Microneedle

Microneedles (MNs) are minimally invasive devices that painlessly by-pass the stratum corneum, (SC) by forming transient aqueous microchannels, thus granting access to the dermal microcirculation located in the inferior skin tissue layers [1].

From: Drug Delivery Devices and Therapeutic Systems , 2021

Microneedles for drug delivery and monitoring

T.R.R. Singh , ... R.F. Donnelly , in Microfluidic Devices for Biomedical Applications, 2013

Abstract:

Microneedles (MN) are micron-sized needles, ranging from 25 to 2000  μm in height, made of a variety of materials and shapes. Application of MNs to the skin can create micron-sized transport pathways that allow enhanced delivery of a wide range of drug molecules. The concept of MNs was first conceived in 1976; however, it was not possible to make them until the first exploitation of microelectromechanical systems (MEMS) in 1998. Therefore, this chapter will focus on the fabrication techniques of MNs using MEMS, the design and material consideration of MNs, and the application of MNs in drug delivery and monitoring biological fluids.

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Drug Delivery Using Microneedles☆

O. Olatunji , D.B. Das , in Reference Module in Biomedical Sciences, 2015

Transdermal Drug Delivery

Microneedles are able to pierce through the stratum corneum and deliver drugs into the body in a minimally invasive manner. This makes them a better candidate for drug delivery compared to ordinary transdermal patches where the effectiveness is limited by the barrier of the stratum corneum, or hypodermic needles which are often painful and carry hazards such as transition of infection due to accidental or intentional needle reuse. Various studies have been carried out which show microneedles to be capable of delivering drugs such as insulin, naltrexone, and antirestenosis drugs.

In the first experiment on the use of microneedles for transdermal drug delivery, (Henry et al., 1998) showed that microneedles were able to increase skin permeability to calcein by up to 3 orders of magnitude when compared to diffusion of calcein through intact skin. In these experiments, silicon microneedles were inserted into the human skin obtained from autopsy; using a Franz diffusion cell, the group measured the permeability of calcein through the epidermis for instances where the skin was first pretreated with microneedles and compared this with the permeability of calcein through intact skin without microneedles inserted ( Figure 9 ). This experiment proved that microneedles increase the transport of drugs through the skin by a great extent and showed the possibilities of applying microneedles for painless drug delivery.

Figure 9. Permeability of human skin treated with different microneedle protocols in vitro compared to permeability of untreated skin (bar 1).

The second bar in the figure shows the results for when the microneedles were inserted and left in the skin, the third shows the results for when they were inserted for 10   s and then removed, and the fourth for removal after insertion for 1   h. Each data point represents the average of seven to nine experiments as reported in Reference 5. The bars show standard deviation.

One of the drugs that have been the most attractive for microneedle delivery is insulin. The possibility of controlled delivery of insulin to diabetic patients using micoroneedles could increase patient compliance and lead to the development of more compact insulin delivery kits to improve patient comfort. McAllister et al., 2003 fabricated hollow microneedles which were used to inject insulin to hairless rat skins. Results from analysis of blood sample showed significant decrease in blood glucose level. Mathematical models based on the results suggested that the transport through the epidermis was principally by diffusion. In the same studies, microneedles were also shown to increase the transport of calcein and bovine serum albumin and latex nanospheres across human cadaver skin. Martanto et al., 2004 have also used laser-cut solid metal microneedles for transdermal insulin delivery using the poke with patch method. The blood glucose level in the diabetic rats was observed to have decreased by as much as 80% following insulin delivery using microneedles. Figure 10 shows the results obtained when blood glucose levels after microneedle and hypodermic needle insulin delivery were compared. In another study, (Wang et al., 2006b) inserted hollow glass microneedles into the skin of hairless rats in vivo and into human cadaver skin in vitro to deliver insulin transdermally. Fluorescence microscopy and histological staining showed that microneedles were able to deliver insulin to precise depths and that retraction of the microneedles did improve the efficiency of the drug delivery.

