Search

Over the last several decades, 3D printing technology, which encompasses many different fabrication techniques, had emerged as a promising tool in many fields of production, including the pharmaceutical industry. Specifically, 3D printing may be advantageous for drug delivery systems, systems aiming to improve the pharmacokinetics of drugs. These advantages include the ease of designing complex shapes, printing of drugs on demand, tailoring dosage to the specific needs of the patient and enhancing the bioavailability of drugs. This paper reviews the most recent advancements in this field, presenting both the abilities and limitations of several promising 3D printing methods.

Intravascular catheters (IVCs) and other medical tubing are commonly made of polymeric materials such as polyurethane (PU). Polymers tend to be fouled by surface absorption of proteins and platelets, often resulting in the development of bacterial infections and thrombosis during catheterization, which can lead to embolism and death. Existing solutions to fouling are based on coating the IVCs with hydrophilic, anti-thrombogenic, or antimicrobial materials. However, the delamination of the coatings themselves is associated with significant morbidity, as reported by the United States Food and Drug Administration (FDA). We developed a lubricious, antimicrobial, and antithrombogenic coating complex, which can be covalently attached to the surface of industrial PU catheters. The coating complex is pre-synthesized and comprises 2-methacryloyloxyethyl phosphorylcholine (MPC) as an antifouling agent, covalently attached to branched polyethyleneimine (bPEI) as a lubricating agent. The two-step coating procedure involves PU-amine surface activation using a diisocyanate, followed by chemical grafting of the bPEI-S-MPC complex. Compared with neat PU, the coating was found to reduce the coefficient of friction of the IVC surface by 30% and the hemolysis ratio by more than 50%. Moreover, the coating exhibited a significant antimicrobial activity under JIS Z2801:2000 standard compared with neat PU. Finally, in in-vivo acute rabbit model studies, the coating exhibited significant antithrombogenic properties, reducing the thrombogenic potential to a score of 1.3 on coated surfaces compared with 3.3 on uncoated surfaces. The materials and process developed could confer lubricious, antithrombogenic, and antimicrobial properties on pre-existing PU-based catheters.

Polyastaxanthin p(ATX) is a family of polymers synthesized from the carotenoid astaxanthin and various dicarboxylic acids, resulting in moldable, high MW polymers, that can be made biodegradable. p(ATX) has previously shown to have antimicrobial properties in vitro, including inhibition of biofilm formation of S. epidermidis 1457, S. aureus MRSA252 and S. aureus MSSA476. In this work, we characterized the in vivo performance of p(ATX). Several in vivo evaluations were performed by implanting polyurethane catheter sections coated with pATXs in immunodeficient mice, followed by infection with S. aureus ATCC 6538. The polymer's capacity to inhibit bacterial biofilm formation on catheters was assessed. Two insights were generated. First, pATX has the capacity to significantly reduce the bacterial burden on coated catheters compared to uncoated catheters. Second, control over the biodegradation rate of the pATX, achieved via the use of hydrophilic diacid-comonomers, is required to maintain antimicrobial properties for at least 96 h. We found that slower degrading polymer is more beneficial in reducing bacterial load compared to rapidly degrading polymers, which begin to degrade immediately once hydrated. Thus, pATX, when appropriately designed, has the potential to perform as an antimicrobial coating for medical devices.

This paper describes a simple, straightforward, and rapid method for producing microspheres from molten polymers by merely printing them in an inkjet-like manner onto a superoleophobic surface (microsphere printing, hence SPHRINT). Similar to 3D printing, a polymer melt is deposited onto a surface; however, in contrast to 2D or 3D printing, the surface is not wetted (i.e. exhibiting high contact angles with liquids, above 150°, due to its low surface energy), resulting in the formation of discrete spherical microspheres. In this study, microspheres were printed using polycaprolactone and poly(lactic-co-glycolic acid) loaded with a model active pharmaceutical ingredient-ibuprofen (IBU). The formation of microspheres was captured by high-speed imaging and was found to involve several physical phenomena characterized by non-dimensional numbers, including the thinning and breakup of highly viscous, weakly elastic filaments, which are first to be described in pure polymer melts. The resulting IBU-loaded microspheres had higher sphericity, reproducible sizes and shapes, and superior drug encapsulation efficiencies with a distinctly high process yield (>95%) as compared to the conservative solvent-based methods used presently. Furthermore, the microspheres showed sustained release profiles.

The interest in photocurable polymers has risen greatly in the past few years, in part due to the additive manufacturing revolution. Still, their widespread use is hindered by various inherent physical properties, such as thermal insulation. This work is aimed towards the development of photopolymerizable polymer composites that are thermally conductive, while maintaining their photocurable characteristics. We developed photocurable acrylic-based photopolymer composites with hexagonal boron nitride (hBN) using the following method: pristine hBN underwent two chemical surface modifications, was added to the monomers, and the mixture then underwent radiation curing. The success of the synthesis was verified in two ways: FTIR and XPS analyses in which the formation of carbonyl groups at the surface of the treated hBN was tracked, as well as tracking the increase in the homogeneity of the pre-polymerized solution. The addition of a reaction accelerator (o-benzoic sulfimide) to the photoinitiator system allowed for an increase of conversion percentage from ∼60% to ∼95%, even with high hBN loadings. Thermal conductivity (measured via modulated differential scanning calorimetry (MDSC)) increased with respect to hBN content by more than 300% when using 35 wt% hBN. Young's modulus and viscosity increased with hBN content, while coefficient of thermal expansion (CTE) decreased. We have thus developed a photocurable monomer system that is thermally conductive and applicable in various radiation curing processes.

