The precise delivery of agrochemicals with minimal environmental impact remains a major challenge in modern agriculture. Microarray Projection Patches (MAPs), inspired by their success in biomedical drug delivery, are emerging as a promising technology for the targeted administration of agri-ceuticals into specific plant tissues. This review provides a concise overview of the evolution of MAPs from transdermal therapeutic platforms to innovative agricultural tools. Various MAP formats, including solid, coated, hollow, hydrogel-forming, and dissolving systems, are discussed in the context of their adaptation for plant applications. Key focus areas include materials selection, fabrication techniques (e.g., micromilling, photolithography), and the physicochemical mechanisms governing delivery into vascular structures such as the xylem and phloem. Recent advances in microfabrication have enabled the development of customisable, cost-effective MAPs as resource-efficient agri-materials, with the potential to improve uptake efficiency, reduce agrochemical waste, and enhance plant health. The review also highlights how these systems contribute to precision agriculture by enabling localised, controlled dosing at the tissue level. Additionally, we examine the comparative environmental footprint of MAP-mediated delivery versus conventional spraying methods and present a preliminary economic perspective on scalability and implementation. By promoting efficient and localised agrochemical application, MAPs offer a transformative approach to boost crop resilience and productivity, with potential implications for sustainable food production and global food security.

BACKGROUND:A holy grail in human skin permeation is to be able to quantify how compounds and nanoparticles are absorbed, distributed, and exert their effects. Traditionally, the processes used have either been destructive or relied upon interpreting what has exited the skin after absorption, be it in in vivo plasma or urine or through ex vivo skin. Multiphoton imaging and other modalities have revolutionized this landscape. SUMMARY:In this review article, we summarize our experiences in using multiphoton tomography and fluorescence lifetime imaging in characterizing the skin absorption, distribution, and redox effects of nanoparticulate and related delivery systems. Much of our work has been focused on the absorption and safety of nano zinc oxide which started off being an apparently unsafe product to now being an FDA GRAS substance. We have found that the skin is a remarkable physical barrier to zinc oxide nanoparticles, as well as to other nanoparticles, under a wide range of formulation and method of use conditions. However, this work has only been made possible for us by the development of confocal, multiphoton, and fluorescence lifetime imaging technologies that can be safely used on human skin. KEY MESSAGES:(1) Multiphoton tomography and fluorescence lifetime imaging have allowed us, for the first time, to safely image the transport of compounds and structures in human skin in vivo and to assess the redox state of the skin after that application. (2) A key use of this instrumentation and related techniques has been to show that the sunscreen, nano zinc oxide, is generally safe when applied to human skin in various formulations and under a wide range of conditions. (3) We have also shown that characterizing nano-zinc oxide skin absorption by urinary zinc isotope excretion is misleading because, in our experience, zinc oxide nanoparticles are hydrolyzed to zinc ions which are readily absorbed into the viable epidermis and will be excreted in the urine. (4) We have also shown other nanoparticles, such as quantum dots, silver, and gold, are poorly absorbed into the skin. (5) However, our imaging does show that nanoparticles can accumulate and be difficult to wash out of skin furrows and hair follicles, creating a reservoir effect. (6) While this review has emphasized studies exploring the safety of topical ZnO-NP and related materials, we have also shown that multiphoton tomography and related techniques may be used in the quality, therapeutic, and theranostic assessment of topical products.

