Fujifilm uses recombinant peptide for regenerative medicine to
1) verify that it substantially raises the survival rate of transplanted cells, and
2) successfully brings blood glucose to a normal level in the transplantation of pancreatic islets in mice models of diabetes

—Epoch-making outcomes of studies on the three-dimensional mosaic cell structure “CellSaic”, which combines cells and scaffolds—

March 27, 2015

FUJIFILM Corporation (President: Shigehiro Nakajima) has developed the micro-sized petaloid µ-pieces of Recombinant Peptide (RCP)*, a scaffold material** required for cell cultivation and transplantation in regenerative medicine. It has been verified that the “CellSaic (Cell and Scaffold, forming Mosaic)”***, which is a three-dimensional mosaic cell structure that consists of RCP petaloid µ-pieces and cells, substantially increases the cells' survival rate in mice transplantation compared to cell-only transplantation. In the study using Type I diabetic*4 model mice, the co-transplantation of CellSaic, which combines RCP petaloid µ-pieces with the human mesenchymal stem cells (hMSC)*5 and the cells from pancreatic islet*6, which controls blood glucose level, successfully lowered the blood glucose level to a normal level.

When cells are cultured with RCP petaloid µ-pieces in a culture plate, after five days, double the number of cells survived compared to the culturing of cells alone.

The research results will dramatically improve the efficiency of cell transplantation to enable the regeneration of tissues and organs. They represent an epoch-making research outcome that makes a significant contribution to the advancement of regenerative medicine.

Petaloid μ-piece

[Photo]

“Petaloid” means “resembling a flower petal”. A petaloid μ-piece has a detailed structure with complex surfaces.

[ Research background ]

Regenerative medicine is a new medical technology that involves regenerating damaged organs and tissues and restores their functionality. Cell transplantation and tissue transplantation, in particular, are considered to be the technologies of greatest potential. In order to make transplanted cells and tissues function properly, it is important to (1) effectively achieve in vivo survival of the transplanted cells and tissues, and (2) enable the supply of nutrients / oxygen to and discharge of waste products from the transplanted tissues and cells. The use of a material that serves as cellular scaffold is generally considered as an effective approach for in vivo survival of transplanted cells and tissues, while the early introduction of blood vessels is considered to be an effective way of facilitating the supply of nutrients / oxygen as well as the discharge of waste products. However, the larger a spheroid the difficult it becomes to supply nutrients / oxygen into its core and facilitate the discharge of waste products. Cells end up dying before a blood vessel can be established.

To counter this problem, Fujifilm used advanced engineering technology to process its proprietary scaffold material “RCP”, which does not contain any animal-derived ingredient*7, to newly develop its micro-sized petaloid μ-pieces. These were combined with cells to create a three-dimensional mosaic cell structure called “CellSaic”, which has been used to produce the following research outcomes:

[ Research Outcome 1 ] Verifying that the CellSaic substantially raises the survival rate of cells transplanted in vivo
  1. 1. Experiment description
    In order to facilitate the supply of nutrients / oxygen and discharge of waste products, the study made subcutaneous transplantation of CellSaic, which combines hMSC with petaloid µ-pieces optimally shaped for cellular survival, into mice's back, and compared the rate of cellular survival against the transplantation of only hMSC spheroids.
  2. 2. Results
    • Combining hMSC with RCP petaloid µ-pieces into “CellSaic” more than doubled the survival activity of cells after seven days of cultivating compared to spheroids of hMSC alone (Fig.1).
    • It was visually confirmed that, despite the growth of the “CellSaic”, the number of dead cells was very small inside the “CellSaic”, suggesting the survival of numerous cells (Fig.2).
    • Seven days after transplantation, compared to hMSC spheroids, CellSaic showed a significantly more prominent introduction of blood vessels, which are passageways of nutrients, oxygen and waste products. At the same time, it was also confirmed that cellular survival was substantially higher in CellSaic (Fig.3).
  3. These results indicate:
    • “RCP” in petaloid μ-pieces secured cell scaffold, and created space inside “CellSaic” at the same time, facilitating the supply of nutrients / oxygen and discharge of waste products.
    • “RCP” and the extra “space” provided channels for in-vivo vascular cells to arrive.
[Photo]
[Photo]
[ Research outcome 2 ] Successfully lowering the blood glucose level in pancreatic islet transplantation in Type I diabetic model mice
  1. 1. Experiment description:
    Pancreatic islet transplantation is an advanced medical treatment available for pancreatic islet dysfunction such as Type I diabetes, which causes difficulty in control of the blood glucose level. Animal tests have reported enhanced treatment outcome of pancreatic islet transplantation, when mesenchymal stem cells (MSC) are co-transplanted. This study prepared “CellSaic” combining hMSC with petaloid µ-pieces, and co-transplanted the CellSaic and pancreatic islets into the Type I diabetic model mice.
  2. 2. Results:
    • The subcutaneous co-transplantation of pancreatic islets and CellSaic, combining hMSC with RCP petaloid µ-pieces, into mice produced a higher treatment effect than the co-transplantation of pancreatic islets and hMSC, and successfully lowered blood glucose to the normal level (Fig.4).

