Surfactant-Polymer Complexation and Competition on Drug Nanocrystal Surfaces Control Crystallinity.

Nanosizing drug crystals has emerged as a successful approach to enabling oral bioavailability, as increasing drug crystal surface area improves dissolution kinetics and effective solubility. Recently, bottom-up methods have been developed to directly assemble nanosized crystals by leveraging polymer and surfactant excipients during crystallization to control crystal size, morphology, and structure. However, while significant research has investigated how polymers and other single additives inhibit or promote crystallization in pharmaceutical systems, there is little work studying the mechanistic interactions of multiple excipients on drug crystal structure and the extent of crystallinity, which can influence formulation performance. This study explores how the structure and crystallinity of a model hydrophobic drug crystal, fenofibrate, change as a result of competitive interfacial chemisorption between common nonionic surfactants (polysorbate 80 and sorbitan monooleate) and a surface-active polymer excipient (methylcellulose). Classical molecular dynamics simulations highlight how key intermolecular interactions, including surfactant-polymer complexation and surfactant screening of the crystal surface, modify the resulting crystal structure. In parallel, experiments generating drug nanocrystals in hydrogel thin films validate that drug crystallinity increases with an increasing weight fraction of surfactant. Simulation results reveal a connection between accelerated dynamics in the bulk crystal and the experimentally measured extent of crystallinity. To our knowledge, these are the first simulations that directly characterize structural changes in a drug crystal as a result of excipient surface composition and relate the experimental extent of crystallinity to structural changes in the molecular crystal. Our approach provides a mechanistic understanding of crystallinity in nanocrystallization, which can expand the range of orally deliverable small molecule therapies.

Dynamics of a self-interacting sheet in shear flow.

Solution processing of 2D materials such as graphene is important for applications thereof, yet a complete fundamental understanding of how 2D materials behave dynamically in solution is lacking. Here, we extend previous work by Silmore et al., Soft Matter, 2021, 17(18), 4707-4718 by adding short-ranged Lennard-Jones interactions to 2D sheets in shear flow. We find that the addition of these interactions allows for a rich landscape of conformations which depend on the balance between shear strength, bending rigidity, and interaction strength as well as the initial configuration of the sheet. We explore this conformational space and classify sheets as flat, tumbling, 1D folded, or 2D folded based on their conformational properties. We use kinetic and energetic arguments to explain why sheets adopt certain conformations within the folded regime. Finally, we calculate the stresslet and find that, even in the absence of thermal fluctuations and multiple sheet interactions, shear-thinning followed by shear-thickening behavior can appear.

A Zwitterionic Hydrogel-Based Heterogeneous Fenton Catalyst for Water Treatment.

Persistent organic pollutants (POPs), including xenoestrogens and polyfluoroalkyl substances (PFAS), demand urgent global intervention. Fenton oxidation, catalyzed by iron ions, offers a cost-effective means to degrade POPs. However, numerous challenges like acid dependency, catalyst loss, and toxic waste generation hinder practical application. Efforts to create long-lasting heterogeneous Fenton catalysts, capable of simultaneously eliminating acid requirements, sustaining rapid kinetics, and retaining iron efficiently, have been unsuccessful. This study introduces an innovative heterogeneous zwitterionic hydrogel-based Fenton catalyst, surmounting these challenges in a cost-effective and scalable manner. The hydrogel, hosting individually complexed iron ions in a porous scaffold, exhibits substantial effective surface area and kinetics akin to homogeneous Fenton reactions. Complexed ions within the hydrogel can initiate Fenton degradation at neutral pH, eliminating acid additions. Simultaneously, the zwitterionic hydrogel scaffold, chosen for its resistance to Fenton oxidation, forms strong bonds with iron ions, enabling prolonged reuse. Diverging from existing designs, the catalyst proves compatible with UV-Fenton processes and achieves rapid self-regeneration during operation, offering a promising solution for the efficient and scalable degradation of POPs. The study underscores the efficacy of the approach by demonstrating the swift degradation of three significant contaminants-xenoestrogens, pesticides, and PFAS-across multiple cycles at trace concentrations.

A Universal Approximation for Conductance Blockade in Thin Nanopore Membranes.

