Development and evaluation of multiphasic, biomimetic substitutes of the dura mater – DuraLayer

The dura mater is the most external meningeal tissue (above arachnoid and pia mater) and consists of a half-rigid membrane located between the central nervous system (brain, spinal cord) and the surrounding bone tissue (skull, vertebrae). The dura mater is made of several layers of collagen fibres with various diameters and orientations and provides essential biological, mechanical and protective functions, such as containing the cerebrospinal fluid (CSF) around the brain and the spinal cord. After neurosurgery implying dura mater filling or suture, the excessive or inappropriate scar of this tissue, known as epidural fibrosis, leads to CSF leakage, pain or even neurological symptoms in up to 20% of patients. Although such issues have been studied for several decades and dura mater substitutes have been developed, their use is no optimal and postoperative complications are still noticed. It is therefore mandatory to develop alternative, innovative solutions to improve patients’ health and well-being while saving costs related to longer and more frequent hospitalization periods (needs for a second surgery).

In this context, this project aims at developing new biomimetic substitutes based on the multiphasic interface created by dura mater and skull bones as candidate substitutes to face these clinical challenges and offer easy handling to clinicians. Electrospinning will be used as the main production method thanks to the high structural similarity between the produced fibres and the dural extracellular matrix as well as the great versatility of this process. Well known in the field of biomaterial development, this technique is however barely investigated for the regeneration of meningeal tissues in despite of such similarities. Random fibres made of polycaprolactone, an FDA-approved polymer, will be turned into composite materials with modified properties (fibre diameter, porosity, alignment, mechanical properties). The objective is here to develop, thanks to an extensive in vitro cell characterization step, specific phases promoting respectively osteointegration, bioactivity of dural cells or dura mater wound healing. This project first aims at optimising the technical parameters allowing for the production of such scaffolds (WP1). After physico-chemical and cytotoxic characterization (WP2), the phases will be combined to create macroscopic structures and study their influence on auto-organization of cell co-cultures (stem cells, dural fibroblasts) and the impact of composition and structure of the biomaterials only on cell differentiation and functionality (WP3). Such an in vitro exhaustive cellular analysis will not only highlight the biomaterial properties leading to the best cell response but will also strengthen our knowledge of the in vitro behaviour of dural cells, still limited nowadays, as well as of the interactions between dura mater and skull bones. The most promising sets of parameters will then be validated through in vivo implantations in a rodent model of cranial defects to evaluate inflammatory reaction, biocompatibility and wound healing in comparison with an existing dural substitute (WP4). This in vivo proof-of-concept study will pave the way towards subsequent projects to refine, improve and complexify the candidate substitutes thanks to the versatility of the multiphasic approach (addition of layers with supplementary specific properties, extension to the other meningeal tissues) before further implantations assessing the influence on function recovery and long-term integration.