Epidural Thin Film Implants of Polymerized Curcumin Downregulate Inflammatory Markers and Improve Functional Recovery After Spinal Cord Injury in Mice

ABSTRACT We demonstrate for the first time that the natural antioxidant curcumin, when copolymerized with PEG and sebacoyl chloride, results in biomaterials that are solution processable into free-standing, epidurally implantable thin films, in mice with spinal cord injury (SCI). We show that these novel products can be epidurally implanted at the lesion site following incomplete contusive spinal cord injury in mice. In the polymeric form, these materials quench reactive oxygen species on-contact and retain their activity for vastly extended timescales relative to the curcumin small molecule itself, which is potent but short lived. The epidural thin film biomaterial implant resulted in a statistically significant improvement in functional recovery after SCI. Mechanistically, myelin staining revealed that the polymerized curcumin materials greatly enhanced white matter sparing. Immunohistochemical analysis also showed that expression of GFAP and Ib1a are significantly downregulated 200 µm rostral (but not caudal) to the injury site. Finally, bulk RNA sequencing analysis showed greatly reduced activation of pro-inflammatory gene expression program. The primary conclusion from these experiments is that polymerized curcumin epidural thin films effectively improve outcomes following SCI. The benefits of these novel biomaterials are demonstrated in vivo, for the first time, and suggest that poly(pro-drug) thin film implants may provide safe chronic, local delivery of active drugs following SCI for extended timescales. Competing Interest Statement The authors have declared no competing interest. Footnotes ↵* Co-first authorship: Carlos A. Toro, Nicholas Johnson