Graphical Abstract

1. Introduction

2. Microneedle Design and Fabrication

2.1. Types of Ophthalmic Microneedles

Different types of ophthalmic microneedles, the materials used, and fabrication methods are listed in Table 1. Also the microneedle material selection and their characteristics are listed in Table 2.

2.1.1. Solid Microneedles

Due to their simplicity and widespread use, solid microneedles have been the primary choice for early research on microneedle drug or vaccine delivery. They are employed as a skin pretreatment, producing temporary micron-sized channels through the stratum corneum and mechanically distorting the epidermis before drug administration. However, solid microneedles alone cannot distribute or facilitate the passage of drugs. [38,39].Then, medications were injected or applied directly to the skin region punctured by microneedles in square patches. Scientists described a method involving the construction of a device utilizing a nanoscale zinc oxide pyramidal rod array. The drug release mechanisms through different types of microneedle patches are presented in Figure 3.

This array consisted of rods measuring 50 µm in length, with tip and base diameters of 60 nm and 150 nm, respectively [40]. These microscopic needles have sturdy, pointed structures that pierce the skin and leave behind tiny channels. Metals, polymers, or silicon are just a few materials that can be used to create solid microneedles. They are frequently applied to extract interstitial fluid for analysis and drug delivery [41]. Solid microneedles composed of biodegradable polymers demonstrate ample mechanical robustness to breach the stratum corneum, thereby augmenting the effectiveness of PLA microneedles and enhancing drug delivery efficiency. Microneedles with an 800 µm depth and 256 microneedles per cm density were discovered to improve drug permeation. Researchers from various fields also study stainless steel microneedles. After employing stainless steel microneedle arrays, researchers investigated the improved delivery of captopril and metoprolol tartrate [42].

2.1.2. Hollow Microneedles

Hollow microneedles, usually shorter (typically less than 1000 µm), have a similar basic structure to conventional hypodermic needles, featuring a hollow core through which the drug solution is delivered. Following hollow microneedles, the drug solution can be administered in either direction [43]. The drug solution can be administered actively, using a pressure-driven flow over the needle lumen, or passively, through diffusion. Occasionally, drug solutions may be injected into the viable epidermis, situated 60 to 130 µm below the stratum corneum. Hollow microneedles can be employed to create pores in the skin for constant delivery from a drug formulation deposited in a reservoir or for sampling body fluids. Hollow microneedles allow for deliberate regulation of drug flow rate using traditional flow-control tools such as syringes and micropumps [44]. Characterized by high molecular weights, proteins, antigens, and oligonucleotides are commonly utilized, and microneedles can effectively administer substantial doses of these drugs at a consistent flow rate. These tiny needles can be used to deliver drugs directly to their intended recipients while minimizing drug waste. In addition to its applications in signal monitoring and blood and tissue sampling, it also has certain drawbacks, such as the needle getting blocked after insertion into the skin. Materials such as silicon, metal, glass, polymers, and ceramic can create hollow microneedles. [45]. Furthermore, force drugs can be delivered via pressure-driven force by integrating a microneedle injection applicator with a syringe pump or electromagnetic applicators. Patients' preferences for better dosage control can be met. As well, hollow microneedles could include a micropump, microfluidic chip, or heater to deliver medications to the skin in a controlled manner [46]. Norman et al. examined the precision and reliability of standard hypodermic syringes (employing the Mantoux technique) [47], hypodermic needle adapters, and hollow microneedles for intradermal injection into pig skin. The percentage of drugs administered using each method showed similar levels of reliability (95.4 ± 4.9%, 97.6 ± 1.5%, and 94.9 ± 0.3%, respectively). Additionally, accuracy, measured as the proportion of the dose concentrated in the dermis, was comparable, at 97 ± 16%, 92 ± 21%, and 99 ± 12%, respectively [48,49].

2.1.3. Dissolving Microneedles

Maltose was a structural framework for fabricating dissolving microneedles due to its ability to transition among three states—liquid, glassy, and solid—through precise temperature control during manufacturing. Maltose transitions into a liquid state above its melting point (Tm), and upon cooling below the glass transition temperature (Tg), the viscosity of the liquid maltose gradually rises, resulting in the formation of a solid state [50]. The triple state of maltose created the perfect conditions for drawing lithography. Maltose was molded into microneedles while in the glassy state, which provided the structural integrity required for skin penetration. When the active compound is in its liquid form, it can be blended with maltose [51]. The viscosity of maltose was measured using a rheometer (TA Instruments, Rheolyst AR1000L Rheometer) equipped with a 4-cm flat plate probe, a 120 µm gap, and a shear rate of 5 s⁻¹. Due to its enzymatic degradation by maltase glucoamylase, maltose readily dissolves and has been extensively utilized as a safe biopolymer for encapsulating bioactive compounds [52].

Y. Wu et al. developed dissolving bilayer microneedles to deliver proteins to the back of the eye for retinal disorders. Using polymers like PVA/PVP, they optimized microneedles to penetrate the sclera and dissolve rapidly while maintaining protein bioactivity. The microneedles were non-irritants and showed enhanced protein permeation through the sclera compared to patches, establishing an efficient and safe intraocular protein delivery system [53]. A nanosuspension of cholecalciferol was prepared using PVA and PVP as stabilizers for enhanced transdermal delivery. The nanosuspension was embedded into hydrophilic polymer-based dissolving microneedles. These dissolving microneedles prepared with PVA/PVP blends showed good mechanical properties and efficient skin penetration [54].

