Macromolecules Innovation Institute (MII)

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Ammonium Bisphosphonate Polymeric Magnetic Nanocomplexes for Platinum Anticancer Drug Delivery and Imaging with Potential Hyperthermia and Temperature-Dependent Drug Release
Zhang, Rui; Fellows, Benjamin; Pothayee, Nikorn; Hu, Nan; Pothayee, Nipon; Jo, Ami; Bohórquez, Ana C.; Rinaldi, Carlos; Mefford, Olin Thompson; Davis, Richey M.; Riffle, Judy S. (Hindawi, 2018-08-05)
Novel magnetite-ammonium bisphosphonate graft ionic copolymer nanocomplexes (MGICs) have been developed for potential drug delivery, magnetic resonance imaging, and hyperthermia applications. The complexes displayed relatively uniform sizes with narrow size distributions upon self-assembly in aqueous media, and their sizes were stable under simulated physiological conditions for at least 7 days. The anticancer drugs, cisplatin and carboplatin, were loaded into the complexes, and sustained release of both drugs was observed. The transverse NMR relaxivities (s) of the complexes were 244 s−1 (mM Fe)−1 which is fast compared to either the commercial T2-weighted MRI agent Feridex IV® or our previously reported magnetite-block ionomer complexes. Phantom MRI images of the complexes demonstrated excellent negative contrast effects of such complexes. Thus, the bisphosphonate-bearing MGICs could be promising candidates for dual drug delivery and magnetic resonance imaging. Moreover, the bisphosphonate MGICs generate heat under an alternating magnetic field of 30 kA·m−1 at 206 kHz. The temperature of the MGIC dispersion in deionized water increased from 37 to 41°C after exposure to the magnetic field for 10 minutes, corresponding to a specific absorption rate of 77.0 W·g−1. This suggests their potential as hyperthermia treatment agents as well as the possibility of temperature-dependent drug release, making MGICs more versatile in potential drug delivery applications.
Bioactive Cellulose Nanocrystal-Poly(epsilon-Caprolactone) Nanocomposites for Bone Tissue Engineering Applications
Hong, Jung Ki; Cooke, Shelley L.; Whittington, Abby R.; Roman, Maren (2021-02-25)
3D-printed bone scaffolds hold great promise for the individualized treatment of critical-size bone defects. Among the resorbable polymers available for use as 3D-printable scaffold materials, poly(epsilon-caprolactone) (PCL) has many benefits. However, its relatively low stiffness and lack of bioactivity limit its use in load-bearing bone scaffolds. This study tests the hypothesis that surface-oxidized cellulose nanocrystals (SO-CNCs), decorated with carboxyl groups, can act as multi-functional scaffold additives that (1) improve the mechanical properties of PCL and (2) induce biomineral formation upon PCL resorption. To this end, an in vitro biomineralization study was performed to assess the ability of SO-CNCs to induce the formation of calcium phosphate minerals. In addition, PCL nanocomposites containing different amounts of SO-CNCs (1, 2, 3, 5, and 10 wt%) were prepared using melt compounding extrusion and characterized in terms of Young's modulus, ultimate tensile strength, crystallinity, thermal transitions, and water contact angle. Neither sulfuric acid-hydrolyzed CNCs (SH-CNCs) nor SO-CNCs were toxic to MC3T3 preosteoblasts during a 24 h exposure at concentrations ranging from 0.25 to 3.0 mg/mL. SO-CNCs were more effective at inducing mineral formation than SH-CNCs in simulated body fluid (1x). An SO-CNC content of 10 wt% in the PCL matrix caused a more than 2-fold increase in Young's modulus (stiffness) and a more than 60% increase in ultimate tensile strength. The matrix glass transition and melting temperatures were not affected by the SO-CNCs but the crystallization temperature increased by about 5.5 degrees C upon addition of 10 wt% SO-CNCs, the matrix crystallinity decreased from about 43 to about 40%, and the water contact angle decreased from 87 to 82.6 degrees. The abilities of SO-CNCs to induce calcium phosphate mineral formation and increase the Young's modulus of PCL render them attractive for applications as multi-functional nanoscale additives in PCL-based bone scaffolds.
