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Microneedles (MNs) have been used as active drug delivery carriers by precisely delivering drugs to the targeted site along with minimal tissue destruction. Earlier, MNs were used for the delivery of drugs to the transdermal site; now they are used as drug delivery carriers to the solid tumor site, mucosal, ophthalmic, and other organ site-specific drug delivery. MNs are considered a boon for trans-barrier delivery because other drug delivery routes, such as systemic and parenteral, face challenges by limiting the optimum amount of drug reaching the skin or other barrier-containing organs. Hence, MN-mediated drug delivery enhances permeation and improves brain and transdermal delivery of drugs by ciliary nasal clearance and crossing the nasal barrier. The current book chapter mainly focuses on the recent advancements in the area of MN-based drug delivery carriers into various parts of the body, their theragnostic applications, mainly the organs containing barriers, and encounters with delivery challenges has been discussed. Also, the comprehensive overview of MN types, fabrication polymers, mechanisms of drug release, effectiveness, and advantages over conventional delivery systems have been summarized.
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow, UP, India
Rahul Shukla
*
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow, UP, India
*Address all correspondence to: rahulshuklapharm@gmail.com, rahul.shukla@niperraebareli.edu.in
1. Introduction
Nanoengineered MNs are an innovative approach in the field of theragnostic, which blends therapeutic and diagnostic features on a single platform. These sophisticated MNs include nanotechnology to boost their efficiency, providing a diverse and successful way for targeted medication delivery and application in diagnosis [1]. MNs are tiny threads that range in length from 50 to 950 mm and are meant to penetrate the skin’s outermost layer, the corneal layer, without reaching nerve endings. This enables medicine delivery with the least discomfort and minimal suffering. Nanoengineering upgrades this technology by adding nanomaterials (NMs) and precision manufacturing methods, resulting in increased performance and versatility [2]. Arguably the most notable benefit of nanoengineered MNs is their ability to deliver medication with pinpoint accuracy. Traditional medication delivery strategies, such as oral or intravenous ingestion, frequently encounter problems such as variable absorption rates, systemic adverse effects, and compliance from patient issues. MNs, on the other hand, can avoid these issues by dispensing drugs in a limited and regulated manner [3]. MNs can be constructed to transport a variety of therapeutic agents, including small-molecule medicines and biologics like vaccines and monoclonal antibodies [4]. The use of MNs facilitates the development of MNs with superior mechanical properties, drug-encapsulating information, and controlled release profiles. For example, biodegradable polymer MNs can release therapeutic payloads over time, eliminating the requirement for frequent administration [5]. Alongside medication administration, nanoengineered MNs are making great progress in diagnostic applications. These MNs can be equipped with nanosensors or functionalized with specific molecules to detect biomarkers linked to certain diseases. This integration allows for real-time monitoring of physiological parameters and early diagnosis of illnesses, including diabetes, infection, and cancer [6]. MNs fitted with glucose sensors, for example, can provide diabetic patients with continuous glucose monitoring, giving them real-time input on their blood sugar levels and eliminating the need for repeated finger pricking [7]. Similarly, MNs loaded with antibodies can identify specific bacteria or cancer signals in interstitial fluid, which may offer a less intrusive and more accessible way of detection than traditional blood testing [8].
Multimodal delivery systems - Nanoengineered MNs have been constructed to perform numerous functions concurrently, making them extremely versatile; for example, MNs can be designed to deliver a combination of pharmaceuticals and diagnostic chemicals [9]. This dual capacity is especially valuable in situations when monitoring and therapy must be synchronized. MNs array might administer a drug while collecting samples for diagnostic tests, such as measuring glucose levels in diabetic patients or tracking blood biomarkers for chronic conditions [7].
Tailored drug release -The architecture of nanoengineered MNs permits highly adjustable medication release characteristics. Researchers can construct controlled mechanisms for drug delivery by altering the material and structure of MNs—either slowly over time or in response to specific physiological cues [10]. This adaptability is useful for treating chronic illnesses that require sustained release, such as hormone therapies or anticancer medication. In contrast, MNs can be developed for quick release in emergency conditions, providing customized therapeutic responses [11].
Difficult but hands-off solution - MNs provide a noninvasive complement to typical injection procedures, which reduces patient discomfort and boosts compliance. The precision of MNs ensures that just the outer layer of skin is penetrated, avoiding nerve endings and reducing pain. This noninvasive property qualifies MNs for use in immunization, cosmetic treatment, and continuous health monitoring, all of which prioritize patient comfort [12].
Customized medicine - MNs may be tailored to suit each patient’s specific needs, which is a key component of personalized treatment. MNs, for example, can be programmed to give drug doses tailored to each person’s genetic or metabolic profile. This technique improves treatment efficacy while avoiding side effects by tailoring the drug delivery mechanism to each patient’s specific needs [13].
3. Manufacturing methods for creating MN-based thermosensors
Micro-Electro-Mechanical Systems (MEMS) are the most promising technology for creating perfect MN designs since it allows MNs to be manufactured accurately and uniformly to make precision devices. Originally, MNs were created by etching arrays of micron-sized needles into silicon using standard microfabrication techniques [14]. They were then developed using a range of materials, including metals like titanium and stainless steel as well as ceramic, glass, polydimethylsiloxane (PDMS), dextrin, and polymers [15]. Other techniques utilized in the production of MNs include laser cutting, micro-molding, 3D printing, lithography, photolithography, and cutting [16]. MN types in various therapeutic applications are explained graphically in Figure 1.
Figure 1.
MN types in various therapeutic applications.
3.1 3D printing
MNs’ commercialization and clinical applications have been delayed because of the high cost and intricate synthesis processes [17]. As a result, not only can MNs be fabricated using the 3D printing technology in a single step (print and fill), but personal customization is also feasible [15]. This method, which creates MNs with a variety of forms and geometries, is based on a computer-aided drug creation model that puts the material selectively layer by layer [18]. A range of 3D printing techniques, including sheet lamination, photopolymerization, material extrusion, powder bed fusion, and binder jetting, is provided to create adaptable MNs for a variety of uses in the medical field [19].
3.2 Photolithography
Photolithographic processes in microelectronic technology require spin-coating a liquid photosensitive polymer, called photographs resist, onto a substrate, which is subsequently heated to a solid state. After that, the photoresist is exposed to UV light through a mask, simulating the structure’s design [20]. Typically, a design is made (known for the main pattern) and is utilized to build a pattern of holes by replicating it onto a thin substrate, usually a silicon wafer [21]. It uses a UV-visible light radiation source to transfer a predetermined shape from the photomask to the substrate, which is often coated beforehand with a photosensitive substance, in order to create hollow MNs [22].
3.3 Etching
This technique involves slicing exposed portions of solid material with a strong liquid (acid) or by hand in order to create a pattern [23]. Dry and wet etching are two of the various etching procedures; the use depends on the building material and the kind of MNs to be produced [24]. While gas is used in dry etching, which is more costly and necessitates techniques like vapor phase or plasma etching, the wet etching technique uses a liquid to remove the layers from the MN’s surface to create the desired shape [25]. MNs were created in a study by utilizing a dry reactive ion etching method with a chromium masking substance [26].
3.4 Cutting
Using CAD software, solid MNs are laser-cut to the required size and shape for the fabrication of stainless steel sheets. This hard material (silicon) MN production process is rarely widely employed since the product deteriorates due to the equipment’s metal blades [27]. MNs are created by electropolishing, which speeds up drug permeation and minimizes the amount of time needed for MN insertion, or by manually bending the MN structure after metal has been cut with an infrared laser [28]. The beam adopts the shape of a needle, cleaning the needle with hot water and bending it at a 90-degree angle before electropolishing it with compressed air to reduce its breadth or sharpen its tips. Consequently, this method—known as 3D laser cutting—uses a laser to cut [19].