2.1.4. Coated Microneedles

An adaptable delivery method is a coated microneedle. A single microneedle patch can deliver diverse substances, encompassing small molecules, deoxyribonucleic acid (DNA), proteins, viruses, and microparticles. Studies have shown that coated microneedles can provide DNA and proteins into the skin with minimal invasiveness [55,56]. The primary objectives of this study were to establish even coatings on microneedles and to identify the range of particles and molecules suitable for coating onto microneedles. Initially, microneedles were crafted individually or in clusters from stainless steel sheets. Subsequently, a novel micron-scale dip-coating method using a generally recognized safe (GRAS) coating formulation was developed to apply even coatings on individual microneedles and arrays consistently [57]. Compounds like bovine serum albumin, calcein, vitamin B, and plasmid DNA were all coated using this method [58]. Microparticles with a diameter of 1 to 20 μm and modified vaccinia virus were also coated. Coatings were selectively applied to the needle shafts, designed to dissolve in the skin of a cadaverous porcine within 20 sec. Histological analysis confirmed that microneedle coatings were injected during insertion and remained intact without wiping off [59]. This research presents an immediate, adaptable, and manageable method for coating microneedles with proteins, DNA, viruses, and microparticles, enabling rapid delivery into the skin [56]. Various materials are used for coated microneedles, including stainless steel, titanium, polycarbonate, silicon, and polymer blends. Stainless steel microneedles offer excellent mechanical strength and durability, making them suitable for clinical applications [60]. Titanium microneedles are lightweight, biocompatible, and corrosion-resistant, ideal for biomedical applications [61]. Silicon microneedles offer precise control over geometry and dimensions, biocompatibility, and compatibility with microfabrication techniques [62]. Polymer blends, such as PEG and PVA blends, offer tunable mechanical properties and biodegradability, catering to specific requirements for drug delivery, including controlled release and biocompatibility. These materials present a diverse array of options for coated microneedles, enabling researchers to select the most suitable material based on the application's requirements and biocompatibility considerations [63].

D. Jakka et al. investigated the development of polymer-coated polymeric (PCP) microneedles for the controlled release of APIs in dermal and intravitreal drug delivery. PCP microneedles demonstrated sustained release of lidocaine hydrochloride for up to 9 hours in skin tissue and voriconazole intravitreally for 6 hours, suggesting their potential for controlled drug delivery [64].

2.1.5. Coating Single Microneedles

Single microneedles were dip-coated by being placed horizontally within a droplet of coating solution held in a 200 μL large-orifice pipette tip. Each microneedle was then immersed in 20–30 μL of the coating solution. Both the microneedle and the pipette tip were securely clamped horizontally on a manual linear micropositioner (A1506K1-S1.5 Unislide, Velmex, Bloomfield, NY, USA) positioned opposite each other. The microneedle was maneuvered manually and observed through a stereo microscope (SZX12, Olympus America), facilitating its insertion and removal from the liquid droplet [55].

2.1.6. Hydrogel-Forming Microneedles

The newest variety of microneedles, HFMs, were first noted in 2012. HFMs are made of crosslinked hydrogels, which can swell and have a more diverse mechanism of action than other materials. Hydrogel-based Flexible Matrices (HFMs) exhibit swelling upon skin insertion owing to their inherent hydrophilicity, facilitating water absorption. This characteristic makes them suitable for biomedical purposes such as Interstitial Fluid (ISF) uptake, predominantly within the dermal layer of the skin, encompassing cellular environments in tissue interstices [65]. HFMs are regarded as minimally invasive because, due to their microscale nature, they do not interact with or activate pain receptors positioned deeper in the dermis layer of the skin. Moreover, hydrogel-forming microneedles (HFMs) address certain limitations of traditional microneedles. Specifically, HFMs offer a variable drug release rate and increased loading capacity. These characteristics are often linked to the polymer crosslinking ratio, a parameter challenging to control in traditional microneedles [66,67]. The feasibility of achieving sustained transdermal delivery of high-dose metformin HCl through a hydrogel-forming microneedle patch has been explored. This approach holds promise for mitigating specific gastrointestinal side effects and addressing fluctuations in negligible intestine absorption associated with oral administration [68]. The microneedle layer, which was made from an aqueous mixture of 20 % weight percent poly (methyl-vinyl ether-co-maleic acid) and 7.5 % weight percent poly (ethylene glycol), was crosslinked by esterification and used to assemble patches (two layers) [69]. More than 90% of metformin from homogeneous drug reservoirs with a molecular weight of 10,000 Da was successfully retrieved. The drug reservoir dissolved in less than 10 minutes in phosphate-buffered saline (PBS) with a pH of 7.4. The microneedle achieved consistent penetration of Parafilm® M, a validated skin model. In vitro experiments conducted in a controlled laboratory setting confirmed that the microneedle effectively improved the permeation of metformin HCl through neonatal porcine skin samples obtained from the dermatome [70].

