An Innovative Polymeric Platform for Controlled and Localized Drug Delivery.

Precision medicine aims to optimize pharmacological treatments by considering patients' genetic, phenotypic, and environmental factors, enabling dosages personalized to the individual. To address challenges associated with oral and injectable administration approaches, implantable drug delivery systems have been developed. These systems overcome issues like patient adherence, bioavailability, and first-pass metabolism. Utilizing new combinations of biodegradable polymers, the proposed solution, a Polymeric Controlled Release System (PCRS), allows minimally invasive placement and controlled drug administration over several weeks. This study's objective was to show that the PCRS exhibits a linear biphasic controlled release profile, which would indicate potential as an effective treatment vehicle for cervical malignancies. An injection mold technique was developed for batch manufacturing of devices, and in vitro experiments demonstrated that the device's geometry and surface area could be varied to achieve various drug release profiles. This study's results motivate additional development of the PCRS to treat cervical cancer, as well as other malignancies, such as lung, testicular, and ovarian cancers.

Military Standard Testing of Commercially Available Supraglottic Airway Devices for Use in a Military Combat Setting.

INTRODUCTION: Airway obstruction is the second leading cause of death on the battlefield. The harsh conditions of the military combat setting require that devices be able to withstand extreme circumstances. Military standards (MIL-STD) testing is necessary before devices are fielded. We sought to determine the ability of supraglottic airway (SGA) devices to withstand MIL-STD testing. METHODS: We tested 10 SGA models according to nine MIL-STD-810H test methods. We selected these tests by polling five military and civilian emergency-medicine subject matter experts (SMEs), who weighed the relevance of each test. We performed tests on three devices for each model, with operational and visual examinations, to assign a score (1 to 10) for each device after each test. We calculated the final score of each SGA model by averaging the score of each device and multiplying that by the weight for each test, for a possible final score of 2.6 to 26.3. RESULTS: The scores for the SGA models were LMA Classic Airway, 25.9; AuraGain Disposable Laryngeal Mask, 25.5; i-gel Supraglottic Airway, 25.2; Solus Laryngeal Mask Airway, 24.4; LMA Fastrach Airway, 24.4; AuraStraight Disposable Laryngeal Mask, 24.1; King LTS-D Disposable Laryngeal Tube, 22.1; LMA Supreme Airway, 21.0; air-Q Disposable Intubating Laryngeal Airway, 20.1; and Baska Mask Supraglottic Airway, 18.1. The limited (one to three) samples available for testing provide adequate preliminary information but restrict the range of failures that could be discovered. CONCLUSIONS: Lower scoring SGA models may not be optimal for military field use. Models scoring sufficiently close to the top performers (LMA Classic, AuraGain, i-gel, Solus, LMA Fastrach, AuraStraight) may be viable for use in the military setting. The findings of our testing should help guide device procurement appropriate for different battlefield conditions.

The Difficult Airway Redefined.

There is no all-encompassing or universally accepted definition of the difficult airway, and it has traditionally been approached as a problem chiefly rooted in anesthesiology. However, with airway obstruction reported as the second leading cause of mortality on the battlefield and first-pass success (FPS) rates for out-of-hospital endotracheal intubation (ETI) as low as 46.4%, the need to better understand the difficult airway in the context of the prehospital setting is clear. In this review, we seek to redefine the concept of the "difficult airway" so that future research can target solutions better tailored for prehospital, and more specifically, combat casualty care. Contrasting the most common definitions, which narrow the scope of practice to physicians and a handful of interventions, we propose that the difficult airway is simply one that cannot be quickly obtained. This implies that it is a situation arrived at through a multitude of factors, namely the Patient, Operator, Setting, and Technology (POST), but also more importantly, the interplay between these elements. Using this amended definition and approach to the difficult to manage airway, we outline a target-specific approach to new research questions rooted in this system-based approach to better address the difficult airway in the prehospital and combat casualty care settings.

Development and Characterization of a Nonelectronic Versatile Oxygenating Perfusion System for Tissue Preservation.

