Poly(ester amide) microspheres are efficient vehicles for long-term intracerebral growth factor delivery and improve functional recovery after stroke

Tamar Memanishvili,Zaal Kokaia,Jemal Tatarishivili,Daniel Tornero,Emanuela Monni,Olle Lindvall,Alexander Tsiskaridze

doi:10.1088/1748-605x/aba4f6

Tamar Memanishvili, Zaal Kokaia + Show 5 more

Open Access

https://doi.org/10.1088/1748-605x/aba4f6

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Abstract

Growth factors promote plasticity in injured brain and improve impaired functions. For clinical application, efficient approaches for growth factor delivery into the brain are necessary. Poly(ester amide) (PEA)-derived microspheres (MS) could serve as vehicles due to their thermal and mechanical properties, biocompatibility and biodegradability. Vascular endothelial growth factor (VEGF) exerts both vascular and neuronal actions, making it suitable to stimulate post-stroke recovery. Here, PEA (composed of adipic acid, L-phenyl-alanine and 1,4-butanediol) MS were loaded with VEGF and injected intracerebrally in mice subjected to cortical stroke. Loaded MS provided sustained release of VEGF in vitro and, after injection, biologically active VEGF was released long-term, as evidenced by high VEGF immunoreactivity, increased VEGF tissue levels, and higher vessel density and more NG2+ cells in injured hemisphere of animals with VEGF-loaded as compared to non-loaded MS. Loaded MS gave rise to more rapid recovery of neurological score. Both loaded and non-loaded MS induced improvement in neurological score and adhesive removal test, probably due to anti-inflammatory action. In summary, grafted PEA MS can act as efficient vehicles, with anti-inflammatory action, for long-term delivery of growth factors into injured brain. Our data suggest PEA MS as a new tool for neurorestorative approaches with therapeutic potential.

Highlights

Ischemic stroke causes brain damage with loss of neurons, glial cells, and vasculature, leading to longterm disability and death
Poly(ester amide) (PEA) 4F4 MS can be efficiently loaded with vascular endothelial growth factor (VEGF) Scanning electron microscopy revealed clear surface differences between VEGF-loaded and non-loaded MS
Providing evidence for the regulation of angiogenesis by VEGF released from the injected, loaded MS in stroke-subjected mice, we found markedly higher vessel density in these mice as compared to animals injected with non-loaded MS or phosphate-buffered saline (PBS) (figures 3(B) and (F))

Summary

Introduction

Ischemic stroke causes brain damage with loss of neurons, glial cells, and vasculature, leading to longterm disability and death. Vascular endothelial growth factor (VEGF) has been shown to regulate formation of new blood vessels and proliferation and differentiation of neuronal precursors (Rosenstein et al 1998, Palmer et al 2000, Krum et al 2002, Sun et al 2003), to promote post-stroke recovery (Hayashi et al 1998, Zhang et al 2000b, Wittko et al 2009) and to be neuroprotective (Sun et al 2003). VEGFloaded PLGA MS with attached human neural stem cells promoted neovascularization in the stroke cavity (Bible et al 2012)

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