Composing drug delivery with light distribution improvement: the use of dissolving microneedles in skin cancer with photodynamic therapy

Advances in microtechnology and biomedical imaging technology has led to extensive research for self-administered and minimally-invasive microneedle (MN) devices to overcome drawbacks of existing transdermal drug delivery modalities. Microneedle mediated drug delivery is an amalgam of the conventional transdermal patch and the hypodermic needle injection. This novel drug delivery method increases the permeability of skin by piercing the stratum corneum barrier to create transient micropores through which drug molecules can passively diffuse. Furthermore, MN treatment is relatively painless and well tolerated by most patients, making it a very realistic technique for clinical implementation. In the first generation of microneedles (MNs), materials such as silicon, stainless steel, titanium and ceramics have been widely used in MN fabrication. However, several drawbacks such as poor biocompatibility, breakage in skin and need for expensive microelectronics technology for fabrication exists. In the contrary, polymeric MNs have attracted extensive attention due to their excellent biocompatibility and biodegradability. Most importantly, different types of polymers display distinct degradation profiles and swelling properties which can be potentially leveraged upon to fabricate polymeric MNs with different mechanical properties and performance. Polymeric MNs have shown to be ideal candidates for both transdermal drug delivery (TDD) and skin interstitial fluid (ISF) extraction. Water-soluble and biodegradable polymers have been used in the fabrication of MNs to achieve different drug release profiles such as bolus or sustained drug release. Swellable MNs fabricated using hydrogel-forming polymers have been investigated for its potential in ISF extraction for clinical biomarker diagnosis. Hence, with the promising outlook of polymer based MN technology this thesis work aims to broaden the scope of existing polymeric MN design and drive the development of novel polymer based MN arrays for clinical applications. In this thesis, polymers are used in the development of novel MN arrays for transdermal drug delivery and ISF extraction. Specifically, a conductive MN for in situ combination with iontophoresis (ITP) is fabricated for directional and fast transdermal drug delivery in a one-step approach. Most of the current polymeric MN platforms rely on passive diffusion driven concentration gradients to facilitate drug movement from the epidermis into the deeper layers of the skin; delaying the onset of drug effect. The use of conductive and biocompatible polymers; poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS) polymer and hyaluronic acid (HA) in the design of the MN array results in aqueous pathways of low electrical resistance to be created in skin resulting in faster flow rate of drug molecules. This approach offers a new strategy for non-invasive and controlled delivery of drug molecules into deeper tissues underlying the epidermis to result in quicker systemic effect. Next, a proof-of-concept for a polymer MN-based minimally invasive glucose sensor that can extract ISF and provide colorimetric detection of glucose in a single step is described. Prepared using a poly(styrene)-block-poly(acrylic acid) (PS-b-PAA) swellable tip and non-swellable polystyrene core, the MN tips are encapsulated with an assay solution that qualitatively produces a color change from colourless to purple in the presence of glucose. This process is achieved within minutes as it leverages on the polymer properties of the MN tips; it is made up of poly(acrylic acid) polymer which contains ionizable carboxylic acid groups that allow sufficient extraction of ISF. The color change observed on the MN tips is easily correlated to the glucose concentration and quantified using an ultraviolet–visible spectrophotometer (UV-VIS). Thus, this work strongly illustrates the potential of using the swellable polymeric MN array for quick determination of glycaemic conditions for patients requiring frequent monitoring. Aside from the development of novel polymeric MN arrays, imaging tools for characterization of MN behaviours such as dissolution and swellability was studied in detail. Current techniques of characterization include mostly in vitro and histological studies. The cumbersome and destructive nature of these studies results in poor accuracy and do not permit real time visualization of MN behaviours in skin. For the first time, optical resolution-photoacoustic microscopy (OR-PAM) is shown to be capable of achieving real time and in vivo monitoring of the spatial distribution of gold nanoparticles (AuNPs) in mice skin when delivered using poly(methyl methacrylate) (PMMA) MNs. Although optical coherence tomography (OCT) imaging has been widely used in MN imaging, poor backscattering ability of polymers results in low resolution images that require post image processing. Taking this into account, a methodology is developed to use iron oxide (Fe3O4) nanoparticles as exogenous contrast agents to enhance image contrast in OCT imaging and shown to enable high resolution and real-time visualization of changes in the profile of poly(styrene)-block-poly(acrylic acid) (PS-b-PAA) MNs when inserted into different types of tissues i.e mice skin and human skin. In the future, the imaging techniques can be applied for optimization of MN design parameters and real time visualization of drug release and ISF extraction to optimize device design.

