Strategies for faster R&D: Change one variable at a time

 

When the Wright brothers were trying to make their great aeronautical leap forward, they didn’t just throw feathers and motors at the problem to see what happened. Rather they tried to determine which of the three key challenges to mastering flight was most critical: wings, engines or control? Looking at the effect of changing one variable at a time helped them to determine that the critical weakness was in control, meaning that they could innovate in this aspect and set the way to their landmark achievement.

Wright brothers

It brings to mind a project where we were developing a cryosurgery probe to kill breast tumours by freezing. We had a functioning system that worked off a heavy gas cylinder but had recently made the exciting discovery that a simple 1 litre flask could be used to drive the probe directly from liquid nitrogen. This was easier to use, smaller, and cheaper, and so a sure-fire commercial advantage for our client. However, when we scaled our new technology up to full size it didn’t work. It wasn’t just slow, it was completely hopeless, and failed to get even remotely cool to the touch. Yet the only difference was the size.

But was it? The new flask was bigger, that’s true. But actually, the bung that sealed it was also a larger diameter. It was also deeper. And it was a different material. And the dip tube was longer to reach to the bottom of the larger flask.

On reflection, there was quite a lot different about the new system, and we had changed it all at once. This meant we didn’t know which thing we had to change to resolve the problem. There was a deadline approaching, and it was tempting to just jump to the end and try stuff in the hope it would work, but with planning we figured that we had a chance to solve the problem in two weeks by starting with the working miniature system and changing one feature per day until we had created the large system. 10 days, 10 features- surely one of those would be the key?

On day 1, we machined a new bung for the small flask out of the same material as we were using for the scaled-up system. It worked perfectly. On day 2 we scaled it up to the larger diameter- still great. On day 3 we extended the dip tube- still chugging along nicely. On day 4 we machined a deeper bung… nothing. A complete failure to freeze. It was now a simple deduction that the deep mass of rubber was sinking heat into our cryoprobe and preventing it from freezing. We added insulation around the tube as it passed through the bung and made ourselves a perfectly working full-size system. All in less than a week, which means we still had time to write the final report for our client who was visiting the next week.

This technique is widely used in science, and is particularly powerful when you have one prototype that you know works, but can’t figure out why another comes up short. If changing one variable at a time does not reveal the problem, there is probably one or more interactions between the variables. We can use techniques in a field of engineering called Design of Experiments to reveal them, but that is a subject for another day.

In the next article we look at how to speed up the development cycle by saving tooling until later.

Please contact Keith Turner if you think we could help you or if you would like to be alerted to the next strategy.

Strategies for faster R&D: High speed video

When the world’s fastest men competed for the 100m Olympic gold medal in Athens, 2004, four athletes crossed the line in a blur. But the event organisers didn’t just squint and pick a winner. Rather, they used high speed video to slow down the motion and changed the method of observation so that it became clear that the new champion was Justin Gatlin.

Olympics

It brings to mind a project I once worked on where we were trying to control air flows inside a dry powder inhaler. The powder kept ending up in the wrong place, and nobody knew why. We had tried different geometries, but to no avail. Finite element modelling hadn’t helped either.

“You can’t see what’s going on because it’s opaque”, people said. Well, true to a point, but with only a little effort it was easy to prototype transparent parts and set up a video camera at 2000 frames per second to visualise the particles. It was beautiful, and you could see each particle whirling about on its journey from the hopper to its final resting place stuck on the side wall. It soon became apparent that the problem started as the particles crossed a particular join in the moulding. This enabled us to focus our attention on that particular problem spot, and we soon found a leak. It was then a simple engineering job to seal the leak and recover the performance that was expected.

We have used high speed video on numerous projects at frame rates over 100,000 per second. Sophisticated techniques can be used to quantify stresses in moving parts and relate their behaviour to material properties. There are also more sophisticated variations, such as stroboscopes and particle image velocimetry, which uses pulsed lasers to visualise the movement of particles over tens of microseconds.

Have you ever had your prototype working, only to see it do something unexpected in its next iteration? In the next article, we look at a technique for staying at the best performance.

Please contact Keith Turner if you think we could help you or if you would like to be alerted to the next strategy.

Strategies for faster R&D: Critical Observation

Nearly 200 years after its inception, Darwin’s theory of evolution still lives as one of science’s greatest breakthroughs. Yet Darwin made this monumental advance in understanding without the use of any computer, internet, or modelling software. He used direct, critical observation and a sceptical mind.

Darwins finches

It brings to mind an occasion when I was trying to work out why an ink-jet filter was blocking. The blue pigment sludge that built up on the filter over 30 minutes was causing the printhead to fail way short of its 100 day lifetime target. We had tried all the obvious things: bigger holes, shaking the mesh, scraping it clean, measuring the reduction in flow-rate, but all without success.

Because the pigment particles were only 1 micron across, we found it hard to work out what was going on. But is it really that difficult? There was a microscope on the bench next door and one of those swan lights that lets you change the illumination angle. With some new brackets and a special transparent cap, it was possible to set the filter up and running on the microscope and watch the particles. As they approached the mesh, some would stick to the wire material. Then the next would stick to the first particle, and another until long chains were formed that bridged the hole and it blocked. Then I tested a mesh with smaller holes and to my amazement, it actually took longer to block. As the particles approached the small holes, they sped up to get through the restriction, rather like a rapid in a river. All this extra speed caused them to dislodge other stuck particles and prevent blockage.

So the answer was to make the holes smaller, not bigger! And it was understood simply by looking very carefully.

In a modern lab there are all sorts of ways to help you look. Optical microscopes, electron microscopes, laser strobe systems are just a few of them.

In the next article, we look at one particularly useful way to assist critical observation.

Please contact Keith Turner if you think we could help you or if you would like to be alerted to the next strategy.

Strategies for faster R&D

Could you really cut R&D times by a factor of five?

Senior R&D managers are constantly under pressure to deliver their new innovations to the market. A plan with stage gates is agreed: proof of principle; detailed design; verification; validation; launch in 18 months from now. But it is frequent that five years later, despite everyone’s best efforts, the product still isn’t on the market. A new plan is in place to launch in 18 months from now.

Does this sound familiar? If it does, you are not alone. Executives want to reward those who can cut time to market yet many innovations get stuck in a cycle of insufficient performance, unexpected failures and unacceptable cost. Months turn into years.