The incorporation of MNs into wearable devices marks a significant development in continuous health monitoring. Smart patches or wearable devices with MNs can measure a variety of health parameters in real time. For example, a wearable patch with glucose-sensing MNs can continually monitor blood sugar levels and automatically alter insulin supply. Similarly, MN patches can monitor hydration, electrolyte balance, and even detect early signs of infection or inflammation. MNs can be incorporated into intelligent medication delivery devices that respond to changing physiological parameters. MNs embedded with sensors might detect specific biomarkers and release medication only when necessary [29].
This clever strategy guarantees that medication is administered precisely when needed, optimizing therapeutic outcomes and reducing unnecessary drug exposure. MNs can perform both diagnostic and therapeutic activities in a single device, resulting in a comprehensive theragnostic tool. The device could be built to detect cancer biomarkers while also administering targeted treatment. This integration enables real-time monitoring of disease progression and quick therapeutic action, which improves treatment efficacy and patient outcomes. The use of MNs in remote health monitoring systems contributes to the emerging field of telemedicine. MN-based devices can collect health information and send it to healthcare specialists for remote analysis. This capacity is especially useful for controlling chronic disease or for remote and underserved locations where access to healthcare institutions may be restricted [30]. In an emergency, MNs can provide quick, on-demand remedies. MNs developed for administering emergency drugs, epinephrine for anaphylaxis, or naloxone for opioid overdose, can be delivered swiftly. MNs are perfect for integrating into first-aid kits or emergency response equipment due to their small size and ease of use. Snakebite infestation is a WHO priority neglected disease that causes numerous local and systemic harmful consequences. Recent research has found certain pharmacological targets that, when administered parentally. Based on the information that is at present accessible, it is hypothesized that a formulation of treatments applied internally through convenient, self-administered MNs will either hinder the lymphatic drainage transit and absorption of HMw venom toxins into the bloodstreams or inhibit the mechanistic pathway of LMw toxins. This formulation might thus be more beneficial for pre-hospital management shortly after a snakebite than PBI alone [31].
NM integration - The use of NM with MN technology has greatly improved its performance. Material including gold NPs, carbon nanotubes, and silica NPs are used to change the physical and chemical properties of MNs. These materials lead to several significant improvements [32]. NPs can encapsulate medications more effectively than traditional approaches. They enable regulated release profiles, which involve delivering medication at a consistent pace over time or in response to specified stimuli. This is especially useful for treatments that require prolonged release, such as hormone therapy or vaccinations. NM can increase MN’s mechanical strength and flexibility, making them less likely to break or bend during insertion. Silicon-based MNs can be coated with tiny layers of NMs to improve endurance while retaining sharpness for efficient penetration. The functionalization of nanoparticles enables tailored medication delivery. Drugs can be precisely delivered to the cells or tissues of interest by attaching specific ligands or antibodies to MNs. This targeting lowers off-target effects while increasing treatment efficacy [33].
MN array - MNs can be assembled in a variety of arrangements, such as arrays or patches, to increase their functionality. Arrays are made up of several MNs placed in a grid pattern, allowing for the delivery of multiple drugs at the same time or complete interstitial fluid sampling [34]. Advanced MN arrays are designed to penetrate various skin levels, enabling both superficial and deeper drug administration [35].
Self-dissolving MNs - They are a novel approach to MN technology. These are constructed of biocompatible materials that disintegrate after being inserted into the skin, releasing the drug payload. This removes the need for needle removal, lowers the danger of infection or discomfort, and makes the procedure more convenient for patients. Researchers created sdMN and found that this approach has great immunization effectiveness in both mice and humans. To understand the process of immune response induction, which is the basis for the efficiency and safety [36].
Nanoengineered MNs represent an evolutionary shift in biomedical technology, providing novel options for therapeutic and diagnostic purposes. These innovative technologies, distinguished by their small size and exquisite engineering, are on the verge of changing healthcare by combining minimal invasiveness with high efficiency [27]. This thorough examination dives into current breakthroughs in nanoengineered MNs, emphasizing their diverse roles in modern medicine and their potential to influence the future of healthcare. Diagnostic-therapeutic potential of MNs is given in Table 1.
S.No.
MNs
Material/Therapeutics
Disease
Outcome
Reference
1
5- amino levulinate-dissolving MN patches
Sodium hyaluronate
Cancer
Tips loaded with 5-aminolevulinic MNs demonstrated a higher melanoma inhibitory rate (97%) than parenteral formulation (66%) when compared to injectable formulation. This is because of the unique properties of MNs, which allow the drug to be delivered at the appropriate time and amount by creating microchannels in the skin, increasing the drug’s bioavailability.
More effective than the traditional technique, the delivery of caffeine along with HA in the form of an MN patch enhances the solubility of caffeine in the formulation and inhibits crystal formation.
In 90% of mice, the creation of hydrogel MN for DTA6 administration showed an improvement in aptamer stability for up to 72 hours, protecting the joints and bones from erosion in collagen-induced arthritis.
A research study created MN of rosiglitazone, a browning agent that, because of the presence of a β-3 adrenoreceptor agonist that releases the medication gradually, changes WAT into BAT for the treatment of obesity.
In one study, topical 4% lidocaine cream displayed its therapeutic effect after 60 minutes, but pretreatment of the skin with solid MNs loaded with lidocaine generated anesthesia in just 30 minutes.
Some transdermal local anesthetics (bupivacaine, lidocaine, etc.] blocked sodium channels and resulted in numbness in the skeletal muscles when applied repeatedly. By releasing MNs patches into the affected area, CGRP8–37, an anti-CGRP peptide, was administered without systemic exposure or negative effects.
Hollow MNs combined with sulforhodamine; the MN array was created using borosilicate micropipette tubes, which have a 10–35 μL drug administration limit.
The preferred treatments for malaria are lumefantrine (LUM) and artemether (ART), yet they have drawbacks such as hydrophobicity and poor oral absorption. In order to improve bioavailability, dissolvable MNs containing the medication in micro-suspension were created, and MN-LUM was shown to be more effective in controlling transdermal administration than oral therapy.
The MNs array was created by the solvent casting process with co-loaded lumefantrine nanoparticles loaded with artemether. The study showed that the array was completely permeated, showing drug release up to 60–70% with a 6-month stability period that extended the release to 24 hours. Therefore, when it came to transepidermal distribution of BCS class II and IV medicines, MNs outperformed oral administration in terms of efficiency and safety.
Swellable MNs aided by methacrylate HA (MEHA) were created to quickly extract almost 1.4 mg of ISF for the detection of metabolites like hyperglycemia and cholesterol.
The skin’s immunological cells are tracked by multifunctional antibodies (MNs). For example, the skin was treated with Poly-l-lysine MNs, which have an alginate hydrogel surface coated in immunological adjuvants and antigens. Leukocytes penetrate the hydrogel layer, activate the adjuvants present in the MN, and attract T-cells for additional analysis. Another study used hydrophilic hollow MNs (MNs) to rapidly identify protein biomarkers in interstitial fluid, particularly Plasmodium falciparum histidine-rich protein 2, a biomarker for malaria.
To detect in vivo concentrations of β-lactam antibiotics, MN-based biosensors are coated with a pH-sensitive iridium oxide layer on the electrode surface. These biosensors are stable and sterilizable for up to two weeks at 20°C. The lactamase enzyme mounted on the electrode surface hydrolyzes the lactam ring, causing a change in local pH that the biosensor measures.