2.1.7. Biodegradable Microneedles

Biodegradable microneedles provide an innovative approach to drug delivery, enabling precise and targeted administration of therapeutics using minimally invasive, disintegrating structures [71]. Utilizing biodegradable polymers such as PLA, chitosan, PGA, or PLGA, biodegradable microneedles can serve as a more patient-friendly option to traditional sustained-delivery techniques. After application, these microneedles break down in the skin, enabling months of continuous medication release. However, to fully utilize the degradation property, they must be inserted and present on the skin for several days [72].

Qiu. Li et al. used biodegradable polymer microneedles made of PLA to enhance drug permeability in skin. They found 600 μm high microneedles were mechanically stable, and 800 μm deep with 256 microneedles per cm² were most effective. Drug concentration increased drug permeation amount, while higher viscosity decreased it. Prolonged drug administration stabilized permeation. In vivo, these microneedles effectively delivered insulin, reducing blood glucose levels in diabetic mice [73]. Scientists created biodegradable microneedles with multiple layers to regulate drug release. They used a sequential spraying process with PLGA and PVP. Tests confirmed strong layer adhesion and successful skin penetration with biphasic drug release. They examined a model protein drug's integrity within the microneedles, finding minor structural changes. In vitro, release studies showed controlled kinetics, with a blank PLGA layer reducing initial burst release. Confocal microscopy verified the barrier formation. Overall, the study highlights these microneedles' potential for transdermal drug delivery [74].

Table 1. Types of microneedles.

Table 1. Types of microneedles.

Sr. No.	Type of microneedles	Material used	Fabrication method	Reference
1	Solid microneedles	(i) Silicon microneedles (ii) Metal microneedles (iii) Polymer microneedles (iv) Ceramic microneedles	Etching	[75]
2	Coated microneedles	(i) Stainless steel (ii) Glass (iii) Chitosan	Spraying	[76]
3	Dissolving microneedles	(i) Polymers (ii) Sugars (iii) Proteins	Encapsulation	[77]
4	Hollow microneedles	(i) Metals (ii) Silicon (iii) Glass (iv) Polymers (v) Nickel	Centrifugation	[77]
5	Hydrogel forming microneedles	(i) PVP (ii) Hydrophilic polymers	Dispersion of solution	[78]
6	Biodegradable microneedle	(i) PVP (ii) PLGA (iii) PGA	Molding or casting	[74]

Table 2. Microneedle material selection and their characteristics.

Table 2. Microneedle material selection and their characteristics.

Material	Mechanical characteristics	Biocompatibility	Drug loading capacity	Transparency	Advantages	Disadvantages	Applications	Reference
Silicon	Excellent mechanical strength	Biocompatible	Moderate to high	Not transparent	Good mechanical properties	Brittle and easily broken	Transdermal sensing and drug delivery	[79]
Metal	High mechanical strength	Biocompatible	Moderate to high	Not transparent	High mechanical strength	Corrosion risk, potential allergic reactions	Diagnostics and drug delivery	[80]
Polymer	Flexible	Biocompatible	Low to moderate	Not transparent	Flexible and easily fabricated	Limited mechanical strength, potential degradation	Drug administration, biosensing	[81]
Glass	Brittle	Biocompatible	Low to moderate	Transparent	Excellent optical transparency	Fragile and can break easily	Transdermal sensing and drug delivery using microneedle arrays	[82]
Dissolving	Varies	Biocompatible	Low to moderate	Varies	Dissolves entirely in the body	Short needle length, limited drug loading capacity	Transdermal drug administration	[83]
Hydrogel	Soft and adaptable	Biocompatible	Low to moderate	Not transparent	Soft and biocompatible	Mechanical weakness, potential swelling	Transdermal drug delivery, wound healing, biosensing	[84]
Ceramic	High mechanical strength	Biocompatible	Moderate to high	Not transparent	High mechanical strength, good chemical stability	Difficulty in fabrication, brittleness	Drug administration, biosensing	[85]
Biodegradable	Varies	Biocompatible	Moderate to high	Varies	Dissolves completely in the body	Limited mechanical strength, potential degradation	Drug administration, biosensing	[86]

2.3. Advantages of Microneedle Drug Delivery

Ophthalmic microneedles provide a targeted and minimally invasive system for delivering drugs directly to the eye's tissues, bypassing systemic circulation and reducing off-target effects. Their small size and precise insertion minimize discomfort and tissue damage, making them well-suited for delicate ocular structures. Microneedle-based drug delivery systems provide a means of controlled release for therapeutic agents, improving drug bioavailability and extending therapeutic effects, thus contributing to enhanced patient compliance. Their customizable design also allows tailored approaches to specific eye conditions, optimizing treatment outcomes. With the potential for combination therapy and improved stability, ophthalmic microneedles hold promise for revolutionizing the therapy of various eye diseases and disorders. Microneedle-mediated drug delivery presents numerous merits, rendering it an increasingly appealing methodology within the domains of pharmaceuticals and healthcare:

Table 5. Advantages of microneedle.

Table 5. Advantages of microneedle.

