Microneedles Research Articles

Single-atom nanozyme liposome-integrated microneedles for in situ drug delivery and anti-inflammatory therapy in Parkinson’s disease

Treatment for Parkinson’s disease (PD) has been impeded by inefficient treatment results and multiple membrane barriers during drug delivery. This study reports the design, synthesis, and application of microneedles (MNs) loaded with mitochondrion-targeted liposome encapsulated iron (Fe)-isolated single-atom nanozymes (Mito@Fe-ISAzyme, MFeI), called MFeI MNs, for in situ drug delivery into the brain parenchyma and efficient enrichment of drugs in lesion sites. In in vitro experiments, MFeI can scavenge reactive oxygen species (ROS) and protect the neurons via mitochondrial targeting, guaranteeing the subsequent treatment of PD. Using PD mouse models, we compared the intravenous injection of MFeI with the brain in situ administration of MFeI MNs (in situ MFeI MNs). Results showed that in situ MFeI MNs significantly improved the deep penetration of the drug into brain parenchyma, especially in the vital pathological sites such as the substantia nigra pars compacta and striatum. Importantly, ROS elimination and neuroinflammatory remission in the lesion site were observed, thereby efficiently alleviating the behavioral disorders and pathological symptoms of PD mice. Therefore, the MNs system for in situ single-atom nanozyme liposome delivery exhibits great potential in PD treatment.Graphical abstract

Production of microneedle patches coated with polyvinyl-alcohol/sucrose/gentamicin sulfate for skin treatment

In this study, resin-based microneedle (MN) patches were fabricated using a digital light processing (DLP) printer. The needles were coated with gentamicin sulfate (GEN)-loaded with 13.3 % PVA/25 % sucrose solution by immersion. The SEM results showed that the coating was homogeneous and uniformly conical. Analysing the in vitro release profiles of GEN, it was found that it was ultimately released within 312 h. The compression test results demonstrated that GEN addition increased the compression strength to the value of 2.17 ± 0.01 N/mm2.

Programmed BRD9 Degradation and Hedgehog Signaling Activation via Silk-Based Core-Shell Microneedles Promote Diabetic Wound Healing.

Wound healing impairment in diabetes mellitus is associated with an excessive inflammatory response and defective regeneration capability with suppressed Hedgehog (Hh) signaling. The bromodomain protein BRD9, a subunit of the non-canonical BAF chromatin-remodeling complex, is critical for macrophage inflammatory response. However, whether the epigenetic drug BRD9 degrader can attenuate the sustained inflammatory state of wounds in diabetes remains unclear. Without a bona fide immune microenvironment, Hh signaling activation fails to effectively rescue the suppressed proliferative ability of dermal fibroblasts and the vascularization of endothelial cells. Therefore, a silk-based core-shell microneedle (MN) patch is proposed to dynamically modulate the wound immune microenvironment and the regeneration process. Specifically, the BRD9 degrader released from the shell of the MNs mitigated the excessive inflammatory response in the early phase. Subsequently, the positively charged Hh signaling agonist is released from the negatively charged core of the silk fibroin nanofibers and promotes the phase transition from inflammation to regeneration, including re-epithelialization, collagen deposition, and angiogenesis. These findings suggest that the programmed silk-based core-shell MN patch is an ideal therapeutic strategy for effective skin regeneration in diabetic wounds.

Swellable Biopolymer Composite Microneedle Patch for Pain-Free Collection of Interstitial Fluid to Analyze Multiple Biomolecules.

Sampling of interstitial fluid (ISF) using microneedle (MN) patch offers a pain-free minimally invasive alternative to syringe needle-based blood sample collection. However, there is a challenge in the development of MN patch that provides swelling behavior with sufficient mechanical strength for skin penetration. Here, we report fabrication of MN patch made of biopolymer composite containing iota-carrageenan, gelatin, and polyethylene glycol. Calcium chloride was used as a crosslinker to improve mechanical strength. MN patch was characterized for integrity, swelling behavior, mechanical strength, aspiration of fluid from agarose gel, and the excised porcine ear skin. An array of 361 MNs was able to aspirate 36 ± 5 and 14 ± 1 μL fluid after application in agarose gel matrix and the ex vivo porcine skin model, respectively. MN patch applied in vivo rat model for 30 min resulted in the collection of ISF containing 267 ± 128 mg/dL, 24 ± 13 mg/dL, and 0.6 ± 0.4 mIU/mL of glucose, uric acid and thyroid stimulating hormone (TSH), respectively. The concentration of glucose, uric acid, and TSH in rat blood was found to be 199 ± 47 mg/dL, 8.4 ± 6 mg/dL, and 1.1 ± 0.6 mIU/mL at the same time. Furthermore, MN patch applied on the forearm of 10 healthy human volunteers for 30 min was able to aspirate 32 ± 14 μL of ISF. The concentration of glucose, uric acid, and TSH determined from ISF samples of human volunteers was 64 ± 25 mg/dL, 4.2 ± 4.1 mg/dL, and 0.16 ± 0.08 mIU/mL, respectively. The visual analogue scale (VAS) pain score after MN application was lower compared with hypodermic syringe needle insertion. Taken together, biopolymer composite-based swellable MN patch can be developed for collection of ISF for simultaneous determination of multiple biomolecules in a minimally invasive manner.