Showed that traditional MNs placed in people for extended periods of time have a danger of breaking due to stress or motion; as a result, researchers created and assessed porous, PDMS matrix MN with an HA coating. Additionally, they demonstrated the effectiveness of flexible MNs in collecting ISF via compression for ongoing glucose monitoring both in vitro and in vivo (mouse).
To treat RA, a methotrexate-loaded MN array with PLGA microspheres of folic acid was developed to boost methotrexate’s bioavailability and allow for dosage reduction.
Vaccine delivery - The development of nanoengineered MNs has transformed vaccine delivery, overcoming various constraints associated with traditional vaccination methods [52]. Traditional vaccine administration, often by intramuscular injections, is often uncomfortable and needs competent staff. MNs represent a promising option that is both less intrusive and maybe more effective. MNs improve vaccine administration by forming microchannels in the skin’s outer layer, allowing antigens to interact directly with immune cells in the epidermis and dermis. This interaction may result in a stronger immunological response than typical injection approaches. Studies have shown that MN-based vaccine delivery can dramatically improve vaccine immunogenicity, as seen by better immune responses to influenza and hepatitis B vaccines. One of the most distinguishing qualities of MNs is their ease of use. MN patches can be self-administered, decreasing the requirement for healthcare personnel and increasing vaccine availability. This trait is especially useful in mass immunization efforts and remote places where healthcare services are limited [53]. MN patches have been demonstrated to improve vaccination coverage and compliance due to their ease of usage. Recent advancements include MNs intended for COVID-19 vaccinations, which have demonstrated encouraging effects in preclinical trials. These MNs not only administer the vaccine effectively, but they also stimulate a powerful immune response while minimizing pain and suffering. Current clinical trials are evaluating the effectiveness of MN-based vaccines in real-world conditions.
Drug delivery - The creation of nanoengineered MNs had a significant impact on drug delivery, opening up new opportunities for precise and regulated administration of medicinal substances [54]. MNs can be designed to release medications at a controlled rate, which is critical for therapies that require continuous or scheduled release. For example, MNs constructed of biodegradable polymers can gradually release medications over time, reducing the frequency of administration [34]. This method has been used for hormone therapy, such as insulin delivery for diabetes control, in which maintaining consistent medication levels is critical for optimal treatment. The detachable dissolving MNs (DDMNs) have an array of needles that can be removed using the administration of the foundation sheet. Here, researchers were established to tackle the problems of insulin storage stability and delivery efficiency [55]. More theragnostic application of MNs using NIR irradiation to treat tumors is explained in Figure 2.
Figure 2.
Theragnostic application of MNs using NIR irradiation to treat tumors.
MNs have a huge benefit in that they may deliver drugs to places within the body. Drugs can be delivered to specific cells or tissues, such as cancer cells or inflammatory areas, by loading MNs with targeting ligands or antibodies. This focused strategy reduces systemic exposure and potential negative effects, which improves therapeutic efficacy. For example, MNs coated with antibodies targeting tumor-specific antigens have demonstrated potential in delivering chemotherapeutic drugs directly to cancer cells [56].
MNs have been studied for localized pain relief, providing an alternative to systemic pain medicines. MNs administer analgesics directly to the source of pain, resulting in localized alleviation with minimal systemic effects. This method is especially useful for controlling chronic pain problems like arthritis, when traditional pain management strategies may be ineffective or have substantial adverse effects. Castilla-Casadiego et al. developed and tested a chitosan MN patch for transdermal delivery of meloxicam to treat pain in cattle. Chitosan and chitosan/meloxicam MN patches were assessed for chemical composition, physical homogeneity, skin penetration, and thermal and thermo-mechanical reaction. MN patches were made with varied acetic acid concentrations: 92 (v/v), 52 (v/v), and 15% (v/v). Additionally, drug release was evaluated by modeling varying percentages of skin penetration and the number of MNs on the patch. Scanning electron microscopy confirmed that MNs were equally distributed on the patch surface for each proportion of acetic acid applied. The MN patches successfully penetrated the skin in a cow’s cadaver ear. The average depth of penetration assessed following complete dehydration of the penetrated skin was 78 ± 1 μm. Higher acetic acid percentages in chitosan and chitosan/meloxicam MN patches resulted in increased compressive force resistance at higher temperatures [57].
Recent innovations include MN patches that deliver anti-inflammatory medicines or local anesthetics transdermally. These patches provide a noninvasive and effective solution to treat problems such as dermatitis and post-surgical discomfort. The development of MNs for hormone replacement therapy demonstrates their usefulness in treating a variety of chronic illnesses. Ropivacaine hydrochloride (RPL) is a local anesthetic commonly used to alleviate pain during or after surgery. However, this medicine is only accessible in parenteral form and may aid in the infiltration of RPL into the plasma, resulting in certain unwanted side effects. Intradermal delivery of RPL using dissolving MNs could be a promising technique for delivering such medications to the epidermis. The researcher created RPL-loaded dissolving MNs (DMN-RPLs) to demonstrate the concept of intradermal delivery of a local anesthetic. The DMN-RPLs were created utilizing either centrifugation or air-pressurized chamber techniques. The DMN-RPLs were made using a variety of polymers, including PVP, PVA, and SH. Thermal characteristics, chemical bonding, mechanical strength, insertion ability, skin-dissolving studies, and drug content were all evaluated on the manufactured DMN-RPLs [58].
For ocular delivery - The sclera is a matrix embedded with a network of randomly ordered collagen fibers that functions as one of the primary static barriers of the eye and prevents drug molecules from penetrating. The choroid-Bruch’s membrane, the sclera, and pigments like melanin all operate as strong static barriers that prevent big molecules from entering the vitreous humor or the site of action. To improve the penetration of medications through tissues, numerous permeation enhancers have been studied. These compounds’ primary drawback is that they irritate the tissues of the eyes, and there are still concerns about biocompatibility and ocular safety. Physical elements like iontophoresis or sonication can improve the penetration of medications through the sclera [25]. The principles of cavitation and vibration underlie sonication’s operation. The disintegration of polymeric MNs may be aided or accelerated by the vibrations produced during sonication. As a result, it helps medicines penetrate the sclera more quickly. Iontophoresis improves the electrostatic force-driven molecular diffusion in a similar manner. Enhancing and controlling the flow of molecules across the barrier is largely dependent on the electrical charge on the molecules. In the presence of an electric charge, iontophoresis increases the penetration of ionized substances through the sclera. These techniques in conjunction with MNs would improve macromolecule penetration, including oligopeptides, peptides, and proteins [59].
Cosmetic applications - MNs have applications beyond traditional medicine, including dermatological and cosmetic therapies. Their capacity to improve the delivery of skincare products has created new opportunities for boosting skin health and beauty. MNs are utilized to administer anti-aging medicines such as retinoids, peptides, and HA straight to the skin. This method improves the penetration and activity of these compounds, resulting in enhanced skin texture and fewer indications of aging. MN-based delivery devices have been shown in studies to greatly boost anti-aging drug absorption when compared to topical treatments. Hyaluronic acid (HA) has numerous applications in human medicine and the cosmetic industry [60].
Microneedling is a process that causes controlled micro-injuries to the skin, boosts collagen formation, and improves skin renewal. When paired with therapeutic chemicals given using MNs, this approach can improve skin restoration and cure diseases, including acne scars and stretch marks. Recent advancements include MN devices that provide growth factors or other regeneration agents to further improve skin results. Photoaging is extremely important for skin health and senescence. UV-vis irradiation disrupts the extracellular matrix microenvironment, degrades collagen, and induces oxidative stress. Traditional HA has a reduced potential to induce regeneration of collagen and is restricted due to its low macromolecule permeability, which limits the therapeutic benefits of photoaging [61].