Figure 10. Changes in blood glucose level of hairless rat after insulin delivery via different routes. Dark triangles indicate microneedle delivery while the X indicates delivery across untreated skin. Other symbols indicate delivery using hypodermic needles.

 Results from Martanto, W.; Moore, J.S.; Couse, T.; Prausnitz, M.R. (2006) Mechanism of fluid infusion during microneedle insertion and retraction, Journal of Controlled Release. 112, 357–361.

Dissolving microneedles have also been used to deliver insulin to mice to have pharmacological effect and maintain bioactivity over a storage period of 1 month at 400   °C (Ito et al., 2006). The pharmacodynamic response to insulin delivered using microneedles has been compared to subcutaneous delivery using hypodermic needles. Davis et al., 2005 fabricated hollow metal microneedles which were used to deliver insulin to diabetic rats. A 47% decrease in blood glucose level was observed and this was comparable to subcutaneous delivery using hypodermic needles.

Nordquist et al., 2007 designed an easy-to-use patch-like integrated microneedle device ( Figure 11 ) which could replace subcutaneous or intravenous insulin therapy. The device comprises of an electric heater attached to an expandable material next to a liquid reservoir that holds the drug. When a voltage is applied, the electrical heater heats up the expandable material which then expands into the liquid reservoir space and consequently forces out the drug via the hollow microneedles. The dispenser can hold up to 12   μl of liquid. Insulin was delivered to 61 diabetic rats using the device and the results compared to those obtained when insulin was subcutaneously delivered. The results showed that by using microneedles a more controlled insulin delivery was achieved as compared to subcutaneous injection.

Figure 11. Photograph of the assembled drug delivery patch device (Wermeling et al., 2007). Scale   =   5   mm.

Furthermore, microneedles have been used to deliver a vast array of other drugs; for example, Wermeling et al., 2007 showed that microneedles were able to enhance the transdermal transport of Naltrexone, a potent drug used to treat opiate and alcohol addiction. The skin of healthy humans was first treated with microneedles, and then transdermal patches containing the drug were placed on the skin surface. Steady-state plasma concentration was achieved within 2   h of application and was maintained for up to 48   h afterwards compared to untreated skin which showed no readable plasma concentration after 72   h. This study showed that microneedles can be used to deliver drugs which are impermeable to the skin for clinical application. Wang et al., 2006 delivered calcein into human cadaver skin and hairless rat skin using hollow glass microneedles inserted to precise depths.

Donnelly et al., 2008 performed experiments on mice in vivo and in vitro which showed that microneedles enhanced the delivery of 5-aminolevulinic acid (ALA) as shown in Figure 12 . The results also showed that treating the skin with microneedles prior to application of ALA also induced dose sparing and reduced application time required to achieve a high level of the photosensitizer protophyrin IX in skin. Poor tissue penetration of ALA, a porphyrin precursor, limits photodynamic therapy of deep or modular skin tumors. ALA is also expensive and degrades rapidly, which makes the ability to reduce the application time and dose required very beneficial for clinical application.

Figure 12. Cumulative amount of 5- aminolevulinic acid (ALA) permeated through intact skin (filled circles) compared to that through microneedle-punctured skin (clear circles).

 Reproduced from Donnelly, F.R.; Morrow, D.I.J.; McCarron, P.A.; et al. (2008) Microneedle-mediated intradermal delivery of 5-aminolevulinic acid: Potential for enhanced topical photodynamic therapy. Journal of Controlled Release. 129, 154–162.

The effectiveness of the commonly available topically applied drugs for acne treatment is limited by the low rate of penetration through the stratum corneum, whereas the main cause of acne scarring occurs deeper inside the skin. Therefore, in order to enhance the effectiveness of the topically applied treatments, the penetration of the drug needs to be deeper into the skin (Kwon, 2006).

The idea to treat skin with microneedles before applying the skin treatment was recently presented by (Wu et al., 2007). An array of microneedles is expected to be used to pierce the stratum corneum after the skin treatment ointment is applied to the skin. Piercing of the skin with microneedles initially will aid the penetration of the compound in order to improve the treatment.

