Delivery Devices Research Articles

Soft Pocket Pump for Multi‐Medium Transportation via an Active Tubular Diaphragm

AbstractRecent developments in small and agile multifunctional autonomous robots, portable and wearable drug delivery devices, and implantable ventricular assist devices have increased the demands for a new class of small and soft pumps that can conform to irregular or even deformable robotic bodies or human organs. In this work, a dual‐chamber pocket‐sized pump with a tubular diaphragm made of multilayered silicone dielectric elastomer actuators, three miniature check valves, and an outer shell is proposed. Dielectric elastomer actuators diaphragm holds well dynamic performances that resonate at 230 Hz, which leads to a no‐load flow rate of 340 mL min−1 and back pressure of 7.5 kPa, with the pump's total volume as only 2.36 cm3 and weight as 2.4 g. Besides, the proposed pump can be bent up to 60° with a negligible drop in its pressure and flow rate. The pump's capability to pump air, water, and its seamless switch is demonstrated. By tuning the amplitude of the driving voltage, the pump's pressure can be precisely controlled. This highly flexible and compact pump can be a potential candidate for driving small robots and biomedical devices.

Numerical analysis of airflow and particle deposition in multi-fidelity designs of nasal replicas following nasal administration

Background and ObjectiveAn improved understanding of flow behaviour and particle deposition in the human nasal airway is useful for optimising drug delivery and assessing the implications of pollutants and toxin inhalation. The geometry of the human nasal cavity is inherently complex and presents challenges and manufacturing constraints in creating a geometrically realistic replica. Understanding how anatomical structures of the nasal airway affect flow will shed light on the mechanics underpinning flow regulation in the nasal pharynx and provide a means to interpret flow and particle deposition data conducted in a nasal replica or model that has reduced complexity in terms of their geometries. This study aims to elucidate the effects of sinus and reduced turbinate length on nasal flow and particle deposition efficiencies. MethodsA complete nasal airway with maxillary sinus was first reconstructed using magnetic resonance imaging (MRI) scans obtained from a healthy human volunteer. The basic model was then modified to produce a model without the sinus, and another with reduced turbinate length. Computational fluid dynamics (CFD) was used to simulate flow in the nasal cavity using transient flow profiles with peak flow rates of 15 L/min, 35 L/min and 55 L/min. Particle deposition was investigated using discrete phase modelling (DPM). ResultsResults from this study show that simplifying the nasal cavity by removing the maxillary sinus and curved sections of the meatus only has a minor effect on airflow. By mapping the spatial distribution of monodisperse particles (10 μm) in the three models using a grid map that consists of 30 grids, this work highlights the specific nasal airway locations where deposition efficiencies are highest, as observed within a single grid. It also shows that lower peak flow rates result in higher deposition differences in terms of location and deposition quantity, among the models. The highest difference in particle deposition among the three nasal models is ∼10%, and this is observed at the beginning of the middle meatus and the end of the pharynx, but is only limited to the 15 L/min peak flow rate case. Further work demonstrating how the outcome may be affected by a wider range of particle sizes, less specific to the pharmaceutical industries, is warranted. ConclusionA physical replica manufactured without sections of the middle meatus could still be adequate in producing useful data on the deposition efficiencies associated with an intranasal drug formulation and its delivery device.

Pharmacokinetics/pharmacodynamics of epinephrine after single and repeat administration of neffy, EpiPen, and manual intramuscular injection

Epinephrine is the first-line treatment for severe allergic reactions, and rapid treatment is associated with lower rates of hospitalization and death. Current treatment options (epinephrine auto-injectors and manual intramuscular injection) are considered cumbersome, and most patients/caregivers fail to use them, even during severe reactions. An intranasal epinephrine delivery device, neffy, has been designed to provide an additional option for patients/caregivers. We sought to assess the comparative pharmacokinetics and pharmacodynamics of neffy 2.0 mg, EpiPen 0.3 mg, and manual intramuscular injection 0.3 mg. This was a phase 1, randomized, 6-treatment, 6-period, 2-part crossover study in 59 healthy subjects. Pharmacokinetic and pharmacodynamic parameters following single and repeat doses of epinephrine were assessed before dosing and at various postdose intervals. The pharmacokinetic profile of neffy was bracketed by approved injection products, with a mean peak plasma level of 481 pg/mL, which fell between EpiPen (753 pg/mL) and epinephrine manual intramuscular injection (339 pg/mL). When dosed both once and twice, neffy resulted in more pronounced increases in pharmacodynamic parameters relative to EpiPen or manual injection. neffy's pharmacokinetic profile was bracketed by approved injection products, with pharmacodynamic responses that were comparable to or better than approved injection products. neffy is expected to be a safe and effective option, particularly for patients/caregivers who are reluctant to carry and use injection devices.

