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Sarah Mayes Project Presentation / Literature Review March 9, 2009 Schmidt Lab

IMMUNOMODULATION OF ACUTE EXPERIMENTAL SPINAL CORD INJURY WITH LAMININ / HA THERMORESPONSIVE GEL ENHANCED WITH GMHA FILM. Sarah Mayes Project Presentation / Literature Review March 9, 2009 Schmidt Lab. Outline. Motivation Literature Review Hypothesis Project Overview Curiosities.

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Sarah Mayes Project Presentation / Literature Review March 9, 2009 Schmidt Lab

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  1. IMMUNOMODULATION OF ACUTE EXPERIMENTAL SPINAL CORD INJURY WITH LAMININ / HA THERMORESPONSIVE GEL ENHANCED WITH GMHA FILM Sarah Mayes Project Presentation / Literature Review March 9, 2009 Schmidt Lab

  2. Outline • Motivation • Literature Review • Hypothesis • Project Overview • Curiosities

  3. Motivation (part 1): spinal cord injuries • 7800 injuries in the US each year (an additional 4860 do not make it to hospital) 1 • 250,000 - 400,000 individuals living with Spinal Cord Injury or Spinal Dysfunction 1 • Highest per capita rate of injury occurs between ages 16-30 (most frequent age is 19) 2 • 45% of all injuries have been complete, 55% incomplete. 2 • Only 43% of injured individuals have private insurance, 10% worker’s comp • Total Cost for 675 patients for FY2005 = $14.47 million 3

  4. a new paradigm for local and sustained release of therapeutic molecules to the injured spinal cord for neuroprotection and tissue repair (Kang et al. Tissue engineering. 2008) • Literature Review

  5. Overview of Study • in vivo • contusion spinal cord injury model • comparison of 3 methods: 1 novel, 2 conventional (bolus local injection and IP administration) • novel method: HAMC with EPO injected into IT space • functional assessment via BBB • histology assessment via general morphology and cavity space area • Hypothesis: Novel method will provide 1) greater neuron count in injured area, 2) white matter sparing leading to a reduction in demyelination and thus an increase in oligodendrocytes, and 3) a reduction in inflammatory response which should lead to an improvement in functional ability.

  6. Experimental Design Sprague-Dawley rats of 200 - 300 g

  7. Results of HAMC degradation study and in vitro epo release • HA degraded quickly, exhibiting a 95% loss in fluorescent area after 24 h. • In contrast, MC showed an initial degradation of 65% after 24 h and then continued to persist within the IT space for at least 4 days. • After 7 days, traces of neither HA nor MC could be detected • Diffusion-mediated EPO release within 16 hours MC HA EPO

  8. Results Maximal cavity area only significant difference between HAMC/EPO and HAMC No long-term improvement in functionality No significant difference in inflammatory response Neuron count significant difference between novel method and traditional methods response measured with ED-1 staining of macrophages and microglia

  9. Implications • Novel delivery of HAMC/EPO through IT injection has positive effects on neural growth via an increased neural count compared to conventional methods of drug delivery • Shown trend in decrease of cavity area compared to conventional methods of drug delivery • Clinically relevant method for drug delivery with quick drug release timing and fast degradation with minimal immune response (to biomaterials)

  10. Issues • This novel approach has not shown to reduce secondary immune response to SCI • Is 16 hrs clinically relevant for drug delivery for SCI? • Is 24 hr degradation clinically relevant for tissue repair in SCI? • Method was not tested with time delay from injury which reduces clinical relevance • No improvement in functionality

  11. Re-evalution of Impact

  12. Hypothesis • What is the question? • What biomaterial(s) can be employed to an injured spinal cord that would a) immunomodulate the innate inflammatory response to the injury, b) minimize or eliminate an immune response to the biomaterials, and c) promote healthy nerve growth into injured area? • Answer? • A thermoresponsive gel / semi-interpenetrating network of laminin and HA placed into the injured spinal cord with a GMHA film enclosing the gel from CSF may provide an immunomodulatory strategy to alleviate cell inflammatory processes that inhibit nerve growth, and to favor recovery processes

  13. Schematic + Laminin / HA gel HA Laminin GMHA film Injured spinal cord (hemisection model shown)

  14. Laminin vs. Methyl Cellulose Hyaluronic acid is a naturally derived, nonimmunogenic, nonadhesive glycosaminoglycan that plays a prominent role in various wound-healing processes, as it is naturally angiogenic when degraded to small fragments (Chen and Abatangelo, 1999)

  15. GMHA

  16. Project Plan

  17. Curiosities • Why wouldn’t the microglia and macrophages attack areas not covered by GMHA? • How is the GMHA going to remain on top of the gel? Is there an adhesive? • What about testing various time of laminectomy post injury? • What if the laminin and GMHA simply counteract each other? How to account for that? • How would we approach a contusion model? • What control do we have over crosslinking of laminin / HA?

  18. Thank you • Erin Moffitt • Zin Khaing • Scott Zawko • Shalu Suri • Christine Schmidt

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