key: cord-0747483-fveth3c4 authors: Ahmed Saeed AL-Japairai, Khater; Mahmood, Syed; Hamed Almurisi, Samah; Reddy Venugopal, Jayarama; Rebhi Hilles, Ayah; Azmana, Motia; Raman, Subashini title: Current Trends in Polymer Microneedle for Transdermal Drug Delivery date: 2020-07-30 journal: Int J Pharm DOI: 10.1016/j.ijpharm.2020.119673 sha: 151d4f0db743601ea91e96b0fb976fe4f2f1c7bf doc_id: 747483 cord_uid: fveth3c4 Polymer microneedle promotes the delivery of chemical and biological drugs through the skin. [Figure: see text] The skin is the outermost and largest organ of the human body, covering an area of 1.8 m 2 and making up close to one-fifth of an average person's total body mass (Brown & Williams, 2019) . Being the first barrier to entry into the body, the skin protects against external threats in the environment, including pathogens, harmful UV rays, toxins, inflammatory agents and dehydration (Yin & Smith, 2016) . Due to the large coverage area of the human skin tissue, it offers a convenient, selective, and non-invasive route for drug delivery. Transdermal drug delivery (TDD) refers to the delivery of therapeutic agents across the skin layer. The delivery of drugs via skin overcomes many of the issues associated with oral drug delivery, including the gastric irritation, elimination of hepatic first-pass metabolism, and poor patient compliance. Additionally, it offers better release over time compared to oral drug delivery (Ita, 2015a; Pegoraro, MacNeil, & Battaglia, 2012) . Moreover, transdermal delivery devices are accessible, replaceable, controllable, and could be self-administered in several cases (Merino, Martin, Kostarelos, Prato, & Vazquez, 2015) . Scopolamine, with a primary indication for managing motion sickness (Transderm-Scop ® ), nicotine for smoking cessation (Nicoderm ® ), and fentanyl for chronic pain (Lexicomp-Online, 2016) are examples of the first generation trans-delivery drug administration is the remedy for disease. The greatest challenge in the delivery of active ingredients across the transdermal route is the stratum corneum (SC) that acts as the first protective layer of the skin and limit the drug absorption. This will significantly reduce the effectiveness of delivery of therapeutic agents and limit the types of drugs that can be delivered into the skin. Recently, there have been several studies on microneedles that penetrate the superficial skin barrier (SC) while avoiding contact with important nerves and capillaries in the epidermis to provide a more efficient and quick method for drug delivery compared to available transdermal drug delivery strategies. The novel approach combines between conventional injection and patch system. The drug is delivered transdermally while removing the pain and invasiveness associated with conventional methods in medicine (Kwon et al., 2017) . Microneedles (MNs) have been conceptualized and introduced several years ago but were only successfully fabricated and applied in the 1990s (Gerstel & Place, 1976; Henry, McAllister, Allen, & Prausnitz, 1998; Prausnitz, 2004) . The classification of microneedles has been done according to the function it performs: solid, coated, hollow, dissolving and hydrogel-forming microneedles (Abiandu & Ita, 2019; Shende, Sardesai, & Gaud, 2018) . The mechanical properties and biocompatibility of the material chosen for the manufacture of MNs are of major importance to the performance of the MNs. Low production cost and high mechanical strength are general considerations for the choice of fabricating materials. In this regard, polymers are the preferred materials for MNs fabrication as it does not elicit an immune response in the body, degrades in the body and can be tailored to perform with different strengths and functions (Lhernould, Deleers, & Delchambre, 2015) . Microneedles play an important role in medical field applications for delivering various drugs ranging from small to macromolecules, especially protein drugs that use for the treatment of several diseases. Thus, biotechnology companies give more attention toward research and development of MNs loaded protein drugs (Kochhar, Tan, Kwang, & Kang, 2019; G. Ma & Wu, 2017; Ryu, Kim, Kim, Wang, & Hwang, 2018) . However, effective use of biotherapeutics is hindered by the large size, hydrophilic nature, poor absorption, and unstable nature of the drug, which prevent efficient uptake through the skin (Ryu et al., 2018) . The progress in MNs research and production technology will lead to the delivery of clinically important drugs in the future (Kochhar et al., 2019) . The skin is a multidimensional organ made of three important layers (Lhernould et al., 2015) as presented in Fig. 1 . The layer's function to protect the internal organs from a host of outside dangers including toxins, external mechanical pressure, and microbial attack from pathogenic species. The skin also functions as a trigger for immune reactions due to the specialized antigenpresenting cells. The first skin layer, i.e. the epidermis layer, is approximately 150-200 mm thick and is composed of viable cells. It is made of five layers according to a degree of cell keratinization: stratum corneum (SC, horny layer), stratum lucidum (clear layer), stratum granulosum (granular layer), stratum spinosum (spinous or prickle layer) and stratum germinativum (basal layer) (Yousef, Alhajj, & Sharma, 2019) . The outermost layer or horny layer SC (10-20μm) has been referred to as "a brick wall-like structure of corneocytes as "bricks" in a matrix of intercellular lipids, with desmosomes acting as molecular rivets between the corneocytes" (Baroni et al., 2012) . Under the SC layer is the viable epidermis layer, which contains the keratinocytes and pigment-producing cells, the melanocytes. This layer is responsible for most drug-related actions, such as drug binding, metabolism, active transport, and surveillance. This layer also contains specialized cells such as the Merkel and Langerhans cells (Monteiro-Riviere, 2010). The second skin layer is the dermis (3-100 mm), which follows the viable epidermis layer. Here, the skin is made up a more complex mix of cells with different functions such as connective tissue, vascular tissue, lymphatic vessel network, sweat and sebum glands, hair follicles and macrophages (Stojic et al., 2019) . This layer not only functions as a host layer for the network of functional tissue but also provides structural support in the skin due to the presence of fibroblasts (Stojic et al., 2019) . The third skin layer, the hypodermis (subcutis) follows the dermis layer, which contains loose connective tissue. The major cells found here are the adipocytes, which function in fat storage for use in body temperature regulation during cold as well as cushioning against outside insults (Sorg, Tilkorn, Hager, Hauser, & Mirastschijski, 2017) . The transfer of molecules via the skin follows an intricate set of steps, involving a number of mechanisms; the intracellular absorption of the molecule passes through the keratin-packed corneocytes by partitioning into and out of the cell membrane; the intercellular absorption where the molecule passes around the corneocytes in the lipid-rich extracellular regions; and appendageal absorption where the molecule moves through the shunts of hair follicles, sweat glands, and sebaceous glands (Tsakovska et al., 2017) . Transdermal delivery is gaining interest as an option for drug administration. The drug reaches the