Review: Biomaterial systems to resolve brain inflammation after traumatic injury.

The inflammatory response within the central nervous system (CNS) is a tightly regulated cascade of events which is a balance of both cytotoxic and cytotrophic effects which determine the outcome of an injury. The two effects are inextricably linked, particularly in traumatic brain injury or stroke, where permanent dysfunction is often observed. Chronic brain inflammation is a key barrier to regeneration.

A Programmed Anti-Inflammatory Nanoscaffold (PAIN) as a 3D Tool to Understand the Brain Injury Response.

Immunology is the next frontier of nano/biomaterial science research, with the immune system determining the degree of tissue repair. However, the complexity of the inflammatory response represents a significant challenge that is essential to understand for the development of future therapies. Cell-instructive 3D culture environments are critical to improve our understanding of the link between the behavior and morphology of inflammatory cells and to remodel their response to injury.

Reducing Astrocytic Scarring after Traumatic Brain Injury with a Multifaceted Anti-Inflammatory Hydrogel System.

Traumatic brain injury results in devastating long-term functional damage due to the growth inhibition of the inflammatory response, and in particular, the complex response of astrocytes. Sustained, nonsteroidal anti-inflammatory approaches that can attenuate this response are of interest to improve therapeutic outcomes, particularly when combined with a tissue engineering construct that recapitulates the physiological microenvironment to facilitate functional repair. Here, we present a multifaceted, therapeutic extracellular-matrix mimic consisting of a coassembled scaffold with a laminin-inspired self-assembling peptide hydrogel, Fmoc-DIKVAV, and the anti-inflammatory macromolecule, fucoidan.

Temporally controlled growth factor delivery from a self-assembling peptide hydrogel and electrospun nanofibre composite scaffold.

Tissue-specific self-assembling peptide (SAP) hydrogels designed based on biologically relevant peptide sequences have great potential in regenerative medicine. These materials spontaneously form 3D networks of physically assembled nanofibres utilising non-covalent interactions. The nanofibrous structure of SAPs is often compared to that of electrospun scaffolds.

Galactose-functionalised PCL nanofibre scaffolds to attenuate inflammatory action of astrocytes in vitro and in vivo.

Astrocytes represent an attractive therapeutic target for the treatment of traumatic brain injury in the glial scar, which inhibits functional repair and recovery if persistent. Many biomaterial systems have been investigated for neural tissue engineering applications, including electrospun nanofibres, which are a favourable biomaterial as they can mimic the fibrous architecture of the extracellular matrix, and are conveniently modified to present biologically relevant cues to aid in regeneration. Here, we synthesised a novel galactose-presenting polymer, poly(l-lysine)-lactobionic acid (PLL-LBA), for use in layer-by-layer (LbL) functionalisation of poly(ε-caprolactone) (PCL) nanofibres, to covalently attach galactose moieties to the nanofibre scaffold surface.

Integrating Biomaterials and Stem Cells for Neural Regeneration.

The central nervous system has a limited capacity to regenerate, and thus, traumatic injuries or diseases often have devastating consequences. Therefore, there is a distinct need to develop alternative treatments that can achieve functional recovery without side effects currently observed with some pharmacological treatments. Combining biomaterials with pluripotent stem cells (PSCs), either embryonic or induced, has the potential to revolutionize the treatment of neurodegenerative diseases and traumatic injuries.

Interleukin-10 conjugated electrospun polycaprolactone (PCL) nanofibre scaffolds for promoting alternatively activated (M2) macrophages around the peripheral nerve in vivo.

Macrophages play a key role in tissue regeneration following peripheral nerve injury by preparing the surrounding parenchyma for regeneration, however, they can be damaging if the response is excessive. Interleukin 10 (IL-10) is a cytokine that promotes macrophages toward an anti-inflammatory/wound healing state (M2 phenotype). The bioactive half-life of IL-10 is dependent on the cellular microenvironment and ranges from minutes to hours in vivo.

Transcriptomic analysis and 3D bioengineering of astrocytes indicate ROCK inhibition produces cytotrophic astrogliosis.

Astrocytes provide trophic, structural and metabolic support to neurons, and are considered genuine targets in regenerative neurobiology, as their phenotype arbitrates brain integrity during injury. Inhibitors of Rho kinase (ROCK) cause stellation of cultured 2D astrocytes, increased L-glutamate transport, augmented G-actin, and elevated expression of BDNF and anti-oxidant genes. Here we further explored the signposts of a cytotrophic, "healthy" phenotype by data-mining of our astrocytic transcriptome in the presence of Fasudil.

3D Electrospun scaffolds promote a cytotrophic phenotype of cultured primary astrocytes.

Astrocytes are a target for regenerative neurobiology because in brain injury their phenotype arbitrates brain integrity, neuronal death and subsequent repair and reconstruction. We explored the ability of 3D scaffolds to direct astrocytes into phenotypes with the potential to support neuronal survival. Poly-ε-caprolactone scaffolds were electrospun with random and aligned fibre orientations on which murine astrocytes were sub-cultured and analysed at 4 and 12 DIV.