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MIFS4BIOMED Report Summary

Project ID: 629251
Funded under: FP7-PEOPLE
Country: Sweden

Final Report Summary - MIFS4BIOMED (Molecularly Imprinted Nanofibres for Tissue Engineering, Affinity Depletion and Biosensor Applications)

Molecular imprinted polymers (MIPs) and electrospun nanofibres are both hot topics individually in the biomedical sciences, with applications including tissue engineering, regenerative medicine, drug release, affinity chromatography and biosensors. This proposal combines these two leading-edge approaches to generate entirely novel materials with broad utility in biomedical engineering. The numbers of papers and reviews in both fields have increased exponentially over the last decade and more than 12,000 article published including topics “molecular imprinting” or “electrospinning” have been cited by 250,000 articles. Molecular imprinting is a form of template assisted synthesis that facilitates the creation of artificial receptors that can have affinity constants as high as or even exceeding their natural counterparts. These polymers have memories that are capable of selectively rebinding the template molecules. This technique is one of the most promising strategies to produce artificial recognition systems because MIPs are usually inexpensive to produce and exhibit excellent physical and chemical stability. Molecularly imprinted polymers are already used for analytical separations and solid-phase extractions, and a large number of publications have described their potential in chemical sensors, drug delivery and as library screening tools etc.
Electrospinning (ES) is one of the most broadly used techniques for fabrication of nanostructured materials. ES, itself a hybrid of two techniques: electrospray and spinning, uses electrical forces to produce continuous fibres having diameters in range of few nanometers to several micrometers using natural or synthetic polymer solutions. ES attracts so much attention because of the possibility to electrospin a wide variety of polymers, converting them into submicron structures, which is difficult to achieve by conventional mechanical spinning techniques. The relative simplicity and robustness of ES is highly attractive and it offers a number of technical advantages such as extremely high surface area per unit volume, tunable porosity, flexibility for adapting it to different shapes and sizes, and possibilities for controlling nanofibre composition according to desired properties and functionalities. Because of these properties, ES nanofibres are intensively studied and used in various fields including nanocatalysis, tissue engineered scaffolds, protective clothing, filtration, biomedicine, pharmaceuticals, optoelectronics, healthcare, biotechnology, defense and security, and environmental engineering.

In this proposal, we have focused on next generation molecular imprinting using reactive electrospinning to obtain, for the first time, directly imprinted nanofibres. We have demonstrated the utility of this new nanofabrication technology in three key areas: active agent carriers in regenerative medicine, affinity-depleting membranes in blood-related proteomics, and biorecognition elements for biosensors and diagnostics. The supported fellow, Dr. Uzun, has wide ranging experience in materials and engineering, molecular imprinting and biosensors. This complementary expertise and experience let us to generate high quality outcomes and provide the fellow with an excellent platform to expand his research and establish stronger links with European leaders in the field. Also, this proposal have sparked new collaboration not only between institutions, but also between countries including Turkey, Sweden, and the UK, by means of scheduled scientific visits. In return, the fellow have started to use his experience to inject fresh ideas for novel materials and biosensors into the rapidly expanding team at Linköping University.

In this study, we utilised reactive electrospinning to produce molecular imprinted nanofibres for three key biomedical applications: active agent carriers in regenerative medicine, affinity depleting membranes in blood-related proteomics, and biorecognition elements for biosensors. The research programme have been managed as five workpackages and to be completed over a 24-month period: WP1: Optimising oligomerisation conditions; WP2: Reactive electrospinning of the oligomers to form molecularly imprinted nanofibres; WP3: Sustained active agent release for regenerative medicine using molecularly imprinted nanofibres; WP4: Affinity depletion of highly abundant proteins with electrospun nanofibres; WP5: Reactive electrospun nanofibres as recognition elements for biosensors via two different approaches as immunoaffinity and molecular imprinting. We thought that this research has the potential to revolutionise the production of both molecularly imprinted nanostructures and electrospun nanofibres leading to a paridigm change in the utility of such materials. Inexpensive, mass manufacture is now the principal limiting factor in the wider application of MIP materials, and improved scaffolds with smart properties are an essential component for the advance of implantable tissue constructs. Very recent work has demonstrated the potential for grafting MIPs on nanofibres, but the seemless integration of the two nanofabrication technologies would lead to a breakthrough in clinical exploration. In this respect, each workpackage could be summarised as

