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3D Printed Medicine Uses Fish Gelatin to Deliver Cancer Treatment

Japanese researchers Jin Liu, Tatsuaki Tagami, and Tetsuya Ozeki have completed a recent study in nanomedicine, releasing their findings in “Fabrication of 3D Printed Fish-Gelatin-Based Polymer Hydrogel Patches for Local Delivery of PEGylated Liposomal Doxorubicin.” Experimenting with a new drug delivery system, the authors report on new potential for patient-specific cancer treatment.

The study of materials science continues to expand in a wide range of applications; however, bioprinting is one of the most exciting techniques as tissue engineering is expected to lead to the fabrication of human organs in the next decade or so. Such research has also proven that bioprinting may yield much more powerful drug delivery whether in using hybrid systems, multi-drug delivery systems, or improved scaffolds.

Here, the materials chosen for drug delivery are more unique as the researchers combined printer ink with semi-synthesized fish gelatin methacryloyl (F-GelMA)—a cold fish gelatin derivative.

In providing aggressive cancer treatment to patients, the use of doxorubicin (DOX) is common as an anti-carcinogen for the treatment of the following diseases:

  • Breast cancer
  • Bladder cancer
  • Kaposi’s sarcoma
  • Lymphoma
  • Acute lymphocytic leukemia

DOX may also cause serious cardiotoxicity, however, despite its use as a broad-spectrum drug. As a solution, PEGylated liposomal DOX, Doxil has been in use for treatment of cancer with much lower cardiotoxity. The nanomedicine has also been approved by the FDA, and is used for targeting local tumors; for instance, this type of drug delivery system could be suitable for treating a brain tumor.

“PEGylating liposomes can prolong their circulation time in blood, resulting in their passive accumulation in cancer tissue, called the enhanced permeability and retention effect,” state the authors.

Using a 3D bioprinter, the authors developed liposomal patches to be directly implanted into cancerous cells.

(a) Synthesis of fish gelatin methacryloyl (F-GelMA). (b) Hybrid gel of cross-linked F-GelMA and carboxymethyl cellulose sodium (CMC) containing PEGylated liposome. The reaction scheme was prepared in previous studies

“We used a hydrogel containing semi-synthetic fish-gelatin polymer (fish gelatin methacryloyl, F-GelMA) to entrap DOX-loaded PEGylated liposomes. Fish gelatin is inexpensive and faces few personal or religious restrictions,” stated the authors.

Fish gelatin has not been used widely in bioprinting, however, due to low viscosity and rapid polymerization. To solve that problem, the authors created a bioink composite with elevated viscosity.

Viscous properties of drug formulations used as printer inks. (a) The appearance of F-GelMA hydrogels containing different concentrations of CMC. (b) The viscosity profiles of F-GelMA hydrogels containing different concentrations of CMC. The data represent the mean ± SD (n = 3).

And while hydrogels are generally attractive for use due to their ability to swell, for this study, the researchers fabricated a variety of different materials—with the combination of 10% F-GelMA and 7% carboxymethyl cellulose sodium (a thickening agent) showing the highest swelling ratio.

Swelling properties of hydrogels after photopolymerization. (a) Swelling ratio of different concentrations of F-GelMA. (b) Swelling ratio of mixed hydrogel (10% F-GelMA with different concentrations of CMC). The data represent the mean ± SD (n = 3).

Design of the different 3D geometries: (a) cylinder, (b) torus, and (c) gridlines.

Patches were printed in three different sample shapes, using a CELLINK bioprinter syringe as the authors tested drug release potential in vivo. Realizing that surface area, crosslinks density, temperature, and shaker speed would play a role, the team relied on a larger surface volume for more rapid release of drugs.

Printing conditions of patches.

While experimenting with the torus, gridline, and cylindrical sample patches, the researchers observed gridline-style patches as offering the greatest potential for sustained release.

Drug release profiles of liposomal doxorubicin (DOX). (a) Influence of shape on drug release. The UV exposure time was set to 1 min. (b) Influence of UV exposure time on drug release. The gridline object was used for this experiment. The data represent the mean ± SD (n = 3).

“These results indicate that CMC is useful for adjusting the properties of printer ink and is a useful and safe pharmaceutical excipient in drug formulations. We also showed that drug release from 3D-printed patches was dependent on the patch shapes and UV exposure time, and that drug release can be controlled. Taken together, the present results provide useful information for the preparation of 3D printed objects containing liposomes and other nanoparticle-based nanomedicines,” concluded the authors.