Topical semisolid formulations such as creams, ointments, and gels play a critical role in dermatological therapy by delivering drugs locally while minimizing systemic exposure. However, their complex microstructures and sensitivity to formulation and process variables pose significant risks to bioequivalence. Quality by Design (QbD), as outlined in ICH guidelines, provides a systematic framework for integrating product and process understanding into development through risk assessment, design of experiments (DoE), and control strategies. This systematic review aimed to critically evaluate the application of QbD principles in the development of topical semisolid formulations, focusing on the identification of Critical Quality Attributes (CQAs), the role of DoE in optimization, and the implementation of control strategies to ensure robust quality, scalability, and regulatory compliance. Following PRISMA 2020 guidelines, a systematic search was conducted in PubMed and Google Scholar (June–August 2025) using predefined Boolean queries. Studies were included if they reported on the application of QbD to topical semisolids with detailed descriptions of CQAs, DoE, and control strategies. A total of 85 articles meeting the eligibility criteria were extracted, evaluated for methodological quality of included articles, and synthesized narratively across thematic categories. Two independent reviewers performed data extraction, with discrepancies resolved through discussion, and findings were synthesized narratively. Out of 5,692 records identified, 85 studies were included from Google Scholar and PubMed: 46 employed factorial/DoE methodologies, 26 investigated bioequivalence and in vitro release/permeation, and 12 involved clinical or pharmacokinetic studies. Evidence demonstrated that QbD enhances formulation robustness and reproducibility by systematically identifying CQAs such as viscosity, particle size, stability, and drug release. DoE approaches, including factorial, central composite, and mixture designs, were shown to optimize formulation and process parameters efficiently while enabling scalability. Control strategies integrating risk management and analytical QbD provided enhanced product understanding but remain underutilized, with gaps in harmonized regulatory standards, microstructural equivalence (Q3), and predictive bioequivalence (Q4) assessments. Overall, the QbD principles significantly improve the development of topical semisolid formulations by ensuring systematic control of formulation and process variability, thereby enhancing product quality, consistency, and regulatory alignment. Persistent challenges remain in achieving microstructural and performance equivalence, scalability, and harmonized global regulatory acceptance. Future directions should emphasize the integration of advanced tools such as process analytical technology (PAT) and patient-centric quality attributes to strengthen clinical relevance and enable reliable therapeutic equivalence.

Vitamin D3-loaded lipid nanoparticles (Vit D3-LNP), integrated into an azulene cream, were developed to enhance the topical delivery and stability of Vitamin D3. The LNP was formulated using a lipid mixture and hot homogenization-ultrasonication, with comprehensive characterization revealing a particle size of 153.9 nm, a high zeta potential (-54.3 mV), and a PDI of 0.216, which TEM confirmed. Encapsulation efficiency was high (96.98

Nanomaterials have improved skin drug delivery by facilitating the creation of smart, stimuli-responsive nanocarriers with increased therapeutic effectiveness. Internal or external stimuli can activate these systems, enabling controlled drug release. Internal stimuli-responsive nanocarriers use pathological alterations in diseased skin, like variations in pH, oxidative stress, enzymatic activity, or glucose concentrations, to trigger drug release exactly at the target sites. Conversely, external stimuli-responsive systems depend on physical stimuli such as temperature, light, electric fields, ultrasound, or magnetic fields, facilitating controlled release at specific times and sites. Collectively, these methods increase localized therapeutic precision, reduce systemic adverse effects, and improve therapeutic outcomes in dermatology. This review explores stimuli-responsive nanocarriers, focusing specifically on their use in skin drug delivery, highlighting their therapeutic advantages and limitations, and summarizing several studies using single- and dual-stimuli responsive systems for skin delivery in the treatment of dermatological disorders. The review also provides a critical overview of the analytical methods used to evaluate these nanocarriers, including in vitro, ex vivo, and in vivo models; physiochemical characterization; and advanced microscopic imaging, it also outlines their advantages and limitations. Finally, the paper concludes by delineating the present status of the field and identifying key challenges for future research to enhance the therapeutic use of stimuli-responsive nanocarriers for skin drug delivery.

