The skin is the largest and most accessible organ of the human body that provides protection from the external environment and maintains homeostasis (Ghasemiyeh and Mohammadi-Samani 2020). It consists of three main layers; epidermis, dermis, and hypodermis (Fig. 1), (Mojumdar and Sparr 2021). The epidermis is about 50–150 µm thick where keratinocytes are the chief component cells (Hadgraft and Guy 1989). The epidermis does not contain blood microcirculation and consequently, the transport of substances from the epidermal/dermal layer to the hypodermis circulation is supported by diffusion process (Benson and Watkinson 2012). The epidermis has two sub-layers; the viable epidermis and the stratum corneum (SC). A 70% of the viable epidermis is water and hence, considered as a hydrophilic layer. In contrast, the SC is hydrophobic in nature with only 13% water content. The SC is the outmost layer of the epidermis which is 10–20 µm thick (Mendelsohn et al. 2006). The SC is known as the rate-limiting membrane of the skin and the main barrier against the topical drug delivery (Scheuplein et al. 1971).

Figure 1. 

The structure of the skin. The epidermis, dermis, and hypodermis. This Figure is generated using ChemDraw professional 16.0.

The dermis is hydrophilic in nature and is supplied with nerves and blood vessels. This layer is 600 to 3000 μm thick that is made up from connective tissue which gives the mechanical strength of the skin (Mendelsohn et al. 2006). Compounds that reach the dermis layer can find portal into the systemic circulation and this provides a concentration gradient that maintains the diffusion process. The dermis is demonstrated as a gel-like matrix of fibrous proteins network such as collagen and contains skin appendages such as hair, sebaceous and sweat glands. Cells such as; fibroblasts, melanocytes, macrophages, and mast cells are located in this skin layer (Hadgraft and Guy 1989; Benson and Watkinson 2012). The hypodermis or the subcutaneous layer consists of adipocytes and is innervated and supplied with blood vessels. The primary functions of this layer are protection and heat insulation (Benson and Watkinson 2012).

SC Stratum Corneum;

MW Molecular weight;

Da Dalton;

MN Microneedle;

TDD Transdermal drug delivery;

CAGR Compound Annual Growth Rate;

BSA Bovine serum albumin;

NSAIDs Non-steroidal anti-inflammatory drugs;

PTH Parathyroid hormone;

CMC Carboxy methyl cellulose;

PVP Polyvinyl pyrrolidone;

PLGA Poly(lactic-co-glycolic acid);

PMMA Poly(methyl methacrylate);

PVA Poly(vinyl alcohol).

Skin stands as a route of drug administration for both local and systemic drug effects (Benson et al. 2019). The knowledge and understanding of skin permeation have led to the development of topical and transdermal delivery (Benson et al. 2019; Aldawood et al. 2021). Drug administration through the skin offers plenty of advantages including; sustained drug delivery, maintained constant plasma levels, low metabolism activity compared to other routes, less inter-subject variability (Iwata et al. 2020; Phatale et al. 2022), escaping first pass hepatic metabolism, less frequent dosing regimens (Lee et al. 2017; Waghule et al. 2019; Ghasemiyeh and Mohammadi-Samani 2020), ability to discontinue regimen by removal of the system (Iwata et al. 2020), accessibility and relatively large surface area available for drug absorption, and being a non-invasive and convenient means of delivering therapeutics (Hamdan et al. 2018; Baveloni et al. 2021; Tiwari et al. 2022). Hence, this route provides a good alternative to oral and parenteral administration as it overcomes considerable limitations encountered by these routes (Benson et al. 2019; Aldawood et al. 2021). The aforementioned advantages possibly can increase patient adherence and ultimately improve their quality of life (Iwata et al. 2020). However, the main restraint of drug delivery by this route is the skin’s barrier properties. Generally, factors that determine skin permeability include; drug solubility, thermodynamic activity, partition coefficient (Benson et al. 2019), drug matrix-skin interaction, and temperature (Benson et al. 2019; Aldawood et al. 2021). Candidate molecules should have intermediate lipophilicity (Log P 1–3), be potent (Pandya et al. 2015), have molecular weight (MW) less than 500 Daltons (Da) (Mamta et al. 2010), and good aqueous solubility characterised by a low melting point (Williams 2003). It is difficult for hydrophilic substances to penetrate the hydrophobic SC layer. Whereas hydrophobic substances may be confined to it, as the following subsequent layer is hydrophilic (Supe and Takudage 2021). So far, limited number of therapeutics possess the optimum physicochemical properties to passively pass the skin’s outermost layer, the SC, and consequently, limiting both topical and transdermal market (Nastiti et al. 2017; Roberts et al. 2017). Many technologies have evolved to enhance the delivery into the skin, thereby extending the number of therapeutics that can be effectively delivered via the skin (Benson et al. 2019). These technologies involve the utilisation of chemical penetration enhancers, micro and nano delivery systems (Nastiti et al. 2017; Roberts et al. 2017), ultrasound, iontophoresis, electroporation, and microneedle (MN) technology (Phatale et al. 2022). Among these approaches, MN arrays stand out as a simple and a relatively low-cost approach to deliver therapeutics (Hamdan et al. 2022).