Sr. No.	Advantages	Description	Reference
1.	Minimally Invasive	(i) Microneedles are tiny, causing minimal trauma during drug delivery. (ii) Patients experience reduced pain and discomfort compared to traditional injections.	[116]
2.	Improved Patient Compliance	(i) Microneedles enhance patient acceptance due to their less invasive nature. (ii) Allows for convenient self-administration, improving patient compliance.	[117]
3.	Enhanced Bioavailability	(i) Microneedles enable targeted delivery, improving drug absorption. (ii) Particularly beneficial for drugs with poor oral bioavailability.	[15]
4.	Rapid Onset of Action	(i) Facilitates quick drug delivery into the bloodstream, leading to a rapid onset of therapeutic effects.	[118]
5.	Preventing First-Pass Metabolism	(i) Bypass the digestive system, preventing first-pass metabolism in the liver.	[119]
6.	Improved Stability of Biologics	(i) Enables the delivery of biologics (proteins, peptides) with enhanced stability, preventing degradation.	[120]
7.	Tailored Release Profiles	(i) Microneedles can be designed for controlled and sustained drug release, ensuring predictable pharmacokinetics.	[121]
8.	Reduced Needlestick Injuries	(i) Smaller needles reduce the risk of needlestick injuries, improving safety.	[122]
9.	Potential for Self-Administration	(i) Empower patients to self-administer treatments, reducing healthcare costs and improving convenience.	[123]
10.	Versatility	(i) Applicable to various administration routes, including transdermal, intradermal, and mucosal surfaces.	[124]

Microneedles also have the advantage of a targeted and controlled-release drug delivery system. Controlled DDSs are engineered to precisely administer therapeutic agents to specific cells, tissues, or organs [125]. Augmentations involving hydrogels, nanoparticles, or siRNA encapsulation within liposomes enhance their efficacy [126]. In contrast to conventional DDSs with limitations such as systemic application and constrained delivery efficiency, microneedle-based controlled transdermal DDSs emerge as a solution [127]. Microneedle-based systems significantly improve the efficiency and precision of drug delivery, offering benefits such as targeted localization, decreased dosing frequency, and simplified self-administration. Consequently, they foster enhanced patient compliance. This technological innovation is especially advantageous for individuals with specific health conditions, including young children, the elderly, and those experiencing challenges such as vomiting and nausea [128]. In polymeric microneedle systems, drug release occurs when drug molecules move from the inner polymeric matrix to its outer surface and are released into the surrounding tissue. The regulation of drug-release kinetics is essential for achieving controlled drug delivery [125]. Chen et al. enhanced a long-acting microneedle patch for blood glucose control by optimizing its rapid separation feature. The hydrogel microneedle system replicates normal insulin secretion, offering a prompt response to elevated glucose levels and controlled release, thereby improving postprandial blood glucose control [129]. The adoption of microneedle drug delivery technology has been linked to a decrease in side effects when compared to traditional methods. This is attributed to microneedle delivery's targeted and controlled nature, allowing for precise administration of therapeutic agents. The minimally invasive approach of microneedles reduces the potential for adverse reactions, as they primarily target specific cells, tissues, or organs [130]. Furthermore, the controlled release and localized action of drugs through microneedles contribute to a more favorable pharmacokinetic profile, minimizing systemic exposure and thus reducing the likelihood of systemic side effects. Consequently, microneedle drug delivery technology is promising to improve therapeutic interventions' overall safety profile [131]. Migdadi et al. researched hydrogel-forming microneedles aimed at transdermal delivery of metformin to alleviate gastrointestinal side effects commonly associated with oral administration. Their findings underscored enhanced permeation and bioavailability of the drug facilitated by the microneedles developed in their study [132].

2.4. Case Studies of Drug-Loaded Microneedles

The case studies presented encompass various drug-loaded microneedle formulations, each demonstrating unique characteristics and encapsulation efficiencies. These formulations utilize various nanoparticle systems, nanosuspensions, solid lipid nanoparticles (SLNs), colloidal nanoparticles, nano microparticles, inclusion complexes with cyclodextrins, microcrystal particles/powder, micelles, and solid dispersions. Solid lipid nanoparticles (SLNs) and nanosuspensions appear frequently among the formulations, indicating their popularity and effectiveness in ocular drug delivery. For instance, paclitaxel-loaded SLNs exhibited an encapsulation efficiency of 54.13 µg per patch, showcasing the potential of SLNs for sustained drug release [133]. Similarly, capsaicin-loaded colloidal nanoparticles demonstrated an impressive encapsulation efficiency of 99.9%, highlighting their suitability for efficient drug distribution to the eye [134]. Additionally, nanosuspensions, such as those containing methotrexate and TA, demonstrated promising characteristics with encapsulation efficiencies ranging from 2.48 mg to 92.52 µg, indicating their potential for delivering an extensive range of drug doses [135]. Moreover, inclusion complexes with cyclodextrins, such as those of levonorgestrel and TA, exhibited encapsulation efficiencies of 66.94 µg to 92.52 µg, suggesting their ability to enhance drug solubility and stability [136,137]. Other formulations, such as solid dispersions and matrix interactions, also showed promising results. For instance, atorvastatin calcium trihydrate in solid dispersion form exhibited encapsulation efficiencies ranging from 1.9 to 3.4 mg, indicating its potential for delivering relatively higher drug doses [138]. Likewise, lidocaine hydrochloride formulated via matrix interaction demonstrated an encapsulation efficiency of 3.43 ± 0.12 mg, indicating its potential for sustained drug release and prolonged therapeutic effect [139]. Furthermore, using PLGA nanoparticles (NPs) for drug delivery was highlighted in several case studies, demonstrating their versatility and efficacy in ocular drug delivery. For instance, PLGA NPs loaded with OVA exhibited encapsulation efficiencies ranging from 4.15 µg to 10 µg, indicating their potential for delivering antigens for ocular immunotherapy [32,140]. Overall, the diverse range of formulations and their respective encapsulation efficiencies showcased in these case studies underscores the potential of various nanoparticle systems for efficient and targeted ocular drug delivery, paving the way for improved treatment outcomes in ophthalmology. However, further research is acceptable to optimize these formulations for clinical translation and address scalability and regulatory approval challenges.