Compared to the conventional approach, this co-transplantation led to the greater in vivo survival of hMSC cells, indicating enhancement of the effect of pancreatic islet transplantation.

[Photo]

(Left) The study subcutaneously transplanted 200 pancreatic islets, and measured subsequent changes to the blood glucose level for 28 days. The transplantation of just pancreatic islets failed to lower the blood glucose level.
The co-transplantation of pancreatic islets and hMSC lowered the blood glucose level but not to the normal level. In the co-transplantation of 200 pancreatic islets and CellSaic combining hMSC and RCP petaloid μ-pieces, the blood glucose level lowered to the level equivalent to that of healthy mice.
(Right) A glucose tolerance test was conducted in mice 28 days after the abovementioned transplantation. After one day of fasting, the mice were forcibly administered with glucose to examine how long it would take for the raised blood glucose level to come down to the normal level (around 150mg/dl). It took very long for the blood glucose level to come down to the normal level for mice that had only pancreatic islets transplanted. However, blood glucose dropped quickly to the normal level for mice that received the combination of pancreatic islets and “CellSaic” combining hMSC with RCP petaloid μ-pieces.

These research outcomes bring high expectations for “CellSaic”, which combines cells with RCP petaloid µ-pieces, in its application to a range of regenerative medical treatments including cell transplantation, tissue regeneration and organ regeneration. The findings were presented to the 14th annual meeting of the Japanese Society for Regenerative Medicine, held at PACIFICO Yokohama on March 19, 2015.

Fujifilm will continue to integrate its expertise in highly-functional materials and engineering technologies, fostered over many years of research in photographic films, with technologies and know-how of its affiliate, Japan Tissue Engineering Co., Ltd., in research, development, production and marketing to further promote R&D in regenerative medicine and contribute to its future industrialization.

  • * Artificial protein, modeled after Human Type I Collagen, produced with yeast cells using genetic engineering
  • ** Collagen and other types of proteins or synthetic materials that serve as the scaffold structure for cells
  • *** Cell and Scaffold, forming Mosaic. A three-dimensional mosaic cell structure that consists of cells and scaffold material. A coined term from the word “cell” and “-saic” from the word “mosaic”.
  • *4 A form of diabetes that results from insulin deficiency, caused by autoimmune disease, etc.
  • *5 Somatic stem cells of the mesenchymal system (bone cells, myocardial cells, chondrocytes, tendon cells, fat cells, etc.). They have differentiation potency mainly towards mesenchymal cells, and are considered to have a strong potential as a cell source for various forms of regenerative medicine.
  • *6 Islet-shaped regions of tissues found in the pancreas. They produce and release insulin according to glucose concentration in blood to control the body's blood glucose level.
  • *7 This means it does not contain any ingredient derived from animals heterologous to humans. It is a property strongly desired for medical materials used in humans.
  • *8 ATP stands for adenosine triphosphate, the energy molecule for cells. Quantitative measurement of ATP in live cells determines the level of their survival activity.

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