Modification and transplantation of anisotropic capillary gels for directed axonal regeneration in the injured spinal cord

• Applicants: Professor Dr. Rainer Müller; Dr. Radhika Puttagunta, Ph.D.; Professor Dr. Norbert Weidner
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2014 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 264301521

Following a traumatic spinal cord injury (SCI), dramatic loss of tissue integrity prohibits axonal regeneration and target reinnervation. For successful functional recovery to occur, axonal growth must be initiated, guided and sustained across a newly formed lesion cavity and its surrounding scar tissue by introducing a permissive physical substrate to support target reinnervation with proper synapse formation. In our first funding cycle we were able to uniquely combine the use of alginate-based anisotropic capillary hydrogels (ACH) with Schwann cell (SC) seeding/transplantation and viral brain-derived neurotrophic factor (BDNF) delivery to successfully generate long-distance axonal growth into the ACH and re-entry into the host spinal cord. In this funding period we will examine in a modified – compared to the lesion proposed in the first funding period - low thoracic complete spinal cord transection the functional relevance of these structural changes in respect to locomotor and bladder function as well as maladaptive plasticity leading to neuropathic pain. To overcome some possible limitations in the extent of regrowth, neonatal astrocytes have begun to be explored as an alternative cell type to SC.Having previously focused on biological factors to improve ACH integration and the neuronal regenerative capacity, we will now modulate the inherent mechanical characteristics of the ACH - namely its viscoelasticity to augment more robust axon regrowth. We aim to develop stable ACH with differing viscoelasticities approaching that of the spinal cord. We will determine 1) the optimal ACH for inducing axonal growth potential in an ex vivo spinal slice culture model. 2) Moving in vivo to a spinal cord lesion, we will explore the potential of these new ACH candidates to limit the host’s response such as inflammation, scar and cyst formation as well as enhance tissue and mechanical continuity, ultimately further enhancing axonal re-entry into the host spinal cord, long distance outgrowth and functional recovery as a structural prerequisite to promote recovery in injury sites remote from neuronal target regions.

• DFG Programme: Research Grants
• Major Instrumentation: Atomic force microscope
• Instrumentation Group: 5091 Rasterkraft-Mikroskope