Implantable Drug Delivery Systems and Foreign Body Reaction: Traversing the Current Clinical Landscape

Precise delivery of therapeutics to the target structures is essential for treatment efficiency and safety. Drug administration via conventional routes requires overcoming multiple transport barriers to achieve and maintain the local drug concentration and commonly results in unwanted off-target effects. Patients’ compliance with the treatment schedule remains another challenge. Implantable drug delivery systems (IDDSs) provide a way to solve these problems. IDDSs are bioengineering devices surgically placed inside the patient’s tissues to avoid first-pass metabolism and reduce the systemic toxicity of the drug by eluting the therapeutic payload in the vicinity of the target tissues. IDDSs present an impressive example of successful translation of the research and engineering findings to the patient’s bedside. It is envisaged that the IDDS technologies will grow exponentially in the coming years. However, to pave the way for this progress, it is essential to learn lessons from the past and present of IDDSs clinical applications. The efficiency and safety of the drug-eluting implants depend on the interactions between the device and the hosting tissues. In this review, we address this need and analyze the clinical landscape of the FDA-approved IDDSs applications in the context of the foreign body reaction, a key aspect of implant–tissue integration.

The ITB dynamics controlled by internal kink modes on HL-2A tokamak

The active control of internal transport barriers (ITBs) is an important issue to achieve high performance plasma in a fusion reactor. A critical challenge of ITB control is to increase the ITB position. The ITBs with internal kink modes (IKMs), such as fishbone instability and long-live mode (LLM) with mode number of m/n = 1/1 are frequently observed on HL-2A tokamak in neutral beam heated discharges. The correlation of fishbone instability/LLM with ITBs is analyzed in order to extend the ITB radius. It has been revealed that fishbone instability and LLM are often excited after the ITB formation. Therefore, fishbone instability and LLM play no role in triggering ITBs on HL-2A tokamak. On the other hand, they may slow down the outward radial expansion and then shrink the foot position of ITB, and damp the gradient growth of ion temperature and rotation velocity. Since the perturbation of LLM is weaker than that of fishbone instability, the shrinking effect of ITB foot and braking effect on gradient growth are slighter than those of fishbone instability. Compared with the LLM, fishbone instability routinely appears in plasmas with lower density, higher heating power and lower plasma current. In addition, large ITBs without IKMs are also discussed on HL-2A tokamak. The large ITB is the largest one, the fishbone ITB is the strongest one and the LLM ITB is the widest one in three ITBs, where the ‘large’, ‘strong’ and ‘wide’ qualifications correspond to ITB position ρITB, the normalized temperature gradient R/LT, and its width W/a. Therefore, the large ITB position may be obtained if the IKMs are effectively controlled in a tokamak.

Drifting Speed of Lagrangian Fronts and Oil Spill Dispersal at the Ocean Surface

Due to its dire impacts on marine life, public health, and socio-economic services, oil spills require an immediate response. Effective action starts with good knowledge of the ocean dynamics and circulation, from which Lagrangian methods derive key information on the dispersal pathways present in the contaminated region. However, precise assessments of the capacity of Lagrangian methods in real contamination cases remain rare and limited to large slicks spanning several hundreds of km. Here we address this knowledge gap and consider two medium-scale (tens of km wide) events of oil in contrasting conditions: an offshore case (East China Sea, 2018) and a recent near-coastal one (East Mediterranean, 2021). Our comparison between oil slicks and Lagrangian diagnostics derived from near-real-time velocity fields shows that the calculation of Lagrangian fronts is, in general, more robust to errors in the velocity fields and more informative on the dispersion pathways than the direct advection of a numerical tracer. The inclusion of the effect of wind is also found to be essential, being capable of suddenly breaking Lagrangian transport barriers. Finally, we show that a usually neglected Lagrangian quantity, the Lyapunov vector, can be exploited to predict the front drifting speed, and in turn, its future location over a few days, on the basis of near-real-time information alone. These results may be of special relevance in the context of next-generation altimetry missions that are expected to provide highly resolved and precise near-real-time velocity fields for both open ocean and coastal regions.

