Dissolving and Swelling Hydrogel-Based Microneedles: An Overview of Their Materials, Fabrication, Characterization Methods, and Challenges
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AbstractPolymeric hydrogels are a complex class of materials with one common feature—the ability to form three-dimensional networks capable of imbibing large amounts of water or biological fluids without being dissolved, acting as self-sustained containers for various purposes, including pharmaceutical and biomedical applications. Transdermal pharmaceutical microneedles are a pain-free drug delivery system that continues on the path to widespread adoption—regulatory guidelines are on the horizon, and investments in the field continue to grow annually. Recently, hydrogels have generated interest in the field of transdermal microneedles due to their tunable properties, allowing them to be exploited as delivery systems and extraction tools. As hydrogel microneedles are a new emerging technology, their fabrication faces various challenges that must be resolved for them to redeem themselves as a viable pharmaceutical option. This article discusses hydrogel microneedles from a material perspective, regardless of their mechanism of action. It cites the recent advances in their formulation, presents relevant fabrication and characterization methods, and discusses manufacturing and regulatory challenges facing these emerging technologies before their approval.
CitationShriky B, Babenko M and Whiteside BR (2023) Dissolving and Swelling Hydrogel-Based Microneedles: An Overview of Their Materials, Fabrication, Characterization Methods, and Challenges. Gels 9(10): 806
Link to publisher’s versionhttps://doi.org/10.3390/gels9100806
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A cost-effective process chain for thermoplastic microneedle manufacture combining laser micro-machining and micro-injection mouldingGülçür, Mert,; Romano, J-M.; Penchev, P.; Gough, Timothy D.; Brown, Elaine C.; Dimov, S.; Whiteside, Benjamin R. (Elsevier, 2021-01)High-throughput manufacturing of transdermal microneedle arrays poses a significant challenge due to the high precision and number of features that need to be produced and the requirement of multi-step processing methods for achieving challenging micro-features. To address this challenge, we report a flexible and cost-effective process chain for transdermal microneedle array manufacture that includes mould production using laser machining and replication of thermoplastic microneedles via micro-injection moulding (micromoulding). The process chain also incorporates an in-line manufacturing data monitoring capability where the variability in the quality of microneedle arrays can be determined in a production run using captured data. Optical imaging and machine vision technologies are also implemented to create a quality inspection system that allows rapid evaluation of key quality indicators. The work presents the capability of laser machining as a cost-effective method for making microneedle moulds and micro-injection moulding of thermoplastic microneedle arrays as a highly-suitable manufacturing technique for large-scale production with low marginal cost.
Process Fingerprinting of Microneedle Manufacturing Using Conventional and Ultrasonic Micro-injection MouldingWhiteside, Benjamin R.; Gough, Timothy D.; Brown, Elaine C.; Gulcur, Mert (University of BradfordFaculty of Engineering and Informatics, 2019)This research work investigates the development and application of process fingerprinting for conventional micro-injection moulding and ultrasonic micro injection moulding manufacturing of microneedle arrays for drug delivery. The process fingerprinting method covers in-depth analysis, interrogation and selection of certain process data features and correlation of these features with product fingerprints which are defined by the geometrical outcomes of the microneedle arrays in micro scale. The method was developed using the data collected using extensive sensor technologies attached to the conventional and ultrasonic micromoulding machines. Moreover, a machine vision based microneedle product evaluation apparatus is presented. Micromachining capabilities of different processes is also assessed and presented where state-of-the-art laser machining was used for microneedle tool manufacturing in the work. By using process fingerprinting procedures, conventional and ultrasonic micromoulding processes has been characterised thoroughly and aspects of the process that is affecting the part quality was also addressed for microneedle manufacturing. It was found that polymer structure is of paramount importance in obtaining sufficient microneedle replication. An amorphous polymer have been found to be more suitable for conventional moulding whereas semi-crystalline materials performed better in ultrasonic micromoulding. In-line captured micromoulding process data for conventional and ultrasonic moulding provided detailed insight of machine dynamics and understanding. Linear correlations between process fingerprints and micro replication efficiency of the microneedles have been presented for both micromoulding technologies. The in-line process monitoring and product quality evaluation procedures presented in this work for micro-injection moulding techniques will pave ways for zero-defect micromanufacturing of miniature products towards Industry 4.0.
Micro-injection moulded microneedles for drug delivery.Whiteside, Benjamin R.; Paradkar, Anant R.; Nair, Karthik Jayan (University of BradfordSchool of Engineering and Informatics, 2016-02-26)The emergence of microneedle (MN) technologies offers a route for a pain free, straightforward and efficient way of transdermal drug delivery, but technological barriers still exist which pose significant challenges for manufacture of MN systems with high volume outputs at low cost. The main aim of this research was to develop new ways for MN manufacture primarily using micro-injection moulding processes with high performance engineering thermoplastics. During the moulding process these polymeric melts will be subjected to extreme stress and temperature gradients and detailed material characterisation combined with in-line monitoring is desirable to optimise the moulding parameters and will help in achieving sharp microneedles with acceptable quality. Hence high shear rheology of these selected materials was performed at wall shear rates carried out in excess of 107 s-1 over a range of temperatures to predict the flow behaviour of polymer melts at such high shear strain rates. This information was fed into injection moulding simulation software tools (Moldflow) to assist the MN production process design. The optimal design was then used to produce a full 3D solid model of the injection mould and mould insert. Furthermore various design of experiments were conducted considering input parameters such as injection pressure, injection speed, melt temperature, filling time and mould cavity temperature. Response variables including product quality and data acquired from the cavity pressure and temperature transducers were used to optimise the manufacturing process. The moulded MNs were geometrically assessed using a range of characterisation techniques such as atomic force microscopy, confocal microscopy and scanning electron microscopy. An attempt to make hollow MNs was performed and encountered many challenges like partial cavity filling and part ejection during processing. Studies were carried out to understand the problem and identified the major problem was in tool design and improvements to the moulding tool design were recommended. Plasma treatment and mechanical abrasion were employed to increase the surface energy of the moulded polymer surfaces with the aim of enhancing protein adsorption. Sample surface structures before and after treatment were studied using AFM and surface energies have been obtained using contact angle measurement and calculated using Owens-Wendt theory. Adsorption performance of bovine serum albumin and release kinetics for each sample set was assessed using a Franz diffusion cell. Results indicate that plasma treatment significantly increases the surface energy and roughness resulting in better adsorption and release of BSA. To assist design-optimisation and to assess performance, a greater understanding of MN penetration behaviour is required. Contact stiffness, failure strength and creep behaviour were measured during compression tests of MN against a steel surface, and in-vitro penetration of MNs into porcine skin. The MN penetration process into porcine skin was imaged using optical coherence tomography. Finally, a finite element model of skin was established to understand the effect of tip geometry on penetration. The output of findings from this research will provide proof of concept level development and understanding of mechanisms of MN penetration and failure, facilitating design improvements for micro-injection moulded polymeric MNs.