A therapeutic convection-enhanced macroencapsulation device for enhancing ß cell viability and insulin secretion.

Islet transplantation for type 1 diabetes treatment has been limited by the need for lifelong immunosuppression regimens. This challenge has prompted the development of macroencapsulation devices (MEDs) to immunoprotect the transplanted islets. While promising, conventional MEDs are faced with insufficient transport of oxygen, glucose, and insulin because of the reliance on passive diffusion. Hence, these devices are constrained to two-dimensional, wafer-like geometries with limited loading capacity to maintain cells within a distance of passive diffusion. We hypothesized that convective nutrient transport could extend the loading capacity while also promoting cell viability, rapid glucose equilibration, and the physiological levels of insulin secretion. Here, we showed that convective transport improves nutrient delivery throughout the device and affords a three-dimensional capsule geometry that encapsulates 9.7-fold-more cells than conventional MEDs. Transplantation of a convection-enhanced MED (ceMED) containing insulin-secreting ß cells into immunocompetent, hyperglycemic rats demonstrated a rapid, vascular-independent, and glucose-stimulated insulin response, resulting in early amelioration of hyperglycemia, improved glucose tolerance, and reduced fibrosis. Finally, to address potential translational barriers, we outlined future steps necessary to optimize the ceMED design for long-term efficacy and clinical utility.

Outcome of congenital tracheal stenosis in children over two decades in a national cardiothoracic surgical unit.

OBJECTIVE: To assess the outcomes of congenital tracheal stenosis among children. MATERIALS AND METHODS: A retrospective review of all children who underwent surgical repair of congenital tracheal stenosis reviewing charts, operative notes, echocardiograms, CT and MRI data from January 2002 to February 2019. RESULTS: Twenty-six children underwent surgical treatment for tracheal stenosis. The median age was 3 months (range 0.3-35 months) and the median weight was 4.7 kg (range 2.5-13 kg) at the time of surgical intervention. Stridor was the most common presenting symptom in 17 patients (65% of patients). Twenty-one patients (81%) had concurrent cardiac anomalies, with pulmonary arterial sling being the most common, present in nine patients (34%). Extracorporeal life support was utilised in seven patients (27%) pre-operatively. Laryngeal release was required in 16 patients. In 7 patients an end-to-end anastomosis was performed, in 18 patients slide tracheoplasty, and 1 patient had a double slide tracheoplasty. The median cardiopulmonary bypass time was 106 minutes (range 25-255 minutes). The median cross-clamp time was 30 minutes (range 5-67 minutes). The median post-operative duration of ventilation was 5 days (range 0.5-16 days). The median ICU length of stay was 12.5 days (range 2-60 days). There were three hospital mortalities with 88% survival. One patient only required reintervention with balloon dilation. Twenty-two patients (85%) remained symptom-free on median follow-up at 7.6 years (range 0.2-17 years). Two patients since 2017 had 3D printed tracheas produced from CT imaging to assist surgical planning. CONCLUSION: Congenital tracheal stenosis can be managed effectively with excellent outcomes and 3D printed models assist in planning the optimal surgical intervention.

Toward Biofunctional Microneedles for Stimulus Responsive Drug Delivery.

Microneedles have recently been adopted for use as a painless and safe method of transdermal therapeutic delivery through physically permeating the stratum corneum. While microneedles create pathways to introduce drugs, they can also act as conduits for biosignal sensing. Here, we explore the development of microneedles as both biosensing and drug delivery platforms. Microneedle sensors are being developed for continuous monitoring of biopotentials and bioanalytes through the use of conductive and electrochemically reactive biomaterials. The range of therapeutics being delivered through microneedle devices has diversified, while novel bioabsorbable microneedles are undergoing first-in-human clinical studies. We foresee that future microneedle platform development will focus on the incorporation of biofunctional materials, designed to deliver therapeutics in a stimulus responsive fashion. Biofunctional microneedle patches will require improved methods of attaching to and conforming to epithelial tissues in dynamic environments for longer periods of time and thus present an assortment of new design challenges. Through the evolution of biomaterial development and microneedle design, biofunctional microneedles are proposed as a next generation of stimulus responsive drug delivery systems.

