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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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Interview with Dr. Vahid Serpooshan, Who Created a ‘Heart Attack Patch’ With the Help of 3D Printing

According to the World Health Organization, cardiovascular disease is the number one cause of death globally. An estimated 17.9 million people died from cardiovascular disease in 2016, representing 31% of all global deaths. Treatments for all manner of cardiovascular impairments are therefore a high priority. A very prevalent ailment in that category is a heart attack which happens to over 735,000 Americans a year. 

A team of researchers led by Dr. Vahid Serpooshan, an assistant professor of Biomedical Engineering and Pediatrics at Georgia Institute of Technology and Emory University School of Medicine, have created a patch with a regenerative protein to treat the infarcted myocardium (cardiac muscle, a part of the heart that gets damaged during a heart attack). According to Georgia Institute of Technology the patch will cover the infarcted tissue with a collagen patch infused with a  protein called FSTL1, which is tailored to fit an area a little larger than the dead tissue. Dr. Serpooshan used bioprinters to develop the patch using a collagen gel. The patch is about to start its pre-clinical trial phase at Emory University’s School of Medicine in Atlanta, and a clinical trial is already ongoing in Europe for a version of this patch device. So it could be a couple more years before they are available for patient treatment. Dr. Serpooshan’s Lab (which has two locations at both Emory University and Georgia Tech) uses a multidisciplinary approach to design and develop micro/nano-scale tissue engineering technologies with the ultimate goal of generating functional tissues and organs. 3DPrint.com reached out to talk to Dr. Serpooshan about his team’s groundbreaking work. 

Professor Vahid Serpooshan sets up the medical 3D printer that will print a patch engineered to strengthen heart muscle damaged in a heart attack. (Photo by Rob Felt, Georgia Institute of Technology)

How has 3D printing helped to engineer the patch?

3D printing has been a huge help in manufacturing the patch in so many ways. It enabled us to incorporate vasculature inside the patch, something that would not have been available with traditional tissue engineering techniques, since they offer really limited potential to create complex, functional vasculature in thick, 3D tissue constructs. Additionally, it allowed us to have a controlled deposition of different cells, biomaterials, and molecules to form heterogenous, complex 3D structures that closely mimic native tissue structure. Also it provided us with patient -and disease- specificity: we utilize MR or CT imaging data obtained from patients to create 3D printed tissue constructs that precisely match the patient’s diseased or damaged tissue. Finally, bioprinting technologies have enabled tissue engineers to markedly enhance resolution and precision in various tissue manufacturing endeavors, making precision medicine even more promising.

What 3D printer do you use to create the patch?

We are mainly using two types of 3D bioprinters for this project. A BioAssemblyBot bioprinting system, made by Advanced Solutions Inc. (an American company in Louisville, Kentucky). This is the ONLY six-axis robotic arm printer in the market, with a resolution down to approximately 20 to 50 μm (microns). The second bioprinter is a BIO-X from Swedish biotech company Cellink, a pioneer in bioprinting.

An illustration of the heart with the cardiac patch already in place (Serpooshan Lab)

How long will it take to manufacture the patch?

Biomanufacturing of a cardiac patch at a clinically-relevant scale would take about 15 to 30 minutes, depending on the number of cell types involved, the vasculature design, and other factors. This enables the clinics, hopefully in the near future, to have heart attack patients come to the clinic, conduct CT or MR imaging, prepare 3D digital model of the damaged tissue, and sending it to the bioprinter to manufacture a patch device customized for that patient.

Vahid Serpooshan designing the myocardial infarct patch (Photo by Rob Felt, Georgia Institute of Technology)

Is there already a procedure in place to apply the patch?

Actually, there already is a procedure to apply the patch. We use a left thoracotomy approach to get access to the surface of the heart and suture the patch onto the epicardial layer of the heart, covering the myocardial infarction (also called a heart attack) area. There are currently some ongoing works trying to minimize the aggressiveness of this surgical procedure, potentially using catheter-based techniques.

What are the benefits of using collagen in the patch?

Collagen is the most abundant protein of the human body. This protein highly supports cell viability, proliferation, and function. It is a biodegradable protein which is a major advantage for in vivo applications, facilitating timely integration of the implant with the host tissue and avoiding long-term immunogenic complications. For our 3D bioprinting works, we use gelatin methacrylate (gelMA). Gelatin is derived from collagen (a hydrolyzed collagen) and offers similar advantages. The main advantages of gelMA for bioprinting of cardiac patches include: acceptable compatibility with cardiac cells (cardiomyocytes), tunable biomimetic mechanical properties (stiffness), controllable degradation rate, and of course, great printability (rheology properties).   

