Gordian-Velez, W. J. | bioRxiv Science

bioRxiv2021

Dopaminergic axon tracts within a hyaluronic acid hydrogel encasement for implantation to restore the nigrostriatal pathway

Parkinsons disease (PD) affects 10 million patients worldwide, making it the second most prevalent neurodegenerative disease. Motor symptoms emerge from the loss of dopamine in the striatum after the death of dopaminergic neurons and the long-projecting axons of the nigrostriatal pathway. Current treatments, such as dopamine replacement, deep brain stimulation or cell therapies, disregard the loss of this pathway at the core of symptoms. We sought to address this by improving our tissue-engineered nigrostriatal pathway (TE-NSP) technology, which consists of a tubular hydrogel with a collagen/laminin core that encases an aggregate of dopaminergic neurons and their axons in a way that resembles the nigrostriatal pathway. These constructs can be implanted to replace the lost neurons and axons with fidelity to the pathway, and thus provide dopamine according to feedback from the host circuitry. While TE-NSPs have been traditionally fabricated with agarose, here we utilized a hyaluronic acid (HA) hydrogel to expand the functionality of the encasement and our control over its properties. Using rat ventral midbrain neurons, we found that TE-NSPs exhibited longer and faster neurite growth with HA relative to agarose, with no differences observed in electrically-evoked dopamine release. When transplanted, HA hydrogels reduced host neuron loss and inflammation around the implant compared to agarose, and the cells and axons within TE-NSPs survived and maintained their cytoarchitecture for at least 2 weeks. HighlightsO_LIWe fabricated engineered dopaminergic axons encased in a tubular hydrogel. C_LIO_LIWe made hydrogels from methacrylated hyaluronic acid and compared them to agarose. C_LIO_LIAxons in HA hydrogels had longer and faster axon growth and displayed evoked dopamine release. C_LIO_LIHA hydrogels reduced the host inflammatory response and supported neuron and axon survival in vivo. C_LIO_LIThis platform may be used to reconstruct the nigrostriatal pathway to treat Parkinsons disease. C_LI

bioengineering↗

bioRxiv2018

Three-dimensional human axon tracts derived from cerebral organoids

Reestablishing cerebral connectivity is a critical part of restoring neuronal network integrity and brain function after trauma, stroke, and neurodegenerative diseases. Creating transplantable axon tracts in the laboratory is a novel strategy for overcoming the common barriers limiting axon regeneration in vivo, including growth-inhibiting factors and the limited outgrowth capacity of mature neurons in the brain. We describe the generation and phenotype of three-dimensional human axon tracts derived from cerebral organoid tissue. These centimeter-long constructs are encased in an agarose shell that permits physical manipulation and are composed of discrete cellular regions spanned by axon tracts and dendrites, mirroring the separation of grey and white matter in the brain. Features of cerebral cortex also are emulated, as evidenced by the presence of neurons with different cortical layer phenotypes. This engineered neural tissue has the translational potential to reconstruct brain circuits by physically replacing discrete cortical neuron populations as well as long-range axon tracts in the brain.\n\neTOC BlurbRestoring axonal connectivity after brain damage is crucial for improving neurological and cognitive function. Cullen, et al. have generated anatomically inspired, three-dimensional human axon tracts projecting from cerebral organoids in a transplantable format that may facilitate the reconstruction of large-scale brain circuits.\n\nHighlightsO_LIA neural tissue engineering approach is applied to human cerebral organoids.\nC_LIO_LIThree-dimensional axon tracts are generated in a transplantable format.\nC_LIO_LIThe growth characteristics of the engineered axons are examined.\nC_LIO_LIThe cellular phenotypes of the organoid tissue and axons are characterized.\nC_LI

bioengineering↗