Optimising Mg-Ca/PLA Composite Filaments for Additive Manufacturing: An Analysis of Particle Content, Size, and Morphology.

Low-temperature additive manufacturing of magnesium (Mg) alloy implants is considered a promising technique for biomedical applications due to Mg's inherent biocompatibility and 3D printing's capability for patient-specific design. This study explores the influence of powder volume content, size, and morphology on the mechanical properties and viscosity of polylactic acid (PLA) matrix composite filaments containing in-house-produced magnesium-calcium (Mg-Ca) particles, with a focus on their application towards low-temperature additive manufacturing. We investigated the effects of varying the Mg-Ca particle content in a PLA matrix, revealing a direct correlation between volume content and bending strength. Particle size analysis demonstrated that smaller particles (D50: 57 µm) achieved a bending strength of 63.7 MPa, whereas larger particles (D50: 105 µm) exhibited 49.6 MPa at 20 vol.%. Morphologically, the filament containing spherical particles at 20 vol.% showed a bending strength that was 11.5 MPa higher than that of the filament with irregular particles. These findings highlight the critical role of particle content, size, and shape in determining the mechanical and rheological properties of Mg-Ca/PLA composite filaments for use in material extrusion additive manufacturing.

Mechanical characterisation of commercial artificial skin models.

Understanding of the mechanical properties of skin is crucial in evaluating the performance of skin-interfacing medical devices. Artificial skin models (ASMs) have rapidly gained attention as they are able to overcome the challenges in ethically sourcing consistent and representative ex vivo animal or human tissue models. Although some ASMs have become commercialised, a thorough understanding of the mechanical properties of the skin models is crucial to ensure that they are suitable for the purpose of the study. In the present study, skin and fat layers of ASMs (Simulab®, LifeLike®, SynDaver® and Parafilm®) were mechanically characterised through hardness, needle insertion, tensile and compression testing. Different boundary constraint conditions (minimally and highly constrained) were investigated for needle insertion testing, while anisotropic properties of the skin models were investigated through different specimen orientations during tensile testing. Analysis of variance (ANOVA) tests were performed to compare the mechanical properties between the skin models. Properties of the skin models were compared against literature to determine the suitability of the skin models based on the material property of interest. All skin models offer relatively consistent mechanical performance, providing a solid basis for benchtop evaluation of skin-interfacing medical device performance. Through prioritising models with mechanical properties that are consistent with human skin data, and with limited variance, researchers can use the data presented here as a toolbox to select the most appropriate ASM for their particular application.

Metallic Microneedles for Transdermal Drug Delivery: Applications, Fabrication Techniques and the Effect of Geometrical Characteristics.

Current procedures for transdermal drug delivery (TDD) have associated limitations including poor administration of nucleic acid, small or large drug molecules, pain and stress for needle phobic people. A painless micro-sized device capable of delivering drugs easily and efficiently, eliminating the disadvantages of traditional systems, has yet to be developed. While polymeric-based microneedle (MN) arrays have been used successfully and clinically as TDD systems, these devices lack mechanical integrity, piercing capacity and the ability to achieve tailored drug release into the systemic circulation. Recent advances in micro/nano fabrication techniques using Additive Manufacturing (AM), also known as 3D printing, have enabled the fabrication of metallic MN arrays, which offer the potential to overcome the limitations of existing systems. This review summarizes the different types of MNs used in TDD and their mode of drug delivery. The application of MNs in the treatment of a range of diseases including diabetes and cancer is discussed. The potential role of solid metallic MNs in TDD, the various techniques used for their fabrication, and the influence of their geometrical characteristics (e.g., shape, size, base diameter, thickness, and tip sharpness) on effective TDD are explored. Finally, the potential and the future directions relating to the optimization of metallic MN arrays for TDD are highlighted.

Towards a Whole Sample Imaging Approach Using Diffusion Tensor Imaging to Examine the Foreign Body Response to Explanted Medical Devices.

