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Snake fang–inspired stamping patch for transdermal delivery of liquid formulations
Abstract
A flexible microneedle patch that can transdermally deliver liquid-phase therapeutics would enable direct use of existing, approved drugs and vaccines, which are mostly in liquid form, without the need for additional drug solidification, efficacy verification, and subsequent approval. Specialized dissolving or coated microneedle patches that deliver reformulated, solidified therapeutics have made considerable advances; however, microneedles that can deliver liquid drugs and vaccines still remain elusive because of technical limitations. Here, we present a snake fang–inspired microneedle patch that can administer existing liquid formulations to patients in an ultrafast manner (<15 s). Rear-fanged snakes have an intriguing molar with a groove on the surface, which enables rapid and efficient infusion of venom or saliva into prey. Liquid delivery is based on surface tension and capillary action. The microneedle patch uses multiple open groove architectures that emulate the grooved fangs of rear-fanged snakes: Similar to snake fangs, the microneedles can rapidly and efficiently deliver diverse liquid-phase drugs and vaccines in seconds under capillary action with only gentle thumb pressure, without requiring a complex pumping system. Hydrodynamic simulations show that the snake fang–inspired open groove architectures enable rapid capillary force–driven delivery of liquid formulations with varied surface tensions and viscosities. We demonstrate that administration of ovalbumin and influenza virus with the snake fang–inspired microneedle patch induces robust antibody production and protective immune response in guinea pigs and mice.
... These BMNS have diverse applications. [7][8][9] Over the ages, nature has created optimized solutions for many problems through the process of evolution. 10 The fascinating properties observed in various natural species offer excellent opportunities to develop BMNs with functionalities that approximate their natural counterparts. ...
... These biomimetic simulations are achieved via manipulation of morphology, structure, and chemistry. 7,8 Representative examples are used in the present review to highlight how properties originating from living organisms (e.g., teeth of limpets, 11 stingers of honeybees, 12 mosquito/endoparasite Pomphorhynchus laevis's proboscis, 13,14 clawed toes of eagles, 8 snake fangs 7 ) may be exploited with mimicking tactics to design MNs with specific functionalities to overcome challenges that are faced by conventional MNs. Bioinspired designs as well as their structures and medical significance are highlighted. ...
... 8 BMNs that contain multiple open grooves on their surfaces are inspired by the mono-grooved fangs of rear-fanged snakes that generate a rapid capillary force-driven delivery system. 7 Likewise, BMN patches with backward-facing curved barbs for enhanced tissue adhesion are enthused by the stinger of honeybees. 12 Painless BMNs designed for blood collection without bleeding are inspired by the proboscis of mosquitoes. ...
Nature contains abundant systems that can significantly alter their structures and properties to adapt to the surrounding environment. Through natural selection and unceasing evolution, hierarchical architectures and sophisticated strategies have been created by nature to achieve optimally adapted materials for biomedical applications. The development of microneedles has advanced to the next generation of bioinspired microneedles, with the goal of improving functions such as amelioration of mechanical properties and tissue adhesion. The biomimetic designs and structures of microneedles are highlighted in the present review. This is followed by an in-depth discussion of the fabrication approaches from molding techniques to 3D and 4D printing. The medical applications of bioinspired microneedles, including drug delivery, regenerative medicine, 3 biopsy sampling and biosensing, are also discussed. Lastly, future opportunities and challenges with respect to clinical translation are also deliberated.
... In addition to commonly investigated MAP types (solid without biocargo, coated, hollow, and dissolving/biodegradable), hydrogel-forming, porous, and hybrid MAPs have been explored (Fig. 5) [216][217][218][219][220][221][222][223][224][225][226][227]. Besides the prevailing pyramid and conical geometries, other microarray shapes, including square and circular obelisk, negative bevel obelisk, undercut, and snake fang, have been fabricated using different materials [218,[228][229][230][231][232]. Ultimately, each MAP design possesses different manufacturability, mechanical strength, skin insertion reliability, painlessness, vaccine dosage capacity, delivery mechanisms, and delivery efficiencies. ...
... Notably, hollow MAPs can deliver liquid cargo solutions without the need for dry vaccine or drug formulations, yet the formulation aspect must still be investigated to achieve effective skin concentrations with the relatively lower volume of solutions that can be delivered to the cutaneous microenvironment. Several different materials, such as metals, polymers, silicon, and glass, have been used to fabricate hollow MAPs with diverse designs [222,232,237,238]. Although hollow MAPs have been used to deliver vaccine components to skin microenvironments, the design, fabrication, and application aspects of hollow MAPs still require extra attention due to their relatively complex shapes, the potential of leakage of vaccine components, the risk of mechanical failure during skin insertion because of their weaker structure, the complicated manufacturing steps required to create hollow MAPs, and the possibility of clogging of microarray openings. ...
... Hollow MAPs have been used for skin-targeted delivery of different types of vaccines, such as peptide, DNA, live attenuated virus, and inactivated virus vaccines, and have been evaluated for several viral infectious diseases, including influenza, mumps, varicella, polio, and HPV, and tested in mouse, rat, and guinea pig models [232,[306][307][308][309][310]. Collectively, these pre-clinical studies suggest that skin vaccination using hollow MAPs is capable of eliciting robust antigen-specific adaptive immune responses. ...
The COVID-19 pandemic is a serious threat to global health and the global economy. The ongoing race to develop a safe and efficacious vaccine to prevent infection by SARS-CoV-2, the causative agent for COVID-19, highlights the importance of vaccination to combat infectious pathogens. The highly accessible cutaneous microenvironment is an ideal target for vaccination since the skin harbors a high density of antigen-presenting cells and immune accessory cells with broad innate immune functions. Microarray patches (MAPs) are an attractive intracutaneous biocargo delivery system that enables safe, reproducible, and controlled administration of vaccine components (antigens, with or without adjuvants) to defined skin microenvironments. This review describes the structure of the SARS-CoV-2 virus and relevant antigenic targets for vaccination, summarizes key concepts of skin immunobiology in the context of prophylactic immunization, and presents an overview of MAP-mediated cutaneous vaccine delivery. Concluding remarks on MAP-based skin immunization are provided to contribute to the rational development of safe and effective MAP-delivered vaccines against emerging infectious diseases, including COVID-19.
... Although no MN-based product is currently on the market, several clinical trials involving MN-based drug delivery systems have already been completed [29]. Furthermore, MN-based drug delivery systems have been proven feasible among current delivery techniques for satisfying the needs of sensitive groups undergoing biological therapy, such as the elderly and pediatric patients [30,31]. MNs are fabricated from various materials, including metals, ceramics, glass, silicon, and polymers [32][33][34]. ...
... Reproduced with permission from [100], e) SEM image of snake fang-inspired polymeric MNs. Reproduced with permission from [30], f) SEM image of a human growth hormone-loaded polymeric MN patch. reproduced with permission from [80], g) SEM image of Insulin-loaded polymeric MNs. ...
The applications of microneedles (MNs) are becoming popular with the promise of efficient and advanced drug delivery. MNs were developed to overcome the limitations of conventional drug delivery systems and bypass biological barriers. While most MN applications in the past decades focused on transdermal biomedical applications, recent advancements in engineering and technology have enabled MNs to be used in a wide range of non-transdermal applications. Compared with the other types of MNs, polymer-based MN composites have attracted more attention for non-transdermal drug delivery because they exhibit excellent biological properties, including being nontoxic, biocompatible, and biodegradable, making them ideal biomaterials for drug delivery applications that overcome the metabolic constraints of drug delivery for macromolecular payloads across a variety of tissues and organs other than the skin. This review provides an overview of recent advancements in polymer-based MN composite carriers that aim to overcome the delivery challenges for non-transdermal drug delivery, specifically in the vascular, ocular, gastrointestinal tract, buccal transmucosal, periodontal, cardiovascular, and vaginal tissue. Furthermore, this review will discuss future perspectives and challenges for polymeric MN composites in non-transdermal drug delivery that must be resolved.
... d grooved microneedles (left: top view, right: lateral view. scale bar: 100 μm) [205]. e magnetorheological lithographed microneedles [209]. ...
... In recent years, emerging porous microneedles were proved to be another solution for transdermal controlled release, with relatively facile fabrication, as shown in Fig. 9b [201][202][203]. Specific physical forms were developed for unique applications as well, such as integrating soluble microneedle tips and bubble structure into a separatable microneedles (Fig. 9c) [204] and grooved microneedles inspired by snake fangs (Fig. 9d) [205] for efficient transdermal and liquidformulations delivery. ...
Developing techniques to effectively and real-time monitor and regulate the interior environment of biological objects is significantly important for many biomedical engineering and scientific applications, including drug delivery, electrophysiological recording and regulation of intracellular activities. Semi-implantable bioelectronics is currently a hot spot in biomedical engineering research area, because it not only meets the increasing technical demands for precise detection or regulation of biological activities, but also provides a desirable platform for externally incorporating complex functionalities and electronic integration. Although there is less definition and summary to distinguish it from the well-reviewed non-invasive bioelectronics and fully implantable bioelectronics, semi-implantable bioelectronics have emerged as highly unique technology to boost the development of biochips and smart wearable device. Here, we reviewed the recent progress in this field and raised the concept of “Semi-implantable bioelectronics”, summarizing the principle and strategies of semi-implantable device for cell applications and in vivo applications, discussing the typical methodologies to access to intracellular environment or in vivo environment, biosafety aspects and typical applications. This review is meaningful for understanding in-depth the design principles, materials fabrication techniques, device integration processes, cell/tissue penetration methodologies, biosafety aspects, and applications strategies that are essential to the development of future minimally invasive bioelectronics.
... The outstanding features in natural species offer promising characteristics to design bioinspired or biomimetic microneedles. For instance, the structure of the teeth of limpets [110], eagle claws [111], grooved fangs of snakes [17], and ice [112] are a great source to design microneedles with greater properties. ...
... A possible solution can be represented by nanoneedles which have the same working principle as MNs, but a smaller size, around nanometer-size (sub-100-nm diameter) that help to pierce the cell membrane and transfer biological cargos directly into the cell interior, reducing skin irritation [113]. Inspired by the grooved fangs of rear-fanged snakes with a rapid capillary forcedriven delivery system, a bio-inspired patch including open grooves on the surface of needles was developed [17]. Such a bio-inspired platform can deliver various therapeutics in liquid form, applying mild thumb pressure without needing a complex pumping system. ...
The study of novel drug delivery systems represents one of the frontiers of the biomedical
research area. Multi-disciplinary scientific approaches combining traditional or engineered technologies are used to provide major advances in improving drug bioavailability, rate of release, cell/tissue
specificity and therapeutic index. Biodegradable and bio-absorbable polymers are usually the building blocks of these systems, and their copolymers are employed to create delivery components.
For example, poly (lactic acid) or poly (glycolic acid) are often used as bricks for the production
drug-based delivery systems as polymeric microparticles (MPs) or micron-scale needles. To avoid
time-consuming empirical approaches for the optimization of these formulations, in silico-supported
models have been developed. These methods can predict and tune the release of different drugs
starting from designed combinations. Starting from these considerations, this review has the aim of
investigating recent approaches to the production of polymeric carriers and the combination of in
silico and experimental methods as promising platforms in the biomedical field
... In this paper, we review the design of materials and structure of microelectronic-based microneedles, and discuss their advances in biological diagnosis. [22] . B：(i) 螳螂爬在一片叶子上的数字图像. ...