Oxygenated machine perfusion of human organs has been shown to improve both preservation quality and time duration when compared to the current gold standard: static cold storage. However, existing machine perfusion devices designed for preservation and transportation of transplantable organs are too complicated and organ-specific to merit use as a solution for all organs. This work presents a novel, portable, and nonelectronic device potentially capable of delivering oxygenated machine perfusion to a variety of organs. An innovative pneumatic circuit system regulates a compressed oxygen source that cyclically inflates and deflates silicone tubes, which function as both the oxygenator and perfusion pump. Different combinations of silicone tubes in single or parallel configurations, with lengths ranging from 1.5 to 15.2 m, were evaluated at varying oxygen pressures from 27.6 to 110.3 kPa. The silicone tubes in parallel configurations produced higher peak perfusion pressures (70% increase), mean flow rates (102% increase), and oxygenation rates (268% increase) than the single silicone tubes that had equivalent total lengths. While pumping against a vascular resistance element that mimicked a kidney, the device achieved perfusion pressures (8.4-131.6 mmHg), flow rates (2.0-40.2 mL min-1), and oxygenation rates (up to 388 µmol min-1) that are consistent with values used in previous kidney preservation studies. The nonelectronic device achieved those perfusion parameters using 4.4 L min-1 of oxygen to operate. These results demonstrate that oxygenated machine perfusion can be successfully achieved without any electronic components.

Portable Medical Suction and Aspirator Devices: Are the Design and Performance Standards Relevant?

Airway clearance refers to the clearing of any airway blockage caused due to foreign objects such as mud, gravel, and biomaterials such as blood, vomit, or teeth fragments using the technology of choice, portable suction devices. Currently available devices are either too heavy and bulky to be carried, or insufficiently powered to be useful despite being in accordance with the ISO 10079-1 standards. When applied to portable suction, the design and testing standards lack clinical relevancy, which is evidenced by how available portable suction devices are sparingly used in pre-hospital situations. Lack of clinical relevancy despite being in accordance with design/manufacturing standards arise due to little if any collaboration between those developing clinical standards and the bodies that maintain design and manufacturing standards. An updated set of standards is required that accurately reflects evidence-based requirements and specifications, which should promote valid, rational, and relevant engineering designs and manufacturing standards in consideration of the unique scenarios facing prehospital casualty care. This paper aims to critically review the existing standards for portable suction devices and propose modifications based on the evidence and requirements, especially for civilian prehospital and combat casualty care situations.

The Use of Portable Oxygen Concentrators in Low-Resource Settings: A Systematic Review.

INTRODUCTION: Portable oxygen concentrators (POCs) are medical devices that use physical means to separate oxygen from the atmosphere to produce concentrated, medical-grade gas. Providing oxygen to low-resources environments, such as austere locations, military combat zones, rural Emergency Medical Services (EMS), and during disasters, becomes expensive and logistically intensive. Recent advances in separation technology have promoted the development of POC systems ruggedized for austere use. This review provides a comprehensive summary of the available data regarding POCs in these challenge environments. METHODS: PubMed, Google Scholar, and the Defense Technical Information Center were searched from inception to November 2021. Articles addressing the use of POCs in low-resource settings were selected. Three authors were independently involved in the search, review, and synthesis of the articles. Evidence was graded using Oxford Centre for Evidence-Based Medicine guidelines. RESULTS: The initial search identified 349 articles, of which 40 articles were included in the review. A total of 724 study subjects were associated with the included articles. There were no Level I systematic reviews or randomized controlled trials. DISCUSSION: Generally, POCs are a low-cost, light-weight tool that may fill gaps in austere, military, veterinary, EMS, and disaster medicine. They are cost-effective in low-resource areas, such as rural and high-altitude hospitals in developing nations, despite relatively high capital costs associated with initial equipment purchase. Implementation of POC in low-resource locations is limited primarily on access to electricity but can otherwise operate for thousands of hours without maintenance. They provide a unique advantage in combat operations as there is no risk of explosive if oxygen tanks are struck by high-velocity projectiles. Despite their deployment throughout the battlespace, there were no manuscripts identified during the review involving the efficacy of POCs for combat casualties or clinical outcomes in combat. Veterinary medicine and animal studies have provided the most robust data on the physiological effectiveness of POCs. The success of POCs during the coronavirus disease 2019 (COVID-19) pandemic highlights the potential for POCs during future mass-casualty events. There is emerging technology available that combines a larger oxygen concentrator with a compressor system capable of refilling small oxygen cylinders, which could transform the delivery of oxygen in austere environments if ruggedized and miniaturized. Future clinical research is needed to quantify the clinical efficacy of POCs in low-resource settings.

