Modeling diffusion-based drug release inside a nerve conduit in vitro and in vivo validation study

Abstract

The objective of this work was to develop a model and understand the diffusion of a drug into and throughout a drug delivering nerve conduit from a surrounding reservoir through a hole in the wall separating the lumen of the conduit and the reservoir. A mathematical model based on Fick’s law of diffusion was developed using the finite difference method to understand the drug diffusion and the effect of varying device parameters on the concentration of drug delivered from a hole-based drug delivery device. The mathematical model was verified using a physical microfluidic (μFD) model and an in vitro/in vivo release test using prototype devices. The results of the mathematical model evaluation and microfluidic device testing offered positive insight into the reliability and function of the reservoir and hole-based drug delivering nerve conduit. The mathematical model demonstrated how changing device parameters would change the drug concentration inside the device. It was observed that the drug release in the conduit could be tuned by both concentration scaling and changing the hole size or number of holes. Based on the results obtained from the microfluidic device, the error in the mathematical drug release model was shown to be less than 10% when comparing the data obtained from mathematical model and μFD model. The data highlights the flexibility of having a hole-based drug delivery system, since the drug release can be scaled predictably by changing the device parameters or the concentration of the drug in the reservoir.

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Acknowledgments

The authors thank their colleagues at the State of Utah Center of Excellence for Biomedical Microfluidics and the Department of Surgery Research Laboratory for their assistance in this work.

Funding

This work is funded by the DOD Award number W81XWH1310363.

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Correspondence to Jayant Agarwal.

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Highlights

• A mathematical drug release model was presented to understand the diffusion and transport of a drug inside a hole-based drug delivering nerve conduit. Different device parameters such as hole location, reservoir drug concentration, and reservoir volume were varied to determine the changes in the concentration range in the nerve conduit lumen using the mathematical model.

• A microfluidic device was fabricated with similar dimensions as the real device and used to show that the mathematical model could predict drug release accurately.

• The drug diffusion inside the conduit was simulated over a period of 30 days using the mathematical model. These results showed that following cell infiltration or nerve growth after 15 days of device implantation, the drug concentration in the conduit lumen reduced by about ~ 45–50% due to the modified diffusion coefficient of the drug in tissue (as opposed to aqueous media).

• The mathematical drug release model was also validated using a preliminary evaluation of the in vitro and in vivo FK506 release from the drug delivery device.

• Finally, this study resulted in the development and detailed evaluation of a mathematically predictable drug delivery device that has the flexibility to be used in combination with a scaffold or without and has the flexibility to change the type of drug release across different types of nerve injuries.

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Labroo, P., Ho, S., Sant, H. et al. Modeling diffusion-based drug release inside a nerve conduit in vitro and in vivo validation study. Drug Deliv. and Transl. Res. 11, 154–168 (2021). https://doi.org/10.1007/s13346-020-00755-y

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Keywords

  • Drug delivery
  • FK506; nerve conduit
  • Drug release model