Nanopore-based sensing platforms have transformed single-molecule detection and analysis. The foundation of nanopore translocation experiments lies in conductance measurements, yet existing models, which are largely phenomenological, are inaccurate in critical experimental conditions such as thin and tightly fitting pores. Of the two components of the conductance blockade, channel and access resistance, the access resistance is poorly modeled. We present a comprehensive investigation of the access resistance and associated conductance blockade in thin nanopore membranes. By combining a first-principles approach, multiscale modeling, and experimental validation, we propose a unified theoretical modeling framework. The analytical model derived as a result surpasses current approaches across a broad parameter range. Beyond advancing our theoretical understanding, our framework's versatility enables analyte size inference and predictive insights into conductance blockade behavior. Our results will facilitate the design and optimization of nanopore devices for diverse applications, including nanopore base calling and data storage.

Predictive Dosimetry and Outcomes of Hepatocellular Carcinoma Treated by Yttrium-90 Resin Microsphere Radioembolization: A Retrospective Analysis Using Technetium-99m Macroaggregated Albumin SPECT/CT and Planning Software.

PURPOSE: To characterize estimated mean absorbed tumor dose (ADT), objective response (OR), and estimated target dose of hepatocellular carcinoma (HCC) after resin microsphere yttrium-90 (90Y) radioembolization using partition dosimetry. MATERIALS AND METHODS: In this retrospective, single-center study, multicompartment dosimetry of index tumors receiving 90Y radioembolization between October 2015 and June 2022 was performed using a commercial software package and pretreatment technetium-99m macroaggregated albumin single photon emission computed tomography (SPECT)/computed tomography (CT). In total, 101 patients with HCC underwent 102 treatments of 127 index tumors. Patients underwent imaging every 2-3 months after treatment to determine best response per modified Response Evaluation Criteria in Solid Tumors (mRECIST). Best response was defined as the greatest response category per mRECIST and categorized as OR or nonresponse (NR). A Cox proportional hazards model evaluated the probability of tumor OR and progression-free survival using ADT. RESULTS: The median follow-up period was 148 days (interquartile range [IQR], 92-273 days). The median ADT of OR was 141.9 Gy (IQR, 89.4-215.8 Gy) compared with the median ADT of NR treatments of 70.8 Gy (IQR, 42.0-135.3 Gy; P < .001). Only ADT was predictive of response (hazard ratio = 2.79 [95% confidence interval {CI}: 1.44-5.40]; P = .003). At 6 months, an ADT of 157 Gy predicted 90.0% (95% CI: 41.3%-98.3%) probability of OR. At 1 year, an ADT of 157 Gy predicted 91.6% (95% CI: 78.3%-100%) probability of progression-free survival. Partition modeling and delivered activity were predictive of progression (P = .021 and P = .003, respectively). CONCLUSIONS: For HCC treated with resin microspheres, tumors receiving higher ADT exhibited higher rates of OR. An ADT of 157 Gy predicted 90.0% OR at 6 months.

Reducing the Environmental and Economic Costs of Single-Department Infectious Waste Disposal.

PURPOSE: The aim of this study was to demonstrate the efficacy of zero-cost interventions on the reduction of infectious waste (IW) stream production in interventional radiology (IR). METHODS: This quality improvement initiative was developed using needs identification through department-wide meetings with IR stakeholders (physicians, nurses, and radiologic technologists). Department leadership identified and implemented two interventions to reduce disposal of noninfectious waste (NIW) in the IW stream. First, hospital waste management provided focused education for sorting IW versus NIW to IR staff members. Next, the number of IW bins was reduced, and the IW bins were strategically placed on the perimeter of the room. Radiologic technologists tracked IW and NIW bags per case for 25 case days before the intervention and 175 case days after the intervention. A run chart was created to visualize change over time. Wilcoxon rank sum and signed rank tests were performed to evaluate the difference in IW and NIW bags per case before and after the intervention. A goal of significant reduction in NIW stream production was set. RESULTS: Before the intervention, the production of IW and NIW bags per case was similar (median, 1.0 [interquartile range (IQR), 0.86-1.31] vs 1.1 [IQR, 0.86-1.40]; P = .20). After the intervention, IW bags per case decreased (median, 1.0 [IQR, 0.86-1.31] vs 0.05 [IQR, 0.00-0.13]; P < .001). Fewer IW bags than NIW bags were produced per case after the intervention (median, 0.05 [IQR, 0.00-0.13] vs 1.53 [IQR, 1.30-1.76]; P < .001). CONCLUSIONS: Zero-cost interventions, including focused education, stakeholder engagement, and strategic placement of waste bins, can significantly reduce the environmental and economic impact of waste produced in IR.