A Market Review of Available Airway Suction Technology.

INTRODUCTION: Airway injuries are the second leading cause of potentially survivable battlefield death and often require airway management strategies. Airway suction, the act of using negative pressure in a patient's upper airway, removes debris that can prevent respiration, decreases possible aspiration risks, and allows clearer viewing of the airway for intubation. The most important characteristics for a portable airway suction device for prehospital combat care are portability, strong suction, and ease of use. METHODS: This market review searched academic papers, military publications, Google searches, and Amazon to identify devices. The search included specific characteristics that would increase the likelihood that the devices would be suitable for battlefield use including weight, size, battery life, noise emission, canister size, tubing, and suction power. RESULTS: Sixty portable airway suction devices were resulted, 31 of which met inclusion criteria - 11 manually powered devices and 20 battery-operated devices. One type of manual suction pump was a bag-like design with a squeezable suction pump that was extremely lightweight but had limited suction capabilities (vacuum pressure of 100mmHg). Another type of manual suction pump had a trigger-like design which is pulled back to create suction with a firm collection canister that had increased suction capabilities (vacuum pressures of 188-600mmHg), though still less than the battery operated, and was slightly heavier (0.23-0.458kg). Battery-operated devices had increased suction capabilities and were easier to use, but they were larger and weighed more (1.18-11.0kg). CONCLUSION: Future research should work to lighten and debulk battery-operated suction devices with high suction performance.

Review of Commercially Available Supraglottic Airway Devices for Prehospital Combat Casualty Care.

BACKGROUND: Airway obstruction is the second leading cause of potentially survivable death on the battlefield. The Committee on Tactical Combat Casualty Care lists airway optimization among the top 5 battlefield research and development priorities; however, studies show that combat medics lack access to the recommended supraglottic airway (SGA) devices. SGA devices are an alternative airway management technique to endotracheal tube intubation. Reports have shown SGA devices are easier to use and take fewer attempts to provide patent airflow to the patient when compared to endotracheal tube intubation. Military settings require a higher degree of skill to perform airway management on patients due to the environment, limited availability of equipment, and potential chaos of the battlefield. Finding the optimal SGA device for the military setting is an unmet need. The International Organization for Standardization describes basic functional requirements for SGA devices, as well as patient configurations and size limitations. Beyond that, no SGA device manufacturer states that their devices are intended for military settings. MATERIALS AND METHODS: We conducted a market review of 25 SGA devices that may meet inclusion into the medics' aid bag. The company's official "Instructions for Use" document, Google Scholar, and FDA reports were reviewed to obtain information for each SGA device. RESULTS: Twenty-five commercially available SGA devices are explored from manufacturer online sources. A commercially available device list is shown later in this paper, which provides the device's features, indications, and contraindications based on the manufacturer's product information documentation. CONCLUSIONS: There are a variety of devices that require further testing to determine whether they should be included in sets, kits, and outfits.

Characterization of thermal and optical properties in porcine pancreas tissue.