Table 6. Case studies of drug-loaded microneedles.

Table 6. Case studies of drug-loaded microneedles.

Sr. No.	Drug	Potential Applications	Loading per patch	Formulation type	Composition / Characteristics	Reference
1.	Paclitaxel	Treatment for a range of malignancies, including lung, ovarian, and breast cancer	54.13 µg	Solid lipid nanoparticles (SLNs)	Cetyl Palmitate and tricaprin, 230 nm	[133]
2.	Capsaicin	Topical analgesia for localized pain relief	EE- 99.9 %	Colloidal nanoparticles	HA and PVP (ratio 1:1), 167 ± 4 nm	[134]
3.	Vitamin D3 / Cholecalciferol	Vitamin D supplementation for individuals with deficiency	265 ± 32 µg	Nano-microparticles	PLGA, 400 nm to 3.6 µm	[141]
4.	IR-780	Near-infrared fluorescence imaging for tumor detection	-	SLNs	Cetyl Palmitate and tricaprin, 230 nm	[133]
5.	Doxycycline	Management of rosacea symptoms	0.84 ± 0.02 mg	SLNs	100 nm	[142]
6.	Albendazole	Control of other parasitic infections (e.g., trichinellosis)	0.94 ± 0.03 mg	SLNs	100 nm	[142]
7.	Cisplatin	Management of bladder cancer	--	Lipid NPs	DOTAP, cholesterol, and DSPE-PEG-AA	[143]
8.	Itraconazole	Therapy for fungal nail infections (onychomycosis)	3.3 mg	Nanosuspension	300 nm	[144]
9.	Rilpivirine		4 mg	Nanosuspension		[145]
10.	Methotrexate (free acid)	Treatment of rheumatoid arthritis	2.48 mg	Nanosuspension	680 nm	[135]
11.	Dutasteride	-	11/12 % (w/w)	Nanosuspension	-	[146]
12.	Curcumin	Treatment of wounds and burns	10.9 ± 1.1 µg	Nanosuspension	520 ± 40 nm	[147]
13.	Ivermectin	-	0.86 ± 0.07 mg	Nanosuspension	98.12 ± 7.76 nm	[148]
14.	Levonorgestrel	Contraception (long-acting reversible contraception)	66.94 µg	Inclusion complexes with cyclodextrins	Hydroxypropyl- β -cyclodextrin (HP-β - CD)	[136]
15.	TA		80.28 to 92.52 µg	Inclusion complexes with cyclodextrins	(HP-β - CD)	[137]
16.	Etonogestrel	Contraception (long-acting reversible contraception)	550 µg	Microcrystal particles/Powder	10 – 30 µm	[149]
17.	Lumefantrine	Treatment for simple malaria brought on by strains of Plasmodium vivax and falciparum	8806 ± 461 µg	Nanosuspension	321.00 ± 16.50 nm	[138]
18.	Artemether	-	30,027 ± 69.5 µg	Nanosuspension	148.10 ± 4.27 nm	[138]
19.	Atorvastatin calcium trihydrate	Management of hypercholesterolemia	1.9 to 3.4 mg	Solid dispersion	-	[138]
20.	TA	-	117.06 ± 9.07 µg	Nanosuspension	264 nm	[150]
21.	Leuprolide acetate	Hormonal therapy for transgender individuals	14.3 µg	Solid dispersion	-	[151]
22.	Shikonin	Promotion of wound healing	0.805 ± 0.017 µg / mg	Micelles	130 ± 8 nm	[152]
23.	Finasteride	Treatment of benign prostatic hyperplasia (BPH)	47.36 ± 0.92 µg	Lipid NPs	Glyceryl monostearate and squalene, 180 nm	[153]
24.	Lidocaine hydrochloride	Pain management during medical or cosmetic procedures (e.g., injections, tattooing)	3.43 ± 0.12 mg	Matrix interaction	-	[139]
25.	Diethylcarbamazine	Treatment of lymphatic filariasis (elephantiasis)	0.55 ± 0.00 mg	SLNs	100 nm	[142]
26.	OVA	-	10 µg	PLGA NPs	358 nm	[154]
27.	5-aminolevulinic acid	Management of superficial basal cell carcinoma. Therapy for acne vulgaris	69.38 ± 4.89 µg	Matrix interaction	-	[155]
28.	Methotrexate	Management of psoriasis	Up to 65.3 ± 2.9 µg	Matrix interaction	-	[156]
29.	OVA	Immunization and vaccination against specific antigens or pathogens	4.15 ± 1.93 µg (delivered 24%)	PLGA NPs	170 nm	[32]
30.	Lidocaine hydrochloride	Local anesthesia for minor surgical procedures	3.43 ± 0.12 mg	Matrix interaction	-	[139]