[Source / Images: ‘Fabrication of 3D Printed Fish-Gelatin-Based Polymer Hydrogel Patches for Local Delivery of PEGylated Liposomal Doxorubicin’]

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Lung Cancer Treatment: 3D Printing Molds for Personalized Airway Stents

Australian scientists are working to improve medical devices for lung cancer treatment, sharing the outcome of their recent study in ‘Incorporating Chemotherapeutic Drug into a Personalizable Silicone Airway Stent for the Treatment of Lung Cancer and Tracheobronchomalacia.’

With a focus on relieving serious symptoms like central airway obstruction (CAO), the research team experimented with 3D printing molds to produce drug-eluting personalized airway stents, incorporated with chemotherapy drugs like Paclitaxel that inhibit the growth of cancer cells.

Interior view of current Y-stents used today, including the metallic Wallstent™ [A] and the Novatech® Dumon™ silicone stent [B] used in many CAO treatments, which do not correlate well with unique patient airway geometries [C].

Because diseases like lung cancer may leave patients struggling to breathe, pharmaceutical treatments and the use of effective devices can be critical to the quality of their lives—and even saving them in some cases. The researchers note that there are challenges with airway stents being used today due to a lack of personalization for patients, resulting in airway stent therapy that is often not effective. There may be other issues too, such as stent migration cased by improper fit.

“Unfortunately, airway stents have not developed, in large due to low relative prevalence of surgery and poor outcomes, since the release of Montgomery and Dumon stents during 1965 and 1989 respectively, despite leaps in 3D imaging and drug release technologies,” explain the researchers.

Drug-eluting stents offer potential in eliminating toxicity in delivery, as well as offering much-needed customizations for patients for better fit—reaping the rewards of one of the greatest benefits of 3D printing for the medical arena today with patient-specific treatment rather than a ‘one-size-fits-all’ premise for everyone. These benefits are heavily evidenced today in areas like prosthetics, heart valves, bio-active patches, and more.

Concentrations used during testing of drug elution from silicone stent materials.

Paclitaxel was added to the silicone molds, leaving the team of researchers to then perform a detailed assay on the Beas-2B cells derived from healthy patients and H23 adenocarcinoma cells derived from nonsmall cell lung cancer patients. The drug was insoluble in PBS, while ‘highly soluble in ethanol.’

Difference (f1) and Similarity (f2) factors used to determine the significance of the difference between release rates of paclitaxel concentrations and formulation methods in cured silicone coupons.

Variances in release rates of drugs demonstrate the potential for further manipulation, with adjustments to the paclitaxel in silicone coupons or via other techniques. The authors reported that there has been similar success with other stents.

Percentage of drug, paclitaxel, released from 250 mg silicone coupons in ethanol at 37°C, over 72 hours (n=3). Table 1 denotes A, B, C, D, E, and F silicone coupon conditions.

Cell viability for Beas-2B and H23 immortalised cell lines, grown on paclitaxel eluting silicone coupons, over 72 hours (n=6). An 80% cut-off was used to determine cellular viability.

“The implications of characterizing a successful controlled release of paclitaxel from cured liquid silicone rubber will allow clinicians to personalize treatment depending on airway geometry and control for the targeted dose of paclitaxel to the area of interest, thereby reducing the side effect profile of paclitaxel and its excipients (i.e. ethanol and polyoxyethylated castor oil) in systemic circulation,” stated the researchers.

“Further assessment in the comparability of paclitaxel release into lung-like environment is needed to characterize the effectiveness of drug release.”

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[Source / Images: ‘Incorporating Chemotherapeutic Drug into a Personalizable Silicone Airway Stent for the Treatment of Lung Cancer and Tracheobronchomalacia’]

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3D Printing Review in Drug Delivery Systems: Pharmaceutical Particulates and Membranes

Researchers from Egypt, India, and the UK are studying the role of 3D printing in drug delivery systems. Their findings are detailed in the recently released ‘Pharmaceutical Particulates and Membranes for the Delivery of Drugs and Bioactive Moleclules,’ as they review new trends and developments.

In reviewing twelve different papers on the subject of pharmaceutical particulates and membranes, the researchers also collaborated with experts regarding design, materials, and applications; for instance, in a study by Kumar et al. [2], the researchers learned of an extended release drug delivery system for nicotine that shows potential for Parkinson’s disease interventions:

“These have been developed in the form of membranes with minimal rates of matrix degradation and retarding nicotine release. This has led to the zero-order release for 50 days following exposure to simulated cerebrospinal fluid (CSF),” stated the researchers.

Mora-Espíet et al. [3] have explored the targeting of microparticles and culturing breast cancer cell lines. Huang et al. [4] confirmed a new process for accelerating drug dissolution with ibuprofen-loaded hydroxypropyl methylcellulose nanoparticles.

