Biodegradable Polymer Microneedles Research Articles

A highly robust approach to fabricate the mass-customizable mold of sharp-tipped biodegradable polymer microneedles for drug delivery

A skin-perforable dissolving microneedle is a promising mediator for painlessly delivering active pharmaceutical compounds across the skin. All the microneedle manufacturing processes so far, however, are much sensitive to input variation and unfavorable for make-to-order approach. Here, a robust method for fabricating mass-customizable master molds is developed to prepare sharp-tipped biodegradable polymer microneedles. Our approach combines the predrying and chip casting (PCC) of an ultrathick photoresist layer with a substrateless, inclined, and rotational exposure (SIR exposure). The PCC achieves the uniform reduction of solvent across the photoresist thickness which is critically required for the formation of a sharp tip; the SIR exposure creates master molds whose geometry is easily customizable and virtually insensitive to a variation in ultraviolet (UV) exposure dose. A theoretical model for the spatiotemporal distribution of UV dose under SIR exposure is established to show the technological superiority of our method. Next, our method’s applicability is proven by fabricating a set of poly(lactic-co-glycolic) acid (PLGA) microneedles and performing both porcine skin penetration test and their in vitro degradation test. Our approach is verified to be robust in manufacturing mass-customizable molds for skin-perforable dissolving microneedles and to have high compatibility with almost all existing biodegradable polymers. The findings of this study lead to both a significant growth of dissolving microneedle-mediated drug delivery and better understanding of drug release kinetics.

Engineered PLGA-PVP/VA based formulations to produce electro-drawn fast\xa0biodegradable microneedles for labile biomolecule delivery

Biodegradable polymer microneedles (MNs) are recognized as non-toxic, safe and stable systems for advanced drug delivery and cutaneous treatments, allowing a direct intradermal delivery and in some cases a controlled release. Most of the microneedles found in the literature are fabricated by micromolding, which is a multistep thus typically costly process. Due to industrial needs, mold-free methods represent a very intriguing approach in microneedle fabrication. Electro-drawing (ED) has been recently proposed as an alternative fast, mild temperature and one-step strategy to the mold-based techniques for the fabrication of poly(lactic-co-glycolic acid) (PLGA) biodegradable MNs. In this work, taking advantage of the flexibility of the ED technology, we engineered microneedle inner microstructure by acting on the water-in-oil (W/O) precursor emulsion formulation to tune drug release profile. Particularly, to promote a faster release of the active pharmaceutical ingredient, we substituted part of PLGA with poly(1-vinylpyrrolidone-co-vinyl acetate) (PVP/VA), as compared to the PLGA alone in the matrix material. Moreover, we introduced lecithin and maltose as emulsion stabilizers. Microneedle inner structural analysis as well as collagenase entrapment efficiency, release and activity of different emulsion formulations were compared to reach an interconnected porosity MN structure, aimed at providing an efficient protein release profile. Furthermore, MN mechanical properties were examined as well as its ability to pierce the stratum corneum on a pig skin model, while the drug diffusion from the MN body was monitored in an in vitro collagen-based dermal model at selected time points.

Non-invasive Production of Multi-Compartmental Biodegradable Polymer Microneedles for Controlled Intradermal Drug Release of Labile Molecules.

