conditions. Wet-spun fibre diameter and morphology were dramatically affected depending on the polypeptide molecular weight, wet-spinning solvent and coagulating medium, resulting in either bulky or porous internal geometry.
Both gelatin and HFC solutions were coagulated in specific non-solvents via a syringe pump. Resulting fibres were crosslinked with activated 1,3-phenylenediacetic acid, showing preserved hydrated morphology. These wet-stable fibres could be used as building block for the design of biomimetic fabric.
Crosslinked chitosan hydrogels with varied drug loading and antimicrobial capabilities
Drug-loaded systems are highly desirable for next generation therapeutics, whereby building defined structure-property-function relationships is crucial. Here, the design of chitosan hydrogels with either negatively charged or neutral crosslinkers was investigated aiming to achieve controlled drug loading via electrostatic complexation of the biopolymer network with model drugs (i.e. methylene blue, methyl orange and allura red).
Resulting samples showed tunable drug-loading behaviour depending on the electrostatic character of the crosslinking segment and target model drugs. On the other hand, decreased antimicrobial activity was observed against P. gingivalis following functionalisation of chitosan with negatively charged sulfonic acid residues. This study highlights how the electrostatic character of chitosan can be leveraged to build drug-loaded hydrogels with use-inspired functionalities.
Triple-helical collagen hydrogels via covalent aromatic functionalisation
Simultaneous control of protein conformation, material properties and biofunctionality is highly challenging in collagen materials. Here, type I collagen was reacted with 1,3-Phenylenediacetic acid (Ph), aiming at reliable biomacromolecular hydrogels. Remarkably, tuneable swellability, degradability, and thermo-mechanical properties were observed, while the triple helix collagen architecture was successfully retained.
Covalent functionalisation of type I collagen with 1,3‑Phenylenediacetic acid (Ph) directly leads to triple-helical hydrogels with controlled degree of crosslinking (C), swelling ratio (SR) and denaturation temperature (Td), in contrast to state-of-the-art carbodiimide crosslinked collagen.
Degradation behavior of polyester urethane networks
The biodegradability of polymeric implants is of paramount importance to ensure clinical biomaterial applicability. The hydrolytic degradation of amorphous star-shaped copolyester urethane networks was studied by looking at the change of physical, thermal, and mechanical properties. The star-shaped network architecture was crucial to secure a controlled change of mechanical properties (e.g. Young's modulus) ensuing from a multi-step degradation mechanism.
Molecular changes of polyester urethane network during hydrolytic degradation. A-B) Uptake of water (blue spots) leads to first bond cleavages resulting in dangling chains (C) and entanglements (D). Further bond cleavages yield mass loss (E) and network disintegration (F).
Design of entropy-elastic gelatin-based hydrogels
Biodegradable, biocompatible, and mechanically-competent biomaterials are highly demanded in regenerative medicine. Gelatin is an attractive collagen-derived biopolymer, due to its biodegradability and low antigenicity. However, gelatin suffers from limited material properties. Crosslinking of randomly-coiled chains successfully enabled the suppression of gelatin chain helicity and the development of tuneable entropy-elastic hydrogels.
Tunable entropy-elastic networks were successfully obtained by crosslinking gelatin coiled chains with hexamethylene diisocyanate (HDI) or lysine ethyl ester diisocyanate (LDI) in aqueous system.
Gelatin-based scaffolds via an integrated foaming-crosslinking process
Biopolymer scaffolds are promising biomaterials for bone regeneration since they can mimic aspects of the extracellular matrix. However, stabilisation of the porous architecture is challenging. An integrated foaming-crosslinking process was developed to accomplish the formation of gelatin-based scaffolds. A gelatin solution was foamed in the presence of a surfactant and the resulting foam fixed by chemical crosslinking with either hexamethylene diisocyanate or lysine ethyl ester diisocyanate.
Resulting scaffolds can be casted in different forms and proved to regenerate a critical size bone defect in rats.
Quantification of the biomaterial immune response in vitro
Lipopolysaccharide endotoxins (LPS) can dramatically impair the clinical biomaterial applicability, since they can induce strong immune responses in vivo. The potential LPS contamination in gelatin scaffolds was quantified by indirectly analysing the TNF-alpha release of whole blood following incubation in vitro. By using medical-grade gelatin, low-endotoxin scaffolds were successfully synthesised in clean room, ensuring scaffold applicability in vivo.
LPS biomaterial contamination and consequent immune response activation in vivo. LPS are heat-stable and can survive after material sterilisation, inducing macrophage activation and immune responses.
Biomineralisation of agarose hydrogels
The formation of biomimetic nanocomposites with defined inorganic phase is especially challenging for bone tissue engineering. A method was developed for the selective in situ mineralisation of agarose hydrogels with hydroxyapatite (HA). Samples were incubated in a solution of calcium phosphates. The solution pH and temperature were adjusted to promote HA precipitation, so that HA lamellae were successfully identified in the retrieved samples.
Agarose samples incubated in a calcium phosphate solution (left) and SEM picture of a mineralised sample displaying HA lamellae structure (right).
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