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Process flow of SiO2/Si3N4 microneedles array a PECVD SiO2 layer deposition, b patterning of the PECVD SiO2 layer, c etching of 800 μm-deep holes using a Bosch process, d removal of the SiO2/photoresist mask, e 2 μm-thick SiO2 growth in a furnace, f 1.5 μm-thick LPCVD Si3N4 deposition, g removal of the SiO2/Si3N4 layer from the back-side of the wafer, h dry etching of silicon (ICP deep RIE), i CMP process for removing the top part (SiO2/Si3N4) of the microneedles, followed by dicing of the wafer, j assembly of the silicon chip together with the polymer funnel, k isotropic release of the needles by dry etching in XeF2
Source publication
Cell transplantation traditionally employs needles to inject donor cells into tissues to treat certain diseases. However, it is difficult for the current method to achieve multiple parallel equidistant injections, which are ideal for cell therapy. This paper presents a new cell transplantation method using an array of ultrathin microneedles. The ma...
Citations
... Research on microneedle-based cell therapy has shown promising results for tissue regeneration, cancer immunotherapy, skin immune monitoring, targeted cell delivery, drug delivery, and biomarker detection [1]. Microneedle use for transdermal delivery [2][3][4][5][6] involves the transport of active components (such as viable cells [7][8][9], insulin [10,11], nanoparticles [12,13], and exosomes [14]) into the skin. The skin is a multilayered organ that consists of three layers: the epidermis, dermis, and hypodermis. ...
A variety of hollow microneedle (HMN) designs has emerged for minimally invasive therapies and monitoring systems. In this study, a design change limiting the indentation depth of the (3D) printed custom microneedle assembly (circular array of five conical frusta with and without a stopper, aspect ratio = 1.875) fabricated using stereolithography has been experimentally validated and modeled in silico. The micro-indentation profiles generated in confined compression on 1 mm ± 0.073 mm alginate films enabled the generation of a Prony series, where displacement ranged from 100 to 250 µm. These constants were used as intrinsic properties simulating experimental ramp/release profiles. Puncture occurred on two distinct hydrogel formulations at the design depth of 150 µm and indentation rate of 0.1 mm/s characterized by a peak force of 3.5 N (H = 31 kPa) and 8.3 N (H = 36.5 kPa), respectively. Experimental and theoretical alignments for peak force trends were obtained when the printing resolution was simulated. Higher puncture force and uniformity inferred by the stopper was confirmed via microscopy and profilometry. Meanwhile, poroviscoelasticity characterization is required to distinguish mass loss vs. redistribution post-indentation through pycnometry. Results from this paper highlight the feasibility of insertion-depth control within the epidermis thickness for the first time in solid HMN literature.
... At present, different types of materials have been used for microneedle fabrication according to the requirement of different applications, such as metals (e.g., titanium [64], stainless steel [65], tantalum [66]), silicon [67], silicon dioxide [68], ceramics and polymers (e.g., carbohydrates, hydrogels) (Table 1) [69,70]. These materials have different mechanical and degradation properties, which determine their applications. ...
Microneedle, as a novel drug delivery system, has attracted widespread attention due to its non-invasiveness, painless and simple administration, controllable drug delivery, and diverse cargo loading capacity. Although microneedles are initially designed to penetrate stratum corneum of skin for transdermal drug delivery, they, recently, have been used to promote wound healing and regeneration of diverse tissues and organs and the results are promising. Despite there are reviews about microneedles, few of them focus on wound healing and tissue regeneration. Here, we review the recent advances of microneedles in this field. We first give an overview of microneedle system in terms of its potential cargos (e.g., small molecules, macromolecules, nucleic acids, nanoparticles, extracellular vesicle, cells), structural designs (e.g., multidrug structures, adhesive structures), material selection, and drug release mechanisms. Then we briefly summarize different microneedle fabrication methods, including their advantages and limitations. We finally summarize the recent progress of microneedle-assisted wound healing and tissue regeneration (e.g., skin, cardiac, bone, tendon, ocular, vascular, oral, hair, spinal cord, and uterine tissues). We expect that our article would serve as a guideline for readers to design their microneedle systems according to different applications, including material selection, drug selection, and structure design, for achieving better healing and regeneration efficacy.
... Based on the locations of the cells in the MNAs, these systems can be divided into cell-delivery MNAs and secretion-delivery MNAs. [86,87]. Cellular viability and functions were evaluated to be similar to those injected by conventional hypodermic needles. ...