At Springboard we employ strategies to reduce these timescales and we repeatedly find that five-year old problems can indeed be overcome in a year. The trick is not to deal with the string of problems more quickly, but to avoid them all together. In the coming months, we will be sharing some of these strategies through a series of blog articles. If you’d like an alert when the next article is released, contact Keith Turner and ask to be sent the link or connect on LinkedIn.

Springboard is a technical consultancy that solves difficult engineering and physics problems in short timescales, helping companies to get successful innovations to market more quickly.

Let the patient decide: an autoinjector with patient-settable injection time

Autoinjectors have to inject the drug within a reasonable range of time.

The minimum injection time is set by potential discomfort.

The maximum injection time is set by one or more of:

  • The patient wanting the injection to be over as soon as possible;
  • It could be difficult to hold an autoinjector steady for more than a few seconds; and/or
  • We cannot expect people to count time accurately, so they might not wait long enough before removing the autoinjector if it takes more than a few seconds.

However, patients are diverse: some might prefer the injection to be over as soon as possible; but others might prefer a longer, more gentle, injection.

So can we design a device to let the patient set the injection time before starting the injection?

There are several injection devices on the market that do this, but they are electronically controlled and so carry a burden of cost and complexity which could not be justified in many cases.

We set ourselves the challenge of designing a mechanical autoinjector where the user can set the injection time, and this is what it could look like:

Autoinjector with patient-settable injection time

 

It is obvious to see that the patient (or carer, parent, doctor, nurse etc.) can move the lever on the right to set the injection time.  Here, they can choose anywhere between 5 seconds and 30 seconds.

The user can then remove the green cap on the left hand end, and press against their skin to trigger the start of injection.

If you are interested in this concept, or any other drug delivery device development questions, please get in touch with Tom Oakley at Springboard.

Appendix: the limits on device design

The article above is written from a user-centred design perspective.  In practice, there are engineering limitations on injection time.

Autoinjectors with low viscosity drugs and/or small injection volumes can inject fast, such as 3 seconds for EpiPen. [1]  On the other hand, some biologics need up to 15 seconds for 1 mL injections. [2], [3]

There are some drugs which require a volume of more than 1 mL to be injected, which could require a longer injection time again.

Typically, the reason that autoinjectors cannot inject viscous drugs quickly is that it takes a large force to push the drug through the needle quickly, and increasing the force can break the syringe or cause problems like creep during storage before use.  We could use a larger diameter needle, but patients prefer thinner needles. [4]

Acknowledgements

Many thanks to my Springboard colleagues Jafarr Adam for the autoinjector CAD model and decals and Rachel Lewis for the renderings.

References

[1] National Institutes of Health, USA

[2] Cimzia AutoClicks Instructions for Use

[3] Enbrel Instructions for Use

[4] Anderson B and Redondo M, “What can we learn from patient-reported outcomes of insulin pen devices“. J Diabetes Sci Technol. 2011

3 sure steps to faster R&D

Are you an R&D manager who would like to get your products to market more quickly?

You may have suffered project delays such as: just can’t get it working; people seem to be busy on other things; you thought it was all fine but after it was all tooled problems started to occur.

Or the worst one of all: a product recall because of an adverse patient safety event.

Everyone wants to avoid problems like these, but the big question is how can you greatly increase the chances of success?

Here’s one good answer:

Many organisations go straight in to step 2. Design the product, do a few tests and then commission production tooling. But often, the production environment is slightly different from R&D. A few changes are made. Aspects that “just worked” before, now “don’t always work”. Problems grow and it is mighty painful to iterate your design within the constraints of already-made tooling. You can spend ages trying to get it to work with minor modifications, and eventually accept that you have to spend that $5m on tooling and automation again. Ouch.

Step 1 is the key to fast, low-cost R&D. If it costs, say $100k to properly understand the science, that is peanuts compared to spending the $5m twice for step 3. A good understanding comes not only from scientific insight, but rigorous and methodical testing of the failure modes, backed up by sufficient statistical evaluation to be sure you have confidence in the results.

Very many companies I work with don’t do step 1 to sufficient detail. As a result, they often suffer delays of, quite literally, many years. For a product worth $50m a year, it’s mad to suffer that loss for the sake of a few $100k up front for a few months. So my advice is to invest effort in step 1 to reduce risk as much as you can. Get the best people you can find to do so. And make sure that when you spend the big money in step 3, you are certain that you’re only going to do it once.

Nanopatterning for medical applications

Nanotechnology appears in popular culture as a cure for everything from cancer to balding. In science nanotechnology is an umbrella term for a variety of structures and molecules used in optics, MEMS, materials, chemicals and some biological systems.

In this new blog series, we shall explore nanopatterning (the engineering of nanoscale structures on surfaces), its prevalence in nature, manufacture and application to medical devices.

Drawing inspiration from nature

Figure 1 – Sunset moth scales macro by Johan J.Ingles-Le Nobel, Cropped, CC BY-NC-ND 2.0

Nanoscale structure plays a fundamental role in numerous biological systems, and in some cases has developed to aid an organism’s survival and proliferation. Nanostructures can impact on the wetting and optical properties of a surface as well as their molecular interactions. Adjusting the spacing and morphology of these structures can change how they behave in contact with solids, liquids, biomolecules and how they catalyse certain chemical reactions. Organisms rely on these structures to stay clean, aid communication, and promote or prevent adhesion. The presence of ordered micro- and nanoscale structure appears to the human eye as iridescence created by the selective scatter of certain wavelengths of light.

Dry adhesion

While the exact mechanisms of adhesion differ, the feet of various tree frogs, insects and lizards rely on nanoscale and microscale structure to cling to and climb vertical or inverted surfaces. Perhaps the most famous climbers that rely on adhesion are geckos. Gecko climbing ability comes from millions of hair or setae on their feet which experience Van der Waals interactions with the substrate [1]. Individually the interactions are weak but collectively give the gecko the adhesive force necessary to hold up to four times its own weight. These setae evolved from tiny hair-like growths present on the bodies of all geckos [2]. Generating setae involves lengthening these hairs and splitting the tips to produce micro- and nanoscale hierarchical structures. Curiously, researchers have found that several gecko species developed these adhesive abilities independently when faced with an environment where climbing aided survival, losing them again over time when the environment changed [2].