3D Polymeric Lattice Microstructure-Based Microneedle Array for Transdermal Electrochemical Biosensing.

Microneedles (MNs) or microneedle arrays (MNAs) are critical components of minimally invasive devices comprised of a single or a series of micro-scale projections. MNs can bypass the outermost layer of the skin and painlessly access microcirculation of the epidermis and dermis layers, attracting great interest in the development of personalized healthcare monitoring and diagnostic devices. However, MN technology has not yet reached its full potential since current micro- and nanofabrication methods do not address the need of fabricating MNs with complex surfaces to facilitate the development of clinically adequate devices. This work presents a new approach that combines 3D printing technology based on two-photon polymerization with soft lithography for cost-effective and time-saving fabrication of complex MNAs. Specifically, this method relies on printing complex 3D objects efficiently replicated into polymeric substrates via soft lithography, resulting in a free-standing polymeric lattice (PL) membrane that can be transferred onto gold-coated MNs and used for electrochemical biosensing. This platform shows excellent electrochemical performance in detecting metabolite (glucose) and protein (insulin) biomarkers with a dynamic linear range sufficient for detecting biomarkers in healthy individuals and patients. The approach holds great potential for fabricating next-generationMNs, including their transfer into clinically adequate devices.

Transformative personalized oxalate biomarker analysis through a wrist-worn microneedle device integrated with duplex nanozyme toolbox

The interstitial fluid (ISF) is valuable for disease diagnosis due to its unique biomarkers. Microneedles (MNs) offer a painless method for ISF sampling, facilitating primary diagnostics. This study introduces a minimally invasive, biocompatible MN patch made from a swellable hydrogel of polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP), which effectively extracts ISF. The hydrogel selectively permits small molecules like oxalate, a kidney disease biomarker, while blocking large biomolecules. The MN patch is integrated with a multilayer sensor via microfluidic channels, featuring cotton fiber, agarose, and Mn3[Fe(CN)6]2, alongside Fe3[Fe(CN)6]3 (AGH-CP/MnFeCN/FeFeCN). These nanozymes exhibit oxidase-like activity, reacting with 3,3′,5,5′-tetramethylbenzidine (TMB) to indicate oxalate levels through a color change from green (no oxalate) to light or dark blue, based on concentration. The designed sensor demonstrates high performance with a detection limit of 0.897 μM and an RSD of 1.22 %, enabling accurate quantification via smartphone image analysis as readout platforms for more accessibility and user-friendliness which helps to reach personalized healthcare goals. This integration facilitates real-time, remote, precise disease detection, biochemical analysis and forsooth miniaturization, leading to the development of portable, flexible, and wearable sensors. The MN patch and integrated sensor show excellent stability, selectivity, sensitivity, reliability, and long-term durability. This minimally invasive sensing system, designed for wristband integration, opens new avenues for precision point-of-care monitoring, enhancing personal healthcare.

Local Release of Copper Manganese Oxide Using HA Microneedle for Improving the Efficacy of Drug-Resistant Wound Inflammation.

The production of bacterial toxins and excessive accumulation of reactive oxygen species (ROS) can induce localized oxidative stress, triggering an exaggerated immune response that impedes wound healing and culminates in chronic wounds. To address this issue, a microneedle (MN) system loaded with copper-manganese oxide (CMO) is developed to modulate the hyperimmune response in wounds. CMO@MN exhibits excellent antimicrobial and anti-inflammatory properties by effectively killing bacteria, scavenging ROS, and modulating macrophage polarization through their multiple enzymatic activities and photothermal properties. RNA sequencing revealed that CMO@MN improved the therapeutic effect on the infected skin of mice by balancing the ratio of M1/M2 macrophages and promoting cell migration and angiogenesis through the regulation of relevant pathways. Overall, this CMO@MN patch skillfully balances the complex issues between the immune response and wound healing and has potential applications in the treatment of other serious bacterial infections.