Polymer Complex Multilayers for Drug Delivery and Medical Devices.

Polymer complex multilayers (PCMs) can be engineered into various structures with tunable properties via layer-by-layer (LBL) assembly driven by noncovalent forces. Due to their ease of preparation, capability of integrating multiple functional components, and excellent substrate compliance, biocompatible PCMs as coating materials or individual entities have attracted extensive attention in biomedical applications. This Spotlight on Applications presents recent progress on PCMs applied for drug delivery and medical devices. We provide several examples to address the importance of using PCM platforms to achieve controlled drug delivery including stimuli-triggered release, sustained release, and spatiotemporal sequential release. The effects of PCM coatings on the bioresponse regulation and performance enhancement of implantable devices are also highlighted. Moreover, the design and fabrication of flexible electrical and optical elements modified with LBL PCMs have been discussed, which demonstrates the great potential to advance emerging wearable devices for disease monitoring and health management.

Activated Metals to Generate Heat for Biomedical Applications.

Delivering heat in vivo could enhance a wide range of biomedical therapeutic and diagnostic technologies, including long-term drug delivery devices and cancer treatments. To date, providing thermal energy is highly power-intensive, rendering it oftentimes inaccessible outside of clinical settings. We developed an in vivo heating method based on the exothermic reaction between liquid-metal-activated aluminum and water. After establishing a method for consistent activation, we characterized the heat generation capabilities with thermal imaging and heat flux measurements. We then demonstrated one application of this reaction: to thermally actuate a gastric resident device made from a shape-memory alloy called Nitinol. Finally, we highlight the advantages and future directions for leveraging this novel in situ heat generation method beyond the showcased example.

Industrial perspectives for personalized microneedles.

Microneedles and, subsequently, microneedle arrays are emerging miniaturized medical devices for painless transdermal drug delivery. New and improved additive manufacturing methods enable novel microneedle designs to be realized for preclinical and clinical trial assessments. However, current literature reviews suggest that industrial manufacturers and researchers have focused their efforts on one-size-fits-all designs for transdermal drug delivery, regardless of patient demographic and injection site. In this perspective article, we briefly review current microneedle designs, microfabrication methods, and industrialization strategies. We also provide an outlook where microneedles may become personalized according to a patient's demographic in order to increase drug delivery efficiency and reduce healing times for patient-centric care.

New Devices in Glaucoma.

Glaucoma remains a leading cause of blindness globally. Minimally invasive treatment techniques are rapidly expanding the availability of therapeutic options for glaucoma. These include devices aimed at enhancing outflow through the subconjunctival space, Schlemm's canal, and suprachoroidal space, sustained-release drug delivery devices, and extraocular devices aiming to reduce glaucomatous progression through other novel means. In this review, we provide an overview of several novel devices either newly available or in development for the medical and surgical management of glaucoma. Further studies are required to determine the long-term efficacy of these devices and how they will integrate into the current landscape of glaucoma management.

Morphometric characterization and temporal temperature measurements during hepatic microwave ablation in swine.