Continuous flow synthesis of a pharmaceutical intermediate: a computational fluid dynamics approach
Armstrong, Cameron T.; Pritchard, Cailean Q.; Cook, Daniel W.; Ibrahim, Mariam; Desai, Bimbisar K.; Whitham, Patrick J.; Marquardt, Brian J.; Chen, Yizheng; Zoueu, Jeremie T.; Bortner, Michael J.; Roper, Thomas D. (2019-03-01)
Continuous flow chemistry has the potential to greatly improve efficiency in the synthesis of active pharmaceutical ingredients (APIs); however, the optimization of these processes can be complicated by a large number of variables affecting reaction success. In this work, a screening design of experiments was used to compare computational fluid dynamics (CFD) simulations with experimental results. CFD simulations and experimental results both identified the reactor residence time and reactor temperature as the most significant factors affecting product yield for this reaction within the studied design space. A point-to-point comparison of the results showed absolute differences in product yield as low as 2.4% yield at low residence times and up to 19.1% yield at high residence times with strong correlation between predicted and experimental percent yields. CFD was found to underestimate the product yields at low residence times and overestimate at higher residence times. The correlation in predicted product yield and the agreement in identifying significant factors in reaction performance reveals the utility of CFD as a valuable tool in the design of continuous flow tube reactors with significantly reduced experimentation.
Development of Recyclable and High-Performance In Situ Hybrid TLCP/Glass Fiber Composites
Chen, Tianran; Kazerooni, Dana; Ju, Lin; Okonski, David A.; Baird, Donald G. (MDPI, 2020-08-24)
By combining the concepts of in situ thermotropic liquid crystalline polymer (TLCP) composites and conventional fiber composites, a recyclable and high-performance in situ hybrid polypropylene-based composite was successfully developed. The recycled hybrid composite was prepared by injection molding and grinding processes. Rheological and thermal analyses were utilized to optimize the processing temperature of the injection molding process to reduce the melt viscosity and minimize the degradation of polypropylene. The ideal temperature for blending the hybrid composite was found to be 305 °C. The influence of mechanical recycling on the different combinations of TLCP and glass fiber composites was analyzed. When the weight fraction ratio of TLCP to glass fiber was 2 to 1, the hybrid composite exhibited better processability, improved tensile performance, lower mechanical anisotropy, and greater recyclability compared to the polypropylene reinforced by either glass fiber or TLCP alone.
Fabrication and characterization of PLGA nanoparticles encapsulating large CRISPR–Cas9 plasmid
Jo, Ami; Ringel-Scaia, Veronica M.; McDaniel, Dylan K.; Thomas, Cassidy A.; Zhang, Rui; Riffle, Judy S.; Allen, Irving C.; Davis, Richey M. (2020-01-20)
Background The clustered regularly interspaced short palindromic repeats (CRISPR) and Cas9 protein system is a revolutionary tool for gene therapy. Despite promising reports of the utility of CRISPR–Cas9 for in vivo gene editing, a principal problem in implementing this new process is delivery of high molecular weight DNA into cells. Results Using poly(lactic-co-glycolic acid) (PLGA), a nanoparticle carrier was designed to deliver a model CRISPR–Cas9 plasmid into primary bone marrow derived macrophages. The engineered PLGA-based carriers were approximately 160 nm and fluorescently labeled by encapsulation of the fluorophore 6,13-bis(triisopropylsilylethynyl) pentacene (TIPS pentacene). An amine-end capped PLGA encapsulated 1.6 wt% DNA, with an encapsulation efficiency of 80%. Release studies revealed that most of the DNA was released within the first 24 h and corresponded to ~ 2–3 plasmid copies released per nanoparticle. In vitro experiments conducted with murine bone marrow derived macrophages demonstrated that after 24 h of treatment with the PLGA-encapsulated CRISPR plasmids, the majority of cells were positive for TIPS pentacene and the protein Cas9 was detectable within the cells. Conclusions In this work, plasmids for the CRISPR–Cas9 system were encapsulated in nanoparticles comprised of PLGA and were shown to induce expression of bacterial Cas9 in murine bone marrow derived macrophages in vitro. These results suggest that this nanoparticle-based plasmid delivery method can be effective for future in vivo applications of the CRISPR–Cas9 system.