The efficacy, safety, and stability of transdermal and topical products (TTPs) are of prime importance to consumer acceptance and compliance. To control the consistent textural quality or overall physical properties of TTPs, texture analysis tests are widely applied to assess potential changes in features and internal structure of products throughout different stages of formulation development, manufacturing, and distribution. As one of the essential texture test types, Texture Profile Analysis (TPA) provides critical insights into the structure, spreadability, adhesion, sensory attributes, and consistency of semisolid formulations via key measured parameters such as hardness, adhesiveness, cohesiveness, elasticity, and compressibility. Recent advancements in automation and multimodal analysis have enhanced the precision and applicability of TPA. For transdermal delivery systems (TDS), adhesion, a critical quality attribute (CQA), which is influenced by viscoelasticity, surface energy, and wetting characteristics of pressure-sensitive adhesives (PSAs), can be assessed through in vitro methods like peel, tack, and shear tests using texture analyzer systems. While in vivo assessments remain subjective, in vitro tests conducted by texture analyzers enable standardized and reproducible evaluations, ensuring reliable comparisons across products and bridging gaps between laboratory and real-world performance. Microneedles (µNDs), another innovative transdermal platform, require robust mechanical strength to ensure effective skin penetration and drug release. Texture analysis plays a pivotal role in characterizing critical properties such as hardness, flexibility, and puncture strength, simulating forces encountered during skin penetration. This analysis offers valuable insights into µND performance, ensuring safety, functionality, and patient compliance. This review systematically curates existing knowledge on using texture analyzers to measure textural properties of pharmaceutical TTPs while highlighting emerging trends and providing methodologies for testing and parameter derivation. By emphasizing the importance of CQA characterization for novel drug delivery platforms, this work underscores the role of texture analysis in optimizing designs of TTPs including µND, focusing on fracture, insertion, and bending forces, ultimately contributing to the development of safer and more efficient transdermal systems.

Human skin provides an effective route of delivery for selected drugs. Topical penetration of molecules is largely attributed to passive diffusion, and the degree of penetration can be represented by in silico, in vitro, and ex vivo models. Percutaneous absorption of pharmaceutical ingredients is a delicate balance between the molecular properties of the drug, the skin properties of the patients, and the formulation properties. Understanding this interplay can aid in the development of products applied to the skin. The kinetics of percutaneous absorption and an understanding of the rate-limiting steps involved can facilitate the optimization of these systems and enhance the degree to which skin drug delivery can be achieved. Solute–vehicle, vehicle–skin, and solute–skin interactions contribute notably to product release as well as the rate of absorption and diffusion across skin layers. These interactions alter the degree of permeation by interfering with the skin barrier or solubility and thermodynamic activity of the active pharmaceutical ingredient. This article aims to provide a concise understanding of some of the factors involved in the skin absorption of topical products, i.e., the pharmacokinetics of percutaneous absorption as well as the solute–vehicle–skin interactions that determine the rate of release of products and the degree of drug diffusion across the skin.

Microarray patches (MAPs) are an emerging platform for transdermal drug delivery, addressing key challenges such as cold-chain dependence, healthcare access, and needle phobia. Solid MAPs, in particular, show promise due to their ease of use, mechanical robustness, and compatibility with thermostable formulations. This review critically examines coating methods and formulation strategies for solid MAPs, focusing on how they influence drug loading, dissolution, adhesion, and skin penetration. Drawing parallels with coating technologies from adjacent sectors (e.g., paints, batteries, tablet coatings), we identify transferable practices to enhance uniformity, reproducibility, and process control, essential for regulatory compliance. Scalability and manufacturing consistency are discussed in the context of quality-by-design (QbD) and good manufacturing practice (GMP) frameworks. Finally, we highlight future directions including 3D bioprinting for spatially precise coatings and AIassisted optimisation for predictive quality control, offering a translational pathway toward regulatory-ready MAP products.

Microneedles (μNDs) have emerged as promising minimally invasive drug delivery systems, offering advantages such as painless administration and enhanced drug permeability. Among various μNDs technologies, responsive μNDs have attracted growing attention for their ability to react to physiological or external stimuli, allowing precise and on-demand drug release for both localized and systemic therapies. This review explores the recent advancements in responsive μNDs triggered by various endogenous and exogenous signals that correspond to specific targeted diseases and/or sites of application. Additionally, the review highlights the challenges associated with scalability, biocompatibility, and regulatory approval of responsive μNDs and provides insights into future directions for clinical translation. By consolidating the latest developments, this review aims to support the design and optimization of next-generation smart drug delivery systems.

