Well spun medical innovations

 

Professor Andrew Steckl, an electrical engineer by origin, and his fellow researchers at the Nanoelectronics Laboratory have been exploring the uses of coaxial electrospinning – a more complex form of electrospinning. 

 

The process involves combining two or more materials into a fine fibre. The team has been experimenting with material combinations to create new applications in healthcare, from brain cancer treatment to contraception.

 

A basic electrospinning setup consists of a syringe pump connected to a nozzle plus a high-voltage power supply and a grounded substrate, on which fibres are collected. 

 

‘With coaxial electrospinning, a coaxial nozzle is used and different polymer solutions are fed through the inner and outer openings,’ explained Steckl. ‘The syringe pumps are programmed to certain flow rates, which push the fluid out. When a high voltage is applied, the polymer solution becomes charged and a very thin liquid jet is extracted. 

 

‘The behaviour of the jet is controlled by a combination of viscoelastic and charge repulsion forces. When first ejected from the nozzle, the liquid jet is relatively thicker, the viscoelastic force dominates and the liquid jet travels in a straight path. During its motion the jet stretches and becomes thinner.’ 

 

At some point, the charge repulsion becomes the dominant force and the jet motion becomes unstable and undergoes a vigorous whipping action. ‘This reduces the diameter even more and accelerates the evaporation of the solvent. Solidified polymeric nanofibres are then deposited on the collector, forming a non-woven porous membrane,’ said Steckl. 

 

The critical benefit of the technique is that it combines different polymers to create a single material with unique properties that cannot be found in nature. ‘What we are doing is essentially producing a fibre within a fibre,’ he added.

 

The team has so far succeeded in electrospinning fibres with a large variety of materials, primarily organic polymers. Examples include synthetic polymers (PCL, PEG, PLGA, PVP, PLA, PMMA, PU, Eudragit and PEO) and natural polymers (chitosan, collagen, gelatin, DNA, cellulose and silk). 

 

In addition to polymers, any material dissolved or dispersed in solution is a possible candidate for coaxial electrospinning. ‘One of the most attractive aspects in coaxial electrospinning is that a non-electrospinnable solution in one layer can be electrospun with assistance from an electrospinnable solution in the other layer,’ said Steckl.

 

But the technique is deceptively simple and comes with its fair set of challenges. ‘We are dealing with two polymer solutions which can interact once they are ejected from the nozzle,’ said Steckl. ‘Dealing with the miscibility of the polymers and their solvents is a complicated challenge. For successful coaxial electrospinning, interactions between core and sheath solutes and solvents are critical considerations. No precipitation or chemical reaction should occur when they come in contact,’ he added. 

 

According to Steckl, while material costs could present some challenges for scale up, the process is not energy-intensive. ‘Although a very high voltage in the several kilovolt range is used for electrospinning, the overall power consumption is not very high because of a very low electric current,’ he said. ‘For lab-scale equipment, a conventional power outlet (115V/20A circuit) is sufficient to operate the electrospinning process. The fabrication process is fairly straight forward. Equipment for manufacturing large area and high throughput conventional (single fluid) electrospinning has been developed and is already in use for commercial products. However, coaxial electrospinning is more complicated to scale-up.’

 

Steckl suspects the more successful commercial outlets for coaxial electrospinning will be in high-value medical applications, such as implanted membranes for controlled release of multiple drugs, post-surgery repair and the sealing of tissues. ‘In these cases,’ he said, ‘the membrane material needed is quite limited, but its medical value is very high.’

 

He also added that new approaches for coaxial electrospinning, including a nozzle-less form, are being explored that have the potential for manufacturing-level fabrication.

 

One of the most significant new applications for the technique has been in the localised treatment of brain tumours. ‘Glioblastoma multiforme (GBM) is the most common and extremely aggressive primary brain cancer. It has a five-year survival rate of 5.1%. A marked resistance to multimodal chemo and radiotherapy (RT) and a mean survival time of less than 15 months,’ explained UC Senior Research Associate, Daewoo Han. ‘Due to the blood-brain barrier, local delivery of therapeutics to the central nervous system has been investigated by placing biocompatible and biodegradable polymeric wafers inside the tumour resection cavity. 