The collagen gel used to develop the 3D printed patch. (Photo by Rob Felt, Georgia Institute of Technology)

What percentage of heart disease patients will benefit from this device?

This therapy is designed for a specific group of heart attack patients, approximately one third of patients who either arrive too late to the clinics or are resistant to current catheter-based reperfusion methods and pharmacologic therapies.

If approved, Dr. Serpooshan’s patch could help over 200,000 patients per year.

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3D Bioprinting: What Can it Do Right Now?

3D bioprinting is a hot term right now, but many people aren’t sure exactly what it’s all about. Bring up bioprinting to someone who is only marginally familiar with it, and their response is likely to be, “Oh, that’s where they’re trying to print organs and stuff, right?” Well…yes, that is one of the ultimate goals of bioprinting. Most people working in the space like to talk about the dream of eliminating donor waiting lists, and creating brand new organs from a patient’s own cells, greatly reducing the risk of rejection. But the day that we see a beating 3D printed heart implanted into the chest of a living human being is still several years away.

Organ transplants are not the be-all, end-all of 3D bioprinting, however. Many people, unless they’re familiar with the industry, are unaware of just how much is being done with the technology already, and how many people are being helped by it, either directly or indirectly. Here are just some of the ways in which bioprinting is already impacting people.

Pharmaceutical Testing

[Image: Organovo]

There are many reasons why new drugs take so long to get approved for the market. One of them is that testing drugs on animal tissue is different from testing it on human tissue. A drug can work perfectly on an animal, but fail on a human – it’s inevitable that that should happen sometimes, as our systems process things differently than those of mice. But companies such as Organovo have developed 3D bioprinted human kidney and liver tissue – and yes, Organovo ultimately wants to be able to transplant working 3D printed livers into humans, but in the meantime, the company has made tremendous strides using its 3D printed tissue for pharmaceutical testing.

Testing drugs on actual human tissue can give researchers a real idea of how the drugs will react in a human system, whether they’ll be effective and if they’ll cause any sort of harmful effects. 3D printed tissue also eliminates the need for testing on animals at all, which is a bonus for those animals.

3D Printed Cartilage and Bone

[Image: St. Vincent’s Hospital

Much research has gone into the 3D printing of 3D printed bone and cartilage. Last year, Australian researchers successfully transplanted 3D printed knee cartilage into sheep, paving the way for human trials and commercialization. While it’s not yet possible to 3D print a functioning organ for human transplant, great progress has been made in treating diseases like arthritis by 3D printing new cartilage. Using a patient’s own stem cells, scientists hope to be able to 3D print pieces of cartilage and transplant them into a diseased or injured joint, where they will integrate with the body, grow and ultimately heal the affected area. This hasn’t actually been done to a human yet, but applications like this are much closer over the horizon than, say, a 3D printed heart.

3D printed bone is also being studied as a way to replace bone that has been lost due to injury or illness. Severe conditions resulting in the loss of bone, if they can be treated at all, are typically treated with bone grafts, which can cause complications or rejection, and may be impossible simply because the patient doesn’t possess enough bone to heal a particular defect. 3D printed bone, again, can be created from a patient’s own cells, making it far less likely to be rejected. It can be 3D printed in any shape or size to match the defect and integrate with existing bone to heal it.

3D Printed Patches

Perhaps we can’t implant a 3D printed organ yet, but work has been done toward 3D printed patches to repair damaged organs, such as hearts after a heart attack. Progress has been made toward getting these 3D printed cell patches to vascularize, meaning that they can form their own blood vessel networks and survive inside the body.

Disease Research

Some diseases are difficult to study because of the lack of access to the affected area, such as the placenta. But a bioprinted placenta allowed scientists to research the dangerous condition preeclampsia more thoroughly than ever before and even come up with potential treatments. As bioprinting progresses, 3D printed organs will lead to better research and treatments even before they can be implanted into humans.

3D Printed Organs

Yes, it may be a long time before organs can be 3D printed and implanted into humans – but they have been, in a few cases, successfully transplanted into animals. A mouse with a 3D printed ovary successfully gave birth to multiple babies, and before that 3D printed thyroid glands were transplanted into mice. Again, there’s a long way between mice and humans, but these cases show that 3D printed organs are a possibility and that they could perhaps be made to function inside the body. In each case, the researchers made known their intentions to eventually transfer this technology to humans. 3D printed, transplantable human organs are likely going to be part of the future – it’s just a matter of when.

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