Transdermal drug delivery (TDD) deals with the drug administration through the skin to achieve systemic effect and is considered as a non-invasive alternative to parenteral route (Soni et al. 2022). The transdermal absorption is a stepwise process which involves (Dhote et al. 2012); (i) penetration: the access of a substance into a certain skin layer, (ii) permeation: the penetration of a substance from one layer of the skin into another, where both layers are functionally and structurally dissimilar, and (iii) absorption: the uptake of a substance into the systemic circulation. Primarily, the drug passes through the SC, then reaches into the epidermis and dermis microcirculation. The medication succeeds to enter the systemic circulation when it manages to reach the dermis (Waghule et al. 2019; Soni et al. 2022). TDD has several advantages such as; avoidance of first-pass effect, self-administration, prolonged drug delivery, less frequency of dosing, enhancement of patient compliance (Ghasemiyeh and Mohammadi-Samani 2020; Iwata et al. 2020). This route of administration is useful for patients who are unconscious or vomiting. However, TDD is not suitable for high-dose and high molecular weight drugs, skin sensitisation and irritation at the site of application is a possibility.

The investments in MN market were approximately $24 billion in 2013 (Azmana et al. 2020). By 2030, the market size of MN drug delivery system will reach to a $1.2 billion and Compound Annual Growth Rate (CAGR) record approaching 6.6% (Aldawood et al. 2021). MN has been extensively investigated in academia and industry to take this technology from laboratory settings in to clinic (Quinn et al. 2014). MN arrays are categorized as one of the direct physical methods and an alternative to conventional hypodermic needle (Benson et al. 2019). MN arrays are a micron-scale devices attached to a patch-like support (Wei-Ze et al. 2010; Benson et al. 2019; Hamdan et al. 2022) that pierce the SC barrier and generate conduits, subsequently, enhance the drug flux and its permeation through the skin (Prausnitz and Langer 2008; Donnelly et al. 2010a; Benson et al. 2019). Perforations created by MN arrays can physically disrupt the intercellular lipids and penetrate the corneocytes in the SC and increase the total surface area of the aqueous pores in the skin (Mikolajewska et al. 2010; Pattani et al. 2012). Pores created by MN projections have been shown to cure within two hours without occlusion, the later can extend closure time up to 24 hours (Gupta et al. 2011). MN arrays have been designed in several needle geometry and densities (25–2000 µm in height, 50–250 µm in base width, 1–25 µm in tip diameter, up to 2000 MN cm^-2) (Singh et al. 2013; Alkilani et al. 2015) without reaching nerve endings or blood vessels, thereby providing a painless administration (Gill et al. 2008) and avoiding needle-stick injuries (Indermun et al. 2014). Several researches have been thoroughly conducted to obtain an optimum MN arrays design (Davis et al. 2004; Verbaan et al. 2008). MN array have been designed in a ‘poke and patch’ or loaded forms (Benson et al. 2019) using various materials and microfabrication techniques (Prausnitz 2004; Lee et al. 2008; Donnelly et al. 2009a, 2010a; Singh et al. 2010; Garland et al. 2011; Migalska