Partition Dosimetry and Outcomes of Metastatic Neuroendocrine Tumors after Yttrium-90 Resin Microsphere Radioembolization.

PURPOSE: To characterize estimated mean tumor-absorbed dose (ADT) and objective response of metastatic neuroendocrine tumor (NET) after resin microsphere yttrium-90 (90Y) hepatic radioembolization using partition dosimetry. MATERIALS AND METHODS: In this retrospective, single-center study, multicompartment dosimetry of index tumors receiving 90Y radioembolization between 2013 and 2022 involved the use of Sureplan (MIM Software, Cleveland, Ohio) and technetium-99m macroaggregated albumin single photon emission computed tomography (SPECT) combined with computed tomography. Thirty-six patients with NET underwent treatment of 56 index tumors. Patients underwent imaging every 3-6 months after treatment to determine best response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified RECIST (mRECIST) criteria. Responses were categorized as objective response (OR) or nonresponse (NR). Wilcoxon rank sum test evaluated differences in continuous variables, and Pearson χ2 test evaluated differences in categorical variables. RESULTS: Median follow-up was 582 days (IQR, 187-1,227 days). Per RECIST 1.1, 27 patients (75%) experienced OR and 9 patients experienced (25%) NR. Of the 36 patients, 33 (92%) showed hypervascular, mRECIST-evaluable tumors. Among them, 28 patients (85%) showed mRECIST OR and 5 patients (15%) showed NR. The mRECIST OR group received a higher ADT than the NR group (median, 107 Gy; IQR, 95.1-154 Gy vs median, 70.4 Gy; IQR, 62.9-87.6 Gy; P = .048). All tumors receiving at least 120 Gy showed mRECIST OR. CONCLUSIONS: In hypervascular metastatic NET treated by 90Y resin microsphere radioembolization, higher tumor dose was associated with better tumor response per mRECIST. Doses of ≥120 Gy led to OR.

Predictive Partition Dosimetry and Outcomes after Yttrium-90 Resin Microsphere Radioembolization of Colorectal Cancer Metastatic to the Liver: A Retrospective Analysis.

PURPOSE: To characterize estimated absorbed tumor dose (ADT), objective response (OR), and estimated target dose of liver metastatic colorectal cancer (mCRC) after resin microsphere yttrium-90 (90Y) radioembolization using partition dosimetry. MATERIALS AND METHODS: In this retrospective, single-center study, multicompartment dosimetry of index tumors undergoing 90Y radioembolization from October 2013 to July 2022 was performed using MIM SurePlan and pretreatment technetium-99m macroaggregated albumin infusion data. Thirty-eight patients with mCRC underwent treatments for 59 index tumors. Patients were imaged every 2-3 months after treatment and then every 3-6 months after disease control to determine the best response per Response Evaluation Criteria in Solid Tumors 1.1. Responses were categorized as OR or nonresponse (NR). A Cox proportional hazards model evaluated the probability of tumor OR and local progression-free survival (LPFS) based on ADT. RESULTS: Patients had a median follow-up of 116 days (interquartile range [IQR], 69-231 days). The ADT was higher for OR patients than for NR patients (median, 130.8 [IQR, 85.6-239.0] vs 40.6 [IQR, 26.0-66.3] Gy; P < .001). A greater percentage of OR than NR patients were treated with activities calculated by partition modeling (54% vs 12%; P = .005). Only ADT predicted response (P = .032). At 6 months, an ADT of 120 Gy predicted a 55% (95% CI, 0.0%-89%) probability of OR. Only ADT (P = .010) and female sex (P = .014) predicted LPFS. At 1 year, an ADT of 120 Gy predicted a 70% (95% CI, 35%-100%) probability of LPFS. CONCLUSIONS: Tumor dose was the strongest predictor of OR for mCRC. Administration of an estimated 120 Gy to mCRC predicted 55% OR with 90Y resin microspheres at 6 months.