Various living organisms have proven to influence human health significantly, either in a commensal or pathogenic manner. Harnessing the creatures may remarkably improve human healthcare and cure the intractable illness that is challenged using traditional drugs or surgical approaches. However, issues including limited biocompatibility, poor biosafety, inconvenience for personal handling, and low patient compliance greatly hinder the biomedical and clinical applications of living organisms when adopting them for disease treatment. Microneedle arrays (MNAs), emerging as a promising candidate of biomedical devices with the functional diversity and minimal invasion, have exhibited great potential in the treatment of a broad spectrum of diseases, which is expected to improve organism-based therapies. In this review, we systemically summarize the technologies employed for the integration of MNAs with specific living organisms including diverse viruses, bacteria, mammal cells and so on. Moreover, their applications such as vaccination, anti-infection, tumor therapy and tissue repairing are well illustrated. Challenges faced by current strategies, and the perspectives of integrating more living organisms, adopting smarter materials, and developing more advanced technologies in MNAs for future personalized and point-of-care medicine, are also discussed. It is believed that the combination of living organisms with functional MNAs would hold great promise in the near future due to the advantages of both biological and artificial species.
... [41] Thick SiO2 layers deposited using careful control of the process parameters were frequently used as masking layers for deep RIE processes. [42][43][44] ...
The deposition of thin films by Plasma Enhanced Chemical Vapor Deposition (PECVD) method is a critical process in the fabrication of MEMS or semiconductor devices. The current paper presents an comprehensive overview of PECVD process. After a short description of the PECVD reactors main layers and their application such as silicon oxide, TEOS, silicon nitride, silicon oxynitride, silicon carbide, amorphous silicon, diamond like carbon are presented. The influence of the process parameters such as: chamber pressure, substrate temperature, mass flow rate, RF Power and RF Power mode on deposition rate, film thickness uniformity, refractive index uniformity and film stress were analysed. The main challenge of thin films PECVD deposition for Microelectromechanical Systems (MEMS)and semiconductor devices is to optimize the deposition parameters for high deposition rate with low film stress which and if is possible at low deposition temperature.
... By contrast, cell delivery with cryoMNs is minimally invasive, generates no sharp hazard, and can be performed by end users with minimal expertise. In MN-based technologies, the packaging and delivery of living therapeutic formulations is one of the most are employed for intradermal infusion of melanocytes into a specific skin layer 37,38 . However, hollow MNs have intrinsic limitations, including the plugging risk of narrow lumen and the breaking risk of a needle inside skin. ...
Cell therapies for the treatment of skin disorders could benefit from simple, safe and efficient technology for the transdermal delivery of therapeutic cells. Conventional cell delivery by hypodermic-needle injection is associated with poor patient compliance, requires trained personnel, generates waste and has non-negligible risks of injury and infection. Here, we report the design and proof-of-concept application of cryogenic microneedle patches for the transdermal delivery of living cells. The microneedles are fabricated by stepwise cryogenic micromoulding of cryogenic medium with pre-suspended cells, and can be easily inserted into porcine skin and dissolve after deployment of the cells. In mice, cells delivered by the cryomicroneedles retained their viability and proliferative capability. In mice with subcutaneous melanoma tumours, the delivery of ovalbumin-pulsed dendritic cells via the cryomicroneedles elicited higher antigen-specific immune responses and led to slower tumour growth than intravenous and subcutaneous injections of the cells. Biocompatible cryomicroneedles may facilitate minimally invasive cell delivery for a range of cell therapies.
... Technically simple, without any pump or loading/coating procedure, small doses can be administered Two-step administration procedure, no exact dosing, drugs need to be reformulated Skin pretreatment for the delivery of insulin [55], cosmetics [56], vaccines [57], potassium chloride [58], monitoring of lactate and glucose [59], urea sensing [60] Delivery of vaccines [67], insulin [68], cell therapy [69], delivery of mRNA [70], DNA (pDNA) [71], biofluid extraction and bio-signal detection [72,73], colorimetric detection of glucose [74] Dissolving No need for any pump or patch, precise dosing is possible, no sharp waste, low preparation costs Small drug doses may be lost throughout the encapsulation/absorption procedure, low strength, low penetration ability, limited to small drug doses, drug reformulation is needed Delivery of vaccines [75,76], insulin [77], therapeutic peptides [78], triamcinolone acetonide [79], doxorubicin [80], epidermal growth factor and ascorbic acid [81], adenosine [82], vitamin B12 [83], near-IR photosensitizer (Redaporfin™) [84], sodium nitroprusside in combination with sodium thiosulfate [85], DNA extraction [86] Hydrogel-forming ...
Organic and inorganic nanoparticles (NPs) have shown promising outcomes in transdermal drug delivery. NPs can not only enhance the skin penetration of small/biomacromolecule therapeutic agents but can also impart control over drug release or target impaired tissue. Thanks to their unique optical, photothermal, and superparamagnetic features, NPs have been also utilized for the treatment of skin disorders, imaging, and biosensing applications. Despite the widespread transdermal applications of NPs, their delivery across the stratum corneum, which is the main skin barrier, has remained challenging. Microneedle array (MN) technology has recently revealed promising outcomes in the delivery of various formulations, especially NPs to deliver both hydrophilic and hydrophobic therapeutic agents. The present work reviews the advancements in the application of MNs and NPs for an effective transdermal delivery of a wide range of therapeutics in cancer chemotherapy and immunotherapy, photothermal and photodynamic therapy, peptide/protein vaccination, and the gene therapy of various diseases. In addition, this paper provides an overall insight on MNs’ challenges and summarizes the recent achievements in clinical trials with future outlooks on the transdermal delivery of a wide range of nanomedicines.