In addition, experiments have also been carried out by applying the TheraJectMATTM dissolving microneedles containing active pharmaceutical ingredients (APIs) in a generally regarded as safe (GRAS) matrix to the surface of human skin with acne. The images of the skin surface before and after microneedle treatment showed an improvement within hours (Kwon, 2006).

Acne affects up to 67.5% of the teenage population in the United Kingdom and studies show the disorder to have an effect on the quality of life of the sufferers (Smithard et al., 2001). According to the experiments discussed above, using microneedles could improve the effectiveness of acne therapeutics. As a result, this would have a significant impact if commercialized.

Microneedles have been used to deliver nanoparticles varying in size from 1 to 20   μm (Gill & Prausnitz, 2007). Gill & Prausnitz, 2007 delivered barium sulfate particles of 1   μm diameter and latex beads of 10 and 20   μm diameters into porcine cadaver skin. The barium sulfate particles were coated on solid microneedles and delivered into the skin without wiping off on the skin surface even at low insertion speed of 0.5–1   mm   s−   1. However, to insert 20   μm particles an insertion speed of 1–2   cm   s−   1 was required and the microneedles had to be designed with holes or 'pockets'. These pockets, where the microparticles were secluded, had the ability to facilitate the delivery of the microparticles without most of them ending up as residue on the skin surface. The delivery of 10   μm particles was successful without pockets at high insertion speed of 1–2   cm   s−   1.

In another study, (McAllister et al., 2003) were able to show that the delivery of particles of 1   μm diameter is enhanced when the skin is pretreated with microneedles by adopting the poke with patch approach. Therefore, the mode of delivery of microparticles is important in controlled/delayed delivery after the drug is inserted into the skin.

Gill & Prausnitz, 2007 have successfully coated a variety of substances such as vitamins and calcein on the surface of solid metal microneedles as shown in Figure 13 . These were inserted into the skin without rubbing off on the surface; the drug coating dissolved within minutes of insertion so that the microneedles could be removed.

Figure 13. A range of molecules coated onto solid microneedles (Gill & Prausnitz, 2006): (a) calcein; (b) vitamin B; (c) bovine serum albumin (BSA); (d) plasmid DNA; (e) Virus; (f) barium sulfate; (g) microparticles. Scale   =   200   μm.

More recent studies have looked at combination of microneedles with other techniques such as low-frequency sonophoresis (Naguib & Kumar, 2013; Nayak & Das, 2013), gene gun (Ito et al., 2013; Hiraishi et al., 2013) and iontophoresis (Olatunji et al., 2014). Combining microneedle technique with other techniques for transdermal drug delivery enables further improvement in the rate and effectiveness of drug delivery. For instance in the case of sonophoresis, the enhancement from low frequency sonophoresis alone is insufficient to effectively deliver high molecular drugs through the stratum corneum, however when combined with microneedles the rate of delivery of bovine serum albumen across porcine skin was increased to 1   μm   s−   1 compared to 0.43 and 0.4   μm   s−   1 when using either microneedle or ultrasound alone (Nayak & Das, 2013).

The studies mentioned above show that microneedles are a very feasible option for transdermal delivery. Companies involved in the manufacture of microneedles for transdermal drug delivery include ZosanoPharma which currently has 6 drugs in phase 1 and 2 clinical trials and 18 more drugs and 5 vaccines in preclinical trials (Daddona et al., 2010). Emory University is currently conducting phase II clinical trials on insulin delivery using microneedles (Sullivan et al., 2010) and Nonopass received FDA approval for the MicroJet device for insulin delivery in February 2010 (Van Damme et al., 2008). The 3 M Company is also involved in microneedle manufacture with a developed solid microneedle system for vaccine delivery and hollow microneedle system for delivery of pharmaceuticals underway (Burton et al., 2010).