systemic circulation through the skin without losing the drug during reaching its target, enhance the bioavailability, improving sustained drug release, minimizing undesirable side effects, and improving physiological and pharmacological response (Mahmood et al., 2014; Rai, Mishra, Yadav, & Yadav, 2018) . For instance, in testosterone replacement studies, transdermal delivery overcomes the issues associated with oral and intramuscular delivery, it bypasses the hepatic first-pass after oral administration, and thus reduce the required dose. Besides, it eliminates the need for recurring injections and a higher concentration of testosterone in the blood (Hathout et al., 2010; Tajbakhsh et al., 2020) . Nevertheless, the delivery of drugs via the transdermal administration route is highly affected by the chemical properties of drugs, which affects absorption through the SC. Hence, few drugs can be delivered in significantly therapeutic amounts via this route (Mittapally, Taranum, & Parveen, 2018) . The drugs applied through transdermal drug delivery system needs to take a tortuous route to bypass through consecutive skin layers containing both aqueous and lipid domains and reach the systemic circulation (Mahmood et al., 2018; Haque & Talukder, 2018) . The drug molecule needs to have ideal properties to pass through SC layer; the molecular weight must be less than 600 Da, the value of Log P between 1 and 3, High, but balanced, SC/vehicle partition coefficient, and Low melting point, correlating with good solubility, as predicted by ideal solubility theory (Chandrasekhar et al., 2013; Flaten et al., 2015; Ye et al., 2018) . Olanzapine is one of the drugs that have required physicochemical properties for effective transdermal drug delivery. It is lipophilic (log P 2.8), has a low molecular weight of 312.4 and a low melting point (195 C°) . The poor bioavailability of olanzapine orally and susceptibility to loss during delivery means that only 40% of the actual dose remains before entering the circulation system. Together, these characteristics make olanzapine a good candidate for delivery via transdermal drug patches (Alyautdin, Khalin, Nafeeza, Haron, & Kuznetsov, 2014; Iqbal, Vitorino, & Taylor, 2017) . Obviously, many medications are unable to follow these stringent requirements for transdermal delivery . There are three generations of transdermal drug delivery, as illustrated in Fig. 2 . In the first generation, the systems used for transdermal drug delivery was patches, the drug candidate that is appropriate for patch formulation is extremely limited and has to fall into optimal ranges of molecular weight, hydrophilicity and effectiveness at low dosage (Economidou, Lamprou, & Douroumis, 2018) . The second generation of TDDS was implemented with a skin permeability enhancement technique to extend its application in transdermal drug delivery. Improvement methods included iontophoresis, chemical enhancers and non-cavitational ultrasound. Nevertheless, these methods struggle to protect the deeper tissues from any physiological harm and increase the distribution of drug molecules through SC (H. . In the third generation, novel chemical enhancers, electroporation, cavitational ultrasound, microneedles, thermal ablation and microdermabrasion were introduced, these techniques allowed the biotherapeutics and large molecules to better penetrate the outer corneum layer, resulting in increased efficacy of transdermal delivery in human clinical trials (Nandagopal, Antony, Rangabhashiyam, Sreekumar, & Selvaraju, 2014) . However, the techniques used abrasion methods, lasers and heat and exposure to radiofrequency, which harmed the skin, caused discomfort in patients and resulted in the application of the drug and treatment of side effects. Such limitations can be solved by using micrometer size needles called microneedles (Battisti et al., 2019) . MNs technology has grown in the last 15 years, permitting drugs to cross the outer corneum layer by puncturing the skin and creation of micro-channels in the outer corneum using micron needles (McAllister et al., 1998; Mitragotri, 2013; Pierre & Rossetti, 2014) . Compared to other transdermal delivery methods, microneedles are able to deliver molecules of larger sizes without disturbing the nerve endings in the skin, hence minimizing or altogether avoiding pain experienced by patients. Furthermore, microneedles can be used in both solid and liquid preparations according to the required specifications of the disease (Cheung & Das, 2016) . The MNs is promising for the future of TDD to facilitate the delivery of drugs with large molecular weight and low lipophilicity, such as proteins, peptides and vaccines, as well as drugs with poor effectiveness at low doses (Waghule et al., 2019; Ye, Yu, Wen, Kahkoska, & Gu, 2018) . Microneedle (MN) technology employs microscopic needles to deliver drugs across the SC layer into the underlying layers with minimal invasiveness. The microneedles used in these delivery systems differ in length; some are just a few micrometers long but can go up to 2000 μm (Tuan- Mahmood et al., 2013) . The short length of MN allows penetration of the SC without touching the nerves in the underlying layers of the skin (Quinn, Kearney, Courtenay, McCrudden, & Donnelly, 2014) . The use of MNs is preferred over conventional drug delivery methods due to its simple delivery mechanism, pain-free, and minimally invasive devices that offer the simplicity of using transdermal while delivering the effectiveness of invasive needles and syringe (Nayak, Babla, Han, & Das, 2016) . Unlike conventional methods, MNs do not require specialized skills or personnel, as they are designed for self-administration by patients. Furthermore, MNs are designed for single-uses; this minimizes the potential for cross-contamination of the drugs (Mahato, 2017) . MNs are categorized into five different groups according to the design: solid, hollow, coated, dissolving, and hydrogel-forming microneedles, as illustrated in Fig. 3 . Solid MN delivery consists of two steps and is known as the "poke and patch" approach; first, holes are introduced into the skin using MN arrays; secondly, a conventional drug formulation is delivered via transdermal drug patch (Omolu, Bailly, & Day, 2017; Tuan-Mahmood et al., 2013) . Coated MNs follow the "coat and patch" approach; here, a drug formulation is coated onto the microneedles prior to application into the skin. Penetration into the skin allows the coating to dissolve; thereafter, the drug is deposited into the skin. In the hollow microneedles approach, the drug is filled into the hollow space in the tip of the microneedle, which is directly deposited into the epidermis or upper dermis layer of the skin upon insertion. In simple terms, this can be described as "poke and flow" (Pamornpathomkul et al., 2017) . Dissolving microneedle is made mainly from dissolving or biodegradable polymers and allows for the simple one-step application process, and hydrogel-forming microneedles which absorb water in large quantities into their polymeric network, resulting in swelling (Waghule et al., 2019) . The mechanism of dissolving and hydrogel-forming MN drug delivery is termed as poke and release; both strategies eliminate the need to use special measures for discarding of the needle and the risk of inadvertent reuse of the MN (Alkilani, McCrudden, & Donnelly, 2015; Vandervoort & Ludwig, 2008) . The material used for microneedle can be