Analysing the composition and organisation of the fibrous capsule formed as a result of the Foreign Body Response (FBR) to medical devices, is imperative for medical device improvement and biocompatibility. Typically, analysis is performed using histological techniques which often involve random sampling strategies. This method is excellent for acquiring representative values but can miss the unique spatial distribution of features in 3D, especially when analysing devices used in large animal studies. To overcome this limitation, we demonstrate a non-destructive method for high-resolution large sample imaging of the fibrous capsule surrounding human-sized implanted devices using diffusion tensor imaging (DTI). In this study we analyse the fibrous capsule surrounding two unique macroencapsulation devices that have been implanted in a porcine model for 21 days. DTI is used for 3D visualisation of the microstructural organisation and validated using the standard means of fibrous capsule investigation; histological analysis and qualitative micro computed tomography (microCT) and scanning electron microscopy (SEM) imaging. DTI demonstrated the ability to distinguish microstructural differences in the fibrous capsules surrounding two macroencapsulation devices made from different materials and with different surface topographies. DTI-derived metrics yielded insight into the microstructural organisation of both capsules which was corroborated by microCT, SEM and histology. The non-invasive characterisation of the integration of implants in the body has the potential to positively influence analysis methods in pre-clinical studies and accelerate the clinical translation of novel implantable devices.

Comparing three-dimensional models of placenta accreta spectrum with surgical findings.

OBJECTIVE: Placenta accreta spectrum (PAS) is associated with significant maternal morbidity mainly related to blood loss. Pre-operative planning is aided by antenatal ultrasound and magnetic resonance imaging. We sought to assess whether three-dimensional (3D) models from MR images were accurate when compared with surgical and pathological findings. METHODS: Digital Imaging and Communications in Medicine files containing MR images with varying severity of PAS (n = 4) were modeled using 3D Slicer. Placenta, bladder, and myometrial defects were modeled. Myometrial defects at three different uterine locations were included-anterior, lateral and inferior. 3D models were used to identify the relationship between the myometrial defect and the internal cervical os. Findings were validated in a larger series of PAS cases (n = 14) where patterns of invasion were compared with estimated blood loss and distance from defect to the internal os. RESULTS: The defect illustrated in the four 3D models correlates to both surgical and pathological findings in terms of depth and pattern of invasion, location of defect, bladder involvement. Blood loss and topography of the defect from 3D modeling were examined in 14 further cases. Inferior defects were associated with increased blood loss compared with anterior defects. Increased distance from cervix was associated with reduced blood loss (R2  = 0.352, P = 0.01). CONCLUSION: Three-dimensional models of PAS provide an accurate preoperative description of placental invasion and should be investigated as a tool for selecting patients for uterine-conserving surgery. Accurate 3D models of placenta accreta spectrum are achievable and may provide additional information, such as distance of the defect from the internal os.

In silico design of additively manufacturable composite synthetic vascular conduits and grafts with tuneable compliance.

Benchtop testing of endovascular medical devices under accurately simulated physiological conditions is a critical part of device evaluation prior to clinical assessment. Currently, glass, acrylic and silicone vascular models are predominantly used as anatomical simulator test beds for in vitro testing. However, most current models lack the ability to mimic the non-linear radial compliance of native vessels and are typically limited to being compliance-matched at a single mean pressure comparison point or not at all. Hence, a degree of caution needs to be shown when analysing results from such models under simulated physiological or pathophysiological conditions. Similarly, the clinical translation of proposed biomimetic compliance-matched vascular grafts has undoubtedly been curtailed due to performance and material limitations. Here, we propose a new design for synthetic vessels where compliance can be precisely modulated across a wide physiological pressure range by customising design parameters. Building on previously demonstrated methods of 3D printing composite compliant cylindrical structures, we demonstrate proof of principle in creating composite vascular constructs designed via a finite element model. Our constructs are 3D printable and consist of a soft silicone matrix with embedded polyurethane fibres. The fibre layer consists of circumferential sinusoidal waves with an amplitude that can be altered to result in tuneable internal radial compliances of 5.2-15.9%/mmHg × 10-2 at a mean pressure of 100 mmHg. Importantly, the design presented here allows preservation of the non-linear exponentially decaying compliance curve of native arteries and veins with an increasing mean pressure. This model offers a design toolbox for 3D printable vascular models that offer biomimetic compliance. The robust nature of this model will lead to rapidly accelerating the design process for biomimetic vascular anatomical simulators, lumped parameter model flow loops, endovascular device benchtop testbeds, and compliance-matched synthetic grafts.