The cosmetic industry has adopted MN technology in the creation of sophisticated skincare products. Home-use MN patches provide patients with improved delivery of moisturizing or brightening chemicals. These products are popular among people looking for noninvasive skincare solutions since they are both convenient and effective. Roussel et al. and colleagues found that inserting BIS-PNIPAm, a crosslinked polymer version, with dissolving MN patches improved mechanical qualities and resulted in a lower MN height decrease of around 10%. MNs made from PNIPAm alone lacked mechanical strength, necessitating the addition of polymeric excipients such as PVA to improve characteristics. The inclusion of a thermoresponsive polymer did not significantly affect needle insertion characteristics (p > 0.05). All formulations were inserted to a similar depth of 600 μm into ex vivo skin. The needles were loaded with a model payload, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindodicarbocyanine perchlorate (DID), and the cargo deposition was tracked via multiphoton microscopy, which revealed a deposit at a depth of around 200 μm. Crosslinked-PNIPAm (Bis-PNIPAm) formulations showed significant dye deposition in the skin after 4 hours, regardless of the excipient matrix utilized. The absence of this phenomenon in non-crosslinked PNIPAm formulations suggests a deposit development in the Bis-PNIPAm MN formulation. This proof-of-concept study suggests that PNIPAm can be used to create dissolving MNs, which can then be used to deposit nanoparticles in the dermis for prolonged drug release [62]. Many dermatological uses of MNs are given in Table 2.
Pain and localized therapy - MNs provide novel alternatives for localized therapy and pain control by exploiting their accuracy and minimum invasiveness. MNs can administer analgesics directly to the source of pain, giving focused relief while avoiding systemic adverse effects. This method is useful for problems such as chronic muscle pain or joint inflammation, where standard pain drugs may be ineffective or create undesirable side effects. Recent research has shown that MNs are effective in delivering local anesthetics for procedures like dental work and small surgery. For chronic illnesses that require continuous treatment, MNs can provide sustained-release formulations that eliminate the need for frequent injection. MNs can be utilized to administer hormone replacement therapy or other chronic drugs, thereby enhancing patient compliance and therapeutic effects [77].
Area of discussion
Methods
Outcome
Reference
1.
Applications of MNs to enhance the look of the skin
An overview of using MNs to improve the appearance of the skin
It is possible to improve the appearance of skin with MNs.
The capacity to tailor medication release profiles to individual demands is a significant advantage of MN technology. One potential method to deal with chronic wounds that reduce damage and encourage healing is early detection followed by prompt treatment. With the recent development of several smart dressings, active intervention, and real-time wound state monitoring are now possible. Inadequate effectiveness of treatment arises from the current smart dressing’s shortcomings, which include limited drug loading capacity and poor drug penetration into deeper wound dermal and subcutaneous tissues. To accomplish simultaneous diagnosis and in-time therapy for chronic wounds, a closed-loop smart dressing with MN integrated has been designed. To track wound impedance and obtain early diagnoses of chronic wounds, simple impedance-detecting electrodes are employed [78]. The MeID drug delivery micropump is immediately activated for in-time therapy based on the sensing data. A practical solution for feeding adequate drug fluid into deeper wound dermal/subcutaneous tissues has been developed using micropump electrodes when combined with a drug reservoir-coupled MN array. Compared to untreated diabetic mice, MelD stimulates faster wound healing in treated animals by supplying sufficient growth factors to the wound and boosting medication access into deep tissue layers. Meanwhile, MelD promotes tissue development and nascent collagen deposition. Meld’s improved drug storage dosage, improved drug penetration, and closed-loop operation enable the first successful attempt to ensure sufficient and efficient drug delivery by miniaturized all-in-one smart dressing, expanding the use of closed-loop chronic wound care from a laboratory demonstration on limited types of superficial wounds to a broader range of wound types. A study found that an ingestible device activated by an external magnet can effectively treat sick locations in the intestinal tract. The capsule is designed to travel through the GI system and deliver MNs to targeted regions. This ingestible technology has the potential to enhance drug treatment efficacy and tolerance, paving the way for more effective GI illness management strategies [79].
6.2 Diagnostic applications
The diagnostic potential of nanoengineered MNs is equally groundbreaking, providing novel approaches for disease detection and monitoring. Continuous glucose monitoring (CGM) is an important part of diabetes therapy, and MNs have considerably improved this technology using the reactive oxygen species mechanism as described in Figure 2. Traditional glucose monitoring requires frequent blood samples, which can be painful and inconvenient for patients. MNs provide a minimally invasive option by capturing interstitial fluid for glucose readings. This strategy increases patient comfort and reduces the necessity for finger pricking, which is especially beneficial for diabetics. Continuous glucose monitors are essential for managing diabetes, but their general use is limited due to intrusive sampling, signal drift, and frequent calibrations. MN sensors provide a minimally invasive platform for real-time monitoring of clinical parameters in interstitial fluid. This study presents a painless and flexible MN sensing patch made of a robust MNs foundation and a thin layer of fluorescent hydrogel sensor for accurate and continuous glucose monitoring. FRET-based hydrogel sensors are made by photopolymerizing acryloylated FRET pairs with glucose-specific phenylboronic acid. The improved hydrogel sensor can measure glucose with reversibility, good selectivity, and signal stability against photobleaching. The MNs base is made of poly(ethylene glycol diacrylate)-polyacrylamide hydrogel, making it easier to pierce the skin and extract biofluid [7].
MN-based glucose sensors give real-time glucose level information, allowing insulin therapy to be adjusted as needed. These sensors can be included in wearable devices that constantly monitor glucose levels and notify patients of probable hypoglycemia or hyperglycemic situations. The real-time nature of these sensors helps to maintain better glucose management and reduce the risk of problems. Detachable MN sensors for continuous glucose monitoring (CGM) have a high therapeutic impact since they enable access to enormous data sets for personalized treatment approaches [80]. MN glucose sensors have advanced with the introduction of flexible and biocompatible materials that improve sensor performance and durability. Sensor technology advancements have resulted in more accurate and dependable glucose measurements, which have improved diabetes care. Ongoing research is aimed at improving the sensitivity and specificity of these sensors, allowing for even more precise glucose monitoring. A powerful wearable H2O2 MN sensor with a Prussian blue (PB)/carbon nanotube (CNT) composite electrode was created, as well as a glucose MN sensor based on it [81].