2.6. Biocompatibility and Safety Considerations

Designing a long-acting drug delivery microneedle must consider several factors to ensure effective and efficient medication delivery. Critical considerations for their biocompatibility and safety include using biocompatible and non-toxic materials, such as metals, polymers, and biodegradable substances, which ensure minimal inflammatory responses and non-toxic degradation products [63]. Mechanical properties are critical; the microneedles must be strong enough to penetrate ocular tissues without breaking and appropriately sized and sharp to minimize tissue damage and pain [167]. Sterilization and maintaining aseptic conditions during manufacturing are essential to prevent infections. Microneedles must also promote rapid healing of the insertion site and deliver drugs in a controlled and targeted manner [168]. Extensive preclinical research in animal models and human clinical trials are needed to prove their safety and efficacy. Regulatory compliance, including meeting FDA or EMA standards and post-market surveillance, is crucial for successful implementation in clinical settings [169]. Here are a few crucial design considerations:

2.6.1. Needle Length and Geometry

In-depth research has been done on microneedle array-based transdermal DDSs to determine their biocompatibility and viability as a commercially viable method of transporting small and large molecules (peptides, drugs, and proteins). Microneedles, manufactured with remarkable precision owing to advancements in microfabrication technology, have demonstrated exceptional efficacy in transdermal delivery by puncturing the stratum corneum. Generally, these microneedles range in length from 150 to 1500 micrometers, with widths spanning 50 to 250 micrometers, and diameters between 1 and 25 micrometers. By puncturing the skin, microneedles create micron-sized pores, and these channels serve as a straight path for drug delivery [170]. Patient compliance and pain management are vital for the success of Minnesota-based drug delivery. However, the length and quantity of microneedles were found to be essential for pain management. The 400-microneedle patch was painless, each microneedle measuring 150 μm in length. However, the pain score escalated significantly by seven and 3-fold, respectively, when the needle length was extended from 500 to 1500 μm (while maintaining a constant number of needles) and when the number of microneedles was increased by 10-fold (while maintaining a continuous length of 620 μm) [171].

Microneedle patches are formed by arranging microneedles in arrays on the backing of a patch. However, for microneedles to serve as effective drug delivery systems, they must meet specific criteria. Microneedles are available in various sizes and shapes, with needle-shaped geometries (sharp, tapered, conical, or bevel-tipped), microblades, or blunt projections being the most common. Regarding array design, fabrication techniques for microneedle arrays typically yield "in-plane" or "out-of-plane" systems. "In-plane" arrays are oriented perpendicular to the surface, whereas "out-of-plane" arrays are aligned parallel to the surface. Davis et al. were pioneering investigators who examined the effect of microneedle geometry on insertion force using both in vitro and in silico experimental approaches. Their findings revealed a direct association between increasing microneedle cross-sectional area and insertion force [172]. On the contrary, the study found a consistent elevation in fracture forces concerning microneedle wall thickness, wall angle, and tip radius variations. Therefore, the researchers determined that the fracture forces corresponding to various geometries were greater than the insertion forces [173]. After analyzing various geometries and dimensions of in-plane silicon microneedle designs, it was found that the skin's inherent resistance to puncture significantly affects the insertion force, thereby influencing the micro needle's penetration capability [174,175].

2.6.2. Material Biocompatibility

Microneedles facilitate the administration of diverse medications, covering small molecules, peptides, vaccines, proteins, and nucleic acids. The suitability of a particular drug for microneedle delivery hinges on various factors:

Physicochemical properties of the drug: Drugs possessing suitable physicochemical properties, such as low molecular weight, adequate solubility, and stability, are generally more compatible with microneedle applications [176]. Particle size is important; the drug particles should be small enough to integrate uniformly into the microneedle matrix without causing blockages or structural issues, with nanoparticles often preferred for enhanced solubility and absorption [177]. Enhancing the solubility of poorly soluble drugs is crucial for overcoming the challenge of delivering small doses via microneedles. By increasing the solubility, higher doses of these drugs can be effectively incorporated into the small dimensions of microneedles. Techniques to enhance solubility include using prodrugs, surfactants, liposomes, salt preparation, pH adjustment, and nanoparticle control technology [178].

Formulation considerations: The formulation of the drug plays a crucial role in its compatibility with microneedles. Different formulation approaches, such as encapsulation in nanoparticles, microspheres, or hydrogels, can be employed to enhance drug compatibility [179]. Lahiji et al. investigated the effects of various microneedle manufacturing parameters, including manufacturing and storage temperatures and drying conditions. They found that maintaining low temperatures during manufacture, using mild drying conditions, ensuring appropriate polymer concentration, and incorporating a protein stabilizer could preserve lysozyme activity at 99.8 ± 3.8%. This study underscores the significance of optimizing manufacturing conditions to maintain protein activity [180].

