FDA Approves First 3D-Printed Drug

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3D printing has been hailed as a revolutionary technology, and now a medical breakthrough has indicated that the technology might deliver on its promise in the medical arena.

On August 3, 2015, Aprecia Phramaceuticals, announced in a press release that the U.S. Food and Drug Administration (FDA) approved its drug for the treatment of epilepsy, named SPRITAM.

The drug is used in the treatment of seizures brought on by epileptic attacks in patients 6 years and older.The company uses 3D printing technology initially developed at MIT, and combines it with its own manufacturing processes.

More specifically, Aprecia manufactures the drug on its own equipment, based on its so-called ZipDose Technology, which uses 3D printing to print layers of medication more tightly, allowing for up to 1,000 mg in a single dose to give a dissolvable final product.

The drug is a pill taken orally, which dissolves rapidly in contact with water. It is assembles by printing layers of powdered drug and then blowing off excess powder.

A video of Aprecia’s ZipDose technology is included below.

 

 

While the first, this is likely not the last drug to be generated using 3D printing technology, as Aprecia themselves claimed they are working on bringing more drugs with this technology to the market in the future.

 

 

Gene Mutation Reprograms Blood Stem Cells in Leukemia

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A new breakthrough study out last week described the discovery of a mutation in a gene in blood cells that is associated with causing abnormal blood cell counts in patients with acute myeloid leukemia (AML).

Acute myeloid leukemia is still plagued by a very low survival rates, and improved treatment options are increasingly needed.

The study, published in Cell Reports (2015; doi:10.1016/j.celrep.2015.06.069) by Professors Peter Cockerill, PhD, and Constanze Bonifer, PhD, both of the University of Birmingham, described mutations in the FLT3 gene that cause abnormal red blood cell production.

FLT3, located in the cell membrane, is responsible for expressing a receptor tyrosine kinase. Mutations in the gene account for 25% of AML malignancies.

The authors found that the mutated FLT3 protein used one specific signaling pathway, connected to two MAP kinase transcription factors, AP-1 and RUNX1, inside the cell to activate a significant number of DNA targets, leading to the abnormal activation of more than 100 genes in patients with the mutation.

This growth factor dependence is the first time that a genetic link has been described that has direct effects on reprogramming of blood stem cells from a “healthy” to a “diseased” state, and, though only preliminary, it presents new hope for advancing new treatments for AML.

Read the paper here.

Organoids: In vitro mini-organs for tissue engineered medicine

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You may have heard of organoids. Over the last few years, they have emerged, in the scientific literature and in the media, as attractive new platforms with the potential to significantly advance regenerative medicine. Such a claim isn’t novel, though organoids have accolades to back it up: a growing body of scientific literature and being named by The Scientist magazine as one of the biggest scientific advancements of 2013.

What is an organoid? In simple terms, it is a three-dimensional tissue structure made up of cells an cellular material that resembles the in vivo tissue or organ from which it originates. In more precise terms, it is an in vitro culture system that allows for the stable expansion of cells that faithfully represent in vivo cells.

Labs around the world have generated large collections of patient organoids from a variety of organs and diseases, which are used to study many diseases including various cancers and further contribute to the scientific community’s understanding of disease bases.

Outside of cells, organoids also include an extracellular matrix components (such as growth factors), which are useful in supporting the expansion and differentiation of organoid stem cells into tissue-specific cells.

A recent review published in Nature Reviews Nephrology gives a thorough overview of the current state-of-the-art in organoid cultures based on adult stem and progenitor cells and highlights areas that have lagged behind in terms of therapeutic utility – the kidney being one of them.

Exciting new developments in the field include developing culture parameters to establish optimal 3D environments to support organoid formation and growth (see this recent paper in Biomaterials Science). These systems include recombinant ECM components to improve the biomechanical responses of such cultures. These are selected on the basis of cell proliferation and differentiation and are usually modeled after in vivo requirements.

We will be looking more closely at organoids in future blog entries as we follow and support further developments in this area by the development of 3D cell culture substrates as well as extracellular matrix components to aid stem cell proliferation.

 

 

 

New polymer reduces ice crystal formation during cryopreservation

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Preventing ice crystal formation is one of the main goals when developing new cryopreservation techniques. Ice crystals cause direct injury to the cells during the freezing and particularly thawing process. The ice is also the main culprit for secondary freezing damage that involves the solutes used in the cryoprotectant solution.

We have been developing alternative cryopreservation solutions that bypass the use of DMSO and reduce as well as minimize the formation of undesirable ice crystals. These solutions are based on naturally-occurring compounds with anti-freeze properties that are biologically compatible with cell membranes. Akron’s family of DMSO-free cryomedia is based on proprietary compositions.

Now,  new polymers are emerging as preferred alternatives to proteins as cryoprotectants because of their wider availability, lower cost and ease of handling and preparation.

In a new paper published in Chemical Communications, a group of researchers from the University of Warwick have synthesized a new polymer that limits ice crystal formation in frozen red blood cells as they thaw. The polymer is based on a biomimetic, polyampholite with ice-recrystallization-inhibiting properties.

The authors successfully demonstrated the new polymer’s ability to preserve red blood cells as they thaw with an efficiency comparable to DMSO and glycerol, traditionally preferred cryoprotectants.