Augmenting dermal collagen synthesis through hyaluronic acid-based microneedle-mediated delivery of poly(l-lactic acid) microspheres

Poly(L-lactic acid) (PLLA) can stimulate collagen synthesis through a foreign body response. However, inappropriate injection techniques and localized PLLA clustering can lead to complications and adverse events. This study developed a composite microneedle (MN) device comprising an array of PLLA microsphere (PLLA MP)-loaded hyaluronic acid needle tips with a supporting patch (PLLA MP-MN). This device was designed to deliver PLLA MPs precisely and uniformly to the dermis and to provide dual stimulation through MN puncture and MP implantation, thereby enabling the rapid and long-lasting regeneration of dermal collagen. When applied to rat skin, the MN array evenly distributed the PLLA MPs throughout the penetrated regions, which prevented local PLLA overdosing and elicited a milder inflammatory response compared with that induced by intradermal PLLA MP injections. An in vivo efficacy study revealed that MN-mediated delivery of PLLA MPs not only promptly initiated collagen production through microwound-triggered wound-healing cascades in the early treatment stage but also enabled the long-term stimulation of collagen deposition through MP-induced foreign body reactions, thereby significantly enhancing neocollagenesis. This innovative PLLA MP-MN system can augment the benefits and minimize the adverse effects associated with traditional PLLA fillers, providing a safe and reliable anti-aging therapeutic option.

Transcutaneous Immunization of 1D Rod-Like Tobacco-Mosaic-Virus-Based Peptide Vaccine via Tip-Loaded Dissolving Microneedles.

Peptide vaccines induce specific neutralizing antibodies and are effective in disease prevention and treatment. However, peptide antigens have a low immunogenicity and are unstable, requiring efficient vaccine carriers to enhance their immunogenicity. Here, we develop a tobacco mosaic virus (TMV)-based peptide vaccine for transdermal immunization using a tip-loaded dissolving microneedle (MN) patch. TMV is decorated with the model peptide antigen PEP3. The prepared TMV-PEP3 promotes dendritic cell maturation and induces dendritic cells to overexpress MHC II, costimulatory factors, and pro-inflammatory factors. By encapsulation of TMV-PEP3 in the tips of a trehalose MN, TMV-PEP3 can be delivered by MN and significantly promote local immune cell infiltration. In vivo studies show that both subcutaneous injection and MN administration of TMV-PEP3 increase the production of anti-PEP3 IgG antibodies and the harvested serum can induce complement-dependent cytotoxicity. This work provides a promising strategy for constructing efficient and health-care-friendly peptide vaccines.

Polymer homologue-mediated formation of hydrogel microneedles for controllable transdermal drug delivery

Poly(ethylene glycol) diacrylate (PEGDA) microneedles (MNs) are hydrogel-based devices that achieve controlled drug delivery kinetics by adjusting the crosslinking density. However, the biosafety of many crosslinking agents used to regulate crosslinking density is not ideal. To avoid crosslinking agents and simplify the preparation process, using two types of polymer homologues with different number-average molecular weights, we have successfully developed a series of PEGDA MNs with controllable crosslinking density (abbreviated as TP-X MNs). The research showed that the mechanical properties and drug release behavior of TP-X MNs could be tuned by simply controlling the weight proportion of two different PEGDA components in MNs. Ex vivo drug delivery experiments indicated that all TP-X MNs exhibited a sustained release profile, and their control range of 336-hour accumulative release rates was from 6.24% to 40.93%. Moreover, we prepared a novel dual-layer PEDGA MN, which can customize the drug loading and release rate in each layer of MN. This work demonstrates a new way to develop hydrogel MNs with adjustable crosslink density and broadens the applications of PEGDA MN in the biomedical field.