Drug delivery systems (DDS) have been the focus of intense research for several decades. Many approaches and strategies have been employed over the years, further expanding this field. For example, the advancements towards targeted drug delivery (TDD) enabled the use of DDS for diagnostic purposes. In addition, DDS research has provided the foundation for tissue engineering and theranostic systems (therapeutic systems with diagnostic properties). Drug delivery research has yielded many successes over the years with a significant amount of therapeutic and diagnostic products out in the market. Nevertheless, many challenges still remain. Herein, in this special edition, we asked various experts to review recent advancements in their field of expertise and report their latest findings. The special edition is well balanced and is comprised of 60% reviews and 40% research articles. One may find up-to-date reviews on advancements made in biomaterials, noninvasive drug delivery, drug conjugations, biosensors, diagnostics, implantable and ingestible devices, nanomaterials, cancer treatment, and endosome-derived vesicles. Additionally, research articles are provided, describing advanced new designs of microneedles (MNs), approaches to enhance tissue engineering capabilities, biomaterials, and DDS. The global market of protein- and nucleotide- based pharmaceutics accounted for $643 million in 2016, and is anticipated to reach over $8000 million by 2028. However, the use of these therapeutics is hindered by issues of immunogenicity, high molecular weight, fast renal clearance, and enzymatic degradation. For these reasons, to date, monoclonal antibodies (mAbs) are administered only via injection. Considering that, Angsantikul et al. propose the use of ionic liquid and eutectic solvent for the oral delivery of mAbs (article number 2002912). Their system reduced the mucosal viscosity and enhanced the paracellular transport of TNFα antibody in vitro. Additionally, Rondon and colleagues review the latest advancements in polymer chemistry and protein engineering in order to overcome part of these limitations (article number 2101633). Another approach to overcome these limitations is by using antibody-drug conjugates (ADCs). Accordingly, Firer and Luboshits review the recent developments employed in ADCs for the treatment of hematological malignancies (article number 2100032). They focus on the important link between the biology of the ADC and clinical efficacy, highlighting newer developments that strengthen this link to provide long-term clinical benefits. One of the most important purposes of drug delivery is achieving TDD. Dacoba and colleagues provide an overview on the concepts of passive and active targeting while exploring current venues for nanotechnology to solve the problems associated with drug delivery (article number 2009860). TDD is especially important for cancer therapy since killing cancerous cells is quite facile, but killing only cancerous cells is extremely challenging. Fu et al. review the latest strategies employed to overcome the barriers of chimeric antigen receptor T cells therapy in solid tumors (article number 2009489). Brain therapy is another challenging route for drug delivery requiring specific TDD system. To this end, Buaron et al. have developed a novel pectic galactan-based gene therapy approach that targets reactive gliosis via specific carbohydrate interaction between galactan and Gal-3 (article number 2100643). Their biocompatible pectin galatcan-plasmid DNA complexes were selectively transfected to glial cells in cortical lesions. Moreover, Avital et al. report their interesting application for nanosized DDS—foliar delivery of siRNA for treating grapevine leafroll associated virus-3 (GLRaV-3) infection that causes major economic losses (article number 2101003). By exploiting a lipid-modified polyethylenimine carrier, they show that a single dose can knock down GLRaV-3 titer, and multiple doses keeps the viral titer at baseline, which triggers the recovery of the vine and berries. Another important aspect of drug delivery research is the development of noninvasive drug administration routes. Rahamim and Azagury review the origins of biomimetic, bioinspired, and bioengineered noninvasive DDS and achievements made in the last decade (article number 2102033). Additionally, Zhang et al. review advances in DDS that access the ear through the tympanic membrane (article number 2008701). Transdermal drug delivery is one of the most used noninvasive drug delivery routes. An exciting approach for transdermal drug delivery is microneedles (MNs). Puigmal and colleagues propose applying MNs array to treat severe burns that simultaneously sample immune cells in the interstitial fluid to diagnose the response (article number 2100128). Their MNs design enables the local delivery of pharmaceutics—the chemokine CCL22 and the cytokine IL-2—thus increasing local immuno-suppression. They found that the immune cell population in the allograft and MN were similar so they can be harvested from the MN for downstream analysis. Moreover, Li et al. have also proposed an improved MNs design where they use a biphasic dissolvable MN patch with water-insoluble backing in order to tackle insufficient drug