metal, polymer, glass, and silicon (Bhatnagar, Dave, & Venuganti, 2017) . Metal, glass, silicon and ceramics are used in the manufacture of MNs. They are rigid, which allows skin penetration, but brittle, risking breakage inside the skin layers, causing pain, swelling and possibly granulomas. The rigid but brittle properties of these materials have been likened to sea urchin thorns made of mineral calcite. As accidents and issues in the administration of the MNs are inescapable, the best materials for MNs should be biodegradable and biocompatible, to avoid complications that occur from accidents such as when the MN tip breaks inside the first few layers of the skin (Dardano et al., 2019b) . Design and manufacture of the MN focus on the shape and geometry to ensure that the needles are able to function optimally. The strength of the needle allows it to keep intact during penetration and delivery, while tip geometry is crucial to evade the nerve endings. MNs made of metals are able to withhold the force of penetrating the skin, but polymer MNs requires additional strengthening. The MNs need to be able to break the skin barrier without breaking or bending (Yung et al., 2011) . MNs can be anywhere between 25 to 2500 μm long, 50 to 250 μm wide, and their tips measure 1 to 25 μm in diameter (T. R. R. Singh, McMillan, Mooney, Alkilani, & Donnelly, 2017; Yung et al., 2011) . The overall shape of the microneedle and the geometry of the tip has been used to classify microneedles; into rectangular, pyramidal, cylindrical, conical, or quadrangular with varying dimensions (T. R. R. Singh et al., 2017) . Silicon is brittle and does not metabolize in the body; hence the use of other materials such as polymers favoured the production of microneedles. Polymers are preferred due to their inexpensive cost, biocompatibility, biodegradability, hygienic use, swelling and dissolving abilities (Doppalapudi, Jain, Khan, & Domb, 2014; Hong et al., 2013b) . Their degradation in vivo in the presence or absence of degrading enzymes yields non-toxic by-products. This property reduces the possibility of infection in the body (Arya et al., 2017) . Polymers are used predominantly in the manufacture of dissolving and hydrogel-forming MNs arrays (Demir, Akan, & Kerimoglu, 2013; McCrudden et al., 2015) . Nevertheless, there are few studies using polymers for the production of coated, solid, and hollow MNs which attributed to the of the weakness of the polymer mechanical strength that is likely to fail during insertion (R. Ali et al., 2020) . The polymeric MNs can be classified according to materials, formulations, construction of MNs and in vivo performance ; In solid polymer microneedles, the drug is not encapsulated in solid microneedles, and they are effective in generating holes through the SC (Li, Zhang, Chen, Wang, & Guo, 2017) . Likewise, hollow microneedles act as external drug reservoir applied after creating microchannels in the skin (Yung et al., 2011) . Also, the drug formulation and polymers can be coated onto MNs using various coating methods such as dipcoating, casting deposition techniques, spray drying, and Inkjet printing (X. Chen et al., 2010; Y. Ma & Gill, 2014; McGrath et al., 2011; Uddin et al., 2015) . However, the drug loading in coating layers of MNs is restricted due to the limited MN quantity (Y. Chen, Chen, Wang, Jin, & Guo, 2017) . Dissolving MNs polymers are considered the most effective approach and have many applications; the drug incorporated into dissolvable or degradable polymeric MNs . As compared to coating MNs, this MNs can significantly enhance the drug loading capacity by encapsulating drug molecules into the whole needle instead of coating on its external surface (Sabri et al., 2019) . The release of drugs depends mainly on dissolving and degradations proprieties of polymer in the skin. Dissolvable MNs can be used to deliver and release molecules quickly. This strategy ensures that drugs are delivered to specific targets and taken up immediately, which is plausible for short term applications M. Wang, Hu, & Xu, 2017) . On the other hand, MNs made of biodegradable polymers are dissolve over a period of time find interesting applications in prolonged/sustained delivery of drugs, the choice of biodegradable polymers is critical to manipulate and control the sustained release profile of drugs according to their degradation rates (Tsioris et al., 2012; Lalitkumar K Vora, Courtenay, Tekko, Larrañeta, & Donnelly, 2020) . Additionally, the hydrogel-forming MNs prepared mainly from polymer that absorbs interstitial skin fluids and swells to form a hydrogel mass to regulate the release of the drug depending on the crosslinking strength of the hydrogel network. This permits slow drug release over a period of several days (Bhatnagar, Gadeela, Thathireddy, & Venuganti, 2019; Caffarel-Salvador et al., 2015) . The advanced approach of MNs combining between polymer and micro-and nano-particles formulations for the delivery of many different types of therapeutics across the skin . For instance, the microparticle insulin embedded in MNs arrays provides a greater hypoglycaemic effect comparing with MNs insulin arrays only (Larrañeta, McCrudden, Courtenay, & Donnelly, 2016) . Furthermore, the recent developments focused on the fabrication of smart MNs (bioresponsive) to control drug delivery. In contrast to dissolving and biodegradable MNs, the bioresponsive MNs release the drug smartly according to the change of the physiological signals that achieved by loading of drugs in bioresponsive polymers or encapsulation of drugs in physiological signal sensitive micro-or nanoparticles such as (Du & Sun, 2020) pH-responsive drug release (Ullah, Khan, Choi, & Kim, 2019) , surface activation of nanoparticle that commonly used in cancer treatment (M. Chen et al., 2020; P. Singh et al., 2019) , glucose that incorporated with insulin in the tips of MNs array (J. Yu et al., 2015) , reactive oxygen species (ROS)-responsive microneedle (MN) patch for anti-acne therapy (Yuqi , and enzymes that triggered or suppress drug release through the inactivity or overexpression of enzymes (Stern, 2005; J. Yu, Zhang, Yan, Kahkoska, & Gu, 2018) . Smart MNs offers opportunities to provide controlled drug delivery based on physiological responses for certain diseases conditions (Kathuria, Kochhar, & Kang, 2018) . For instance, Zhang et al. (2017) employed glucose-responsive nanoparticles to encapsulate rosiglitazone as the browning agents that further combined into the polymer MNs array. The pH-sensitive nanoparticle gradually degraded under the physiological glucose condition to release the browning agents into the subcutaneous adipocytes in a sustained manner that leads to increases whole-body energy expenditure and improves type-2 diabetes in a diet-induced obesity mouse model (Yuqi Zhang et al., 2017) . The most frequently used matrix materials for dissolving polymer MNs are sodium hyaluronate, that is naturally present in the skin (Hiraishi et al., 2013; Matsuo et al., 2012) , sodium carboxymethylcellulose (Marin & Andrianov, 2011) , poly(vinylalcohol) (PVA) (Nguyen et al., 2018) , poly(vinylpyrrolidone) (PVP) (Sun et al., 2013) , methylvinylether-co-maleic anhydride (PMVE/MA) (Gantrez AN-139 ® ) (Donnelly, Singh, Garland, et al., 2012) , dextran (Ito, Kashiwara, Fukushima, & Takada, 2011) , sodium chondroitin sulphate (Ito, Yoshimitsu, Shiroyama, Sugioka, & Takada, 2006) , hydroxypropyl cellulose (HPC) (Baek, Ahn, & Baek, 