Insights into the mechanics of solid conical microneedle array insertion into skin using the finite element method.

In order to develop optimum microneedle designs, researchers must first develop robust, repeatable and adaptable test methods which are representative of in vivo conditions. However, there is a lack of experimental tools which can accurately comparatively interrogate functional microneedle penetration of tissue. In this study, we seek to develop a state of the art finite element model of microneedle insertion into and penetration of human skin. The developed model employs a 3D hyperelastic, anisotropic pre-stressed multi-layered material which more accurately reflects in vivo skin conditions, while the microneedle is modeled as an array, which can capture the influence of adjacent microneedles on the overall response. Using the developed finite element model, we highlight the importance of accurate computational modeling which can decipher the mechanics of microneedle insertion, including the influence of its position within an array and how it correlates well with experimental observations. In particular, we have concluded that, for our model microneedle array, increasing skin pretension from 0 to 10% strain reduces the penetration force by 13%, ultimate local deformation about the microneedle by 22% and the ultimate penetration efficiency by 15%. We have also concluded that the presence of a base plate limits the penetration efficiency by up to 24%, while the penetration efficiency across a 5 × 1 microneedle array may vary by 27%. This model elucidates, for the first time, the combined effects of skin tension and needle geometry on accurately predicting microneedle penetration efficiency. STATEMENT OF SIGNIFICANCE: Microneedles arrays (MNAs) are medical devices with microscale protrusions, typically designed to penetrate the outermost layer of the skin, that upon optimisation, could lead to disruptive minimally-invasive disease management. However, the mechanics of MNA insertion are complex, due in part to a 'bed of nails' effect, and difficult to elucidate experimentally. Therefore, comparisons between designs, functional assessment of production batches and ultimately the likelihood of clinical translation are challenging to predict. Here, we have develop the most sophisticated in silico model of MNA insertion into pre-tensioned human skin to predict the extent of MNA penetration and therefore the likelihood of successful therapeutic delivery. Researchers can customise this model to predict the penetration efficiency of any MNA design.

Additive Manufacturing of Multi-Scale Porous Soft Tissue Implants That Encourage Vascularization and Tissue Ingrowth.

Medical devices, such as silicone-based prostheses designed for soft tissue implantation, often induce a suboptimal foreign-body response which results in a hardened avascular fibrotic capsule around the device, often leading to patient discomfort or implant failure. Here, it is proposed that additive manufacturing techniques can be used to deposit durable coatings with multiscale porosity on soft tissue implant surfaces to promote optimal tissue integration. Specifically, the "liquid rope coil effect", is exploited via direct ink writing, to create a controlled macro open-pore architecture, including over highly curved surfaces, while adapting atomizing spray deposition of a silicone ink to create a microporous texture. The potential to tailor the degree of tissue integration and vascularization using these fabrication techniques is demonstrated through subdermal and submuscular implantation studies in rodent and porcine models respectively, illustrating the implant coating's potential applications in both traditional soft tissue prosthetics and active drug-eluting devices.

Assessing the Effects of VEGF Releasing Microspheres on the Angiogenic and Foreign Body Response to a 3D Printed Silicone-Based Macroencapsulation Device.

