Extravasation of biodegradable microspheres in the rat brain
Anne-Eva van der Wijk1,2,3, Theodosia Georgakopoulou1,2,3, Rob Steendam4
1Deparment of Biomedical Engineering and Physics, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.
Abstract:
Drug development for neurological diseases is greatly impeded by the presence of the blood-brain barrier (BBB). We and others previously reported on extravasation of micrometer-sized particles from the cerebral microcirculation - across the BBB - into the brain tissue over the course of several weeks. This mechanism could potentially be used for sustained parenchymal drug delivery after extravasation of biodegradable microspheres. As a first step toward this goal, we set out to evaluate the extravasation potential in the rat brain of three classes of biodegradable microspheres with drug-carrying potential, having a median diameter of 13 µm (80% within 8-18 µm) and polyethylene glycol concentrations of 0%, 24% and 36%. Extravasation, capillary recanalization and tissue damage were determined in a rat cerebral microembolization model at day 14 after microsphere injection. Microspheres of all three classes had the potential to extravasate from the vessel into the brain parenchyma, with microspheres without polyethylene glycol extravasating the fastest. Microembolization with biodegradable microspheres led to impaired local capillary perfusion, which was substantially restored after bead extravasation. We did not observe overt tissue damage after microembolization with any microsphere: we found very limited BBB disruption (IgG extravasation), no microgliosis (Iba1 staining) and no large neuronal infarctions (NeuN staining). In conclusion, biodegradable microspheres with different polymer compositions can extravasate into the brain parenchyma while causing minimal tissue damage.
Insights
Biodegradable microspheres can cross the blood-brain barrier (BBB) into brain tissue. This offers potential for sustained drug delivery with minimal observed tissue damage.
Area of Science:
- Biomedical Engineering
- Neuroscience
- Drug Delivery Systems
Background:
- The blood-brain barrier (BBB) significantly hinders drug development for neurological diseases.
- Previous research demonstrated micrometer-sized particle extravasation across the BBB into brain tissue over weeks.
- This extravasation mechanism presents a potential route for sustained parenchymal drug delivery using biodegradable microspheres.
Purpose of the Study:
- To evaluate the extravasation potential of three classes of biodegradable microspheres in the rat brain.
- To assess the impact of varying polyethylene glycol (PEG) concentrations on microsphere extravasation.
- To determine the extent of capillary recanalization and tissue damage following microsphere injection.
Main Methods:
- Utilized a rat cerebral microembolization model.
- Injected three classes of biodegradable microspheres (median diameter 13 µm) with 0%, 24%, and 36% PEG concentrations.
- Assessed extravasation, capillary recanalization, and tissue damage (IgG extravasation, Iba1, NeuN staining) at day 14 post-injection.
Main Results:
- All tested microsphere classes demonstrated extravasation from cerebral vessels into the brain parenchyma.
- Microspheres without PEG exhibited the fastest extravasation rates.
- Microembolization led to transient capillary perfusion impairment, which recovered post-extravasation.
- Minimal tissue damage was observed, including limited BBB disruption, no microgliosis, and no large neuronal infarctions.
Conclusions:
- Biodegradable microspheres of varying compositions can successfully extravasate into the brain parenchyma.
- This extravasation occurs with minimal disruption to the blood-brain barrier and surrounding brain tissue.
- These findings support the potential of biodegradable microspheres for targeted, sustained drug delivery across the BBB.
