Localized and sustained release of brain-derived neurotrophic factor from injectable hydrogel/microparticle composites fosters spinal learning after spinal cord injury

Khaing, Zin Z.; Agrawal, Nikunj; Park, James; Xin, Shangjing; Plumton, Glendon; Lee, Kuan H.; Huang, Ya-Ching; Niemerski, Ashley; Schmidt, Christine E.; Grau, James W.

doi:10.1039/c6tb01602b

Cited by 32 publications

(21 citation statements)

References 79 publications

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“…This maladaptive plasticity has been linked to the release of BDNF from activated microglia (Coull et al, 2005). In contrast, after SCI, BDNF inhibits the development of nociceptive sensitization and promotes adaptive plasticity (Huang et al, 2017; Huie et al, 2012; Khaing et al 2016). BDNF appears to do so by restoring GABA-dependent inhibition through an increase in membrane-bound KCC2.…”

Section: Discussionmentioning

confidence: 99%

Ionic plasticity and pain: The loss of descending serotonergic fibers after spinal cord injury transforms how GABA affects pain

Huang

Grau

2018

Experimental Neurology

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Activation of pain (nociceptive) fibers can sensitize neural circuits within the spinal cord, inducing an increase in excitability (central sensitization) that can foster chronic pain. The development of spinally-mediated central sensitization is regulated by descending fibers and GABAergic interneurons. In adult animals, the co-transporter KCC2 maintains a low intracellular concentration of the anion Cl. As a result, when the GABA-A receptor is engaged, Cl flows in the neuron which has a hyperpolarizing (inhibitory) effect. Spinal cord injury (SCI) can down-regulate KCC2 and reverse the flow of Cl. Under these conditions, engaging the GABA-A receptor can have a depolarizing (excitatory) effect that fosters the development of nociceptive sensitization. The present paper explores how SCI alters GABA function and provides evidence that the loss of descending fibers alters pain transmission to the brain. Prior work has shown that, after SCI, administration of a GABA-A antagonist blocks the development of capsaicin-induced nociceptive sensitization, implying that GABA release plays an essential role. This excitatory effect is linked to serotonergic (5HT) fibers that descend through the dorsolateral funiculus (DLF) and impact spinal function via the 5HT-1A receptor. Supporting this, blocking the 5HT-1A receptor, or lesioning the DLF, emulated the effect of SCI. Conversely, spinal application of a 5HT-1A agonist up-regulated KCC2 and reversed the effect of bicuculline treatment. Finally, lesioning the DLF reversed how a GABA-A antagonist affects a capsaicin-induced aversion in a place conditioning task; in sham operated animals, bicuculline enhanced aversion whereas in DLF-lesioned rats biciculline had an antinociceptive effect.

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Section: Discussionmentioning

confidence: 99%

Ionic plasticity and pain: The loss of descending serotonergic fibers after spinal cord injury transforms how GABA affects pain

Huang

Grau

2018

Experimental Neurology

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“…The shear-thinning and self-healing properties were attributed to polymer chain entanglement; although, the exact gel recovery time was not specified [91]. In the context of the CNS, HAMC scaffolds have been used to study neural progenitor/stem cell viability and differentiation in vitro [89], as drug delivery vehicles in rodent stroke models [93,94], and to treat SCI in rodent models [95,96].…”

Section: Noncovalent Cross-linking Mechanismsmentioning

confidence: 99%

“…The chemical modifications further diversify the processing and fabrication techniques that may be employed to generate 3D HA scaffolds. Simple modifications to processing procedures enables the formation of HA hydrogels [74], granular hydrogels (microgels) [107], electrospun fibers [106], and composite HA-based materials [96]. Different forms of HA scaffolds have unique properties that provide different benefits to CNS regenerative medicine (Figure 3).…”

Section: Therapeutic Relevance Of Ha-based Materials In the Cnsmentioning

confidence: 99%

Hyaluronic Acid Biomaterials for Central Nervous System Regenerative Medicine

Jensen

Holloway

Stabenfeldt

2020

Cells

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Hyaluronic acid (HA) is a primary component of the brain extracellular matrix and functions through cellular receptors to regulate cell behavior within the central nervous system (CNS). These behaviors, such as migration, proliferation, differentiation, and inflammation contribute to maintenance and homeostasis of the CNS. However, such equilibrium is disrupted following injury or disease leading to significantly altered extracellular matrix milieu and cell functions. This imbalance thereby inhibits inherent homeostatic processes that support critical tissue health and functionality in the CNS. To mitigate the damage sustained by injury/disease, HA-based tissue engineering constructs have been investigated for CNS regenerative medicine applications. HA’s effectiveness in tissue healing and regeneration is primarily attributed to its impact on cell signaling and the ease of customizing chemical and mechanical properties. This review focuses on recent findings to highlight the applications of HA-based materials in CNS regenerative medicine.

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“…In particular, this strategy involves putting the most common features of both hydrogels into practice: biocompatibility and biodegradability in the case of natural hydrogels and the ability to “tune” the physical and mechanical properties of the resultant materials when using synthetic hydrogels. This combination allows the preparation of functionalized materials to provide protection at the injured site as well as deliver neurotrophic factors and neural stem cells . Detailed information on the progress and uses of these composites is shown in Table S1, Supporting Information.…”

Section: Introductionmentioning

confidence: 99%

Alginate Hydrogels as Scaffolds and Delivery Systems to Repair the Damaged Spinal Cord

Grijalvo

Nieto‐Díaz

Maza

et al. 2019

Biotechnology Journal

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Alginate (ALG) is a lineal hydrophilic polysaccharide present in brown algae cell walls, which turns into a gel state when hydrated. Gelation readily produces a series of three dimensional (3D) architectures like fibers, capillaries, and microspheres, used as biosensors and bio‐actuators in a plethora of biomedical applications like drug delivery and wound healing. Hydrogels have made a great impact on regenerative medicine and tissue engineering because they are able to mimic the mechanical properties of natural tissues due to their high water content. Recent advances in neurosciences have led to promising strategies for repairing and/or regenerating the damaged nervous system. Spinal cord injury (SCI) is particularly challenging, owing to its devastating medical, human, and social consequences. Although effective therapies to repair the damaged spinal cord (SC) are still lacking, multiple pharmacological, genetic, and cell‐based therapies are currently under study. In this framework, ALG hydrogels constitute a source of potential tools for the development of implants capable of promoting axonal growth and/or delivering cells or drugs at specific damaged sites, which may result in therapeutic strategies for SCI. In this mini‐review, the current state of the art of ALG applications in neural tissues for repairing the damaged spinal cord is discussed.

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Localized and sustained release of brain-derived neurotrophic factor from injectable hydrogel/microparticle composites fosters spinal learning after spinal cord injury

Abstract: Injectable hydrogel allows for sustained delivery of growth factor resulting in spinal mediated learning after injury.

Cited by 32 publications

References 79 publications

Ionic plasticity and pain: The loss of descending serotonergic fibers after spinal cord injury transforms how GABA affects pain

Ionic plasticity and pain: The loss of descending serotonergic fibers after spinal cord injury transforms how GABA affects pain

Hyaluronic Acid Biomaterials for Central Nervous System Regenerative Medicine

Alginate Hydrogels as Scaffolds and Delivery Systems to Repair the Damaged Spinal Cord

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