Transdermal drug delivery represents an appealing alternative to conventional drug administration systems. In fact, due to their high patient compliance, the development of dissolvable and biodegradable polymer microneedles has recently attracted great attention. Although stamp-based procedures guarantee high tip resolution and reproducibility, they have long processing times, low levels of system engineering, are a source of possible contaminants, and thermo-sensitive drugs cannot be used in conjunction with them. In this work, a novel stamp-based microneedle fabrication method is proposed. It provides a rapid room-temperature production of multi-compartmental biodegradable polymeric microneedles for controlled intradermal drug release. Solvent casting was carried out for only a few minutes and produced a short dissolvable tip made of polyvinylpyrrolidone (PVP). The rest of the stamp was then filled with degradable poly(lactide-co-glycolide) (PLGA) microparticles (μPs) quickly compacted with a vapor-assisted plasticization. The outcome was an array of microneedles with tunable release. The ability of the resulting microneedles to indent was assessed using pig cadaver skin. Controlled intradermal delivery was demonstrated by loading both the tip and the body of the microneedles with model therapeutics; POXA1b laccase from Pleurotus ostreatus is a commercial enzyme used for the whitening of skin spots. The action and indentation of the enzyme-loaded microneedle action were assessed in an in vitro skin model and this highlighted their ability to control the kinetic release of the encapsulated compound.

Drug loaded biodegradable polymer microneedles fabricated by hot embossing

This study demonstrates a fast low temperature method for fabrication of drug loaded polymer microneedles (MNs). First, arrays of tapered pillar MNs with a length of 275 ± 3 μm (mean ± SD) and a diameter of 84 ± 1 μm were fabricated in Si with a three-step deep reactive ion etching (DRIE) process. The Si MNs were used as a template for fabrication of polydimethylsiloxane (PDMS) stamps. The stamps were applied for replication of the MNs in spin coated poly‑ε‑caprolactone (PCL) films by hot embossing at 60 °C and a pressure of 1.4 MPa for 3 min. The resulting PCL MNs perfectly resembled the Si MNs and had a length of 270 ± 5 μm and a diameter of 84 ± 3 μm. The MNs had sufficient mechanical strength to penetrate the surface of a 10 w/w% gelatine gel without deformation. Finally, PCL MNs containing 20 w/w% of furosemide were fabricated and drug release by diffusion was demonstrated.

Electro-drawn polymer microneedle arrays with controlled shape and dimension

Biodegradable polymer microneedles are recognized as a valuable route for transdermal drug delivery as well as for cutaneous treatments. According to the industrial needs, the present trend is to fabricate microneedles through stamp-less techniques. Electro-drawing has been recently proposed as an alternative fast and mild temperature strategy to the stamp based techniques for the fabrication of biodegradable polymer microneedles. However, previously presented electro-drawn microneedles were fabricated by a point-like thermal stimulation, thus, they could not be electro-drawn in parallel and displayed a pedestal at their basis. Here, we present a novel electro-drawing set up and strategy to parallelize the process and to avoid the pedestal at the microneedle basis. The new set-up is based on titanium micro-heaters integrated onto the pyroelectric substrate which is the electric field generator enabling the electro-drawing. The micro-heaters configuration has been chosen starting from numerical simulations to guarantee uniform heating on large areas, in contrast to the local heating by hot tip, allowing the generation of a uniform electric field which is a basic condition for an in parallel fabrication of microneedles. Additionally, thanks to the stronger electric field, it was possible to apply a double step electro-drawing, where the second step is carried out at higher distance in order to avoid microneedle shrinkage while avoiding further growing of the microneedles.

Simple and cost-effective fabrication of solid biodegradable polymer microneedle arrays with adjustable aspect ratio for transdermal drug delivery using acupuncture microneedles

Polymer microneedle arrays (MNAs) have received much attention for their use in transdermal drug delivery and microneedle therapy systems due to the advantages they offer, such as low cost, good mechanical properties, and a versatile choice of materials. Here, we present a simple and cost-effective method for the fabrication of a biodegradable polymer MNA in which the aspect ratio of each microneedle is adjustable using commercially available acupuncture microneedles. In our process, a master template with acupuncture microneedles, whose shape will be the final MNA, was carefully prepared by fixing them onto a plastic substrate with selectively drilled holes which, in turn, determine the aspect ratios of the microneedles. A polylactic acid (PLA; a biodegradable polymer) MNA was fabricated by a micromolding process with a polydimethylsiloxane (PDMS) mold containing the cavity of the microneedles, which was obtained by the PDMS replica molding against the master template. The mechanical force and degradation behavior of the replicated PLA MNA were characterized with the help of a compression test and an accelerated degradation test, respectively. Finally, the transdermal drug delivery performance of the PLA MNA was successfully simulated by two different methods of penetration and staining, using the skin of a pig cadaver. These results indicated that the proposed method can be effectively used for the fabrication of polymer MNAs which can be used in various microneedle applications.