MNs are making progress in the identification of illness biomarkers, providing a less invasive way to diagnose and monitor a variety of disorders. MNs loaded with particular antibodies or molecular probes can detect cancer indicators in interstitial fluid. This noninvasive technique allows for early cancer identification and disease progression tracking. MNs have been shown in studies to detect biomarkers associated with a variety of malignancies, including breast, prostate, and colorectal. This capability enables timely intervention and individualized treatment solutions. There are numerous ways for early tumor detection, including identifying circulating tumor DNA, detecting circulating tumor cells, and imaging with tumor-targeting contrast agents. However, these assays are time-consuming and may cause discomfort for the patient during the biopsy collection procedure. We present a simple approach for early tumor diagnosis that involves collecting exosomes from interstitial fluid (ISF) with hydrogel MNs (MNs). The hydrogel MNs stretch in the skin to absorb the ISF, and tumor exosomes in the ISF bind to glypican-1 antibodies within the MN hydrogel. Exosomes are separated from the ISF and analyzed for tumor-related biomarkers when the hydrogel on the MNs is removed. Finally, colon cancer can be detected by ELISA in colorectal cancer-induced model mice. This noninvasive hydrogel MN method for obtaining exosome samples would be very useful in early cancer diagnosis [82]. MNs can also be employed to detect infections by capturing microbial or viral biomarkers. For example, MNs functionalized with probes for specific pathogens can provide rapid diagnostic results, facilitating early treatment and containment of infectious diseases. Recent advancements include the development of MNs for detecting biomarkers associated with emerging infectious diseases, such as COVID-19. A polymeric MNs coupled electrochemical sensor array (MNESA) was used by the researchers to monitor kidney biomarkers in the skin interstitial fluid (ISF) in real time, with minimal invasiveness and self-administration [83]. The combination of MNs with microfluidic technologies has improved biomarker detection and analysis. These sophisticated systems have higher sensitivity and specificity for identifying a wide range of biomarkers, making them useful for both research and clinical diagnosis. Innovations in NM coatings and sensor technology are propelling this sector forward. MNs can enhance drug delivery by penetrating the skin, creating microchannels that allow for targeted release. This process can induce the production of Reactive oxygen species (ROS), which plays a role in signaling and can contribute to therapeutic effects, especially in treatments like cancer therapy, as explained in Figure 3.
Figure 3.
MNs can enhance drug delivery by penetrating the skin, creating microchannels that allow for targeted release. This process can induce the production of Reactive oxygen species (ROS), which plays a role in signaling and can contribute to therapeutic effects, especially in treatments like cancer therapy.
Scaling up the manufacturing of MNs necessitates complicated fabrication techniques and quality control procedures. Maintaining uniformity and reproducibility in large-scale manufacturing presents a substantial challenge. Manufacturing advancements, including roll-to-roll processing and injection molding, are being investigated to make large-scale production more practical. Research into cost-effective and scalable fabrication methods is vital for the broad adoption of MN technology. A unique manufacturing procedure for creating MN arrays has been developed and tested. The prototype can manufacture 14-14 MN arrays and can be scaled up, making it suitable for transitioning from lab to industry and commercialization. To create silicone MN molds using injection molding, metal master templates must be custom-designed. This innovative approach was compared to centrifugation, a conventional method for creating aqueous hydrogel-forming MN arrays. Both approaches produced MN arrays of equivalent quality, indicating no significant difference in outcomes. Both types of MN arrays can be successfully placed into skin simulants. In both cases, the insertion depth was roughly 70% of the needle length, with a height reduction of about 3% [84].
MNs must be composed of biocompatible materials that do not cause harmful responses in the body. The interaction of MNs with biological tissues, especially over long periods of time, requires extensive examination. The risk of immunological responses or local inflammation at the MN’s insertion site must be assessed. MNs’ safety and efficacy depend on ensuring that they do not elicit undesired immunological responses. The long-term effects of MNs on the skin and underlying tissues, particularly with frequent use, should be thoroughly investigated. Chronic exposure or recurrent use may result in skin damage or other issues [85]. Research into biodegradable MN materials can help to solve long-term biocompatibility and environmental problems. Biodegradable MNs dissolve or degrade harmlessly in the body, lowering the risk of side effects. The development of improved coatings that reduce immune reactions and increase biocompatibility would improve MN safety. Coatings that interact with the skin in a non-inflammatory manner are critical to assuring patient comfort and safety. Extensive preclinical and clinical experiments are required to evaluate the long-term safety and biocompatibility of MNs. Detailed investigations on their effects on various skin types and demographics will help us better understand their safety profile [86].
The integration of nanotechnology into medical equipment complicates regulatory authorization. Regulations governing the usage of NMs and their interactions with the human body are constantly changing. Gaining regulatory approval for MN-based devices requires extensive testing and documentation to demonstrate safety, efficacy, and quality. The procedure can be time-consuming and expensive [25]. Engaging with regulatory bodies early in the development phase can assist in resolving potential issues and speeding up the approval process. Collaborative efforts can result in clearer guidelines and faster regulatory processes. Establishing consistent testing techniques for MN products will make regulatory assessments go more smoothly and assure product uniformity. It is critical for worldwide deployment to navigate different countries’ regulatory constraints. Harmonizing international rules and developing a single approach can help to accelerate the global adoption of MN technologies [85].
Considering that MN systems are a relatively new technology in the pharmaceutical industry and that, as previously mentioned, there are four different types of MN systems that are manufactured using a variety of technologies, industry, and researchers need standardized guidelines for the use of established techniques for production, evaluation, test criteria for approval, and quality control. Consequently, the FDA released “Regulatory Considerations for Microneedling Devices” and “Scientific Considerations for MN Products” in 2017 to support the development of MNs as medical devices in accordance with Section 201 (h) of the Federal Food, Drug, and Cosmetic Act [87].
MNs are medical devices designed to treat or track a certain ailment. MNs are classified as class II devices under 21 CFR 878.4430 and come with a variety of sharp ends, similar to hypodermic needles. These goods fall into one of two categories: combination products, which are overseen by the US FDA’s CBER (Center for Biological Evaluation and Research) or CDER (Center for Drug Evaluation and Research) divisions, or medical devices, which are governed by the CDRH (Center for Devices and Radiological Health). The labeling for these kinds of devices must contain information on the device’s components, technical specifications (such as needle geometry and insertion depth), recommended course of treatment, disposal guidelines, processing instructions for reusable items, and expiration date. Comprehensive research on metabolism and elimination pathways is undoubtedly needed by regulatory bodies, which could delay commercialization. Authorities require that MN systems be sterile since, in contrast to conventional transdermal and topical drug delivery systems, they come into contact with live skin cells [28]. Clinical trial of diagnostic MNs given in Table 3.
Clinical trial
Disease/disorder
Analyte
Outcome
NCT02682056
Pediatric diabetes
Glucose
Comparative analysis of the effectiveness of intravenous catheters versus MN patches over lancets for the monitoring of blood glucose in children with diabetes.
NCT05546229
Opioid abuse disorders
Buprenorphine
Use of MNs to examine the detectability of popular drugs used to treat opioid use disorders and their metabolites in dISF.
NCT03847610
Resistance to antibiotics
Beta-lactam
An assessment of the effectiveness of an MN electrochemical biosensor for benzylpenicillin level monitoring in relation to microdialysis and blood collection techniques.
NCT04238611
Thresholds for anaerobic metabolism
Lactate
Validation of an MN-based instrument for continuous lactate monitoring during physical activity.
NCT01908530
Type 1 diabetes
Glucose
An electrochemical microprobe array with entrapped glucose oxidase for continuous glucose monitoring is evaluated for safety and effectiveness.
NCT05922176
Opioid abuse disorders
Methadone
Detectability evaluation of popular drugs used to treat opioid use disorders and their metabolites in dISF using MNs.
NCT05998876
Opioid abuse disorder
methadone
Using differential pulse voltammetry integrated on an MN electrode array, methadone detection in ISF and continuous monitoring of methadone adherence.
