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The field of microneedle research is new and rapidly changing in its focus. The idea that a needle needs only penetrate the epidermis in order to deliver therapeutic agents is generally thought to be first found in a patent by Gerstel and Place in 1976 [24]. The principles used by the device are summarised in Figure 6.3. Like the majority of microneedles reported in the literature since [25], the device is not a single needle, but an array of identical microstructures, defined as

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around 5 to 100 µm tall in the patent. The needles are hollow (not visible in Figure 6.3), and connect to a shared reservoir containing the drug to be injected. However, it is not apparent if the patent ever led to any viable devices, and further research was delayed for decades due to the limitations of the microfabrication techniques of the time.

The development of the field can be tracked by review papers found in the literature. McAllister et al [8] in 2000 categorised microneedles by the scale of the treatment provided by the microneedle structures, with sections on cellular, localised and systemic drug delivery within the body. The majority of the devices reviewed were based on the micromachining of silicon. Advances in this area had allowed Lin et al [26] to produce what are possibly the first microneedles from silicon in their conference paper of 1993, with a later full journal follow-up in 1999 [27]. These devices, 1 to 3 mm in length, were produced laterally upon a silicon substrate using surface micromachining, and included an integrated “blinking bubble” thermopneumatic micropump. The silicon processing steps used in the fabrication of the devices, along with micrographs of the finished structure, can be seen in Figure 6.4.

Figure 6.3 – Drawing showing the principles used my microneedle devices. An array of microstructures 5 to 100 µm tall pierces the skin through the stratum corneum and into the basal layer of the epidermis. The microneedles are hollow (not shown in figure) and connect to a shared reservoir containing the drug. Taken from Gerstel and Place, 1976 [24].

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Figure 6.4 – In-plane microneedles developed by Lin et al [27].

A later review in 2004 by Reed and Lye [11] grouped the devices by their plane relative to their substrate. This silicon-micromachining-based approach to categorisation was viable at the time, as the majority of devices were still silicon based. The change in characterisation reflected the movement away from single-needle “in-plane” structures, such as those presented by Lin et al [26, 27], Brazzle et al [28, 29], Papautsky et al [30], Talbot and Pisano [31] and Chen et al [32]. These structures were complex, both in design and fabrication. Although this meant that additional design features could be integrated, such as MEMS actuators and microsensors, it also made them expensive to manufacture. As a result, most have been used only in neuroscience as probes for sensing and influencing cellular processes.

However, the designs shown earlier in the patent of Gerstel and Place [24] were “out of plane”, and arranged in multi-structure arrays, and the high aspect-ratio fabrication techniques required for their realisation were being developed. In 1998, Henry et al [33] produced arrays of

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out-of-plane microneedles using reactive ion etching (RIE), which has been a popular fabrication technique since for such silicon-based devices. The structures fabricated can be seen in Figure 6.5.

As can be seen, these structures are similar to those postulated by Gerstel and Place’s [24] 1976 patent. However, they lack the inner hole or “lumen” found in macroscale hypodermic needles. These types of structures are still useful in therapeutic situations, and are classified in the 2008 review paper by Arora et al [25] as “solid” microneedles. The review reflected the evolving field of microneedle research by classifying microneedles under 4 categories: the aforementioned “solid” structures, “hollow” devices, “dissolving” microneedles and “coated” microneedles. All these groups are out-of-plane microneedle arrays, which has now become the prevalent design in therapeutic use, with the area of in-plane devices being dropped entirely. These categories are outlined in Figure 6.6.

Figure 6.5 – Scanning electron micrographs of microneedles made by the reactive ion etching technique. Taken from Henry et al [33].

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Figure 6.6 - Schematic of drug delivery using different designs of microneedles: (a) solid microneedles for permeabilizing skin via formation of micron-sized holes across stratum corneum. The needle patch is withdrawn followed by application of drug-containing patch, (b) solid microneedles coated with dry drugs or vaccine for rapid dissolution in the skin, (c) polymeric microneedles with encapsulated drug or vaccine for rapid or controlled release in the skin, (d) hollow microneedles for injection of drug solution. Taken from Arora et al [25].

There are a number of reasons out-of-plane microneedles have become more prevalent in the literature. They are less complex in fabrication than their in-plane forefathers, reducing costs and allowing the structures to head towards the $0.10-1.00 per-device barrier that would need to be crossed to allow commercialisation [25]. Fabrication is also simplified by the fact that the dimensions of the needle structure and/or lumen is controlled lithographically via masks, rather than via film or dope layers that can rarely increase beyond a few tens of micron. They are also in general stronger, as they are part of an array rather than a single fragile structure [11].

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