Figure 2 – Gecko’s secret power by Matteo Gabaglio, Annotation, Order, CC BY-SA 3.0

In the last 20 years, the adhesive strength, reusability and non-fouling properties have attracted increased interest in gecko-inspired adhesives. Manmade micro- and nanoscale hierarchical patterns produced by embossing, casting or roll-to-roll printing have resulted in several tape and patch analogues. As popular as this topic has been, it has not been without its challenges. In addition to difficulties in manufacturing, gecko mimetic adhesives experience poor adhesion to wet and contaminated surfaces [3]. Water disrupts the surface interactions which is also the reason why PTFE (which exhibits weak Van der Waals dispersion forces) is one of few materials that a gecko can’t climb on [4].

Wet adhesion

For wet adhesion it makes more sense to look to water dwelling organisms. Mussels create an adhesive containing a tyrosine residue called DOPA, which has seen increased attention. DOPA and similar coatings are key to allowing nanopattern based adhesives to work in wet conditions. The structure of DOPA allows mussels to form strong and reversible bonds with a variety of substrates [5]. Mussels use this to anchor their pads to rocks and withstand significant punishment from tides and currents. Researchers have so far used DOPA and analogues in an attempt to develop improved surgical adhesives, particularly for amniotic sac repair[6]. Some have combined this with the gecko adhesive above to produce all-purpose hybrids named “Geckel” [7]. These hybrid surfaces consist of a microstructure coated in mussel mimetic adhesive to achieve adhesion in wet or dry conditions. As with any novel technology, achieving a robust product and scalable process has likely limited its implementation. Alternative adhesive-free-adhesives for wet conditions look to the octopus for inspiration. Although an octopus sucker is far larger than the other features we have discussed, its design has been the inspiration for many micro- and nanoscale mimics. Octopodes use suckers as muscular-hydrostats where the internal volume is increased to generate low pressure (≤ 2.7 bar below ambient pressure when submerged) [8]. The octopus vulgaris differs from other species in that it utilises a ball in cup morphology to maintain adhesion and resist shear [9].  Its unique morphology creates two regions of low pressure with the ball protrusion sealing the two volumes and mechanically locking the sucker configuration.

Figure 3 A.) Suckers of octopus by Steve Lodefink, Suckers of octopus by Steve Lodefink, CC BY 2.0. B.) Illustration of sucker adhesion mechanism of Octopus vulgaris.

Octopus mimetic surfaces produced by vacuum casting use microscale suction cups (~ 100 μm) with a similar ball in cup morphology to generate suction [10]. This approach has seen some applications targeting skin but so far appears limited to working on flat surfaces and generating relatively weak vacuums. Some commercial materials such as REGABOND micro-suction foam are aimed for the general consumer market and work on a similar principle [11].

Repulsion

Some plants use micro- and nanoscale texture for an alternative purpose, the “lotus effect” being the most famous example. The lotus effect arises from the ability of micro- and nanostructures to amplify the natural tendency of a surface, making hydrophobic materials superhydrophobic. A lotus leaf has arrays of hydrophobic waxy hierarchical micropillars on its surface [12]. The high roughness and low contact area of these pillars forces water droplets to adopt a Cassie-Baxter state where air is trapped below the fluid meniscus. To reduce the Gibbs free energy of the system the water droplets adopt a highly rounded shape. This allows them to slide off and pick up dirt in the process, keeping the leaves free of debris. The springtail takes this effect further with a cuticle that has a re-entrant or overhanging surface structure [13]. These structures resemble nanoscale mushrooms which pin the fluid line to prevent even low surface tension fluids from fully wetting the surface in what is referred to as oleophobicity. The springtail uses this for survival creating an air trap around its body when submerged. Both superhydrophobicity and oleophobicity are found in industry, often finding use in semipermeable membranes and self-cleaning coatings. The surface energy and morphology of the of the coating material dictate the degree of nonwetting. These structures are still vulnerable in high pressure applications where the structures or the film of air can collapse.

Figure 4 – The springtail cuticle has been used as inspiration for manmade re-entrant omniphobic surfaces A.) Springtails. B.) Springtail submerged in water. C.) Springtail submerged in oil. Scale bars: 1 mm. Image from R. Hensel et al. [13], CC BY-NC 3.0.

A very different, and potentially more robust approach is used by the pitcher plant. In these plants a microporous surface is used to retain a lubricating fluid film. The films are created when water or nectar becomes locked into microscale textures in the surface of the plant creating a continuous layer of lubrication. The film is immiscible in the oil on the insect’s feet resulting in a surface that easily shears away on contact and very low friction. Unlucky insects which land on the plant’s lip end up sliding down into the plants digestive fluid to become a snack. The film is replenished by capillary effects which redistribute fluid across the film surface. The advantage of this arrangement is the immiscible fluid is incompressible unlike the air used by the lotus leaf and allowing it to serve in higher pressure applications.

Figure 5 A.) Sarracenia pitcher anatomy by Noah Elhardt, Sarracenia pitcher anatomy basic, marked as public domain. B-E.) Microstructure of N. gracilis waxy surfaces. Scale bars shown. Image from Bauer et al. [14], CC BY 4.0.

Pitcher plant mimetic surfaces have been named “slippery liquid-infused porous surface(s)” or SLIPS. These surfaces can be tailored and often use a lubricant which is immiscible in the target substance. The porous substrate consists of open interconnected pores to retain the lubricating fluid. While evidence of industrial application is limited, it is a promising route to stain-resistant coatings for optics.

Optical effects

Certain organisms use micro and nanostructures to produce iridescence that makes the rest of the animal kingdom pale by comparison. While many rely on chemicals for coloration, using microscale structures is called structural coloration or physical colour. Butterflies use this effect for visual communication to find mates or scare away would-be predators. The most famous example is the Morpho butterfly native to Latin America [15]. The Morpho is an underwhelming (but well hidden) shade of brown with its wings closed but a bright iridescent blue when they open. The blue iridescence comes from tiny chitin gratings on the surface of a butterfly’s wings [3]. The layering of these structures causes diffraction and constructive interference of visible light waves according to Bragg’s law, producing the visual perception of a very intense colour [17]. The angle at which the butterfly is observed changes the colour we perceive the wings to be, shifting from blue to copper when viewed at an angle. The papilionidae family of butterflies use similar architectures combined with fluorophores to harvest NIR light to create luminescence [18].

Figure 6 – A.) Blue morpho butterfly by Gregory Phillips, Blue morpho butterfly, CC BY-SA 3.0. B.) Nanoscale Structures on a Blue Morpho Butterfly Wing Image from Potyrailo et al. [19], CC BY 4.0.