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.

Optimal Design of Microneedles Inserts into Skin by Numerical Simulation

The purpose of this research is to find the optimal design for biodegradable polymer microneedle patches. Based on the mechanical properties of different skin layers and the failure criterion of the material, this research designs a microneedle of four types and three sizes, then discusses the insertion force and the variation of stress during the process of PLA microneedle insertion into skin by numerical simulation. This research uses the dynamic finite element software ANSYS / LS-DYNA to simulate the processing for PLA microneedle inserts into skin. The master microneedle array was fabricated by the MEMS process. This research uses PDMS to fabricate the mould for microneedles. Finally, a biodegradable polymer polylactic acid (PLA) microneedle patch was fabricated using a PDMS mould micro hot embossing method.

Engineered microneedle arrays for transcutaneous HIV vaccine delivery (113.17)

Abstract Microneedle skin patches represent a promising approach for safe, convenient, and rapid delivery of vaccines and therapeutics to the skin through pain-free disruption of the stratum corneum to access epidermal and dermal immune-competent cell populations. We have developed a ‘nano-layer’-coated microneedle (MN) delivery platform in which vaccines/therapeutics encapsulated in surface coatings on biodegradable polymer MNs are rapidly delivered upon application to the skin of mice. Layer-by-layer deposition of plasmid DNA (pDNA) and nucleic acid TLR agonists together with biodegradable polymers on the surface of microneedle arrays gave thin coatings with tunable dosages of vaccine cargo and vaccine release rates. Following application of coated MN arrays to the skin of mice for ~5 min, intact film coatings were rapidly implanted in the skin for sustained release of vaccine components over time. Microneedle delivery of DNA vaccines encoding SIV-gag proteins induced 5-fold increased antigen-specific T-cell expansion and generation of serum IgG titers 5-fold in excess of that observed for traditional i.m. or i.d. immunizations; further, responses obtained with MN delivery were quantitatively similar to those observed for i.m. delivery with in vivo electroporation. MN delivery also induced enhanced generation of long-lived memory T-cells. Together these results demonstrate the potential for MN delivery to improve vaccine performance in the context of HIV immunization.

Hydrogel swelling as a trigger to release biodegradable polymer microneedles in skin

Biodegradable polymeric microneedles were developed as a method for achieving sustained transdermal drug release. These microneedles have potential as a patient-friendly substitute for conventional sustained release methods. However, they have limitations related to the difficulty of achieving separation of the needles into the skin. We demonstrated that microneedle separation into the skin was mediated by hydrogel swelling in response to contact with body fluid after the needles were inserted into the skin. The hydrogel microparticles were synthesized by an emulsification method using poly-N-isopropylacrylamide (PNIPAAm). The microneedles were fabricated by micromolding poly-lactic-co-glycolic acid (PLGA) after filling the cavities of the mold with the hydrogel microparticles. The failure of microneedle tips caused by hydrogel swelling was studied in regard to contact with water, insertion of microneedles into porcine cadaver skin in vitro, stress–strain behavior, and insertion into the back skin of a hairless mouse in vivo. The drug delivery property of the hydrogel particles was investigated qualitatively by inserting polymer microneedles into porcine cadaver skin in vitro, and the sustained release property of PLGA microneedles containing hydrogel microparticles was studied quantitatively using the Franz cell model. The hydrogel particles absorbed water quickly, resulting in the cracking of the microneedles due to the difference in volume expansion between the needle matrix polymer and the hydrogel particles. The swollen particles caused the microneedles to totally breakdown, leaving the microneedle tips in the porcine cadaver skin in vitro and in the hairless mouse skin in vivo. Model drugs encapsulated in biodegradable polymer microneedles and hydrogel microparticles were successfully delivered by releasing microneedles into the skin.