 

‘As GBM recurrence occurs close to the original lesion area, effective local cancer therapy reduces the recurrence rate. Although a carmustine (BCNU)impregnated polyanhydride wafer, Gliadel, is clinically available, there is a strong demand to provide a novel long-term drug delivery vehicle for more effective, localised therapy.

 

‘Using coaxial electrospinning, we managed to incorporate the carmustine drug into the fibre core and encapsulate it with a hydrophobic sheath. Biocompatible hydrophobic sheath enables gradual wetting from the outside of the disc, leading to exceptionally long-term release of up to 150 days.’

 

While a conventional solid wafer releases most of its drug cargo very quickly, this multi-layered membrane can release the incorporated drug in a sustained way, noted Han. 

 

‘Moreover, with our approach we can incorporate two different anti-cancer drugs into the multi-layered membrane discs and control them to be released sequentially or concurrently, which not only brings a therapeutic synergistic effect but also prevents tumours from developing drug resistance,’ said Han. 

 

But why are electrospun fibres so suited for drug delivery? According to Steckl, the large surface area and custom properties of the fibres make them an ideal drug-delivery system. ‘When you select functional polymers and design the fibre structure, one or multiple drugs can be conveniently incorporated into these fibres and very unique release kinetics can be obtained,’ explained Han. 

 

Besides drug delivery, other promising applications  in healthcare include cell scaffolds for tissue engineering and repair, as well as antimicrobial textiles and wound dressings. ‘Considerable research has been conducted for these applications and there is significant potential for these to be translated into the clinic within five to 10 years.’

 

The lab is also working on alternative contraception for women, where electrospun materials are being adopted to create new contraceptive devices that do not involve hormones. 

 

‘Electrospun membranes have extremely high surface-to-volume ratio, leading to very fast responses to external stimuli or environmental change. We have investigated bio-responsive nanofibre devices for contraceptive application that do not require any hormonal agents,’ explained Han. 

 

The fibre membrane is made of hydroxypropyl methylcellulose (HPMC) and Carbopol 974P composite polymers. ‘The device provides a mucoadhesive and highly viscous hydrogel network from HPMC and a pH buffering capacity with high viscosity from Carbopol polymers. Upon contact with seminal fluid, HPMC/Carbopol nanofibre membranes immediately convert into a hydrogel, providing a physical barrier by swelling, and with an acidic pH environment that acts as a spermicidal agent,’ said Han. 

 

‘This non-hormonal bio-responsive contraceptive device is highly attractive for women’s health, providing excellent spermicidal performance without affecting the user’s hormonal conditions.’ The next phase will involve translating this research into a clinical test to assess viability and mass production. 

 

The team has also achieved novel material properties by combining an electrospinnable polymer core solution and non-electrospinnable Teflon sheath solution to create Teflon-coated polymer fibres. The result being a microporous, super hydrophobic or oleophobic membrane. ‘A similar approach was used to form tissue-engineered scaffolds that provide both good mechanical properties due to the synthetic polymer core, and excellent biocompatibility from the gelatin sheath,’ said Steckl. And, the list goes on.

 

While UC’s research group is not the first to study electrospun fibres, its multidisciplinary research group led by Steckl – who has no biomedical background – is producing big results. And, his electrical engineering background seems to have given him a somewhat unique outlook.

 

‘My training and background as an electrical engineer has been in semiconductor devices. So, I’m a “device” person at heart,’ he said. ‘A definition of a device for me is a means for transforming a readily available item into a scarce, desired item. For example, converting voltage to current, or photons to electrons. 

 

‘That device mind-set has enabled me to see other opportunities beyond the semiconductor world. For example, into materials, where combining materials in novel ways can provide properties not otherwise available and biomedical devices – where we can tap biochemical reactions to produce detectable changes in optical properties, and so on.’

 

His work validates the value of interdisciplinary research, particularly when dealing with materials. But it is also about curiosity, said Steckl. ‘I really try to instil in my students a sense of curiosity. Of looking for opportunities to use your knowledge and new ways of looking at devices, so we can make a difference.’