Hydrogel‐Forming Microneedle Arrays for Enhanced Transdermal Drug Delivery

Unique microneedle arrays prepared from crosslinked polymers, which contain no drug themselves, are described. They rapidly take up skin interstitial fluid upon skin insertion to form continuous, unblockable, hydrogel conduits from attached patch‐type drug reservoirs to the dermal microcirculation. Importantly, such microneedles, which can be fabricated in a wide range of patch sizes and microneedle geometries, can be easily sterilized, resist hole closure while in place, and are removed completely intact from the skin. Delivery of macromolecules is no longer limited to what can be loaded into the microneedles themselves and transdermal drug delivery is now controlled by the crosslink density of the hydrogel system rather than the stratum corneum, while electrically modulated delivery is also a unique feature. This technology has the potential to overcome the limitations of conventional microneedle designs and greatly increase the range of the type of drug that is deliverable transdermally, with ensuing benefits for industry, healthcare providers and, ultimately, patients.     

Microfabricated Drug Delivery Devices: Design,Fabrication, and Applications

Microfabrication technology has enabled the development of novel controlled‐release devices that possess an integration of structural, mechanical, and perhaps electronic features, which may address challenges associated with conventional delivery systems. In this feature article, microfabricated devices are described in terms of materials, mechanical design, working principles, and fabrication methods, all of which are key features for production of multifunctional, highly effective drug delivery systems. In addition, the current status and future prospects of different types of microfabricated devices for controlled drug delivery are summarized and analyzed with an emphasis on various routes of administration including ocular, oral, transdermal, and implantable systems. It is likely that microfabrication technology will continue to offer new, alternative solutions to design advanced and sophisticated drug delivery devices that promise to significantly improve medical care.     

Targeted Delivery of Anesthetic Agents to Bone Tissues using Conductive Microneedles Enhanced Iontophoresis for Painless Dental Anesthesia

Pain management during dental procedures is a cornerstone for successful daily practice. In current practice, the traditional needle and syringe injection is used to administer local anesthesia. However, the appearance of long needles and the pain associated with it often leads to dental anxiety deterring timely interventions. Microneedles (MNs) have emerged as a minimally invasive alternative to hypodermic needles and shown to be effective in transdermal drug delivery applications. In this article, the potential use of MNs for local anesthesia delivery in dentistry is explored. The development of a novel conductive MN array that can be used in combination with iontophoresis technique to achieve drug penetration through the oral mucosa and the underlying bone tissue is presented. The conductive MN array plays a dual-role, creating micro-conduits and lowering the resistance of the oral mucosa. The reduced tissue resistance further enhances the application of a low-voltage current that is able to direct and accelerate the drug molecules to target the sensory nerves supplying teeth. The successful delivery of lidocaine using this new strategy in a clinically relevant rabbit incisor model is shown to be as effective as the current gold standard.     

Polylactide‐block‐Polypeptide‐block‐Polylactide Copolymer Nanoparticles with Tunable Cleavage and Controlled Drug Release

A versatile nanoparticle system is presented in which drug release is triggered by enzymatic polymer cleavage, resulting in a physicochemical change of the carrier. The polylactide‐block‐peptide‐block‐polylactide triblock copolymer is generated by initiation of the ring‐opening polymerization of L‐lactide with a complex bifunctional peptide having an enzymatic recognition and cleavage site (Pro‐Leu‐Gly‐Leu‐Ala‐Gly). This triblock copolymer is specifically bisected by matrix metalloproteinase‐2 (MMP‐2), an enzyme overexpressed in tumor tissues. Triblock copolymer nanoparticles formed by nonaqueous emulsion polymerization are readily transferred into aqueous media without aggregation, even in the presence of blood serum. Cleavage of the triblock copolymer leads to a significant decrease of the glass transition temperature (T_g) from 39 °C to 31 °C, likely mediating cargo release under physiological conditions. Selective drug targeting is demonstrated by hampered mitosis and increased cell death resulting from drug release via MMP‐2 specific cleavage of triblock copolymer carrier. On the contrary, nanocarriers having a scrambled (non‐recognizable) peptide sequence do not cause enhanced cytotoxicity, demonstrating the enzyme‐specific cleavage and subsequent drug release. The unique physicochemical properties, cleavage‐dependent cargo release, and tunability of carrier bioactivity by simple peptide exchange highlight the potential of this polymer‐nanoparticle concept as platform for custom‐designed carrier systems.     

