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An injectable hydrogel enhances tissue repair after spinal cord injury by promoting extracellular matrix remodeling.

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.The cystic cavity that develops following injuries to brain or spinal cord is a major obstacle. Here the authors show an injection of imidazole poly(organophosphazenes), a hydrogel with thermosensitive sol-gel transition behavior, almost completely eliminates cystic cavities in a clinically relevant rat spinal cord injury model.

SUBMITTER: Hong LTA

PROVIDER: S-EPMC5599609 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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An injectable hydrogel enhances tissue repair after spinal cord injury by promoting extracellular matrix remodeling.

Hong Le Thi Anh LTA Kim Young-Min YM Park Hee Hwan HH Hwang Dong Hoon DH Cui Yuexian Y Lee Eun Mi EM Yahn Stephanie S Lee Jae K JK Song Soo-Chang SC Kim Byung Gon BG

Nature communications 20170914 1

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 ...[more]

PMID: 28912446

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Project description:In clinical trials, new scaffolds for regeneration after spinal cord injury (SCI) should reflect the importance of a mechanically optimised, hydrated environment. Composite scaffolds of nonwovens, self-assembling peptides (SAPs) and hydrogels offer the ability to mimic native spinal cord tissue, promote aligned tissue regeneration and tailor mechanical properties. This work studies the effects of an aligned electrospun nonwoven of P11-8-enriched poly(ε-caprolactone) (PCL) fibres, integrated with a photo-crosslinked hydrogel of glycidylmethacrylated collagen (collagen-GMA), on neurite extension. Mechanical properties of collagen-GMA hydrogel in compression and shear were recorded, along with cell viability. Collagen-GMA hydrogels showed J-shaped stress-strain curves in compression, mimicking native spinal cord tissue. For hydrogels prepared with a 0.8-1.1 wt.% collagen-GMA concentration, strain at break values were 68 ± 1-81 ± 1% (±SE); maximum stress values were 128 ± 9-311 ± 18 kPa (±SE); and maximum force values were 1.0 ± 0.1-2.5 ± 0.1 N (±SE). These values closely mimicked the compression values for feline and porcine tissue in the literature, especially those for 0.8 wt.%. Complex shear modulus values fell in the range 345-2588 Pa, with the lower modulus hydrogels in the range optimal for neural cell survival and growth. Collagen-GMA hydrogel provided an environment for homogenous and three-dimensional cell encapsulation, and high cell viability of 84 ± 2%. Combination of the aligned PCL/P11-8 electrospun nonwoven and collagen-GMA hydrogel retained fibre alignment and pore structure, respectively, and promoted aligned neurite extension of PC12 cells. Thus, it is possible to conclude that scaffolds with mechanical properties that both closely mimic native spinal cord tissue and are optimal for neural cells can be produced, which also promote aligned tissue regeneration when the benefits of hydrogels and electrospun nonwovens are combined.

Project description:Immediately following spinal cord injury, further injury can occur through several secondary injury cascades. As a consequence of cell lysis, an increase in extracellular Ca(2+) results in additional neuronal loss by inducing apoptosis. Thus, hydrogels that reduce extracellular Ca(2+) concentration may reduce secondary injury severity. The goal of this study was to develop composite hydrogels consisting of alginate, chitosan, and genipin that interact with extracellular Ca(2+) to enable in situ gelation while maintaining an elastic modulus similar to native spinal cord (∼1000 Pa). It was hypothesized that incorporation of genipin and chitosan would regulate hydrogel electrostatic characteristics and influence hydrogel porosity, degradation, and astrocyte behavior. Hydrogel composition was varied to create hydrogels with statistically similar mechanical properties (∼1000 Pa) that demonstrated tunable charge characteristics (6-fold range in free amine concentration) and degradation rate (complete degradation between 7 and 28 days; some blends persist after 28 days). Hydrogels demonstrate high sensitivity to Ca(2+) concentration, as a 1 mM change during fabrication induced a significant change in elastic modulus. Additionally, hydrogels incubated in a Ca(2+)-containing solution exhibited an increased linear viscoelastic limit (LVE) and an increased elastic modulus above the LVE limit in a time dependent manner. An extension of the LVE limit implies a change in hydrogel cross-linking structure. Attachment assays demonstrated that addition of chitosan/genipin to alginate hydrogels induced up to a 4-fold increase in the number of attached astrocytes and facilitated astrocyte clustering on the hydrogel surface in a composition dependent manner. Furthermore, Western blots demonstrated tunable glial fibrillary acid protein (GFAP) expression in astrocytes cultured on hydrogel blends, with some hydrogel compositions demonstrating no significant increase in GFAP expression compared to astrocytes cultured on glass. Thus, alginate/chitosan/genipin hydrogel composites show promise as scaffolds that regulate astrocyte behavior and for the prevention of Ca(2+)-related secondary neuron damage during acute SCI.

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An injectable hydrogel enhances tissue repair after spinal cord injury by promoting extracellular matrix remodeling.

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An injectable hydrogel enhances tissue repair after spinal cord injury by promoting extracellular matrix remodeling.

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