Polymer Microneedles for Controlled-Release Drug Delivery

As an alternative to hypodermic injection or implantation of controlled-release systems, this study designed and evaluated biodegradable polymer microneedles that encapsulate drug for controlled release in skin and are suitable for self-administration by patients. Arrays of microneedles were fabricated out of poly-lactide-co-glycolide using a mold-based technique to encapsulate model drugs--calcein and bovine serum albumin (BSA)--either as a single encapsulation within the needle matrix or as a double encapsulation, by first encapsulating the drug within carboxymethylcellulose or poly-L: -lactide microparticles and then encapsulating drug-loaded microparticles within needles. By measuring failure force over a range of conditions, poly-lactide-co-glycolide microneedles were shown to exhibit sufficient mechanical strength to insert into human skin. Microneedles were also shown to encapsulate drug at mass fractions up to 10% and to release encapsulated compounds within human cadaver skin. In vitro release of calcein and BSA from three different encapsulation formulations was measured over time and was shown to be controlled by the encapsulation method to achieve release kinetics ranging from hours to months. Release was modeled using the Higuchi equation with good agreement (r2 > or = 0.90). After microneedle fabrication at elevated temperature, up to 90% of encapsulated BSA remained in its native state, as determined by measuring effects on primary, secondary, and tertiary protein structure. Biodegradable polymer microneedles can encapsulate drug to provide controlled-release delivery in skin for hours to months.

Biodegradable polymer microneedles: Fabrication, mechanics and transdermal drug delivery

To overcome the skin's barrier properties that block transdermal delivery of most drugs, arrays of microscopic needles have been microfabricated primarily out of silicon or metal. This study addresses microneedles made of biocompatible and biodegradable polymers, which are expected to improve safety and manufacturability. To make biodegradable polymer microneedles with sharp tips, micro-electromechanical masking and etching were adapted to produce beveled- and chisel-tip microneedles and a new fabrication method was developed to produce tapered-cone microneedles using an in situ lens-based lithographic approach. To replicate microfabricated master structures, PDMS micromolds were generated and a novel vacuum-based method was developed to fill the molds with polylactic acid, polyglycolic acid, and their co-polymers. Mechanical testing of the resulting needles measured the force at which needles broke during axial loading and found that this failure force increased with Young's modulus of the material and needle base diameter and decreased with needle length. Failure forces were generally much larger than the forces needed to insert microneedles into skin, indicating that biodegradable polymers can have satisfactory mechanical properties for microneedles. Finally, arrays of polymer microneedles were shown to increase permeability of human cadaver skin to a low-molecular weight tracer, calcein, and a macromolecular protein, bovine serum albumin, by up to three orders of magnitude. Altogether, these results indicate that biodegradable polymer microneedles can be fabricated with an appropriate geometry and sufficient strength to insert into skin, and thereby dramatically increase transdermal transport of molecules.

Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: fabrication methods and transport studies.

Arrays of micrometer-scale needles could be used to deliver drugs, proteins, and particles across skin in a minimally invasive manner. We therefore developed microfabrication techniques for silicon, metal, and biodegradable polymer microneedle arrays having solid and hollow bores with tapered and beveled tips and feature sizes from 1 to 1,000 microm. When solid microneedles were used, skin permeability was increased in vitro by orders of magnitude for macromolecules and particles up to 50 nm in radius. Intracellular delivery of molecules into viable cells was also achieved with high efficiency. Hollow microneedles permitted flow of microliter quantities into skin in vivo, including microinjection of insulin to reduce blood glucose levels in diabetic rats.