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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’]

The post 3D Printed Medicine Uses Fish Gelatin to Deliver Cancer Treatment appeared first on 3DPrint.com | The Voice of 3D Printing / Additive Manufacturing.

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Marine-Based Hyrdogels Used to Develop New Bioink for 3D Bioprinting

One of the challenges in the field of bioprinting is developing bioinks that are safe and effective. In a paper entitled “Marine Biomaterial-Based Bioinks for Generating 3D Printed Tissue Constructs,” a group of researchers discusses the development of a bioink using alginate and fish gelatin (f-gelatin). They created a marine-based interpenetrating polymer network (IPN) consisting of alginate and f-gelatin methacryloyl (f-GelMA) networks via physical and chemical crosslinking methods, respectively.

“In this study, four different concentrations of alginate (1%, 2%, 3%, and 4%) and three low concentrations of f-GelMA (4%, 5%, and 6%) were investigated and found to form double networked alginate/f-GelMA hydrogels,” the researchers explain. “In the mechanical properties test, the pure alginate hydrogel showed a typical increase in mechanical strength with the increase of concentration and low mechanical strength when its compressive modulus was around 40 kPa, even at 4% alginate, compared with alginate/f-GelMA IPN hydrogel where the modulus of alginate/f-GelMA was approximately 40 kPa at 1% alginate.”

This showed that the mechanical strength of hydrogels was significantly increased by employing an alginate and f-GelMA double network. According to the researchers, the tunable mechanical strength range in alginate/f-GelMA hydrogel would be sufficient to meet the diverse requirements of different tissues.

The researchers also performed swelling tests with pure alginate hydrogel as a control group, and found that the mass swelling ratio decreased with the increase in concentration of alginate.

“For the alginate/f-GelMA hydrogel, the mass swelling ratio for all tested groups was lower than for the pure alginate group,” the researchers continue. “This was due to the increased crosslinking density from the addition of f-GelMA which generated additional polymeric networks via covalent bonding…The swelling properties of hydrogel mainly depend on the hydrogel pore size, polymer concentration, density of cross-linking, and the interaction with solvents.”

The researchers also investigated the degradation characteristics of the hyrdogels. The degradation rate of the alginate/f-GelMA in a saline solution was similar for 2% and 4% alginate, though the 2% degraded faster. The morphology of the hydrogels was tested as well, and the alginate/f-GelMA exhibited a highly porous structure, which can provide enough space for the transport of nutrients and gas exchange for cell survival.

“To assess the cell behavior and examine the feasibility (cell viability, adhesion, and cell proliferation) of alginate/f-GelMA hydrogel, cell adhesion and 3D cell encapsulation assays were performed to examine the ability to bind to alginate/f-GelMA scaffold which is crucial for cell survival,” the researchers state. “…Encapsulated NIH-3T3 cells were cultured for seven days and cell viability was determined using LIVE/DEAD assay kits. As shown in Figure 3C, cells maintained high viability during the culture period (one, three, five, and seven days) and demonstrated that cells can maintain long-term survival rates in alginate/f-GelMA hydrogel.”

The results of the testing showed that alginate/f-GelMA hydrogel has a lot of promise for tissue engineering applications, including 3D bioprinting. To further confirm the morphology and cell viability in the process of 3D printing, a two-layer scaffold was printed and Live/Dead assay was carried out to investigate the cell survival ratio. The scaffold displayed a satisfactory 3D arrangement under microscopy with high cell viability.

This study was the first incidence of using alginate and f-GelMA for 3D bioprinting, and the successful results mean that marine biopolymers could feasibly replace biopolymers from mammalian resources, which can carry diseases or be subject to religious restrictions.

Authors of the paper include Xiaowei Zhang, Gyeong Jin Kim, Min Gyeong Kang, Jung Ki Lee, Jeong Wook Seo, Jeong Tae Do, Kwonho Hong, Jae Min Cha, Su Ryon Chin and Hojae Bae.

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