A Hydrogel Bridge Incorporating Immobilized Growth Factors and Neural Stem/Progenitor Cells to Treat Spinal Cord Injury

Li, Hang; Ham, Trevor R.; Neill, Nicholas J.; Farrag, Mahmoud; Mohrman, Ashley E; Koenig, Andrew M.; Leipzig, Nic D.

doi:10.1002/adhm.201500810

Cited by 73 publications

(71 citation statements)

References 81 publications

(101 reference statements)

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“…Encapsulating NSCs within a biomimetic hydrogel conduit can provide protection, locate the cells within the injury site, control lineage specification, and guide neurite outgrowth. [7] To guide the differentiation of encapsulated NSCs, the material can be functionalized with lineage directing (signaling) proteins. In fact, platelet-derived growth factor-AA (PDGF-AA) can be used to specify oligodendrocytes,[3, 8] bone morphogenetic protein-2 (BMP-2) to specify astrocytes,[3] and interferon- γ (IFN- γ ) to specify neurons.…”

Section: Introductionmentioning

confidence: 99%

Covalent growth factor tethering to direct neural stem cell differentiation and self-organization

2017

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Tethered growth factors offer exciting new possibilities for guiding stem cell behavior. However, many of the current methods present substantial drawbacks which can limit their application and confound results. In this work, we developed a new method for the site-specific covalent immobilization of azide-tagged growth factors and investigated its utility in a model system for guiding neural stem cell (NSC) behavior. An engineered interferon-γ (IFN-γ) fusion protein was tagged with an N-terminal azide group, and immobilized to two different dibenzocyclooctyne-functionalized biomimetic polysaccharides (chitosan and hyaluronan). We successfully immobilized azide-tagged IFN-γ under a wide variety of reaction conditions, both in solution and to bulk hydrogels. To understand the interplay between surface chemistry and protein immobilization, we cultured primary rat NSCs on both materials and showed pronounced biological effects. Expectedly, immobilized IFN-γ increased neuronal differentiation on both materials. Expression of other lineage markers varied depending on the material, suggesting that the interplay of surface chemistry and protein immobilization plays a large role in nuanced cell behavior. We also investigated the bioactivity of immobilized IFN-γ in a 3D environment in vivo and found that it sparked the robust formation of neural tube-like structures from encapsulated NSCs. These findings support a wide range of potential uses for this approach and provide further evidence that adult NSCs are capable of self-organization when exposed to the proper microenvironment.

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Section: Introductionmentioning

confidence: 99%

Covalent growth factor tethering to direct neural stem cell differentiation and self-organization

2017

Self Cite

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“…Despite the complexity of the CNS and the challenges of developing effective neuroregeneration methods, there is a considerable amount of data regarding disease models focusing on repair of the nervous system (1–12). One widely explored approach involves the utilization of structural support by biodegradable, biocompatible, injectable hydrogels in stroke and SCI applications, along with sustained and targeted release of trophic factors and/or stem cells to trigger an endogenous neuroregenerative response (7–12).…”

Section: Introductionmentioning

confidence: 99%

“…One widely explored approach involves the utilization of structural support by biodegradable, biocompatible, injectable hydrogels in stroke and SCI applications, along with sustained and targeted release of trophic factors and/or stem cells to trigger an endogenous neuroregenerative response (7–12). In the following section we will mention some of the significant achievements in preclinical research work based on small animal models (i.e., rats, mice) that have allowed us to move closer from bench to bedside treatment protocols.…”

Section: Introductionmentioning

confidence: 99%

Advancing Research in Regeneration and Repair of the Motor Circuitry: Non-Human Primate Models and Imaging Scales as the Missing Links for Successfully Translating Injectable Therapeutics to the Clinic