A library of novel high molecular weight polymers based on the natural carotenoid astaxanthin (ATX) has been successfully synthesized. ATX is a powerful antioxidant, known for its various therapeutic properties including anti-inflammatory and antimicrobial activities. It is a xanthophyll with a symmetric chemical structure bearing two hydroxyl groups. Thus, its copolymerization with various diacids resulted in “polyactive” polyesters with varying chemico–physio–mechanico properties (e.g., storage moduli range: 125–1300 MPa and wetting angles of 40–110°). The potential of pATX as an antimicrobial agent was demonstrated in vitro against clinically relevant bacteria (Staphylococcus aureus MRSA252 and MSSA476; S. epidermidis 1457) showing significant reduction of both bacterial growth and biofilm formation. Lastly, we establish using pATX films in vivo had no adverse effect in direct contact with open wounds, or on the complete physiological process of whole animal wound healing.

Tungsten disulfide nanotubes (INT-WS2) have been implemented as reinforcing and antiballistic agent in PMMA (poly(methyl methacrylate)) matrix. The performance of the native polymer through addition of INT-WS2 was characterized by the dynamic mechanical analysis (DMA), split-Hopkinson pressure bar (SHPB), flexural, tensile and impact tests. The composites were prepared by a twin screw extruder via optimizing extrusion parameters, INTs concentrations, with and without usage of compatibilizer. Under the best conditions, these nancomposites exhibited homogeneous dispersion with average increase of 39% for the flexural strength accompanied by 83% enhancement in strain at break, compared to pristine. In tensile test an improvement of ~13% for the tensile strength and of 25% in elongation at break were achieved. Impact strength of the composite was also improved by 23% compared to the neat polymer, which is at par or even superior to existing fillers for PMMA. These results demonstrate improvement in the impact resistance without compromising the elastic domain. In the SHPB test, an average enhancement of 31% in the energy absorption capacity (toughness) and of 43% in elongation at break, compared to neat PMMA, were observed. The reinforcing mechanism of INT-WS2 was attributed to homogeneous distribution and alignment of nanotubes in the molded samples.

A novel approach for producing carbon nanotube fi bers (CNF) composed with the polysaccharide agarose is reported. Current attempts to make CNFs require the use of a polymer or precipitating agent in the coagulating bath that may have negative effects in biomedical applications. It is shown that, by taking advantage of the gelation properties of agarose, one can substitute the bath with distilled water or ethanol and, hence, reduce the complexity associated with alternating the bath components or the use of organic solvents. It is also demonstrated that these CNF can be chemically functionalized to express biological moieties through available free hydroxyl groups in agarose. Agarose CNF are not only conductive and nontoxic; in addition, their functionalization is shown to facilitate cell attachment and response both in vitro and in vivo. Our fi ndings suggest that agarose/CNT hybrid materials are excellent candidates for applications involving neural tissue engineering and biointerfacing with the nervous system.

The objective of this research was to examine the capabilities of QSPR (Quantitative Structure Property Relationship) modeling to predict specific biological responses (fibrinogen adsorption, cell attachment and cell proliferation index) on thin films of different polymethacrylates. Using 33 commercially available monomers it is theoretically possible to construct a library of over 40,000 distinct polymer compositions. A subset of these polymers were synthesized and solvent cast surfaces were prepared in 96 well plates for the measurement of fibrinogen adsorption. NIH 3T3 cell attachment and proliferation index were measured on spin coated thin films of these polymers. Based on the experimental results of these polymers, separate models were built for homo-, co-, and terpolymers in the library with good correlation between experiment and predicted values. The ability to predict biological responses by simple QSPR models for large numbers of polymers has important implications in designing biomaterials for specific biological or medical applications.

Next-generation neuroprosthetic limbs will require a reliable long-term neural interface to residual nerves in the peripheral nervous system (PNS). To this end, we have developed novel biocompatible materials and a fabrication technique to create high site-count microelectrodes for stimulating and recording from regenerated peripheral nerves. Our electrodes are based on a biodegradable tyrosine-derived polycarbonate polymer system with suitable degradation and erosion properties and a fabrication technique for deployment of the polymer in a porous, degradable, regenerative, multiluminal, multielectrode conduit. The in vitro properties of the polymer and the electrode were tuned to retain mechanical strength for over 24 days and to completely degrade and erode within 220 days. The fabrication technique resulted in a multiluminal conduit with at least 10 functioning electrodes maintaining recording site impedance in the single-digit kOhm range. Additionally, in vivo results showed that neural signals could be recorded from these devices starting at four weeks postimplantation and that signal strength increased over time. We conclude that our biodegradable regenerative-type neural interface is a good candidate for chronic high fidelity recording electrodes for integration with regenerated peripheral nerves.