... C：蜜蜂启发的微针示意图 [24] ) Fig. 1 Some bionic artificial MNs. (A) Photograph of the snake fang-inspired MN array [22] . (B) (i) Digital image of a mantis climbing on a leaf. ...
Microneedles have been developed rapidly in the field of transdermal administration in the past few decades. In recent years, the development of microelectronics technology has expanded the applications of microneedles by combining with microelectronic systems, especially in biological diagnosis and treatment. Different types of microneedles have been designed to extract blood and tissue fluids for detection, or as electrodes to directly detect blood sugar, melanoma and pH in real-time in vivo, both show good prospects for real-time detection applications. In this paper, we review the design of materials and structure of microelectronic-based microneedles, and discuss their advances in biological diagnosis.
... As shown in Figure 2c, Jeong and coworkers were inspired by snake teeth; they fabricated a microneedle patch for transdermal delivery of liquid drugs, comprising two main parts: a PDMS chamber and an MNA. 34 The MNA is formed over a thin PEG-DA film containing microholes using a replica mounding process. The cured PEG-DA film is peeled from the PDMS column array to obtain a PEG-DA film with holes. ...
... The venom delivery mechanism is categorised based on the snake's family. Duvernoy's gland is commonly found in rear-fanged snakes such as the Colubridae, while the venom gland is mainly found in the front-fanged snakes family which are the Elapidae and Viperidae (Bae et al. 2019;Rex 2017). The envenomation creates local and systemic manifestations. ...
The World Health Organization (WHO) has categorised snake-related injuries as a neglected tropical disease which can cause permanent disability, or worse, can lead to death if not treated timely and appropriately. Medical students are exposed to snakebite patients predominantly in their clinical years and depending on the location of their medical postings. This study aimed to determine the perceived awareness, knowledge and confidence level of medical students in providing information and managing snake-related injuries. A quantitative cross-sectional
study was designed and the data were collected using a Likert scale questionnaire. The perceived awareness, knowledge and confidence level between pre-clinical and clinical students were tested by an independent sample t-test. A p-value of ≤ .05 was interpreted as statistically significant. Analysis revealed a statistically significant difference of perceived knowledge (p= .009) and perception of confidence level (p= .025) between clinical and pre-clinical students. However, no difference was found in terms of perceived awareness (p> .05). Clinical medical
students have a better perception of knowledge and confidence level in providing information and managing snake-related injuries than pre-clinical students. An in-depth study on this topic should be conducted to include all medical students in Malaysia. Steps should be taken to improve the knowledge and confidence level
of medical students in managing snake-related injuries in Malaysia.
... MN systems have emerged as an appealing transdermal drug delivery technique for the painless administration of macro and micro-active molecules [15][16][17][18][19]. MN-based systems for controlled medication delivery can significantly increase drug delivery efficiency and control. They can provide accurate drug localization with lower dose frequency, and the simplicity of self-administration and less invasive administration enhances patient satisfaction [20,21]. This innovation might benefit everyone, from little toddlers to elderly adults with difficulty swallowing and suffering from nausea and vomiting [22]. ...
Microneedles (MNs) have attracted the interest of researchers. Polymeric MNs offer tremendous promise as drug delivery vehicles for bio-applications because of their high loading capacity, strong patient adherence, excellent biodegradability and biocompatibility, low toxicity, and extremely cheap cost. Incorporating enhanced-property nanomaterials into polymeric MNs matrix increases their features such as better mechanical strength, sustained drug delivery, lower toxicity, and higher therapeutic effects, therefore considerably increasing their biomedical application. This paper discusses polymeric MN fabrication techniques and the present status of polymeric MNs as a delivery method for enhanced drug delivery in cancer therapeutic applications. Furthermore, the opportunities and challenges of polymeric MNs for improved drug delivery in cancer therapy are highlighted.
... The mechanism of MN-based vaccines to enhance skin immunity through structural design may originate from unique morphological designs such as mushroom-like morphology can make MNs better embedded in the skin, which is not easy to fall off, thereby continuously releasing antigens to induce immune response. In another study, snake-fang-inspired MNs allowed liquid formulations with different surface tensions to be quickly injected into the skin [119]. Due to the multiple open groove architectures simulating the grooved fangs of snakes, the MNs did not need a pumping system and only needed to be gently pressed to deliver the vaccine through the skin (Fig. 4B). ...
As microneedle-based vaccines possess advantages of high compliance, moderate invasiveness and convenience that are highly relevant to their unique design, they are becoming an indispensable piece of the puzzle in the field of medical applications. By selecting appropriate materials and methods convenient for precise control over the structure and morphology, MN-based vaccines with strong mechanical properties and variable forms can be fabricated, and specific biomolecules can be used for monitoring or augmenting human immunity. The structural design strategies of MN-based vaccines are highlighted in this review, following a brief discussion of the mechanism of skin immunity and the classification and fabrication approaches of MNs. The biomedical applications of MN-based vaccines, including sampling from interstitial fluid and therapy in infectious diseases and cancers, have also been demonstrated. Finally, the central challenges in this field and opportunities for future developments are also deliberated.
... The mixture of polyethylene glycol diacrylate (PEG-DA) and photoinitiator can be considered a negative photoresist. PEG-DA can be cured under UV light irradiation [25,26]. PEG-DA is used due to its satisfactory biocompatibility and sufficient mechanical properties to penetrate the skin after curing [27][28][29]. ...
Microneedle (MN) is a novel technique of the biomedical engineering field because of its ability to evaluate bioinformation via minimal invasion. One of the urgent requirements for ground-breaking health care monitoring is persistent monitoring. Hollow microneedles are extremely attractive to extract skin interstitial fluid (ISF) for analysis, which makes them perfect for sensing biomarkers and facilitating diagnosis. Nevertheless, its intricate fabrication process has hampered its extensive application. The present research demonstrates an easy one-step preparation approach for hollow MNs on the foundation of the refraction index variations of polyethylene glycol diacrylate (PEGDA) in the process of photopolymerization. The fabricated hollow microneedle exhibited ideal mechanical characteristics to penetrate the skin. Hydrodynamic simulations showed that the liquid was risen in a hollow microneedle by capillary force. Furthermore, a paper-based glucose sensor was integrated with the hollow microneedle. We also observed that the MN array smoothly extracted ISF in vitro and in vivo by capillary action. The outcomes displayed the applicability of the MN patch to persistent blood glucose (GLU) monitoring, diagnosis-related tests for patients and pre-diabetic individuals.
... A hollow MN is often a MN into which a liquid drug from the reservoir located underside of MN is delivered via a needle tube or an opened channel (Hickerson et al. 2013). The flow rate and pressure are generally controlled by a separate device (Mansoor et al. 2015;Bae et al. 2019;Cárcamo-Martínez et al. 2021). A comparatively large amount of drug can be delivered precisely with a hollow MN than with other types of MN. ...
Background
Nucleic acid-based gene therapy is a promising technology that has been used in various applications such as novel vaccination platforms for infectious/cancer diseases and cellular reprogramming because of its fast, specific, and effective properties. Despite its potential, the parenteral nucleic acid drug formulation exhibits instability and low efficacy due to various barriers, such as stability concerns related to its liquid state formulation, skin barriers, and endogenous nuclease degradation. As promising alternatives, many attempts have been made to perform nucleic acid delivery using a microneedle system. With its minimal invasiveness, microneedle can deliver nucleic acid drugs with enhanced efficacy and improved stability.Area coveredThis review describes nucleic acid medicines' current state and features and their delivery systems utilizing non-viral vectors and physical delivery systems. In addition, different types of microneedle delivery systems and their properties are briefly reviewed. Furthermore, recent advances of microneedle-based nucleic acid drugs, including featured vaccination applications, are described.Expert opinionNucleic acid drugs have shown significant potential beyond the limitation of conventional small molecules, and the current COVID-19 pandemic highlights the importance of nucleic acid therapies as a novel vaccination platform. Microneedle-mediated nucleic acid drug delivery is a potential platform for less invasive nucleic acid drug delivery. Microneedle system can show enhanced efficacy, stability, and improved patient convenience through self-administration with less pain.
... It is because microneedles can reach down to the epidermis layer at a limited penetration depth without irritating dermis layers associated with pain and tissue damage [2,3]. Thus, microneedles in various shapes have been used for transcutaneous delivery of diverse drugs [4][5][6][7][8] even including recombinant COVID-19 vaccines [9,10]. Recent publications have also shown that microneedles can be applied to blood vessels [11], vesicles [12], corneas [13], heart [14], and plants [15,16], demonstrating a possibility of a much broader array of applications. ...
Out-of-plane microneedle structures are widely used in various applications such as transcutaneous drug delivery and neural signal recording for brain machine interface. This work presents a novel but simple method to fabricate high-density silicon (Si) microneedle arrays with various heights and diverse cross-sectional shapes depending on photomask pattern designs. The proposed fabrication method is composed of a single photolithography and two subsequent deep reactive ion etching (DRIE) steps. First, a photoresist layer was patterned on a Si substrate to define areas to be etched, which will eventually determine the final location and shape of each individual microneedle. Then, the 1st DRIE step created deep trenches with a highly anisotropic etching of the Si substrate. Subsequently, the photoresist was removed for more isotropic etching; the 2nd DRIE isolated and sharpened microneedles from the predefined trench structures. Depending on diverse photomask designs, the 2nd DRIE formed arrays of microneedles that have various height distributions, as well as diverse cross-sectional shapes across the substrate. With these simple steps, high-aspect ratio microneedles were created in the high density of up to 625 microneedles mm ⁻² on a Si wafer. Insertion tests showed a small force as low as ~ 172 µN/microneedle is required for microneedle arrays to penetrate the dura mater of a mouse brain. To demonstrate a feasibility of drug delivery application, we also implemented silk microneedle arrays using molding processes. The fabrication method of the present study is expected to be broadly applicable to create microneedle structures for drug delivery, neuroprosthetic devices, and so on.
... The microneedles are generally arranged in a patterned grid on a solid base support for better handling and efficient penetration. Recently, MNs have been of interest to the scientific and clinical community as a minimally invasive alternative to hypodermic needles for parenteral drug delivery, and recent advances in fabrication techniques have also promised to reduce manufacturing cost (Bae et al., 2019;Donnelly et al., 2010;Tsioris et al., 2012). MNs are classified on the basis of material (polymeric, metallic, or ceramic) and also as solid, porous, hollow, hydrogel-forming, and dissolvable MNs (Kim et al., 2012;Ma and Wu, 2017). ...
A 3D printed assembly of hollow microneedles (HMNs) array, conjoined with a reservoir void, was designed and additively manufactured using stereolithography (SLA) technology utilizing a proprietary class-I resin. The HMNs array was utilized for transdermal delivery of high molecular weight antibiotics, i.e., rifampicin (Mw 822.94 g/mol), which suffers from gastric chemical instability, low bioavailability, and severe hepatotoxicity. HMNs morphology was designed with sub-apical holes present in a quarter of the needle tip to improve its mechanical strength and integrity of the HMNs array. The HMNs array was characterized by optical microscopy and electron microscopy to ascertain the print quality and uniformity across the array. The system was also subjected to mechanical characterization for failure and penetration analyses. The ex vivo permeation and consequent transport of rifampicin across porcine skin were systematically evaluated. Finally, in vivo examinations of rifampicin administration through the microneedle reservoir system in SD rats revealed efficient penetration and desired bioavailability.
