This study aimed to prepare and assess active microneedle (MN) patches based on a novel biomaterial and their effective coupled (physical and electrical) transdermal delivery of a model drug (Linezoid). Modified MN patches (e.g. fabricated from Linezoid, boronated chitosan, polyvinyl alcohol and D-sorbitol) were engineered using a vacuum micromoulding method. Physicochemical, FTIR (Fourier transform infrared), in-silico, structural and thermal analysis of prepared formulations were conducted to ascertain MN quality, composition and integrity. In-vitro mechanical tests, membrane toxicity, drug release, antibiofilm, ex-vivo mucoadhesion, insertion and in-vivo antibiofilm studies were performed to further validate viability of the coupled system. Optimized MN patch formulation (CSHP3 - comprising of 3 % w/v boronated chitosan, 3.5 % w/v PVA and 10 % w/w D-sorbitol) exhibited sharp-tipped, equi-distant and uniform-surfaced micron-scaled projections with conforming physicochemical features. FTIR analysis confirmed modification (i.e., boronation) of chitosan and compatibility as well as interaction between CSHP3 constituents. In-silico analysis indicated non-covalent interactions between all formulation constituents. Moreover, boronated chitosan-mucin glycoprotein complex showed a stronger bonding (∼1.86 times higher CScore) as compared to linezolid-mucin counterpart. Thermal analysis indicated amorphous nature of CSHP3. A ∼ 1.42 times higher tensile strength was displayed by CSHP3 as compared to control (i.e., pure chitosan, polyvinyl alcohol and D-sorbitol-based MN patch). Membrane toxicity study indicated non-toxic and physiological compatible nature of CSHP3. Within 90 min, 91.99 ± 2.3 % linezolid was released from CSHP3. During release study on agarose gel, CSHP3-iontophoresis treatment resulted in a ∼ 1.78 and ∼ 1.20 times higher methylene blue-covered area and optical density, respectively, within 60 min as compared to CSHP3 treatment alone. Staphylococcus aureus biofilms treated with CSHP3 exhibited 65 ± 4.2 % reduction in their mass. CSHP3 MN patches remained adhered to the rabbit oral mucosa for 6 ± 0.15 h. Mucosa treated with CSHP3 and CSHP3-iontophoresis combination showed a generation of pathways in the epithelium layers without any damage to the underlying lamina propria. Eradication of Staphylococcus aureus from oral mucosal wounds and complete tissue regeneration was recorded following 7-day treatment using CSHP3-iontophoresis coupled approach.

The eye, a complex organ isolated from the systemic circulation, presents significant drug delivery challenges owing to its protective mechanisms, such as the blood-retinal barrier and corneal impermeability. Conventional drug administration methods often fail to sustain therapeutic levels and may compromise patient safety and compliance. Polysaccharide-based microneedles (PSMNs) have emerged as a transformative solution for ophthalmic drug delivery. However, a comprehensive review of PSMNs in ophthalmology has not been published to date. In this review, we critically examine the synergy between polysaccharide chemistry and microneedle technology for enhancing ocular drug delivery. We provide a thorough analysis of PSMNs, summarizing the design principles, fabrication processes, and challenges addressed during fabrication, including improving patient comfort and compliance. We also describe recent advances and the performance of various PSMNs in both research and clinical scenarios. Finally, we review the current regulatory frameworks and market barriers that are relevant to the clinical and commercial advancement of PSMNs and provide a final perspective on this research area.

Microneedle array patches (MAPs) are extensively studied for transdermal drug delivery. Additive manufacturing enables precise control over MAP customization and rapid fabrication. However, the scope of 3D-printable, bioresorbable materials is limited. Dexamethasone (DXM) is widely used to manage inflammation and pain, but its application is limited by systemic side effects. Thus, it is crucial to achieve high local drug concentrations while maintaining low serum levels. Here, poly(propylene fumarate-co-propylene succinate) oligomers are fabricated into DXM-loaded, bioresorbable MAPs via continuous liquid interface production 3D printing. Thiol-ene click chemistry yields MAPs with tailorable mechanical and degradation properties. DXM-loaded MAPs exhibit controlled elution of drug in vitro. Transdermal application of DXM-loaded MAPs in a murine tibial fracture model leads to substantial relief of postoperative pain. Pharmacokinetic analysis shows that MAP administration is able to control pain at a significantly lower dose than intravenous administration. This work expands the material properties of 3D-printed poly(propylene fumarate-co-propylene succinate) copolyesters and their use in drug delivery applications.

