Study of PEG-b-PLA/Eudragit S100 Blends on the Nanoencapsulation of Indigo Carmine Dye and Application in Controlled Release.

A nanocapsule shell of poly(ethylene glycol)-block-poly(d,l-lactic acid) (PEG-b-PLA) mixed with anionic Eudragit S100 (90/10% w/w) was previously used to entrap and define the self-assembly of indigo carmine (IC) within the hydrophilic cavity core. In the present work, binary blends were prepared by solution mixing at different PEG-b-PLA/Eudragit S100 ratios (namely, 100/0, 90/10, 75/25, and 50/50% w/w) to elucidate the role of the capsule shell in tuning the encapsulation of the anionic dye (i.e., IC). The results showed that the higher content of Eudragit S100 in the blend decreases the miscibility of the two polymers due to weak intermolecular interactions between PEG-b-PLA and Eudragit S100. Moreover, with an increase in the amount of Eudragit S100, a higher thermal stability was observed related to the mobility restriction of PEG-b-PLA chains imposed by Eudragit S100. Formulations containing 10 and 25% Eudragit S100 exhibited an optimal interplay of properties between the negative surface charge and the miscibility of the polymer blend. Therefore, the anionic character of the encapsulating agent provides sufficient accumulation of IC molecules in the nanocapsule core, leading to dye aggregates following the self-assembly. At the same time, the blending of the two polymers tunes the IC release properties in the initial stage, achieving slow and controlled release. These findings give important insights into the rational design of polymeric nanosystems containing organic dyes for biomedical applications.

Identification of a humanized mouse model for functional testing of immune-mediated biomaterial foreign body response.

Biomedical devices comprise a major component of modern medicine, however immune-mediated fibrosis and rejection can limit their function over time. Here, we describe a humanized mouse model that recapitulates fibrosis following biomaterial implantation. Cellular and cytokine responses to multiple biomaterials were evaluated across different implant sites. Human innate immune macrophages were verified as essential to biomaterial rejection in this model and were capable of cross-talk with mouse fibroblasts for collagen matrix deposition. Cytokine and cytokine receptor array analysis confirmed core signaling in the fibrotic cascade. Foreign body giant cell formation, often unobserved in mice, was also prominent. Last, high-resolution microscopy coupled with multiplexed antibody capture digital profiling analysis supplied spatial resolution of rejection responses. This model enables the study of human immune cell-mediated fibrosis and interactions with implanted biomaterials and devices.

Disinfectants role in the prevention of spreading the COVID-19 and other infectious diseases: The need for functional polymers!

The spreading of coronavirus through droplets and aerosols of an infected person is a well-known mechanism. The main protection methods from this virus are using disinfectants/sanitizers, face masks, keeping social distance, and vaccination. With the rapid mutations of the virus accompanied by its features and contagions changing, new advanced functional materials development is highly needed. The usage of disinfectants/sanitizers in excess generates poisonous effects among the general public. Effective and simultaneously, human-friendly sanitizers or disinfectants are required to prevent the poisoning and the associated issues. They minimize the toxic effects of the currently available materials by rapid action, high potential, long-term stability, and excellent biocompatible nature. Here, we summarize the available antiviral materials, their features, and their limitations. We highlight the need to develop an arsenal of advanced functional antiviral polymers with intrinsic bioactive functionalities or released bioactive moieties in a controlled manner for rapid and long-term actions for current and future anticipated viral outbreaks.

Long-term implant fibrosis prevention in rodents and non-human primates using crystallized drug formulations.

Implantable medical devices have revolutionized modern medicine. However, immune-mediated foreign body response (FBR) to the materials of these devices can limit their function or even induce failure. Here we describe long-term controlled-release formulations for local anti-inflammatory release through the development of compact, solvent-free crystals. The compact lattice structure of these crystals allows for very slow, surface dissolution and high drug density. These formulations suppress FBR in both rodents and non-human primates for at least 1.3 years and 6 months, respectively. Formulations inhibited fibrosis across multiple implant sites-subcutaneous, intraperitoneal and intramuscular. In particular, incorporation of GW2580, a colony stimulating factor 1 receptor inhibitor, into a range of devices, including human islet microencapsulation systems, electrode-based continuous glucose-sensing monitors and muscle-stimulating devices, inhibits fibrosis, thereby allowing for extended function. We believe that local, long-term controlled release with the crystal formulations described here enhances and extends function in a range of medical devices and provides a generalized solution to the local immune response to implanted biomaterials.