Growth Inhibition of Triple-Negative Breast Cancer: The Role of Spatiotemporal Delivery of Neoadjuvant Doxorubicin and Cisplatin

Combinations of platinum-based compounds with doxorubicin in free and/or in liposomal form for improved safety are currently being evaluated in the neoadjuvant setting on patients with advanced triple-negative breast cancer (TNBC). However, TNBC may likely be driven by chemotherapy-resistant cells. Additionally, established TNBC tumors may also exhibit diffusion-limited transport, resulting in heterogeneous intratumoral delivery of the administered therapeutics; this limits therapeutic efficacy in vivo. We studied TNBC cells with variable chemosensitivities, in the absence (on monolayers) and presence (in 3D multicellular spheroids) of transport barriers; we compared the combined killing effect of free doxorubicin and free cisplatin to the killing effect (1) of conventional liposomal forms of the two chemotherapeutics, and (2) of tumor-responsive lipid nanoparticles (NP), specifically engineered to result in more uniform spatiotemporal microdistributions of the agents within solid tumors. This was enabled by the NP properties of interstitial release, cell binding/internalization, and/or adhesion to the tumors’ extracellular matrix. The synergistic cell kill by combinations of the agents (in all forms), compared to the killing effect of each agent alone, was validated on monolayers of cells. Especially for spheroids formed by cells exhibiting resistance to doxorubicin combination treatments with both agents in free and/or in tumor-responsive NP-forms were comparably effective; we not only observed greater inhibition of outgrowth compared to the single agent(s) but also compared to the conventional liposome forms of the combined agents. We correlated this finding to more uniform spatiotemporal microdistributions of agents by the tumor-responsive NP. Our study shows that combinations of NP with properties specifically optimized to improve the spatiotemporal uniformity of the delivery of their corresponding therapeutic cargo can improve treatment efficacy while keeping favorable safety profiles.

Harnessing stratospheric diffusion barriers for enhanced climate geoengineering

Stratospheric sulfate aerosol geoengineering is a proposed method to temporarily intervene in the climate system to increase the reflectance of shortwave radiation and reduce mean global temperature. In previous climate modeling studies, choosing injection locations for geoengineering aerosols has, thus far, only utilized the average dynamics of stratospheric wind fields instead of accounting for the essential role of time-varying material transport barriers in turbulent atmospheric flows. Here we conduct the first analysis of sulfate aerosol dispersion in the stratosphere, comparing what is now a standard fixed-injection scheme with time-varying injection locations that harness short-term stratospheric diffusion barriers. We show how diffusive transport barriers can quickly be identified, and we provide an automated injection location selection algorithm using short forecast and reanalysis data. Within the first 7 d days of transport, the dynamics-based approach is able to produce particle distributions with greater global coverage than fixed-site methods with fewer injections. Additionally, this enhanced dispersion slows aerosol microphysical growth and can reduce the effective radii of aerosols up to 200–300 d after injection. While the long-term dynamics of aerosol dispersion are accurately predicted with transport barriers calculated from short forecasts, the long-term influence on radiative forcing is more difficult to predict and warrants deeper investigation. Statistically significant changes in radiative forcing at timescales beyond the forecasting window showed mixed results, potentially increasing or decreasing forcing after 1 year when compared to fixed injections. We conclude that future feasibility studies of geoengineering should consider the cooling benefits possible by strategically injecting sulfate aerosols at optimized time-varying locations. Our method of utilizing time-varying attracting and repelling structures shows great promise for identifying optimal dispersion locations, and radiative forcing impacts can be improved by considering additional meteorological variables.

Observations of large-scale coherent structures in gravity currents: implications for flow dynamics

Density driven flows, also known as gravity currents, comprise a head, body, and tail. Yet whilst the body typically forms the largest part of such flows, its structure remains poorly understood. In this work, experimental data gathered using particle image velocimetry enables the instantaneous, whole-field dynamics of constant-influx solute-based gravity currents to be resolved. While averaged turbulent kinetic energy profiles are comparable to previous work, the instantaneous data sets reveal significant temporal variation, with velocity measurements indicating large-scale wave-like motions within the body. Spectral analysis and dynamic mode decomposition, of streamwise and vertical velocity, are used to identify the frequencies and structures of the dominant motions within the flow. By considering an idealised theoretical density profile, it is suggested that these structures may be internal gravity waves that form a critical layer within the flow located at the height of the maximum internal velocity. Irreversible internal wave breaking that has been postulated to occur at this critical layer suggests formation of internal eddy transport barriers, demonstrating that new dynamic models of turbulent mixing in gravity currents are needed. Graphic abstract