Traumatic Brain Injuries (TBIs) result in a range of complex neurophysiological and functional deficits, severe long-term disability, and poor prognosis for the affected individuals. The significant brain tissue loss encountered post-TBI is a major contributor to these poor outcomes. Current interventions that target single components of TBI related trauma have largely failed to prevent widespread brain tissue loss and promote repair and functional recovery. Transplanted and host Neural Stem Cells (NSCs) possess multifaceted therapeutic potential, owing to their ability to produce efficacious amounts of neuroprotective factors in addition to facilitating complex large-scale repair and reconstruction of damaged brain tissue. However, current strategies fail to augment endogenous NSC and trophic factor activity necessary to promote long-lasting repair and recovery after a moderate-to-severe TBI. We hypothesize that the transplantation of allogeneic exogenous NSCs in a selectively engineered glycomaterial matrix capable of attracting and retaining endogenous NSCs and protective factors will facilitate functional repair of brain tissue post TBI. The creation of an ectopic NSC niche as proposed here can maintain NSCs in their undifferentiated state, and help confer neuroprotection and preservation of function chronically post-TBI. Toward this goal, we will exploit the unique structural and functional attributes of Chondroitin Sulfate Glycosaminoglycan (CS-GAG) sulfation to design novel engineered CS-GAG (eCS-GAG) matrices that are capable of enriching trophic factors, and maintaining transplanted and host NSCs in their undifferentiated state. We will implant eCS-GAG matrices either alone or in combination with NSCs in a rodent model of moderate-to-severe TBI. We will evaluate the enhanced potential of trophic factor enriching eCS-GAG matrices to promote NSC self-renewal and facilitate neuroprotection and functional recovery chronically post-TBI when compared to other sulfated and unsulfated GAG matrix controls. Our approach is novel in that it exploits the compositional and functional diversity of CS-GAG sulfation to facilitate the haptotaxis of endogenous NSCs, and presentation of endogenous protective factors within the engineered chemistry of the matrix to significantly improve NSC efficacy after moderate-to-severe TBI.

Public Health Relevance

There are currently no effective treatments for Traumatic Brain Injuries (TBI). In order to address this gap, we propose to deliver Neural Stem Cells (NSCs) in selectively engineered glycomaterial carriers that can preserve the undifferentiated state of NSCs to promote brain tissue repair after TBI. In doing so, we hope to promote functional recovery after TBI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS099596-03
Application #
9704095
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Lavaute, Timothy M
Project Start
2017-07-15
Project End
2022-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Georgia
Department
Type
Schools of Veterinary Medicine
DUNS #
004315578
City
Athens
State
GA
Country
United States
Zip Code
30602
Birdwhistell, Kate E; Karumbaiah, Lohitash; Franklin, Samuel P (2018) Sustained Release of Transforming Growth Factor-?1 from Platelet-Rich Chondroitin Sulfate Glycosaminoglycan Gels. J Knee Surg 31:410-415
Logun, Meghan; Zhao, Wujun; Mao, Leidong et al. (2018) Microfluidics in Malignant Glioma Research and Precision Medicine. Adv Biosyst 2:
Latchoumane, Charles-Francois V; Jackson, LaDonya; Sendi, Mohammad S Eslampanah et al. (2018) Chronic Electrical Stimulation Promotes the Excitability and Plasticity of ESC-derived Neurons following Glutamate-induced Inhibition In vitro. Sci Rep 8:10957
Sanjay Sarma, O V; Betancur, Martha; Pidaparti, Ramana et al. (2018) Lesion Volume Estimation from TBI-MRI. Prog Adv Comput Intell Eng 563:197-207
Tehrani, Kayvan Forouhesh; Sun, Min Kyoung; Karumbaiah, Lohitash et al. (2017) Fast axial scanning for 2-photon microscopy using liquid lens technology. Proc SPIE Int Soc Opt Eng 10070: