HIV and hepatitis B are two of the most prevalent viruses globally, and despite readily available preventive treatments unforgiving treatment regimens still exist, such as daily doses of medicine that are challenging to maintain especially in poorer countries. More advanced and longer-lasting delivery vehicles can potentially overcome this problem by reducing maintenance requirements and significantly increase access to medicine. Here, we designed a technology to control the delivery of an antiviral drug over a long timeframe via a nanofiber based delivery scaffold that is both easy to produce and use. An antiviral prodrug containing tenofovir alafenamide (TAF) was synthesized by initial conjugation to glycerol monomethacrylate followed by polymerization to form a diblock copolymer (pTAF) using reversible addition-fragmentation chain transfer (RAFT). In order to generate an efficient drug delivery system this copolymer was fabricated into an electrospun nanofiber (ESF) scaffold using blend electrospinning with poly(caprolactone) (PCL) as the carrier polymer. SEM images revealed that the pTAF-PCL ESFs were uniform with an average diameter of (787 ± 0.212 nm), while XPS analysis demonstrated that the pTAF was overrepresented at the surface of the ESFs. Additionally, the pTAF exhibited a sustained release profile over a 2 month period in human serum (HS), suggesting that these types of copolymer-based drugamers can be used in conjunction with electrospinning to produce long-lasting drug delivery systems.

Pulmonary melioidosis is a bacterial disease with high morbidity and a mortality rate that can be as high as 40% in resource-poor regions of South Asia. This disease burden is linked to the pathogen's intrinsic antibiotic resistance and protected intracellular localization in alveolar macrophages. Current treatment regimens require several antibiotics with multi-month oral and intravenous administrations that are difficult to implement in under-resourced settings. Herein, we report that a macrophage-targeted polyciprofloxacin prodrug acts as a surprisingly effective pre-exposure prophylactic in highly lethal murine models of aerosolized human pulmonary melioidosis. A single dose of the polymeric prodrug maintained high lung drug levels and targeted an intracellular depot of ciprofloxacin to the alveolar macrophage compartment that was sustained over a period of 7 days above minimal inhibitory concentrations. This intracellular pharmacokinetic profile provided complete pre-exposure protection in a BSL-3 model with an aerosolized clinical isolate of Burkholderia pseudomallei from Thailand. This total protection was achieved despite the bacteria's relative resistance to ciprofloxacin and where an equivalent dose of pulmonary-administered ciprofloxacin was ineffective. For the first time, we demonstrate that targeting the intracellular macrophage compartment with extended antibiotic dosing can achieve pre-exposure prophylaxis in a model of pulmonary melioidosis. This fully synthetic and modular therapeutic platform could be an important therapeutic approach with new or re-purposed antibiotics for melioidosis prevention and treatment, especially as portable inhalation devices in high-risk, resource-poor settings.

Biofilms are one of the most challenging obstacles in bacterial infections. By providing protection against immune responses and antibiotic therapies, biofilms enable chronic colonization and the development of antibiotic resistance. As previous clinical observations and studies have shown, traditional antibiotic therapy alone cannot effectively treat and eliminate biofilm forming infections due to the protection conferred by the biofilm. A new strategy specifically targeting biofilms must be developed. Here, we specifically target and bind to the PAO1 biofilm and elucidate the molecular mechanism behind the interaction between a glycan targeted polymer and biofilm using a continuous flow biofilm model. The incubation of biofilms with fluorescent glycan targeted polymers demonstrated strong and persistent interactions with the mannose-containing polymer even after 24 h of continuous flow. To evaluate the role of major biofilm proteins LecB and CdrA, loss of function experiments with knockout variants established the dual involvement of both proteins in mannose targeted polymer retention. These results identify a persistent and specific targeting strategy to the biofilm, emphasizing its potential value as a delivery strategy and encouraging further exploration of biofilm targeted delivery.

Sub-wavelength grating (SWG) metamaterials have been considered to provide promising solutions in the development of next-generation photonic integrated circuits. In recent years, increasied interest has been paid to silicon photonic planar biosensors based on SWG geometries for performance enhancement. In this work, we demonstrate a highly sensitive label-free phase-shifted Bragg grating (PSBG) sensing configuration, which consists of sub-wavelength block arrays in both propagation and transverse directions. By introducing salt serial dilutions and electrostatic polymers assays, bulk and surface sensitivities of the proposed sensor are characterized, obtaining measured results up to 579.2 nm/RIU and 1914 pm/nm, respectively. Moreover, the proposed multi-box PSBG sensor presents an improved quality factor as high as ∼8000 , roughly 3-fold of the microring-based counterpart, which further improves the detection limit. At last, by employing a biotin-streptavidin affinity assay, the capability for small molecule monitoring is exemplified with a minimum detectable concentration of biotin down to 2.28×10-8M .

The authors wish to make the following corrections in their published paper in Sensors [...]