Typical clinical “in use” conditions for topical semisolids involve their application as a thin film, often with rubbing that can induce metamorphic stress. Yet, product quality and performance tests often characterize the manufactured product, and may not consider product metamorphosis (e.g., shear history) during dispensing and administration. This work sought to elucidate how such metamorphosis might alter product quality and performance. We evaluated the effect of “in use” stresses on drug crystal metamorphosis in acyclovir creams by optical microscopy. The amount of dissolved acyclovir was determined by separation of the cream base by ultra-centrifugation and quantification by HPLC. IVPT was undertaken on Zovirax® US and Aciclostad® comparing static and “in use” application of a finite dose. A mechanistic IVPT study was also conducted to understand the influence of acyclovir particle size reduction by “in use” rubbing on skin permeation. Reduction in acyclovir particle size was seen after “in use” rubbing with increases in the amount of dissolved acyclovir after rubbing (30 and 60 s) compared to static for both products. “In use” application resulted in significantly higher acyclovir permeation from both products. The mechanistic IVPT study proved the role of product metamorphosis. These results highlight the role of metamorphosis of product microstructure and its influence on performance.

PURPOSE:To develop a toolkit of test methods for characterizing potentially critical quality attributes (CQAs) of topical semisolid products and to evaluate how CQAs influence the rate and extent of active ingredient bioavailability (BA) by monitoring cutaneous pharmacokinetics (PK) using an In Vitro Permeation Test (IVPT). METHODS:Product attributes representing the physicochemical and structural (Q3) arrangement of matter, such as attributes of particles and globules, were assessed for a set of test acyclovir creams (Aciclostad® and Acyclovir 1A Pharma) and compared to a set of reference acyclovir creams (Zovirax® US, Zovirax® UK and Zovirax® Australia). IVPT studies were performed with all these creams using heat-separated human epidermis, evaluated with both, static Franz-type diffusion cells and a flow through diffusion cell system. RESULTS:A toolkit developed to characterize quality and performance attributes of these acyclovir topical cream products identified certain differences in the Q3 attributes and the cutaneous PK of acyclovir between the test and reference sets of products. The cutaneous BA of acyclovir from the set of reference creams was substantially higher than from the set of test creams. CONCLUSIONS:This research elucidates how differences in the composition or manufacturing of product formulations can alter Q3 attributes that modulate myriad aspects of topical product performance. The results demonstrate the importance of understanding the Q3 attributes of topical semisolid drug products, and of developing appropriate product characterization tests. The toolkit developed here can be utilized to guide topical product development, and to mitigate the risk of differences in product performance, thereby supporting a demonstration of bioequivalence (BE) for prospective topical generic products and reducing the reliance on comparative clinical endpoint BE studies.

The limited regeneration capacity of articular cartilage (AC) is attributed to the hypocellular nature of the cartilage tissue and the absence of vascularization. On the other hand, degenerative joint disease, such as osteoarthritis (OA), is characterized by irreversible AC degeneration and synovial inflammation, leading to pain, discomfort, and restricted joint mobility. The existing treatment options for OA mostly provide symptomatic relief. Therefore, it is vital to explore several approaches, such as cartilage regeneration and maintenance of cartilage homeostasis. During OA pathogenesis, significant changes are observed in the gene expression and phenotype of articular chondrocytes. Some of these changes include chondrocyte hypertrophy, expansion of the endoplasmic reticulum-Golgi apparatus, secretion of stiffer collagen matrix like collagen type X, increased matrix metalloproteinases (MMPs)-3, −9, and −13 and alkaline phosphatase levels; and decrease of SOX9, proteoglycans, and collagen type II. The changes seen in chondrocytes are similar to those observed during endochondral ossification. Therefore, modulating key molecular players like bone morphogenetic protein (BMP) and wingless-related integration site (Wnt) Wnt/β-catenin signaling pathways using their antagonists and agonists, respectively, has been shown to effectively inhibit OA progression. These advancements have been further explored in the context of cartilage tissue engineering to design artificial AC-like scaffolds that mimic former physicochemical properties and can be applied as a substitute for damaged cartilage. However, modern science still has unaccomplished objectives that can completely translate our understanding of AC maintenance into the complete restoration of healthy joints. Therefore, in this review, we looked at how understanding the cellular and molecular behavior of articular chondrocytes may be used in confluence with other existing non-surgical therapeutic approaches, such as nanomedicines, regenerative biology, and tissue engineering combined, to find a cure for OA.