Functionalized Cellulose Nanocrystal Nanocomposite Membranes with Controlled Interfacial Transport for Improved Reverse Osmosis Performance
Smith, Ethan D.; Hendren, Keith D.; Haag, James; Foster, Earl Johan; Martin, Stephen M. (MDPI, 2019-01-20)
Thin-film nanocomposite membranes (TFNs) are a recent class of materials that use nanoparticles to provide improvements over traditional thin-film composite (TFC) reverse osmosis membranes by addressing various design challenges, e.g., low flux for brackish water sources, biofouling, etc. In this study, TFNs were produced using as-received cellulose nanocrystals (CNCs) and 2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO)-oxidized cellulose nanocrystals (TOCNs) as nanoparticle additives. Cellulose nanocrystals are broadly interesting due to their high aspect ratios, low cost, sustainability, and potential for surface modification. Two methods of membrane fabrication were used in order to study the effects of nanoparticle dispersion on membrane flux and salt rejection: a vacuum filtration method and a monomer dispersion method. In both cases, various quantities of CNCs and TOCNs were incorporated into a polyamide TFC membrane via in-situ interfacial polymerization. The flux and rejection performance of the resulting membranes was evaluated, and the membranes were characterized via attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), transmission electron microscopy (TEM), and atomic force microscopy (AFM). The vacuum filtration method resulted in inconsistent TFN formation with poor nanocrystal dispersion in the polymer. In contrast, the dispersion method resulted in more consistent TFN formation with improvements in both water flux and salt rejection observed. The best improvement was obtained via the monomer dispersion method at 0.5 wt% TOCN loading resulting in a 260% increase in water flux and an increase in salt rejection to 98.98 ± 0.41% compared to 97.53 ± 0.31% for the plain polyamide membrane. The increased flux is attributed to the formation of nanochannels at the interface between the high aspect ratio nanocrystals and the polyamide matrix. These nanochannels serve as rapid transport pathways through the membrane, and can be used to tune selectivity via control of particle/polymer interactions.
Gradient Poly(ethylene glycol) Diacrylate and Cellulose Nanocrystals Tissue Engineering Composite Scaffolds via Extrusion Bioprinting
Frost, Brody A.; Sutliff, Bradley P.; Thayer, Patrick; Bortner, Michael J.; Foster, Earl Johan (2019-10-18)
Bioprinting has advanced drastically in the last decade, leading to many new biomedical applications for tissue engineering and regenerative medicine. However, there are still a myriad of challenges to overcome, with vast amounts of research going into bioprinter technology, biomaterials, cell sources, vascularization, innervation, maturation, and complex 4D functionalization. Currently, stereolithographic bioprinting is the primary technique for polymer resin bioinks. However, it lacks the ability to print multiple cell types and multiple materials, control directionality of materials, and place fillers, cells, and other biological components in specific locations among the scaffolds. This study sought to create bioinks from a typical polymer resin, poly(ethylene glycol) diacrylate (PEGDA), for use in extrusion bioprinting to fabricate gradient scaffolds for complex tissue engineering applications. Bioinks were created by adding cellulose nanocrystals (CNCs) into the PEGDA resin at ratios from 95/5 to 60/40 w/w PEGDA/CNCs, in order to reach the viscosities needed for extrusion printing. The bioinks were cast, as well as printed into single-material and multiple-material (gradient) scaffolds using a CELLINK BIOX printer, and crosslinked using lithium phenyl-2,4,6-trimethylbenzoylphosphinate as the photoinitiator. Thermal and mechanical characterizations were performed on the bioinks and scaffolds using thermogravimetric analysis, rheology, and dynamic mechanical analysis. The 95/5 w/w composition lacked the required viscosity to print, while the 60/40 w/w composition displayed extreme brittleness after crosslinking, making both CNC compositions non-ideal. Therefore, only the bioink compositions of 90/10, 80/20, and 70/30 w/w were used to produce gradient scaffolds. The gradient scaffolds were printed successfully and embodied unique mechanical properties, utilizing the benefits of each composition to increase mechanical properties of the scaffold as a whole. The bioinks and gradient scaffolds successfully demonstrated tunability of their mechanical properties by varying CNC content within the bioink composition and the compositions used in the gradient scaffolds. Although stereolithographic bioprinting currently dominates the printing of PEGDA resins, extrusion bioprinting will allow for controlled directionality, cell placement, and increased complexity of materials and cell types, improving the reliability and functionality of the scaffolds for tissue engineering applications.
