Angiogenic microspheres promote neural regeneration and motor function recovery after spinal cord injury in rats

Abstract

This study examined sustained co-delivery of vascular endothelial growth factor (VEGF), angiopoietin-1 and basic fibroblast growth factor (bFGF) encapsulated in angiogenic microspheres. These spheres were delivered to sites of spinal cord contusion injury in rats, and their ability to induce vessel formation, neural regeneration and improve hindlimb motor function was assessed. At 2–8 weeks after spinal cord injury, ELISA-determined levels of VEGF, angiopoietin-1, and bFGF were significantly higher in spinal cord tissues in rats that received angiogenic microspheres than in those that received empty microspheres. Sites of injury in animals that received angiogenic microspheres also contained greater numbers of isolectin B4-binding vessels and cells positive for nestin or β III-tubulin (P < 0.01), significantly more NF-positive and serotonergic fibers, and more MBP-positive mature oligodendrocytes. Animals receiving angiogenic microspheres also suffered significantly less loss of white matter volume. At 10 weeks after injury, open field tests showed that animals that received angiogenic microspheres scored significantly higher on the Basso-Beattie-Bresnahan scale than control animals (P < 0.01). Our results suggest that biodegradable, biocompatible PLGA microspheres can release angiogenic factors in a sustained fashion into sites of spinal cord injury and markedly stimulate angiogenesis and neurogenesis, accelerating recovery of neurologic function.

Neuromuscular Activity Induces Paracrine Signaling and Triggers Axonal Regrowth after Injury in Microfluidic Lab-On-Chip Devices

“…Here, we analyzed the expression of different soluble factors that have been described as being expressed in muscle and muscle-like cell lines, as well as being involved in regenerative events in different tissues or neuronal types such as the interleukin 6 family members CNTF and LIF in inducing axonal regeneration on retinal ganglion cells and dorsal root ganglia neurons [53][54][55][56] and the angiogenic factors VEGF and angiopoietin I [57]. The latter has recently been described as being secreted by muscular cells to induce vascularization after injury [45] and was also described as boosting regeneration in dorsal root ganglia (DRGs) [58], Fgfb [57] implicated in the development and regeneration of spinal cord, liver, heart, and photoreceptors from the zebrafish [59]. Moreover, released by the muscle in an autocrine fashion after injury [60] is the glial-derived neurotrophic factor GDNF, whose direct muscle delivery with human mesenchymal stem cells improves motor neuron survival and function in an amyotrophic lateral sclerosis (ALS) model [61].…”

The Role of Biomaterials as Angiogenic Modulators of Spinal Cord Injury: Mimetics of the Spinal Cord, Cell and Angiogenic Factor Delivery Agents

“…The positive impact of MSCs on the angiogenesis and vascularization of SCI was probably driven by the secretome of these cells which is extremely rich in pro-angiogenic GFs ( Ranganath et al, 2012 ). Accordingly, several researchers have taken advantage of the aforementioned features of biomaterials to explore delivery of angiogenic GFs in SCI animal models and assess their impact on recovery following injury ( De Laporte et al, 2011 ; Kang et al, 2012 ; Des Rieux et al, 2014 ; Wen et al, 2016 ; Yu et al, 2016 ). Combinatorial approaches utilizing different angiogenic GFs perhaps represent the best way of attaining better functional outcomes following SCI.…”

“…Biomaterials can aid modulation of the vascular response following SCI via two distinct mechanisms, namely acting as vehicles for the delivery of pro-angiogenic molecules ( Yu et al, 2016 ) or as ECM-mimetic platforms that support cell growth and proliferation ( Rauch et al, 2009 ). The capacity that biomaterials have for protecting cells and therapeutic agents from the harsh conditions found in SCI lesion sites puts them in a privileged position for the development of targeted regenerative therapies.…”

Treatment withIL‐19improves locomotor functional recovery after contusion trauma to the spinal cord

“…Angiogenesis after SCI promoted endogenous repair and supported neural regeneration (Figley et al ., ; Yu et al ., ). In the aortic ring model of angiogenesis (Kako et al ., ) and the hindlimb ischaemia induced by femoral artery ligation (Gabunia and Autieri, ; Richards et al ., ), IL‐19 increased angiogenesis.…”