Future studies could focus on creating MNs with several functions, such as diagnostic and therapeutic capabilities. MNs that can detect biomarkers as well as administer medications would be extremely useful in theragnostic applications. The use of smart technologies, such as sensors and microelectronic components, may allow MNs to adapt to physiological changes or environmental variables. Smart MNs could regulate medicine release rates or deliver real-time diagnostic information dependent on the patient’s state. Expanding the use of MNs to treat chronic diseases other than diabetes and cancer is a critical area of development. MNs could be used to treat cardiovascular illness, neurological diseases, and respiratory ailments, providing long-term drug delivery or monitoring options. MNs can be further improved to support personalized medicine techniques, which adjust diagnosis and treatment based on individual genetic, metabolic, or physiological characteristics. Personalized MN devices may increase the precision and effectiveness of healthcare interventions. Integrating MNs with wearable technologies, such as smart patches or health monitoring systems, may increase their usefulness in continuous health monitoring and illness management. Wearable devices using MNs might monitor vital signs, glucose levels, and other health metrics in real time. MN-based diagnostic technologies could be integrated into telemedicine platforms to provide remote health monitoring and data collection. This connection would allow healthcare providers to better manage patient care and intervene quickly when needed. Creating novel biocompatible polymers and nanocomposites for MNs will improve their performance and safety. Research into materials with higher mechanical strength, longevity, and biocompatibility will improve the overall effectiveness of MN devices. Integrating self-healing materials into MNs may increase their durability and lifetime. Self-healing materials could fix slight damage to MNs while in use, assuring consistent performance and decreasing the need for frequent replacements.
Nanoengineered MNs are on the verge of transforming both therapeutic and diagnostic uses in modern medication. Their versatility in delivering medications, vaccines, and therapeutic agents, combined with the promise of increased diagnostic capabilities, makes them a critical technology for the future of healthcare. Despite manufacturing, biocompatibility, and regulatory approval hurdles, current research and innovation show promise in overcoming these barriers and realizing MN’s full potential. The future of MN technology is to improve functionalization, increase clinical application, integrate with digital health technologies, and advance material science. By addressing present obstacles and following these future paths, MNs will help to progress the field of theragnostic, providing more effective, tailored, and accessible healthcare options. As technology advances, nanoengineered MNs have the potential to significantly improve patient care and shape the future of medicine.
Abbreviation
HA
hyaluronic acid
MN
microneedle
NM
nanomaterial
sdMN
self-dissolving MNs
References
1.Amani H, Shahbazi MA, Damico C, Fontana F, Abbaszadeh S, Santos HA. Microneedles for painless transdermal immunotherapeutic applications. Journal of Controlled Release. 2021;330:185-217
2.Haridass IN, Wei JCJ, Mohammed YH, Crichton ML, Anderson CD, Henricson J, et al. Cellular metabolism and pore lifetime of human skin following microprojection array mediation. Journal of Controlled Release. 2019;306:59-68
3.Chen X, Xiao H, Zhao Q, Xu X, Cen Y, Xiao D. Research hotspot and trend of microneedles in biomedical field: A bibliometric analysis from 2011 to 2020. Burns. 2022;48(4):959-972
4.Deng J, Wang Z, Zhou Z, Yu W, Li X, Song Z, et al. Transdermal delivery of Fluoropolymer-modified microneedle vaccines against rabies elicits potent humoral immunity. Chemical Engineering Journal. 2023;474:145496
5.Yang G, Xu W, Xu B, Yang Y, Li P, Yu A, et al. Two decades’ advancements and research trends in needle-type sensor technology: A scientometric analysis. Heliyon. 2024;10(6):e27399
6.Park K. Collective progress in drug delivery. Journal of Controlled Release. 2019;300:197-199
7.Hu Y, Pan Z, De Bock M, Tan TX, Wang Y, Shi Y, et al. A wearable microneedle patch incorporating reversible FRET-based hydrogel sensors for continuous glucose monitoring. Biosensors & Bioelectronics. 2024;262:116542
8.Donadei A, Kraan H, Ophorst O, Flynn O, O’Mahony C, Soema PC, et al. Skin delivery of trivalent Sabin inactivated poliovirus vaccine using dissolvable microneedle patches induces neutralizing antibodies. Journal of Controlled Release. 2019;311-312:96-103
9.Wang W, Zhong Z, Peng S, Fu J, Chen M, Lang T, et al. “All-in-one” metal polyphenol network nanocapsules integrated microneedle patches for lipophagy fueled ferroptosis-mediated multimodal therapy. Journal of Controlled Release. 2024;373:599-616
10.Yan Q, Weng J, Shen S, Wang Y, Fang M, Zheng G, et al. Finite element analysis for biodegradable dissolving microneedle materials on skin puncture and mechanical performance evaluation. Polymers (Basel). 2021;13(18):3043
11.Yao Z, Xue T, Xiong H, Cai C, Liu X, Wu F, et al. Promotion of collagen deposition during skin healing through Smad3/mTOR pathway by parathyroid hormone-loaded microneedle. Materials Science and Engineering: C. 2021;119:111446
12.Park Y, Kim KS, Chung M, Sung JH, Kim B. Fabrication and characterization of dissolving microneedle arrays for improving skin permeability of cosmetic ingredients. Journal of Industrial and Engineering Chemistry. 2016;39:121-126
13.Tan G, Ioannou N, Mathew E, Tagalakis AD, Lamprou DA, Yu-Wai-Man C. 3D printing in ophthalmology: From medical implants to personalised medicine. International Journal of Pharmaceutics. 2022;625:122094
14.Kumar S, Shukla R. Advancements in microneedle technology: Current status and next-generation innovations. Journal of Microencapsulation. 2024;41(8):782-803
15.Krieger KJ, Bertollo N, Dangol M, Sheridan JT, Lowery MM, O’Cearbhaill ED. Simple and customizable method for fabrication of high-aspect ratio microneedle molds using low-cost 3D printing. Microsystems and Nanoengineering. 2019;5(1):42
16.Liu GS, Kong Y, Wang Y, Luo Y, Fan X, Xie X, et al. Microneedles for transdermal diagnostics: Recent advances and new horizons. Biomaterials. 2020;232:119740
17.Economidou SN, Douroumis D. 3D printing as a transformative tool for microneedle systems: Recent advances, manufacturing considerations and market potential. Advanced Drug Delivery Reviews. 2021;173:60-69
18.Li R, Zhang L, Jiang X, Li L, Wu S, Yuan X, et al. 3D-printed microneedle arrays for drug delivery. Journal of Controlled Release. 2022;350:933-948
19.Yang J, Liu X, Fu Y, Song Y. Recent advances of microneedles for biomedical applications: Drug delivery and beyond. Acta Pharmaceutica Sinica B. 2019;9(3):469-483
20.Kang L, Kochhar C, Zou S. Protein encapsulation in polymeric microneedles by photolithography. International Journal of Nanomedicine. 2012;3143