Heat-induced destruction of cancer cells via microwave ablation (MWA) is emerging as a viable treatment of primary and metastatic liver cancer. Prediction of the impacted zone where cell death occurs, especially in the presence of vasculature, is challenging but may be achieved via biophysical modeling. To advance and characterize thermal MWA for focal cancer treatment, an in vivo method and experimental dataset were created for assessment of biophysical models designed to dynamically predict ablation zone parameters, given the delivery device, power, location, and proximity to vessels. MWA zone size, shape, and temperature were characterized and monitored in the absence of perfusion in ex vivo liver and a tissue-mimicking thermochromic phantom (TMTCP) at two power settings. Temperature was monitored over time using implanted thermocouples with their locations defined by CT. TMTCPs were used to identify the location of the ablation zone relative to the probe. In 6 swine, contrast-enhanced CTs were additionally acquired to visualize vasculature and absence of perfusion along with corresponding post-mortem gross pathology. Bench studies demonstrated average ablation zone sizes of 4.13±1.56cm2 and 8.51±3.92cm2, solidity of 0.96±0.06 and 0.99±0.01, ablations centered 3.75cm and 3.5cm proximal to the probe tip, and temperatures of 50 ºC at 14.5±13.4s and 2.5±2.1s for 40W and 90W ablations, respectively. In vivo imaging showed average volumes of 9.8±4.8cm3 and 33.2±28.4cm3 and 3D solidity of 0.87±0.02 and 0.75±0.15, and gross pathology showed a hemorrhagic halo area of 3.1±1.2cm2 and 9.1±3.0cm2 for 40W and 90W ablations, respectfully. Temperatures reached 50ºC at 19.5±9.2s and 13.0±8.3s for 40W and 90W ablations, respectively. MWA results are challenging to predict and are more variable than manufacturer-provided and bench predictions due to vascular stasis, heat-induced tissue changes, and probe operating conditions. Accurate prediction of MWA zones and temperature in vivo requires comprehensive thermal validation sets.

Evaluating the Usefulness and Ease of Use of a Next-Generation-Connected Drug Delivery Device for Growth Hormone Therapy: Qualitative Study of Health Care Professionals' Perceptions.

Digital solutions targeting children's health have become an increasingly important element in the provision of integrated health care. For the treatment of growth hormone deficiency (GHD), a unique connected device is available to facilitate the delivery of recombinant human growth hormone (r-hGH) by automating the daily injection process and collecting injection data such that accurate adherence information is available to health care professionals (HCPs), caregivers, and patients. The adoption of such digital solutions requires a good understanding of the perspectives of HCPs as key stakeholders because they leverage data collection and prescribe these solutions to their patients. This study aimed to evaluate the third generation of the easypod device (EP3) for the delivery of r-hGH treatment from the HCP perspective, with a focus on perceived usefulness and ease of use. A qualitative study was conducted, based on a participatory workshop conducted in Zaragoza, Spain, with 10 HCPs experienced in the management of pediatric GHD from 7 reference hospitals in Spain. Several activities were designed to promote discussion among participants about predefined topics based on the Technology Acceptance Model and the Unified Theory of Acceptance and Use of Technology to provide their perceptions about the new device. Participants reported 2 key advantages of EP3 over previous easypod generations: the touch screen interface and the real-time data transmission functionality. All participants (10/10, 100%) agreed that the new device should be part of a digital health ecosystem that provides complementary functionalities including data analysis. This study explored the perceived value of the EP3 autoinjector device for the treatment of GHD by HCPs. HCPs rated the new capabilities of the device as having substantial improvements and concluded that it was highly recommendable for clinical practice. EP3 will enhance decision-making and allow for more personalized care of patients receiving r-hGH.

Controlling release from encapsulated drug-loaded devices: insights from modeling the dissolution front propagation.

Dissolution of drug from its solid form to a dissolved form is an important consideration in the design and optimization of drug delivery devices, particularly owing to the abundance of emerging compounds that are extremely poorly soluble. When the solid dosage form is encapsulated, for example by the porous walls of an implant, the impact of the encapsulant drug transport properties is a further confounding issue. In such a case, dissolution and diffusion work in tandem to control the release of drug. However, the interplay between these two competing processes in the context of drug delivery is not as well understood as it is for other mass transfer problems, particularly for practical controlled-release considerations such as an encapsulant layer around the drug delivery device. To address this gap, this work presents a mathematical model that describes controlled release from a drug-loaded device surrounded by a passive porous layer. A solution for the drug concentration distribution is derived using the method of eigenfunction expansion. The model is able to track the dissolution front propagation, and predict the drug release curve during the dissolution process. The utility of the model is demonstrated through comparison against experimental data representing drug release from a cylindrical drug-loaded orthopedic fixation pin, where the model is shown to capture the data very well. Analysis presented here reveals how the various geometrical and physicochemical parameters influence drug dissolution and, ultimately, the drug release profile. It is found that the non-dimensional initial concentration plays a key role in determining whether the problem is diffusion-limited or dissolution-limited, whereas the nature of the problem is largely independent of other parameters including diffusion coefficient and encapsulant thickness. We expect the model will prove to be a useful tool for those designing encapsulated drug delivery devices, in terms of optimizing the design of the device to achieve a desired drug release profile.