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Nanocomposite for transdermal drug delivery

Rabinarayan Parhi , in Applications of Nanocomposite Materials in Drug Delivery, 2018

16.5.4 Nanocomposite as microneedle

Microneedle is a recent noninvasive physical technique widely used for intra- and transdermal delivery of small drugs, nanoparticles, macromolecules [128], and extraction of fluids [129]. In a microneedle array, there are presence of number of micron size needles and are used to create transient aqueous pores across the SC without any contact with nerve fibers [130]. Microneedles are generally classified into two types: Solid and hallow. Solid microneedles are intended to pierce the skin to increase drug permeation whereas hallow microneedles possess hallow core to retain liquid formulation for active injection [131,132]. Based on the mode of application microneedles are categorized into four classes as:

1.

Poke and patch or poke and flow (microporation followed by application of a drug-loaded patch or a liquid formulation).

2.

Coat and poke (coating solid microneedles with a drug formulation).

3.

Poke and release (soluble microneedles with drug encapsulated in them).

4.

Poke and flow (hollow microneedles).

Microneedles are manufactured employing insoluble metals alloys such as stainless steel [133,134], titanium, nickel-iron [3] and occasionally, insoluble silicon [135] or soluble polymers including polycarbonate [136], PLGA, carboxymethyl-cellulose [3], polyvinyl pyrrolidone (PVP), and hyaluronic acid (HA) [137]. There are four important parameters that have been taken into consideration in the designing of microneedles: (1) loading of drugs in desired amount; (2) mechanical strength; (3) geometry; and (4) the ability to release drug in controlled manner. Loading of drug in required amount as well as the design flexibility are limited when the incorporation of drug into the array is performed. Microneedles, when made up of polymers, must have sufficient mechanical strength to withstand certain amount of pressure during application so that it will be able to pierce the skin in order to breach SC. The microneedle geometries (includes length, base width, and tip diameter) should be appropriate in order to minimize pain during injection. The typical geometries vary from 150 to 1500   µm in length, 50 to 250   µm in base width and 1 to 25   µm in tip diameter [138]. It is not only important to ensure the loaded drug is released after insertion into the skin, but also to make sure that the drug is released in controlled manner for a prolonged period. Microneedles developed from nanocomposite material have the ability to simultaneously exhibit sufficient mechanical strength, pre-loading of drug in required amount, and controlling the drug release.

Nanocomposite based on CS and varying concentrations (0, 0.25, 0.5, 1, 2, 5, 7 and 10   wt%) of reduced-GO (rGO) was prepared with an aim to develop microneedle for transdermal delivery of fluorescein sodium (FL) as shown in Fig. 16.16. Addition of rGO not only improved the mechanical strength with strongest nanocomposite at 1 and 2   wt% rGO, but also increased the electrical conductivity thereby allowing it to be used for iontophoresis or electroporation drug delivery application. It was observed that quicker and more substantial drug release with increasing concentration of rGO facilitated due to bonding of drugs on the surface of rGO. Drug release from prepared nanocomposite was found to be dependent on pH of medium, with a decreased release rate in the presence of acidic medium. With the addition of rGO, biodegradation rate of CS was found to be decreased while biodegradation rate of nanocomposite remained independent of rGO concentrations [11].

Figure 16.16. Optical microscopy images of microneedles array developed from chitosan and 2   wt% rGO-fluorescein sodium nanocomposites. (A) Microneedle array and (B) magnified image showing individual microneedle.

 Reproduced from Ref. [115] with permission from the Royal Society of Chemistry.

A novel multifunctional biocompatible, biodegradable nanocomposite microneedle with CS and graphene quantum dots (GQDs) for the tracked delivery of both small and large molecular weight drugs was developed. GQDs at 0.25–2   wt% in CS were found to be significantly improved electrical conductive with maintaining similar mechanical properties and biodegradation rate at 1   wt% GQDs. Microneedle arrays designed by taking CS and 1   wt% GQD nanocomposite, which were strong enough to bear the force of insertion into skin. Prepared nanocomposite microneedle containing small molecular weight model drug exhibited higher drug release than microneedle without GQD. But for the release of large molecular weight drug, iontophoresis was necessary. Thus nanocomposite microneedles provided a platform for tracked and iontophoretic delivery of both small and large molecular weight drugs [115].