Mitigation of bidirectional solute flux in forward osmosis via membrane surface coating of zwitterion functionalized carbon nanotubes
Zou, Shiqiang; Smith, Ethan D.; Lin, Shihong; Martin, Stephen M.; He, Zhen (Elsevier, 2019-07-08)
Forward osmosis (FO) has emerged as a promising membrane technology to yield high-quality reusable water from various water sources. A key challenge to be solved is the bidirectional solute flux (BSF), including reverse solute flux (RSF) and forward solute flux (FSF). Herein, zwitterion functionalized carbon nanotubes (Z-CNTs) have been coated onto a commercial thin film composite (TFC) membrane, resulting in BSF mitigation via both electrostatic repulsion forces induced by zwitterionic functional groups and steric interactions with CNTs. At a coating density of 0.97 gm⁻², a significantly reduced specific RSF was observed for multiple draw solutes, including NaCl (55.5% reduction), NH₄H₂PO₄(83.8%), (NH₄)₂HPO₄ (74.5%), NH₄Cl (70.8%), and NH₄HCO₃ (61.9%). When a synthetic wastewater was applied as the feed to investigate membrane rejection, FSF was notably reduced by using the coated membrane with fewer pollutants leaked to the draw solution, including NH₄⁺-N (46.3% reduction), NO₂⁻₋N (37.0%), NO₂⁻₋N (30.3%), K⁺ (56.1%), PO₄³⁻₋P (100%), and Mg²⁺ (100%). When fed with real wastewater, a consistent water flux was achieved during semi-continuous operation with enhanced fouling resistance. This study is among the earliest efforts to address BSF control via membrane modification, and the results will encourage further exploration of effective strategies to reduce BSF.
Nanoscale Bacteria‐Enabled Autonomous Drug Delivery System (NanoBEADS) Enhances Intratumoral Transport of Nanomedicine
Suh, SeungBeum; Jo, Ami; Traore, Mahama Aziz; Zhan, Ying; Coutermarsh-Ott, Sheryl; Ringel-Scaia, Veronica M.; Allen, Irving C.; Davis, Richey M.; Behkam, Bahareh (Wiley, 2018-12-05)
Cancer drug delivery remains a formidable challenge due to systemic toxicity and inadequate extravascular transport of nanotherapeutics to cells distal from blood vessels. It is hypothesized that, in absence of an external driving force, the Salmonella enterica serovar Typhimurium could be exploited for autonomous targeted delivery of nanotherapeutics to currently unreachable sites. To test the hypothesis, a nanoscale bacteria‐enabled autonomous drug delivery system (NanoBEADS) is developed in which the functional capabilities of the tumor‐targeting S. Typhimurium VNP20009 are interfaced with poly(lactic‐co‐glycolic acid) nanoparticles. The impact of nanoparticle conjugation is evaluated on NanoBEADS' invasion of cancer cells and intratumoral transport in 3D tumor spheroids in vitro, and biodistribution in a mammary tumor model in vivo. It is found that intercellular (between cells) self‐replication and translocation are the dominant mechanisms of bacteria intratumoral penetration and that nanoparticle conjugation does not impede bacteria's intratumoral transport performance. Through the development of new transport metrics, it is demonstrated that NanoBEADS enhance nanoparticle retention and distribution in solid tumors by up to a remarkable 100‐fold without requiring any externally applied driving force or control input. Such autonomous biohybrid systems could unlock a powerful new paradigm in cancer treatment by improving the therapeutic index of chemotherapeutic drugs and minimizing systemic side effects.
Prediction of Young’s Modulus for Injection Molded Long Fiber Reinforced Thermoplastics
Chen, Hongyu; Baird, Donald G. (MDPI, 2018-08-06)
In this article, the elastic properties of long-fiber injection-molded thermoplastics (LFTs) are investigated by micro-mechanical approaches including the Halpin-Tsai (HT) model and the Mori-Tanaka model based on Eshelby’s equivalent inclusion (EMT). In the modeling, the elastic properties are calculated by the fiber content, fiber length, and fiber orientation. Several closure approximations for the fourth-order fiber orientation tensor are evaluated by comparing the as-calculated elastic stiffness with that from the original experimental fourth-order tensor. An empirical model was developed to correct the fibers’ aspect ratio in the computation for the actual as-formed LFTs with fiber bundles under high fiber content. After the correction, the analytical predictions had good agreement with the experimental stiffness values from tensile tests on the LFTs. Our analysis shows that it is essential to incorporate the effect of the presence of fiber bundles to accurately predict the composite properties. This work involved the use of experimental values of fiber orientation and serves as the basis for computing part stiffness as a function of mold filling conditions. The work also explains why the modulus tends to level off with fiber concentration.

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