Abstract
The cystic cavity that develops following injuries to brain or spinal cord is a major obstacle for tissue repair in central nervous system (CNS). Here we report that injection of imidazole-poly(organophosphazenes) (I-5), a hydrogel with thermosensitive sol–gel transition behavior, almost completely eliminates cystic cavities in a clinically relevant rat spinal cord injury model. Cystic cavities are bridged by fibronectin-rich extracellular matrix. The fibrotic extracellular matrix remodeling is mediated by matrix metalloproteinase-9 expressed in macrophages within the fibrotic extracellular matrix. A poly(organophosphazenes) hydrogel lacking the imidazole moiety, which physically interacts with macrophages via histamine receptors, exhibits substantially diminished bridging effects. I-5 injection improves coordinated locomotion, and this functional recovery is accompanied by preservation of myelinated white matter and motor neurons and an increase in axonal reinnervation of the lumbar motor neurons. Our study demonstrates that dynamic interactions between inflammatory cells and injectable biomaterials can induce beneficial extracellular matrix remodeling to stimulate tissue repair following CNS injuries.
Highlights
The cystic cavity that develops following injuries to brain or spinal cord is a major obstacle for tissue repair in central nervous system (CNS)
The present study reports that a polymer-based injectable hydrogel almost completely eliminates cystic cavities and leads to enhanced tissue repair in a clinically relevant contusive spinal cord injury (SCI) model in rats
Our data showed that the histamine moiety in the hydrogel and its physical interaction with macrophages plays an important role in the extracellular matrix (ECM) remodeling
Summary
The cystic cavity that develops following injuries to brain or spinal cord is a major obstacle for tissue repair in central nervous system (CNS). Our study demonstrates that dynamic interactions between inflammatory cells and injectable biomaterials can induce beneficial extracellular matrix remodeling to stimulate tissue repair following CNS injuries. Since in most cases of human SCIs, the injuries are incomplete with a significant portion of the white matter spared[20], surgical procedures involving the implantation of scaffolds or matrices are prone to aggravating functional deficits In this regard, there is a mounting consensus on the necessity of using injectable, in situ gelling hydrogels for future clinical translation[7, 14, 21]. The present study reports that a polymer-based injectable hydrogel almost completely eliminates cystic cavities and leads to enhanced tissue repair in a clinically relevant contusive SCI model in rats. Our study proposes that dynamic interaction between inflammatory cells in the host tissue and injectable hydrogel can be a principal mechanism underlying biomaterial-mediated tissue repair following CNS injuries
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