Microneedle array was synthesized from fish scale derived collagen-nanocellulose (15   wt%) blend loaded with different concentrations of lidocaine (2.5–10   wt%) with an intention of delivering the drug across the skin in controlled manner. The microneedles containing lidocaine are shown in the Fig. 16.17. Fig. 16.18A demonstrating TEM image nanocellulose fibers before nanocomposite preparation and Fig. 16.18B showing nanocellulose fibers retained their dimensions and existed as individual fibers rather than cluster in the nanocomposite. It was found that microneedles have negligible swellability resulting into proper sticking of microneedle to tissue when inserted and also demonstrated adequate mechanical strength to pierce through the SC and release the drug. Lidocaine permeation rate was found to be increased from 2.5% to 7.5% w/w after 36   h of permeation study and pseudo steady state drug release profile was observed for microneedles containing 5%–10% w/w of drug. Higher release was observed for microneedle patches loaded with 5% w/w lidocaine than those loaded with 2.5% w/w lidocaine [116].

Figure 16.17. Microneedles of lidocaine prepared from fish scale biopolymer and nanocellulose [116].

 Reproduced with permission of Springer Ltd.

Figure 16.18. (A) TEM showing cellulose microfibrils prior to composite preparation, (B) HR-SEM demonstrating fish scale biopolymer-nanocellulose composite at (a) 350x, (b) 12,000x, (c) 15,000x, and (d) 70,000x resolution [116].

 Reproduced with permission of Springer Ltd.

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Polymeric Transdermal Drug Delivery Systems

Mohammad Shahrousvand , ... Mohsen Shahrousvand , in Modeling and Control of Drug Delivery Systems, 2021

6.7 Microneedles

Microneedles are a group of TDDSs that increase the diffusivity of the drug to the stratum corneum by creating micron-size pores in the skin. These carriers do not stimulate the nerves and are therefore painless. Microneedles are also known as excellent drug protectors and gradual release systems. A multilayer structure of microneedles can be designed to deliver the drugs needed for each stage of wound healing at appropriate times.

Microneedles can be classified into four groups: (1) Solid microneedles that allow drug penetration by creating pores in the epidermis. (2) Drug-coated microneedles that perform drug delivery from their outer surface while creating pores. (3) Drug container microneedles that are soluble in the physiological environment of the skin. After their penetration within the tissue and sojourning there, their degradation begins and simultaneously the encapsulated drug inside them gets released. (4) Hollow microneedles that penetrate the tissue and remain there. They facilitate drug transfer from the upper reservoir to the target site [7] (Fig. 9).

Fig. 9

Fig. 9. Microneedle arrays as transdermal drug delivery tools in skin care. (A) Schematic showing different types of microneedles used for transdermal drug delivery. (B) Bilayer microneedles with dissolvable tips carrying insulin before and after implantation. (C, D) Microneedles with swellable tips used for better adhesion of skin flaps to the surrounding tissues. (E, F) Swellable microneedles used as self-locking drug delivery tools.

 (From S. Saghazadeh, et al., Drug delivery systems and materials for wound healing applications, Adv. Drug Deliv. Rev. 127 (2018) 138–166, with permission.)

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Medical Biotechnology and Healthcare

O. Olatunji , D.B. Das , in Comprehensive Biotechnology (Second Edition), 2011

5.48.7.2 Dissolving Polymer Microneedles

Polymer microneedles serve as an alternative to silicon microneedles because they are made up of cheaper and relatively strong material, which could reduce tissue damage [64]. On the other hand, polymers are limited by their mechanical properties – the tips of microneedles fabricated using polymers are inevitably blunt due to the low modulus and yield strength of polymers [48, 61, 65]. Figure 3 shows arrays of polymer microneedles with calcein encapsulated within the tips.

Figure 3. Two different arrays of polymer microneedles with calcein encapsulated within the tip [66]. Scale   =   250   µm.

