American Society for Peripheral Nerve

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Modulation of the Acute Inflammatory Process with Processed Umbilical Cord Membrane: Potential Applications for Management of Post-Traumatic Inflammation Mediated Neuritis
Kiri Hamaker, MS; Jason Park, MS; Mindy E Sadik, PhD; Ivica Ducic, MD PhD; Anne Engemann, PhD; Erick DeVinney, BS
AxoGen, Alachua, FL

Post-traumatic inflammation in and around the nerve can contribute to neuritis and both short and long-term nerve dysfunction. While inflammation is a natural part of the healing process, increases in local intraneural pressure caused by an inflammatory response can create an internal compression within nerve. This reduces blood supply, reduces axoplasmic flow and can lead to ischemia, demyelination, and impaired nerve function. This study aims to evaluate the immunomodulatory effect of an implantable membrane derived from human umbilical cord (UCM) through use of mitogen-stimulated human macrophage and peripheral blood mononuclear cell (PBMC) culture models. Immunomodulatory effect is determined in this study by evaluation of a panel of immune response factors, including changes in the polarization states of treated macrophages between classical M1 phenotype and alternative M2 phenotype, activity of key inflammatory enzyme: indoleamine 2,3-dioxygenase (IDO), and cellular secretion of extracellular cytokines as well as chemokines.

Materials & Methods
Human PBMCs and CD14+ monocytes were isolated from human peripheral blood donors. CD14+ monocytes matured into M0 macrophages. PBMCs and M0 macrophages were conditioned with UCM (AviveŽ Soft Tissue Membrane, AxoGen) derived extract stimulated with lipopolysaccharide (LPS), and evaluated for: CD14, CD68, CD80, CD86, CD163, CD200R, and TLR4 surface marker expression; intracellular Arginase-1 and inducible nitric oxide synthase (iNOS); extracellular kynurenine and tryptophan levels, as well as extracellular cytokine and chemokine levels.

M0 macrophages responses were examined for differences in subsequent M1/M2 polarization phenotype characteristics as well as differences in expression of immune-modulating enzymes such as IDO in preliminary tests. PBMCs in preliminary tests were evaluated for shifts in kynurenine/tryptophan ratio, as well as altered secretion responses of extracellular cytokines and chemokines such as NAP-2, Eotaxin-2, and ICAM-1.

Preliminary data suggests that umbilical cord derived membrane induced a concentration-dependent difference that was observed in immune enzyme activity as well as chemokine and cytokine secretion responses in mitogen-stimulated macrophage and PBMC cultures. Changes in kynurenine/tryptophan ratio in response to umbilical cord membrane suggests modulatory effects on the activity of the inflammatory enzyme IDO. Differences observed in the immune responses of human macrophage and PBMC cultures by conditioning with umbilical cord tissue suggests paracrine signaling effects on immune cell types including neutrophils, and that an overall anti-inflammatory effect can be seen. These effects may have the potential to modulate the local inflammatory response in the tissue bed, offering a novel option for the management of post-traumatic inflammation mediated neuritis.

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