The unique physical, chemical, and optical properties of these structures have led to interest in several industries. Extensive research and development efforts have gone into mimicking these effects for energy harvesting, sensing and photocatalysis [19]. For medical applications they have a role to play in optical biosensing. By coating a grating in environmentally responsive molecules or hydrogels an optical indicator can be constructed. Structures such as this have been coined hydrogel-actuated integrated responsive systems (HAIRS)[20].

We hope that this has been an interesting read. The next edition will discuss the practicality of fabricating these structures, and their suitability for parts used in medical devices.

If you have any questions about micro engineering and smart surfaces, please do not hesitate to get in touch or find me on LinkedIn.

Bibliography

[1]        K. Autumn and N. Gravish, “Gecko adhesion: evolutionary nanotechnology,” Philos. Trans. R. Soc. A Math. Phys. Eng. Sci., vol. 366, no. 1870, p. 1575 LP-1590, May 2008.

[2]        T. Gamble, E. Greenbaum, T. R. Jackman, A. P. Russell, and A. M. Bauer, “Repeated origin and loss of adhesive toepads in Geckos,” PLoS One, vol. 7, no. 6, 2012.

[3]        A. Y. Stark, T. W. Sullivan, and P. H. Niewiarowski, “The effect of surface water and wetting on gecko adhesion,” J. Exp. Biol., vol. 215, no. 17, p. 3080 LP-3086, Sep. 2012.

[4]        A. Y. Stark et al., “Adhesive interactions of geckos with wet and dry fluoropolymer substrates,” J. R. Soc. Interface, vol. 12, no. 108, p. 20150464, Jul. 2015.

[5]        J. H. Waite, “Mussel adhesion – essential footwork,” J. Exp. Biol., vol. 220, no. 4, p. 517 LP-530, Feb. 2017.

[6]        M. Perrini, D. Barrett, N. Ochsenbein-Koelble, R. Zimmermann, P. Messersmith, and M. Ehrbar, “A comparative investigation of mussel-mimetic sealants for fetal membrane repair,” J. Mech. Behav. Biomed. Mater., vol. 58, pp. 57–64, 2016.

[7]        H. Lee, B. P. Lee, and P. B. Messersmith, “A reversible wet/dry adhesive inspired by mussels and geckos,” Nature, vol. 448, p. 338, Jul. 2007.

[8]        J. J. Wilker, “How to suck like an octopus,” Nature, vol. 546, p. 358, Jun. 2017.

[9]        F. Tramacere, L. Beccai, M. Kuba, A. Gozzi, A. Bifone, and B. Mazzolai, “The Morphology and Adhesion Mechanism of Octopus vulgaris Suckers,” PLoS One, vol. 8, no. 6, p. e65074, Jun. 2013.

[10]      S. Baik, D. Wan Kim, Y. Park, T.-J. Lee, S. Ho Bhang, and C. Pang, “A wet-tolerant adhesive patch inspired by protuberances in suction cups of octopi,” Nature, vol. 546, pp. 396–400, 2017.

[11]      “materialdistrict.com.” [Online]. Available: https://materialdistrict.com/material/regabond-s. [Accessed: 05-Sep-2018].

[12]      T. Darmanin and F. Guittard, “Superhydrophobic and superoleophobic properties in nature,” Mater. Today, vol. 18, no. 5, pp. 273–285, 2015.

[13]      R. Hensel, C. Neinhuis, and C. Werner, “The springtail cuticle as a blueprint for omniphobic surfaces,” Chem. Soc. Rev., vol. 45, no. 2, pp. 323–341, 2016.

[14]      U. Bauer, B. Di Giusto, J. Skepper, T. U. Grafe, and W. Federle, “With a Flick of the Lid: A Novel Trapping Mechanism in Nepenthes gracilis Pitcher Plants,” PLoS One, vol. 7, no. 6, p. e38951, Jun. 2012.

[15]      Y. Ding, S. Xu, and Z. L. Wang, “Structural colors from Morpho peleides butterfly wing scales,” J. Appl. Phys., vol. 106, no. 7, pp. 1–6, 2009.

[16]      R. Yan et al., “Bio-inspired Plasmonic Nanoarchitectured Hybrid System Towards Enhanced Far Red-to-Near Infrared Solar Photocatalysis,” Sci. Rep., vol. 6, no. December 2015, pp. 1–11, 2016.

[17]      S. Zhang and Y. Chen, “Nanofabrication and coloration study of artificial Morpho butterfly wings with aligned lamellae layers,” Sci. Rep., vol. 5, pp. 1–10, 2015.

[18]      E. Van Hooijdonk, C. Vandenbem, S. Berthier, and J. P. Vigneron, “Bi-functional photonic structure in the Papilio nireus (Papilionidae): modeling by scattering-matrix optical simulations,” Opt. Express, vol. 20, no. 20, p. 22001, 2012.

[19]      R. A. Potyrailo et al., “Towards outperforming conventional sensor arrays with fabricated individual photonic vapour sensors inspired by Morpho butterflies,” Nat. Commun., vol. 6, p. 7959, Sep. 2015.

[20]      J. M. J. den. Toonder and P. R. Onck, “Artificial cilia.” Royal Society of Chemistry, Cambridge, 2013.

What does ‘rapid’ really mean?

One of the real strengths of working with a consultancy is the ability to increase the size of your team, bring in extra skills and get a project off the ground very quickly.  When you’re behind schedule on a market launch, regulatory submission, or faced with an unexpected verification test failure or recall, this speed can be the difference between successful and unsuccessful outcomes for your project.

So what does ‘rapid’ actually mean?  How fast is fast?  Let’s illustrate with an example of a project Springboard completed recently:

One Wednesday, we received a call from a client already known to us, asking us for help with an urgent problem.  This would require a mix of literature-based scientific research and practical testing in the lab.  Results were needed as quickly as possible, and certainly in time for a meeting three weeks later.

Springboard pulled out all the stops to plan the project and write a detailed proposal within two days, submitting this to the client on Friday morning.  The client was able to send written authorisation the same day, and put parts in the post for next day delivery.

The project leader briefed his team at 10 am on Monday morning.  The team – comprising two PhD-level scientists and a graduate engineer, with technical oversight from one of Springboard’s directors – hit the ground running.  Devices were disassembled and testing began before lunchtime.

The first update call to the client was delivered at lunchtime on Thursday.  This was a 30-slide PowerPoint presentation rich in technical detail, all of which was backed up with either laboratory experiments or cited academic papers.  In discussion with the client’s team members, we agreed the priorities for the next week of research.