Stability: Drugs must remain stable during microneedle fabrication and storage. Some drugs may require special protection or stabilization techniques to prevent degradation [176]. Permeation enhancers: In some cases, chemical permeation enhancers may be necessary to facilitate drug delivery across the skin barrier. Drug compatibility may vary based on the microneedles' design and fabrication method. Experimental investigations and formulation refinements are frequently required to ascertain the compatibility of a specific drug with microneedles [181]. Selecting materials and formulations to preserve protein drug stability is challenging, particularly in large-scale storage and production for clinical applications. Chen et al. developed a microneedle incorporating phenylboronic acid, demonstrating glucose responsiveness and temperature stability for insulin delivery in diabetes treatment [182]. Antibody delivery encounters multiple challenges, including reduced efficacy and the risk of immunogenicity resulting from protein inactivation. To address these issues, it is crucial to ensure the stability of the antibody within the microneedle and carefully consider formulation aspects. Zhu et al. examined the stability of vaccine-loaded microneedles and discovered that using trehalose during the manufacturing process provided significantly greater stability compared to sucrose, retaining 80% of the initial antigenicity under stress conditions (60 °C for 3 months) [183].

Loading capacity: The microneedles' loading capacity indicates the drug volume that can be accommodated within the microneedle array [184]. Several factors influence the loading capacity: The microneedles' size, geometry, and material impact their loading capacity. Microneedles can vary in length, width, and shape, allowing for different drug-loading possibilities [185]. Various drug formulation strategies can be employed to improve loading capacity. For example, drugs can be layered onto the surface of microneedles, encapsulated within the microneedles (such as in dissolving microneedles), or incorporated into biodegradable matrices that surround the microneedles [186]. The required therapeutic dose of the drug also influences the loading capacity. Microneedles are typically used for delivering small to moderate drug doses, especially for localized or targeted applications [187]. The loading capacity of microneedles is often limited compared to other DDSs like patches or injections. However, researchers continuously optimize microneedle designs and drug formulations to increase loading capacity and improve drug delivery efficiency [176]. This study identifies biocompatibility and minimal invasiveness as essential for advancing next-generation microneedle medical treatments. Consequently, selecting candidate materials should prioritize biocompatibility and low cell toxicity. Traditional materials employed in medical applications often consist of metals to ensure robustness and rigidity. Thus, non-ferrous metals emerge as promising candidates for microneedles. The materials must withstand insertion while remaining intact during drug release. Microneedle fabrication frequently employs silicon, biodegradable polymers, and metals such as stainless steel or titanium [188].

Table 7. Metal biocompatibility for medical applications.

Table 7. Metal biocompatibility for medical applications.

Hypersensitivity-inducing element	Cr, Co, V
Poor cellular compatibility element	Cu, Co, V, Fe
Excellent cellular compatibility element	Mo, Ti, Sn, Zr
Enhanced mechanical strength	Zr, Sn
β-phase stabilizing element	Ta, Nb, V, Cr, Mo, Fe

3. Route of Administration for Ocular Microneedles

3.2. Intravitreal Injection

Intravitreal injection delivery of ophthalmic microneedles involves precisely inserting extremely fine needles directly into the eye's vitreous cavity. These microneedles are designed to penetrate the ocular tissues with minimal trauma, facilitating the targeted distribution of medications or therapeutic agents into the vitreous humor. Once inserted, the microneedles can release drugs directly into the vitreous, allowing for enhanced drug bioavailability at the site of action while minimizing systemic side effects [190].

Figure 6. The ophthalmic medication routes involving injection sites for better therapeutics.

Figure 6. The ophthalmic medication routes involving injection sites for better therapeutics.

4. Therapeutic Agents Delivered via Microneedles

5. Applications of Microneedles in Ocular Disease

6. Clinical Trials and Regulatory Considerations

6.1. Overview of Ongoing Clinical Trials

Ongoing clinical trials investigate the potential applications of ophthalmic microneedles, showcasing a surge in interest from various pharmaceutical and biotech companies. These trials aim to assess the safety, effectiveness, and feasibility of microneedle-based drug delivery systems (DDSs) for different ocular diseases. Several ongoing trials specifically investigate microneedles' potential in treating retinal conditions such as age-related macular degeneration (AMD) and diabetic retinopathy, among others. Advancements in the field include novel formulations, design modifications, and innovative delivery strategies, which contribute to ongoing research efforts.