Tsintou¹

2016

Int J Stem Cell Res Ther

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Regeneration and repair is the ultimate goal of therapeutics in trauma of the central nervous system (CNS). Stroke and spinal cord injury (SCI) are two highly prevalent CNS disorders that remain incurable, despite numerous research studies and the clinical need for effective treatments. Neural engineering is a diverse biomedical field, that addresses these diseases using new approaches. Research in the field involves principally rodent models and biologically active, biodegradable hydrogels. Promising results have been reported in preclinical studies of CNS repair, demonstrating the great potential for the development of new treatments for the brain, spinal cord and peripheral nerve injury. Several obstacles stand in the way of clinical translation of neuroregeneration research. There seems to be a key gap in the translation of research from rodent models to human applications, namely non-human primate models, which constitute a critical bridging step. Applying injectable therapeutics and multimodal neuroimaging in stroke lesions using experimental rhesus monkey models is an avenue that a few research groups have begun to embark on. Understanding and assessing the changes that the injured brain or spinal cord undergoes after an intervention with biodegradable hydrogels in non-human primates seem to represent critical preclinical research steps. Existing innovative models in non-human primates allow us to evaluate the potential of neural engineering and injectable hydrogels. The results of these preliminary studies will pave the way for translating this research into much needed clinical therapeutic approaches. Cutting edge imaging technology using Connectome scanners represents a tremendous advancement, enabling the in vivo, detailed, high-resolution evaluation of these therapeutic interventions in experimental animals. Most importantly, they also allow quantifiable and clinically meaningful correlations with humans, increasing the translatability of these innovations to the bedside.

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“…[57] Biotintagged interferon-γ (IFN-γ) and PDGF-AA have been immobilized to a streptavidin functionalized methacryamide chitosan hydrogel via the well-known biotin-streptavidin conjugation. [58] These materials showed improved neural regeneration in vivo in spinal cord injury in rats, showing increased neuron count relative to treatment with the hydrogel material alone. [58] Similar immobilized IFN-γ in chitosan hydrogel materials were tested with NSCs.…”

Section: Immobilization Of Drugs In Hydrogelsmentioning

confidence: 99%

“…[58] These materials showed improved neural regeneration in vivo in spinal cord injury in rats, showing increased neuron count relative to treatment with the hydrogel material alone. [58] Similar immobilized IFN-γ in chitosan hydrogel materials were tested with NSCs. [59] When cultured in hydrogels functionalized with either immobilized or soluble IFN-γ, both conditions resulted in a similar improvement in neuronal differentiation compared to medium alone, but the immobilized drug showed fewer semicommitted and immature neurons, indicated by the lower copresentation of Nestin and βIII tubulin.…”

Section: Immobilization Of Drugs In Hydrogelsmentioning

confidence: 99%

Dynamic and Responsive Growth Factor Delivery from Electrospun and Hydrogel Tissue Engineering Materials

Bruggeman

Williams

Nisbet

2017

Adv Healthcare Materials

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Tissue engineering scaffolds are designed to mimic physical, chemical, and biological features of the extracellular matrix, thereby providing a constant support that is crucial to improved regenerative medicine outcomes. Beyond mechanical and structural support, the next generation of these materials must also consider the more dynamic presentation and delivery of drugs or growth factors to guide new and regenerating tissue development. These two aspects are explored expansively separately, but they must interact synergistically to achieve optimal regeneration. This review explores common tissue engineering materials types, electrospun polymers and hydrogels, and strategies used for incorporating drug delivery systems into these scaffolds.

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A Hydrogel Bridge Incorporating Immobilized Growth Factors and Neural Stem/Progenitor Cells to Treat Spinal Cord Injury

Cited by 73 publications

References 81 publications

Covalent growth factor tethering to direct neural stem cell differentiation and self-organization

Covalent growth factor tethering to direct neural stem cell differentiation and self-organization

Advancing Research in Regeneration and Repair of the Motor Circuitry: Non-Human Primate Models and Imaging Scales as the Missing Links for Successfully Translating Injectable Therapeutics to the Clinic

Dynamic and Responsive Growth Factor Delivery from Electrospun and Hydrogel Tissue Engineering Materials

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