The tendency to move toward polyampholytic polymers has, in recent years, emerged with interesting solutions that have challenged the traditionally-accepted DMSO as the cryoprotectant of choice and the notion that other solutions are unable to match its broad efficacy. Polyampholites are, however, not the only polymer compound with cryoprotective properties: companies such as Akron have researched alternative solutions with performance that surpasses DMSO. Though there is still a battle to fight as we learn of the new solutions’ clinical utility, the growing body of work is contributing to the field’s move forward.

Contact us if you would like to enquire about our cell and tissue-specific cryopreservation solutions.

 

 

Genetically Corrected Pluripotent Stem Cells Show Promise for Mitochondrial Disease

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Last week, a new study published in Nature described a promising new approach for the treatment of metabolic disease based on genetically modified pluripotent stem cells.

The high mutation rate in the mitochondrial genome may lead to a number of significant complications, which include neurological, gastrointestinal, cardiac, respiratory, endocrinal and ophthalmological issues and diseases that often have serious, and even fatal, consequences. Avoiding or controlling such mutations has significant medical impact.

The new study described successfully generating genetically-corrected induced pluripotent stem cells (iPSCs) derived from patients with heteroplasmic mutations causing mitochondrial encephalomyopathy, stroke-like episodes and Leigh syndrome. The authors used spontaneous segregation of heteroplasmic mtDNA as well as somatic cell nuclear transfer (SCNT) enabled to generate corrected iPSCs. These genetically “corrected” displayed normal metabolic function compared to that observed in mutant cells.

 

The study was led by Dr. Shoukhrat Mitalipov at Oregon Health and Sciences University, together with collaborators at the Salk institute for Biological Sciences, the University of California San Diego, the Mayo Clinic and the University of Oxford.

This reprogramming approach is unique and significant in that it successfully generated “healthy” cells from mutated cells in diseased subjects, and represents a new paradigm for the potential therapeutic use of such reprogramming techniques to obtain wild-type mtDNA.

 

Fibronectin Immobilization on Nanobioactive Scaffolds Improves Bone Regeneration

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Fibronectin-scaffold composites have emerged as promising three-dimensional substrates for tissue regenerative applications. These structures have shown potential in the regeneration of a variety of tissues. Among those, bone tissue has been of particular interest. The integration of nanotechnology with scaffold fabrication approaches has given rise to new families of structures that allow more thorough integration of biological components that promote tissue repair.

Now, a new paper, titled “Fibronectin immobilization on to robotic-dispensed nanobioactive glass/polycaprolactone scaffolds for bone tissue engineering”, describes the use of robotics, nanotechnology and biomedical engineering to create composite scaffolds for bone regeneration. Moreover, they use the ligand-like properties of fibronectin to improve the attachment of mesenchymal stem cells seeded on the scaffolds.

The authors, led by Dr. Hae-Won Kim at Dankook University in South Korea, described the use of robotics assembly of sol-gel-based glass-PCL scaffolds with immobilized fibronectin which were then used for bone cell proliferation as precursors for osteogenesis. The scaffolds were manufactured by a robotic platform called EZROBO3, in addition to a number of chemical lab complexation steps.

The authors showed that the FN-nBG/PCL scaffolds significantly improved cell responses, including attachment and subsequent cell proliferation of the mesenchymal stem cells seeded on the scaffolds. These effects are dependent on the cell-binding characteristics of fibronectin and are unique to the molecule.

Fibronectin/scaffold composites were previously described in the literature and are emerging as a new paradigm for next-generation three-dimensional tissue regeneration platforms, which are going to require ECM components to generate the kind of in vivo-mimicking responses that have the most medical potential.

Fibronectin is also one of Akron’s leading ECM proteins, which we are now offering in research grade and GMP grade as well with custom MSC-based bioassays. Contact us for information.

 

iPSCs Reprogrammed into Patient-specific Heart Cells to Study Heart Disease

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Up until now, understanding and investigating the molecular and genetic cues for disease has involved carrying studies in unhealthy individuals, by mobilizing cells that have been affected by the disease. This has been the case for dilated cardiomyopathy (DCM) – a deficiency which affects the heart’s ability to supply blood efficiently.

A new study published in Cell this week, turned this paradigm around by converting induced pluripotent stem cells (iPSCs) from healthy individuals into DCM-impacted cells.

Led by Joseph Wu at Stanford University’s School of Medicine, the authors matched the upregulation of phosphodiesterases (PDEs) 2A and PDE3A that occurs in DCM patient tissue to upregulation in DCM iPSC-CMs. This was important as is further demonstrated the successful reprogramming of iPSCs into DCM cells. The protein TNNT2, which is mutated in DCM patient tissue, was also observed as such in iPSC-derived DCM tissue.

This study is significant not only because it shed further light on the molecular basis for a severe condition such as DCM, but it is remarkable in its use of reprogrammed iPSCs to mimic patient cells. This opens up opportunities for clinical-level studies that will no longer require high-risk studies on sick patients. While this particular study focused on matching patient DCM conditions to genetic cues on iPSC-derived cells, rather than uncovering novel therapeutic outcomes, it is a remarkable first example that such work might soon be possible.

At Akron, we support research into reprogramming of iPSCs by providing media, solutions and new technologies for such investigations. Contact us for more information.