A self-unfolding proximity enabling device for oral delivery of macromolecules

Oral delivery of macromolecules remains highly challenging due to their rapid degradation in the gastrointestinal tract and poor absorption across the tight junctions of the epithelium. In the last decade, researchers have investigated several medical devices to overcome these challenges using various approaches, some of which involve piercing through the intestine using micro and macro needles. We have developed a new generation of medical devices called self-unfolding proximity enabling devices, which makes it possible to orally deliver macromolecules without perforating the intestine. These devices protect macromolecules from the harsh conditions in the stomach and release their active pharmaceutical ingredients in the vicinity of the intestinal epithelium. One device version is a self-unfolding foil that we have used to deliver insulin and nisin to rats and pigs respectively. In our study, this device has shown a great potential for delivering peptides, with a significant increase in the absorption of solid dosage of insulin by ∼12 times and nisin by ∼4 times in rats and pigs, respectively. With the ability to load solid dosage forms, our devices can facilitate enhanced absorption of minimally invasive oral macromolecule formulations.

Langmuir-Blodgett-Mediated Formation of Antibacterial Microneedles for Long-Term Transdermal Drug Delivery.

Microneedles (MNs) have become versatile platforms for minimally invasive transdermal drug delivery devices. However, there are concerns about MN-induced skin infections with long-term transdermal administration. Using the Langmuir-Blodgett (LB) technique, a simple method for depositing antibacterial nanoparticles of various shapes, sizes, and compositions onto MNs is developed. This strategy has merits over conventional dip coating techniques, including controlled coating layers, uniform and high coverage, and a straightforward fabrication process. This provides MNs with a fast-acting and long-lasting antibacterial effect. Thisstudy demonstrates that antibacterial MNs achieve superior bacterial elimination in vitro and in vivo without sacrificing payload capacity, drug release, or mechanical strength. It isbelieved that such a functional nanoparticle coating technique offers a platform for the expansion of MNs function, especially in long-term transdermal drug delivery fields.

Smart Sensors and Microtechnologies in the Precision Medicine Approach against Lung Cancer.

The therapeutic interventions against lung cancer are currently based on a fully personalized approach to the disease with considerable improvement of patients' outcome. Alongside continuous scientific progresses and research investments, massive technologic efforts, innovative challenges, and consolidated achievements together with research investments are at the bases of the engineering and manufacturing revolution that allows a significant gain in clinical setting. The scope of this review is thus to focus, rather than on the biologic traits, on the analysis of the precision sensors and novel generation materials, as semiconductors, which are below the clinical development of personalized diagnosis and treatment. In this perspective, a careful revision and analysis of the state of the art of the literature and experimental knowledge is presented. Novel materials are being used in the development of personalized diagnosis and treatment for lung cancer. Among them, semiconductors are used to analyze volatile cancer compounds and allow early disease diagnosis. Moreover, they can be used to generate MEMS which have found an application in advanced imaging techniques as well as in drug delivery devices. Overall, these issues represent critical issues only partially known and generally underestimated by the clinical community. These novel micro-technology-based biosensing devices, based on the use of molecules at atomic concentrations, are crucial for clinical innovation since they have allowed the recent significant advances in cancer biology deciphering as well as in disease detection and therapy. There is an urgent need to create a stronger dialogue between technologists, basic researchers, and clinicians to address all scientific and manufacturing efforts towards a real improvement in patients' outcome. Here, great attention is focused on their application against lung cancer, from their exploitations in translational research to their application in diagnosis and treatment development, to ensure early diagnosis and better clinical outcomes.