delivery with MN (article number 2103359). Their new design enables a drug delivery efficiency of >90% into the skin within 5 min. Biomaterials are the building blocks of drug delivery, diagnostics, and tissue engineering research. Therefore, there is an ever-growing need for novel biomaterials with new functionalities and improved properties. To this end, Arun et al. present an exclusive coverage of biocompatible injectable pasty or liquid polymers without the use of any solvent for drug delivery and regenerative medicine applications (article number 2010284). Moreover, Khait et al. review novel biomaterial-based strategies used to modulate the immune response post ischemic stroke while providing their perspective on the potential clinical translation of these therapies (article number 2010674). Additionally, Redenski et al. developed a new composite tissue made of soft-tissue matrices and decellularized bone for bone defect repair (article number 2008687). The use of their novel tissue composite supported a long-term bone defect repair, as well as muscle defect bridging. These aforementioned applications and additional applications use cell-based therapeutics. The major obstacles of cell-based therapeutics are their low yields (i.e., difficult to scale-up), insufficient drug loading, and inconsistencies. For this reason, Guo et al. have developed a scaled-up and facile magnetic-based extrusion method for preparing endosome-derived vesicles (article number 2008326). An additional application of diagnostics and therapeutics is implantable and ingestible devices. In this special edition, Yang and colleagues provide an up-to-date review on the state-of-the-art of powering technologies for implantable and ingestible electronics—one of the greatest challenges for ingestible devices (article number 2009289). Welch et al. have focused their review on the complex hierarchical nano-structures and nano-materials used in biosensors and diagnostic technologies (article number 2104126). Additionally, they discuss their unique advantages and clinical applications while proposing future directions. In this special edition Nakonechny and Nisnevitch provide an up-to-date review focused on ultrasound applications used to combat infections caused by microorganisms, and to promote the local release of antimicrobial drugs from liposomes and medical implants (article number 2011042). Precise and well-controlled scaffolds are highly desired for tissue engineering and regenerative medicine purposes. For example, Dubay et al. review the recent achievements of single-cell microgels and their potential alternatives, which are used when single cell resolution is needed, for example—modular bio-inks and 3D cellular microenvironments (article number 2009946). Another challenge for implantable devices is a foreign body response (FBR). Kutner et al. review the recent advantageous technologies used to overcome the FBR effect via surface modifications and localized DDS (article number 2010929). One such surface modification is reported by Israeli et al. who developed a general and versatile technology to engineer light-responsive protein-based biomaterials (article number 2011276). These novel biomaterials—consist of azobenzene containing elastin-like polypeptides—are capable of forming self-assembled nanostructures and exhibit a reversible, light-mediated phase transition, with up to a 12 °C difference in the transition temperature. We are certain that this assemblage of reviews and research papers on the use of DDS for therapeutic and diagnostic purposes is of high interest for anyone working in this field. It provides up-to-date reviews on state-of-the-art topics and research papers with promising results to further propel drug delivery research. Understanding what has been done in the past, while learning of new approaches and techniques, is crucial for any scholar who wishes to advance their personal research. Joseph Kost D.Sc. is a University Distinguished Professor, he holds The Abraham and Bessie Zacks Chair in Biomedical Engineering and was the Dean of the Faculty of Engineering Sciences at Ben-Gurion University of the Negev (BGU). He is a member of AIMBE, NAE, CRS, and the Israel Academy of Sciences and Humanities. His research interests are in the fields of biomedical engineering, biomaterials science, controlled drug delivery, gene therapy, and ultrasound. Edith Mathiowitz is a full Professor of Medical Science and Engineering at Brown University, Department of Department of Pathology and Laboratory Medicine. She Is an AIMBE, CRS, and NAI fellow member. She founded and directed the ABC/Biotechnology Graduate Program at Brown. Her interdisciplinary research is focused on developing smart oral bioadhesive delivery systems and novel insights in polymer morphology. Her laboratory serves as an incubator for several start-up companies such as Spherics, Perosphere, and Therapyx. Aharon (Roni) Azagury is an Assistant Professor in the Department of Chemical and Biotechnology Engineering in Ariel University. He received his PhD in chemical engineering from BGU. He is a member of the CRS, ICRS, and NAI societies. His current research focuses on developing novel noninvasive biomimetic and bioinspired drug delivery systems.