Simultaneous spatiotemporal tracking and oxygen sensing of transient implants in vivo using hot-spot MRI and machine learning.

A varying oxygen environment is known to affect cellular function in disease as well as activity of various therapeutics. For transient structures, whether they are unconstrained therapeutic transplants, migrating cells during tumor metastasis, or cell populations induced by an immunological response, the role of oxygen in their fate and function is known to be pivotal albeit not well understood in vivo. To address such a challenge in the case of generation of a bioartificial pancreas, we have combined fluorine magnetic resonance imaging and unsupervised machine learning to monitor over time the spatial arrangement and the oxygen content of implants encapsulating pancreatic islets that are unconstrained in the intraperitoneal (IP) space of healthy and diabetic mice. Statistically significant trends in the postimplantation temporal dependence of oxygen content between aggregates of 0.5-mm or 1.5-mm alginate microcapsules were identified in vivo by looking at their dispersity as well as arrangement in clusters of different size and estimating oxygen content on a pixel-by-pixel basis from thousands of 2D images. Ultimately, we found that this dependence is stronger for decreased implant capsule size consistent with their tendency to also induce a larger immunological response. Beyond the bioartificial pancreas, this work provides a framework for the simultaneous spatiotemporal tracking and oxygen sensing of other cell populations and biomaterials that change over time to better understand and improve therapeutic design across diverse applications such as cellular transplant therapy, treatments preventing metastatic formation, and modulators for improving immunologic response, for all of which oxygen is a major mechanistic component.

Protective Layer Development for Enhancing Stability and Drug-Delivery Capabilities of DES Surface-Crystallized Coatings.

Carrier-free drug-eluting stents (DES)-based crystalline coatings are gaining prominence because of their function, skipping many limitations and clinical complications of the currently marketed DES. However, their usage has been humbled by inflexibility of the crystalline coating and limited mechanical and physical properties. This study reports for the first time the development of a protective top coating for enhancing the merits and delivery capabilities of the crystalline coating. Flexible and water-soluble polysaccharide top coating was developed and applied onto rapamycin (RM) crystalline carpet. The top coating prevented crystalline coating delamination during stent crimping and expansion without affecting its release profile. Crystalline coating strata and its interfaces with the metallic substrate and top coating were fully studied and characterized. The crystalline top-coated stents showed significant physical, mechanical, and chemical stability enhancement with ∼2% RM degradation after 1 year under different storage conditions. Biocompatibility study of the top-coated stents implanted subcutaneously for 1 month into SD rats did not provoke any safety concerns. Incorporating RM into the top coating to develop a bioactive protective coating for multilayer release purposes was also investigated. The developed protective coating had wide applicability and may be further implemented for various drugs and implantable medical devices.

Crystalline paclitaxel coated DES with bioactive protective layer development.

Drug eluting stents (DES) based on polymeric-carriers currently lead the market, however, reports on clinical complications encourage the development of safer and more effective DES. We recently reported on carrier-free DES based on rapamycin crystalline coating as a potential therapeutic solution. Here, we report for the first time surface crystallization of paclitaxel (PT) onto metallic stents. The physicochemical principles of crystallization and key process parameters were extensively studied for fabrication of controllable and homogeneous crystalline coatings on stent scaffolds. Stents loaded with nearly 100µg PT were chosen as a potential therapeutic device with a multilayer coating of 4-7µm thickness. In vitro PT release from these coated stents shows constant release for at least 28days with 10% cumulatively released. The effect of fast dissolving top coating on the physical stability of the coated stent was determined. The top coating enhances the mechanical stability of the crystalline coating during deployment and expansion simulations. Also, incorporating PT in the protective top coating for developing bioactive top coating for multilayer controlled release purpose was intensively studied. This process has wide applications that can be further implemented for other drugs for effective local drug delivery from implantable medical devices.

Reduction of measurement noise in a continuous glucose monitor by coating the sensor with a zwitterionic polymer.