Potential biocide roles of violacein

Violacein is a pigment produced by Gram-negative bacteria, which has shown several beneficial biological activities. The most relevant activities of violacein include the interference in the physiological activities of biological membranes, inhibition of cell proliferation, antioxidant, and anti-inflammatory activities. Moreover, the antiviral activities of violacein against some enveloped and non-enveloped viruses have also been reported. Violacein showed a wide spectrum of protease inhibition, both experimentally and in silico. Other in silico studies have suggested that violacein binds to the SARS-CoV-2 spike. Empirical physicochemical studies indicate that violacein (or, occasionally, its derivatives) may be administered orally to treat different disorders. In addition, different alternatives to product violacein, and molecular devices for delivery of this pigment are reviewed.

α-Substituted ketones as reagent for Passerini modification of carboxymethyl cellulose: Toward dually functionalized derivatives and thermo-sensitive chemical hydrogels

The present works describes the Passerini modification of carboxymethyl cellulose (CMC) by using a library of nine α-substituted ketones derivatives, differing in their hydrophobicity and reactivity, conjointly with cyclohexyl isocyanide. The Passerini ligation, achieved in aqueous and mild conditions, was shown to be successful, leading to a large panel of dually functionalized CMC derivatives, in an eco-friendly manner. A particular attention was dedicated to the influence of the experimental parameters such as the stoichiometry, the nature of a co-solvent or the temperature, which allowed to tune the extent of modification. The reactivity of the ketone was proven to be governed by its i) compatibility with water, ii) sterical accessibility, and by iii) the presence of neighboring electron-withdrawing group. The resulting Passerini CMC products modified by methacrylate moieties (CMC-MA) were used as reactive macromonomer under a “grafting through” approach. The copolymerization of CMC-MA with oligoethylene glycol methacrylate (OEGMA) and diethylene glycol methacrylate (DEGMA) upon thermal radical reaction conditions enabled to generate tightly cross-linked chemical hydrogels, with a thermo-sensitive and thermo-reversible behavior, reflected by a macroscopical shrinkage/swelling response, and confirmed by SAXS analysis. Such chemical strategy paves the way toward multifunctional polysaccharide-based networks with potential utilizations as drug delivery devices, dye removals or actuators.

Reviewing the Risk of Ketene Formation in Dabbing and Vaping Tetrahydrocannabinol-O-Acetate.

Introduction: In the wake of continued consumer demand despite increasing regulatory scrutiny, there is a need to develop systematic methods for identifying the harm profile of new psychoactive substances derived from hemp. Tetrahydrocannabinol-O (THC-O)-acetate, colloquially known as THCO, is the acetate ester of the principal psychoactive compound in cannabis. The heating of THCO can create ketene gas, which is harmful to the lungs. Materials and Methods: The research team used a multidisciplinary, iterative process to develop a survey to incorporate consumers' perspectives of semisynthetic cannabinoids. The survey was then distributed across the social media platform Reddit to learn about delivery device preferences and associated use styles when consuming THCO. Results: Most participants (74.9%) vaped THCO and one-quarter of participants (24.3%) dabbed THCO and tended to report higher temperatures for dabbing than vaping THCO. A small portion (12.0%) of participants reported concerns regarding ketene risk. Conclusion: As there are multiple variables associated with the formation of ketene, and consumer responses indicate temperatures use that might enable ketene formation, more research is needed to understand the risk profile of hemp-derived substances like THCO. Further studies are needed to understand the how various routes of administration and delivery devices used with THCO may exacerbate the risk of ketene formation and other potential harms.

Comparison of intranasal medication delivery devices before and after functional endoscopic sinus surgery using Phacon sinus surgery models.

