The central premise of our research is that we can improve treatments for various brain and spinal cord disorders by developing new bioengineered strategies that can favorably regulate glial cell functions.
Across all projects we aim to achieve two key outcomes: (i) Contribute to furthering fundamental glia biology knowledge, and (ii) Developing new bioengineering solutions or tools that have translational potential.
1. REPAIRING CNS INJURIES USING GLIA ENGINEERING
Our Approach: Using innovative bioengineering tools we are testing strategies to promote glia based repair of traumatic central nervous system (CNS) injuries using rodent models of spinal cord injury (SCI) and stroke. Sources of glia for this work include exogenous sources derived from neural progenitor cell (NPC) grafts as well as recruited endogenous host glia. We are innovating new biomaterials that specifically target barriers to glia repair in CNS lesion core environment (e.g. from peripherally derived immune cells, extravasated serum proteins and fibrosis etc.).
Why is this important?: In traumatic CNS injuries destruction of neural tissue initiates a natural wound healing response that results in lesion formation. CNS injury lesions are composed of non-neural lesion cores that are isolated from adjacent viable neural tissue by a glial limitans border. At the lesion site, there is no spontaneous regeneration of new neural tissue. Instead, the non-neural lesion core that persists chronically lacks the structural and molecular support necessary for neural circuit repair and as a consequence spontaneous regeneration through large CNS lesions does not occur. In the healthy CNS this structural and molecular support is usually provided by a diversity of glia.
Current projects related to this initiative:
I. Developing and testing immunomodulatory biomaterials to improve NPC graft survival and glia differentiation in CNS injury lesions.
II. Testing biomaterial based molecular delivery strategies to promote endogenous host glia repair of CNS injury lesions.
III. Developing biomaterial based strategies for enzymatic debridement and glia repair of chronic CNS injuries.
IV. Developing new biomaterials to improve sustained bioactive delivery of repair directing molecules to CNS injuries.
2. REGULATING THE BIOMATERIAL-NEURAL INTERFACE USING GLIA ENGINEERING
Our Approach: Using our bioengineering tools and standardized in vivo methods we: (i) study the functions of specific CNS glial cell types in the CNS foreign body response (FBR) to biomaterials, (ii) evaluate material properties that dominantly regulate FBR severity, and (iii) develop strategies that manipulate glia to minimize the FBR to CNS implant systems. We believe that developing bioengineering strategies that manipulate how glia perceive or respond to biomaterials/foreign bodies may be leveraged to develop better performing CNS implants.
Why is this important?: The implantation of neuroprostheses and other biomaterial-based devices (e.g. local drug delivery carriers or tissue engineering scaffolds) into the CNS initiates a foreign body response (FBR) that is unique to the CNS but mimics many characteristic features of the CNS wound response. We have developed an immunohistochemistry (IHC) based framework that permits the characterization of FBR to biomaterials in the CNS. The FBR to biomaterials in the CNS exists on a severity spectrum that is determined by definable biomaterial properties. We are beginning to understand how such biomaterial properties can be modified to minimize or evoke specific responses but much remains unstudied. A severe FBR can disrupt the long-term function of devices used in the CNS and represents a significant and current clinical problem across all neural interfacing fields. Since glia are principal actors in the orchestrated multicellular FBR to biomaterials we are targeting these cells for further study and manipulation.
3. TARGETED GLIA DRUG DELIVERY FOR CNS DISEASE
Our Approach: Using our bioengineering tools we develop and test non-viral strategies to deliver therapies preferentially to specific glia that may be used to mitigate dysfunctional cellular activities or address mutations that are responsible for disease.
Why is this important?: Glia dysfunction or mutations can lead to loss of healthy neural tissue function and cause disease. Identifiable glia dysfunction has been implicated in numerous CNS disorders including Huntington’s (HD), Parkinson’s, glioblastoma, neurodevelopmental and neurodegenerative diseases. Targeting drugs or gene therapies to dysfunctional glial cell populations in these CNS diseases in a clinically appropriate way will be important for furthering treatments. While viral vector-based delivery of therapeutics is used routinely in preclinical CNS models, numerous limitations of this technology exist. Additionally, various CNS tissue barriers present drug delivery challenges that remain to be addressed.