2018) , carboxymethyl cellulose (CMC) (Park et al., 2016) Ideal polymeric microneedles should be biocompatible, non-immunogenic, mechanically strong, and able to carry large complex drugs without damage (Du & Sun, 2020) . Thus the development of polymeric microneedles must consider the type of polymer used, manufacturing process, and design of the MN tip length, width and shape (M. Wang et al., 2017) . Each polymer in studies provides own characterisation in term of strength permeation capability, and drug release either immediate or sustained release. The major challenge associated with polymeric MNs is the penetration of MNS through the skin layer. Mostly, the mechanical strength is weaker in water-soluble polymers compared to nondissolving materials such as silicon or metal, and drug encapsulation may further compromise the strength of the MNs (Donnelly et al., 2009; Lalitkumar K Vora et al., 2020) . Mechanical Strength, elastic modulus and fracture toughness of polymer MNs are important; it is reflecting the insertion ability of polymer-based microneedle arrays. Stronger needles will be able to withstand forces without bending and breakage (Juster, van der Aar, & de Brouwer, 2019) . Therefore, researchers can combine two or more polymers and additional materials to improve the mechanical strength of MNs (Lalit K Vora et al., 2017) . Besides, target tissue for MN either transdermal or non-transdermal must be considered during select of MNs polymers. Nontransdermal targets such as eye tissue, vascular tissues, and the digestive system are often required MNs that are bendable and simple to use surgically, the right balance of strength and flexibility must be considered when targeting soft tissues that may not be able to handle the pressure of high-strength MN insertion (K. Lee et al., 2019) . Another factor meaningful to consider is environmental humidity because higher moisture levels weakened the MNs strength depend on the polymer used and the level of humidity (Q. L. . Furthermore, the active ingredient added into the polymer MNs patch might enhance the mechanical strength but sometimes increase of drug loading led to a decrease in MN mechanical strength (Hiraishi et al., 2013; Permana et al., 2019) . Additionally, the mechanical strength of MNs could diminish in case the drug distributed in the needles and baseplates of MNs arrays that indicated by cracking of the baseplate following mechanical evaluation whereas localization the drug in needles not just solve the mechanical strength issue but also results in a reduction in drug wastage as well (Permana et al., 2019; Ramöller, Tekko, McCarthy, & Donnelly, 2019) . Microneedle design is an essential aspect determining the effectiveness of the MN form and function (Davis, Prausnitz, & Allen, 2003; M. Wang et al., 2017) . Microneedles are organized as arrays of structures either in cone or pyramid form, which function to pierce the human skin to deliver drugs (Tomono, 2019) Wang et al., 2015) . 3D printing has also been described recently in published reports as an alternative manufacture technique for MNs (Bhatnagar et al., 2019) . The fabrication process for microneedles should take into consideration factors such as the sharpness of the MNs tips, take place at ambient temperatures, absence of organic solvents, and preservation of the bioactivity of the loaded drug molecules (Sean Padraic Sullivan, 2009) . Polymer MNs are able to improve the flux of the molecules ranging from small hydrophilic molecules such as alendronate to macromolecules, including heparins, insulin and vaccines Waghule et al., 2019) as illustrated in Table 1 and 2. Several studies have shown the effectiveness of MNs array for the transdermal delivery of low molecular weight drugs, biological therapies and vaccines (Gualeni et al., 2018) . Biotherapeutics are more complex and expensive than a small molecule pharmaceutical product; they produce through a biological process from living organisms rather than chemical synthesis including biotechnology methods (Nongkhlaw, Patra, Chavrasiya, Jayabalan, & Dubey, 2020) . Opposite to small molecule, the macromolecules and proteins are too large to diffuse into blood capillaries but are able to enter into the lymphatic vessel (Chandran, Tohit, Stanslas, & Mahmood, 2019) . The biotherapeutics classified to different types including vaccine-based products, blood component, allergenic, gene therapy, human tissue, proteins and peptides (Nongkhlaw et al., 2020) . These biotherapeutics are normally delivered via needle injection due to their poor properties. However, it is well documented that patient compliance with this route is poor due to the pain encountered and potential for contamination and infection (Yamamoto, Ukai, Morishita, & Katsumi, 2020) . The introduction of MNs that are able to penetrate the skin at constant depths allows for the introduction of macromolecules to their targets in a rapid and effective manner while avoiding the pain associated with injections due to the absence of contact with nerve endings in the deeper layers of the skin . Beside, delivers of biotherapeutics such as vaccines through MNs inducing a more potent long-lasting immune response with less vaccine comparing with subcutaneous or intramuscular injection as the vaccines would be closer to antigen-presenting cells present in human skin as well as the biotherapeutics usually do not need to be administered in large doses that means the dose limitations associated with coated or dissolving microneedle systems are not a concern (K. J. Lee et al., 2020) . Furthermore, improvements in vaccine stabilization technologies, it may be possible to create microneedle vaccines that avoid the need for refrigeration (Chu et al., 2016) . Altogether, this suggests that microneedle vaccines should be able to be stockpiled under much less costly conditions and possibly at a greater number of locations. Polymer MNs can be also used to deliver the drug to the eye and is considered an effective method in enhancing ocular delivery of both small and macromolecules. (Thakur et al., 2016) . Poly ( The stability of lysozyme (LYS) as a model protein was preserved in the polymer MNs by keeps the fabrication process at low temperature, and mild drying condition. Besides, using specific polymer concentration and add protein stabilizer. These findings highlight the importance of (Lahiji et al., 2018) optimizing polymer MNs fabrication parameters to maintain the activity of polymer MNs encapsulated proteins or antigens. Parathyroid hormone (PTH) Hyaluronic acid (HA) Dissolving MNs MNs were approximately 800μm long, 160μm in base diameter, 40μm tip diameter, and spaced 600μm wide between each row of needles. The polymer MNs of PTH show excellent performance for transdermal drug delivery in a rat model of osteoporosis with relative bioavailability reaches to 100±4% compared to normal injection. These findings indicate that the low absorption issue associated with oral dosage form or painful frequent injections could be replaced with self-administration of dissolving MNs. (Naito et al., 2018) Monoclonal immunoglobulin G (IgG) Hyaluronic acid (HA) MNs (4 × 4)array and the length was 300 μm. The polymer MNs of (IgG) using HA provide rapid non-invasive intradermal protein delivery as well as maintain the stability of protein. (Mönkäre et al., 2015) DNA vaccine for cervical cancer The temperature-responsive pNIPAM provides control drug (Chi et al., 