Organically modified montmorillonite clays were incorporated at a 5% loading level into film grade of poly-L-lactic acid (PLLA) using a variety of masterbatches based on either semi-crystalline or amorphous poly-(lactic acid), as well as biodegradable aromatic aliphatic polyester. The PLLA masterbatches and compounded formulations were prepared using a twin screw compounding extruder, while the films were prepared using a single screw cast film extruder. The thermal and mechanical properties of the films were examined in order to determine the effect of the clay and different carriers on the polymer–clay interactions. In the optimal case, when a PLLA-based masterbatch was used, the tensile modulus increased by 30%, elongation increased by 40%, and the cold crystallization temperature decreased by 15 °C, compared to neat PLLA. The properties improvement of PLLA films containing nano clays demonstrated the possibility to extend the range of biodegradable film applications, especially in the field of packaging.

Composite electrodes made of the polysaccharide agarose and carbon nanotube fibers (A-CNE) have shown potential to be applied as tissue-compatible, micro-electronic devices. In the present work, A-CNEs were functionalized using neuro-relevant proteins (laminin and alpha-melanocyte stimulating hormone) and implanted in brain tissue for 1 week (acute response) and 4 weeks (chronic response). Qualitative and quantitative analysis of neuronal and immunological responses revealed significant changes in immunological response to implanted materials depending on the type of biomolecule used. The potential to manipulate tissue response through the use of an anti-inflammatory protein, alpha-melanocyte stimulating hormone, was shown in the reduction of astroglia presence near the implant site during the glial scar formation. These results suggest that A-CNEs, which are soft, flexible, and easily made bioactive, have the ability to modify brain tissue response through surface modification as a function of the biomolecule used.

The challenging paradigm of bioresorbable polymers, whether in drug delivery or tissue engineering, states that a fine-tuning of the interplay between polymer properties (e.g., thermal, degradation), and the degree of cell/tissue replacement and remodeling is required. In this paper we describe how changes in the molecular architecture of a series of terpolymers allow for the design of polymers with varying glass transition temperatures and degradation rates. The effect of each component in the terpolymers is quantified via design of experiment (DoE) analysis. A linear relationship between terpolymer components and resulting Tg (ranging from 34 to 86 °C) was demonstrated. These findings were further supported with mass-per-flexible-bond (MPFB) analysis. The effect of terpolymer composition on the in vitro degradation of these polymers revealed molecular weight loss ranging from 20 to 60% within the first 24 hours. DoE modeling further illustrated the linear (but reciprocal) relationship between structure elements and degradation for these polymers. Thus, we describe a simple technique to provide insight into the structure property relationship of degradable polymers, specifically applied using a new family of tyrosine-derived polycarbonates, allowing for optimal design of materials for specific applications.

We have recently reported on an ultra fast degrading tyrosine-derived terpolymer that degrades and resorbs within hours, and is a suitable for use in cortical neural prosthetic applications. Here we further characterize this polymer, and describe a new tyrosine-derived fast degrading terpolymer in which the poly(ethylene glycol) (PEG) is replaced by poly(trimethylene carbonate) (PTMC). This PTMC containing terpolymer showed similar degradation characteristics but its resorption was negligible in the same period. Thus, changes in the polymer chemistry allowed for the development of two ultrafast degrading polymers with distinct difference in resorption properties. The in vivo tissue response to both polymers used as intraparenchymal cortical devices was compared to poly(lactic-co-glycolic acid) (PLGA). Slow resorbing, indwelling implant resulted in continuous glial activation and loss of neural tissue. In contrast, the fast degrading tyrosine-derived terpolymer that is also fast resorbing, significantly reduced both the glial response in the implantation site and the neuronal exclusion zone. Such polymers allow for brain tissue recovery, thus render them suitable for neural interfacing applications.

We have identified a polymeric system based on a novel tyrosine-derived terpolymer that offers desirable insertion capability for flexible neural prosthetic devices. To test this concept, flexible films were coated with this terpolymer and their suitability for peranchyma insertion was visualized. The effect of the polymer on neural recording was evaluated using coated microwire probes. The stiff but readily resorbable polymer rapidly degrades (molecular weight half-life of 170 min) while turning into a soft gel, followed by complete resorption within 240 min. This polymeric platform maintains sufficient stiffness to facilitate pial penetration with a dry elastic modulus of 393±44 MPa but loses its strength within 30 min once immersed in saline. In vitro, the polymer's ability to locally deliver dexamethasone has been confirmed through a first order release profile over a 360 min period. In vitro, coated microwire probes regained their original impedance values of 0.5 KΩ within 20 min of wetting via water absorption and polymer resorption. In vivo, the retention of electrical recording capability was also demonstrated through multiple waveform detection in live animals. The ultrafast resorbing polymer as a platform to facilitate the implantation of micronized flexible probes can be utilized in future designs of chronic neural devices.