BACKGROUND: Photothermal therapies have shown promise for treating pancreatic ductal adenocarcinoma when they can be applied selectively, but off-target heating can frustrate treatment outcomes. Improved strategies leveraging selective binding and localized heating are possible with precision medical approaches such as functionalized gold nanoparticles, but careful control of optical dosage and thermal generation would be imperative. However, the literature review revealed many groups assume liver properties for pancreas tissue or rely on insufficiently rigorous characterization studies. OBJECTIVE: The objective of this study was to determine the thermal conductivity and optical properties at 808/1064 nm wavelengths in healthy samples of fresh and frozen porcine pancreas ex vivo. METHODS: Thermal conductivity of the porcine pancreas tissue was measured by utilizing a hot plate and two K-type thermocouples. Experimental variables such as tissue sample thickness, hot plate temperature, and heat convection coefficient were estimated through the control experiments utilizing specimens with known thermal conductivity. Optical evaluations assessed light attenuation at the 808 and 1064 nm wavelengths (continuous wave, collimated beam) by measuring the light transmittance and reflectance of different tissue thicknesses. In turn, these measurements were input into an inverse adding-doubling program to estimate the optical absorption and reduced scattering coefficients. RESULTS: Interestingly, pancreas tissue thermal conductivity was demonstrated to have no significant difference (p > 0.5) between samples that were fresh, frozen for 7 days, or frozen for 14 days. Conversely, optical property assessment exhibited a significant difference (p < 0.001) between fresh and frozen tissue samples, with increased absorbance and reflectance within the frozen group. However, the optical attenuation values measured were substantially less than that of the liver or reported in previous pancreas studies, suggesting a wide overestimation of these properties. CONCLUSIONS: These thermal and optical properties are critical to the development of novel therapeutic strategies like plasmonic photothermal therapy, but perhaps more importantly, are invaluable towards informing better surgical planning and operative technique among the existing thermal approaches for treating pancreas tissue.

Evaluating the Performance of a Nonelectronic, Versatile Oxygenating Perfusion System across Viscosities Representative of Clinical Perfusion Solutions Used for Organ Preservation.

Introduction: On the United States' Organ Transplantation Waitlist, approximately 17 people die each day waiting for an organ. The situation continues to deteriorate as the discrepancy between harvested organs and the number of patients in need is increasing. Static cold storage is the clinical standard method for preserving a harvested organ but is associated with several drawbacks. Machine perfusion of an organ has been shown to improve preservation quality as well as preservation time over static cold storage. While there are machine perfusion devices clinically available, they are costly and limited to specific organs and preservation solutions. This study presents a versatile oxygenating perfusion system (VOPS) that supplies oxygen and pulsatile perfusion. Materials and Methods: Experiments evaluated the system's performance with a human kidney mimicking hydraulic analog using multiple compressed oxygen supply pressures and aqueous solutions with viscosities ranging from 1 to 6.5 cP, which simulated viscosities of commonly used organ preservation solutions. Results and Conclusions: The VOPS produced mean flow rates ranging from 0.6 to 28.2 mL/min and perfusion pressures from 4.8 to 96.8 mmHg, which successfully achieved the desired perfusion parameters for human kidneys. This work provides evidence that the VOPS described herein has the versatility to perfuse organs using many of the clinically available preservation solutions.

Assessment and Modeling of Plasmonic Photothermal Therapy Delivered via a Fiberoptic Microneedle Device Ex Vivo.

Plasmonic photothermal therapy (PPTT) has potential as a superior treatment method for pancreatic cancer, a disease with high mortality partially attributable to the currently non-selective treatment options. PPTT utilizes gold nanoparticles infused into a targeted tissue volume and exposed to a specific light wavelength to induce selective hyperthermia. The current study focuses on developing this approach within an ex vivo porcine pancreas model via an innovative fiberoptic microneedle device (FMD) for co-delivering light and gold nanoparticles. The effects of laser wavelengths (808 vs. 1064 nm), irradiances (20-50 mW·mm-2), and gold nanorod (GNR) concentrations (0.1-3 nM) on tissue temperature profiles were evaluated to assess and control hyperthermic generation. The GNRs had a peak absorbance at ~800 nm. Results showed that, at 808 nm, photon absorption and subsequent heat generation within tissue without GNRs was 65% less than 1064 nm. The combination of GNRs and 808 nm resulted in a 200% higher temperature rise than the 1064 nm under similar conditions. A computational model was developed to predict the temperature shift and was validated against experimental results with a deviation of <5%. These results show promise for both a predictive model and spatially selective, tunable treatment modality for pancreatic cancer.