Two more updates were delivered before the client’s original deadline, and the client went into their meeting briefed and confident.  A 42-page report, backing up all of the observations and conclusions drawn with full references, followed a week later.

Project timeline

Two days to plan and propose a project.  One week to deliver first results.  One month to deliver a complete project yielding real technical insight to drive policymaking.  No ongoing commitment.  A real illustration of how an agile consultancy can react much faster than a large corporation, and so add real value to urgent development and troubleshooting projects.

Connected drug delivery

The need for connected drug delivery devices

Most people would agree that drug delivery devices have improved in recent years, particularly with the increased focus on usability (or ‘human factors’).  However, adherence remains a challenge and payers are looking for ways to increase the cost-effectiveness of healthcare.  One strategy for managing both issues is connecting drug delivery devices to the internet.

The potential benefits of connected drug delivery devices have been much discussed and can be summarised for stakeholders as follows:

  • Patient
    • Reminders
    • Training
    • Evidence for incentives
    • Hawthorne effect
    • Peer support
  • Carer
    • Reminders
    • Training
  • Payer
    • (Non)adherence data
    • Reduced costs (50% of patients suffering chronic illness do not take their medication as prescribed, costing US $100 billion to $300 billion annually in avoidable direct healthcare costs in the US alone [1])
  • Healthcare professional
    • (Non)adherence data
    • Additional support for least adherent
    • Adverse events
  • Healthcare provider, or regulatory authority
    • (Non)adherence data
    • Adverse events
    • Clinical trial data (pre and post market)
    • Population trends
  • Pharma
    • Adverse events
    • (Non)adherence data
    • Clinical trial data (pre and post market)
    • Reimbursement evidence
    • Market understanding
    • Product and training improvements
    • Increased sales by increased adherence. (Non-adherence causes US $637 billion lost pharma revenue annually [2])

The disadvantages of connecting drug delivery devices to the internet are:

  • Increased cost of devices and infrastructure.
  • Potential increase in usability risks.
  • Reliability risks due to technical complexity.
  • Concerns over data privacy and robustness against hacking and malware.
  • Unclear regulatory landscape due to the unfamiliarity of the technologies in the regulatory context.
  • Environmental concerns for disposal of electronic waste.

Nevertheless, for some drugs and indications the advantages are compelling, so we should look at how connectivity might be implemented in a drug delivery device.

Device strategies

There are 3 main strategies for implementing connectivity in a drug delivery device:

  1. An add-on, typically to an existing design.
  2. An upgrade, which is integrated but does not change the core functionality or use case.
  3. Built-in, which can change the core functionality and use case.

Many pharmaceutical companies and drug delivery device manufacturers already have devices either on the market or in late stage development.

An industry survey of inhalers, for example, shows various companies using one or more of the three strategies.  Note that we see the same trends in the injector industry.

Add-ons

Add-ons have the advantages that:

  • They can be added to existing devices, in most cases without interfering with the existing device function.
  • They could be reusable even if the existing device is disposable.
  • Patients could pay for the add-on themselves, whereas the existing drug delivery device might be paid for by an insurer or national health service.
  • There is less development risk due to limited revalidation of the existing device.

Propeller and Adherium are notable because they support a wide range of existing inhalers.

Propeller Health

Propeller Health’s smart phone app, and inhaler add-on

Adherium

Adherium’s add-ons fitted to various commercial inhalers, and Adherium’s smart phone app

Cohero provides a spirometer so patients can measure their lung function.  This combination of drug delivery device and diagnostic device is powerful because it can provide direct disease management results to help patients and clinicians assess progress and can enable payment-by-results rather than pay-per-dose.  Linking delivery devices with diagnostics was pioneered by the insulin pens (and to a greater degree, insulin pumps) and blood glucose meters used for diabetes.  The obvious benefit is that the drug delivery device can respond to changes in the biomarker in real-time.  In addition, it gives much better insight than measuring only the quantity and time of dose taken because the patient and healthcare professional can see how the body responds to the drug. Perhaps the diagnostics could be used to identify more subtle problems.  For example, if outcomes were poor in a certain area, an investigation might reveal poor training by the local healthcare facility.

Cohero's add-on

Cohero Health’s BreatheSmart™ app, HeroTracker™ sensors, and spirometer.

Inspair measures inspiratory flowrate so can determine both if the patient’s breathing profile is correct, and if they actuated the inhaler at the right point in their inspiration. Devices which provide feedback like this can be used for ‘continuous improvement’ training, which is more interactive and personalised than a static training video or patient instruction leaflet.  It helps with the ‘learn-ability’ of the device, which was identified as a major challenge in recent industry-wide research performed by Springboard.

Biocorp Inspair

Biocorp Inspair

However, it is important to consider that add-ons have the obvious disadvantage that the existing geometry is not modified so:

  • Add-ons cannot be integrated into the existing device, and thus add bulk to the device, and there are additional use steps to attach them.
  • Technical possibilities are limited. For example, it is more difficult to sample the air flow.

Upgrades

A strategy to overcome the limitations of the add-ons is to upgrade an existing design.  Novartis is supporting the Propeller add-on [3], but is also upgrading the Breezhaler to the cloudhaler and adding built-in connectivity by working with Qualcomm Life. [4, 5]

Novartis Cloudhaler

Novartis Cloudhaler

H&T Presspart is working with Cohero to upgrade standard Metered Dose Inhaler actuators with connectivity. [6]  A notable feature of the Presspart strategy is that the connected functionality is optional.  That is, the drug delivery and dose counter functions are still entirely mechanical, so the patient can, in principle, use the device safely and effectively even if the electronic functions fail.

Presspart eMDI

H&T Presspart eMDI

An alert reader will notice that the upgraded devices do not change the use steps or core functionality of the devices.  If we want to use electronics and connectivity to change fundamentally the way the patients (and carers, trainers etc.) interact with their device, we need to build the electronics and connectivity into the device from the ground up.

Built-in connectivity

Devices which have connectivity built into them from the beginning can make significant changes in user interaction.  The design being built-in also allows more substantial changes to the device, such as advanced features and sensing options. For example, the 3M Intelligent Control Inhaler actively adapts the flowrate to suit the patient and delivers the dose automatically at the right point in the inspiration. A similar example is Opko’s Inspiromatic active dry powder inhaler, and Aptar is partnering with Propeller to develop a new connected metered dose inhaler. [7]

3M Intelligent Control Inhaler

3M Intelligent Control Inhaler

The disadvantages of built-in connectivity mirror substantially the advantages of add-ons.  For example, a device with built-in connectivity could be more difficult to make reusable, which adds built-in cost and environmental impact.