... Computer software (XT Microscope control, Quanta Oregon, USA) was used to analyse SEM images. 34 ...
Objectives:
This work illustrates a novel method of fabrication of polymeric microneedle (MN) construct using bees wax as mould and development of coated polymeric MNs for drug delivery.
Materials and methods:
A novel method of MN fabrication using bees wax as mould was established. The porous chitosan MN arrays were fabricated and coated with polylactic acid (PLA). The optimized MN arrays were coated with bovine serum albumin (BSA). The MNs were subjected to physiochemical and tensile strength characterization, followed by drug release study. The skin penetration and irritation study were performed in vivo in Wistar Albino rats.
Results:
The constructed MN arrays contain MNs with 0.9 mm length, 600 μm width at the base, 30-60 μm diameter at the tip, and 1.5 mm distance between 2 needles. These MNs patch was having good mechanical strength (0.72 N/needle) and tensile strength 15.23 Mpa. The MN array patch had 6.26% swelling index and 98.5% drug release was observed on the 50th hr. Good penetration and no skin irritation was observed for optimized MN batch.
Conclusion:
Polymeric MN arrays were successfully developed using bees wax mould and were successfully coated with PLA to deliver the BSA through skin epidermis layer.
... Receptor compartment was filled with a buffer solution (pH 7.4) having SLS (1%) maintained at 37 ± 1°C using hotplate stirrer throughout the test period. At predetermined intervals (1,2,3,4,5,6,7,8,10,12,16,20,24,30,36,42, and 48 h), 0.5 mL of the sample was withdrawn from the arm of recipient chamber and replaced with an equal volume of fresh medium maintained at 37 ± 1°C. The samples were analysed using HPLC as reported earlier (33). ...
Microneedle patch is a prominent strategy with minimal invasion and painless application to improve skin penetration of drug molecules. Herein, we report microneedle patch (MNP) as an alternative to the oral route for the systemic delivery of tacrolimus (TM), an immunosuppressant drug. Thiolated chitosan (TCS) based microneedle patch was fabricated and characterized in vitro and in vivo for its mechanical strength, skin penetration, drug release, and skin irritation. The MNP having 225 needles with 575 μm showed good mechanical properties in terms of tensile strength and percentage elongation. The skin penetration showed 84% penetration with no breakage. Histology of the mice skin after insertion showed the penetration of needles into the dermis. In vitro release and ex vivo permeation studies through Franz diffusion cell showed the sustained release (82.5%) of TM from the MNP with significantly higher (p < 0.05) skin permeation as compared with controls, respectively. Moreover, in vivo biocompatibility in rats showed the safety of the material and patch. Thus, the TCS microneedle patch has the potential to be developed as a transdermal delivery system for tacrolimus with improved bioavailability and sustained release over a longer period.
... The deposition of TEOS on PECVD reactors are a viable solution for MEMS and IC applications. [27][28][29][30][31][32][33] We demonstrate the controlling the deposition process deposition rates above 200nm/min can be achieved. Based on the results, we are able to recommend the following parameters for the TEOS PECVD process. ...
The deposition of silicon dioxide layers on Silicon substrate using tetraethyl-orthosilicate (TEOS) by Plasma Enhanced Chemical Vapor Deposition (PECVD) method was characterized in this work. Deposition rate, film thickness uniformity, refractive index uniformity and film stress were analyzed in relation to variation of process parameters such as: chamber pressure, substrate temperature, RF Power and mass flow rate (of oxygen and TEOS) had been investigated. The challenge is to optimize the film deposition for (a) a high deposition rate with low film stress which is significant for Microelectromechanical Systems (MEMS) and (b) a high deposition rate at a low temperature (200°C) which is relevant aspect for microelectronics packaging applications.
The delivery of therapeutical molecules through the skin, particularly to its deeper layers, is impaired due to the stratum corneum layer, which acts as a barrier to foreign substances. Thus, for the past years, scientists have focused on the development of more efficient methods to deliver molecules to skin distinct layers. Microneedles, as a new class of biomedical devices, consist of an array of microscale needles. This particular biomedical device has been drawing attention due to its ability to breach the stratum corneum, forming micro-conduits to facilitate the passage of therapeutical molecules. The microneedle device has several advantages over conventional methods, such as better medication adherence, easiness, and painless self-administration. Moreover, it is possible to deliver the molecules swiftly or over time. Microneedles can vary in shape, size, and composition. The design process of a microneedle device must take into account several factors, like the location delivery, the material, and the manufacturing process. Microneedles have been used in a large number of fields from drug and vaccine application to cosmetics, therapy, diagnoses, tissue engineering, sample extraction, cancer research, and wound healing, among others.