... Silicone-based elastomers have been attractive candidates for the fabrication of tissue engineering scaffolds, implants (stents, catheters, prostheses, etc.) [101][102][103][104][105], biomedical devices for drug delivery [106][107][108], microfluidics [108][109][110], and wearable electronics applications [10,[111][112][113][114]. The broad range of silicone in medical applications is mainly due to its flexibility, bioinert character, nontoxicity, thermal and chemical stability [115,116]. ...
This dissertation focuses on the development of architected structures via direct additive manufacturing (AM) and novel template-assisted techniques for sensing and tissue engineering applications. Although AM technologies have eased the fabrication of architected structures, limitations arise while printing high-flex 3D complex shapes. To date, no feasible fabrication method has been introduced for high-flex electronics with architected complex geometries in a three-dimensional system. In the current thesis, employing a high-speed material jetting system for direct 3D printing of high-viscose silicone-based inks with carbon fiber additives is introduced. The 3D printed sandwich-like sensors with a silicone-carbon fiber layer (as the sensitive counterpart) and two silicone layers (as the protective and packaging layers) showed enhanced durability for biomonitoring applications. The carbon fiber content was optimized and set to 30 wt.% for printability, UV curability, and electrical conductivity so that high piezoresistive sensitivity (gauge factor in order of ∼400) was obtained. However, due to the limitations of direct 3D printing, a novel template-assisted fabrication process is introduced for the development of elastomeric structures with complex-shape designs. The silicone prepolymer was engineered with additives allowing on-demand structural shrinkage upon solvent treatment, and consequently, fabrication of micrometer-size features was feasible. This enabled 3D printing at a larger scale compatible with extrusion 3D printer resolution followed by isotropic shrinkage. This procedure led to a volumetric shrinkage of up to ~70% in a highly controllable manner. In this way, pore sizes in the order of 500–600 μm were obtained. The proposed low-cost fabrication method not only enabled the high-resolution fabrication of complex-shaped elastomeric structures but was adopted and modified for the fabrication of 3D flexible electronics. In this dissertation, a fabrication scheme based on accessible methods is introduced to surface-dope porous silicone sensors with graphene. The sensors are internally shaped using fused deposition modeling (FDM) 3D printed sacrificial molds. The presented procedure exhibited a stable coating on the porous silicone samples with long term electrical resistance durability over ∼12 months period and high resistance against harsh conditions (exposure to organic solvents). Besides, the sensors retained conductivity upon severe compressive deformations (over 75% compressive strain) with high strain-recoverability and behaved robustly in response to cyclic deformations (over 400 cycles), temperature, and humidity. The sensors exhibited a gauge factor as high as 10 within the compressive strain range of 2−10% and showed strong capability in sensing movements as rigorous as walking and running to the small deformations resulted by human pulse. This dissertation also introduces a robust and scalable approach for forming 3D multilayered complexly architected perfusable networks within highly cellularized hydrogel constructs. Perfusable interconnected networks could assist in sustaining thick cellularized tissue constructs through uniform perfusion of body fluids. The hydrogel constructs were patterned through two-step sacrificial molding. The cell-laden hydrogel scaffolds showed high cell viability of over 90% and robust mechanical behavior. Besides, conflicting design criteria in tissue engineering scaffolds necessitate investigating the structure-properties of the tissue engineering scaffolds and implants. This research shows that defining high local macroporosity at the implant/tissue interface improves the biological response. Gradually decreasing macroporosity from the surface to the center of the porous constructs provides mechanical strength. Furthermore, mechanical studies on the unit cell topology effects suggest that the bending dominated architectures can provide significantly enhanced strength and deformability, compared to stretching-dominated architectures in the case of complex loading scenarios.
... For this reason, it is essential to develop DMNs without organic solvents in order to protect them from the potential risks of these solvents as well as to ensure low costs. In the case of sustained release via DMNs, rapid separation of DMNs from the patch is necessary to prevent potential risks of skin irritation and patient inconvenience since long-term release of DMNs may adhere to the skin until the drug is completely released [24]. ...
(1) Background: Dissolving microneedles (DMNs), a transdermal drug delivery system, have been developed to treat various diseases in a minimally invasive, painless manner. However, the currently available DMNs are based on burst release systems due to their hydrophilic backbone polymer. Although hydrophobic biodegradable polymers have been employed on DMNs for sustained release, dissolution in an organic solvent is required for fabrication of such DMNs. (2) Method: To overcome the aforementioned limitation, novel separable polycaprolactone (PCL) DMNs (SPCL-DMNs) were developed to implant a PCL-encapsulated drug into the skin. PCL is highly hydrophobic, degrades over a long time, and has a low melting point. Under thermal melting, PCL encapsulated capsaicin and could be fabricated into a DMN without the risk of toxicity from an organic solvent. (3) Results: Optimized SPCL-DMNs, containing PCL (height 498.3 ± 5.8 µm) encapsulating 86.66 ± 1.13 µg capsaicin with a 10% (w/v) polyvinyl alcohol and 20% (w/v) polyvinylpyrrolidone mixture as a base polymer, were generated. Assessment of the drug release profile revealed that this system could sustainably release capsaicin for 15 days from PCL being implanted in porcine skin. (4) Conclusion: The implantable SPCL-DMN developed here has the potential for future development of toxicity-free, sustained release DMNs.
... Moreover, MN can allow patients to self-administer, which brings great convenience [26,27]. Collectively, MN is an attractive alternative to conventional intralesional multi-injection [28,29]. However, conventional MN seldom concerns the retention behavior of different drugs. ...
Hypertrophic scar (HS) is an undesirable skin abnormality following deep burns or operations. Although intralesional multi-injection with the suspension of triamcinolone acetonide (TA) and 5-fluorouracil (5-Fu) has exhibited great promise to HS treatment in clinical, the difference of metabolic behavior between TA and 5-Fu remarkably compromised the treatment efficacy. Besides, the traditional injection with great pain is highly dependent on the skill of the experts, which results in poor compliance. Herein, a bilayer dissolving microneedle (BMN) containing TA and 5-Fu (TA-5-Fu-BMN) with biphasic release profile was designed for HS therapy. Equipped with several micro-scale needle tips, the BMN could be self-pressed into the HS with uniform drug distribution and less pain. Both in vitro permeation and in vivo HS retention tests revealed that TA and 5-Fu could coexist in the scar tissue for a sufficient time period due to the well-designed biphasic release property. Subsequently, the rabbit ear HS model was established to assess therapeutic efficacy. The histological analysis showed that TA-5-Fu-BMN could significantly reduce abnormal fibroblast proliferation and collagen fiber deposition. It was also found that the value of scar elevation index was ameliorated to a basal level, together with the downregulation of mRNA and protein expression of Collagen I (Col I) and transforming growth factor-β1 (TGF-β1) after application of TA-5-Fu-BMN. In conclusion, the BMN with biphasic release profiles could serve as a potential strategy for HS treatment providing both convenient administrations as well as controlled drug release behavior.
Despite remarkable progress in the last decade in transdermal microneedle drug delivery systems, great difficulties in precisely manufacturing microneedles with sophisticated microstructures still strongly retard their practical applications. Herein we propose morphology-customized microneedles (spiral, conical, cylindroid, ring-like, arrow-like and tree-like) fabricated by stereolithography (SLA) based 3D-printing technique, and in-depth investigate the correlation between the customized morphologies and the received qualities of the corresponding microneedles such as the mechanical properties and skin penetration behavior, drug loading capacity and the drug release profiles. Results indicated that 3D-printed morphology-customized microneedles not only enhanced the mechanical strength but also improved both drug loading capacity and drug release behavior, which resulted from their highly controllable and 3D-printable morphologies (surface area and volume). And the in vivo study demonstrated that the 3D-printed morphology-customized microneedles successfully promoted the transdermal delivery of the loaded drug (verapamil hydrochloride) with an enhanced therapeutic efficacy for the treatment of hypertrophic scar.
A microneedle has been greatly recognized as one of the most promising devices for novel transdermal drug delivery system due to its capacity of piercing the protective stratum corneum with a minimally invasive and painless manner. During the past two decades, although numerous achievements have been made in the structure and material combination of microneedles, they mostly focus on the pharmacology and functionality of microneedles, and little is reported about how to design the shape of microneedles to reduce insertion force and especially improve penetration efficiency. Using the developed finite element method, we designed three-section microneedles (TSMN) with various sizes and evaluated their maximum insertion force, penetration efficiency, drug delivery amount and strength. The simulation results demonstrate that the well-designed TSMN with shaft width of 60 μm exhibits a lower maximum insertion force of 116.68 mN relative to 167.92 mN of conical microneedle and an effective penetration length of 81.6% relative to 71.38% of conical microneedle. Besides, the optimized TSMN with shaft width of 80 μm shows similar maximum insertion force and 2.3 times the drug delivery amount compared to conical microneedle. These excellent properties are attributed to the optimized design of the shape curve of TSMN sidewall. Such results may provide an inspiration of microneedle design for low insertion force and high penetration efficiency.
While a majority of wireless microrobots has shown multi‐responsiveness to implement complex biomedical functions, their functional executions are strongly dependent on the range of stimulus inputs, which curtails their functional diversity. Furthermore, their responsive functions are coupled to each other, which results in the overlap of the task operations. Here, we demonstrate a 3D‐printed multifunctional microrobot inspired by pollen grains with three hydrogel components: FePt nanoparticle‐embedded PETA, pNIPAM, and pNIPAM‐AAc structures. Each of these structures exhibits their respective targeted functions: responding to magnetic fields for torque‐driven surface rolling and steering, exhibiting temperature responsiveness for on‐demand surface attachment (anchoring), and pH‐responsive cargo release. The versatile multifunctional pollen grain‐inspired robots conceptualized here pave the way for various future medical microrobots to improve their projected performance and functional diversity. This article is protected by copyright. All rights reserved
Protein and peptide drugs are predominantly administered by injection to achieve high bioavailability, but this greatly compromises patient compliance. Oral and transdermal drug delivery with minimal invasiveness and high adherence represent attractive alternatives to injection administration. However, oral and transdermal administration of bioactive proteins must overcome biological barriers, namely the gastrointestinal and skin barriers, respectively. The rapid development of new materials and technologies promises to address these physiological obstacles. This review provides an overview of the latest advances in oral and transdermal protein delivery, including chemical strategies, synthetic nanoparticles, medical microdevices, and biomimetic systems for oral administration, as well as chemical enhancers, physical approaches, and microneedles in transdermal delivery. We also discuss challenges and future perspectives of the field with a focus on innovation and translation.
Protein and peptide drugs are predominantly administered by injection to achieve high bioavailability, but this greatly compromises patient compliance. Oral and transdermal drug delivery with minimal invasiveness and high adherence represent attractive alternatives to injection administration. However, oral and transdermal administration of bioactive proteins must overcome biological barriers, namely the gastrointestinal and skin barriers, respectively. The rapid development of new materials and technologies promises to address these physiological obstacles. This review provides an overview of the latest advances in oral and transdermal protein delivery, including chemical strategies, synthetic nanoparticles, medical microdevices, and biomimetic systems for oral administration, as well as chemical enhancers, physical approaches, and microneedles in transdermal delivery. We also discuss challenges and future perspectives of the field with a focus on innovation and translation.
Microneedles technology is a powerful platform to achieve efficient transdermal delivery of bioactive molecules for local or systemic therapies attributing to their minimally invasive delivery mode that circumvents the use of hypodermic needles. Building on its success in transdermal delivery, the applications of microneedles have been expanded to non-dermatological purposes including oral, buccal, intramyocardial, and ocular delivery. Additionally, with the advancement of materials and analysis techniques, microneedle-integrated point-of-care devices have shown promise for fast and efficient biomolecular sampling for patient health monitoring and disease diagnosis. In this review, we discuss the design principles of microneedles to overcome the biological barriers of various administration routes for drug delivery, in addition to more recent innovations employing microneedles for biomolecular and cellular sampling applications.