Uptake and retention of connected devices

Public interest in connected drug delivery devices has not been measured on a wide scale yet, but we can draw inferences from health-related smartphone apps.  More than 50% of US smartphone users downloaded a health-related app in 2015.  Individuals more likely to use health-related apps tended to:

  • Be younger,
  • Have higher incomes,
  • Be more educated,
  • Be Latino/Hispanic, and
  • Have a body mass index (BMI) in the obese range (all P<0.05). [8]

However, weekly retention of apps is poor, even for apps which tend to be associated with hardware such as Fitbit, Garmin and Nike+.

Market Share of the Top 5 Fitness Apps

Market Share of the Top 5 Fitness Apps

The reasons for people stopping the use of health apps were primarily:

  • High data entry burden 45%
  • Loss of interest 41%
  • Hidden costs 36%

Out of 1604 people, 662 (41%) said they would not pay anything for a health app. [8]

In November 2017, an analyst from Ernst & Young identified the following hurdles to the widespread adoption of connectivity in drug delivery devices: [9]

  1. Devices and services.
  2. Evidence.
  3. Data infrastructure.
  4. Business model.

Let us assess the progress and challenges in each area in turn.

Devices and services

Merck Group launched easypod for human growth hormone in 2006, which gained connectivity in 2012, [10] and RebiSmart for multiple sclerosis, which was launched in 2007 and gained connectivity in 2011.  They use the easypod Connect [11] and MSdialog [12] web platforms, respectively, for uploading patient data from the device and adding supporting information manually.

One of the challenges is gaining regulatory approval of medical devices that connect to smartphones, but AliveCor has pioneered the way here by being the first to gain FDA approval for smartphone-based medical device software with its atrial fibrillation diagnostic app.

In diabetes, Roche has bought the mySugr web platform, whose Bolus Calculator has Class IIb approval in the EU, and the logbook has Class I approval in both the EU and USA.

So, we can see that connected drug delivery devices are breaking through onto the market, and the regulatory approval and services around them are entirely feasible.

Evidence

Payers and regulators (not to mention patients and healthcare professionals) will want to see clinical evidence for the efficacy of connectivity.  Fortunately, the evidence is mounting.  Data from Propeller Health, for example, shows reduced short-acting beta agonist use, [13] reduced hospitalisations and reduced emergency room visits. [14]  Adherium claims similar clinical evidence. [15]

If efficacy is proven for certain indications, we would still need evidence for preference and adherence.  Fortunately, several studies have been done in these areas too.  For example:

  • An observational study on the RebiSmart device found that 91% liked using the device, and 96% found it ‘easy or very easy to use’. [16]
  • An autoinjector preference patient survey found that 82% of BetaConnect patients were ‘highly satisfied’ compared to 67% of RebiSmart and 60% of ExtaviPro patients. [17] The first two devices have connectivity, but the latter does not.
  • A retrospective adherence study on patients with multiple sclerosis using RebiSmart found ‘greater than 95% adherence’ over a 140-week duration (N = 110). [18]

Unfortunately, evidence of malware and hacking has also appeared.  For example, remote hacking exploits have been demonstrated on some Medtronic insulin pumps, [19] Hospira infusion pumps, [20] and Animas OneTouch Ping insulin pumps. [21]

Data infrastructure

It is logical for companies to roll out their connectivity infrastructure using the following building blocks:

  1. Adding connectivity to the drug delivery device.
  2. Optionally connecting the drug delivery device to a ‘mobile medical app’. This can be an app running on a smart phone (such as AliveCor’s KardiaMobile app), or on a dedicated device (such as Abbot’s FreeStyle Libre device).
  3. Cloud storage and web apps that can be accessed through a web browser.
  4. Electronic Health Records.

The main cloud computing providers (Amazon Web Services, Google Cloud Platform and Microsoft Azure) have various offering that are HIPAA compliant, so can be used for some medical data in the United States, but HIPAA compliance is not regarded as strong enough protection for the data of EU citizens.  The  General Data Protection Regulation (in force from 25 May 2018) places further requirements on the controllers and processors of personal data.

Several companies and collaborations are creating cloud technologies to handle data from connected medical devices. For example, Salesforce.com (in the form of its force.com platform), Qualcomm Life and Philips HealthSuite are working on patient data platforms.  Roche bought Flatiron which developed the OncologyCloud, claimed by them to be the ‘industry-leading electronic medical record for oncology, advanced analytics, patient portal and integrated billing management’, [22] Medicom is handling the data services for Bayer’s BetaConnect device, and Redox is developing a way to share healthcare data between heterogenous technologies.  In effect, Redox can take data from any input, perform transformations and analytics on it, and convert it into a given Electronic Health Record format.

Business models

Payers are trying to reduce costs, so simply adding connectivity and expecting to be able to charge more is not a convincing strategy.  However, a holistic view of the health economics of a given indication can reveal compelling business models in some cases.

Example business models already in use include:

  • A collaboration between Amgen and Humana whereby Amgen analyses real-world evidence from Humana’s members with data from wearable devices, apps and smart drug delivery devices. [9]
  • A collaboration between Amgen and Harvard Pilgrim Healthcare whereby Amgen will fully refund the cost of Repatha if the patient is hospitalised by a stroke or myocardial infarction. Naturally, Harvard Pilgrim will need to show that the patient had adhered to the Repatha regimen and connectivity is a convincing way to do this.
  • Abbot did not get reimbursement initially when it developed the FreeStyle Libre flash glucose sensor, so sold it direct to patients. It has since been approved for purchasing by the UK National Health Service. [23]

Summary and final thought

From what Springboard sees in its day-to-day work, every company involved in drug delivery devices either has a connected technology or is developing one. Clinical evidence for improved adherence exists, and evidence for other clinical benefits is mounting.  The data infrastructure exists, although systems are not familiar to patients or healthcare professionals yet, and there are legal hurdles to overcome when transferring patient data between legal jurisdictions. Traditional business models have struggled, but innovative business models are progressing.