et al. 2011). It was found that the rate and extent of transdermal delivery were influenced by the configuration and application mode of the MN batch (Verbaan et al. 2008; Yan et al. 2010). It was reported that an increase in MN arrays height has led to an increase in the depth of MN arrays penetration into the skin (Donnelly et al. 2010b). However, the application of MN arrays with height 900 µm was perceived by volunteers to be relatively painful (Garland et al. 2012a). Further, higher MN arrays density resulted in a higher number of conduits formed within the skin. Yet, high MN density would affect bed of nail effect (Lee et al. 2008; Yan et al. 2010). Various combinations of MN arrays systems and other techniques have been studied for a number of drugs. All combined approaches enhanced the TDD of the tested compounds. MN arrays systems were coupled with iontophoresis (Katikaneni et al. 2009), ‘in-skin’ electroporation (Yan et al. 2010), phospholipid vesicle systems (Badran et al. 2009), sonophoresis (Chen et al. 2010), Skin occlusion (Gupta et al. 2011). A unique triple strategy based on MN arrays, iontophoresis and nanovesicle was also reported (Chen et al. 2009).

MN arrays proved to enhance skin permeability, and hence, drug penetration into the skin (Hamdan et al. 2018; Tekko et al. 2020). The rate limiting step to the drug delivery through the skin is mostly attributed to the diffusion of the drug solute to the underlying dermal capillary bed. Thus, the drug release kinetics is likely to be controlled by the delivery system, rather than the SC (Donnelly et al. 2011). MN systems are capable of delivering macromolecules and biotherapeutics which are considered not good candidates for transdermal delivery. Worthy to mention, the administration of such therapeutics is limited to the parenteral route, and are susceptible to degradation when administered orally (Quinn et al. 2014). MN arrays are minimally-invasive devices, and have delivery capabilities similar to hypodermic injection (Donnelly et al. 2011; Seok et al. 2016; Aldawood et al. 2021). MN arrays are short and thin to reach the underlying dermal nerves or capillaries, thereby, their insertion into the skin is generally perceived as being painless and causes no bleeding (Donnelly et al. 2010b, 2011; Mikolajewska et al. 2010). Risk to develop MN-associated skin infections is negligible (Donnelly et al. 2011; Johnson and Procopio 2019). MN arrays generate transient microscopic pores in the SC, with minimal or even without signs of erythema or local adverse skin reactions (Bal et al. 2008; Van Damme et al. 2009). Heavy occlusion to the MN-pre-treated area extends barrier disruption and improves the permeation of the drug into the skin (Haq et al. 2009). MN arrays are considered patient-friendly devices, easy to apply with no need for hospitalisation (Pattani et al. 2012; Larrañeta et al. 2016b). On the other hand, hypodermic needles cause skin trauma and bleeding. Needle-stick injuries are possible with parenteral injections, hence, safe and correct disposal are essential but rather challenging to accomplish in developing countries (Donnelly et al. 2009b, 2012b; Pattani et al. 2012). Generally, the advantages offered by MN arrays reflect the versatility of MN approach as a delivery system (Quinn et al. 2014)