2020) . height with 5μm tip diameter and 300μm base diameter) release drugs via temperature rising associated with inflammation response at the site of the wound. Besides, chitosan MNs possesses a natural antibacterial property that promotes inflammatory inhibition, collagen deposition, angiogenesis, and tissue regeneration during wound closure. Designing polymer microneedles, the materials and manufacturing process are important parameters to consider; effective MNs for drug delivery depends on the mechanical strength, skin permeation, and release kinetics that subsequently affect drug delivery as simplifying in Fig. 4 . The morphology and dimensions of MNs including the tip radius, heights, widths, lengths and interspacing of the polymer MNs can be observed using stereomicroscopy, transmission electron microscopy (TEM) or scanning electron microscopy (SEM). The amount of drug encapsulated in the MN is affected by the structural properties of the MN, which is determined by the type and stability of the drug of interest (Jeong W Lee, Park, & Prausnitz, 2008) . The mechanical strength is commonly investigated by using a Texture Analyser in compression mode (Lalitkumar K Vora et al., 2020) or motorized force measurement test stand (M. C. He, Chen, Ashfaq, & Guo, 2018) . For fracture testing, the MN arrays are subjected to a microscope observation before and after the tests to determine differences in height. The shape of the microneedle is an important aspect of MN design; it decides how much force can be applied to the MN before the needle breaks. The diameter and angle of the tip, as well as the height and base measurements of the MN, determine safe and reliable insertion of the microneedle into the skin (Bal, Caussin, Pavel, & Bouwstra, 2008) . Generally, a smaller tip diameter, smaller tip angle, as well as a high ratio of height to base width result in successful needle insertion . Most incomplete insertions occurred due to skin distortions when the length of MNs is short, or aspect ratio is small (Coulman et al., 2011) . This situation can be avoided by increasing the length of the needle or manipulating the forces used during manual needle insertion. The force applied during insertion can also be controlled by using special MN applicators that decrease skin distortion and standardize the amount of applied pressure (Daddona, Matriano, Mandema, & Maa, 2011; Haq et al., 2009) . The skin on different locations of the body have different degrees of distortion; hence the MN design and insertion methods should be individually tailored to achieve successful MN application in these locations . MNs are applied to the skin surface and pierce the epidermis, creating microscopic holes through which drugs diffuse to the dermal microcirculation. The success of microneedle penetration can be assessed using either parafilm or carefully prepared porcine skin; this porcine skin has close physical properties to human skin, it can be used as a good human skin model (B. Z. Chen, Ashfaq, Zhang, Zhang, & Guo, 2018; I.-C. Lee, He, Tsai, & Lin, 2015; Lalitkumar K Vora et al., 2020) . The holes produce by applying MNs in the parafilm, or porcine skin can be visually observed after removal of MNs using methylene blue staining, and the number the blue dots of methylene blue dividing with the number of microneedles on the array, the percentage of successful skin penetration was obtained (Xenikakis et al., 2019 ). The "penetration success rate" is related to the number of microneedles that penetrate the skin. A 100% success rate indicates that all MN arrays will observe in the skin (Donadei et al., 2019) . Generally, .parameters such as the tip diameter, base width, length of the microneedle, type of microneedle and its mechanical strength play a critical role in the dimensions of the created microchannel (Kalluri & Banga, 2011) . The microchannel dimensions created by MN can be estimated by histology examination (Sivaraman & Banga, 2017) . However, the sample preparation for histological examination may alter skin structure during the freezing and sectioning steps that lead to inaccurate assessment of the microneedle penetration into the skin (Loizidou et al., 2016; Nguyen et al., 2018) . Thus, a real-time non-invasive method optical coherence tomography (OCT) can be used for skin characterization (Donnelly et al., 2010) . In addition, the measurement of transepidermal water loss (TEWL) is usually carried to evaluate the effect of microneedle application on the skin barrier integrity (Sabri et al., 2019) . The common side effect during microneedle insertion includes mild and transient erythema at the site of application that can simply be observed by dermatoscopic or stereo microscopy (Zhu, Wang, Liu, & Guo, 2016) . Besides, the time required for skin recovery to its original state must be noted to evaluate the skin tolerability towards microneedle application (Sabri et al., 2019) . The quantity of drug release through the skin or drug encapsulation in MNs can be assessed using Franz diffusion with the neonatal porcine skin attached facing upwards in the donor compartment of the diffusion cell, and phosphate-buffered saline at pH 7.4 and temperature at 37°C in the receiver compartment of the cell. The MNs array is applied to the test 'skin' and at set time intervals, samples are taken from the sampling arms of the cell and evaluated. Likewise, the MNs are placed inside a beaker or glass vial phosphate-buffered saline (PBS) or any other suitable buffer at pH 7.4 at 37 °C for in vitro drug release, and samples are taken at set intervals, samples are taken at set intervals to determine drug concentrations . The drug release also can be evaluated using in vivo animal model; appropriate rat or mice are commonly employed. The anaesthetized animals' fur is removed, then the underlying skin is pierced firmly using the MN patch. Upon skin penetration, other parameters related to the efficacy of MN can be evaluated such as the MN strength, penetration power, and irritation (Shende et al., 2018) . Most MN studies are performed in vivo in animal models or ex vivo on human skin. However, it has been pointed out that the structure and immune response in the animal model differs significantly from humans. Furthermore, the biochemical properties of human skin ex vivo are different compared to intact human skin (Coulman et al., 2011) . Hence, in moving towards clinical trials, human tests need to be included in studies for the results to accurately represent MN function in humans (Arya et al., 2017) . The greater acceptance of microneedle-based devices in patients has encouraged an increase in market entry, decreased the cost of innovation and accelerated market growth of MNs. Developments in the field are saturated, as evidenced by the increased number of academic publications and patents on MNs annually. Continuous efforts to transfer scientific research into the clinical application has been ongoing for the past 20 years, with research groups now taking initial commercializing steps (Dardano et al., 2019a) . This jump from experimental research to an initial commercialization stage is evidenced in the number of concluded clinical trials in the USA, as can be accessed via https://clinicaltrials.gov/. The global transdermal drug delivery market is estimated to be worth approximately $95.57 billion by 2025 (Businesswire). Currently, there are no MN-containing drug or protein products in the market; only MN-based