Studies on drug delivery from dissolving microneedle and its uptake in tissue

Abstract In this study, a mathematical model for transdermal drug administration using a dissolving conical microneedle (MN) is developed. The drug is absorbed in the blood compartment after passing through the skin’s viable epidermis. Reversible reaction kinetics then allow the drug to enter the tissue compartment. An unsteady reaction equation is used to predict the drug’s distribution into the skin following MN’s dissolution. An unsteady reaction mechanism is used to determine the concentrations in the blood and tissue compartments. Using the fourth-order Runge–Kutta method, the governing equations with their initial conditions are solved numerically. The MN is expected to dissolve completely in 108.1 s, according to the predicted results, while the concentration in the skin peaks at 94.4 s. The concentrations in the tissue and blood compartments, however, reach their respective maximal amounts later on. In this investigation, the impacts of the drug’s mass fraction, volume fraction, and penetration rate cannot be completely ruled out. A thorough sensitivity analysis has been carried out for some of the parameters involved. Our findings closely align with the findings reported in the literature.

Multifunctional Microneedle Patch with Diphlorethohydroxycarmalol for Potential Wound Dressing.

Treatment of skin wounds with diverse pathological characteristics presents significant challenges due to the limited specific and efficacy of current wound healing approaches. Microneedle (MN) patches incorporating bioactive and stimulus materials have emerged as a promising strategy to overcome these limitations and integrating bioactive materials with anti-bacterial and anti-inflammatory properties for advanced wound dressing. We isolated diphlorethohydroxycarmalol (DPHC) from Ishige okamurae and assessed its anti-inflammatory and anti-bacterial effects on macrophages and its antibacterial activity against Cutibacterium acnes. Subsequently, we fabricated polylactic acid (PLA) MN patches containing DPHC at various concentrations (0-0.3%) (PDPHC MN patches) and evaluated their mechanical properties and biological effects using in vitro and in vivo models. Our findings demonstrated that DPHC effectively inhibited nitric oxide production in macrophages and exhibited rapid bactericidal activity against C. acnes. The PDPHC MN patches displayed potent antibacterial effects without cytotoxicity. Moreover, in 2,4-Dinitrochlorobenzene-stimulated mouse model, the PDPHC MN patches significantly suppressed inflammatory response and cutaneous lichenification. The results suggest that the PDPHC MN patches holds promise as a multifunctional wound dressing for skin tissue engineering, offering antibacterial properties and anti-inflammatory properties to promote wound healing process.

Sawtooth-shaped microsaws for enhanced transdermal drug delivery: Improved drug loading and piercing efficiency

This study presents a novel approach to transdermal drug delivery with the introduction of sawtooth-shaped MicroSaws (MSs), a bioinspired microneedle design that significantly enhances drug loading and piercing efficiency. Unlike traditional microneedles (MNs), MSs, with dimensions of 0.2 mm width, 0.4 mm length, and 0.65 mm height, are engineered using epoxy acrylate (EA) via digital light processing (DLP) 3D printing and coated with polyethylene glycol diacrylate (PEGDA) to ensure biocompatibility. Experimental results demonstrate that MSs outperform conventional MNs in both mechanical piercing tests and drug release studies, showcasing a 30 % increase in drug loading capacity and a 25 % improvement in pierceability. The unique sawtooth design not only facilitates deeper penetration but also creates microchannels that enhance drug diffusion across the stratum corneum. This innovation in microneedle technology holds significant promise for improving patient compliance and therapeutic outcomes in transdermal drug delivery systems.

NIR Enhanced pH-Responsive Microneedles for Synergetic Therapy of Melanoma.

Melanoma has emerged as a significant threat to human life and health. Microneedle (MN)-mediated transdermal drug delivery (TDD) has garnered attention in melanoma treatment for bypassing the first-pass effect. However, the propensity of melanoma to metastasize presents substantial challenges for MN mediated local treatment. Developing systemic therapies, such as immunotherapy in combination with TDD, is crucial for achieving effective melanoma treatment. Herein, a polyvinyl alcohol (PVA) MN-mediated multifunctional TDD system, designated MN@PDA@1-MT/CUR/DOX@HA (MN@PMCDH), was developed for synergetic chemotherapy/photothermal/immunotherapy of melanoma. PMCDH nanomedicines penetrate deep skin layers through MNs, accumulate at tumor sites guided by hyaluronic acid (HA), and selectively release drugs in response to the acidic tumor microenvironment and near-infrared (NIR) stimulation. Released curcumin (CUR) significantly enhances the efficacy of photothermal therapy (PTT) and chemotherapy, as well as improves the induction of immunogenic cell death (ICD) by increasing melanoma sensitivity to polydopamine (PDA)-mediated photothermal effects and doxorubicin (DOX). Moreover, the incorporation of 1-methyltryptophan (1-MT) to reverse the tumor immunosuppressive microenvironment can further enhance the effects of immunotherapy. In vitro studies revealed that the MN@PMCDH system can effectively induce ICD and inhibit tumor cell growth. Additionally, remarkable deep tumor cell inhibition effects are also achieved in 3D tumor models.