Macroencapsulation systems have been developed to improve islet cell transplantation but can induce a foreign body response (FBR). The development of neovascularization adjacent to the device is vital for the survival of encapsulated islets and is a limitation for long-term device success. Previously we developed additive manufactured multi-scale porosity implants, which demonstrated a 2.5-fold increase in tissue vascularity and integration surrounding the implant when compared to a non-textured implant. In parallel to this, we have developed poly(ε-caprolactone-PEG-ε-caprolactone)-b-poly(L-lactide) multiblock copolymer microspheres containing VEGF, which exhibited continued release of bioactive VEGF for 4-weeks in vitro. In the present study, we describe the next step towards clinical implementation of an islet macroencapsulation device by combining a multi-scale porosity device with VEGF releasing microspheres in a rodent model to assess prevascularization over a 4-week period. An in vivo estimation of vascular volume showed a significant increase in vascularity (* p = 0.0132) surrounding the +VEGF vs. -VEGF devices, however, histological assessment of blood vessels per area revealed no significant difference. Further histological analysis revealed significant increases in blood vessel stability and maturity (** p = 0.0040) and vessel diameter size (*** p = 0.0002) surrounding the +VEGF devices. We also demonstrate that the addition of VEGF microspheres did not cause a heightened FBR. In conclusion, we demonstrate that the combination of VEGF microspheres with our multi-scale porous macroencapsulation device, can encourage the formation of significantly larger, stable, and mature blood vessels without exacerbating the FBR.

A biomimetic urethral model to evaluate urinary catheter lubricity and epithelial micro-trauma.

The standard method of evaluating the lubricity of intermittent urinary catheters with coefficient of friction (CoF) testing is not physiologically relevant, while there is also a dearth of published research on catheter-associated urethral micro-trauma. We developed a novel human urethral epithelial cell-seeded model of the urethra to replace the rubber counter-surface used in standard CoF testing. This cell-seeded model, in conjunction with a novel testing device, allows an investigation of catheter-associated epithelial micro-trauma in vitro for the first time. The CoF of four brands of commercially-available hydrophilic-coated intermittent catheters was measured using both the rubber and urethral model counter-surfaces. Post-catheterisation of the urethral model, the damage to the epithelial layer was analysed using standard cell imaging. The rubber counter-surface was shown to over-estimate the CoF of gel-coated catheters compared to our urethral model due to stick-slip behaviour caused by polymer-on-polymer interaction of the catheter base material on the rubber counter-surface. We identified no deleterious effect due to the presence or design of catheter eyelets to either the CoF measurements or the degree of epithelium damage in our model. Furthermore, the epithelial damage did not correlate with the measured CoF of the low friction catheters, suggesting a more nuanced pathogenesis of urethral irritation and casting doubt on the translatability of a solely mechanical assessment of lubricity of urinary catheters to a clinical effect.

Vascular Endothelial Growth Factor-Releasing Microspheres Based on Poly(ε-Caprolactone-PEG-ε-Caprolactone)-b-Poly(L-Lactide) Multiblock Copolymers Incorporated in a Three-Dimensional Printed Poly(Dimethylsiloxane) Cell Macroencapsulation Device.

Pancreatic islet transplantation is a promising advanced therapy that has been used to treat patients suffering from diabetes type 1. Traditionally, pancreatic islets are infused via the portal vein, which is subsequently intended to engraft in the liver. Severe immunosuppressive treatments are necessary, however, to prevent rejection of the transplanted islets. Novel approaches therefore have focused on encapsulation of the islets in biomaterial implants which can protect the islets and offer an organ-like environment. Vascularization of the device's surface is a prerequisite for the survival and proper functioning of transplanted pancreatic islets. We are pursuing a prevascularization strategy by incorporation of vascular endothelial growth factor (VEGF)-loaded microspheres in 3-dimensional printed poly(dimethylsiloxane)-based devices prior to their prospective loading with transplanted cells. Microspheres (~50 µm) were based on poly(ε-caprolactone-PEG-ε-caprolactone)-b-poly(L-lactide) multiblock copolymers and were loaded with 10 µg VEGF/mg microspheres, and subsequently dispersed in a hyaluronic acid carrier liquid. In vitro release studies at 37°C demonstrated continuous release of fully bioactive VEGF for 4 weeks. In conclusion, our results demonstrate that incorporation of VEGF-releasing microspheres ensures adequate release of VEGF for a time window of 4 weeks, which is attractive in view of the vascularization of artificial pancreas implants.

