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.

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.

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.

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.

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.

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.

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.

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.

Additive Manufacture of Composite Soft Pneumatic Actuators.

This article presents a direct additive manufacturing method for composite material soft pneumatic actuators that are capable of performing a range of programmable motions. Commonly, molding is the method used to manufacture soft fluidic actuators. This is material, labor, and time intensive and lacks the design freedom to produce custom actuators efficiently. This article proposes an alternative semiautomated method of designing and manufacturing composite soft actuators. An affordable, open-source, desktop three-dimensional (3D) printer was modified into a four-axis, combined, fused deposition modeling, and paste extrusion printer. A Grasshopper 3D algorithm was devised to implement custom actuator designs according to user inputs, resulting in a G-code print file. Bending, contracting, and twisting motion actuators were parametrically designed and subsequently additively manufactured from silicone and thermoplastic elastomer (TPE) materials. Experimental testing was completed on these actuators along with their constitutive materials. Finite element models were created to simulate the actuator's kinematic performance. Having a platform method to digitally configure and directly additively manufacture custom-motion, composite soft actuators has the potential to accelerate the development of more intricate designs and lead to potential impacts in a range of areas, including in-clinic personalization of soft assistive devices and patient-specific biomedical devices.

A self-adherent, bullet-shaped microneedle patch for controlled transdermal delivery of insulin.

Proteins are important biologic therapeutics used for the treatment of various diseases. However, owing to low bioavailability and poor skin permeability, transdermal delivery of protein therapeutics poses a significant challenge. Here, we present a new approach for transdermal protein delivery using bullet-shaped double-layered microneedle (MN) arrays with water-swellable tips. This design enabled the MNs to mechanically interlock with soft tissues by selective distal swelling after skin insertion. Additionally, prolonged release of loaded proteins by passive diffusion through the swollen tips was obtained. The bullet-shaped MNs provided an optimal geometry for mechanical interlocking, thereby achieving significant adhesion strength (~1.6Ncm-2) with rat skin. By harnessing the MN's reversible swelling/deswelling property, insulin, a model protein drug, was loaded in the swellable tips using a mild drop/dry procedure. The insulin-loaded MN patch released 60% of insulin when immersed in saline over the course of 12h and approximately 70% of the released insulin appeared to have preserved structural integrity. An in vivo pilot study showed a prolonged release of insulin from swellable MN patches, leading to a gradual decrease in blood glucose levels. This self-adherent transdermal MN platform can be applied to a variety of protein drugs requiring sustained release kinetics.

A Growth-Accommodating Implant for Paediatric Applications.

Medical implants of fixed size cannot accommodate normal tissue growth in children, and often require eventual replacement or in some cases removal, leading to repeated interventions, increased complication rates and worse outcomes. Implants that can correct anatomic deformities and accommodate tissue growth remain an unmet need. Here, we report the design and use of a growth-accommodating device for paediatric applications that consists of a biodegradable core and a tubular braided sleeve, with inversely related sleeve length and diameter. The biodegradable core constrains the diameter of the sleeve, and gradual core degradation following implantation enables sleeve and overall device elongation in order to accommodate tissue growth. By using mathematical modeling and ex vivo experiments using harvested swine hearts, we demonstrate the predictability and tunability of the behavior of the device for disease- and patient-specific needs. We also used the rat tibia and the piglet heart valve as two models of tissue growth to demonstrate that polymer degradation enables device expansion and growth accommodation in vivo.

Bulk Metallic Glasses for Implantable Medical Devices and Surgical Tools.

With increasing knowledge of the materials science of bulk metallic glasses (BMGs) and improvements in their properties and processing, they have started to become candidate materials for biomedical devices. A dichotomy in the types of medical applications has also emerged, in which some families of BMGs are being developed for permanent devices whilst another family - of Mg-based alloys - is showing promise in bioabsorbable implants. The current status of these metallurgical and technological developments is summarized.

A light-reflecting balloon catheter for atraumatic tissue defect repair.

A congenital or iatrogenic tissue defect often requires closure by open surgery or metallic components that can erode tissue. Biodegradable, hydrophobic light-activated adhesives represent an attractive alternative to sutures, but lack a specifically designed minimally invasive delivery tool, which limits their clinical translation. We developed a multifunctional, catheter-based technology with no implantable rigid components that functions by unfolding an adhesive-loaded elastic patch and deploying a double-balloon design to stabilize and apply pressure to the patch against the tissue defect site. The device uses a fiber-optic system and reflective metallic coating to uniformly disperse ultraviolet light for adhesive activation. Using this device, we demonstrate closure on the distal side of a defect in porcine abdominal wall, stomach, and heart tissue ex vivo. The catheter was further evaluated as a potential tool for tissue closure in vivo in rat heart and abdomen and as a perventricular tool for closure of a challenging cardiac septal defect in a large animal (porcine) model. Patches attached to the heart and abdominal wall with the device showed similar inflammatory response as sutures, with 100% small animal survival, indicating safety. In the large animal model, a ventricular septal defect in a beating heart was reduced to <1.6 mm. This new therapeutic platform has utility in a range of clinical scenarios that warrant minimally invasive and atraumatic repair of hard-to-reach defects.

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.