devices used to administer drug are available (Chandran et al., 2019; Richter-Johnson, Kumar, Choonara, du Toit, & Pillay, 2018) , Some of MNs devices presented in Table 3 . The main focus of MN clinical trials up to this point has been to overcome the skin barrier for initial penetration, improving delivery, assessing immunologic reactions to large molecular drugs, investigating sensory reactions in the skin and general patient attitude towards MN use (Moreira et al., 2019) . Recent findings in MN research report the poor biocompatibility of silicon for use in MNs, as well as the possibility of abuse of MNs that do not break off/ dissolve after administration to the patient. As a result, current investigations are directed towards the preparation of MNs from biocompatible polymers approved by the FDA (Donnelly, Singh, Morrow, & Woolfson, 2012) . The outcomes of human clinical study trial (phase 1) using dissolvable MN arrays to administer a vaccine against influenza, patients had favourable reactions, and the drug delivered initiated favourable therapeutic responses in the human tests (Rouphael et al., 2017) . Moving forward, the biggest hurdle would be the development of straightforward processes that enable efficient, robust and high throughput production of the polymer microneedles at an industrial scale. Current production methods employ batch production processes, which are limiting (McGrath et al., 2014) . Polymers used in MN fabrication can be hygroscopic; absorption of water from the production facility compromises the structural integrity and strength of the finished product, affecting the performance of the final MN product (M. C. . Huge measures will need to be implemented in production methods and facilities for successful fabrication of MNs. As MN array-based product innovation has been in full force, no pharmacopoeia standards are currently in place. The successful implementation of MNs may be required to make significant investments in equipment and processing technology. Since no pharmacopoeia standards currently exist for MN array-based products, due mainly to the innovative nature of this technology. As companies propose to introduce MN patches into the pharmaceutical market in the future, the need for standardization and regulation regarding sterility, durability, safety, application and disposal of MNs will arise (Larraneta, Lutton, Woolfson, & Donnelly, 2016) . Thus far, the requirements and restrictions related to sterility and safety of the products up to the disposal of MNs after use depended mainly on the application sector (Dardano et al., 2019b) . Moreover, there is insufficient data on the side effects of polymer MN such as skin irritation, changes in skin barrier function and microbial penetration as well as more investigation are required to select a polymer that minimises the skin irritation (Rodgers, Courtenay, & Donnelly, 2018) . Polymer deposition from MN has great interest currently as the polymers never used before intradermally in spite of are typically approved pharmaceutical excipients. Regulators may require more information on the amounts of polymer left behind in skin after MN removal and information on clearance rates and routes (Donnelly & Woolfson, 2014) . The deposition of polymers inside the human body might be a non-issue in case of single MN administration but could be important if a polymer MN was regularly used, it is theorised that repeated application polymer of MN could lead to distribution and deposition of polymer throughout the body, hepatic accumulation, build-up of polymer in the dermal tissue, and immunological reaction (Larraneta et al., 2016; Rodgers et al., 2018) . The study conducted by Vicente-Perez et al. (2017) to investigate the effect of repeated application polymeric microneedle arrays on the skin using an animal model. Two types of MN were prepared; hydrogel-forming MN using Gantrez ® S-97 BF, and Polyethylene glycol as well as dissolving MN prepared using Gantrez ® S-97 BF and, (polyvinyl pyrrolidone). The result shows that all mice displayed mild erythema after MN removal, but no permanent change in skin observed in dissolving MN. In addition, both dissolving and hydrogel-forming MN arrays do not stimulate the humoral immune system or cause infection or trigger an inflammatory response cascade. Nevertheless, the long-term effects of polymer deposition will require further investigation to ensure they do not represent a toxicity issue (Lalitkumar K Vora et al., 2020) . In general, widespread application of polymer microneedle for transdermal delivery is still pending due to the lack of human clinical trials, and the need for improvements in production scale and cost. The skin and other target tissues are moist and amenable to distortion and contain nerve endings that are painful when stimulated. In administering MNs to these tissues, MN dissolvability, structure, and application method are important factors to consider for MNs. There is also a need for skilled personnel in the administration of the MNs. Although much has been discovered on successful MN application in the skin, much remains to be discovered for its application in other tissues. Future research and developments in MNs will need to consider the structure of the target tissue and the target disease. This will determine the MN design, type of drug that can be used and amounts for effective delivery into the target tissue (Jeong Woo Lee & Prausnitz, 2018) . (Beran et al., 2009; Donnelly, Singh, Morrow, et al., 2012) 6 NanoPass Technologies It is a single-use, microneedlebased device for intradermal delivery of drugs, proteins and (Donnelly, Singh, Morrow, et al., 2012; Ita, 2015b) This MN helps to treat some skin conditions (N Nalluri et al., 2015) 6. Conclusion programs must be combined to accelerating the production of polymeric MNs in large-scale, and more effort required to establish guideline regarding the sterilization process, and further awareness of the long-term adverse effects of polymeric MNs in regenerative medicine. Transdermal delivery of potassium chloride with solid microneedles DNA vaccination for cervical cancer; a novel technology platform of RALA mediated gene delivery via polymeric microneedles Transdermal microneedles-a materials perspective Transdermal drug delivery: innovative pharmaceutical developments based on disruption of the barrier properties of the stratum corneum Nanoscale drug delivery systems and the blood-brain barrier usability and acceptability of dissolving microneedle patch administration in human subjects Method of manufacturing microneedle and microneedle manufactured thereby In vivo assessment of safety of microneedle arrays in human skin Structure and function of the epidermis related to barrier properties Non-invasive production of multi-compartmental biodegradable polymer microneedles for controlled intradermal drug release of labile molecules Intradermal influenza vaccination of healthy adults using a new microinjection system: a 3-year randomised controlled safety and immunogenicity trial Microneedles in the clinic Microneedlebased drug delivery: materials of construction Hydrogel-forming microneedle arrays allow detection of drugs and glucose in vivo: potential for use in diagnosis and therapeutic drug monitoring Recent Advances and Challenges in Microneedle-Mediated Transdermal Protein and Peptide Drug Delivery In vitro and in vivo assessment of polymer microneedles for controlled