Self-Powered Controllable Transdermal Drug Delivery System

Traditional topical ointment applied on the skin surface has poor drug penetration due to the thickening of the stratum corneum for psoriasis. Microneedles (MNs) provide a desirable opportunity to promote drug penetration. However, the common MNs are difficult to meet the requirement of on-demand drug delivery. In this study, a smart electrical responsive MNs is fabricated by introducing conductive material of polypyrrole (PPy). Further, a self-powered controllable transdermal drug delivery system (sc-TDDS) based on piezoelectric nanogenerator (PENG) is developed. The sc-TDDS can control drug release by collecting and converting mechanical energy into electrical energy. The sc-TDDS can release 8.5 ng dexamethasone (Dex) subcutaneously per electrical stimulation. When treating psoriasis-like skin disease with sc-TDDS, the inflammatory skin returned to normal after 5 days, which is obviously better than treating with traditional Dex solution coating. This work provides a promising approach of on-demand transdermal drug release for various disease treatment scenarios.     

Latch Applicator for Efficient Delivery of Dissolving Microneedles Based on Rapid Release of Elastic Strain Energy by Thumb Force (Adv. Funct. Mater. 11/2023)

Dissolving microneedle (DMN) is an attractive alternative to parenteral and enteral drug administration owing to its painless self-administration and safety due to non-generation of medical waste. For reproducible and efficient DMN administration, various DMN application methods, such as weights, springs, and electromagnetic devices, have been studied. However, these applicators have complex structures that are complicated to use and high production costs. In this study, a latch applicator that consists of only simple plastic parts and operates via thumb force without any external complex device is developed. Protrusion-shaped latches and impact distances are designed to accumulate thumb force energy through elastic deformation and to control impact velocity. The optimized latch applicator with a pressing force of 25 N and an impact velocity of 5.9 m s⁻¹ fully inserts the drug-loaded tip of the two-layered DMN into the skin. In an ovalbumin immunization test, DMN with the latch applicator shows a significantly higher IgG antibody production rate than that of intramuscular injection. The latch applicator, which provides effective DMN insertion and a competitive price compared with conventional syringes, has great potential to improve delivery of drugs, including vaccines.     

Templated Assembly of pH‐Labile Polymer‐Drug Particles for Intracellular Drug Delivery

The preparation of pH‐labile polymer‐drug particles via mesoporous silica‐templated assembly for anticancer drug delivery into cancer cells is reported. The polymer‐drug conjugate is synthesized via thiol‐maleimide click chemistry using thiolated poly(methacrylic acid) (PMA_SH) and a pH‐labile doxorubicin (Dox) derivative. Drug‐loaded polymer particles that are stable under physiological conditions are obtained through infiltration of the conjugates into mesoporous silica particles, followed by cross‐linking the PMA_SH chains, and subsequent removal of the porous silica templates. The encapsulated Dox is released from the particles through cleavage of the hydrazone bonds between Dox and PMA_SH at endosomal/lysosomal pH. Cell viability assays show that the assembled PMA_SH particles have negligible cytotoxicity to LIM1899 human colorectal cancer cells. In comparison, Dox‐loaded PMA_SH particles cause significant cell death following internalization. The reported particles represent a novel and versatile class of stimuli‐responsive carriers for controlled drug delivery.     

Self‐Assembling Doxorubicin Silk Hydrogels for the Focal Treatment of Primary Breast Cancer

Standard care for early stage breast cancer includes tumor resection and local radiotherapy to achieve long‐term remission. Systemic chemotherapy provides only low locoregional control of the disease; to address this, self‐assembling silk hydrogels that can retain and then deliver doxorubicin locally are described. Self‐assembling silk hydrogels show no swelling, are readily loaded with doxorubicin under aqueous conditions, and release drug over 4 weeks in amounts that can be fine‐tuned by varying the silk content. Following successful in vitro studies, locally injected silk hydrogels loaded with doxorubicin show excellent antitumor response in mice, outperforming the equivalent amount of doxorubicin delivered intravenously. In addition to reducing primary tumor growth, doxorubicin‐loaded silk hydrogels reduce metastatic spread and are well tolerated in vivo. Thus, silk hydrogels are well suited for the local delivery of chemotherapy and provide a promising approach to improve locoregional control of breast cancer.     