Keratins, the most abundant proteins in human hair, are excellent hair nutrients for growth. However, the complex components of keratin extract hinder their mechanism investigation, and the pure recombinant keratin with poor solubility limited its hair growth promotion efficiency. Here, the water-soluble recombinant keratins (RKs) of K31 and K81 are rationally designed through QTY Code methodology, which are then used to fabricate the microneedles to study the effect of keratin on hair growth. Interestingly, it is discovered that more than 40% of the hair follicles (HFs) in the RK81QTY group entered the anagen on day 12 and the diameter of new hair is 15.10 ± 2.45 µm, which significantly promoted growth and development of HFs and improved new hair quality compared to RK31QTY. Water-soluble RKs significantly enhanced HFs activity and de novo regeneration of robust hairs compared to extract and minoxidil by upregulating the PI3K/AKT/Nf-κB signaling axis. These findings highlight the potential of designing solubilized recombinant keratins with distinct properties to improve therapeutical effects and open new avenues to designing keratin-based proteins.

The global demand for an enhanced quality of life and extended lifespan has driven significant advancements in tissue engineering and regenerative medicine. These fields utilize a range of interdisciplinary theories and techniques to repair structurally impaired or damaged tissues and organs, as well as restore their normal functions. Nevertheless, the clinical efficacy of medications, materials, and potent cells used at the laboratory level is always constrained by technological limitations. A novel platform known as adaptable microneedles has been developed to address the abovementioned issues. These microneedles offer a solution for the localized distribution of various cargos while minimizing invasiveness. Microneedles provide favorable patient compliance in clinical settings due to their effective administration and ability to provide a painless and convenient process. In this review article, we summarized the most recent development of microneedles, and we started by classifying various microneedle systems, advantages, and fundamental properties. Subsequently, it provides a comprehensive overview of different types of microneedles, the material used to fabricate microneedles, the fundamental properties of ideal microneedles, and their applications in tissue engineering and regenerative medicine, primarily focusing on preserving and restoring impaired tissues and organs. The limitations and perspectives have been discussed by concluding their future therapeutic applications in tissue engineering and regenerative medicines.

Chitosan is an extensively used polymer for drug delivery applications in particulate and non-particulate carriers. Chitosan-based particulate, nano-, and microparticle, carriers have been the most extensively studied for the delivery of therapeutics and vaccines. However, chitosan has also been used in vaccine applications for its adjuvant properties in various hydrogels or as a carrier coating material. The focus of this review will be on the usage of chitosan as a vaccine adjuvant based on its intrinsic immunogenicity; the various forms of chitosan-based non-particulate delivery systems such as thermosensitive hydrogels, microneedles, and conjugates; and the advantages of its role as a coating material for vaccine carriers.

Transdermal microneedles have demonstrated promising potential as an alternative to typical drug administration routes for the treatment of various diseases. As microneedles offer lower administration burden with enhanced patient adherence and reduced ecological footprint, there is a need for further exploitation of microneedle devices. One of the main objectives of this work was to initially develop an innovative biobased photocurable resin with high biobased carbon content comprising isobornyl acrylate (IBA) and pentaerythritol tetraacrylate blends (50:50 wt/wt). The optimization of the printing and curing process resulted in μNe3dle arrays with durable mechanical properties and piercing capacity. Another objective of the work was to employ the 3D printed hollow μNe3dles for the treatment of osteoporosis in vivo. The 3D printed μNe3dle arrays were used to administer denosumab (Dmab), a monoclonal antibody, to osteoporotic mice, and the serum concentrations of critical bone minerals were monitored for six months to assess recovery. It was found that the Dmab administered by the 3D printed μNe3dles showed fast in vitro rates and induced an enhanced therapeutic effect in restoring bone-related minerals compared to subcutaneous injections. The findings of this study introduce a novel green approach with a low ecological footprint for 3D printing of biobased μNe3dles, which can be tailored to improve clinical outcomes and patient compliance for chronic diseases.