In this paper, a novel silicon photonic waveguide for a high sensitivity label-free sensor is presented. We use silicon-on-insulator subwavelength waveguides that consist of five rows of periodic silicon squares with 60 nm gap distances between each square (multibox structure) to construct microring resonators to achieve higher bulk and surface sensitivities than the resonators using conventional strip waveguides. Due to the high surface contact area and low optical confinement of the proposed multibox waveguides, the sensitivity of the microring resonator can be significantly increased. By exposing the multibox microring resonators to ultrapure water and different concentrations of isopropyl alcohol solution, we show a bulk sensitivity of 579.5 nm/RIU, which is an increase compared to recently published subwavelength grating waveguides and strip waveguides in transverse magnetic polarization microring resonators. Finally, a standard biological sandwich assay is employed to demonstrate the multibox sensor's ability, with an enhanced surface sensitivity of 1900 pm/nm.

We present a system-level integration of active silicon photonic biosensors. With on-chip photodetectors, sensors are characterized in the photovoltaic mode. A biotin-avidin affinity assay is employed to exemplify the detection of small molecule interactions, showing a detection limit in the order of 10 -5 M.

Radiant star nanoparticle prodrugs were synthesized in a two-step process by first homopolymerizing RAFT transmers followed by copolymerization from the hyperbranched polymer core.

Thanks to advanced semiconductor microfabrication technology, chip-scale integration and miniaturization of lab-on-a-chip components, silicon-based optical biosensors have made significant progress for the purpose of point-of-care diagnosis. In this review, we provide an overview of the state-of-the-art in evanescent field biosensing technologies including interferometer, microcavity, photonic crystal, and Bragg grating waveguide-based sensors. Their sensing mechanisms and sensor performances, as well as real biomarkers for label-free detection, are exhibited and compared. We also review the development of chip-level integration for lab-on-a-chip photonic sensing platforms, which consist of the optical sensing device, flow delivery system, optical input and readout equipment. At last, some advanced system-level complementary metal-oxide semiconductor (CMOS) chip packaging examples are presented, indicating the commercialization potential for the low cost, high yield, portable biosensing platform leveraging CMOS processes.

Novel sub-wavelength silicon photonic waveguides for label-free sensors are demonstrated in this article. We use silicon-on-insulator (SOI) waveguides that consist of sub-wavelength grating (SWG) structures, where the waveguides are made of small silicon arrays (180 × 180 nm2 rectangles with 60 nm gaps). They are used to form microring and Bragg grating resonators which measure the change of refractive index by monitoring the resonant wavelength shift. Due to the high surface contact area and low optical confinement of the proposed waveguide, the sensitivity (both bulk and surface) can be significantly increased. The bulk sensitivity of 580 nm/RIU for the microring and 610 nm/RIU for the Bragg grating are better than other recently published resonator sensors. Moreover, a standard biological sandwich assay demonstrates an enhanced surface sensitivity of 2050 pm/nm for both devices. Theoretical models and experimental results are investigated, indicating the predominant losses are from the water absorption at 1550 nm and scattering by sidewall roughness.

Alveolar macrophages resident in the lung are prominent phagocytic effector cells of the pulmonary innate immune response, and paradoxically, are attractive harbors for pathogens. Consequently, facultative intracellular bacteria, such as Francisella tularensis, can cause severe systemic disease and sepsis, with high morbidity and mortality associated with pulmonary infection. Current clinical treatment, which involves exhaustive oral or intravenous antibiotic therapy, has limitations such as systemic toxicity and off-target effects. Pulmonary administration represents a promising alternative to systemic dosing for delivering antibiotics directly to the lung. Here, we present synthesized mannosylated ciprofloxacin polymeric prodrugs for efficient pulmonary delivery, targeting, and subsequent internalization by alveolar macrophages, We demonstrate significant improvement in efficacy against intracellular infections in an otherwise uniformly lethal airborne Francisella murine model (F. novicida). When administered to the lungs of mice in a prophylactic regimen, the mannosylated ciprofloxacin polymeric prodrugs led to 50% survival. In a treatment regimen that was concurrent with infection, the survival of mice increased to 87.5%. Free ciprofloxacin antibiotic was ineffective in both cases. This significant difference in antibacterial efficacy demonstrates the impact of this delivery platform based on improved physiochemical, pharmacokinetic, and pharmacodynamic properties of ciprofloxacin administered via our glycan polymeric prodrug. This modular platform provides a route for overcoming the limitations of free drug and increasing efficacy in treatment of intracellular infection.

A simplified liposome formulation with three functionalities to enhance antibiotic bioavailability to cytosolic bacteria: carbohydrate-mediated targeting; pH-responsive release; endosomal-release activity.