Characterizing and Tuning Perfusion Parameters Within an Innovative, Versatile Oxygenating Perfusion System.

The advantages of oxygenated perfusion are continuing to be demonstrated by many groups focused on improving the efficacy of tissue preservation for transplant, bioreactors for studies of basic tissue physiology, and closed-loop resuscitation. This work presents a novel and portable device that supplies oxygenated and pulsatile perfusion, both of which are regulated by a single pump-oxygenator component comprised of silicone tubes that are cyclically inflated/deflated with compressed oxygen. In this study, pump variables (oxygen supply pressure and length of a silicone tube) were evaluated against hydraulic elements that mimicked the vascular resistance of kidneys, livers, and hearts. The perfusion pressures, flow rates, and oxygenation rates produced by the device were characterized for all configurations of pump variables, and the pulse rates were tuned to improve performance. The device supplied perfusion pressures ranging from 3.5 to 109 mmHg, flow rates ranging from 1.4 to 71.8 mL min-1, and oxygenation rates up to 316.6 µmol min-1. From those results, it was determined that the device was capable of achieving perfusion parameters used in previous kidney, liver, and heart preservation studies. Ultimately, this research demonstrated the efficacy of a novel device that is designed to supply oxygenated perfusion across a range of applications.

Comprehensive Decision Support for Prehospital Combat Casualty Care: The Airway Clearance Model.

Airway management is a foremost priority for combat medics treating battlefield casualties, as a compromised airway is the second leading cause of potentially survivable death on the battlefield, accounting for 1 in 10 preventable combat deaths. Effective suction is a critical component of airway clearance. However, currently available commercial devices are too heavy and bulky for combat medics to carry, and/or lack sufficient power to be useful. Clinical decision support systems (DSS) can close the gap between existing commercial devices and their clinical use and enhance combat medic clinical performance by providing the right "tooth-to-tail" tools to accomplish the task of clearing the airway. Our DSS approach will provide a focused, real-time set of guidelines and recommendations that are tailored to the combat medic. Our proposal will create a knowledge-based algorithm and clinical guideline regarding the use of suction, delivering to the combat medic the "right information, to the right person, in the right format, through the right channel at the right time."

Novel expandable architected breathing tube for improving airway securement in emergency care.

Life-saving interventions utilize endotracheal intubation to secure a patient's airway, but performance of the clinical standard of care endotracheal tube (ETT) is inadequate. For instance, in the current COVID-19 crisis, patients can expect prolonged intubation. This protracted intubation may produce health complications such as tracheal stenosis, pneumonia, and necrosis of tracheal tissue, as current ETTs are not designed for extended use. In this work, we propose an improved ETT design that seeks to overcome these limitations by utilizing unique geometries which enable a novel expanding cylinder. The mechanism provides a better distribution of the contact forces between the ETT and the trachea, which should enhance patient tolerability. Results show that at full expansion, our new ETT exerts pressures in a silicone tracheal phantom well within the recommended standard of care. Also, preliminary manikin tests demonstrated that the new ETT can deliver similar performance in terms of air pressure and air volume when compared with the current gold standard ETT. The potential benefits of this new architected ETT are threefold, by limiting exposure of healthcare providers to patient pathogens through streamlining the intubation process, reducing downstream complications, and eliminating the need of multiple size ETT as one architected ETT fits all.

Airway Clearance Using Suction Devices in Prehospital Combat Casualty Care: A Systematic Review.