Beveled tip and tapered microneedles have been fabricated using biodegradable polymers [61, 67, 66]. Polyglycolic acid (PGA) has been chosen as the main material for the fabrication of many polymer microneedles because it is relatively inexpensive and believed to be mechanically strong [68].

Kolli and Banga [69] introduced solid maltose microneedles, which were found to be more suitable for self-dissolving microneedles compared to those made up of biodegradable polymer. This is due to the fact that maltose microneedles dissolve within minutes unlike biodegradable polymer microneedles, which take a longer period to dissolve [69].

Fabrication of polymer microneedles usually involves melting of the polymer at high temperatures and sometimes encapsulating microneedles using a nonbiocompatible polymer. Lee et al. [20] designed a novel method for making dissolving microneedles that do not require such high temperatures and which allow for the delivery of sensitive molecules such as protein. An example of the dissolving microneedles fabricated by the group is shown in Figure 4 .

Figure 4. Dissolving microneedles containing bovine serum albumin fabricated by Lee et al. [38]. Scale   =   600   µm.

Polymer microneedles are rarely used for hollow microneedles [70], despite the fact that polymers are cheap, biocompatible materials [22] with a lower melting temperature than silicon [71]. Moreover the viscoelastic property of polymers may allow more mechanical flexibility of the materials, thus reducing chances of damage during handling [22, 72].

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MEMS-based hollow microneedles for transdermal drug delivery

Richa Mishra , T.K. Bhattacharyya , in Drug Delivery Devices and Therapeutic Systems, 2021

5 Applicators for microneedle arrays

The microneedle applicator is an important element in improving patient acceptability and compliance. The applicator design should consider the force, velocity, and energy required for the microneedle insertion into the skin. The interface of the microneedle array in the drug delivery device has to withstand the mechanical stresses introduced by the mishandling of the microneedle patch. Also, day-to-day handling and storage conditions can generate mechanical stress. Taking these factors into account at the design stage reduces the time to market for this product [56]. The microneedle array requires very uniform insertion into the skin. Mishandling may result in large shear forces and consequently the microneedle breakage before skin insertion. Thus, it is recommended to use an applicator that allows safe positioning of the microneedles onto the skin and also facilitates the generation of a uniform force during insertion and retraction. A few designs of marketed microneedle applicators are reviewed hereafter.

Dermaroller is an FDA-approved device dedicated to skin appearance improvement (Fig. 12). Lee et al. [57] used a microneedle roller with solid microneedles as an applicator. The handle of the microneedle roller is pressed against the skin, inducing the movement of the roller drum and such that the microneedles are inserted into the skin with uniform pressure.

Fig. 12

Fig. 12. (A) Microneedle roller discs stacked together with a shaft passing through the center hole of the roller discs and held by a handle which removably supports both ends of the shaft, and (B) individual roller disc with microneedles protruding at various angles [57].

The company 3M and The Technology Partnership (TTP) jointly developed a microneedle applicator for convenient and reliable drug delivery. The device is equipped with a stick and a head that allows the user to insert the microneedles anywhere on the skin. The button on the device controls the force applied to the skin during injection [58].

The MicroCor applicator is a simple device consisting of a central solid disc surrounding an elastic membrane (Fig. 13). The microneedles are loaded on the solid disc. The outer portion is pressed against the skin creating a slight vacuum and then the solid disc is pressed onto the microneedles to uniformly puncture the skin. Tautman et al. (Alza Corporation) proposed a microneedle applicator design where the microneedles were protected by a membrane cover during storage (Fig. 13) [59]. The impact applicator, loaded with microneedles, presses the microneedles against the skin, and then retracts, leaving the microneedle patch on the skin [59].

Fig. 13

Fig. 13. (i) MicroCorTM applicator and (ii) Zosano's Macroflux [59].

The DebioJect system integrates a microneedle and its applicator that keeps the microneedle in place during the entire injection process (Fig. 14). DebioJect allows controlled and reproducible injections up to 500   μL in a few seconds.

Fig. 14

Fig. 14. Innovative microneedle applicator DebioJect [46].