Intracellular bacterial infections localized to the lung alveolar macrophage (AM) remain one of the most challenging settings for antimicrobial therapy. Current systemic antibiotic treatment fails to deliver sustained doses to intracellular bacterial reservoirs, which necessitates prolonged treatment regimens. Herein, we demonstrate a new intracellular enzyme-cleavable polymeric prodrug with tailored ciprofloxacin release profiles in the lungs and AM. The targeted polymeric prodrug, termed "drugamers", incorporates (1) hydrophilic mannose residues to solubilize the antibiotic cargo and to target and enhance AM uptake and intracellular delivery, and (2) enzymecleavable linkage chemistry to provide high and sustained intracellular AM drug dosing. Prodrug monomers, derived from the antibiotic ciprofloxacin, were synthesized with either an intracellular protease cleavable dipeptide linker or a hydrolytic phenyl ester linker. RAFT polymerization was used to copolymerize the prodrug monomers and mannose monomer to synthesize well-defined drugamers without requiring a post-polymerization conjugation step. In addition to favorable in vivo safety profiles following intratracheal administration, a single dose of the drugamers sustained ciprofloxacin dosing in lungs and AMs above the minimum inhibitory concentration (MIC) over at least a 48 h period. The enzyme-cleavable therapeutic achieved a > 10-fold increase in sustained ciprofloxacin in AM, and maintained a significantly higher whole lung PK as well. Ciprofloxacin dosed in identical fashion displayed rapid clearance with a half-life of approximately 30 min. Notably, inhalation of the mannose-targeted ciprofloxacin drugamers achieved full survival (100%) in a highly lethal mouse model of pneumonic tularemia, contrasted with 0% survival using free ciprofloxacin. These findings demonstrate the versatility of the drugamer platform for engineering the intracellular pharmacokinetic profiles and its strong therapeutic activity in treating pulmonary intracellular infections.

Silicon photonic integrated circuits have gained a lot of attention over the last decade. Although the driving force remains high-speed telecommunications, the same platform has been used to design highly sensitive label-free biosensors. The high refractive index contrast between silicon and silica, or other surrounding media, allows one to build very compact circuits which can be mass produced at low cost by leveraging CMOS foundries. Over the same period, a novel packaging technique, known as Fan-Out Wafer-Level-Packaging (FOWLP), has emerged to address the growing need for miniaturized system-on-a-package chips. Whereas researchers have pushed the limit of detection of photonic sensing devices, system-level integration has received less attention. In this work, we demonstrate the potential of combining silicon photonics with FOWLP to design low-cost multiplexed biosensors. By using on-chip germanium photodetectors, 1 mm2 dies integrating 16 microring resonators are packaged into epoxy cartridges with electrical interconnects and microfluidic channels. This new architecture reduces the silicon die size while simplifying the microfluidic and optical integration for a more compact and affordable reader device. The biosensors exhibit similar sensitivities as passive circuits. We believe this architecture will pave the way for the commercial deployment of highly multiplexed, yet low-cost point-of-care diagnostic devices.

This chapter focuses on biosensor design considerations in medicine research, diagnostics, etc., nearly all of the devices have far-reaching applications beyond the exclusive domain of biomedical research. For instance, a biosensor for detecting malaria could also be implemented to detect pathogenic organisms in food, or as a research tool to screen for inhibitors to prevent disease. Optical biosensors are the most widely used label-free biosensing platforms to study biomolecular interactions because of their relative ease of use, high sensitivity, and the high information content of the data they generate. Silicon photonic optical biosensors are the most promising candidate technology with the potential to integrate all of these design features. Electrochemical biosensors operate by detecting the change in the resistance or capacitance on an electrical sensing component in response to the formation of binding complexes or to environmental perturbations. Electrical impedance spectroscopy (EIS), in the case of affinity biosensors, measures the change in the impedance of an electrical circuit.

Biosensors based on silicon photonic integrated circuits have attracted a growing interest in recent years. The use of sub-micron silicon waveguides to propagate near-infrared light allows for the drastic reduction of the optical system size, while increasing its complexity and sensitivity. Using silicon as the propagating medium also leverages the fabrication capabilities of CMOS foundries, which offer low-cost mass production. Researchers have deeply investigated photonic sensor devices, such as ring resonators, interferometers and photonic crystals, but the practical integration of silicon photonic biochips as part of a complete system has received less attention. Herein, we present a practical system-level architecture which can be employed to integrate the aforementioned photonic biosensors. We describe a system based on 1 mm2 dies that integrate germanium photodetectors and a single light coupling device. The die are embedded into a 16x16 mm2 epoxy package to enable microfluidic and electrical integration. First, we demonstrate a simple process to mimic Fan-Out Wafer-level-Packaging, which enables low-cost mass production. We then characterize the photodetectors in the photovoltaic mode, which exhibit high sensitivity at low optical power. Finally, we present a new grating coupler concept to relax the lateral alignment tolerance down to ± 50 μm at 1-dB (80%) power penalty, which should permit non-experts to use the biochips in a"plug-and-play" style. The system-level integration demonstrated in this study paves the way towards the mass production of low-cost and highly sensitive biosensors, and can facilitate their wide adoption for biomedical and agro-environmental applications.