Melanoma is one of the most significant and dangerous superficial skin tumors with a high fatality rate, thanks to its high invasion rate, drug resistance and frequent metastasis properties. Unfortunately, researchers for decades have demonstrated that the outcome of using conventional therapies like chemotherapy and immunotherapy with normal drug delivery routes, such as an oral route to treat melanoma was not satisfactory. The severe adverse effects, slow drug delivery efficiency and low drug accumulation at targeted malignancy sites all lead to poor anti-cancer efficacy and terrible treatment experience. As a novel transdermal drug delivery system, microneedles (MNs) have emerged as an effective solution to help improve the low cure rate of melanoma. The excellent characteristics of MNs make it easy to penetrate the stratum corneum (SC) and then locally deliver the drug towards the lesion without drug leakage to mitigate the occurrence of side effects and increase the drug accumulation. Therefore, loading chemotherapeutic drugs or immunotherapy drugs in MNs can address the problems mentioned above, and MNs play a crucial role in improving the curative effect of conventional treatment methods. Notably, novel tumor therapies like photothermal therapy (PTT), photodynamic therapy (PDT) and chemodynamic therapy (CDT) have shown good application prospects in the treatment of melanoma, and MNs provide a valid platform for the combination of conventional therapies and novel therapies by encompassing different therapeutic materials in the matrix of MNs. The synergistic effect of multiple therapies can enhance the therapeutic efficacy compared to single therapies, showing great potential in melanoma treatment. Dissolving MNs have been the most commonly used microneedles in the treatment of melanoma in recent years, mainly because of their simple fabrication procedure and enough drug loading. So, considering the increasing use of dissolving MNs, this review collects research studies published in the last four years (2020-2024) that have rarely been included in other reviews to update the progress of applications of dissolving MNs in anti-melanoma treatment, especially in synergistic therapies. This review also presents current design and fabrication methods of dissolving MNs; the limitations of microneedle technology in the treatment of melanoma are comprehensively discussed. This review can provide valuable guidance for their future development.