Synthetic bioresorbable poly-α-hydroxyesters as peripheral nerve guidance conduits; a review of material properties, design strategies and their efficacy to date.

Implantable tubular devices known as nerve guidance conduits (NGCs) have drawn considerable interest as an alternative to autografting in the repair of peripheral nerve injuries. At present, there exists a lack of biodegradable, biocompatible materials for the fabrication of NGCs with physical properties which suitably match the native nerve tissue. Most of the existing reports have been confined to the traditional synthetic aliphatic polyesters due to their naturally-occurring degradation by-products, suitably slow in vivo resorption timeframes and relatively diverse and tailorable range of material properties. Moreover, these thermoplastic polymers can be processed into NGCs from various methods and further tweaking of physical properties can be achieved during fabrication. Although there have been many successful reports of nerve gap repair using NGCs made from these materials, the majority have been confined to basic tubular designs across short to medium nerve gaps with at best equivalent outcomes to autografts. This article reviews the performance of poly-α-hydroxyester tubes to date (including modifications to basic hollow conduits) and is intended to aid researchers as they aim to create biomimetic NGCs capable of bridging larger nerve gaps with superior results to autografting. Based on the existing reports, a next-generation bioresorbable NGC should involve a highly flexible poly-α-hydroxyester outer tube, most suitably from a lactide-caprolactone co-polymer, with some combination of internal lumen contact guidance and bioactive neurotrophic factors. However, detailed further experimentation and an interdisciplinary approach will be required to arrive at an ideal final configuration.

A Radial Clutch Needle for Facile and Safe Tissue Compartment Access.

Efficient and safe access to targeted therapeutic sites is a universal challenge in minimally invasive medical intervention. Percutaneous and transluminal needle insertion is often performed blindly and requires significant user skill and experience to avoid complications associated with the damage of underlying tissues or organs. Here, we report on the advancement of a safer needle with a radial mechanical clutch, which is designed to prevent overshoot injuries through the automatic stopping of the needle once a target cavity is reached. The stylet-mounted clutch system is inexpensive to manufacture and compatible with standard hypodermic or endoscopic needles, and therefore can be adapted to achieve safe access in a myriad of minimally invasive procedures, including targeted drug delivery, at-home and in-hospital intravenous access, laparoscopic and endo- and trans-luminal interventions. Here, we demonstrate the clutch needle design optimization and illustrate its potential for rapid and safe minimally invasive cannulation.

Simple and customizable method for fabrication of high-aspect ratio microneedle molds using low-cost 3D printing.

We present a simple and customizable microneedle mold fabrication technique using a low-cost desktop SLA 3D printer. As opposed to conventional microneedle fabrication methods, this technique neither requires complex and expensive manufacturing facilities nor expertise in microfabrication. While most low-cost 3D-printed microneedles to date display low aspect ratios and poor tip sharpness, we show that by introducing a two-step "Print & Fill" mold fabrication method, it is possible to obtain high-aspect ratio sharp needles that are capable of penetrating tissue. Studying first the effect of varying design input parameters and print settings, it is shown that printed needles are always shorter than specified. With decreasing input height, needles also begin displaying an increasingly greater than specified needle base diameter. Both factors contribute to low aspect ratio needles when attempting to print sub-millimeter height needles. By setting input height tall enough, it is possible to print needles with high-aspect ratios and tip radii of 20-40 µm. This tip sharpness is smaller than the specified printer resolution. Consequently, high-aspect ratio sharp needle arrays are printed in basins which are backfilled and cured in a second step, leaving sub-millimeter microneedles exposed resulting microneedle arrays which can be used as male masters. Silicone female master molds are then formed from the fabricated microneedle arrays. Using the molds, both carboxymethyl cellulose loaded with rhodamine B as well as polylactic acid microneedle arrays are produced and their quality examined. A skin insertion study is performed to demonstrate the functional capabilities of arrays made from the fabricated molds. This method can be easily adopted by the microneedle research community for in-house master mold fabrication and parametric optimization of microneedle arrays.