Injectable hydrogel particles for amorphous solid formulation of biologics.

The fast pace of breakthroughs in cancer immunotherapy, combined with the new paradigm of moving toward high-concentration dosages and combinatorial treatments, is generating new challenges in the formulation of biologics. To address these challenges, we describe a method of formulation that enables high-concentration injectable and stable formulation of biologics as amorphous solids in aqueous suspension. This technology combines the benefits of liquid formulation with the stability of solid formulation and eliminates the need for drying and reconstitution. This widely applicable formulation integrates the amorphous solid forms of antibodies with the injectability, lubricity, and tunability of soft alginate hydrogel particles using a minimal process. The platform was evaluated for anti-PD-1 antibody pembrolizumab and human immunoglobulin G at concentrations up to 300 mg/mL with confirmed quality after release. The soft nature of the hydrogel matrix allowed packing the particles to high volume fractions.

Machine Learning Models to Predict Kidney Stone Recurrence Using 24 Hour Urine Testing and Electronic Health Record-Derived Features.

Objective: To assess the accuracy of machine learning models in predicting kidney stone recurrence using variables extracted from the electronic health record (EHR). Methods: We trained three separate machine learning (ML) models (least absolute shrinkage and selection operator regression [LASSO], random forest [RF], and gradient boosted decision tree [XGBoost] to predict 2-year and 5-year symptomatic kidney stone recurrence from electronic health-record (EHR) derived features and 24H urine data (n = 1231). ML models were compared to logistic regression [LR]. A manual, retrospective review was performed to evaluate for a symptomatic stone event, defined as pain, acute kidney injury or recurrent infections attributed to a kidney stone identified in the clinic or the emergency department, or for any stone requiring surgical treatment. We evaluated performance using area under the receiver operating curve (AUC-ROC) and identified important features for each model. Results: The 2- and 5- year symptomatic stone recurrence rates were 25% and 31%, respectively. The LASSO model performed best for symptomatic stone recurrence prediction (2-yr AUC: 0.62, 5-yr AUC: 0.63). Other models demonstrated modest overall performance at 2- and 5-years: LR (0.585, 0.618), RF (0.570, 0.608), and XGBoost (0.580, 0.621). Patient age was the only feature in the top 5 features of every model. Additionally, the LASSO model prioritized BMI and history of gout for prediction. Conclusions: Throughout our cohorts, ML models demonstrated comparable results to that of LR, with the LASSO model outperforming all other models. Further model testing should evaluate the utility of 24H urine features in model structure.

Orthogonal Gelations to Synthesize Core-Shell Hydrogels Loaded with Nanoemulsion-Templated Drug Nanoparticles for Versatile Oral Drug Delivery.

Hydrophobic active pharmaceutical ingredients (APIs) are ubiquitous in the drug development pipeline, but their poor bioavailability often prevents their translation into drug products. Industrial processes to formulate hydrophobic APIs are expensive, difficult to optimize, and not flexible enough to incorporate customizable drug release profiles into drug products. Here, a novel, dual-responsive gelation process that exploits orthogonal thermo-responsive and ion-responsive gelations is introduced. This one-step "dual gelation" synthesizes core-shell (methylcellulose-alginate) hydrogel particles and encapsulates drug-laden nanoemulsions in the hydrogel matrices. In situ crystallization templates drug nanocrystals inside the polymeric core, while a kinetically stable amorphous solid dispersion is templated in the shell. Drug release is explored as a function of particle geometry, and programmable release is demonstrated for various therapeutic applications including delayed pulsatile release and sequential release of a model fixed-dose combination drug product of ibuprofen and fenofibrate. Independent control over drug loading between the shell and the core is demonstrated. This formulation approach is shown to be a flexible process to develop drug products with biocompatible materials, facile synthesis, and precise drug release performance. This work suggests and applies a novel method to leverage orthogonal gel chemistries to generate functional core-shell hydrogel particles.

Templated Reactive Crystallization of Active Pharmaceutical Ingredient in Hydrogel Microparticles Enabling Robust Drug Product Processing.