ROS-responsive tegafur-pheophorbide a conjugate-loaded microneedles for deep drug delivery and chemo-photodynamic therapy of superficial tumors

Port-wine stains are a kind of dermatological disease of congenital capillary malformation. Based on the biological characteristics of port-wine stains and the advantages of microneedle transdermal administration, we intend to construct a nanodrug co-loaded with rapamycin (RPM), an anti-angiogenesis drug, and photochlor (HPPH), a photosensitizer, and integrate the nanodrug with dissolvable microneedles (MN) to achieve anti-angiogenesis and photodynamic combination therapy for port-wine stains. First, RPM and HPPH co-loaded nanoparticles (RPM-HPPH NP) were prepared by the emulsification solvent-volatilization method, and its ability to generate reactive oxygen species (ROS) was investigated under 660 nm laser irradiation. Mouse hemangioendothelioma endothelial cells (EOMA) were used as the subjects of the study. The cellular uptake behaviors were examined by fluorescence microscopy and flow cytometry. The cytotoxicity effects of RPM-HPPH NP with or without 660 nm laser irradiation on EOMA cells were examined by MTT assays (with free RPM serving as the control). Then, hyaluronic acid (HA) dissolvable microneedles loaded with RPM-HPPH NP (RPM-HPPH NP@HA MN) were obtained by compounding the nanodrug with HA dissolvable microneedle system through the molding method. The morphological characteristics and mechanical properties of RPM-HPPH NP@HA MN were investigated by scanning electron microscope and electronic universal testing machine. The penetration ability of RPM-HPPH NP@HA MN on the skin of nude mice was evaluated by trypan blue staining and H&E staining experiment. The RPM-HPPH NP prepared in the study had a particle size of 150 nm and generated large amounts of ROS under laser irradiation. At the cellular level, RPM-HPPH NP was taken up by EOMA cells in a time-dependent manner. The cytotoxicity of RPM-HPPH NP was higher than that of free RPM with or without laser irradiation. Under laser irradiation, RPM-HPPH NP exhibited stronger cytotoxic effects and the difference was statistically significant (P<0.05). The height of the needle tip of RPM-HPPH NP@HA MN was 600 µm and the mechanical property of a single needle was 0.75048 N. Trypan blue staining and HE staining showed that pressing on the microneedles could produce pores on the skin surface and penetration of the stratum corneum. RPM-HPPH NP@HA MN can deliver RPM-HPPH NP percutaneously to the lesion tissue and realize the synergistic treatment of port-wine stains with anti-angiogenic therapy and photodynamic therapy, providing a new strategy for the construction of nanodrug-loaded microneedle delivery system and the clinical treatment of port-wine stains.

Optical coherence tomography is a valuable tool in the study of the effects of microneedle geometry on skin penetration characteristics and in-skin dissolution

Microneedles (MNs), with its numerous advantages over the traditional transdermal drug delivery approaches, represent a cutting-edge and idea-inspiring technology in the field of biomedical engineering. Over the past decades, great achievements have been made on the optimization of the MNs’ fabrication techniques, expending the various features of the MNs and generation of the MNs with multiple functions. MN is an innovative transdermal drug delivery strategy that overcome the limitations from invasive or inefficient conventional approaches. It create micropores on the skin in a non-invasive and painless manner to aid the efficient delivery of the therapeutics across the skin. Additionally, biomarker sampling and detection by accessing the skin interstitial fluid (ISF) is also achievable by swelling MNs with incorporated sensors. In this thesis, the application of MNs for Chinese herb herbal medicine extract delivery is proposed and demonstrated. Specifically, Chinese herb herbal medicine extract could be premixed with dissolvable polymers and made into MNs through micro-molding. The fabricated drug loaded MNs possess good mechanical strength for human skin penetration. The delivering of the Chinese herb herbal medicine extract via MN to hypertrophic scar fibroblast showed unaffected therapeutic efficiency and localized treatment effect. Additionally, a versatile drug coating methodology is proposed and discussed. In such methodology, drug solution is spray coated onto the frozen MNs and solidified upon contact with the cold MNs’ surface. Subsequent lyophilization could fix the solid drug on the surface of the MNs without affecting the properties of the MN core. As a proof of concept, insulin was coated onto swellable MNs for simultaneously diabetic treatment and glucose sampling. In a more advanced design, the MNs are made from bubble-generating materials which could help to deliver therapeutics deeper and more efficiently into the skin. Incorporating with ultrasound technology, the bubble-generating MNs show advances in delivering both small and big molecules that are frozen coated on the surface of MNs into the mice skin. Moreover, it is demonstrated that the delivering of photosensitizer into the tumor bearing-mouse through the skin by bubble-generating MNs and ultrasound synergistically enhance the penetration and subsequent therapeutic efficiency. Aside from maintaining the MN core properties, the efficiency of therapeutics, when coated onto the MN via the above-mentioned technology could be retained due to the fast fabrication process and low temperature condition that prevent the drug from being degraded or oxidized. Moreover, the therapeutics are in solid state after lyophilization, which further guaranteed their stability. Such property makes the frozen coating strategy a versatile strategy for incorporating various of therapeutics with various types of MNs depending on the application. In conclusion, a facile, versatile drug coating strategy to make functional MNs is introduced in this thesis. Such strategy has the potential for wide range of biomedical applications including controlled drug delivery, multiple drug delivery, biosensing and monitoring.