Microneedle‐Array Patch Fabricated with Enzyme‐Free Polymeric Components Capable of On‐Demand Insulin Delivery

Achieving persistent glycemic control in a painless and convenient way is the ultimate goal of diabetes management. Herein, an “enzyme‐free” polymeric microneedle (MN)‐array patch composed of a boronate‐containing hydrogel semi‐interpenetrated by biocompatible silk fibroin is developed. Consistent with the previous reports, the presence of the boronate‐hydrogel allows for glucose‐responsive diffusion‐control of insulin, while the crystalline fibroin component serves as a matrix‐stiffener to validate skin penetration. Remarkably, this “enzyme‐free” smart artificial on‐skin pancreas prototype remains stable for at least 2 months in an aqueous environment. Furthermore, it establishes sustained as well as acute glucose‐responsive insulin delivery, and is to the authors' knowledge, the first successful material design addressing such two technical challenges at once on an MN format. This long‐acting, on‐demand insulin delivery technology may offer a candidate for a next‐generation diabetes therapy that is remarkably stable, safe, economically efficient, and capable of providing both acute‐ and continuous glycemic control in a manner minimally dependent on patient compliance.     

Electro‐Drawn Drug‐Loaded Biodegradable Polymer Microneedles as a Viable Route to Hypodermic Injection

Hypodermic needle injection is still the most common method of drug delivery despite its numerous limitations and drawbacks, such as pain, one‐shot administration, and risk of infection. Seeking a viable, safe, and pain‐free alternative to the over 16 billion injections per year has therefore become a top priority for our modern technological society. Here, a system that uses a pyroelectric cartridge in lieu of the syringe piston as a potential solution is discussed. Upon stimulation, the cartridge electro‐draws, at room temperature, an array of drug‐encapsulated, biodegradable polymer microneedles, able to deliver into hypodermic tissue both hydrophobic and hydrophilic bioactive agents, according to a predefined chrono‐programme. This mould‐free and contact‐free method permits the fabrication of biodegradable polymer microneedles into a ready‐to‐use configuration. In fact, they are formed on a flexible substrate/holder by drawing them directly from drop reservoirs, using a controlled electro‐hydrodynamic force. Tests of insertion are performed and discussed in order to demonstrate the possibility to prepare microneedles with suitable geometric and mechanical properties using this method.     

Doxorubicin‐Conjugated Immuno‐Nanoparticles for Intracellular Anticancer Drug Delivery

A polymeric nanoparticle comprised of surface furan groups is used to bind, by Diels–Alder (DA) coupling chemistry, both targeting anti‐human epidermal growth factor receptor 2 (anti‐HER2) antibodies and chemotherapeutic doxorubicin (DOX) for targeted, intracellular delivery of DOX. In this new approach for delivery, where both chemotherapeutic and targeting ligand are attached, for the first time, to the surface of the delivery vehicle, the nuclear localization of DOX in HER2‐overexpressing breast cancer SKBR‐3 cells is demonstrated, as determined by confocal laser scanning microscopy. Flow cytometric analysis shows that the conjugated DOX maintains its biological function and induces similar apoptotic progression in SKBR‐3 cells as free DOX. The viable cell counts of SKBR‐3 cancer cells following incubation with different nanoparticle formulations demonstrates that the combined DOX and anti‐HER2 nanoparticle is more efficacious than the nanoparticle formulation with either DOX or anti‐HER2 alone. While free DOX shows similar cytotoxicity against both cancerous SKBR‐3 cells and healthy HMEC‐1 cells, the combined DOX‐anti‐HER2 nanoparticle is significantly more cytotoxic against SKBR‐3 cells than HMEC‐1 cells, suggesting the benefit of nanoparticle‐conjugated DOX for cell type‐specific targeting. The DOX‐conjugated immuno‐nanoparticle represents an entirely new method for localized co‐delivery of chemotherapeutics and antibodies.     

Charge‐Reversal Drug Conjugate for Targeted Cancer Cell Nuclear Drug Delivery

DNA‐toxin anticancer drugs target nuclear DNA or its associated enzymes to elicit their pharmaceutical effects, but cancer cells have not only membrane‐associated but also many intracellular drug‐resistance mechanisms that limit their nuclear localization. Thus, delivering such drugs directly to the nucleus would bypass the drug‐resistance barriers. The cationic polymer poly(L ‐lysine) (PLL) is capable of nuclear localization and may be used as a drug carrier for nuclear drug delivery, but its cationic charges make it toxic and cause problems in in‐vivo applications. Herein, PLL is used to demonstrate a pH‐triggered charge‐reversal carrier to solve this problem. PLL's primary amines are amidized as acid‐labile β‐carboxylic amides (PLL/amide). The negatively charged PLL/amide has a very low toxicity and low interaction with cells and, therefore, may be used in vivo. But once in cancer cells' acidic lysosomes, the acid‐labile amides hydrolyze into primary amines. The regenerated PLL escapes from the lysosomes and traverses into the nucleus. A cancer‐cell targeted nuclear‐localization polymer–drug conjugate has, thereby, been developed by introducing folic‐acid targeting groups and an anticancer drug camptothecin (CPT) to PLL/amide (FA‐PLL/amide‐CPT). The conjugate efficiently enters folate‐receptor overexpressing cancer cells and traverses to their nuclei. The CPT conjugated to the carrier by intracellular cleavable disulfide bonds shows much improved cytotoxicity.     