Dissolving microneedle (DMN) patches are emerging as a minimally-invasive and efficient transdermal drug delivery platform. Generally, noncrystalline, water-soluble, and high-molecular-weight polymers are employed in DMN because their sufficient intermolecular interactions can endow DMN with necessary mechanical strength and toughness. However, high viscosity and heavy chain entanglement of polymer solutions greatly hinder processing and dissolution of polymeric DMNs. Here, we describe a strong and tough supramolecular DMN made of highly water-soluble cyclodextrin (CD) derivatives. Due to the synergy of multiple supramolecular interactions, CD DMN patch exhibits robust mechanical strength outperforming the state-of-the-art polymeric DMNs. CD DMN displays ultrafast dissolution (< 30 s) in skin models by virtue of the dynamic and weak noncovalent bonds, which also enables CD DMN and its payloads to diffuse rapidly into the deep skin layer. Moreover, the unique supramolecular structure of CD allows CD DMN to load not only hydrophilic drugs (e.g., rhodamine B as model) but also hydrophobic model drugs (e.g., ibuprofen). As a proof-of-concept, CD DMN loading ibuprofen shows a rapid onset of therapeutic action in a xylene-induced acute inflammation model in mice. This work opens a new avenue for the development of mechanically robust supramolecular DMN and broadens the applications of supramolecular materials. This article is protected by copyright. All rights reserved.
Blood glucose (BG) monitoring in patients with diabetes is critical for diabetes management. Minimally invasive BG monitoring is urgently required to increase the patient compliance. Herein, based on a responsive hydrogel system, we developed a smart microneedle patch system for minimally invasive glucose monitoring. The patch consisted of a transparent substrate of photocurable resin and microneedles made of a pH-responsive and glucose-responsive hydrogel. The responsive hydrogel was composed of a photocrosslinkable hydrogel of gelatin methacrylate (GelMA) together with a pH-responsive nanogel (nano(CMC-pHEA)) and glucose oxidase (GOx). The composite hydrogel showed fast response and high sensitivity to glucose levels in physiological range, mainly due to the ionization of CMC-pHEA component and proton balance. The microneedles showed sufficient mechanical strength to penetrate the skin of mice with minimal invasion, and achieved in situ extraction of glucose in interstitial fluid (ISF) and in situ glucose-responsive reaction. We demonstrated the rapid glucose monitoring by microneedle patch system in skin-mimicking gels in vitro and in diabetic mice in vivo. The microneedles quickly and sensitively responded to glucose concentrations, allowed quantitative readouts of glucose levels through the changes of microneedle heights and swelling ratios. Moreover, the readouts in mice in vivo were consistent with BG levels measured by glucometer. This smart microneedle system has potentials to replace blood sampling, and minimize patient discomfort during BG testing, therefore has potentials in minimally invasive, rapid and reliable BG monitoring.
Skin microbiome sampling is currently performed with tools such as swabs and tape strips to collect microbes from the skin surface. However, these conventional approaches may be unable to detect microbes deeper in the epidermis or in epidermal invaginations. We describe a sampling tool with a depth component, a transepidermal microprojection array (MPA), which captures microbial biomass from both the epidermal surface and deeper skin layers. We leveraged the rapid customizability of 3D printing to enable systematic optimization of MPA for human skin sampling. Evaluation of sampling efficacy on human scalp revealed the optimized MPA was comparable in sensitivity to swab and superior to tape strip, especially for nonstandard skin surfaces. We observed differences in species diversity, with the MPA detecting clinically relevant fungi more often than other approaches. This work delivers a tool in the complex field of skin microbiome sampling to potentially address gaps in our understanding of its role in health and disease.
Transdermal delivery through the skin barriers is an important medical procedure to transfer drugs into the human body. However, there is an urgent requirement to design microneedle‐based transdermal delivery systems with superior delivery efficiency, low toxicity, excellent mechanical property, and simple synthetic process. Herein, perpendicular calcite microneedle arrays with a length of about 8 µm are synthesized on the prism layer of mollusk shells via oriented dissolution while dextran sulfate sodium is applied as an additive. Ordered patterns of long calcite microneedles with a length about 45 µm are synthesized in a large scale for the first time on mollusk prism layers via oriented dissolution while circular masks are covered on the prism layers during the dissolution process. The long calcite microneedle arrays with the ordered pattern are found to be efficient for transdermal delivery of dexamethasone and for therapy of ear psoriasis in mice. The calcite microneedle arrays are also applied to transport Cy3 fluorescent biomolecules through cell membranes in this work. These calcite microneedle arrays can be applied as efficient transportation substrates for both transdermal and intracellular delivery, which exhibit advantages such as high drug loading capacity, superior biocompatibility, nontoxicity, high mechanical properties, and easy synthesis strategy. Dense calcite microneedle arrays and patterned long calcite microneedles with length about 45 mm are synthesized for the first time on the mollusk shells via oriented dissolution. These calcite microneedle arrays have been applied for both transdermal and intracellular delivery, which exhibit advantages such as high drug loading capacity, superior biocompatibility, high mechanical properties, and easy synthesis strategy.
The key to controlling the spread of the coronavirus disease 2019 (COVID-19) and reducing mortality is highly dependent on the safe and effective use of vaccines for the general population. Current COVID-19 vaccination practices (intramuscular injection of solution-based vaccines) are limited by heavy reliance on medical professionals, poor compliance, and laborious vaccination recording procedures, resulting in a waste of health resources and low vaccination coverage, etc. In this study, we developed a smart mushroom-inspired imprintable and lightly detachable (MILD) microneedle platform for the effective and convenient delivery of multidose COVID-19 vaccines and decentralized vaccine information storage. The mushroom-like structure allows the MILD system to be easily pressed into the skin and detached from the patch base, acting as a "tattoo" to record the vaccine counts in situ without any storage equipment, offering quick accessibility and effortless readout, saving a great deal of valuable time and energy for both patients and health professionals. After loading inactivated SARS-CoV-2 virus-based vaccines, MILD system induced a high level of antibodies against the SARS-CoV-2 receptor-binding domain (RBD) in vivo without eliciting systemic toxicity and local damage. Collectively, this smart delivery platform serves as a promising carrier to improve COVID-19 vaccination efficacy through its dual capabilities of vaccine delivery and in situ data storage, thus exhibiting great potential for helping to contain the COVID-19 pandemic or a resurgence.
Microneedles (MNs) are micron-sized needles that can penetrate the stratum corneum, enabling the non-invasive and painless administration of drugs and vaccines. In this work, fabrication conditions for high-aspect-ratio MNs by the photopolymerization of polyethylene glycol diacrylate (PEGDA) were investigated. Ultraviolet (UV) light was used to crosslink photocurable prepolymers in specific areas defined by a photomask. The aspect ratio of solidified MNs is too small to penetrate the stratum corneum if the degree of polymerization is insufficient. However, if the degree of polymerization is too high, a film is formed between the MNs by solidification of an undesired area owing to the scattering effect, reducing needle height. The influence of prepolymer molecular weight and the degree of UV absorption by the photoinitiator (PI) were studied to optimize the conditions for obtaining high-aspect-ratio MNs. Additionally, the effect of spacing ratio on high-aspect-ratio MNs without film formation has been discussed. A penetration test was conducted with porcine skin to analyze the effect of mechanical properties of MN. This study could guide the fabrication of MNs by the photopolymerization of biocompatible polymers with a photomask.
Cardiovascular disease is the leading cause of global mortality, with anticoagulant therapy being the main prevention and treatment strategy. Recombinant hirudin (r-hirudin) is a direct thrombin inhibitor that can potentially prevent thrombosis via subcutaneous (SC) and intravenous (IV) administration, but there is a risk of haemorrhage via SC and IV. Thus, microneedle (MN) provides painless and sanitary alternatives to syringes and oral administration. However, the current technological process for the micro mould is complicated and expensive. The micro mould obtained via three-dimensional (3D) printing is expected to save time and cost, as well as provide a diverse range of MNs. Therefore, we explored a method for MNs array model production based on 3D printing and translate it to micro mould that can be used for fabrication of dissolving MNs patch. The results show that r-hirudin-loaded and hyaluronic acid (HA)-based MNs can achieve transdermal drug delivery and exhibit significant potential in the prevention of thromboembolic disease without bleeding in animal models. These results indicate that based on 3D printing technology, MNs combined with r-hirudin are expected to achieve diverse customizable MNs and thus realize personalized transdermal anticoagulant delivery for minimally invasive and long-term treatment of thrombotic disease.
Macroencapsulation has been widely used in cell therapy due to its capability to provide immune-privileged sites for implanted allogeneic or xenogeneic cells. Macroencapsulation also serve to provide mechanical and physiochemical support for maintaining cell expansion and promoting therapeutic functions. Macroencapsulation devices such as membrane-controlled release systems, hydrogels, microneedle (MN) array patches, and three-dimensional (3D) stents have shown promising in-lab and preclinical results in the maintenance of long-term cell survival and the strengthening of treatment efficacy. Recent studies focus on expanding the applications of these devices to new cell-based areas such as chimeric antigen receptor (CAR)-T cell delivery, cardiovascular disease therapy, and the exploration of new materials, construction methods, and working principles to augment treatment efficacy and prolong therapy duration. Here, we survey innovative platforms and approaches, as well as translation outcomes, for advancing the performance and applications of macrodevices for cell-based therapies. A discussion and critique regarding future opportunities and challenges is also provided.
Theranostic system combined diagnostic and therapeutic modalities is critical for the real-time monitoring of disease-related biomarkers and personalized therapy. Microneedles, as a multifunctional platform, are promising for transdermal diagnostics and drug delivery. They have showed attractive properties including painless skin penetration, easy self-administration, prominent therapeutic effects, and good biosafety. Herein, we give an overview of the microneedles-based diagnosis, therapies, and theranostic systems. Four microneedles-based detection methods are concluded based on the sensing mechanism: i) electrochemistry, ii) fluorometric, iii) colorimetric, and iv) Raman methods. Additionally, robust microneedles are suitable for implantable drug delivery. Microneedles-assisted transdermal drug delivery can be primarily classified as passive, active, and responsive drug release, based on the release mechanisms. Microneedles-assisted oral and implantable drug delivery mechanisms are also presented in this review. Furthermore, the key frontier developments in microneedles-mediated theranostic systems as the major selling points are emphasized in this review. These systems are classified into open-loop and closed-loop theranostic systems based on the indirectness and directness of feedback between the transdermal diagnosis and therapy, respectively. Finally, conclusions and future perspectives for next-generation microneedles-mediated theranostic systems are also discussed. Taken together, microneedle-based systems are promising as the new avenue for diagnosis, therapy and disease-specific closed-loop theranostic applications.
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Living creatures often adopt multiple strategies that utilize materials, structures, and dynamic motions to efficiently prevent surface fouling. However, previous synthetic antifouling materials are typically based on single strategies using materials, structures, or physical motions, which lead to limited antifouling performance. Here, we present a hybrid approach that integrates bacteria-killing nanostructures and bacteria-repelling dynamic surfaces in a multilayered responsive composite. The composite exhibited undulatory dynamic motions in response to an applied magnetic field. The dynamic surface motion of the composite can induce strong vortices near the composite surface and thus prevent bacterial attachment, while the nanospikes can physically damage the membrane of the attached cells. Accordingly, the proposed dynamic nanospike composite can suppress bacterial film formation for a prolonged period of 7 days without using toxic biocides or chemicals.
