There are many approaches currently used for the delivery of drugs and therapeutic agents including oral administration, conventional hypodermic needles, topical creams and transdermal patches [1]. Oral drug delivery is considered one of the most desired routes of administration when compared to other routes due to high patient compliance, cost-effectiveness, less sterility constraints, flexibility in dosage delivery and the ease of production. However, it results in the poor bioavailability of drugs due to factors relating to dissolution, permeability, and solubility [2]. Conventional hypodermic needles can cause pain to the patient as they penetrate deep into the dermis where pain receptors are present. Their use is particularly challenging for needle phobic patients. The traditional use of subcutaneous injection for the delivery of macromolecules also has safety concerns for healthcare workers as needle stick injuries are a common occurrence. In some cases, subcutaneous injections are expensive as there may be a need for multiple or chronic administration by trained medical professionals [3]. The topical application and administration of drugs, using a topical cream, gel or ointment or a non-invasive transdermal patch, allows for the penetration of the drug into the skin without pain [4]. These topical methods have a limited ability to administer drugs with large particles (e.g., nucleic acids, large drug molecules) as the stratum corneum layer of the skin acts as a natural barrier [5]. The ability of a drug to penetrate the skin is influenced by the skin physiology and permeability, and various other factors including the physiochemical properties of the drug (i.e., size, molecular weight, concentration, partition coefficient and solubility) and formulation characteristics (i.e., release rate, ingredients and the presence of permeation enhancer) [6]. Additionally, the administration of ionic drugs, drugs of high concentrations or with very low/high partition coefficient can create problems such as skin irritation, non-systematic circulation and poor permeability [7]. Overall, while these topical methods have the advantage of being painless, they lack bioavailability and can lead to skin irritations, allergic reactions or non-controlled drug release [8].

As a result of the disadvantages of existing techniques, there is an increasing imperative for innovative methods for the delivery of therapeutic agents. For this reason, many studies have focused on the investigation of microneedle (MN) arrays as transdermal drug delivery (TDD) systems. MN arrays are minimally-invasive devices that can penetrate the stratum corneum, one of the most important barriers for topically-applied drugs, thus creating a pathway for drug permeation to the dermal tissue below [9]. MN arrays can enhance skin permeability compared to non-invasive patches enabling a faster onset of action and good bioavailability. The use of minimally invasive MN-based transdermal patches for TDD offers several important advantages over traditional drug delivery methods. These advantages include: (1) easy and controlled drug delivery; (2) the enhancement of therapeutic efficiency with fewer side effects; (3) less pain than with traditional hypodermic needles; and (4) the maintenance of a steady plasma level of the drug ^[10][11][10,11]. To date, MN arrays have been used in several biomedical applications including diabetes treatment [12], cancer diagnosis and therapy [13], for infections, inflammation and chronic pain treatment and the treatment and control of obesity [14], and also for other applications including the sampling of blood and interstitial fluids [15]. However, current MN-based TDD systems have associated limitations including incomplete insertion, particularly for polymeric MNs, which results in limited drug delivery efficiency and the wastage of valuable medication [16].

Metallic MN offer potential to overcome the challenges associated with polymeric MNs systems. However, several existing challenges limiting the translation of metallic MN arrays as a successful TDD systems remain, including: (1) current methods for metallic MN array fabrication involve a multi–step process that is not cost-effective; (2) the lack of clinical data relating to cytotoxicity of the metals used for MN fabrication; (3) limited drug loading; and (4) challenges in maintaining mechanical properties and piercing capacity.

2. Types of Microneedle Arrays

MN arrays can be characterized as: (1) solid, (2) coated, (3) hollow and (4) dissolvable (Figure 1) ^[17][18][19][18,19,20]. They can be further categorized based on their mode of drug delivery, and the materials used for their manufacture ^[20][21]. In general, there are four different modes of drug delivery: (1) ‘poke–detach–diffuse’ for solid MNs (Figure 2a); (2) ‘coat and poke’ for solid coated MNs (Figure 2b); (3) ‘poke and flow’ for hollow MNs (Figure 2c); and (4) ‘poke and release’ using dissolvable MNs (Figure 2d) ^[21][22]. The ‘poke-detach-diffuse’ method involves the use of solid MNs to create micro-channels through the epidermis into the dermis [14]. After the removal of the MN system, the drug formulation is applied to the skin surface by applying topical creams or transdermal patches and the drug is delivered through the created micro-channels ^[17][18]. Coated MN systems are solid MNs coated with a particular drug formulation. They deliver the drug during the insertion of the needles into the skin, termed the ‘coat and poke’ method [14]. The coating of the MNs can be achieved by dipping or spraying the surface of the solid MNs with the solubilized drug ^[22][23]. For coated MNs, following the penetration of the MN into the skin, the delivery of the drug is achieved by the dissolution of the coating which allows diffusion of the drug and the MNs are subsequently removed ^[22][23]. Solid MNs can be fabricated from metals (e.g. stainless steel or titanium), ceramics (silicon) and polymers (poly D, L-lactic-co-glycolic acid (PLGA) and poly-ethylene glycol (PEG)) using different fabrication methods ^[14][21][23][14,22,24]. The length and the shape of the channels formed depend on the needle geometry and design. Martiano et al. used triangular shape stainless steel MNs (height = 1 mm, width = 0.2 mm) for the TDD of insulin based on the ‘poke–detach–diffuse’ method ^[24][25]. Theirs study demonstrated the potential for effective TDD of macromolecular drugs using solid MNs. The “coat and poke” method has also been used with titanium solid MNs of 330 µm height in an area of 1 cm² coated with protein antigen for vaccine delivery ^[24][25]. Their study demonstrated rapid and reproducible intracutaneous administration of dry-coated antigen ^[24][25]. More recently, porosity have been introduced within the structure of solid MNs, made by metals, polymers or ceramics, to enhance their ability to delivery drugs and therapeutic agents ^[25][26]. These porous MNs have different percentages of porosity, ranging between ~30% to 40% with average pore diameter 1.3 μm to 2.22 μm within their structure offering the unique ability to absorb drugs within their pores and release them upon insertion into the skin ^[26][27][28][27,28,29]. While these MNs show potential for enabling improved TDD, the volume of voids within the structure can result in MN tip collapse due to the porous structure ^[26][27]. In particular, the porosity reduced the strength to only 2 N compressive force for titanium MNs and 0.6 N for polymeric MNs. In addition to the decrease of mechanical properties, decrease of tip sharpness was also observed with increased fragility during the fabrication process ^[27][29][28,30]. Thus, further optimization of the selected particle size of the powder material and the pore diameter of the final part, is required to achieve porous MNs that meet the clinical requirements ^[26][27]. Hollow MN systems contain an empty cavity within the MN and a bore at the tip. Drug delivery is achieved through the ‘coat and flow’ method whereby micro-volumes of a drug can be delivered directly into the skin. They can deliver relatively large amounts of drugs with higher accuracy in dose, directly to the skin ^[14][17][14,18]. Hollow MNs are typically fabricated from metals and ceramics with similar fabrication techniques as used for solid MN arrays ^[20][21]. The final type of MN systems are dissolvable MNs, which are biodegradable and can be manufactured from water-soluble materials or degradable polymers ^[19][20]. The matrix of the MNs contains the drug and has sufficient mechanical stability to enable insertion into the skin, therein the matrix dissolves and the drug is released as a consequence, thus achieving drug delivery via the ‘poke and release’ method ^[20][21].