Antibiotic‐Releasing Silk Biomaterials for Infection Prevention and Treatment

Effective treatment of infections in avascular and necrotic tissues can be challenging due to limited penetration into the target tissue and systemic toxicities. Controlled‐release polymer implants have the potential to achieve the high local concentrations needed while also minimizing systemic exposure. Silk biomaterials possess unique characteristics for antibiotic delivery, including biocompatibility, tunable biodegradation, stabilizing effects, water‐based processing, and diverse material formats. The functional release of antibiotics spanning a range of chemical properties from different material formats of silk (films, microspheres, hydrogels, coatings) is reported. The release of penicillin and ampicillin from bulk‐loaded silk films, drug‐loaded silk microspheres suspended in silk hydrogels and bulk‐loaded silk hydrogels is investigated and the in vivo efficacy of the ampicillin‐releasing silk hydrogels is demonstrated in a murine infected‐wound model. Silk sponges with nanofilm coatings are loaded with gentamicin and cefazolin, and release is sustained for 5 and 3 days, respectively. The capability of silk antibiotic carriers to sequester, stabilize, and then release bioactive antibiotics represents a major advantage over implants and pumps based on liquid drug reservoirs, where instability at room or body temperature is limiting. The present studies demonstrate that silk biomaterials represent a novel, customizable antibiotic platform for focal delivery of antibiotics using a range of material formats (injectable to implantable).     

Smart Hydrogels Co‐switched by Hydrogen Bonds and π–π Stacking for Continuously Regulated Controlled‐Release System

A series of hydrogels with continuously regulatable release behavior can be achieved by incorporating hydrogen bonding and π–π stacking co‐switches in polymers. A poly(nitrophenyl methacrylate‐co‐methacrylic acid) hydrogel (NPMAAHG) for control over drug release is fabricated by copolymerizing 4‐nitrophenyl methacrylate and methacrylic acid using ethylene glycol dimethacrylate as a crosslinker. The carboxylic acid groups and nitrylphenyl groups form hydrogen bonds and π–π stacking interactions, respectively, which act as switches to control the release of guest molecules from the polymers. As revealed by the simulated gastrointestinal tract drug release experiments, the as‐synthesized NPMAAHG hydrogels can be regulated to release only 4.7% of drugs after 3 h in a simulated stomach and nearly 92.6% within 43 h in the whole digestive tract. The relation between the release kinetics and structures and the mechanism of the smart release control are analyzed in terms of diffusion exponent, swelling interface number, drug diffusion coefficient, and velocity of the swelling interface in detail. The results reveal that the release of guest molecules from the hydrogels can be continuously regulated for systemic administration by controlling the ratio of the hydrophilic hydrogen bonds and the hydrophobic π–π stacking switches.     

Dual‐Drug Delivery Using Dextran‐Functionalized Nanoparticles Targeting Cardiac Fibroblasts for Cellular Reprogramming

The inability of the heart to recover from an ischemic insult leads to the formation of fibrotic scar tissue and heart failure. From the therapeutic strategies under investigation, cardiac regeneration holds the promise of restoring the full functionality of a damaged heart. Taking into consideration the presence of vast numbers of fibroblasts and myofibroblasts in the injured heart, direct fibroblast reprogramming into cardiomyocytes using small drug molecules is an attractive therapeutic option to replenish the lost cardiomyocytes. Here, a spermine‐acetalated dextran‐based functional nanoparticle is developed for pH‐triggered drug delivery of two poorly water soluble small molecules, CHIR99021 and SB431542, both capable of increasing the efficiency of direct reprogramming of fibroblast into cardiomyocytes. Upon functionalization with polyethylene glycol and atrial natriuretic peptide, the biocompatibility of the nanosystem is improved, and the cellular interactions with the cardiac nonmyocytes are specifically augmented. The dual delivery of the compounds is verified in vitro, and the compounds exerted concomitantly anticipate biological effects by stabilizing β‐catenin (CHIR99021) and by preventing translocation of Smad3 to the nucleus of (myo)fibroblasts (SB431542). These observations highlight the potential of this nanoparticle‐based system toward improved drug delivery and efficient direct reprogramming of fibroblasts into cardiomyocyte‐like cells, and thus, potential cardiac regeneration therapy.