Increasing needs of painless, self-administrable and readily available home healthcare applications have driven the advancement of transdermal drug delivery system (TDD), aiming to replace current therapeutic and health monitoring schemes that require physical attendance and sophisticated process. Microneedle (MN) technology as third generation TDD system has been exploited in many bio-functional applications such as transdermal drug delivery and biosensing due to its greater skin disruption in minimal invasive manner as compared to previous generations that have molecular size limit and with needs of external power supply. MN device is designed in patch form with a collection of microscale-needles attachment as this allows simultaneous breaching of skin barrier in wider area for drug delivery and biosensing purposes. An ideal MN system should allow consistent and uniform penetration over target skin region especially when human skin is curved at most body areas while viscoelastic in nature. MN patch that failed to conform effectively onto target site could lead to under-desired therapeutic outcome and poor signal recording. Moreover, current MN systems are designed for finger-pressing administration therefore often in miniatured size, limiting the adaptability for most protein and peptide delivery dosage. To date, these issues have not been addressed effectively, hindering global commercialization of MN technology. Inspired by brilliant evolution of ancient fish armour system which has shown co-existence of rigidity and flexibility, we have found that they possess great similarities with the ideal MN system from micro- to macroscale aspects. Therefore, in this thesis, I mainly focus on improvement on penetration efficiency of individual MN tips through 1) mechanical reinforcement at micro-scale (Chapter 3) and 2) adaptive tip configuration of flexible MN substrates depending on surface geometry at macro-scale (Chapter 4). Particularly, in this thesis, rapid dissolving biopolymer low molecular weight hyaluronic acid (HA) was used for dissolving MN (DMN) systems due to its high dissolution rates and abundant availability in human body naturally with reasonable drug loading capabilities. However, the degradable polymer-based MN systems often experience significantly reduced transdermal penetration, especially when polymers have intrinsically weak mechanical strength as compared to other non-biodegradable materials like metal. Therefore, first, an in situ precipitation of silica network in HA matrix was proposed to improve intrinsic mechanical strength and improved physiological stability during administration of MN patches. Silica is a widely used bioactive additive with rapid physiological decay rate. Optimization of silica content in HA matrix was first studied through structural characterization to ensure minimal morphological defects in fabricated MN. Moreover, chemical analyses were used to characterize micro-structure and distribution of silica network in HA matrix. The HA-Si MNs fabricated demonstrated improved penetration efficiency and slight effect on dissolution behavior to pure HA MNs. Moreover, no cytotoxicity was found in the optimized HA-Si sample, indicating that the proposed hybridization of bioactive additive was encouraging. Moreover, MN system comprises of tip region and base substrate where flexible and continuous base substrates have been proposed in previous studies to address skin conformity issue of traditional MN systems with rigid base substrate. However, existing flexible MN system only offers bidirectional flexibility, therefore not yet able to address conformity issues at movable joint regions like elbow. Furthermore, upscaling of MN patch dimension is expected in future market in order to resolve issue of limited drug loading and skin coverage for biosensing of wider body areas. Therefore, in this project, a kirigami-based auxetic fractal cut pattern was introduced into the flexible base substrate design, resembling that of wavy patterned fish tissue. Numerical and experimental evaluations have demonstrated significant improvement in terms of contact stability, complex skin geometry coverage, penetration depth and insulin delivery. These tests were designed and compared among traditional rigid, flexible continuous and proposed flexible fractal cut patch. Moreover, novel two-step fabrication of proposed fractal cut MN patch using DLP printing was accomplished with high precision, lower production time/cost and promising functionality by exploiting working principle of DLP printing. Finally, customizability of FF MN patch in terms of patch size, subunit shape design and heterogeneity of MN material-drug formulation were displayed and proven to be a promising platform for diverse biomedical applications. The two approaches presented in this thesis have shown to be the key aspects to consider when designing an ideal MN patch with excellent penetration efficiency, high drug loading and skin coverage, in micro- and macroscopic perspectives. With further development of such flexible MN system, MN technology will soon to be adopted in more therapeutic and biosensing applications, finally bringing revolution to the biomedical fields as a pain-free and multipurpose healthcare tool.