Although MN have a lot of advantages, yet there are some drawbacks. The MN application may necessitate a good mechanical strength, extended application time, multiple patches (Jeong et al. 2017). The pharmacokinetic parameters are more likely challenging to acquire, and hence, adverse side effects may appear as a result of inaccurate dosing (Rzhevskiy et al. 2018). The shapes and conformation of needle structures may affect their efficacy and ability to poke the skin (Kawahara and Tojo 2007; Ramadon et al. 2021). One of the major long-term safety issues of MN devices is the polymer deposition inside the body when using dissolving MN arrays, however, a ‘one-off’ delivery platform such in the case of vaccination would overcome this problem (Bal et al. 2008). The chances to develop immunological skin reactions such as; skin irritation, redness, pain, swelling (Kawahara and Tojo 2007; Ramadon et al. 2021).upon the application of MN arrays would be considered as a health concern issue (Bal et al. 2008).

The major MN types used for drug delivery purposes are solid non-coated/coated, hollow, dissolvable/swellable polymeric MN arrays devices (Aldawood et al. 2021).

Swellable microneedles

Swellable MN arrays are hydrogels typically developed from a crosslinked polymers where the needle matrix contains no drug (Donnelly et al. 2012b; Tekko et al. 2020). When poked into the skin, these MN arrays imbibe skin interstitial fluid, swell, and form an open-channels that connect a patch-type drug reservoir to the underlying dermal microcirculation (Donnelly et al. 2014b, d; Seong et al. 2017). Swellable MN arrays are capable of delivering small and macromolecules, such as metronidazole and insulin respectively (Donnelly et al. 2012b, 2014a; Chang et al. 2017). In such hydrogel system, the rate and capacity of polymer swelling, and subsequently, the drug release rate, can be tailored by varying the polymer crosslink density. As the drug concentration in interstitial fluid usually reflects plasma drug concentration, MN arrays are applied in drug diagnostic monitoring (Donnelly et al. 2014a; Chang et al. 2017). Compared to dissolving MN arrays in which polymer deposition is a cumbersome, hydrogels are removed completely intact and cannot be re-inserted (Donnelly et al. 2012b). The later reflects appreciable mechanical strength of the swollen hydrogel and eliminates material safety concerns. Hydrogels are known to possess inherent antimicrobial properties which reflect their safe use (Donnelly et al. 2012b; Hong et al. 2013; McCrudden et al. 2014).

Figure 2. 

Schematic representation of MN types and delivery approaches. A. Solid non-coated; B. Solid coated; C. Dissolving; D. Hollow and E. Swellable MNs.

The delivery of several compounds assisted by MN arrays has been attained via four main strategies:

• ‘poke-with-patch’ approach: the MN arrays are applied to the skin surface to create microchannels, then detached to apply drug formulation such as drug-laden patch, gel or solution (Martanto et al. 2004).
• ‘coat-and-poke’ approach: the formulation of the drug is coated onto the projections of MN arrays, then MN arrays are inserted into the skin (Matriano et al. 2002).
• ‘poke and-flow’ approach: hollow MN arrays pierce the skin and the liquid drug payload is injected into the skin (Davis et al. 2005).
• ‘poke-and-release’ approach: the drug molecules and the polymeric material are combined in to a matrix, the resulting MN arrays matrix are subsequently inserted into skin (Park et al. 2006).

A variety of materials are used to fabricate MN arrays. Generally, selected materials should be available, inert, non-brittle, biocompatible, have a good mechanical strength and of low cost.

MN array system, by design and necessity, should be sharp enough to puncture the skin with low insertion force i.e. below its break force (Davis et al. 2004; Park et al. 2005; Gill et al. 2008). The performance of MN arrays can be optimised by controlling needle dimensions, design, type of material, and fabrication technique (Aldawood et al. 2021). Several methods have been developed for MN fabrication including laser ablation, lithography, micro-molding. injection molding, additive manufacturing (Prausnitz 2017; Rodgers et al. 2018; Ye et al. 2018; Juster et al. 2019; Parupelli and Desai 2019; Aldawood et al. 2021).