Development of Specially Designed Nanoparticle‐coated 3D‐printed Gelatin Methacryloyl Patches for Potential Tissue Engineering Applications

AbstractTympanic membrane (TM) perforation is a serious ear discomfort that can cause hearing loss and make the middle ear vulnerable to infections. In this study, a unique TM patch is designed to mimic the structure of the natural eardrum for tissue engineering of TM perforations. Gelatin methacryloyl (GelMA)‐based TM patches are equipped with microneedles (MNs) to better adhere to the perforation site and developed using the digital light processing (DLP) based 3D printing technique. To impart biofunctionality to the 3D‐printed patches, their surfaces are coated with gentamicin (GEN) loaded poly(vinyl alcohol) (PVA) nanoparticles (NPs) using the Electrohydrodynamic Atomization (EHDA) method. The physicochemical characteristics, drug release behaviour, antimicrobial properties and biocompatibility of GelMA, PVA NP‐coated GelMA, and GEN@PVA NP‐coated GelMA patches are investigated. Morphological analyses confirmed that 3D‐printed GelMA patches are fabricated in desired sizes and geometries and successfully coated with NPs. In vitro antibacterial tests revealed that GEN@PVA NP‐coated GelMA patches have antibacterial activities against Staphylococcus aureus and Escherichia coli. Moreover, in vitro cell culture studies indicated that all GelMA‐based patches have no cytotoxic effect on L929 mouse fibroblast cells. Considering all, these specially designed biofunctional 3D‐printed GelMA patches can be an effective therapeutic approach for repairing TM perforations.

Lidocaine-Loaded Iontophoresis-Driven Fiber-Based Microneedle Patch for Controllable and Long-Lasting Transdermal Local Analgesia

AbstractThe acute pain induced by clinical procedures, such as venipuncture, dental operations, and dermatological treatments, as well as postoperative pain, drives the advancement of anesthetic techniques aimed at alleviating discomfort. This situation underscores the ongoing significance of effective pain management strategies within the field of anesthesia. This paper presents an integrated iontophoresis (ITP)-driven fiber-based microneedle patch (IFMP) regulated by a smartphone for controllable, long-lasting lidocaine transdermal delivery. The IFMP integrates pure cotton fiber canvas-based dissolving microneedles (MNs) with ITP into a patch, with the MNs tips and gel layers significantly increasing the drug-loading capacity, achieving a one-step drug administration strategy of “dissolution, diffusion, and ITP.” Lidocaine is released via the microchannels of MNs by passive diffusion. Additionally, an electric current initiates active ITP for lidocaine delivery, creating synergy. User-requirement-based drug release by precisely modulating electrical signals in rat pain models is described herein. A smartphone application enables precise dosage control. It offers three different delivery modes: single-dose, pulse delivery, and sustained-release, ensuring rapid onset, and long-lasting pain relief. This versatility makes the system suitable for various pain conditions. The IFMP represents a promising system for patient-controlled local analgesia treatment, enabling active and long-term local self-controlled pain management in a safe and regulated manner. Graphical Abstract The iontophoresis-driven fiber-based microneedle patch combines fiber-based dissolving microneedles with iontophoresis, facilitating controlled lidocaine release through diffusion and electrical activation for enhanced effect. Precise modulation of electrical signals allows user-requirement-based drug release in rat pain models. A smart application supports precise dosing in single-dose, pulse, or sustained-release modes, ensuring efficient and prolonged pain management.

Biocompatible Core-Shell Microneedle Sensor Filled with Zwitterionic Polymer Hydrogel for Rapid Continuous Transdermal Monitoring.

Microneedle (MN)-based electrochemical biosensors hold promising potential for noninvasive continuous monitoring of interstitial fluid biomarkers. However, challenges, such as instability and biofouling, exist. This study proposes a design employing hollow MN to encapsulate a zwitterionic polymer hydrogel sensing layer with excellent biocompatibility and antifouling properties to address these issues. MN shell isolates the internal microporous sensing layer from subcutaneous friction, and the hydrogel filling leverages the MNs' three-dimensional structures, enabling high-dense loading of biorecognition elements. The hollow MNs are successfully fabricated from high-molecular-weight polylactic acid via drawing lithography, exhibiting sufficient strength for effective epidermis penetration. Additionally, a high-performance gold nanoconductive layer is successfully deposited inside the MN hollow channel, establishing a stable electrical connection between the polymer MN and the hydrogel sensing layer. To support the design, numerical simulations of position-based diffusive analyte solutes reveal fast-responsive electrochemical signals attributed to the high diffusion coefficient of the hydrogel and the concentrated structure of the hollow channel encapsulation. Experimental results and numerical simulations underscore the advantages of this design, showcasing rapid response, high sensitivity, long-term stability, and excellent antifouling properties. Fabricated MN sensors exhibited biosafety, feasibility, and effectiveness, with accurate and rapid in vivo glucose monitoring ability. This study emphasizes the significance of rational design, structural utilization, and micro-nanofabrication to unlock the untapped potential of MN biosensors.

