Skin in the game

IN THE game

THE OUTER LAYER OF HUMAN SKIN (THE STRATUM CORNEUM) IS JUST 0.02MM THICK, BUT PRESENTS A MAJOR BARRIER TO THE PASSAGE OF SUBSTANCES BOTH INTO AND OUT OF THE BODY. COLLABORATIVE RESEARCH LED FROM IRELAND IS TACKLING THIS CHALLENGE HEADON, IN ORDER TO MAXIMISE THE EXTRAORDINARY POTENTIAL OF THE SKIN AS A GATEWAY FOR THERAPEUTIC AND DIAGNOSTIC APPLICATIONS.BY SORCHA CORCORAN

Imagine a world where the hypodermic needle was no longer the go-to form of skin penetration for everything from vaccines to managing diabetes – and on top of this that there were pain-free methods of delivering drugs and sampling biomarkers through the skin that resulted in increased patient adherence and treatment efficacy. →

Scientists at Tyndall National Institute in Cork are striving to make this type of world a reality, backed up by a 20-year track record in microneedle research and development (R&D). Led by Principal Researcher Dr Conor O’Mahony, the team there is focused on the development of micro transdermal interface platforms (MicroTIPs). These wearable systems combine elements of transdermal delivery, diagnostics and communications capabilities. They are essentially ‘smart patches’ incorporating microneedles that interact with the outermost skin layers in a minimally-invasive manner.

Generally around 0.5mm in length, the microneedles developed by Tyndall are sharp-tipped, micron-scale structures made using advanced microfabrication technologies. They are available in a variety of solid or hollow formats. Made from silicon or polymer, the solid microneedles create transient perforations in the stratum corneum, thereby increasing the permeability of the barrier layer to large molecules by several orders of magnitude. Hollow silicon microneedles include a narrow bore through which therapeutic agents can be infused directly into the upper skin layers.

Because of their tiny length, microneedles don’t strike the nerve endings or blood vessels that lie deeper in the skin, and therefore their application is perceived as “The wearable patch technology will allow a controlled and programmable delivery, detect that the dose has been delivered, and communicate this back to the doctor, helping to determine if the treatment is efficacious and being adhered to properly by the patient.”

painless by the user. In addition to deliveryfocused technologies, some of the latest cutting-edge research at Tyndall is using microneedles to test for biomarkers that exist in the skin’s interstitial fluid in order to detect and understand how the body behaves in response to certain drug formulations or stimuli.

Tyndall works with R&D teams worldwide to develop new transdermal interface technologies based around microneedles. “Tyndall is one of the top centres in the world for microneedle research. Many of the other academic groups working in this field as well as numerous global industry partners have accessed microneedles developed by Tyndall at some stage for use in their own research,” says Carlo Webster, Senior Strategic Business Executive at Tyndall.

“The development of MicroTIPs is worldleading in terms of transdermal drug delivery, diagnostics and systems integration. It is focused on building a whole ecosystem around microneedles, including highly miniaturised sensors, control electronics, wireless communications and artificial intelligence. Work so far has experimentally confirmed the feasibility of combining micropumps with microneedle arrays for applications in transdermal drug delivery.

“The wearable patch technology will allow a controlled and programmable delivery, detect that the dose has been delivered, and communicate this back to the doctor, helping to determine if the treatment is efficacious and being adhered to properly by the patient.”

Following in the same vein, Tyndall is working with electronics manufacturing services provider Sanmina Corporation on ELSAH, a four-year collaborative project in the area of electronic smart systems. Coordinated by the Austrian Institute of Technology and including a total of ten European partners, the objective of this

project is to develop and demonstrate an integrated wearable sensor system (the ‘ELSAH patch’) for microneedle-based, continuous monitoring of lactate and glucose levels.

The ultimate aim of ELSAH and similar research programmes is, for the first time, to create wearables that provide truly evidence-based support to healthy living. This is expected to cause a reduction in the prevalence of diseases such as diabetes, obesity, cardiovascular diseases and high blood pressure.

When it comes to drug delivery, a limitation with microneedles up until now has been their ability to deliver the large volumes possible with the hypodermic needle, according to O’Mahony. However, this is changing: “An R&D partnership with West Pharmaceutical Services has led to Tyndall showing how hollow microneedles can achieve highly controllable infusion rates, delivering 1-4 millilitres over a period of tens of minutes,” he notes.

Employing over 1,000 people across two different manufacturing sites in Dublin and Waterford, West Pharmaceutical Services has been collaborating with Tyndall on developments of drug delivery systems for injectable medicines since 2016.

“West Pharmaceutical Services is a global leader of containment and delivery systems for injectable drugs. We recognise Tyndall as one of Europe’s leading ICT research centres and have been pleased to partner with them,” says Dr Alex Lyness, Senior Manager, Research & Technology at West Pharmaceutical Services.

“We have had great success engaging with Dr Conor O’Mahony and his impressive research team focused on applying cuttingedge sensing technologies to future needs in drug delivery. We have learnt a lot through our collaborative project.”

Tyndall is one of the key partners involved in Moore4Medical, a multimillion euro EUfunded project led by Philips Research in the Netherlands. Leveraging the wideranging expertise of 66 partners from 12 countries, Moore4Medical is developing open technology platforms that will accelerate innovation and applications for emerging medical science. Tyndall is leading one strand of the project, which is focused on developing a wearable autoinjector platform for intelligent drug delivery, intended to improve patient adherence and reduce the cost of medication programmes.

Based out of Sligo, a team of ten people led by Jeff Redmond, Combination Products Director, Science & Technology at AbbVie, is also part of the Moore4Medical project and is working closely with Tyndall. AbbVie employs around 5,000 people in Ireland and makes many of its pharmaceutical products here, including drugs for treating hepatitis, eye diseases and arthritis.

“The use of multiple microneedles in a patch to allow drugs to absorb into the skin would be a much more acceptable approach, especially for people who don’t like injections.”

“As a Moore4Medical partner, we are researching new ways to simplify autoinjector pens and make them more intelligent using temperature sensors. We also want to establish whether we can extend the shelf life of a prescribed drug by reconverting it into liquid and freezedrying it so that it is in powder form. This is very novel,” says Redmond.

“AbbVie is exploring several new methods for delivering medicines that are more precise and impactful, as well as being simpler and easier to use for the patient. The use of multiple microneedles in a patch to allow drugs to absorb into the skin would be a much more acceptable approach, especially for people who don’t like injections.

“The original technology problem of getting microneedles manufacturable and scalable has been nearly solved and the next stage is to look at specific applications for them. Not every drug can be delivered this way, but we are interested in how it might open up a pathway for some products.”