Sustained delivery of neurotrophic factors to treat spinal cord injury

Abstract

Acute spinal cord injury (SCI) is a devastating condition that results in tremendous physical and psychological harm and a series of socioeconomic problems. Although neurons in the spinal cord need neurotrophic factors for their survival and development to reestablish their connections with their original targets, endogenous neurotrophic factors are scarce and the sustainable delivery of exogeneous neurotrophic factors is challenging. The widely studied neurotrophic factors such as brain-derived neurotrophic factor, neurotrophin-3, nerve growth factor, ciliary neurotrophic factor, basic fibroblast growth factor, and glial cell-derived neurotrophic factor have a relatively short cycle that is not sufficient enough for functionally significant neural regeneration after SCI. In the past decades, scholars have tried a variety of cellular and viral vehicles as well as tissue engineering scaffolds to safely and sustainably deliver those necessary neurotrophic factors to the injury site, and achieved satisfactory neural repair and functional recovery on many occasions. Here, we review the neurotrophic factors that have been used in trials to treat SCI, and vehicles that were commonly used for their sustained delivery.

The Role of Tissue Geometry in Spinal Cord Regeneration

“…Treatments that target intracellular pathways involved in axonal transport, such as the mechanistic target of rapamycin (mTOR), phosphatase and tensin homolog (PTEN) and growth-associated protein 43 (GAP-43), offer potential therapeutic targets for enhancing axonal growth and functional recovery [33][34][35][36][37][38][39][40]. Similar evidence has been obtained for the use of neurotrophic factors, which can also contribute to greater regeneration and/or collateral sprouting [41][42][43][44]. Enhancing the intrinsic growth potential of axons, however, is unlikely to be sufficient if disruption of tissue organization prevents axonal navigation of the injury site.…”

“…That is, they seek the requisite trophic support provided by their target tissues. The need for trophic support has also been incorporated into some repair strategies by including growth factors or cells secreting such factors into the materials used to promote growth [41,42,[196][197][198][199].…”

Biomaterials delivery strategies to repair spinal cord injury by modulating macrophage phenotypes

“…Neurotrophic factors in the spinal cord need neurotrophic factors to survive and develop to re-establish connections to the original target. 75 However, endogenous neurotrophic factors at the site of injury are insufficient to maintain nerve repair. 76 The strategy of delivering exogenous neurotrophic factors is more conducive to nerve repair.…”

Biomaterial-Mediated Factor Delivery for Spinal Cord Injury Treatment

“…However, as already pointed out, all of these methods show many disadvantages, such as the inaccessibility of the BSCB, no control of the release, and problems due to surgery (such as placement of a catheter, creation of a pouch for a pump, etc.). In order to solve these problems, HGs were chosen as promising biomaterials that can sustain the release of growth factors directly at the injury site—a winning point when also considering their short bioavailability [ 87 , 88 , 89 ]. Indeed, HGs demonstrated good ability to preserve the bioactivity of GDNF [ 90 ], NT-3 [ 91 , 92 ], BDNF [ 93 , 94 ], and fibroblast growth factor-2 (FGF-2) [ 95 , 96 ].…”