The ABM CDT is a partnership between The Universities of Manchester and Sheffield. ALL APPLICATIONS should however, be submitted via the Manchester application system only.
This project will involve the use of a family of natural, sustainable, and highly biocompatible biomaterials produced using bacterial fermentation, Polyhydroxyalkanoates (PHAs) for the development of lung related drug delivery system. In addition, a PHA-based advanced 3D human lung model will be developed using human cells seeded on the 3D printed PHA scaffolds which will be used for the testing the efficacy of the drug delivery system. These 3D models will be placed in a novel Bioreactor system, the Quasi Vivo® System, an in vitro transwell-based culture system developed by Kirkstall Ltd. The system allows dynamic perfusion and hence mimics the in vivo conditions very well. This system will be far superior and much more representative as compared to the use of animal models which are distinctly different from humans in nature. In addition, this will be by far a much more ethical route for testing of the novel drug delivery system.
Lung is an attractive but challenging target for drug delivery. The enormous surface area of the lung is well-suited for both topical and systemic absorption of medications. On the other hand, lung has efficient mechanical, chemical, and immunological mechanisms that can protect the body from unwanted inhaled materials. Clinically inhalation has been used as the major route for pulmonary drug administration. Thus, developing less immunogenic vehicles is crucial for pulmonary drug delivery. However, preclinical development of pulmonary drug delivery using in vivo models is not very efficient due to a significant difference between human and animal lungs. The barrier functions from the transwell-based in vitro lung models generally depend on the mechanical properties of the transwell insert scaffolds, which is far from clinically relevant. Therefore, advanced pulmonary models are needed to reflect the alveolar-capillary barrier and the relevant immune response.
Quasi Vivo® System is an in vitro transwell-based culture systems developed by Kirkstall Ltd. The system allows dynamic perfusion. A lung/immune cell co-culture model using this technology has been recently developed by Chandorkar et al. and showed better airway cell development and improved barrier function.
Polyhydroxyalkanoates (PHAs) are FDA-approved, bacteria derived polyesters with tunable mechanical and physical properties, which make them suitable bioscaffolds for advanced lung/immune cell models. They are also less immunogenic compared to conventional drug delivery biomaterials such as PLA and PLGA.
In this project, we aim to develop PHA-based biomaterials to advance the functionality of lung/immune cell models in the Quasi Vivo® System and manufacture PHA-based pulmonary drug delivery vehicles.
Main questions to be answered
The main questions to be addressed in this project are:
- Production and characterisation of two types of PHAs, a stiff PHA, Poly(3-hydroxybutyrate), P(3HB) and an elastomeric one, a Medium chain length PHA, MCL-PHA.
- Optimisation of the conditions to produce advanced in vitro lung/immune cell models using PHA-based 3D-scaffolds using 3D printing/electrospinning and the Quasi Vivo® System
- Characterisation of the advanced in vitro lung/immune cell models
- Manufacture of the pulmonary delivery vehicles using PHAs
- Application of the drug delivery on the advanced in vitro lung/immune cell models