Commercialization of most promising active pharmaceutical ingredients (APIs) is impeded either by poor bioavailability or challenging physical properties leading to costly manufacture. Bioavailability of ionizable hydrophobic APIs can be enhanced by its conversion to salt form. While salt form of the API presents higher solution concentration than the non-ionized form, poor physical properties resulting from particle anisotropy or non-ideal morphology (needles) and particle size distribution not meeting dissolution rate targets can still inhibit its commercial translation. In this regard, API physical properties can be improved through addition of non-active components (excipients or carriers) during API manufacture. In this work, a facile method to perform reactive crystallization of an API salt in presence of the microporous environment of a hydrogel microparticle is presented. Specifically, the reaction between acidic antiretroviral API, raltegravir and base potassium hydroxide is performed in the presence of polyethylene glycol diacrylamide hydrogel microparticles. In this bottom-up approach, the spherical template hydrogel microparticles for the reaction lead to monodisperse composites loaded with inherently micronized raltegravir-potassium crystals, thus improving API physical properties without hampering bioavailability. Overall, this technique provides a novel approach to reactive crystallization while maintaining the API polymorph and crystallinity.

Crystalline Antibody-Laden Alginate Particles: A Platform for Enabling High Concentration Subcutaneous Delivery of Antibodies.

Subcutaneous (SC) administration is a desired route for monoclonal antibodies (mAbs). However, formulating mAbs for small injection volumes at high concentrations with suitable stability and injectability is a significant challenge. Here, this work presents a platform technology that combines the stability of crystalline antibodies with injectability and tunability of soft hydrogel particles. Composite alginate hydrogel particles are generated via a gentle centrifugal encapsulation process which avoids use of chemical reactions or an external organic phase. Crystalline suspension of anti-programmed cell death protein 1 (PD-1) antibody (pembrolizumab) is utilized as a model therapeutic antibody. Crystalline forms of the mAb encapsuled in the hydrogel particles lead to stable, high concentration, and injectable formulations. Formulation concentrations as high as 315 mg mL-1 antibody are achieved with encapsulation efficiencies in the range of 89-97%, with no perceivable increase in the number of antibody aggregates. Bioanalytical studies confirm superior maintained quality of the antibody in comparison with formulation approaches involving organic phases and chemical reactions. This work illustrates tuning the alginate particles' disintegration by using partially oxide alginates. Crystalline mAb-laden particles are evaluated for their biocompatibility using cell-based in vitro assays. Furthermore, the pharmacokinetics (PK) of the subcutaneously delivered human anti-PD-1 mAb in crystalline antibody-laden alginate hydrogel particles in Wistar rats is evaluated.

Microfluidic Particle Engineering of Hydrophobic Drug with Eudragit E100─Bridging the Amorphous and Crystalline Gap.

Co-processing active pharmaceutical ingredients (APIs) with excipients is a promising particle engineering technique to improve the API physical properties, which can lead to more robust downstream drug product manufacturing and improved drug product attributes. Excipients provide control over critical API attributes like particle size and solid-state outcomes. Eudragit E100 is a widely used polymeric excipient to modulate drug release. Being cationic, it is primarily employed as a precipitation inhibitor to stabilize amorphous solid dispersions. In this work, we demonstrate how co-processing of E100 with naproxen (NPX) (a model hydrophobic API) into monodisperse emulsions via droplet microfluidics followed by solidification via solvent evaporation allows the facile fabrication of compact, monodisperse, and spherical particles with an expanded range of solid-state outcomes spanning from amorphous to crystalline forms. Low E100 concentrations (≤26% w/w) yield crystalline microparticles with a stable NPX polymorph distributed uniformly across the matrix at a high drug loading (∼89% w/w). Structurally, E100 incorporation reduces the size of primary particles comprising the co-processed microparticles in comparison to neat API microparticles made using the same technique and the as-received API powder. This reduction in primary particle size translates into an increased internal porosity of the co-processed microparticles, with specific surface area and pore volume ∼9 times higher than the neat API microparticles. These E100-enabled structural modifications result in faster drug release in acidic media compared to neat API microparticles. Additionally, E100-NPX microparticles have a significantly improved flowability compared to neat API microparticles and as-received API powder. Overall, this study demonstrates a facile microfluidics-based co-processing method that broadly expands the range of solid-state outcomes obtainable with E100 as an excipient, with multiscale control over the key attributes and performance of hydrophobic API-laden microparticles.