Functional endoscopic sinus surgery for chronic rhinosinusitis improves sinus drainage and intranasal medication delivery. This study compares medication delivery with commonly used devices in normal and altered anatomy (post functional endoscopic sinus surgery) using sinus surgery models (Phacon). Medication delivery was simulated via nasal drops, nasal spray and an irrigation device (Neilmed Sinus Rinse). Coverage was then calculated from endoscopic pictures taken at various anatomical sites in the normal nose and post functional endoscopic sinus surgery. In the normal nose, nasal spray did not penetrate the sphenoid sinus, and drops bypassed the vestibule anteriorly. Neilmed Sinus Rinse provided superior coverage at the sphenoid site following sphenoidectomy and the frontal site following Draf III. After ethmoidectomy, nasal drops overall provided less coverage than the other methods. Neilmed Sinus Rinse generally provided the best distribution, followed by the nasal spray and then nasal drops. The type and extent of surgery also affects medication delivery.

From Plants to Wound Dressing and Transdermal Delivery of Bioactive Compounds.

Transdermal delivery devices and wound dressing materials are constantly improved and upgraded with the aim of enhancing their beneficial effects, biocompatibility, biodegradability, and cost effectiveness. Therefore, researchers in the field have shown an increasing interest in using natural compounds as constituents for such systems. Plants, as an important source of so-called "natural products" with an enormous variety and structural diversity that still exceeds the capacity of present-day sciences to define or even discover them, have been part of medicine since ancient times. However, their benefits are just at the beginning of being fully exploited in modern dermal and transdermal delivery systems. Thus, plant-based primary compounds, with or without biological activity, contained in gums and mucilages, traditionally used as gelling and texturing agents in the food industry, are now being explored as valuable and cost-effective natural components in the biomedical field. Their biodegradability, biocompatibility, and non-toxicity compensate for local availability and compositional variations. Also, secondary metabolites, classified based on their chemical structure, are being intensively investigated for their wide pharmacological and toxicological effects. Their impact on medicine is highlighted in detail through the most recent reported studies. Innovative isolation and purification techniques, new drug delivery devices and systems, and advanced evaluation procedures are presented.

Polycaprolactone and its derivatives for drug delivery

AbstractPolycaprolactone (PCL) is polymer of 21st centuries. PCL is a biodegradable and biocompatible polymer used for various healthcare applications. This review explores the properties, synthesis, and processing of PCL. The use of PCL polymer for nanoparticles (NPs), microparticles, films, and fibers offers several advantages for biomedical applications. The review highlights the potential of PCL‐based materials for tissue engineering, drug delivery, wound healing, and implantable medical devices. We also critically analyzed challenges in PCL‐based materials and the strategies used to overcome for successful translation into clinical applications. Overall, this review provides a comprehensive overview of PCL as a valuable biomaterial for healthcare applications.

"In Vitro" Evaluation of Energy-Based Sealing of Graft Side Branches in Bypass Surgery.

Our objective was to compare the in vitro efficacy of electrothermal bipolar [EB] vessel sealing and ultrasonic harmonic scalpel [HS] versus mechanical interruption, with conventional ties or surgical clips (SC), in sealing saphenous vein (SV) collaterals, during its eventual preparation for bypass surgery. Experimental in vitro study on 30 segments of SV. Each fragment included two collaterals at least 2mm in diameter. One of them was sealed by ligation with 3/0 silk ties (control) and the other one with EB (n = 10), HS (n = 10) or medium-6mm SC (n = 10). After incorporation in a closed circuit with pulsatile flow, the pressure was progressively increased until causing rupture. Collateral diameter, burst pressure, leak point, and histological study were recorded. Burst pressure was higher for SC (1320.20 ± 373.847mmHg) as compared with EB (942.2 ± 344.9mmHg, p = 0.065), and especially with HS (637.00 ± 320.61mmHg, p = 0.0001). No statistically significant difference between EB and HS was found, and bursting always happened at supraphysiological pressures. The leak point for HS was always detected in the sealing zone (10/10), while for EB and SC, it occurred in the sealing zone only in 6/10(60%) and 4/10(40%), respectively (p = 0.015). Energy delivery devices showed similar efficacy and safety in sealing of SV side branches. Although bursting pressure was lower than with tie ligature or SC, non-inferiority efficacy was shown at the range of physiological pressures in both, EB and HS. Due to their speed and easy handling, they may be useful in the preparation of the venous graft during revascularization surgery. However, remaining questions about healing process, potential spread of tissue damage and sealing durability, will require further analysis.