Sustained Delivery of Dibutyryl Cyclic Adenosine Monophosphate to the Transected Spinal Cord Via Oligo [(Polyethylene Glycol) Fumarate] Hydrogels

Abstract

This study describes the use of oligo [(polyethylene glycol) fumarate] (OPF) hydrogel scaffolds as vehicles for sustained delivery of dibutyryl cyclic adenosine monophosphate (dbcAMP) to the transected spinal cord. dbcAMP was encapsulated in poly(lactic-co-glycolic acid) (PLGA) microspheres, which were embedded within the scaffolds architecture. Functionality of the released dbcAMP was assessed using neurite outgrowth assays in PC12 cells and by delivery to the transected spinal cord within OPF seven channel scaffolds, which had been loaded with Schwann cells or mesenchymal stem cells (MSCs). Our results showed that encapsulation of dbcAMP in microspheres lead to prolonged release and continued functionality in vitro. These microspheres were then successfully incorporated into OPF scaffolds and implanted in the transected thoracic spinal cord. Sustained delivery of dbcAMP inhibited axonal regeneration in the presence of Schwann cells but rescued MSC-induced inhibition of axonal regeneration. dbcAMP was also shown to reduce capillary formation in the presence of MSCs, which was coupled with significant functional improvements. Our findings demonstrate the feasibility of incorporating PLGA microsphere technology for spinal cord transection studies. It represents a novel sustained delivery mechanism within the transected spinal cord and provides a platform for potential delivery of other therapeutic agents.

The Application of Stem Cell Based Tissue Engineering in Spinal Cord Injury Repair.

“…OPF can be cross-linked by UV light and more importantly, its molecular weight controls the mechanical properties and degradation speed of the hydrogel. These properties make it broadly used in bone [58], osteochondral [59], musculotendinous [60], cardiovascular [61] and neural tissue engineering [62,63]. OPF could serve as spinal cord regeneration matrix mainly due to its compressive and flexural modulus which is similar to that of rat spinal cord [64].…”

“…Bone marrow derived MSCs were suspended in matrigel and seeded into scaffolds and transplanted into transected rat spinal cord injury model. The authors believed the sustained release of dbcAMP rescued axonal regeneration from MSCs induced inhibition and capillary formation, which in turn improved motor function [62].…”

Neural ECM mimetics

“…Acute PEG treatment after spinal cord trauma has also been reported to exert neuroprotective effects via the reduction of oxidative stress reactions . PEG is a widely used material for the design of biodegradable synthetic cross-linked hydrogels (Burdick et al, 2006;Cong et al, 2009;Gunn et al, 2005;Herten et al, 2009;Phelps et al, 2010;Qiao et al, 2005;Raeber et al, 2005;Rooney et al, 2011). PEG has several beneficial features, which are advantageous for soft tissue regeneration.…”

Positively Charged Oligo[Poly(Ethylene Glycol) Fumarate] Scaffold Implantation Results in a Permissive Lesion Environment after Spinal Cord Injury in Rat

“…Previous studies in our laboratory have evaluated various polymers and cell types for nervous system repair. [32][33][34][35][36][37][38][39][40][41][42][43][44] Schwann cells loaded into polymer scaffold channels have demonstrated an increased capacity for supporting axonal regeneration when compared with other cell types such as neural stem cells or mesenchymal stem cells. 37,42 We have shown that biodegradable polymer hydrogel scaffolds seeded with Schwann cells are able to bridge the growth inhibitory lesion site and support axon regeneration in vivo.…”

“…[32][33][34][35][36][37][38][39][40][41][42][43][44] Schwann cells loaded into polymer scaffold channels have demonstrated an increased capacity for supporting axonal regeneration when compared with other cell types such as neural stem cells or mesenchymal stem cells. 37,42 We have shown that biodegradable polymer hydrogel scaffolds seeded with Schwann cells are able to bridge the growth inhibitory lesion site and support axon regeneration in vivo. 36,40 We have also compared the mechanical properties and regeneration supporting potential of various polymers, including poly(lactic-co-glycolic acid) (PLGA), poly(caprolactone fumarate) (PCLF), a neutral oligo[(polyethylene glycol) fumarate] (OPF) hydrogel, and a positively charged oligo [(polyethylene glycol) fumarate] (OPF+) hydrogel and determined that scaffolds fabricated from OPF+ support the most axon regeneration and have similar compression and flexural moduli to rat spinal cord.…”