Vaccination is one of the most successful and cost-effective prophylactic measures against diseases, especially infectious diseases including smallpox and polio. However, the development of effective prophylactic or therapeutic vaccines for other diseases such as cancer remains challenging. This is often due to the imprecise control of vaccine activity in vivo which leads to insufficient/inappropriate immune responses or short immune memory. The development of new vaccine types in recent decades has created the potential for improving the protective potency against these diseases. Genetic and subunit vaccines are two major categories of these emerging vaccines. Owing to their nature, they rely heavily on delivery systems with various functions, such as effective cargo protection, immunogenicity enhancement, targeted delivery, sustained release of antigens, selective activation of humoral and/or cellular immune responses against specific antigens, and reduced adverse effects. Therefore, vaccine delivery systems may significantly affect the final outcome of genetic and other novel vaccines and are vital for their development. This review introduces these studies based on their research emphasis on functional design or administration route optimization, presents recent progress, and discusses features of new vaccine delivery systems, providing an overview of this field.
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Fungal keratitis (FK) remains a serious clinical problem worldwide, so the ultimate goal of the treatment is to develop a minimally invasive, safe, and effective method for ocular drug delivery. Here, a minimally invasive delivery system is reported for treating FK by using a dissolving microneedle (MN)-array patch based on Poly(D,L-lactide) (PLA) and hyaluronic acid (HA). By altering the concentration of PLA, MN patches with excellent properties are modified and optimized. The 30% PLA-HA MN patches penetrate the corneal epithelial layer reversibly with no apparent ocular irritation as well as a short recovery time of less than 12 h, and increase the residence time by 2.5 h in the conjunctival sac, thereby offering higher drug bioavailability. Remarkably, the rabbit model of FK shows that the topical MN(+) patch medication exerts superior therapeutic effects compared with the conventional eye drop formulation, and also presents comparable therapeutic efficacy with that of the clinical mainstay strategy (i.e., intrastromal injection). Therefore, the MN patch, acting as an ocular drug delivery system with high efficacy and ability of rapid corneal healing, promises a cost-effective household solution for the treatment of FK, which may also lead to a new approach for treating FK in clinics.
This paper presents a novel concept design for microneedles that can perform dual release patterns by utilizing outer grooves as a pathway for instant delivery, dissolving body microneedles which are loaded with stimuli-responsive nanocarriers for sustained delivery and a bore for extraction diagnosis purposes. ANSYS software is used to analyze the performance of the proposed design involving mechanical structural and mechanical-fluid dynamics analysis. The effect of various grooved designs on skin puncture performance on the tri-layer skin model has been investigated, and the presence of grooves can minimize contact interaction, leading to low insertion force. Then, instant delivery via the outer grooves, which involves open-channel and closed-channel, is studied (0.033 μl/min). For dissolution performance for limited and sustained source loading is investigated using analytical analysis. With a set extraction flow rate of about 0.0015 μl/min and a vacuum pressure of 10kPa, the bore design is optimized to minimize vortex formation. Lastly, the structural strength of the proposed microneedle is investigated by applying axial and transverse loads which show the generated stress is less than the material strength. Overall, simulation results confirm that the proposed microneedles can provide both sustained-instant release of insulin simultaneously and perform extraction with minimal vortex formation to provide precise sampling amount and avoid delay of fluid movement. This design has high potential to be used in developing a closed-loop system for transdermal insulin delivery and diagnosis, known as "artificial pancreas".
Smart attachable systems have attracted much attention owing to their capabilities in terms of body performance evaluation, disease diagnostics, and drug delivery. Recent advances in chemical and engineering techniques provide many opportunities to improve device fabrication and applications owing to the advantages of being lightweight and easy to control as well as their battery absence and functional diversity. This review highlights the latest developments in the field of chemical engineering-based lightweight and miniaturized attachable systems, which are mainly inspired by the natural world. Their applications for real-time monitoring, point-of-care sampling, biomarker detection, and controlled release are discussed thoroughly with respect to specific products/prototypes. The perspectives of the field, including persistence guarantee, burden reduction, and personality improvement, are also discussed. It is believed that chemical engineering-based lightweight and miniaturized attachable systems have good potential in both clinical and industrial fields, indicating a large potential to improve human lives in the near future.
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There is a lack of actively targeting drug delivery carriers for the topical treatment of epidermal diseases, which results in drug waste and an increased incidence of toxic side effects in the clinic. We recently discovered that epidermal cells (HaCaT cells) have homologous targeting functions and developed HaCaT cell membrane-coated pH-sensitive micelles for therapeutic active targeting of skin disease. We encapsulated shikonin in these biomimetic nanocarriers and found that the nanocarriers accumulated mainly in the active epidermis when delivered with karaya gum-fabricated water-soluble microneedles. The nanocarriers were internalized by the target cells, resulting in swelling of histidine fragments with protonation and subsequent triggering of drug release, which increased the therapeutic efficacy of shikonin against imiquimod-induced psoriatic epidermal hyperplasia. This emerging biomimetic delivery strategy is a new approach for improving the treatment of skin diseases and is also very promising for use in the field of cosmetics. Additionally, we found abnormally high protein expression of Na+/K+-ATPase in diseased skin; thus, this protein may be a biomarker of psoriasis.
Minimizing the thermal contact resistance (TCR) at the boundary between two bodies in contact is critical in diverse thermal transport devices. Conventional thermal contact methods have several limitations, such as high TCR, low interfacial adhesion, a requirement for high external pressure, and low optical transparency. Here, a self-interfacing flexible thermal device (STD) that can form robust van der Waals mechanical contact and low-resistant thermal contact to planar and non-planar substrates without the need for external pressure or surface modification is presented. The device is based on a distinctive integration of a bioinspired adhesive architecture and a thermal transport layer formed from percolating silver nanowire (AgNW) networks. The proposed device exhibits a strong attachment (maximum 538.9 kPa) to target substrates while facilitating thermal transport across the contact interface with low TCR (0.012 m² K kW⁻¹) without the use of external pressure, thermal interfacial materials, or surface chemistries.
For successful wound treatment, therapeutics must be delivered directly to the wound. Various issues restrict the delivery of antibiotics to wounds, including the barrier mannered by necrotic tissue and biofilms, which create an extracellular polymeric layer that impedes the efficient administration of therapeutics. For achieving break of the necrotic tissue barrier and biofilm, in addition, improving antibiotics penetration through a painless administration, we fabricated porous polymer coatings on microneedles (MNs) which had the ability of automatic “release” therapeutics in response to wound pH conditions. In the pores of the porous polymer film, the model drug was packed using aqueous gelatin porogen, and the porous layer was coated with a Eudragit S100 film to cap the pores to prevent drug leakage and provide a wound pH-responsive drug release. By combining the advantages of porous and pH-responsive polymer coatings, the coated MNs exhibited remarkably enhanced therapeutic results. This formulation showed both in vivo (in rats) and in vitro (in phosphate-buffered saline and in porcine skin) wound pH-sensitive drug release with rapid responsiveness. At healthy skin pH (pH 4.5), an insignificant release was noticed for MNs in the test media. However, drug release considerably increased when MNs were exposed to wound pH conditions (pH 7.5). The present study provides proof-of-concept evidence that developed MNs have the potential of enhanced treatment protocol for wound infections with the flexibility of coating materials and antimicrobials and offers significant scope for further variations and advancement.
Microneedles (MNs) is one of intriguing approach for efficient transdermal drug delivery that penetrates the protective skin barrier in a painless and less invasive way. In recent years, multidisciplinary studies have been conducted to improve their properties in order to meet stringent requirements and obtain market release approval. This review aims to summarize the latest concept design with unique properties in the advancement of transdermal MNs for diagnosis and therapeutic application. Numerous significant innovation strategies in improving MNs in aspects of adhesion ability, dosing capacity, drug-controlled release, diffusion control ability, site-targeted and on-demand drug delivery and biomarker or drug release monitoring, are presented. Given that the majority of technologies employed in such design are exclusively laboratory-based, striving towards commercialization is a critical aspect of the revolution. Key challenges and future perspectives in industrial and economic aspects are identified with the intention of translating the reviewed technologies into marketable products.
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Microneedles (MNs) as a minimally invasive tool have drawn increasing attention recently. They possess many prominent advantages, including pain-free, self-administration, and ease-of-disposal, when compared to the traditional administration tools. This review summarizes the latest developments of the MN technology and focuses on the advanced applications in stimuli-responsive drug delivery, disease theranostics, and bioinspired functions. Starting from a brief overview of different types of MNs based on their structures and materials, we then detail the fabrication strategies, including hot embossing, micro-molding, thermal-drawing lithography, magnetorheological lithography, laser-drilling, and the emerging 3D printing techniques. Later, the recent biomedical applications of these MNs are highlighted, including stimuli-responsive drug release for disease therapy, biosensing for disease diagnosis, and bioinspired applications.
Sharks, marine creatures that swim fast and have an antifouling ability, possess dermal denticle structures of micrometer-size. Because the riblet geometries on the denticles reduce the shear stress by inducing the slip of fluid parallel to the stream-wise direction, shark skin has the distinguished features of low drag and antifouling. Although much attention has been given to low-drag surfaces inspired from shark skin, it remains an important challenge to accurately mimic denticle structures in the micrometer scale and to finely control their structural features. This paper presents a novel method to create shark skin-mimetic denticle structures for low drag by exploiting a photoreconfigurable azopolymer. The light-designed denticle structure exhibits superior hydrophobicity and an antifouling effect as sharks do. This work suggests that our novel photoreconfiguration technology, mimicking shark skin and systematically manipulating various structural parameters, can be used in a reliable manner for diverse applications requiring low-drag surfaces.
The transdermal delivery of macromolecular drugs has become one of the focused topics in pharmaceutical research since it enables highly specific and effective delivery, while avoiding the pain and needle phobia associated with injection, or incidences like drug degradation and low bioavailability of oral administration. However, the passive absorption of macromolecular drugs via skin is highly restricted by the stratum corneum owing to high molecular weight. Therefore, various strategies have been extensively developed and conducted to facilitate the transdermal delivery of macromolecular drugs, among which, mechanical force-assisted techniques occupy dominant positions. Such techniques include ultrasound, needle-free jet injection, temporary pressure and microneedles. In this review, we focus on recent transdermal enhancing strategies utilizing mechanical force, and summarize their mechanisms, advantages, limitations and clinical applications respectively.
Medical patches have been widely explored and applied in various medical fields, especially in wound healing, tissue engineering, and other biomedical areas. Benefiting from emerging biomaterials and advanced manufacturing technologies, great achievements have been made on medical patches to evolve them into a multifunctional medical device for diverse health-care purposes, thus attracting extensive attention and research interest. Here, we provide up-to-date research concerning emerging functional biomaterials as medical patches. An overview of the various approaches to construct patches with micro- and nanoarchitecture is presented and summarized. We then focus on the applications, especially the biomedical applications, of the medical patches, including wound healing, drug delivery, and real-time health monitoring. The challenges and prospects for the future development of the medical patches are also discussed.