A micropump can be copackaged with the microneedles and the applicator. The micropump is required for the controlled infusion of a drug. Mishra et al. [60] developed a hollow SU-8 microneedle array (10 × 10) with microfluidic conduits and a micropump attached to the substrate (Fig. 15). This micropump had a gold-coated Nafion membrane as actuator membrane [60]. The drug reservoir was connected to the micropump chamber by a valveless diffuser structure. The Nafion membrane was actuated electrically. Low voltages of about 3–6   V can generate flowrate in the range 20–45   μL/min by varying the actuation frequency between 0.1 and 0.5   Hz. Fig. 15 shows the integrated transdermal drug delivery device consisting of a micropump and a microneedle array.

Fig. 15

Fig. 15. (A) Conceptual layout of the microneedle assembly and (B) PLA-based Insulin delivery device fabricated by 3D printing with SU-8 hollow microneedle array in the inset [60].

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Transdermal and Intravenous Nano Drug Delivery Systems

Monica Sharma , in Applications of Targeted Nano Drugs and Delivery Systems, 2019

4.2.1 Microneedles

Microneedle (MN) array–based TDDSs have been intensively explored for their biocompatibility and as a mean of transport of small and large molecules (drugs, peptides, and proteins) at a commercial level [26]. With the emergence of sophisticated microfabrication technology in recent times, microneedles have been produced with much precision, and they are found to be very efficient in transdermal delivery by piercing the stratum corneum. Microneedles are of 150–1500   μm size in length, 50–250   μm in width, and 1–25   μm in diameter [27,28]. Microneedles cause micron-sized pore formation due to skin puncturing, and these channels act as a direct route of drug delivery. The success of MN-based drug delivery depends on its patient compliance and pain reduction. However, it was experienced that the length and microneedles' number are vital for the managing pain. The patch having 400 microneedles of 150   μm length was found to be painless [29]. When the needle length is increased from 500 to 1500   μm (constant needle number) and there is10 times increase in the number of microneedles (at constant length 620   μm), the pain score was increased by 7- and 3-fold, respectively [30,31].

Microneedles are organized in arrays on the backing of the patch, and resultant product is known as microneedle patch [32]. However, it is paramount for microneedles to meet certain criteria to qualify as an efficient drug delivery vehicle. These characteristics are: (1) the microneedles should be inserted deep into the skin tissue without breaking [33]; and (2) they should have optimum dimensions (neither too short nor too long) because needles that are too short would not pierce deeper into tissue and long needles would not having enough strength and rigidness and can break before penetration [34].

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Porous silicon microneedles and nanoneedles for biomedical applications

C. Chiappini , in Porous Silicon for Biomedical Applications (Second Edition), 2021

Abstract

Micro- and nanoneedles have emerged as effective platforms for topical biosensing and drug delivery thanks to their minimal invasiveness, and effective ability to transfer biological material to and from cells and tissues. Porous silicon is a promising material to develop micro- and nanoneedles since combines mechanical strength with bioresorbability and the potential for either sustained drug release or efficient harvesting of biomolecules due to the mesoporous structure. This chapter surveys design approaches developed to fabricate porous silicon micro- and nanoneedles and provides an overview of biomedical applications which are being advanced by this technology.

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Microfabrication for novel products in drug delivery

Regina Luttge , in Nano- and Microfabrication for Industrial and Biomedical Applications (Second Edition), 2016

8.1.1 Desk Research: MNAs, Microfabrication and Transdermal Delivery of Insulin

Microneedles are a next-generation drug delivery devices, that targets the skin. As yet, few original research papers consider this type of insulin delivery, so a review of MNA microfabrication technology and its possible applications in transdermal delivery of insulin is presented. A small subset of publications has been identified that demonstrate the proof-of-principle for insulin delivery by microneedles. The results of these papers are compared. However, the specific criteria that a microneedle device must fulfill to be used in this way are unclear, and a variety of hypotheses can be derived from this desk research.