Connected drug delivery devices are already with us, and more are coming to market.  The idea that connectivity itself will solve the adherence problem is unrealistic.  However, for the first time, healthcare professionals will be able to identify who is adherent and who is not, which will allow them to refocus efforts on those who have the most difficulty adhering.

If you are from a pharmaceutical company or medical device manufacturer and wish to talk with us at Springboard about any medical device development questions, please get in touch.

References

[1] Iuga AO, McGuire MJ, “Adherence and health care costs”. Risk Manag Healthc Policy, 2014, Vol 7, pp 35–44.

[2] Forissier T, Firlik K, “Estimated Annual Pharmaceutical Revenue Loss Due to Medication Nonadherence”. Capgemini and HealthPrize white paper, 2016.

[3] Tyer D, “Novartis Signs ‘Connected Inhaler’ Deal with Propeller Health”. PMLive, Feb 2017.  Accessed May 2018

[4] “Network Connected Inhaler for COPD”. myAirCoach. (Accessed May 2018)

[5] Pai A, “Novartis, Qualcomm Life to Develop Connected Inahler for COPD”. MobiHealthNews, Jan 2016. (Accessed May 2018)

[6] H&T Presspart eMDI product webpage. (Accessed May 2018)

[7] Comstock J, “Propeller Health, Aptar Partner to Create Connected Metered Dose Inhalers”. MobiHealthNews, Feb 2016. (Accessed May 2018)

[8] Krebs P, Duncan DT, “Health App Use Among US Mobile Phone Owners: A National Survey”. JMIR mHealth uHealth, Nov 2015, Vol 3(4), epub.

[9] Handschuh T, “Smart Devices – How to Unlock Their Potential in the Real World.” Presentation at PDA Universe of Prefilled Syringes and Injection Devices, Vienna, Nov 2017.

[10] “Merck Serono Launches easypod™ Connect in Europe”. Merck Serono press release, Oct 2011. (Accessed May 2018)

[11] easypod® Connect product webpage. (Accessed May 2018)

[12] RebiSmart MSdialog product webpage. (Accessed May 2018)

[13] Merchant RK, Inamdar R, Quade RC, “Effectiveness of population health management using the Propeller Health Asthma Platform: A randomized clinical trial”. J Allergy Clin Immunol Pract, May-Jun 2016, Vol 4(3), pp 455–463.

[14] Merchant RK et al, “Interim results of the impact of a digital health intervention on asthma healthcare utilization”. J Allergy Clin Immunol, Feb 2017, Vol 139(2), p AB250.

[15] “The Medication Nonadherence Epidemic”. (Accessed May 2018)

[16] D’Arcy C et al, “Patient assessment of an electronic device for subcutaneous self-injection of interferon ß-1a for multiple sclerosis: an observational study in the UK and Ireland”. Patient Prefer Adherence, Jan 2012, Vol 6, pp 55–61.

[17] Limmroth V et al, “Autoinjector preference among patients with multiple sclerosis: results from a national survey”. Patient Prefer Adherence, Aug 2017, Vol 11, pp 1325–1334.

[18] Solsona E et al, “Impact of adherence on subcutaneous interferon beta-1a effectiveness administered by RebiSmart® in patients with multiple sclerosis”. Patient Prefer Adherence, Mar 2017, Vol 11, pp 415–421.

[19] Goodin D, “Insulin pump hack delivers fatal dosage over the air“.  The Register.  Accessed July 2018.

[20] Finkle J, “FDA warns of security flaw in Hospira infusion pumps.”  Reuters.  Accessed July 2018.

[21] Finkle J, “J&J warns diabetic patients: Insulin pump vulnerable to hacking.”  Reuters.  Accessed July 2018.

[22] Kewon A, “Drug Giant Roche Buys Former Google Execs’ Flatiron in $1.9B Deal”. BioSpace, Feb 2018. (Accessed May 2018)

[23] Woodfield J, “FreeStyle Libre to be available on the NHS from November”. Diabetes.co.uk, Sep 2017. (Accessed May 2018)

An introduction to needlestick protection and safety syringes

The need

Needlestick injuries are second only to back injuries as a cause of injury to healthcare workers (HCW), with up to 1,000,000 cases estimated annually in the EU [1]. The risk transmission of blood-borne viruses has been shown to be around 1 in 3 if the patient is Hepatitis B Virus positive, 1 in 30 if Hepatitis C Virus positive and 1 in 300 if HIV positive [2, 3]. Even when infections are not transmitted such an injury can cause considerable fear and stress [4].

In many cases, it is not feasible to eliminate injections or use another administration method as a substitute.  Therefore, the hazard is most effectively handled by engineering solutions which separate those at risk from the sharps (Figure 1). Research by the UK’s Health and Safety Executive has found that education and training related to safer sharps is only effective when combined with safer sharps devices [5] and the UK’s Health Protection Agency recommends that Primary Care Trusts and hospitals adopt safety devices in place of conventional devices [2].  In the US, the CDC estimated that up to 88% of sharps injuries in hospitals could be prevented by using safer medical devices [6].

Figure 1 – Hierarchy of hazard controls with increasing effectiveness (Source: National Institute for Occupational Safety and Health)

The legal requirements

Many regulators around the world require needlestick protection, and others are in the process of implementing it.  Examples are:

The international standard ISO 23908:2011 defines the requirements and test methods for sharps protection features on single-use hypodermic needles, introducers for catheters, and needles used for blood sampling.

‘Active’ and ‘passive’ solutions

Broadly, solutions can be classed as:

  • Active (the user must take some type of action to initiate the feature) or
  • Passive (the feature is activated automatically, without user intervention).

Active solutions rely on the HCW completing an extra step, which relies on training and changing existing behaviours. The UK National Health Service Employers organisation recommends that needle safety mechanisms should be an integral part of the device, require little change of technique and are preferably activated automatically or with a single hand [7].

A simple active solution is to cap the exposed needle with a shield after use, such as Smith Medical’s Point-Lok® needle protection device (Figure 2).  The device sits on a flat surface to accept and lock onto the exposed needle.