Efficient hemostasis is of great significance in clinical and medical fields. Herein, inspired by the hierarchical microstructure of feet or stings of insects, we present a dodecyl-modified chitosan (DCS)-coated pagoda-like multilayer microneedle patch for tissue fixation and rapid hemostasis. Such a microneedle patch is fabricated by a step-by-step mold replication, which is easy-to-operate, flexible, and highly adjustable. The multilayer structure enables the microneedle patch to strongly fix onto diverse tissues via physical interlocking and is not affected by large blood loss or other conditions; while the DCS coating can anchor onto the cell membrane, bring about blood cell coagulation, and thus actively promote hemostasis. It was demonstrated from in vivo rabbit experiments that acute tissue injuries including liver bleeding, spleen bleeding, and kidney bleeding can be repaired immediately by employing these DCS-coated multilayer microneedle patches. These distinctive features indicate that the presented microneedle patches can find applications in hemostasis and many other biomedical fields.
Biofouling of tubular fluidic devices limits the stability, accuracy, and long-term uses of lab on-a-chip systems. Healthcare-associated infection by biofilm formations on body-indwelling and extracorporeal tubular medical devices is also a major cause of mortality and morbidity in patients. Although diverse antifouling techniques have been developed to prevent bacterial contamination of fluidic devices based on antimicrobial materials or nanoscale architectures, they still have limitations in biocompatibility, long-term activity, and durability. In this study, a new conceptual tubular fluidic device model that can effectively suppress bacterial contamination based on dynamic surface motions without using bactericidal materials or nanostructures is proposed. The fluidic device is composed of a magneto-responsive multilayered composite. The composite tube can generate dynamic surface deformation with controlled geometries along its inner wall in response to a remote magnetic field. The magnetic field-derived surface waves induces the generation of vortices near the inner wall surface of the tube, enabling sweeping of bacterial cells from the surface. As a result, the dynamic composite tube could effectively prevent biofilm formation for an extended time of 14 days without surface modification with chemical substances or nanostructures.
Skin tissue defects make a major threat to human health. It is of vital importance for researchers to develop ideal novel adhesives with strong adhesion, good biocompatibility, low cost and simple production. Inspired by the phenomenon that polyphenols scavenge free radical as well as polyphenols improve mechanical properties of flour products, tannic acid-thioctic acid (TATA) supramolecular hydrogel was synthesized via the ring-opening polymerization of thioctic acid as well as the thiyl radical-polyphenol Michael addition. The synthetic procedure was robust, facile, time-saving and low-cost, which followed the rules of green chemistry. Successful intermolecular crosslinking was confirmed by X-ray photoelectron spectroscopy (XPS). Multiple hydrogen bonding formed between polyphenol residues and carboxyl groups entitled the hydrogel self-healing as well as injectable properties. Additionally, the TATA hydrogel was used as adhesive for skin wound healing with decreased therapeutic time and enhanced regeneration effect compared with suture treatment. This hydrogel also showed antibacterial property against Methicillin resistant Staphylococcus aureus in a burn wound infection model. Based on these above features, the TATA hydrogel exhibited potential as a surgical antibacterial bioadhesive for a broad range of medical applications.
Transdermal drug-delivery systems (TDDS) offer an attractive alternative to the oral route for delivery of biotherapeutics. Technological advancements in the past few decades have revolutionized the fabrication of micro-structured devices including creation of microneedles (MC). These devices are used for delivering peptides, macromolecules such as proteins and DNA, and other therapeutics through the skin. Here, we review the current use of MCs as a cost effective method for the self-administration of therapeutics. We will then review the current and common use of MCs as an effective treatment strategy for a broad range of diseases and their utility in the generation of effective vaccination delivery platforms. Finally, we will summarize the currently FDA approved MCs and their applications, along with the ongoing clinical trials that use such devices.
Emerging micro-scale medical devices are showing promise, whether in delivering drugs or extracting diagnostic biomarkers from skin. In progressing these devices through animal models towards clinical products, understanding the mechanical properties and skin tissue structure with which they interact will be important. Here, through measurement and analytical modelling, we advanced knowledge of these properties for commonly used laboratory animals and humans (~30 g to ~150 kg). We hypothesised that skin’s stiffness is a function of the thickness of its layers through allometric scaling, which could be estimated from knowing a species’ body mass. Results suggest that skin layer thicknesses are proportional to body mass with similar composition ratios, inter- and intra-species. Experimental trends showed elastic moduli increased with body mass, except for human skin. To interpret the relationship between species, we developed a simple analytical model for the bulk elastic moduli of skin, which correlated well with experimental data. Our model suggest that layer thicknesses may be a key driver of structural stiffness, as the skin layer constituents are physically and therefore mechanically similar between species. Our findings help advance the knowledge of mammalian skin mechanical properties, providing a route towards streamlined micro-device research and development onto clinical use.
The dermal route is an attractive route for vaccine delivery due to the easy skin accessibility and a dense network of immune cells in the skin. The development of microneedles is crucial to take advantage of the skin immunization and simultaneously to overcome problems related to vaccination by conventional needles (e.g. pain, needle-stick injuries or needle re-use). This review focuses on dissolving microneedles that after penetration into the skin dissolve releasing the encapsulated antigen. The microneedle patch fabrication techniques and their challenges are discussed as well as the microneedle characterization methods and antigen stability aspects. The immunogenicity of antigens formulated in dissolving microneedles are addressed. Finally, the early clinical development is discussed.
Electrochemical analysis of sweat using soft bioelectronics on human skin provides a new route for noninvasive glucose monitoring without painful blood collection. However, sweat-based glucose sensing still faces many challenges, such as difficulty in sweat collection, activity variation of glucose oxidase due to lactic acid secretion and ambient temperature changes, and delamination of the enzyme when exposed to mechanical friction and skin deformation. Precise point-of-care therapy in response to the measured glucose levels is still very challenging. We present a wearable/disposable sweat-based glucose monitoring device integrated with a feedback transdermal drug delivery module. Careful multilayer patch design and miniaturization of sensors increase the efficiency of the sweat collection and sensing process. Multimodal glucose sensing, as well as its real-time correction based on pH, temperature, and humidity measurements, maximizes the accuracy of the sensing. The minimal layout design of the same sensors also enables a strip-type disposable device. Drugs for the feedback transdermal therapy are loaded on two different temperature-responsive phase change nanoparticles. These nanoparticles are embedded in hyaluronic acid hydrogel microneedles, which are additionally coated with phase change materials. This enables multistage, spatially patterned, and precisely controlled drug release in response to the patient’s glucose level. The system provides a novel closed-loop solution for the noninvasive sweat-based management of diabetes mellitus.
PurposeTo evaluate the combination of a pressure-indicating sensor film with hydrogel-forming microneedle arrays, as a method of feedback to confirm MN insertion in vivo. Methods
Pilot in vitro insertion studies were conducted using a Texture Analyser to insert MN arrays, coupled with a pressure-indicating sensor film, at varying forces into excised neonatal porcine skin. In vivo studies involved twenty human volunteers, who self-applied two hydrogel-forming MN arrays, one with a pressure-indicating sensor film incorporated and one without. Optical coherence tomography was employed to measure the resulting penetration depth and colorimetric analysis to investigate the associated colour change of the pressure-indicating sensor film. ResultsMicroneedle insertion was achieved in vitro at three different forces, demonstrating the colour change of the pressure-indicating sensor film upon application of increasing pressure. When self-applied in vivo, there was no significant difference in the microneedle penetration depth resulting from each type of array, with a mean depth of 237 μm recorded. When the pressure-indicating sensor film was present, a colour change occurred upon each application, providing evidence of insertion. Conclusions
For the first time, this study shows how the incorporation of a simple, low-cost pressure-indicating sensor film can indicate microneedle insertion in vitro and in vivo, providing visual feedback to assure the user of correct application. Such a strategy may enhance usability of a microneedle device and, hence, assist in the future translation of the technology to widespread clinical use.
Transdermal drug delivery offers a number of advantages for the patient, due not only its non-invasive and convenient nature, but also factors such as avoidance of first pass metabolism and prevention of gastrointestinal degradation. It has been demonstrated that microneedle arrays can increase the number of compounds amenable to transdermal delivery by penetrating the skin's protective barrier, the stratum corneum, and creating a pathway for drug permeation to the dermal tissue below. Microneedles have been extensively investigated in recent decades for drug and vaccine delivery as well as minimally invasive patient monitoring/diagnosis. This review focuses on a range of critically important aspects of microneedle technology, namely their material composition, manufacturing techniques, methods of evaluation and commercial translation to the clinic for patient benefit and economic return. Microneedle research and development is finally now at the stage where commercialisation is a realistic possibility. However, progress is still required in the areas of scaled-up manufacture and regulatory approval.
Significance
For exploiting synthetic glucose-responsive insulin delivery systems, challenges remain to demonstrate a strategy that would combine ( i ) fast responsiveness, ( ii ) ease of administration, and ( iii ) excellent biocompatibility. We have developed a novel glucose-responsive insulin delivery device using a painless microneedle-array patch containing hypoxia-sensitive hyaluronic acid-based vesicles. The vesicles quickly dissociate and release encapsulated insulin under the local hypoxic environment, caused by the enzymatic oxidation of glucose in the hyperglycemic state. This “smart insulin patch” with a new enzyme-based glucose-responsive mechanism can regulate the blood glucose of type 1 diabetic mice to achieve normal levels, with faster responsiveness compared with the commonly used pH-sensitive formulations, and can avoid the risk of hypoglycemia.
Animal venoms represent a diverse source of potentially valuable therapeutic compounds due to the high specificity and the potent biological activity of many toxins. Snake venom toxins, particularly disintegrins and proteases from viper venoms, have yielded therapeutics with anti-cancer and hemostatic dysfunction activities. However, venoms from rear-fanged ''colubrid'' snakes have rarely been analyzed from the perspective of potential lead compound development. Here, we discuss recent progress in the analysis of these venoms, focusing on several studies of specific venom components as well as transcriptomic and proteomic surveys. Currently available –omic technologies largely circumvent the problematic low venom yields of most rear-fanged snakes, and because their basic biology is often very different from the well-studied front-fanged snakes, there is great potential for novel compound discovery in their venoms.
Microneedles are being fast recognized as a useful alternative to injections in delivering drugs, vaccines, and cosmetics transdermally. Owing to skin's inherent elastic properties, microneedles require an optimal geometry for skin penetration. In vitro studies, using rat skin to characterize microneedle penetration in vivo, require substrates with suitable mechanical properties to mimic human skin's subcutaneous tissues. We tested the effect of these two parameters on microneedle penetration. Geometry in terms of center-to-center spacing of needles was investigated for its effect on skin penetration, when placed on substrates of different hardness. Both hard (clay) and soft (polydimethylsiloxane, PDMS) substrates underneath rat skin and full-thickness pig skin were used as animal models and human skins were used as references. It was observed that there was an increase in percentage penetration with an increase in needle spacing. Microneedle penetration with PDMS as a support under stretched rat skin correlated better with that on full-thickness human skin, while penetration observed was higher when clay was used as a substrate. We showed optimal geometries for efficient penetration together with recommendation for a substrate that could better mimic the mechanical properties of human subcutaneous tissues, when using microneedles fabricated from poly(ethylene glycol)-based materials. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
In this paper, we present a new design of hollow, out-of-plane polymeric microneedle with cylindrical side-open holes for
transdermal drug delivery (TDD) applications. A detailed literature review of existing designs and analysis work on microneedles
is first presented to provide a comprehensive reference for researchers working on design and development of micro-electromechanical
system (MEMS)-based microneedles and a source for those outside the field who wish to select the best available microneedle
design for a specific drug delivery or biomedical application. Then, the performance of the proposed new design of microneedles
is numerically characterized in terms of microneedle strength and flow rate at applied inlet pressures. All the previous designs
of hollow microneedles have side-open holes in the lumen section with no integrated reservoir on the same chip. We have proposed
a new design with side-open holes in the conical section to ensure drug delivery on skin insertion. Furthermore, the present
design has an integrated drug reservoir on the back side of the microneedles. Since MEMS-based, hollow, side-open polymeric
microneedles with integrated reservoir is a new research area, there is a notable lack of applicable mathematical models to
analytically predict structural and fluid flow under various boundary conditions. That is why, finite element (FE) and computational
fluid dynamic (CFD) analysis using ANSYS rather than analytical systems has been used to facilitate design optimization before
fabrication. The analysis has involved simulation of structural and CFD analysis on three-dimensional model of microneedle
array. The effect of axial and transverse loading on the microneedle during skin insertion is investigated in the stress analysis.