A variety of microneedle designs (tip shapes, length, diameter, materials, etc.) in three distinct design categories have been produced. These are: silicon micromachined, replicated, fine, and mechanically manufactured MNAs. Despite the fact that microneedles can be used to target the skin as a route for delivery in a nearly painless manner, none of the designs show an appropriate level of technological readiness for clinical applications and are still vividly researched in clinical studies. Many different MNA designs have been presented in the scientific literature, but so far, clinical evaluation is limited. To bring any of these minimally invasive devices to market, one has to develop a suitable model which allows clinical researchers to benchmark the emerging microneedle techniques with respect to the conventional hypodermic needle injection for insulin. The case study discussed here will highlight the essential research and development stages concerned with microfabrication of MNAs.

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Wearable Bio and Chemical Sensors

Shirley Coyle , ... Dermot Diamond , in Wearable Sensors, 2014

2.1.2 Microneedle Technology

Microneedle arrays offer a minimally invasive means of biosensing through highly integrated biocompatible devices. There is the possibility of making them wearable through small devices and patches directly in contact with the skin. The trend is to make these arrays easy to fabricate on an industrial scale and at low cost.

The principal applications of these microneedle arrays involve fluid sampling [24] and extraction [25] since they provide the opportunity to overcome the skin barrier and thereby reach dermal biofluids, which are more reflective of systemic levels of key analytes. This novel technology can be used as a therapeutic tool for transdermal drug delivery, including insulin, and more recently as a diagnostic tool for the analysis of the biofluid contents. In this regard, glucose is being intensely investigated using microneedles in interstitial fluid. For instance, Sakaguchi et al. [26] developed a sweat-monitoring patch for measuring glucose using a minimally invasive interstitial fluid extraction technology based on microneedles. The advantage of this technique is that sweat contamination during interstitial fluid glucose extraction is avoided. Good correlations were found between interstitial fluid and reference plasma glucose levels.

Other analytes measured using microneedle sampling were hydrogen peroxide and ascorbic acid in which sampling was integrated with sensing via chemically modified carbon fiber bundles [27], and lactate, using carbon paste microneedle arrays. In the latter case, the need for integrated microchannels was avoided and extraction of the interstitial fluid was avoided, as the microneedles themselves were provided with inherent sensing capabilities [28]. Highly linear lactate detection was achieved over the entire physiological range, along with high selectivity, sensitivity, and stability of the carbon paste microneedle array. Recently, Miller et al. [29] reported the use of similar microneedle configurations for the simultaneous detection of multiple analytes in physiologically relevant tissue environments. The microneedles selectively detected changes in pH, lactate, and glucose, showing their potential use for applications in sports science. Biopotential measurements were demonstrated by O´Mahony et al. [30] using microneedles as dry electrodes for detecting electrocardiography (ECG) and electromyography (EMG). The microneedle-based dry electrodes compared to conventional wet electrodes are shown in Figure 5.

Figure 5. (a) Traditional wet electrode (top left), assembled prototype electrodes (bottom left), and microneedle arrays (right). (b) Microneedle-based dry electrode, illustrating an array of microneedles [30].

The fabrication of functional wearable devices that incorporate microneedle technology is very challenging. Nowadays, micro-fluidics are becoming the most reliable approach to control fluid transport in these sensors systems, where in many cases, only small sample volumes may be available (e.g., interstitial fluid flow is lower than 10   µL h−1). In this regard, Strambani et al. [31] developed a silicon microchip for transdermal injection/sampling applications. The microneedles were connected with a number of independent reservoirs integrated in the back side of a silicon die. Flow rate through the needle array as a function of the pressure drop applied to the chip for injection/drawing purposes was investigated. Using an array with 38,000 active needles, the flow rate can be finely controlled from a few mL min−1 up to tens of mL min−1. Other considerations that need to be taken into account when using microneedle arrays for in vivo sensing are the clogging of the microneedles and the potential of structural deformation upon their insertion into the skin, which may change the dynamics of the sampling and thereby introduce an unpredictable delay from time of sampling to detection.

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https://www.sciencedirect.com/science/article/pii/B9780124186620000027