Microneedle (MN) devices, which consist of needles of micron size arranged on a small patch, have been considered minimally invasive, painless, and self-administered drug delivery systems where drugs are delivered through the transdermal route. In this study, a drug delivery system integrating an MN patch with a pumpless microfluidic (MF) device was proposed. Depending on the material, MNs exhibit various functions; herein, polymer MNs with a dissolution function were developed. Ideal MNs should exhibit high mechanical strength and stable geometries to permit skin penetration without breaking. Hence, polyvinylpyrrolidone (PVP)-M MNs with improved strength were developed. A porous coating method was employed to improve the drug delivery of the existing coated MNs. By coating a porous layer on the MN surface, its surface area increased, rendering advantages of increased drug storage for enhanced delivery. A pumpless MF device was developed to improve low drug storage due to the MN structural limitations. An external power source was not required to transmit pressure, and it was transmitted using the capillary force of filter paper. The drug stored in the microchannel was released to the outlet because of the applied pressure. It is a powerful device and exhibits a very simple structure that is easy to operate, flexible, and miniature. The results revealed that the proposed system has increased drug storage; as a result, drug delivery via this system was dramatically enhanced in comparison with that using the existing coated MNs. Moreover, dual drug delivery was also possible if the type of drug applied to the MNs and the device was different. The developed device is expected to contribute significantly to the future development in the biomedical field.

Dissolving polymeric microneedle arrays for electrically assisted transdermal drug delivery

Enzyme-mediated fabrication of nanocomposite hydrogel microneedles for tunable mechanical strength and controllable transdermal efficiency

Recent advances in microneedle designs and their applications in drug and cosmeceutical delivery

