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Bilayered ON-Demand Scaffolds: On-Demand Delivery from induced Pluripotent Stem Cell Derived Scaffolds for Diabetic Foot Ulcers

Periodic Reporting for period 2 - BONDS (Bilayered ON-Demand Scaffolds: On-Demand Delivery from induced Pluripotent Stem Cell Derived Scaffolds for Diabetic Foot Ulcers)

Reporting period: 2019-04-01 to 2020-09-30

Diabetes affects over 420 million people globally, with 627 thousand diabetes-related deaths and expenditure exceeding €175 billion in Europe alone (2015). Diabetic foot ulcers (DFUs) are complex skin wounds prevalent in 16.5million diabetics and ~20% of diabetics will get a DFU in their lifetime. Chronic DFUs are infection-prone and can have the devastating consequence of lower leg amputation. The goal of BONDS is to develop a new type of wound healing device for DFUs. This wound healing device will be unique as (1) we will use a new source of material to build the device , and (2) the device will be functionalised with on-demand delivery of genes for coordinated healing of diabetic foot ulcers. For (1) the goal is to use a special type of cells grown from a special source of cells called induced pluripotent stem cells (iPS cells). When an adult's skin cells are cycled through iPS reprogramming and redifferentiated back into skin cells, they result in rejuvenated cells that produce more proteins and these proteins can help accelerate repair. We will collect these proteins and convert them into a scaffold - a porous template that the bodies own cells can migrate into and grow new tissue. For (2), we will build on a technology we previously developed to control when nanoparticles are released by using ultrasound. Herein, we will adapt this technology to deliver genes on demand. These genes will be released at specific points of the healing process where they will be used to direct healing. With >100 million current diabetics expected to get a DFU, the BONDS would have a powerful clinical impact. Furthermore, the technologies developed can be adopted for application in other challenging environments where tissue growth is required.
"To date, we have successfully characterised the pre- and post-iPS skin cells (""fibroblasts"") and demonstrated differences in the matrix produced by the post-iPS cells. The post-iPS cells produced more matrix, and certain proteins produced are consistent with a younger type of matrix, including a factor that promotes blood vessel growth. Next, we developed techniques to convert this matrix into a new wound healing device. These scaffolds could be seeded with normal and diabetic foot ulcer fibroblasts, supporting their growth, and producing a wide variety of matrix proteins, which are conducive to wound healing. Furthermore, the cells produced more of a protein associated with new blood vessel growth. Finally, the scaffolds had a favourable immune response, enabling the immune system to direct whether an anti- or pro-inflammatory environment was created, which is beneficial for wound healing which requires both phases as healing progresses.
The on-demand delivery system was successfully adapted for releasing genes at specific timepoints. However, to fully enhance their activity, further optimisation is required. In parallel, we developed an alternative, more stable, DNA-based nanoparticle, which we could successfully release and demonstrated its bioactivity. This nanoparticle could be loaded with chemotherapeutic drugs and was capable of limiting cancer cell growth in vitro.
Ultimately, we believe the two systems need to be combined together to form an effective wound healing device. Thus, we have developed two versions of the device. In the first, the on-demand delivery system is integrated throughout the scaffold. We demonstrated its ability to release nanoparticles on demand within the scaffold. In the second version, we incorporated the drug delivery device in discrete locations within the scaffold. This enables the operator to release different drugs at different timepoints by targeting the discrete areas."
To our knowledge, this work is the first time a tissue engineering scaffold has been produced from tissue grown by iPS cells. Additionally, technologies for on-demand delivery of DNA-based nanoparticles have not been widely developed previously. And, finally, the combination of these within a scaffold offers a new platform for tissue engineering. TO BE EDITED
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