Abstract
Spinal cord injury (SCI) results in massive secondary damage characterized by a prolonged inflammation with phagocytic macrophage invasion and tissue destruction. In prior work, sustained subdural infusion of anti-inflammatory compounds reduced neurological deficits and reduced pro-inflammatory cell invasion at the site of injury leading to improved outcomes. We hypothesized that implantation of a hydrogel loaded with an immune modulating biologic drug, Serp-1, for sustained delivery after crush-induced SCI would have an effective anti-inflammatory and neuroprotective effect. Rats with dorsal column SCI crush injury, implanted with physical chitosan-collagen hydrogels (CCH) had severe granulomatous infiltration at the site of the dorsal column injury, which accumulated excess edema at 28 days post-surgery. More pronounced neuroprotective changes were observed with high dose (100 µg/50 µL) Serp-1 CCH implanted rats, but not with low dose (10 µg/50 µL) Serp-1 CCH. Rats treated with Serp-1 CCH implants also had improved motor function up to 20 days with recovery of neurological deficits attributed to inhibition of inflammation-associated tissue damage. In contrast, prolonged low dose Serp-1 infusion with chitosan did not improve recovery. Intralesional implantation of hydrogel for sustained delivery of the Serp-1 immune modulating biologic offers a neuroprotective treatment of acute SCI.
Highlights
Spinal cord injury (SCI) causes prolonged morbidity and mortality with secondary physiological, economical, and psychological complications
Hemorrhage and necrosis are accompanied by acute inflammation with macrophage invasion, swelling and edema, and irreversible destruction forming a cavity of injury (COI) [3]
The functional recovery after high dose Serp-1 delivered by chitosan-collagen hydrogel was significantly improved at days seven to fourteen, but prolonged additional low dose Serp-1 infusion did not further improve outcomes, potentially due to secondary injury caused by catheter implant together with a protracted infusion
Summary
Spinal cord injury (SCI) causes prolonged morbidity and mortality with secondary physiological, economical, and psychological complications. We recently reported that administration of the myxoma virus-derived immune modulating serpin, Serp-1, infused locally for seven days starting immediately after balloon crush SCI, reduced inflammation and improved functional recovery in rat models [13]. Serp-1 binds and inhibits tissueand urokinase-type plasminogen activators (tPA and uPA, respectively), plasmin in the thrombolytic cascade, and thrombin and factor X in the coagulation/thrombotic cascade. This serpin protein biologic has proven efficacy for reducing vascular inflammation and improving mortality in a wide range of vascular injury, inflammation, and transplant models. We studied whether Serp-1 delivered by chitosan-collagen hydrogel implant provides therapeutic efficacy in a forceps crush-induced spinal cord injury model
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