Localized and Sustained Delivery of Fibroblast Growth Factor-2 from a Nanoparticle-Hydrogel Composite for Treatment of Spinal Cord Injury

Abstract

After traumatic spinal cord injury, grossly injured blood vessels leak blood and fluid into the parenchyma, leading to a large cystic cavity. Fibroblast growth factor-2 (FGF2) can reduce immediate vasoconstriction of vessels in the tissue surrounding the primary injury and promote angiogenesis. A localized delivery system would both achieve restricted delivery of FGF2 to the spinal cord and limit possible systemic effects such as mitogenesis. To enhance the endogenous angiogenic response after spinal cord injury, FGF2 was encapsulated in poly(lactide-co-glycolide) (PLGA) nanoparticles which were embedded in a biopolymer blend of hyaluronan and methylcellulose (HAMC) and then injected into the intrathecal space. Treatment began immediately after a 26 g clip compression spinal cord injury in rats and consisted of intrathecal delivery of FGF2 from the HAMC/PLGA/FGF2 composite. Control animals received intrathecal HAMC loaded with blank nanoparticles, intrathecal HAMC alone or intrathecal artificial cerebrospinal fluid alone. Sustained and localized delivery of FGF2 from composite HAMC/PLGA/FGF2 achieved higher blood vessel density in the dorsal horns 28 days post-injury, due to either greater angiogenesis near the epicenter of the injury or vasoprotection acutely after spinal cord injury. Importantly, delivery of FGF2 from composite HAMC/PLGA/FGF2 did not produce proliferative lesions that had been previously reported for FGF2 delivered locally using a minipump/catheter. These results suggest that localized and sustained delivery with composite HAMC/PLGA/FGF2 is an excellent system to deliver biomolecules directly to the spinal cord, thereby circumventing the blood spinal cord barrier and avoiding systemic side effects.

Repair of spinal cord injury by implantation of bFGF-incorporated HEMA-MOETACL hydrogel in rats

“…Furthermore, a comparative study of four methacrylate hydrogels indicated that the HEMA-MOETACl hydrogel was the best carrier of mesenchymal stem cells (MSCs) in vitro and in vivo 29 . The HAMC hydrogel and the composite of HAMC/PLGA have also been shown to be excellent delivery systems where biomolecules are delivered directly to the injured spinal cord 15,33 . These findings indicate that a suitable hydrogel, combined with appropriate neurotrophic factors or stem cells seems to be a promising approach in the treatment of SCI.…”

“…bFGF is abundantly expressed in the nervous system, where it has vital roles, and was previously shown to support the survival and growth of neurons and neural stem cells in vitro 14 . After SCI, seriously injured blood vessels leak blood and fluid into the parenchyma, leading to a large pseudocyst cavity, and bFGF can decrease immediate vasoconstriction of blood vessels in the tissue near the epicenter of the injury and promote angiogenesis 15 . Previous findings have also shown that bFGF infusion or transgene therapy may promote the regeneration of neurons and axons 16,17 .…”

Neurotrophic Factors Used to Treat Spinal Cord Injury

“…Intrathecal administration typically involves osmotic pumps to continuously deliver FGF to (or near) the lesion over days or weeks Kojima & Tator, 2002;Lee et al, 1999;Rabchevsky et al, 1999). FGF has also been delivered in association with Schwann cells or peripheral nerve (PN) grafts, released by carriers such as gelfoam, gelatin, fibrin glue, HEMA-MOETACL hydrogels alginate scaffolds or from nanoparticles (Chen et al, 2015;Furuya et al, 2013;Grulova et al, 2015;Guzen et al, 2012;Kang et al, 2013;Lee et al, 2008Lee et al, , 2010Meijs et al, 2004;Meng et al, 2008;Shin et al, 2014;Tsai et al, 2006;Wu et al, 2008). A recent study successfully delivered FGF2 (a known mitogen for stem cell self-renewal) via subcutaneous injection to give improved outcomes (Goldshmit et al, 2014).…”

“…Changes in astrocyte phenotype after FGF administration to the injured spinal cord are not always extensive (Kang et al, 2013;Kim et al, 2006), although FGF2 (Grulova et al, 2015) and FGF1 (Lee et al, 2008) may reduce astrocytic reactivity and macrophage infiltration. In zebrafish SCI studies (Goldshmit et al, 2012), subcutaneous administration of FGF2 in adult mice reduced inflammation, microglia and macrophage activation, and astrocyte reactivity at 2 weeks.…”

Nanoparticle Technologies in the Spinal Cord

“…However, as with chondroitinase ABC (chABC), the method of delivery to the spinal cord lesion utilized in many of these studies is not effectively translated to use in humans. Since these factors will be needed for extended periods of time, they can be incorporated into nanoparticles as well as hydrogels or scaffolds for sustained release [Baumann et al, 2010;Stanwick et al, 2012;Kang et al, 2013;des Rieux et al, 2014;Elliott Donaghue et al, 2014. Some of these formulations could potentially function to both stimulate and guide axon regrowth along a specific path though the spinal cord.…”