transdermal drug delivery Nanoparticles-encapsulated polymeric microneedles for transdermal drug delivery Microneedle-array patches loaded with dual mineralized protein/peptide particles for type 2 diabetes therapy Improved DNA vaccination by skin-targeted delivery using dry-coated densely-packed microprojection arrays Fabrication of coated polymer microneedles for transdermal drug delivery Microneedles for drug delivery: trends and progress Antibacterial and angiogenic chitosan microneedle array patch for promoting wound healing Enhanced stability of inactivated influenza vaccine encapsulated in dissolving microneedle patches DNA vaccination via RALA nanoparticles in a microneedle delivery system induces a potent immune response against the endogenous prostate cancer stem cell antigen In vivo, in situ imaging of microneedle insertion into the skin of human volunteers using optical coherence tomography Polymer Microneedle mediated local aptamer delivery for blocking the function of vascular endothelial growth factor Parathyroid hormone (1-34)-coated microneedle patch system: clinical pharmacokinetics and pharmacodynamics for treatment of osteoporosis Polymeric microneedle arrays: versatile tools for an innovative approach to drug administration Polymeric Microneedle Arrays: Versatile Tools for an Innovative Approach to Drug Administration Fabrication of low-cost composite polymer-based micro needle patch for transdermal drug delivery Fabrication and characterization of laser micromachined hollow microneedles Solid-State Sensors, Actuators and Microsystems. Digest of Technical Papers (Cat Characterization of polymeric microneedle arrays for transdermal drug delivery Skin delivery of trivalent Sabin inactivated poliovirus vaccine using dissolvable microneedle patches induces neutralizing antibodies Optical coherence tomography is a valuable tool in the study of the effects of microneedle geometry on skin penetration characteristics and in-skin dissolution Processing difficulties and instability of carbohydrate microneedle arrays Hydrogel-forming microneedle arrays for enhanced transdermal drug delivery Microneedlemediated transdermal and intradermal drug delivery Patient safety and beyond: what should we expect from microneedle arrays in the transdermal delivery arena? Therapeutic delivery Biodegradable polymers-an overview Current Advances in Sustained Release Microneedles 3D printing applications for transdermal drug delivery Multiscale simulations of drug distributions in polymer dissolvable microneedles Two-layered dissolving microneedles for percutaneous delivery of peptide/protein drugs in rats Highly porous silk fibroin scaffold packed in PEGDA/sucrose microneedles for controllable transdermal drug delivery Transdermal delivery of gentamicin using dissolving microneedle arrays for potential treatment of neonatal sepsis Minimally invasive and targeted therapeutic cell delivery to the skin using microneedle devices Clinical administration of microneedles: skin puncture, pain and sensation Chemical enhancer: a simplistic way to modulate barrier function of the stratum corneum Microemulsion formulations for the transdermal delivery of testosterone Dissolving microneedles loaded with etonogestrel microcrystal particles for intradermal sustained delivery Intradermal implantable PLGA microneedles for etonogestrel sustained release Assessment of mechanical stability of rapidly separating microneedles for transdermal drug delivery Microfabricated microneedles: a novel approach to transdermal drug delivery Performance and characteristics evaluation of a sodium hyaluronate-based microneedle patch for a transcutaneous drug delivery system Dissolving and biodegradable microneedle technologies for transdermal sustained delivery of drug and vaccine. Drug design Dissolving and biodegradable microneedle technologies for transdermal sustained delivery of drug and vaccine. Drug design, development and therapy How can lipid nanocarriers improve transdermal delivery of olanzapine? Transdermal delivery of drugs with microneedles-potential and challenges Transdermal delivery of drugs with microneedles: Strategies and outcomes Two-layered dissolving microneedles for percutaneous delivery of sumatriptan in rats Self-dissolving microneedles for the percutaneous absorption of EPO in mice A review on microfabrication of thermoplastic polymer-based microneedle arrays Formation and closure of microchannels in skin following microporation Evaluation of microneedles in human subjects Micro and nanoneedles for drug delivery and biosensing Microneedle-mediated delivery of donepezil: potential for improved treatment options in Alzheimer's disease Rapid systemic delivery of zolmitriptan using an adhesive dermally applied microarray Microneedle array delivered recombinant coronavirus vaccines: Immunogenicity and rapid translational development Successful transdermal allergen delivery and allergen-specific immunotherapy using biodegradable microneedle patches Dual-nozzle spray deposition process for improving the stability of proteins in polymer microneedles Physicochemical study of ascorbic acid 2-glucoside loaded hyaluronic acid dissolving microneedles irradiated by electron beam and gamma ray Clinical insights into a new, disposable insulin delivery device Recent Trends in Microneedle Development & Applications in Medicine and Cosmetics Formulation, characterization and evaluation of mRNA-loaded dissolvable polymeric microneedles (RNApatch) Microneedles: quick and easy delivery methods of vaccines Effects of dissolving microneedle fabrication parameters on the activity of encapsulated lysozyme Microneedle arrays as transdermal and intradermal drug delivery systems: Materials science, manufacture and commercial development Microneedles: a new frontier in nanomedicine delivery Device-assisted transdermal drug delivery Bleomycin-coated microneedles for treatment of warts Fabrication of a novel partially dissolving polymer microneedle patch for transdermal drug delivery Dissolving microneedles for transdermal drug delivery Drug delivery using microneedle patches: not just for skin Non-transdermal microneedles for advanced drug delivery A practical guide to the development of microneedle systems-In clinical trials or on the market Diphtheria toxoid dissolving microneedle vaccination: adjuvant screening and effect of repeated-fractional dose administration A solid polymer microneedle patch pretreatment enhances the permeation of drug molecules into the skin Evaluation of geometrical effects of microneedles on skin penetration by CT scan and finite element analysis Biodegradable gelatin methacryloyl microneedles for transdermal drug delivery Biodegradable 3D printed polymer microneedles for transdermal drug delivery Microneedle, bio-microneedle and bio-inspired microneedle: A review Coating Solid Dispersions on Microneedles via a Molten Dip-Coating Method: Development and In Vitro Evaluation for Transdermal Delivery of a Water-Insoluble Drug Microneedles in Drug Delivery Experimental design and optimization of raloxifene hydrochloride loaded nanotransfersomes for transdermal application Transdermal delivery of raloxifene HCl via ethosomal system: Formulation, advanced characterizations and pharmacokinetic evaluation Carboxymethylcellulose-Chitosan-coated microneedles with modulated hydration properties A low-invasive and effective transcutaneous immunization system using a novel dissolving microneedle