Impact of Microbial Uptake on the Nutrient Plume around Marine Organic Particles: High-Resolution Numerical Analysis.

The interactions between marine bacteria and particulate matter play a pivotal role in the biogeochemical cycles of carbon and associated inorganic elements in the oceans. Eutrophic plumes typically form around nutrient-releasing particles and host intense bacterial activities. However, the potential of bacteria to reshape the nutrient plumes remains largely unexplored. We present a high-resolution numerical analysis for the impacts of nutrient uptake by free-living bacteria on the pattern of dissolution around slow-moving particles. At the single-particle level, the nutrient field is parameterized by the Péclet and Damköhler numbers (0 < Pe < 1000, 0 < Da < 10) that quantify the relative contribution of advection, diffusion and uptake to nutrient transport. In spite of reducing the extent of the nutrient plume in the wake of the particle, bacterial uptake enhances the rates of particle dissolution and nutrient depletion. These effects are amplified when the uptake timescale is shorter than the plume lifetime (Pe/Da < 100, Da > 0.0001), while otherwise they are suppressed by advection or diffusion. Our analysis suggests that the quenching of eutrophic plumes is significant for individual phytoplankton cells, as well as marine aggregates with sizes ranging from 0.1 mm to 10 mm and sinking velocities up to 40 m per day. This microscale process has a large potential impact on microbial growth dynamics and nutrient cycling in marine ecosystems.

Producing shape-engineered alginate particles using viscoplastic fluids.

Non-spherical hydrogel particles are of fundamental interest and can find use in a variety of applications ranging from pharmaceuticals to biomedical to food. Here, we report a new method that leverages the yield stress property of viscoplastic fluids to synthesize shape-engineered alginate particles. By dripping an aqueous viscoplastic solution composed of sodium alginate and a yield-stress material into an ionic gelation bath, droplets are controllably deformed and crosslinked, producing a wide assortment of shapes. We find that by tuning the yield stress of the solution and the nozzle tip orientation, a range of shapes from symmetric and near-spherical, to asymmetric and anisotropic (e.g., egg-, rice grain-, arc-, ring-, snail shell-, tear-, and tadpole-like) can be produced. We explain our observations using scaling analysis of the forces exerted on the droplet at different stages of particle production. We show that the main factors that determine the degree of droplet deformation during bath entry and the final appearance of the alginate particles are the initial shape of the droplets, the timescales of the viscoplastic fluid relaxation versus the crosslinking reaction, and the physico-chemical properties of the yield-stress material.

Systematic Approach to Address Early Pandemic's Diagnostic Unmet Needs.

During the first few months of the global Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic, the medical research community had to expeditiously develop, select, and deploy novel diagnostic methods and tools to address the numerous testing challenges presented by the novel virus. Integrating a systematic approach to diagnostic selection with a rapid validation protocol in a clinical setting can shorten the timeline to bring new technologies to practice. In response to the urgent need to provide tools for identifying SARS-CoV-2-positive individuals, we developed a framework for assessing technologies against a set of prioritized performance metrics to guide device selection. We also developed and proposed clinical validation frameworks for the rapid screening of new technologies. The rubric described here represents a versatile approach that can be extended to future technology assessments and can be implemented in preparation for future emerging pathogens.

Coarse-grained molecular dynamics simulations of immobilized micelle systems and their interactions with hydrophobic molecules.

Micelles immobilized in polymer materials are of emerging interest in drug delivery, water treatment and other applications. Immobilization removes the need for membrane-based separation to eliminate micelles from the medium, enabling facile extraction and delivery in diverse industries. This work lays out a coarse-grained molecular dynamics simulations framework for the rapid identification of surfactants for use in immobilized micelle systems. Micelles are immobilized by constraining one end of the constituent surfactants in space, mimicking what would occur in a copolymer system. We demonstrate that constraints affect how the micelles interact with small hydrophobic molecules, making it important to account for their effects in various drug-micelle and pollutant-micelle simulations. Our results show that in several systems there is stronger interaction between hydrophobic small molecules and micelles in immobilized systems compared to unconstrained systems. These strengthened interactions can have important implications for the design of new micelle-based extraction and delivery processes.