Airway management is at the forefront for combat medics dealing with battlefield trauma. For military service members, compromised airways are the second leading cause of potentially survivable death on the battlefield, accounting for one in ten preventable combat deaths. Effective suction is a critical component of airway clearance. However, currently available devices are too heavy and bulky to be carried by combat medics and are insufficiently powered. The industry has not responded to the need, with companies continuing to produce models using 1970s technology. A literature review was completed with the assistance of a librarian. The databases searched included: Biomedical Research Database (BRD), Computer Retrieval of Information of Scientific Projects (CRISP), Federal Research in Progress (FEDRIP), Defense Technical Information Center (DTIC), Pub Med/Medline, and OVID. Additionally, a Google Scholar search was performed to identify nonstandard sources. After screening, a total of 40 articles were used. There were no randomized controlled trials or other high-quality evidence that addressed the issues; there was limited peer-reviewed literature on the use, effectiveness, adverse effects, and safety of suction for use in combat casualty care. A review of the available literature revealed no standards, either proposed, validated, or accepted, for the safety or avoidance of adverse effects for portable suction device use in combat casualty care. Similarly, there are no accepted standards to guide the safe use and anticipated adverse effects of suction for use in prehospital combat or emergency care. Nevertheless, there are meaningful data that can be extracted from the few studies available combined with non-clinical studies, narrative reviews and case reports, and expert opinions.

Mechanical characterization of a fiberoptic microneedle device for controlled delivery of fluids and photothermal excitation.

Current clinical approaches for treating pancreatic cancer have been demonstrated as ineffective at improving midterm survival. A primary obstacle to local drug delivery is the desmoplastic nature of the peritumoral environment, which acts as a significant barrier to circulating macromolecules. To address this need, our group presents a sharp fiberoptic microcatheter capable of accessing the pancreas through transduodenal endoscope and penetrating a tumor to locally co-deliver photothermal and fluid-based therapies. Experiments sought to characterize the mechanical penetration capabilities and fluid mechanics of the fiberoptic microneedle design. A refined off-center fusion splicing technique was developed for joining a multimode fiber to the annular core of a light-guiding capillary, allowing light transmission with minimal optical loss. A novel and frugal technique for assessing the penetration force of the microneedle was conducted in a bovine gelatin tissue phantom with a Young's modulus stiffer than the high range for pancratic tissue or tumor. Buckling forces for different microneedle lengths were measured and compared against theoretical values obtained from Euler's Critical Load equation under fixed-pinned column conditions. Hydraulic resistance of different capillary lengths was evaluated and compared against the theoretical values from Hagen-Poiseuille's law, allowing assessment of contributions from different segments of the device. The results demonstrated that the microcatheter can robustly and repeatably penetrate a soft tissue phantom chosen to be a conservative model of pancreatic tissue for penetration properties. Experiments showed that a 1.5 N insertion force was required for phantom penetration with a 45° beveled needle at a 5 mm unsupported length, while the critical buckling load was measured to be approximately 4 N. In addition, the design was demonstrated to efficiently transport 1064 nm light and aqueous fluids with a 70-75% light coupling efficiency and 12,200 Pa.s/µl hydraulic resistance, respectively. These findings motivate the FMD's further development as a treatment platform for pancreatic cancer.

Multiphysics Modeling of Plasmonic Photothermal Heating Effects in Gold Nanoparticles and Nanoparticle Arrays.

Induced hyperthermia has been demonstrated as an effective oncological treatment due to the reduced heat tolerance of most malignant tissues; however, most techniques for heat generation within a target volume are insufficiently selective, inducing heating and unintended damage to surrounding healthy tissues. Plasmonic photothermal therapy (PPTT) utilizes light in the near-infrared (NIR) region to induce highly localized heating in gold nanoparticles, acting as exogenous chromophores, while minimizing heat generation in nearby tissues. However, optimization of treatment parameters requires extensive in vitro and in vivo studies for each new type of pathology and tissue targeted for treatment, a process that can be substantially reduced by implementing computational modeling. Herein, we describe the development of an innovative model based on the finite element method (FEM) that unites photothermal heating physics at the nanoscale with the micron scale to predict the heat generation of both single and arrays of gold nanoparticles. Plasmonic heating from laser illumination is computed for gold nanoparticles with three different morphologies: nanobipyramids, nanorods, and nanospheres. Model predictions based on laser illumination of nanorods at a visible wavelength (655 nm) are validated through experiments, which demonstrate a temperature increase of 5 °C in the viscinity of the nanorod array when illuminated by a 150 mW red laser. We also present a predictive model of the heating effect induced at 810 nm, wherein the heating efficiencies of the various morphologies sharing this excitation peak are compared. Our model shows that the nanorod is the most effective at heat generation in the isolated scenario, and arrays of 91 nm long nanorods reached hyperthermic levels (an increase of at least 5 °C) within a volume of over 20 µm3.