The analysis predicts that the resultant stresses due to applied bending and axial loads are in the safe range below the yield
strength of the material for the proposed design of the microneedles. In CFD analysis, fluid flow rate and pressure drop in
the microneedles at applied inlet pressures are numerically and theoretically investigated. The CFD analysis predicts uniform
flow through the microneedle array for each microneedle. Theoretical and numerical results for the flow rate and pressure
drop are in close agreement with each other, thereby validating the CFD analysis. For the proposed design of microneedles,
feasible fabrication techniques such as micro-hot embossing and ultraviolet excimer laser methods are proposed. The results
of the present theoretical study provide valuable benchmark and prediction data to fabricate optimized designs of the polymeric,
hollow microneedles, which can be successfully integrated with other microfluidic devices for TDD applications.
We present a novel microfabrication method for a tapered hollow metallic microneedle array and its complete microfluidic packaging
for drug delivery and body fluid sampling applications. Backside exposure of SU-8 through a UV transparent substrate was investigated
as a means of fabricating a dense array of tall (up to 400μm) uniformly tapered SU-8 pillar structures with angles in the
range of 3.1–5° on top of the SU-8 mesa. Conformal electroplating of metals on top of the array of the tapered SU-8 pillars,
lapping of the tip of the metallic microneedles with planarizing polymer, and removal of the SU-8 sacrificial layers resulted
in an array of tapered hollow metallic microneedles with a fluidic reservoir on the backside. A microfluidic interconnector
assembly was designed and fabricated using SU-8 and conventionally machined PMMA in a way that it has a male interconnector,
which directly fits into the fluidic reservoir of the microneedle array at one end and the other male interconnector, which
provides fluidic interconnection to external devices at the other end. The fluid flow rate was measured and it showed 0.69μL/s.
per microneedle when the pressure of 6.89KPa (1psi) was applied.
In the majority of venomous snakes, and in many other reptiles, venom is conveyed from the animal's gland to the prey's tissue through an open groove on the surface of the teeth and not through a tubular fang. Here we focus on two key aspects of the grooved delivery system: the hydrodynamics of venom as it interacts with the groove geometry, and the efficiency of the tooth-groove-venom complex as the tooth penetrates the prey's tissue. We show that the surface tension of the venom is the driving force underlying the envenomation dynamics. In so doing, we explain not only the efficacy of the open groove, but also the prevalence of this mechanism among reptiles.
Influenza prophylaxis would benefit from a vaccination method enabling simplified logistics and improved immunogenicity without the dangers posed by hypodermic needles. Here we introduce dissolving microneedle patches for influenza vaccination using a simple patch-based system that targets delivery to skin's antigen-presenting cells. Microneedles were fabricated using a biocompatible polymer encapsulating inactivated influenza virus vaccine for insertion and dissolution in the skin within minutes. Microneedle vaccination generated robust antibody and cellular immune responses in mice that provided complete protection against lethal challenge. Compared to conventional intramuscular injection, microneedle vaccination resulted in more efficient lung virus clearance and enhanced cellular recall responses after challenge. These results suggest that dissolving microneedle patches can provide a new technology for simpler and safer vaccination with improved immunogenicity that could facilitate increased vaccination coverage.
The purpose of this work is to demonstrate rapid intradermal delivery of up to 1.5 mL of formulation using a hollow microneedle delivery device designed for self-application.
3M's hollow Microstructured Transdermal System (hMTS) was applied to domestic swine to demonstrate delivery of a variety of formulations including small molecule salts and proteins. Blood samples were collected after delivery and analyzed via HPLC or ELISA to provide a PK profile for the delivered drug. Site evaluations were conducted post delivery to determine skin tolerability.
Up to 1.5 mL of formulation was infused into swine at a max rate of approximately 0.25 mL/min. A red blotch, the size of the hMTS array, was observed immediately after patch removal, but had faded so as to be almost indistinguishable 10 min post-patch removal. One-mL deliveries of commercial formulations of naloxone hydrochloride and human growth hormone and a formulation of equine anti-tetanus toxin were completed in swine. With few notable differences, the resulting PK profiles were similar to those achieved following subcutaneous injection of these formulations.
3M's hMTS can provide rapid, intradermal delivery of 300-1,500 µL of liquid formulations of small molecules salts and proteins, compounds not typically compatible with passive transdermal delivery.
Influenza virus-like particles (VLPs) are a promising cell culture-based vaccine, and the skin is considered an attractive immunization site. In this study, we examined the immunogenicity and protective efficacy of influenza VLPs (H1N1 A/PR/8/34) after skin vaccination using vaccine dried on solid microneedle arrays. Coating of microneedles with influenza VLPs using an unstabilized formulation was found to decrease hemagglutinin (HA) activity, whereas inclusion of trehalose disaccharide preserved the HA activity of influenza VLP vaccines after microneedles were coated. Microneedle vaccination of mice in the skin with a single dose of stabilized influenza VLPs induced 100% protection against challenge infection with a high lethal dose. In contrast, unstabilized influenza VLPs, as well as intramuscularly injected vaccines, provided inferior immunity and only partial protection (</=40%). The stabilized microneedle vaccination group showed IgG2a levels that were 1 order of magnitude higher than those of other groups and had the lowest lung viral titers after challenge. Also, levels of recall immune responses, including hemagglutination inhibition titers, neutralizing antibodies, and antibody-secreting plasma cells, were significantly higher after skin vaccination with stabilized formulations. Therefore, our results indicate that HA stabilization, combined with vaccination via the skin using a vaccine formulated as a solid microneedle patch, confers protection superior to that with intramuscular injection and enables potential dose-sparing effects which are reflected by pronounced increases in rapid recall immune responses against influenza virus.
We studied whether MF59-adjuvanted influenza vaccine improves immunity against drifted influenza strains in institutionalised elderly with underling chronic health conditions. Sera from a randomized study, comparing MF59-adjuvanted (Sub/MF59, n=72), virosomal (SVV, n=39), and split (n=88) vaccines, were retested using a hemagglutination inhibition (HI) assay against homologous (Northern Hemisphere [NH] 1998/99) and drifted (NH 2006/07) strains. Corrected postvaccination HI antibody titres were significantly higher with Sub/MF59 than SVV for all strains; GMTs against homologous A/H3N2 and B and both drifted A strains were significantly higher for Sub/MF59 than split. Seroprotection rates and mean-fold titer increases were generally higher with Sub/MF59 for all A influenza strains. MF59-adjuvanted influenza vaccine induced greater and broader immune responses in elderly people with chronic conditions, than conventional virosomal and split vaccines, particularly for A/H1 and A/H3 strains, potentially giving clinical benefit in seasons where antigenic mismatch occurs.
This study sought to determine the effects of microneedle coating formulation, drying time and storage time on antigen stability and in vivo immunogenicity of influenza microneedle vaccines.
The stability of inactivated influenza virus vaccine was monitored by hemagglutination (HA) activity and virus particle aggregation as a function of storage time and temperature with or without trehalose. In vivo immunogenicity of inactivated influenza vaccines coated onto microneedles was determined in mice by virus-specific antibody titers and survival rates.
In the absence of trehalose, HA activity decreased below 10% and to almost zero after 1 h and 1 month of drying, respectively. Addition of trehalose maintained HA activity above 60% after drying and above 20% after 1 month storage at 25°C. Loss of HA activity generally correlated with increased virus particle aggregation. Administration of microneedles coated with trehalose-stabilized influenza vaccine yielded high serum IgG antibody titers even after 1 month storage, and all animals survived with minimal weight loss after lethal challenge infection.
Inactivated influenza virus vaccine coated on microneedles with trehalose significantly improved the HA activity as well as in vivo immunogenicity of the vaccine after an extended time of storage.
Many promising therapeutic agents are limited by their inability to reach the systemic circulation, due to the excellent barrier properties of biological membranes, such as the stratum corneum (SC) of the skin or the sclera/cornea of the eye and others. The outermost layer of the skin, the SC, is the principal barrier to topically-applied medications. The intact SC thus provides the main barrier to exogenous substances, including drugs. Only drugs with very specific physicochemical properties (molecular weight < 500 Da, adequate lipophilicity, and low melting point) can be successfully administered transdermally. Transdermal delivery of hydrophilic drugs and macromolecular agents of interest, including peptides, DNA, and small interfering RNA is problematic. Therefore, facilitation of drug penetration through the SC may involve by-pass or reversible disruption of SC molecular architecture. Microneedles (MNs), when used to puncture skin, will by-pass the SC and create transient aqueous transport pathways of micron dimensions and enhance the transdermal permeability. These micropores are orders of magnitude larger than molecular dimensions, and, therefore, should readily permit the transport of hydrophilic macromolecules. Various strategies have been employed by many research groups and pharmaceutical companies worldwide, for the fabrication of MNs. This review details various types of MNs, fabrication methods and, importantly, investigations of clinical safety of MN.
Microneedles are being developed to administer vaccines and therapeutics to and through skin. To date there has been no qualitative or quantitative research into public and health professionals' views on this new delivery technique.
Focus groups (n=7) comprising public and healthcare professionals were convened to capture the perceived advantages for, and concerns with, microneedles. Discussions were audio-recorded and transcribed. Transcript analysis identified themes that were explored using a questionnaire identifying consensus or otherwise.
Participants identified many potential benefits of the microneedle delivery system, including reduced pain, tissue damage and risk of transmitting infections compared with conventional injections, as well as potential for self-administration (subject to safeguards such as an indicator to confirm dose delivery). Delayed onset, cost, accurate and reliable dosing and the potential for misuse were raised as concerns. A range of potential clinical applications was suggested. The public (100%) and professional (74%) participants were positive overall about microneedle technology.
This exploratory research study captured the views of the eventual end-users of microneedle technology. Microneedle researchers should now reflect on their research and development activities in the context of stakeholder engagement in order to facilitate the transfer of this new technology 'from bench to bedside.'