Continuous glucose monitors (CGMs), used by patients with diabetes mellitus, can autonomously track fluctuations in blood glucose over time. However, the signal produced by CGMs during the initial recording period following sensor implantation contains substantial noise, requiring frequent recalibration via fingerprick tests. Here, we show that coating the sensor with a zwitterionic polymer, found via a combinatorial-chemistry approach, significantly reduces signal noise and improves CGM performance. We evaluated the polymer-coated sensors in mice as well as in healthy and diabetic non-human primates, and show that the sensors accurately record glucose levels without the need for recalibration. We also show that the polymer-coated sensors significantly abrogated immune responses to the sensor, as indicated by histology, fluorescent whole-body imaging of inflammation-associated protease activity, and gene expression of inflammation markers. The polymer coating may allow CGMs to become standalone measuring devices.

Colony stimulating factor-1 receptor is a central component of the foreign body response to biomaterial implants in rodents and non-human primates.

Host recognition and immune-mediated foreign body response to biomaterials can compromise the performance of implanted medical devices. To identify key cell and cytokine targets, here we perform in-depth systems analysis of innate and adaptive immune system responses to implanted biomaterials in rodents and non-human primates. While macrophages are indispensable to the fibrotic cascade, surprisingly neutrophils and complement are not. Macrophages, via CXCL13, lead to downstream B cell recruitment, which further potentiated fibrosis, as confirmed by B cell knockout and CXCL13 neutralization. Interestingly, colony stimulating factor-1 receptor (CSF1R) is significantly increased following implantation of multiple biomaterial classes: ceramic, polymer and hydrogel. Its inhibition, like macrophage depletion, leads to complete loss of fibrosis, but spares other macrophage functions such as wound healing, reactive oxygen species production and phagocytosis. Our results indicate that targeting CSF1R may allow for a more selective method of fibrosis inhibition, and improve biomaterial biocompatibility without the need for broad immunosuppression.

Physical and mechanical properties of PLA, and their functions in widespread applications - A comprehensive review.

Poly(lactic acid) (PLA), so far, is the most extensively researched and utilized biodegradable aliphatic polyester in human history. Due to its merits, PLA is a leading biomaterial for numerous applications in medicine as well as in industry replacing conventional petrochemical-based polymers. The main purpose of this review is to elaborate the mechanical and physical properties that affect its stability, processability, degradation, PLA-other polymers immiscibility, aging and recyclability, and therefore its potential suitability to fulfill specific application requirements. This review also summarizes variations in these properties during PLA processing (i.e. thermal degradation and recyclability), biodegradation, packaging and sterilization, and aging (i.e. weathering and hygrothermal). In addition, we discuss up-to-date strategies for PLA properties improvements including components and plasticizer blending, nucleation agent addition, and PLA modifications and nanoformulations. Incorporating better understanding of the role of these properties with available improvement strategies is the key for successful utilization of PLA and its copolymers/composites/blends to maximize their fit with worldwide application needs.

Antimicrobial evaluation of quaternary ammonium polyethyleneimine nanoparticles against clinical isolates of pathogenic bacteria.

Peritonitis is a disease caused by bacterial strains that have become increasingly resistant to many antibiotics. The development of alternative therapeutic compounds is the focus of extensive research, so novel nanoparticles (NPs) with activity against antibiotic-resistant bacteria should be developed. In this study, the antibacterial activity of quaternary ammonium polyethyleneimine (QA-PEI) NPs was evaluated against Streptococcus viridans, Stenotrophomonas maltophilia and Escherichia coli. To appraise the antibacterial activity, minimal inhibitory concentration (MIC), minimal bactericidal concentration and bactericidal assays were utilised with different concentrations (1.56-100 µg/ml) of QA-PEI NPs. Moreover, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and annexin V/propidium iodide toxicity assays were performed in cell cultures. MICs for S. maltophilia and E. coli isolates were 12.5 and 25 µg/ml, respectively, whereas the MIC for S. viridans was 100 µg/ml. Furthermore, the growth curve assays revealed that these QA-PEI NPs at a concentration of 12.5 µg/ml significantly inhibited bacterial growth for the bacterial isolates studied. On the other hand, QA-PEI NPs lacked significant toxicity for cells when used at concentrations up to 50 µg/ml for 48 h. The present findings reveal the potential therapeutic value of this QA-PEI NPs as alternative antibacterial agents for peritonitis, especially against Gram-negative bacteria.