Microneedles (MNs) have been developed as minimally invasive tools for diagnostic and therapeutic applications. However, in recent years, there has been an increasing interest in developing smart multifunctional MN devices to provide automated and closed-loop systems for body fluid extraction, biosensing, and drug delivery in a stimuli-responsive manner. Although this technology is still in its infancy and far from being translated into the clinic, preclinical trials have shown some promise for the broad applications of multifunctional MN devices. The main challenge facing the fabrication of smart MN patches is the integration of multiple modules, such as drug carriers, highly sensitive biosensors, and data analyzers in one miniaturized MN device. Researchers have shown the feasibility of creating smart MNs by integrating stimuli-responsive biomaterials and advanced microscale technologies, such as microsensors and microfluidic systems, to precisely control the transportation of biofluids and drugs throughout the system. These multifunctional MN devices can be envisioned in two distinct strategies. The first type includes individual drug delivery and biosensing MN units with a microfluidic system and a digital analyzer responsible for fluid transportation and communication between these two modules. The second type relies on smart biomaterials that can function as drug deliverers and biosensors by releasing drugs in a stimuli-responsive manner. These smart biomaterials can undergo structural changes when exposed to external stimuli, such as pH and ionic changes, mimicking the biological systems. Studies have demonstrated a high potential of hydrogel-based MN devices for a wide variety of biomedical applications, such as drug and cell delivery, as well as interstitial fluid extraction. Biodegradable hydrogels have also been advantageous for fabricating multifunctional MNs due to their high loading capacity and biocompatibility with the drug of choice. Here, we first review a set of MN devices that can be employed either for biosensing or delivery of multiple target molecules and compare them to the conventional and more simple systems, which are mainly designed for single-molecule sensing or delivery. Subsequently, we expand our insight into advanced MN systems with multiple competencies, such as body fluid extraction, biosensing, and drug delivery at the point of care. The improvement of biomaterials knowledge and biofabrication techniques will allow us to efficiently tune the next generation of smart MNs and provide a realistic platform for more effective personalized therapeutics.

Microneedles (MNs) have drawn rising attention owing to their merits of convenience, noninvasiveness, flexible applicability, painless microchannels with boosted metabolism, and precisely tailored multifunction control. MNs can be modified to serve as novel transdermal drug delivery, which conventionally confront with the penetration barrier caused by skin stratum corneum. The micrometer-sized needles create channels through stratum corneum, enabling efficient drug delivery to the dermis for gratifying efficacy. Then, incorporating photosensitizer or photothermal agents into MNs can conduct photodynamic or photothermal therapy, respectively. Besides, health monitoring and medical detection by MN sensors can extract information from skin interstitial fluid and other biochemical/electronic signals. Here, this review discloses a novel monitoring, diagnostic, and therapeutic pattern by MNs, with elaborate discussion about the classified formation of MNs together with various applications and inherent mechanism. Hereby, multifunction development and outlook from biomedical/nanotechnology/photoelectric/devices/informatics to multidisciplinary applications are provided. Programmable intelligent MNs enable logic encoding of diverse monitoring and treatment pathways to extract signals, optimize the therapy efficacy, real-time monitoring, remote control, and drug screening, and take instant treatment.

Transdermal Drug Delivery Systems (TDDS) represent a significant advancement in therapeutic administration by allowing drugs to bypass the gastrointestinal system and first-pass hepatic metabolism, enhancing patient compliance, and enabling sustained drug release. However, traditional TDDS face limitations, including resistance from the skin's natural barrier and limited efficacy in delivering large or hydrophilic molecules. Microneedle (MN) technology offers a breakthrough solution, using minimally invasive micron-sized needles to bypass the stratum corneum, facilitating efficient drug delivery without significant pain or discomfort. This review explores the evolution and recent advancements in microneedle technology, highlighting its role in overcoming the limitations of conventional TDDS. Microneedles have been shown to enhance drug bioavailability, reduce side effects, and expand the range of deliverable therapeutics, including vaccines, insulin, and genetic materials. The development of bioinspired 4D microneedles further extends their application to diagnostics and cosmetic treatments, positioning MNs as a versatile tool in modern medicine. Key sections of the review focus on the types of microneedles—solid, coated, dissolving, hollow, and hydrogel-forming—and their respective fabrication methods, materials, and drug delivery mechanisms. The review also discusses the challenges related to scaling up production, ensuring consistent quality, and regulatory hurdles in achieving clinical approval. Future directions include the integration of microneedles with nanotechnology, combination therapies, and sustainable design, particularly in developing regions where biodegradable materials may address environmental and disposal concerns. The potential for microneedle technology to revolutionize transdermal drug delivery, diagnostics, and therapeutic monitoring is significant, with ongoing research paving the way for multifunctional applications that can reshape patient care and treatment modalities.