Clearside Biomedical, Inc. conducted a Phase 3 Randomized, Masked, Controlled Clinical Trial to evaluate the safety and effectiveness of TA Injectable Suspension (CLS-TA 4 mg/ml) for treating macular edema resulting from non-infectious uveitis [284]. In October 2021, FDA approval was granted for XIPERE®, a single stainless steel hollow microneedle designed to deliver TA suspension into the suprachoroidal area for treating diabetic macular edema (DME). The SCS Microinjector® device, as shown in Figure 9, enables precise and localized drug delivery into the suprachoroidal space (SCS) by utilizing the pressure difference within this space to disperse the medication. Additionally, a phase 3 randomized trial (PEACHTREE, NCT02595398) was conducted to assess the suprachoroidal injection of CLS-TA [11]. At week 24, the primary endpoint was defined as achieving a Best Corrected Visual Acuity (BCVA) improvement of at least 15 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters. Results revealed that 46.9% of patients who received a 4 mg CLS-TA suprachoroidal injection on Day 0 and at week 12 met this endpoint, compared to only 15.6% in the sham group. Safety endpoints were also met, with just over half of patients (51%) experiencing adverse ocular events, compared to 58% in the sham group. The most common adverse event in the sham group was cystoid macular edema, with 11.5% experiencing elevated intraocular pressure (IOP) and 12.5% reporting pain [285]. The TA formulation (40 mg/ml) was administered, and changes in SCS thickness were measured shortly after in early Clearside Biomedical trials as HULK (NCT02949024). optical coherence tomography (OCT) was used to confirm that, even though there was a noticeable rise in thickness (65.1 µm to 75.1 µm) right after treatment, there were no appreciable differences in SCS thickness between treated and untreated eyes until nearly five months later [286]. The potential advantages of combining aflibercept were investigated in a Phase 2 trial known as TYBEE (NCT03126786). Patients were divided into two groups: the control group received a single intravitreal injection of aflibercept every four weeks until week 12. In contrast, the treatment group received a combined dose of CLS-TA (40 mg/mL) and aflibercept (2 mg/0.05 mL) on day zero, followed by a single aflibercept injection at week 12. Despite no significant disparity in mean BCVA scores, the combination therapy exhibited a reduction in the overall number of required treatments. Importantly, both groups demonstrated similar benefits, suggesting the possibility of alleviating the clinical burden associated with treating diabetic macular edema (DME) [287]. Clearside Biomedical, Inc. also conducted a phase 1/2 study (NCT01789320) to evaluate the safety and tolerability of a single microinjection of TA (TRIESENCE^®) within the suprachoroidal space (SCS) of patients with non-infectious uveitis. This research included non-infectious intermediate, posterior, or pan-uveitis patients who underwent a singular suprachoroidal injection. Specifically, the injection involved administering 4 mg of TA in 100 μL directly into the eye under study. Subsequently, a comprehensive follow-up was conducted for 26 weeks to examine the outcomes and effects of this treatment method. In this study, nine subjects were enrolled, with three participants having anterior and intermediate uveitis, one with intermediate uveitis alone, and five with pan-uveitis. Of all the 38 AEs that were reported, the majority had mild to severe severity. The majority of AEs (almost half) were ocular. Four subjects who complained of ocular pain at or adjacent to the injection site reported the most frequent adverse event. Every systemic adverse event was unrelated to the drug under examination. There were no increases in IOP associated with steroids, and none of the subjects needed medication to decrease their IOP. The visual acuity of all eight efficacy-evaluable patients improved. Through week 26, the average improvement in visual acuity was greater than two lines for four participants who did not require extra therapy. At week 26, macular edema was present in three out of four patients; in two, it had decreased by at least 20 %. After these results, they initiated a phase 3 study in patients with ME related to non-infectious uveitis [288]. The University Hospitals Leuven conducted a Phase I experiment for central retinal vein occlusion using robot-aided retinal vein cannulation with ocriplasmin infusion. In addition, a robotic system that ensured proper needle alignment and a pump that adjusted the infusion rate managed the microneedle administration. At 26 weeks, macular edema substantially declined in all four patients under study, indicating the viability of ocriplasmin delivery using microneedles. However, there was one case of a microneedle tip breaking, suggesting that there may be more safety issues with the microneedle itself than with the formulation [289].

Table 8. Ongoing clinical trials on ophthalmic microneedles.

Table 8. Ongoing clinical trials on ophthalmic microneedles.

NCT number	Sponsor	Drug	Phase	Dose	Time	Status	Indication
NCT02747030	Universitaire Ziekenhuizen Leuven	Ocriplasmin intravenously	Phase I	-	12/2016–08/11/2017	Completed	Central retinal vein occlusion
NCT03203447	Clearside Biomedical, Inc.	Suprachoroidal CLS-TA	Phase III	4 mg in 0.1 mL	03/05/2018-12/18/2018	Terminated	Macular edema
NCT03126786	Clearside Biomedical, Inc.	IVT aflibercept	Phase II	4 mg in 0.1 mL	07/11/2017–04/17/2018	Completed	Diabetic macular edema
NCT02949024	Clearside Biomedical, Inc.	Suprachoroidal CLS-TA	Phase I/II	4 mg in 0.1 mL	11/10/2016–10/17/2017	Completed	Diabetic macular edema
NCT03097315	Clearside Biomedical, Inc.	Suprachoroidal CLS-TA	Phase III	4 mg in 0.1 mL	04/04/2017–01/24/2018	Completed	Non-infectious Uveitis
NCT02595398	Clearside Biomedical, Inc.	Suprachoroidal CLS-TA	Phase III	4 mg in 0.1 mL	11/17/2015–01/18/2018	Completed	Macular edema with non-infectious uveitis
NCT02255032	Clearside Biomedical, Inc.	CLS-TA	Phase II	0.8 mg in 0.1 mL	10/2014-01/ 2016	Completed	Macular edema with non-infectious uveitis
NCT02895815	Janssen Pharmaceutical K.K.	CNTO 2476 (6.0 × 104 cells) in 50 μL	Phase II	-	04/09/2018–08/19/2022	Withdrawn	Visual acuity

https://clinicaltrials.gov, 1 April 2024.

7. Challenges and Future Directions

8. Conclusions

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