3D printing of microneedles (μNDs) for transdermal therapy has the potential to enable patient personalization based on the target disease, site of application, and dosage requirements. To convert this concept to reality, it is necessary that the 3D printing technology can deliver high resolution, an affordable cost, and large print volumes. With the introduction of benchtop 4K and 8K 3D printers, it is now possible to manufacture medical devices like μNDs at sufficient resolution and low cost. In this research, we systematically optimized the 3D printing design parameters such as resin viscosity, print angle, layer height, and curing time to generate customizable μNDs. We have also developed an innovative 3D coating microtank device to optimize the coating method. We have applied this to the development of novel μNDs to deliver an established NAD+ precursor molecule, nicotinamide mononucleotide (NMN). A methacrylate-based polymer photoresin (eSun resin) was diluted with methanol to adjust the resin viscosity. The 3D print layer height of 25 μm yielded a smooth surface, thus reducing edge-ridge mismatches. Printing μNDs at 90° to the print platform yielded 84.28 ± 2.158% (n = 5) of the input height thus increasing the tip sharpness (48.52 ± 10.43 μm, n = 5). The formulation containing fluorescein (model molecule), sucrose (viscosity modifier), and Tween-20 (surface tension modifier) was coated on the μNDs using the custom designed microtank setup, and the amount deposited was determined fluorescently. The dye-coated μND arrays inserted into human skin (in vitro) showed a fluorescence signal at a depth of 150 μm (n = 3) into the skin. After optimization of the 3D printing parameters and coating protocol using fluorescein, NMN was coated onto the μNDs, and its diffusion was assessed in full-thickness human skin in vitro using a Franz diffusion setup. Approximately 189 ± 34.5 μg (5× dipped coated μNDs) of NMN permeated through the skin and 41.2 ± 7.53 μg was left in the skin after 24 h. Multiphoton microscopy imaging of NMN-coated μND treated mouse ear skin ex vivo demonstrated significantly (p < 0.05) increased free-unbound NADPH and reduced fluorescence lifetime of NADPH, both of which are indicative of cellular metabolic rates. Our study demonstrates that low-cost benchtop 3D printers can be used to print high-fidelity μNDs with the ability to rapidly coat and release NMN which consequently caused changes in intracellular NAD+ levels.

Transdermal drug delivery systems (TDDS), commonly refered to as "patches", present a nonintrusive technique to provide medication without the need for invasive procedures. These products adhere to the skin and gradually release a specific dosage of medicine at a defined rate into the bloodstream. Compared with other methods of drug delivery, TDDS offer benefits such as reduced invasiveness, convenience for patients, and avoidance of the metabolic processes that occur when drugs are orally consumed. Throughout time, TDDS have been used to provide medications for various medical conditions (such as nicotine, fentanyl, nitroglycerin, and clonidine), and their potential for delivering biologics is currently being explored. This review investigates the current literature on the drug delivery efficacy of medical TDDS through the transdermal route. Additionally, the review addresses potential risks and failure modes associated with TDDS design and development as well as strategies for mitigating such risks. A thorough understanding of failure modes provides a blueprint to mitigate failure and produce high-quality efficacious therapeutics.