Nanofluidic microsystem for sustained intraocular delivery of therapeutics.

Globally, 145.2 million people suffer from moderate to severe vision impairment or blindness due to preventable or treatable causes. However, patient adherence to topical or intravitreal treatment is a leading cause of poor outcomes. To address this issue, we designed an intraocularly implantable device called the nanofluidic Vitreal System for Therapeutic Administration (nViSTA) for continuous and controlled drug release based on a nanochannel membrane that obviates the need for pumps or actuation. In vitro release analysis demonstrated that our device achieves sustained release of bimatoprost (BIM) and dexamethasone (DEX) at concentrations within clinically relevant therapeutic window. In this proof of concept study, we constructed an anatomically similar in silico human eye model to simulate DEX release from our implant and gain insight into intraocular pharmacokinetics profile. Overall, our drug-agnostic intraocular implant represents a potentially viable platform for long-term treatment of various chronic ophthalmologic diseases, including diabetic macular edema and uveitis.

Transcutaneously refillable nanofluidic implant achieves sustained level of tenofovir diphosphate for HIV pre-exposure prophylaxis.

Pre-exposure prophylaxis (PrEP) with antiretroviral (ARV) drugs are effective at preventing human immunodeficiency virus (HIV) transmission. However, implementation of PrEP presents significant challenges due to poor user adherence, low accessibility to ARVs and multiple routes of HIV exposure. To address these challenges, we developed the nanochannel delivery implant (NDI), a subcutaneously implantable device for sustained and constant delivery of tenofovir alafenamide (TAF) and emtricitabine (FTC) for HIV PrEP. Unlike existing drug delivery platforms with finite depots, the NDI incorporates ports allowing for transcutaneous refilling upon drug exhaustion. NDI-mediated drug delivery in rhesus macaques resulted in sustained release of both TAF and FTC for 83 days, as indicated by concentrations of TAF, FTC and their respectively metabolites in plasma, PBMCs, rectal mononuclear cells and tissues associated with HIV transmission. Notably, clinically relevant preventative levels of tenofovir diphosphate were achieved as early as 3 days after NDI implantation. We also demonstrated the feasibility of transcutaneous drug refilling to extend the duration of PrEP drug delivery in NHPs. Overall, the NDI represents an innovative strategy for long-term HIV PrEP administration in both developed and developing countries.

Unexpected behaviors in molecular transport through size-controlled nanochannels down to the ultra-nanoscale.

Ionic transport through nanofluidic systems is a problem of fundamental interest in transport physics and has broad relevance in desalination, fuel cells, batteries, filtration, and drug delivery. When the dimension of the fluidic system approaches the size of molecules in solution, fluid properties are not homogeneous and a departure in behavior is observed with respect to continuum-based theories. Here we present a systematic study of the transport of charged and neutral small molecules in an ideal nanofluidic platform with precise channels from the sub-microscale to the ultra-nanoscale (<5 nm). Surprisingly, we find that diffusive transport of nano-confined neutral molecules matches that of charged molecules, as though the former carry an effective charge. Further, approaching the ultra-nanoscale molecular diffusivities suddenly drop by up to an order of magnitude for all molecules, irrespective of their electric charge. New theoretical investigations will be required to shed light onto these intriguing results.