21.Dardano P, Caliò A, Di Palma V, Bevilacqua M, Di Matteo A, De Stefano L. A photolithographic approach to polymeric microneedles Array fabrication. Materials. 2015;8(12):8661-8673
22.Kathuria H, Kang K, Cai J, Kang L. Rapid microneedle fabrication by heating and photolithography. International Journal of Pharmaceutics. 2020;575:118992
23.Li Y, Zhang H, Yang R, Laffitte Y, Schmill U, Hu W, et al. Fabrication of sharp silicon hollow microneedles by deep-reactive ion etching towards minimally invasive diagnostics. Microsystems and Nanoengineering. 2019;5(1):41
24.Bolton CJW, Howells O, Blayney GJ, Eng PF, Birchall JC, Gualeni B, et al. Hollow silicon microneedle fabrication using advanced plasma etch technologies for applications in transdermal drug delivery. Lab on a Chip. 2020;20(15):2788-2795
25.Singh M, Shukla R. Leveraging nanoengineered microneedle-augmented drug delivery in oncological intervention. Particle and Particle Systems Characterization. 2024
26.Donnelly RF, Singh TRR, Garland MJ, Migalska K, Majithiya R, McCrudden CM, et al. Hydrogel-forming microneedle arrays for enhanced transdermal drug delivery. Advanced Functional Materials. 2012;22(23):4879-4890
27.Shukla S, Mamale KB, Arya RKK, Kaundal RK, Shukla R. Therapeutic potential of microneedles based delivery systems for the management of atopic dermatitis. Journal of Drug Delivery Science and Technology. 2023;84:104493
28.Larrañeta E, Lutton REM, Woolfson AD, Donnelly RF. Microneedle arrays as transdermal and intradermal drug delivery systems: Materials science, manufacture and commercial development. Materials Science and Engineering: R: Reports. 2016;104:1-32
29.Zhong G, Liu Q, Wang Q, Qiu H, Li H, Xu T. Fully integrated microneedle biosensor array for wearable multiplexed fitness biomarkers monitoring. Biosensors and Bioelectronics. 2024;265:116697
30.Forvi E, Bedoni M, Carabalona R, Soncini M, Mazzoleni P, Rizzo F, et al. Preliminary technological assessment of microneedles-based dry electrodes for biopotential monitoring in clinical examinations. Sensors and Actuators A: Physical. 2012;180:177-186
31.Tiwari N, Aggarwal G, Jain GK, Mittal G. Multi-drug loaded microneedles for emergency treatment of snakebite envenomation. Medical Hypotheses. 2022;165:110908
32.Wu D, Wu X, Luan Q, Tang Q, Fan L, Shou X, et al. Dynamic hydrogel-integrated microneedle patch with extracellular vesicles encapsulation for wound healing. Chemical Engineering Journal. 2024;493:152252
33.Lin Y, Chen Y, Deng R, Qin H, Li N, Qin Y, et al. Delivery of neutrophil membrane encapsulated non-steroidal anti-inflammatory drugs by degradable biopolymer microneedle patch for rheumatoid arthritis therapy. Nano Today. 2023;49:101791
34.Arora P, Shukla R. Microneedles along with conventional therapies: An in-depth observational review in alopecia areata treatment. Journal of Drug Delivery Science and Technology. 2024;95:105627
35.Zhang X, Chen H, Song T, Wang J, Zhao Y. Controllable histotomy based on hierarchical magnetic microneedle array robots. Engineering. 2024;42
36.Ito S, Hirobe S, Yamashita R, Sugiyama A, Takeuchi H, Eguchi R, et al. Analysis of immune response induction mechanisms implicating the dose-sparing effect of transcutaneous immunization using a self-dissolving microneedle patch. Vaccine. 2022;40(6):862-872
37.Kim JY, Han MR, Kim YH, Shin SW, Nam SY, Park JH. Tip-loaded dissolving microneedles for transdermal delivery of donepezil hydrochloride for treatment of Alzheimer’s disease. European Journal of Pharmaceutics and Biopharmaceutics. 2016;105:148-155
38.Danne T, Heinemann L, Bolinder J. New insulins, biosimilars, and insulin therapy. Diabetes Technology and Therapeutics. 2016;18(S1):S-43-S-55
39.Cao J, Zhang N, Wang Z, Su J, Yang J, Han J, et al. Microneedle-assisted transdermal delivery of etanercept for rheumatoid arthritis treatment. Pharmaceutics. 2019;11(5):235
40.Dangol M, Kim S, Li CG, Fakhraei Lahiji S, Jang M, Ma Y, et al. Anti-obesity effect of a novel caffeine-loaded dissolving microneedle patch in high-fat diet-induced obese C57BL/6J mice. Journal of Controlled Release. 2017;265:41-47
41.Cao J, Su J, An M, Yang Y, Zhang Y, Zuo J, et al. Novel DEK-targeting aptamer delivered by a hydrogel microneedle attenuates collagen-induced arthritis. Molecular Pharmaceutics. 2021;18(1):305-316
42.Zhang Y, Liu Q, Yu J, Yu S, Wang J, Qiang L, et al. Locally induced adipose tissue browning by microneedle patch for obesity treatment. ACS Nano. 2017;11(9):9223-9230
43.Li B, Lu G, Liu W, Liao L, Ban J, Lu Z. Formulation and evaluation of PLGA nanoparticulate-based microneedle system for potential treatment of neurological diseases. International Journal of Nanomedicine. 2023;18:3745-3760
44.Tan S, Wang Y, Wei X, Xiao X, Gao L. Microneedle-mediated drug delivery for neurological diseases. International Journal of Pharmaceutics. 2024;661:124400
45.Jiang J, Gill HS, Ghate D, McCarey BE, Patel SR, Edelhauser HF, et al. Coated microneedles for drug delivery to the eye. Investigative Opthalmology and Visual Science. 2007;48(9):4038
46.Martanto W, Moore JS, Kashlan O, Kamath R, Wang PM, O’Neal JM, et al. Microinfusion using hollow microneedles. Pharmaceutical Research. 2006;23(1):104-113
47.Yenkoidiok-Douti L, Barillas-Mury C, Jewell CM. Design of dissolvable microneedles for delivery of a Pfs47-based malaria transmission-blocking vaccine. ACS Biomaterials Science and Engineering. 2021;7(5):1854-1862
48.Matsuo K, Hirobe S, Yokota Y, Ayabe Y, Seto M, Quan YS, et al. Transcutaneous immunization using a dissolving microneedle array protects against tetanus, diphtheria, malaria, and influenza. Journal of Controlled Release. 2012;160(3):495-501
49.Carey JB, Pearson FE, Vrdoljak A, McGrath MG, Crean AM, Walsh PT, et al. Microneedle array design determines the induction of protective memory CD8+ T cell responses induced by a recombinant live malaria vaccine in mice. PLoS One. 2011;6(7):e22442
50.Jamaledin R, Yiu CKY, Zare EN, Niu L, Vecchione R, Chen G, et al. Advances in antimicrobial microneedle patches for combating infections. Advanced Materials. 2020;32(33)
51.Gadziński P, Froelich A, Wojtyłko M, Białek A, Krysztofiak J, Osmałek T. Microneedle-based ocular drug delivery systems – Recent advances and challenges. Beilstein Journal of Nanotechnology. 2022;13:1167-1184
52.Phoka T, Thanuthanakhun N, Visitchanakun P, Dueanphen N, Wanichwecharungruang N, Leelahavanichkul A, et al. Detachable-dissolvable-microneedle as a potent subunit vaccine delivery device that requires no cold-chain. Vaccine X. 2023;15:100398
53.Nguyen TT, Van Vo G. Microneedle-mediated vaccine delivery. In: Design and Applications of Microneedles in Drug Delivery and Therapeutics. Jamia Hamdard, New Delhi, India: Department of Pharmaceutics, School of Pharmaceutical Education and Research; 2024. pp. 433-448
54.Qiu H, Gong L, Slezak P, He S, Lu F, Yu K, et al. Magnetic-navigable silk fibroin microneedles for oral drug delivery: Ensuring long-lasting helicobacter pylori eradication and rapid hemostasis in the stomach. International Journal of Biological Macromolecules. 2024;275:133584