Response of mesenchymal stem cells to the biomechanical environment of the endothelium on a flexible tubular silicone substrate.

Understanding the response of mesenchymal stem cells (MSCs) to forces in the vasculature is very important in the field of cardiovascular intervention for a number of reasons. These include the development of MSC seeded tissue engineered vascular grafts, targeted or systemic delivery of MSCs in the dynamic environment of the coronary artery and understanding the potential pathological calcifying role of mechanically conditioned multipotent cells already present in the vessel wall. In vivo, cells present in the coronary artery are exposed to the primary biomechanical forces of shear stress, radial stress and hoop stress. To date, many studies have examined the effect of these stresses in isolation, thereby not presenting the complete picture. Therefore, the main aim of this study is to examine the combined role of these stresses on MSC behaviour. To this end, a bioreactor was configured to expose MSCs seeded on flexible silicone substrates to physiological forces - namely, a pulsatile pressure between 40 and 120mmHg (5.33-1.6x10(4)Pa), radial distention of 5% and a shear stress of 10dyn/cm(2) (1Pa) at frequency of 1Hz for up to 24h. Thereafter, the 'pseudovessel' was assessed for changes in morphology, orientation and expression of endothelial and smooth muscle cell (SMC) specific markers. Hematoxylin and eosin (H&E) staining revealed that MSCs exhibit a similar mechanosensitive response to that of endothelial cells (ECs); they reorientate parallel with direction of flow and have adapted their morphology to be similar to that of ECs. However, gene expression results show the cells exhibit greater levels of SMC-associated markers alpha-smooth muscle actin and calponin (p<0.05).

Metallic microneedles with interconnected porosity: A scalable platform for biosensing and drug delivery.

Metallic-based microneedles (MNs) offer a robust platform for minimally invasive drug delivery and biosensing applications due to their mechanical strength and proven tissue and drug compatibility. However, current designs suffer from limited functional surface area or challenges in manufacturing scalability. Here, porous 316L stainless steel MN patches are proposed. Fabricated through a scalable manufacturing process, they are suitable for storage and delivery of drugs and rapid absorption of fluids for biosensing. Fabrication of these MNs involves hot embossing a patch of stainless steel-based feedstock, sintering at 1100 °C and subsequent electropolishing. Optimisation of this manufacturing process yields devices that maintain mechanical integrity yet possess high surface area and associated porosity (36%) to maximise loading capacity. Similarly, a small pore size has been targeted (average diameter 2.22 µm, with 90% between 1.56 µm and 2.93 µm) to maximise capillarity and loading efficiency. This porous network has a theoretical wicking rate of 4.7 µl/s and can wick-up 27 ±â€¯5 µl of fluid through capillary action which allows for absorption of pharmaceuticals for delivery. When inserted into a metabolite-loaded skin model, the MNs absorbed and recovered 17 ±â€¯3 µl of the metabolite solution. The drug delivery performance of the porous metallic MNs (22.4 ±â€¯4.9 µg/cm2) was found to be threefold higher than that of topical administration (7.1 ±â€¯4.3 µg/cm2). The porous metallic MN patches have been shown to insert into porcine skin under a 19 N load. These results indicate the potential of design-for-manufacturing porous stainless steel MNs in biosensing and drug delivery applications. STATEMENT OF SIGNIFICANCE: Microneedles are micro-scale sharp protrusions used to bypass the stratum corneum, the skin's outer protective layer, and painlessly access dermal layers suitable for drug delivery and biosensing. Despite a depth of research in the area we have not yet seen large-scale clinical adoption of microneedle devices. Here we describe a device designed to address the potential barriers to adoption seen by other microneedles devices. We have developed a scalable, cost effective process to produce medical grade stainless steel microneedle patches which passively absorb and store drugs or interstitial fluid though a porous network and capillary action. This device, with low manufacturing and regulatory burdens may help the large-scale adoption of microneedles.