Figure 2 – Smith Medical’s Point-Lok® needle protection device

Active Sharps Injury Protection (sheath)

Syringes with integral sharps injury protection (SIP) often use a cover that shields the user from the needle after use.  This cover can be an extendable tube (Figure 3). The syringe is pulled back into the sheath, which clicks and locks into place. The sheath covers the outer surface of the barrel during the injection.  These syringes should be held by the flange, so the sheath is not displaced before the end of the injection. This may require a change in habit for HCWs. Example of this type of safety syringe include:

  • BD Safety-Lok™ Syringe (1, 3, 5 & 10 mL, takes luer Lok needles)
  • EasyTouch® ShealthLock™ Safety Syringe (fixed needle 1 & 3 mL, exchangeable needle 3, 5 & 10 mL)
  • Medtronic Monoject™ Safety Syringe (with needle, for insulin and tuberculin)
  • Sol-Millenium Sol-Guard™ Safety Syringe (with needle, for insulin and tuberculin)
  • UltiMed Ulticare® Safety Syringe (1, 1.5 & 3 mL permanently attached needle)
  • Vogt Medical VM® Safety syringe (1, 3, 5 & 10 mL)

Figure 3 – BD Safety-Lok™ Syringe, an example of a safety syringe with a tubular SIP feature

A similar solution is the Raumedic RauSafe, which uses a telescopic sheath that is manually extended and locked out over the needle after the injection.  This avoids covering the external surface of the barrel before and during the injection

Figure 4 – Raumedic RauSafe shown with the protective sheath extended

Active Sharps Injury Prevention (hinge)

The needle safety feature can also take the form of a hinged cover.  The cover can be pushed down with a finger or against a hard surface so only one hand is required. The cover can be incorporated into the syringe, such as:

  • EasyTouch® FlipLock™ Safety Syringe (fixed needle, 1 & 3 mL, exchangeable needle 3, 5 & 10 mL)
  • Medtronic Magellan™ Safety Syringe (fixed needle insulin & turerculin)
  • Vogt Medical VM® Safety syringe (1, 3, 5, 10 & 20 mL)

The same feature can be incorporated into attachable needles, such as:

  • BD Eclipse™ Safety Needle (18 – 30G)
  • EasyTouch® FlipLock™ Safety Syringe (18 – 31G)
  • Medtronic Monoject™ Safety Needle (18 – 30G)
  • Terumo SurGuard®3 Safety Needle (18 – 30G)
  • Smiths Medical Jelco® Needle-Pro® EDGE™ Safety Needle (18 – 30G)
  • Sol-Millenium Sol-Care™ Safety Needle (18 – 30G)
  • Vogt Medical VM® Safety needle (20 – 27G)

A potentially cost-effective and versatile solution is Schreiner MediPharm’s Needle-Trap, which incorporates the hinged cover into the syringe label.

Figure 5 – Hinged SIP covers (left: EasyTouch® FlipLock™ Safety Syringe, middle: Terumo SurGuard®3 Safety Needle, right: Schreiner MediPharm Needle-Trap)

There are some multi-hinged needle covers available that can facilitate easier one-handed application:

  • BD SafetyGlide™ Needle
  • Medtronic Magellan™ Safety Needle

Figure 6 – Left: BD SafetyGlide™ Needle, Right: Medtronic Magellan™ Safety Needle

Active Sharps Injury Prevention (needle retraction)

Instead of shielding the needle after use, the needle can be retracted into the syringe after the injection.  There are products available to do this manually, by pulling back on the plunger rod, such as:

  • EasyTouch® Retractable Safety Syringe
  • Numedico ClickZip™ Needle Retractable Safety Syringe
  • Sol-Millennium SOL-CARE™ Safety Syringe

 

Figure 7 – EasyTouch® Retractable Safety Syringe instructions (adapted from http://mhcmed.com/products/easytouch-safety-products/safety-syringes/)

Similar retraction technology is available as a needle with luer lock connection, such as in the Retractable technologies EasyPoint® Needle.  The sharp is automatically captured in an adjacent chamber but an additional user step is required to activate this process.

Figure 8 – EasyPoint® retractable needle

Passive Sharps Injury Protection (needle retraction)

There are syringes available which retract the needle into the barrel automatically using a spring, eliminating any extra user steps. Examples include:

  • BD Intergra™ Syringe (3 mL, requires detachable BD Integra needles)
  • Retractable technologies VanishPoint® Syringe (attached needle, 0.5, 1, 3, 5, and 10 mL)
  • DMC Medical SureSafe™ Syringe (fixed needle 0.5 & 1 mL, changeable needle 3ml, 5ml & 10ml)

Figure 9 – BD Intergra™ Syringe retracting syringe

Passive Needle Safety devices

An alternative solution is to encompass the syringe in a safety device.

The BD Preventis™ allows a 0.5 ml or 1.0 ml pre-filled syringe to be packaged inside a casework that incorporates an automatic safety lock system. The safety device uses a spring to extend a protective sheath after injection.

Figure 10 – BD Preventis™ needle shielding system

Such single-use devices can be used with syringes and shift the act of shielding the needle from the user to the device.  Typically, a syringe is inserted inside such a device and the injection is performed by depressing a plunger rod, then after the injection is complete a spring acts to withdraw the syringe and shield the needle.

In the Biocorp Newguard, the user’s push on the plunger rod acts on a spring which causes a needle retraction and lockout after injection.  The Nemera Safe’n’Sound and the BD Ultrasafe™ does not require the user to work against a spring but uses an unclipping mechanism release the compressed spring at end of injection to activate the retraction.

The Owen Mumford Unisafe™ avoids using a spring altogether and retracts the syringe by transferring the plunger rod stroke through a threaded interface.  This can help the user see the syringe and its contents before and during the injection.

Figure 11 – Left: Nemera Safe’n’Sound, Middle: Biocorp New guard, Right: Owen Mumford Unisafe™

If you would like to know more about needle safety devices, or have a need to procure or develop one, please get in touch. Springboard develops injection technologies, and conducts technology scouting, technology procurement, due diligence and usability engineering projects for our clients.

References

[1] European Parliament. Preventing needle-stick injuries in the health sector, 11th February 2010.

[2] Health Protection Agency, Eye of the Needle – United Kingdom Surveillance of Significant Occupational Exposures to Bloodborne Viruses in Healthcare Workers,
November 2008

[3] UK Health Departments, Guidance for Clinical Health Workers: Protection Against Infection with Blood-borne Viruses, April 1998

[4] Royal College of Nursing, Sharps safety – RCN Guidance to support the implementation of The Health and Safety (Sharp Instruments in Healthcare
Regulations), 2013

[5] Health and Safety Executive, An evaluation of the efficacy of safer sharps devices, 2012

[6] U.S. Occupational Safety and Health Administration, Needlestick/Sharps Injuries, Accessed March 2018

[7] NHS Employers, Managing the risks of sharps injuries, December 2015