Diabetic wounds are characterized by the disruption and cessation of essential healing stages, which include hemostasis, inflammation, proliferation, and remodeling. However, traditional treatments for diabetic wounds concentrate on individual stages of the healing process. Herein, this study utilizes mask-mediated sequential polymerization and varied cross-linking techniques to develop dual-modular microneedles (MNs) with fast- and slow-module, exhibiting varying degradation rates tailored for the full spectrum of diabetic wound healing. First, MNs incorporating calcium ions and dopamine synergistically promote rapid hemostasis. Second, fast-module physically cross-linked MNs rapidly D-mannose/dopamine-enhanced tripolyphosphate-quaternized chitosan (mDTC) nanoparticles (NPs) loaded with microRNA-147 (miRNA-147) to manage inflammation and oxidative stress in diabetic wounds. Additionally, dopamine in these NPs enhances their internalization and safeguards miRNA-147 from oxidative stress and RNase degradation. Finally, slow-module chemically cross-linked MNs facilitate the continuous release of deferoxamine (DFO) and dopamine, accelerating angiogenesis and tissue regeneration during the proliferation and remodeling stages. Manganese/dopamine-enhanced calcium peroxide NPs within the MNs initiate a blast-like generation of oxygen bubbles, not only enhancing the delivery of miRNA-mDTC NPs and DFO but also alleviating tissue hypoxia. Consequently, dual-modular MNs are instrumental in promoting rapid and complete healing of diabetic wounds through all stages of healing.

One of the advancements of the transdermal drug delivery system (TDDS) is the development of microneedles (MNs). These micron-sized needles are used for delivering various types of drugs to address the disadvantage of other transdermal techniques as well as oral drug delivery systems. MNs have high patient acceptance due to self-administration with minimally invasive and pain compared to the parenteral drug delivery. Over the years, various methods have been adopted to evolve the MNs and make them more cost-effective, accurate, and suitable for multiple applications. One such method is the 3D printing of MNs. The development of MN platforms using 3D printing has been made possible by improved features like precision, printing resolution, and the feasibility of using low-cost raw materials. In this review, we have tried to explain various types of MNs, fabrication methods, materials used in the formulation of MNs, and the recent applications that utilize 3D-printed MNs.

5-aminolevulinic acid photodynamic therapy (ALA-PDT) is an emerging therapeutic strategy for skin cancer due to its noninvasiveness and high spatiotemporal selectivity. However, poor skin penetration, poor intratumoral delivery, the instability of aqueous ALA, and the tumor\'s inherent hypoxia microenvironment are major hurdles hindering the efficacy of ALA-PDT. Herein, we aim to address these challenges by using microneedles (MNs) to assist in delivering nanoparticles based on natural polymeric tea polyphenols (TP NPs) to self-assemble and load ALA (ALA@TP NPs). The TP NPs specifically increase cellular uptake of ALA by A375 and A431 cells and reduce mitochondrial membrane potential. Subsequently, the photosensitizer protoporphyrin IX derived from ALA accumulates in the tumor cells in a dose-dependent manner with TP NPs, generating reactive oxygen species to promote apoptosis and necrosis of A375 and A431 cells. Interestingly, TP NPs can ameliorate the tumor\'s inherent hypoxia microenvironment and rapid oxygen consumption during PDT by inhibiting hypoxia inducible factor-1α, thereby boosting reactive oxygen species (ROS) generation and enhancing ALA-PDT efficacy through a positive feedback loop. After ALA@TP NPs are loaded into MNs to fabricate ALA@TP NPs@MNs, the MNs enhance skin penetration and storage stability of ALA. Importantly, they exhibit remarkable antitumor efficacy in A375-induced melanoma and A431-induced squamous cell carcinoma with a reduced dose of ALA and reverse hypoxia in vivo. This study provides a facile and novel strategy that integrates MNs and green NPs of TP for addressing the bottlenecks of ALA-PDT and enhancing the ALA-PDT efficacy against skin cancers for future clinical translation.