Immunofluorescence analysis by confocal laser scanning microscope (CLSM) of cells cultured in static conditions. Confocal images of D492 and D492HER2 cells cocultured in static conditions and incubated with microparticles biofunctionalized with a non-specific secondary antibody (µP-secAb) or a specific anti-HER2 antibody (µP-antiH). Cells, constitutively expressing green fluorescent protein (GFP, green), were incubated with Alexa Fluor® 546 Phalloidin (red) to label actin microfilaments and Alexa Fluor® 405 conjugate secondary antibody (blue) to label HER2 in the plasma membrane. The arrows point to some examples of µPs located inside the cells. From ‘Cell Internalization in Fluidic Culture Conditions Is Improved When Microparticles Are Specifically Targeted to the Human Epidermal Growth Factor Receptor 2 (HER2).’

“During this process, it was shown that a key parameter, i.e., the spreading angle of atomization could provide a linkage among the working process, the property of generated nanoparticles and their functional performance,” stated the researchers. “They confirmed that the nanoparticle diameter (prepared based on a modified technique) has a profound influence on the drug release performance.”

Shah et al. [5] contributed a study as they moved forward to refine the effectiveness of moxifloxacin, an antibiotic used to treat a variety of bacterial infections. With a new system for optimizing nanoemulsion, they were able to ‘enhance the therapeutic effects of moxifloxacin,’ resulting in safe delivery.

Another development, contributed by Wan et al. [6], allowed for sustained release of loxoprofen sodium (LXP), with the addition of a unique coating:

“Their results identified both the citric acid (CA) and ADEC as the dissolution and diffusion-rate controlling materials significantly decreasing the drug release rate,” stated the researchers. “The optimal formulation for a pH-independent drug release in media has been suggested as at a pH above 4.5 and at slightly slow release in acid medium.”

“The pharmacokinetic studies have revealed that a more stable and prolonged plasma drug concentration profile of the optimal pellets has been achieved, with a relative bioavailability of 87.16% compared with the conventional tablets.”

Studying magnetic nanoparticles, Iglesias et al. [7] stated that BMNPs (biometic) were superior to MNPs (inorganic) for drug loading of molecules ‘positively charged at neutral pH.’ MNPs, however, have the potential for suitable transport abilities while under a magnetic field. Savin et al [8] explored gel formulations for skin melanoma treatment, along with fabricating breast cancer cells in 3D models—following one of the major trends in medicine today using models for treatment, training, and surgical planning too.

“The in vitro results for the tested CD-NHF-loaded gel formulations have revealed that the new composites can affect the number, size, and cellular organization of spheroids and impact individual tumor cell ability to proliferate and aggregate in spheroids,” stated the researchers.

Guadarrama-Acevedo et al. [9] created a new wound dressing made of alginate membrane and polycaprolactone nanoparticles, loaded with curcumin for healing. Integrating nanocarriers allows for drug permeation into multiple layers of skin, thus eliminating solubility issues with curcumin. Rancan et al. [10] performed research showing that after six hours, nanofiber mats offer the best drug concentration upon delivery.

Morphology and porosity of alginate membranes. (a) Micrographs by scanning electronic microscopy of the alginate membrane surface (A, B, D, and E) and membrane thickness (C and F). Magnification of 100× for A, D; 220× in B, C, E and F; the scale bar is 100 μm; (b) pore diameter and membrane thickness of M4 and CNp‒M4 membranes, mean ± SE, n = 3. * indicates that p < 0.05 is statistically significant. From ‘Development and Evaluation of Alginate Membranes with Curcumin-Loaded Nanoparticles for Potential Wound-Healing Applications.’

Further, Lian et al. [11] developed a system for using red blood cell membrane-camouflaged ATO-loaded sodium alginate nanoparticles (RBCM-SA-ATO-NPs, RSANs) to eliminate toxicity of ATO. Their work also showed that RSANS have lower levels of cytotoxicity, upon comparison with normal cells; RSANS also displayed antitumor effects on NB4 cells and 7721 cells.

Adeleke et al. [12] developed an isoniazid suspension as an antitubercular agent against TB, offering extended release:

RDS has been dispersible and stable in the dried and reconstituted states over 4 months and 11 days respectively, under common storage conditions.

Representative graphs displaying: (a) particle size distribution, (b) zeta potential distribution, as well as TEM micrographs showing different surface topographies and characteristics of the reconstitutable dry suspension (RDS) particles at different scales: (c) 1μm and (d) 5 μm, respectively. ‘Development and Evaluation of a Reconstitutable Dry Suspension Containing Isoniazid for Flexible Pediatric Dosing.’

“The published papers are also being compiled as an edited e-book, to be published by MDPI,” stated the researchers.

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[Source / Images: ‘Pharmaceutical Particulates and Membranes for the Delivery of Drugs and Bioactive Moleclules’]

 

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