Antimicrobial N-brominated hydantoin and uracil grafted polystyrene beads.

Hydantoin-N-halamine derivatives conjugated on polystyrene beads are promising disinfectants with broad antimicrobial activity affected by the gradual release of oxidizing halogen in water. The objective of this work was to identify and test of hydantoin-like molecules possessing urea moiety, which may provide N-haloamines releasing oxidizing halogens when exposed to water at different rates and release profiles for tailored antimicrobial agents. In this work, several hydantoin (five member ring) and for the first time reported, uracil (six member ring) derivatives have been conjugated to polystyrene beads and tested for their lasting antimicrobial activity. Four molecules of each series were conjugated onto polystyrene beads from the reaction of the N-potassium hydantoin or uracil derivatives onto chloromethylated polystyrene beads. A distinct difference in bromine loading capacity and release profiles was found for the different conjugated derivatives. All tested materials exhibit strong antimicrobial activity against Escherichia coli and bacteriophages MS2 of 7 and ~4 log reduction, respectively. These results highlight the antimicrobial potential of halogenated cyclic molecules containing urea groups as water disinfection agents.

Quaternary ammonium polyethylenimine nanoparticles for treating bacterial contaminated water.

This study highlights the potential application of antimicrobial quaternary ammonium nanomaterials for water disinfection. Quaternary ammonium polyethylenimine (QA-PEI) nanoparticles (NPs) were synthesized by polyethylenimine crosslinking and alkylation with octyl iodide followed by methyl iodide quaternization. Particles modified with octyldodecyl alkyl chains were also prepared and evaluated. The antimicrobial activity of QA-PEI NPs was studied after anchoring in non-leaching polymeric coatings and also in aqueous suspension. Particles at different loadings (w/w) were embedded in polyethylene vinyl acetate and polyethylene methacrylic acid coatings and tested for antimicrobial activity against four representative strains of bacteria in static and dynamic modes. Coatings embedded with fluorescent labelled particles tracked by Axioscope fluorescence microscope during the antimicrobial test indicates no particles leaching out. Coatings loaded with 5% w/w QA-PEI exhibited strong antibacterial activity. Aqueous suspension was tested and found effective for bacterial decontamination at 0.1 ppm and maintains its activity for several weeks.

N-bromo-dimethylhydantoin polystyrene resin for water microbial decontamination.

N-bromo-dimethylhydantoin polystyrene beads were synthesized and tested as antimicrobial agents for water microbial decontamination. Optimization of synthetic process was thoroughly investigated, including solvents used, ratio of reactants and reaction conditions, kilogram scale production, and detailed spectral analysis. The microbial inactivation efficiency was studied according to the NSF-231 Guide Standard and Protocol for Testing Microbiological Water Purifiers against Escherichia coli and MS2 phage. The tested resins maintained their activity for 550 L. Thus, N-bromo-dimethylhydantoin-polystyrene beads synthesized under optimized conditions at kilogram quantities have a potential use in water purification filters.

Quaternary ammonium poly(diethylaminoethyl methacrylate) possessing antimicrobial activity.

Quaternary ammonium (QA) methacrylate monomers and polymers were synthesized from a N-alkylation of N,N-diethylaminoethyl methacrylate (DEAEM) monomer. Linear copolymers, and for the first time reported crosslinked nanoparticles (NPs), based QA-PDEAEM were prepared by radical polymerization of the quaternized QA-DEAEM monomers with either methyl methacrylate (MMA) or a divinyl monomer. QA-PDEAEM NPs of 50-70 nm were embedded in polyethylene vinyl acetate coating. QA-polymers with N-C8 and N-C18 alkyl chains and copolymers with methyl methacrylate were prepared at different molar ratios and examined for their antimicrobial effectiveness. These coatings exhibited strong antibacterial activity against four representative Gram-positive and Gram-negative bacteria.

Antimicrobial polymers.