array for soluble and particulate antigens Considerations in the sterile manufacture of polymeric microneedle arrays. Drug delivery and translational research Determination of parameters for successful spray coating of silicon microneedle arrays Production of dissolvable microneedles using an atomised spray process: effect of microneedle composition on skin penetration Nanocomposite hydrogels: 3D polymer-nanoparticle synergies for on-demand drug delivery Microneedles-A Potential Transdermal Drug Delivery IgG-loaded hyaluronan-based dissolving microneedles for intradermal protein delivery Structure and function of skin Microneedle-based delivery devices for cancer therapy: a review In vitro skin permeation enhancement of sumatriptan by microneedle application Characterization of Hepatitis B Surface Antigen Loaded Polylactic Acid-Based Microneedle and Its Dermal Safety Profile Self-dissolving microneedle arrays for transdermal absorption enhancement of human parathyroid hormone (1-34) Overview of microneedle system: a third generation transdermal drug delivery approach. Microsystem technologies Lidocaine carboxymethylcellulose with gelatine co-polymer hydrogel delivery by combined microneedle and ultrasound Poly (vinyl alcohol) microneedles: fabrication, characterization, and application for transdermal drug delivery of doxorubicin Biologics: Delivery options and formulation strategies Assessment of solid microneedle rollers to enhance transmembrane delivery of doxycycline and inhibition of MMP activity A combined approach of hollow microneedles and nanocarriers for skin immunization with plasmid DNA encoding ovalbumin Intradermal delivery of STAT3 siRNA to treat melanoma via dissolving microneedles Fabrication of degradable carboxymethyl cellulose (CMC) microneedle with laser writing and replica molding process for enhancement of transdermal drug delivery Transdermal drug delivery: from micro to nano Solid lipid nanoparticle-based dissolving microneedles: A promising intradermal lymph targeting drug delivery system with potential for enhanced treatment of lymphatic filariasis Microneedles for transdermal drug delivery The role of microneedles for drug and vaccine delivery Nanoemulsion as pharmaceutical carrier for dermal and transdermal drug delivery: Formulation development, stability issues, basic considerations and applications Novel Technologies Mark the Future of Insulin Rapidly dissolving bilayer microneedle arrays-A minimally invasive transdermal drug delivery system for vitamin B12 Therapeutic applications and pharmacoeconomics of microneedle technology. Expert review of pharmacoeconomics & outcomes research Dissolving microneedles for intradermal vaccination: manufacture, formulation, and stakeholder considerations The safety, immunogenicity, and acceptability of inactivated influenza vaccine delivered by microneedle patch (TIV-MNP 2015): a randomised, partly blinded, placebocontrolled, phase 1 trial Synergistic Transdermal Delivery of Biomacromolecules Using Sonophoresis after Microneedle Treatment Intradermal and transdermal drug delivery using microneedles-Fabrication, performance evaluation and application to lymphatic delivery Micro to nanoneedles: a trend of modernized transepidermal drug delivery system Polymeric microneedles for controlled transdermal drug delivery Fabrication of Microneedles Novel in situ forming hydrogel microneedles for transdermal drug delivery. Drug delivery and translational research Skin wound healing: an update on the current knowledge and concepts Randomized, double-blind, placebo-controlled, parallel-group, multi-center study of the safety and efficacy of ADAM zolmitriptan for the acute treatment of migraine Hyaluronan metabolism: a major paradox in cancer biology Skin tissue engineering Polymer microneedles for transdermal delivery of biopharmaceuticals. PhD diss; Georgia institute of Technology Dissolving polymer microneedle patches for influenza vaccination Polyvinylpyrrolidone microneedles enable delivery of intact proteins for diagnostic and therapeutic applications Fabrication and Characterization of a Biodegradable Hollow Microneedle from Chitosan An investigation on parameters affecting the optimization of testosterone enanthate loaded solid nanoparticles for enhanced transdermal delivery Rapidly dissolving polymeric microneedles for minimally invasive intraocular drug delivery A new way to control the internal structure of microneedles: a case of chitosan lactate Quantitative structure-skin permeability relationships Fabrication of silk microneedles for controlled-release drug delivery Microneedles for intradermal and transdermal drug delivery Inkjet printing of transdermal microneedles for the delivery of anticancer agents Smart microneedles with porous polymer coatings for pH-responsive drug delivery Sanofi Pasteur Ships First 2015-2016 Seasonal Influenza Vaccine Doses in United States Microneedles for transdermal drug delivery: a minireview Safety, tolerability and efficacy of intradermal rabies immunization with DebioJect™ Repeat application of microneedles does not alter skin appearance or barrier function and causes no measurable disturbance of serum biomarkers of infection, inflammation or immunity in mice in vivo Pullulanbased dissolving microneedle arrays for enhanced transdermal delivery of small and large biomolecules Novel bilayer dissolving microneedle arrays with concentrated PLGA nanomicroparticles for targeted intradermal delivery: Proof of concept Microneedles: A smart approach and increasing potential for transdermal drug delivery system Core-shell microneedle gel for self-regulated insulin delivery Recent advances in the design of polymeric microneedles for transdermal drug delivery and biosensing Investigation on fabrication process of dissolving microneedle arrays to improve effective needle drug distribution Effect of humidity on mechanical properties of dissolving microneedles for transdermal drug delivery A fabrication method of microneedle molds with controlled microstructures Fabrication and finite element analysis of stereolithographic 3D printed microneedles for transdermal delivery of model dyes across human skin in vitro Rapid dissolving microneedle patch for synergistic gene and photothermal therapy of subcutaneous tumor Approaches to improve intestinal and transmucosal absorption of peptide and protein drugs Evaluation needle length and density of microneedle arrays in the pretreatment of skin for transdermal drug delivery Polymeric microneedles for transdermal protein delivery Nuclear receptor function in skin health and disease: therapeutic opportunities in the orphan and adopted receptor classes. Cellular and molecular life sciences Anatomy, skin (integument) Advances in bioresponsive closedloop drug delivery systems Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery Polymer microneedles fabricated from alginate and hyaluronate for transdermal delivery of insulin Sharp tipped plastic hollow microneedle array by microinjection moulding ROS-Responsive Microneedle Patch for Acne Vulgaris Treatment Microneedles fabricated from alginate and maltose for transdermal delivery of insulin on diabetic rats Locally induced adipose tissue browning by microneedle patch for obesity treatment Rapidly separating microneedles for transdermal drug delivery The authors are thankful to the university Malaysia Pahang for providing support in the form of an internal grant (RDU 180336 and RDU 180371).