55.Phoka T, Wanichwecharungruang N, Dueanphen N, Thanuthanakhun N, Kietdumrongwong P, Leelahavanichkul A, et al. Converting short-acting insulin into thermo-stable longer-acting insulin using multi-layer detachable microneedles. Journal of Pharmaceutical Sciences. 2024;113
56.Huang J, Yao Z, Li B, Ping Y. Targeted delivery of PROTAC-based prodrug activated by bond-cleavage bioorthogonal chemistry for microneedle-assisted cancer therapy. Journal of Controlled Release. 2023;361:270-279
57.Castilla-Casadiego DA, Carlton H, Gonzalez-Nino D, Miranda-Muñoz KA, Daneshpour R, Huitink D, et al. Design, characterization, and modeling of a chitosan microneedle patch for transdermal delivery of meloxicam as a pain management strategy for use in cattle. Materials Science and Engineering: C. 2021;118:111544
58.Ramadon D, Karn PR, Anjani QK, Kim MH, Cho DY, Hwang H, et al. Development of ropivacaine hydrochloride-loaded dissolving microneedles as a local anesthetic agent: A proof-of-concept. International Journal of Pharmaceutics. 2024;660:124347
59.Glover K, Mishra D, Gade S, Vora LK, Wu Y, Paredes AJ, et al. Microneedles for advanced ocular drug delivery. Advanced Drug Delivery Reviews. 2023;201:115082
60.Zhang JN, Chen BZ, Ashfaq M, Zhang XP, Guo XD. Development of a BDDE-crosslinked hyaluronic acid based microneedles patch as a dermal filler for anti-ageing treatment. Journal of Industrial and Engineering Chemistry. 2018;65:363-369
61.Tang Z, Liu Z, Zhang Y, Luo S, Xu Y, Ren L. Functional hyaluronic acid microneedles for skin photoaging based on collagen induction and oxidative stress regulation strategies. International Journal of Biological Macromolecules. 2024;277:134080
62.Roussel S, Udabe J, Bin Sabri A, Calderón M, Donnelly R. Leveraging novel innovative thermoresponsive polymers in microneedles for targeted intradermal deposition. International Journal of Pharmaceutics. 2024;652:123847
63.Chang H, Zheng M, Yu X, Than A, Seeni RZ, Kang R, et al. A swellable microneedle patch to rapidly extract skin interstitial fluid for timely metabolic analysis. Advanced Materials. 2017;29(37)
64.Shende P, Salunke M. Transepidermal microneedles for co-administration of folic acid with methotrexate in the treatment of rheumatoid arthritis. Biomedical Physics and Engineering Express. 2019;5(2):025023
65.Lee JW, Park JH, Prausnitz MR. Dissolving microneedles for transdermal drug delivery. Biomaterials. 2008;29(13):2113-2124
66.Goh GD, Sing SL, Yeong WY. A review on machine learning in 3D printing: Applications, potential, and challenges. Artificial Intelligence Review. 2021;54(1):63-94
67.Lau S, Fei J, Liu H, Chen W, Liu R. Multilayered pyramidal dissolving microneedle patches with flexible pedestals for improving effective drug delivery. Journal of Controlled Release. 2017;265:113-119
68.Jung J, Dos Santos e Lucato SL. A CDM-based binary model for the progressive damage prediction of sic/sic ceramic matrix composites under tension loading. International Journal for Multiscale Computational Engineering. 2021;19(5):1-15
69.Kim YC, Park JH, Prausnitz MR. Microneedles for drug and vaccine delivery. Advanced Drug Delivery Reviews. 2012;64(14):1547-1568
70.Liu S, Jin M, Shu QY, Kamiyama F, Kusamori K, Katsumi H, et al. Transdermal delivery of relatively high molecular weight drugs using novel self-dissolving microneedle arrays fabricated from hyaluronic acid and their characteristics and safety after application to the skin. European Journal of Pharmaceutics and Biopharmaceutics. 2014;86(2):267-276
71.Aust MC, Knobloch K, Reimers K, Redeker J, Ipaktchi R, Altintas MA, et al. Percutaneous collagen induction therapy: An alternative treatment for burn scars. Burns. 2010;36(6):836-843
72.Tiller W. In memoriam Wolfgang Boehm. Computer-Aided Design and Applications. 2018;15(6):779-779
73.Kumar A, Naguib YW, Shi Y, chun, Cui Z. A method to improve the efficacy of topical eflornithine hydrochloride cream. Drug Delivery. 2014;23(5):1-7
74.Orentreich DS, Orentreich N. Subcutaneous incisionless (subcision) surgery for the correction of depressed scars and wrinkles. Dermatologic Surgery. 1995;21(6):543-549
75.Kim M, Yang H, Kim H, Jung H, Jung H. Novel cosmetic patches for wrinkle improvement: Retinyl retinoate- and ascorbic acid-loaded dissolving microneedles. International Journal of Cosmetic Science. 2014;36(3):207-212
76.Prausnitz MR, Mikszta JA, Cormier M, Andrianov AK. Microneedle-Based Vaccines. Shivaprasad Gadag, Manipal, Karnataka, India: Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education; 2009. pp. 369-393
77.Gadag S, Narayan R, Nayak AS, Catalina Ardila D, Sant S, Nayak Y, et al. Development and preclinical evaluation of microneedle-assisted resveratrol loaded nanostructured lipid carriers for localized delivery to breast cancer therapy. International Journal of Pharmaceutics. 2021;606:120877
78.Jha A, Kumar M, Goswami P, Manjit M, Bharti K, Koch B, et al. Hyaluronic acid-oleylamine and chitosan-oleic acid conjugate-based hybrid nanoparticle delivery via. Dissolving microneedles for enhanced treatment efficacy in localized breast cancer. Biomaterials. Advances. 2024;160:213865
79.Levy JA, Straker MA, Stine JM, Beardslee LA, Ghodssi R. Magnetically triggered ingestible capsule for localized microneedle drug delivery. Device. 2024;100438
80.Li L, Zhou Y, Sun C, Zhou Z, Zhang J, Xu Y, et al. Fully integrated wearable microneedle biosensing platform for wide-range and real-time continuous glucose monitoring. Acta Biomaterialia. 2024;175:199-213
81.Zhu J, Wang L, Xu S, Peng L, Gao Z, Liu S, et al. A high-performance wearable microneedle sensor based on a prussian blue-carbon nanotube composite electrode for the detection of hydrogen peroxide and glucose. Sensors and Actuators B: Chemical. 2024;419:136436
82.Park W, Maeng SW, Mok JW, Choi M, Cha HJ, Joo CK, et al. Hydrogel microneedles extracting exosomes for early detection of colorectal cancer. Biomacromolecules. 2023;24(3):1445-1452
83.Zheng L, Zhu D, Xiao Y, Zheng X, Chen P. Microneedle coupled epidermal sensor for multiplexed electrochemical detection of kidney disease biomarkers. Biosensors and Bioelectronics. 2023;237:115506
84.Lutton REM, Larrañeta E, Kearney MC, Boyd P, Woolfson AD, Donnelly RF. A novel scalable manufacturing process for the production of hydrogel-forming microneedle arrays. International Journal of Pharmaceutics. 2015;494(1):417-429
85.Wendong Y, Xingxing Y, Xianze X, Qiaomei F, Yujun S, Shanshan Z, et al. Nanoformulation-assisted microneedle transdermal drug delivery system: An innovative platform enhancing rheumatoid arthritis treatment. Biomedicine and Pharmacotherapy. 2024;178:117219
86.Wu C, Yu Q, Huang C, Li F, Zhang L, Zhu D. Microneedles as transdermal drug delivery system for enhancing skin disease treatment. Acta Pharmaceutica Sinica B. 2024;14
87.Babity S, Roohnikan M, Brambilla D. Advances in the Design of Transdermal Microneedles for diagnostic and monitoring applications. Small. 2018;14(49)
Written By
Mansi Singh and Rahul Shukla
Submitted: 11 September 2024Reviewed: 22 January 2025Published: 27 February 2025
Open access peer-reviewed chapter