Long‐Lasting Simultaneous Epidermal and Dermal Microneedle‐Enabled Drug Delivery

AbstractDifferent skin diseases, such as cancers, inflammatory conditions, and bacterial infections, manifest at distinct skin depths. Microneedle arrays, recognized for their painless and minimally invasive drug administration, can be customized to penetrate these layers simultaneously. Here, the design of the microneedles (MNs) in nonlinear ways with diverse needle heights on the array enabling concurrent drug delivery to various skin layers is engineered. Additionally, varying the base diameter of the needles in the array facilitates prolonged or intermittent drug release, depending on the biodegradation kinetics of these needles. MNs, microfabricated with a biocompatible and biodegradable polymer, are validated by skin administration. The nonlinear design of the MNs on the array introduces a novel perspective on addressing skin diseases at varying depths of the skin.

Enhanced long-acting simvastatin delivery via effervescent powder-carrying hollow microneedles and nanocrystal-loaded microneedles

Hyperlipidemia and its associated cardiovascular complications are the major causes of mortality and disability worldwide. Simvastatin (SIM) is one of the most commonly prescribed lipid-lowering drugs for the treatment of hyperlipidemia by competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. However, the extensive first-pass metabolism leading to low oral bioavailability and frequent daily doses may lead to poor patient compliance and adverse effects caused by plasma fluctuations. To overcome these challenges, this work purposed two microneedle (MN) delivery strategies for the potential enhancement of SIM delivery. Firstly, nanocrystal (NC) formulations of SIM were investigated, followed by incorporation into a trilayer dissolving microneedle (DMN) design. Furthermore, a novel effervescent powder-carrying MN (EMN) design was developed to enhance intradermal delivery by incorporating the effervescent agents into the drug powder. Both MN approaches exhibited significantly improved permeation and in-skin deposition ability in the Franz cell study, with the ex vivo delivery efficiency of 64.33 ± 6.17 % and 40.11 ± 4.53 % for EMNs and DMNs, respectively. Most importantly, in vivo studies using a female Sprague-Dawley rat model confirmed the successful delivery of SIM from NCs-loaded DMNs (Cmax = 287.39 ± 106.82 ng/mL) and EMNs (Cmax = 203.05 ± 17.07 ng/mL) and maintain therapeutically relevant plasma concentrations for 15 days following a single application. The enhanced bioavailabilities of DMNs and EMNs were 24.28 % and 103.82 %, respectively, which were both significantly higher than that of conventional oral administration.

Customized Corneal Cross-Linking with Microneedle-Mediated Riboflavin Delivery for Keratoconus Treatment.

In this study, a novel customized corneal cross-linking (CXL) treatment is explored that utilizes microneedles (MNs) for targeted riboflavin (RF) administration prior to the CXL procedure. Unlike the conventional "one-size-fits-all" approach, this protocol offers an option for more precise and efficacious treatment. To simulate a customized corneal crosslinking technique, four distinct microneedle (MN) molds designs, including circular, semi-circular, annular and butterfly shaped, are crafted for loading an optimized RF-hyaluronic acid solution and for the subsequent fabrication of MN arrays with varying morphologies. These MNs can gently puncture the corneal epithelium while preserving the integrity of the underlying stromal layer. Following the application of these microneedles, RF solution is replenished to enhance the RF content within the stroma through the punctures created by the MNs, resulting in exceptional customized corneal cross-linking effects that are comparable to the conventional epi-off CXL protocol. Additionally, it flattened the corneal curvature within the treated zone and facilitated rapid postoperative recovery of corneal tissue. These findings suggest that the integration of customized microneedle RF delivery with corneal crosslinking technology represents a potential novel treatment modality, holding promise for the tailored treatment of corneal pathologies, and offering a more precise and efficient alternative to traditional methods.