WP1: Optimizing oligomerization conditions
Task 1.1. Evaluation of optimal condition for oligomerization
Task 1.2. Reactive electrospinning of oligomers without molecules to be templated
Report: Under this workpackage, we optimised the oligomerisation conditions for different functional monomers before electrospinning process. Herein, we also evealuated the electrospinining of oligomers and the stability of the nanofibres produced. In this respect, we crosslinked the nanofibres via in-situ and post-crosslinking approaches to compare structural stability of the nanofibres in different kinds of solvents. As a result, we determined optimum conditions for hydrophilic/hydrophobic monomers during reactive electrospinning process.

WP2: Reactive electrospinning of the oligomers to form molecularly imprinted nanofibres
Task 2.1: Preparation of molecularly imprinted nanofibres for all issues.
Task 2.2: Characterization of molecularly imprinted nanofibres.
Report: Under this workpackage, we prepared epinefrin and pyruvic acid imprinted reactive electrospun nanofibres beside functional nanofibres including glycidyl groups. These nanofibres were characterised by Fourier transform infrared spectroscopy (FTIR) and scanning electron (SEM) and atomic force (AFM) microscopy measurements. In addition, water contact angle and surface energy measurements were performed after returning to Turkey.

WP3: Sustained drug release for regenerative medicine with molecularly imprinted nanofibres
Task 3.1: Optimization of sustained drug release conditions.
Task 3.2: Cell growth, proliferation and differentiation under optimal conditions using the nanofibres.
Report: Under this workpackage, we imprinted epinefrin, the one of the cell promoters, and evaluated its controlled release from reactive electrospun nanofibres. Herein, we used amino acid based functional monomer, N-methacryloyl-L-phenylalanine, as a coordinating monomer due to its hydrophobicity that make easily construct a stable template:monomer complexes through hydrophobic interactions. The controlled epinefrin release was performed while investigating the effecting factors such as pH, time, ionic strength and temperature.

WP4: Affinity depletion of high abundant proteins with molecularly imprinted nanofibres
Task 4.1: Adsorption from aqueous solutions.
Task 4.2: Depletion of albumin and IgG in singular and simultaneous manner from plasma
Report: Under this workpackage, we followed dye-affinity protein depletion strategy by using polycaprolactone nanofibres as a adsorbent. Herein, we activated polycaprolactone naofibres through a partial hydrolysis by using dilute ethanol amine solution in order to insert active hydroxyl group into polymeric chain. Then, the one of the mostly used dye ligand, Cibacron Blue F3GA was immobilised on the nanofibres activated. After characterisation studies, we evaluated the depletion parameters while considering the effects of pH, concentration, interaction time, ionic strength and temperature. Finally, we used these nanofibres for albumin depletion from human serum samples as well.

WP5: Molecularly imprinted nanofibres as recognition elements for biosensors
Task 5.1. Use of the nanofibres as biorecognition elements on piezosensor.
Task 5.2. Use of the nanofibres as biorecognition elements on electrochemical sensor.
Task 5.3. Comparison of the sensor performances.
Report: Under this workpackage, we performed two different strategies, immunoaffinity and molecularly imprinted biosensors. For the first one, we synthesised the glycidyl methacrylate nanofibres through reactive electrospinning approach. After that, we immobilised anti-albumin antibodies on these nanofibres as a recognition element. Immunoaffinity albumin detection conditions were optimised via evaluating the parameters such as interaction time, pH, concentration and ionic strength through impedimetric measurements. Finally, this biosensors were used fro albumin detetection from real samples by using human serum. In the second one, we developed a pyruvic acid, the one of metabolites of protein metabolism disorders, imprinted nanofibres to show the effeiciency of reactive electrospinning approach. In the same way, we evaluated the effective parameters for this section as well.

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