Better health is basic requirement of human being, but the rapid growth of harmful pathogens and their serious health effects pose a significant challenge to modern science. Infections by pathogenic microorganisms are of great concern in many fields such as medical devices, drugs, hospital surfaces/furniture, dental restoration, surgery equipment, health care products, and hygienic applications (e.g., water purification systems, textiles, food packaging and storage, major or domestic appliances etc.) Antimicrobial polymers are the materials having the capability to kill/inhibit the growth of microbes on their surface or surrounding environment. Recently, they gained considerable interest for both academic research and industry and were found to be better than their small molecular counterparts in terms of enhanced efficacy, reduced toxicity, minimized environmental problems, resistance, and prolonged lifetime. Hence, efforts have focused on the development of antimicrobial polymers with all desired characters for optimum activity. In this Review, an overview of different antimicrobial polymers, their mechanism of action, factors affecting antimicrobial activity, and application in various fields are given. Recent advances and the current clinical status of these polymers are also discussed.

Morphological, spectral and chromatography analysis and forensic comparison of PET fibers.

Poly(ethylene terephthalate) (PET) fiber analysis and comparison by spectral and polymer molecular weight determination was investigated. Plain fibers of PET, a common textile fiber and plastic material was chosen for this study. The fibers were analyzed for morphological (SEM and AFM), spectral (IR and NMR), thermal (DSC) and molecular weight (MS and GPC) differences. Molecular analysis of PET fibers by Gel Permeation Chromatography (GPC) allowed the comparison of fibers that could not be otherwise distinguished with high confidence. Plain PET fibers were dissolved in hexafluoroisopropanol (HFIP) and analyzed by GPC using hexafluoroisopropanol:chloroform 2:98 v/v as eluent. 14 PET fiber samples, collected from various commercial producers, were analyzed for polymer molecular weight by GPC. Distinct differences in the molecular weight of the different fiber samples were found which may have potential use in forensic fiber comparison. PET fibers with average molecular weights between about 20,000 and 70,000 g mol(-1) were determined using fiber concentrations in HFIP as low as 1 µg mL(-1). This GPC analytical method can be applied for exclusively distinguish between PET fibers using 1 µg of fiber. This method can be extended to forensic comparison of other synthetic fibers such as polyamides and acrylics.

Electrospun rapamycin-eluting polyurethane fibers for vascular grafts.

PURPOSE: To develop rapamycin-eluting electrospun polyurethane (PU) vascular grafts that could effectively suppress local smooth muscle cell (SMC) proliferation. METHODS: Rapamycin (RM) was incorporated in PU fibers by blend electrospinning using three distinct blending methods. The drug release profiles and the bioavailability of RM-containing PU fibers in the form of fibrous mats and vascular grafts were evaluated up to 77 days in vitro. RESULTS: RM-contained PU fibers generated by the three distinct blending methods exhibited significantly different fiber diameters (200-500 nm) and distinct RM release kinetics. Young's moduli of the electrospun fibrous mats increased with higher RM contents and decreased with larger fiber diameters. For all blending methods, RM release kinetics was characteristic of a Fickian diffusion for at least 77 days in vitro. RM-PU fibers generated via powder blending showed the highest encapsulation efficiency. The RM in grafts made of these fibers remained bioactive and was still able to inhibit smooth muscle cell proliferation after 77 days of continual in vitro release. CONCLUSIONS: Electrospun RM-containing PU fibers can serve as effective drug carriers for the local suppression of SMC proliferation and could be used as RM-eluting scaffolds for vascular grafts.

Carrier free rapamycin loaded drug eluting stent: in vitro and in vivo evaluation.

In the search for improving the performance of drug eluting stent (DES) various developments are in progress worldwide including use of carrier free DES, use of biodegradable polymers, biodegradable stents etc. In this work, carrier free-rapamycin (RM) coated DES has been prepared, and evaluated by in vitro and in vivo procedures necessary for clinical development. In vitro drug release from the developed stents was carried in different release media, normal saline-isopropanol (NS-IP), phosphate buffer (PB), phosphate buffer saline (PBS) and in human plasma. Simultaneously, drug released at site of implantation and biocompatibility of developed stents was determined after subcutaneous implantation in the SD rats. Developed stent coating method enables fabrication of controllable and homogeneous crystalline RM coatings on stent scaffolds. Continuous release of RM was observed in different release conditions with different release rate, maximum in NS-IP and least in PB. Similarly, after subcutaneous implantation of these stents, RM was found in surrounding tissues and in implanted stent up to 28 days. Biocompatibility studies showed no evidence for presence of necrosis, foreign body giant cell reaction or any type of increased severity of inflammatory reaction, proving potential of developed stents for further clinical development.