The fundamental knowledge of the mechanics of needle insertion into the skin is very essential to optimise the performance of MN devices. Needles that have sharp tips are capable to poke the skin with the minimum force for insertion. However, the later would reduce the strength close to the needle tip and bending of needles tips may take place, especially for needle prototype with very thin tips (< 20°) (Zhang et al. 2009). It was documented that the higher the thickness of the needle wall, the higher is the fracture force, therefore, needle prototypes with small tip diameter and high wall thickness are preferable for insertion (Prausnitz 2004; Zhang et al. 2009). Needle density of a baseplate of a certain area can also affect the penetration force. The high needle density would result in the bed of nails effect. Generally, there are two kinds of failure styles related to the insertion of the needles into the skin; fracture or buckling (Zhang et al. 2009). Failure takes place when the load leads to either fracture or buckling. Consequently, MN mechanical characterization during their design is of paramount importance (Khann et al. 2010). The main mechanical tests which include; axial force, transverse force, and insertion force are usually conducted for MN arrays and are listed in (Table 1).

Many clinical trials were completed on MN-based delivery for multiple conditions. One study that demonstrated the use of MN devices to deliver insulin had reached to phase III trial (Norman et al. 2013). It was revealed that the delivery of insulin using a single, hollow MN array was perceived with less pain and faster onset of action. Another phase III clinical study had tested zolmitriptan-containing MN system which is indicated for the treatment of migraine (Spierings et al. 2018). It was shown that the drug delivered through the MN device provided significant pain relief and lessened symptoms associated with migraine compared to placebo (Spierings et al. 2018). There are ongoing clinical trials and recruiting for patients to prove the feasibility of MN system to deliver various drug substances used for multiple clinical conditions.

To prevent the COVID-19 pandemic, global mass vaccination is a necessity. The vaccine strength, transport chain, needle phobia, and needle waste are major challenges for global outreach (Hassan et al. 2022). The delivery of vaccines via the skin using MN arrays is a good alternative to conventional invasive hypodermic needle and syringe-associated needlestick injuries (Benson et al. 2019). The use of MN arrays for COVID-19 vaccination is painless, secures higher vaccine coverage, offers higher product thermal stability and shelf-life, and allows for self-administration. Many researches support the use of dissolvable MN-mediated COVID-19 vaccination system (Hassan et al. 2022). On the other hand, MN-based oropharyngeal swabs were introduced for COVID-19 testing and monitoring (Chen et al. 2020). The latter allow reduction of false COVID-19 tests and perform testing with high accuracy.

Despite the extent and diversity of research in the field of MN technology, there are few marketed MN products (Table 2) (Butola 2022). MicronJet and Soluvia (Arora et al. 2008; Benson et al. 2019) are MN devices which demonstrated superior immune responses to influenza vaccine compared to IM injection. Commercially, there exist no biodegradable polymer-based MN device (Li et al. 2017), nor protein- loaded MN device (Al-Japairai et al. 2020). The regulatory bodies may ask for MN finished product sterilization or their manufacture under aseptic conditions to assure the safety of the final product (Bal et al. 2008). MN devices classification whether it is transdermal or intradermal delivery, transdermal patch platform or injection is still unclear (Donnelly et al. 2012b). Regulatory bodies are concerned with the guidelines and instructions of MN devices in terms of scale-up instructions (Quinn et al. 2014), packaging, disposal, directions to use, and safety issues (Larrañeta et al. 2016b). The optimisation of MN array products with respect to engineering, design, and usability will facilitate their approval within the regulatory bodies. The perception for easy-to-use product and the contemplation of long term safety profile for MN devices will certainly extend the degree of acceptance of these devices in the market (Quinn et al. 2014). Moving forward with MN technology in terms of their manufacture and commercialisation require consensus on a harmonised specifications for MN system (Quinn et al. 2014; Larrañeta et al. 2016b). Although these hurdles exist, MN-based skin delivery shows a promising future toward the management of chronic diseases and global vaccination programs particularly in pandemics (Benson et al. 2019).