The threat of pandemic influenza and other public health needs motivate the development of better vaccine delivery systems. To address this need, microneedles have been developed as micron-scale needles fabricated using low-cost manufacturing methods that administer vaccine into the skin using a simple device that may be suitable for self-administration. Delivery using solid or hollow microneedles can be accomplished by (1) piercing the skin and then applying a vaccine formulation or patch onto the permeabilized skin, (2) coating or encapsulating vaccine onto or within microneedles for rapid, or delayed, dissolution and release in the skin, and (3) injection into the skin using a modified syringe or pump. Extensive clinical experience with smallpox, TB, and other vaccines has shown that vaccine delivery into the skin using conventional intradermal injection is generally safe and effective and often elicits the same immune responses at lower doses compared to intramuscular injection. Animal experiments using microneedles have shown similar benefits. Microneedles have been used to deliver whole, inactivated virus; trivalent split antigen vaccines; and DNA plasmids encoding the influenza hemagglutinin to rodents, and strong antibody responses were elicited. In addition, ChimeriVax-JE against yellow fever was administered to nonhuman primates by microneedles and generated protective levels of neutralizing antibodies that were more than seven times greater than those obtained with subcutaneous delivery; DNA plasmids encoding hepatitis B surface antigen were administered to mice and antibody and T cell responses at least as strong as hypodermic injections were generated; recombinant protective antigen of Bacillus anthracis was administered to rabbits and provided complete protection from lethal aerosol anthrax spore challenge at a lower dose than intramuscular injection; and DNA plasmids encoding four vaccinia virus genes administered to mice in combination with electroporation generated neutralizing antibodies that apparently included both Th1 and Th2 responses. Dose sparing with microneedles was specifically studied in mice with the model vaccine ovalbumin. At low dose (1 microg), specific antibody titers from microneedles were one order of magnitude greater than subcutaneous injection and two orders of magnitude greater than intramuscular injection. At higher doses, antibody responses increased for all delivery methods. At the highest levels (20-80 microg), the route of administration had no significant effect on the immune response. Concerning safety, no infections or other serious adverse events have been observed in well over 1,000 microneedle insertions in human and animal subjects. Bleeding generally does not occur for short microneedles (<1 mm). Highly localized, mild, and transient erythema is often observed. Microneedle pain has been reported as nonexistent to mild, and always much less than a hypodermic needle control. Overall, these studies suggest that microneedles may provide a safe and effective method of delivering vaccines with the possible added attributes of requiring lower vaccine doses, permitting low-cost manufacturing, and enabling simple distribution and administration.
Important cell populations reside within tissues and are not accessed by traditional blood draws used to monitor the immune system. To address this issue at an essential barrier tissue, the skin, we created a microneedle-based technology for longitudinal sampling of cells and interstitial fluid, enabling minimally invasive parallel monitoring of immune responses. Solid microneedle projections were coated by a cross-linked biocompatible polymer, which swells upon skin insertion, forming a porous matrix for local leukocyte infiltration. By embedding molecular adjuvants and specific antigens encapsulated in nanocapsules within the hydrogel coating, antigen-specific lymphocytes can be enriched in the recovered cell population, allowing for subsequent detailed phenotypic and functional analysis. We demonstrate this approach in mice immunized with a model protein antigen or infected in the skin with vaccinia virus. After vaccination or infection, sampling microneedles allowed tissue-resident memory T cells (T RM s) to be longitudinally monitored in the skin for many months, during which time the antigen-specific T cell population in systemic circulation contracted to low or undetectable counts. Sampling microneedles did not change the immune status of naïve or antigen-exposed animals. We also validated the ability of cell sampling using human skin samples. This approach may be useful in vaccines and immunotherapies to temporally query T RM populations or as a diagnostic platform to sample for biomarkers in chronic inflammatory and autoimmune disorders, allowing information previously accessible only via invasive biopsies to be obtained in a minimally invasive manner from the skin or other mucosal tissues.
The utility of layer-by-layer (LbL) coated microneedle (MN) skin patches for transdermal drug delivery has been proven a promising approach, with advantages over hypodermal injection due to painless and easy self-administration. However, the long epidermal application time required for drug implantation by existing LbL MN strategies (15 to 90 minutes) can lead to potential medication noncompliance. Here, we developed a MN platform to shorten the application time in MN therapies based on a synthetic pH-induced charge-invertible polymer poly(2-(diisopropylamino) ethyl methacrylate-b-methacrylic acid) (PDM), requiring only 1-minute skin insertion time to implant LbL films in vivo. Following MN-mediated delivery of 0.5 μg model antigen chicken ovalbumin (OVA) in the skin of mice, this system achieved sustained release over 3 days and led to an elevated immune response as demonstrated by significantly higher humoral immunity compared with OVA administration via conventional routes (subcutaneously and intramuscularly). Moreover, in an ex vivo experiment on human skin, we achieved efficient immune activation through MN-delivered LbL films, demonstrated by a rapid uptake of vaccine adjuvants by the antigen presenting cells. These features—rapid administration and the ability to elicit a robust immune response—can potentially enable a broad application of microneedle-based vaccination technologies.
A skin adhesive patch is the most fundamental and widely used medical device for diverse health‐care purposes. Conventional skin adhesive patches have been mainly utilized for routine medical purposes such as wound management, fixation of medical devices, and simple drug release. In contrast to traditional skin adhesive patches, recently developed patches incorporate multiple key functions of bulky medical devices into a thin, flexible patch based on emerging nanomaterials and flexible electronic technologies. Consequently, the meaning of the term “skin adhesive patch” becomes broader and smarter compared to the traditional term. This review summarizes recent efforts undertaken in the development of multifunctional advanced skin adhesive patches, and briefly describes future directions and challenges toward the next generation of smart skin adhesive patches for ubiquitous personalized health care. This review article introduces multifunctional advanced skin adhesive patches that incorporate multiple key functions of bulky medical devices into a thin flexible patch based on emerging nanomaterials and flexible electronic technologies. Fundamental functions of conventional skin adhesives, skin adhesion mechanisms, advanced functions of recently developed skin adhesive patches, and future directions and challenges are discussed.
Significance
Diagnosis and monitoring of disease is often done by measuring biomarkers found in blood, urine, saliva, and other bodily fluids. Another rich source of biomarkers is the interstitial fluid that surrounds cells and tissues in the body, but difficulty in accessing this fluid has limited its use in research and medicine. Here, we conducted experimental studies coupled with theoretical modeling to design a patch containing microscopic needles that puncture into superficial layers of skin and thereby enable withdrawal of interstitial fluid through micropores in a simple, minimally invasive manner. This patch can help researchers access interstitial fluid to advance discovery of novel biomarkers and enable doctors to use interstitial fluid for possible future diagnosis and monitoring of disease.
Conventional wound healing materials suffer from low efficiency, poor mechanical strength, and nontunable properties. Responsive hydrogels are appealing candidates for tissue engineering. Herein, we developed a double-cross-linked hydrogel system composed of hyperbranched PEG-based polymer, comprising pre-cross-linked acetal structure and numerous terminal acrylate groups, which can form hydrogels in situ and can be further strengthened by UV irradiation. The hyperbranched glycidyl methacrylate-co-poly(ethylene glycol) diacrylate polymers (HB-GMA-PEGs) were first synthesized via in situ deactivation enhanced atom transfer radical polymerization (DE-ATRP). A series of pre-cross-linked materials were achieved after postfunctionalization. The material can absorb a high amount of water to form hydrogels, and the gel stiffness was evaluated in detail before and after UV irradiation. The in vitro cytotoxicity experiments were conducted with the resulting materials and have demonstrated their good biocompatibility. The results indicate that this type of hydrogel with high water uptake capacity has appealing potential as a responsive biomaterial for wound closure.
Self-regulating glucose-responsive insulin delivery systems have great potential to improve clinical outcomes and quality of life among patients with diabetes. Herein, an H2O2-labile and positively charged amphiphilic diblock copolymer is synthesized, which is subsequently used to form nano-sized complex micelles (NCs) with insulin and glucose oxidase of pH-tunable negative charges. Both NCs are loaded into the crosslinked core of a microneedle array patch for transcutaneous delivery. The microneedle core is additionally coated with a thin sheath structure embedding H2O2-scavenging enzyme to mitigate the injury of H2O2 toward normal tissues. The resulting microneedle patch can release insulin with rapid responsiveness under hyperglycemic conditions owing to an oxidative and acidic environment because of glucose oxidation, and can therefore effectively regulate blood glucose levels within a normal range on a chemically induced type 1 diabetic mouse model with enhanced biocompatibility.
This study presents wet-responsive, shape-reconfigurable, and flexible hydrogel adhesives that exhibit strong adhesion under wet environments based on reversible interlocking between reconfigurable microhook arrays. The experimental investigation on the swelling behavior and structural characterization of the hydrogel microstructures reveal that the microhook arrays undergo anisotropic swelling and shape transformation upon contact with water. The adhesion between the interlocked microhook arrays is greatly enhanced under wet conditions because of the hydration-triggered shape reconfiguration of the hydrogel microstructures. Furthermore, wet adhesion monotonically increases with water-exposure time. A maximum adhesion force of 79.9 N cm–2 in the shear direction is obtained with the hydrogel microhook array after 20 h of swelling, which is 732.3% greater than that under dry conditions (i.e., 9.6 N cm–2). A simple theoretical model is developed to describe the measured adhesion forces. The results are in good agreement with the experimental data.
Obesity is one of the most serious public health problems in the 21st century that may lead to many comorbidities such as type-2 diabetes, cardiovascular diseases, and cancer. Current treatments toward obesity including diet, physical exercise, pharmacological therapy, as well as surgeries are always associated with low effectiveness or undesired systematical side effects. In order to enhance treatment efficiency with minimized side effects, we developed a transcutaneous browning agent patch to locally induce adipose tissue transformation. This microneedle-based patch can effectively deliver browning agents to the subcutaneous adipocytes in a sustained manner and switch on the "browning" at the targeted region. It is demonstrated that this patch reduces treated fat pad size, increases whole body energy expenditure, and improves type-2 diabetes in vivo in a diet-induced obesity mouse model.
Skin interstitial fluid (ISF) is an emerging source of biomarkers for disease diagnosis and prognosis. Microneedle (MN) patch has been identified as an ideal platform to extract ISF from the skin due to its pain-free and easy-to-administrated properties. However, long sampling time is still a serious problem which impedes timely metabolic analysis. In this study, a swellable MN patch that can rapidly extract ISF is developed. The MN patch is made of methacrylated hyaluronic acid (MeHA) and further crosslinked through UV irradiation. Owing to the supreme water affinity of MeHA, this MN patch can extract sufficient ISF in a short time without the assistance of extra devices, which remarkably facilitates timely metabolic analysis. Due to covalent crosslinked network, the MN patch maintains the structure integrity in the swelling hydrated state without leaving residues in skin after usage. More importantly, the extracted ISF metabolites can be efficiently recovered from MN patch by centrifugation for the subsequent offline analysis of metabolites such as glucose and cholesterol. Given the recent trend of easy-to-use point-of-care devices for personal healthcare monitoring, this study opens a new avenue for the development of MN-based microdevices for sampling ISF and minimally invasive metabolic detection.
A glucose-responsive closed-loop insulin delivery system mimicking pancreas activity without long-term side effect has the potential to improve diabetic patients' health and quality of life. Here, we developed a novel glucose-responsive insulin delivery device using a painless microneedle-array patch containing insulin-loaded vesicles. Formed by self-assembly of hypoxia and H2O2 dual-sensitive diblock copolymer, the glucose-responsive polymersome-based vesicles (d-GRPs) can disassociate and subsequently release insulin triggered by H2O2 and hypoxia generated during glucose oxidation catalyzed by glucose specific enzyme. Moreover, the d-GRPs were able to eliminate the excess H2O2, which may lead to free radical-induced damage to skin tissue during the long-term usage and reduce the activity of GOx. In vivo experiments indicated that this smart insulin patch could efficiently regulate the blood glucose in the chemically induced type 1 diabetic mice for 10 h.
Ebola DNA vaccine is incorporated into PLGA-PLL/γPGA nanoparticles and administered to skin using a microneedle (MN) patch. The nanoparticle delivery system increases vaccine thermostability and immunogenicity compared to free vaccine. Vaccination by MN patch produces stronger immune responses than intramuscular administration.