Project: Peripheral nerve injuries (PNIs) associated with prone positioning of patients with COVID-19-related ARDS

Lead lab members and collaborators: George R. Malik, Alexis R. Wolfe, Rachna Soriano, Leslie Rydberg,  Lisa F. Wolfe,  Swati Deshmukh, Jason H. Ko, Ryan P. Nussbaum, Prakash Jayabalan, James M. Walter, Colin K. Franz

1. Hospitals based in the United States have been incorporating prone positioning (PP) into the COVID-19-related ARDS treatment plan at a higher rate than normal. Our lab has seen a number of patients admitted to a single inpatient rehabilitation hospital who were subsequently diagnosed with acquired focal/multifocal peripheral nerve injury (PNI) in association with the use of PP for COVID-19-related ARDS. The reason for the high rate of PNI associated with PP in COVID-19 ARDS is likely multifactorial, but may include an underlying state of hyperinflammation and hypercoagulability already linked to other the neurological sequelae of COVID-19. We are also working with Dr John Rogers’ lab to place pressure sensors on vulnerable sites of patients at risk of these PNIs (such as the ulnar nerve at the elbow), to study the mechanics involved in acquiring these injuries.

Project: Novel tools for in vitro electrophysiology and neurotrauma modeling (R01NS113935)

Lead lab members: Kristen Cotton, Ally Togliatti, Dr. Colin Franz
Collaborators: Dr. John Finan lab, Dr. John Rogers lab, Yonggang Huang

1. Complex three-dimensional cultures, known as spheroids, organoids, and assembloids, have been developed to recreate structural features of human neuronal tissues in vitro not adequately modelled by two-dimensional cultures. The goal of this project to is to create new technology and techniques for studying electrophysiology and neurotrauma with three-dimensional cultures. This includes three-dimensional multi-electrode arrays, oxygen sensors, heaters, and LEDs. We use these in combination with our in-vitro three-dimensional neural cultures and devices to study neurotrauma and electrophysiological behavior in networked neurons.

Project: Modeling effects of common polymorphisms on peripheral nerve injury recovery using isogenic iPSCs

Lead lab members: Dr. Claire McGregor, Dr. Colin Franz
Collaborators: Dr John Rogers lab

1. Every year, over 200,000 Americans sustain a peripheral nerve injury (PNI). Although peripheral nerves have the ability to spontaneously regenerate, 90% of PNI patients do not regain full motor function. Despite ongoing research, the main treatment for peripheral nerve injury—surgery— continues to be performed without the assistance of any medication or other therapies to enhance the rate of axon regrowth. Moreover, genetic differences have been shown to alter regeneration after injury as well as attenuate response to experimental treatments, indicating the need to stratify clinical trials by patient genotypes. Our research aims to evaluate how common genetic differences alter regeneration after peripheral nerve injury as well as potential response to treatment. The brain derived neurotrophic factor (BDNF) Val66Met polymorphism affects approximately 30% of the American population, whereas the apolipoprotein E (ApoE) E4 isoform is present in approximately 14% of the population. In preclinical models, both of these genetic polymorphisms have resulted in altered regeneration after nerve injury. We use human isogenic stem cell models to study how these polymorphisms affect axon regeneration in iPSC-derived motoneurons. We also research how genetic differences alter the response to therapies for nerve regeneration such as electrical stimulation. We aim to find alternative treatments for this large proportion of the population who are not served by current treatment options. This research will further the understanding of how genetics alters response to treatment, with the goal of using precision medicine to optimize rehabilitative treatment strategies and outcomes.

Project: Electrical stimulation and Botox combination therapy to enhance peripheral nerve regeneration after injury.

Lead lab members: Dom D’Andrea, Dr. Colin Franz
Collaborators: Dr. John Rogers, Dr. Sue Jordan, Jie Zhao, Hexia Guo.

1. One-hour treatment of injured peripheral nerves with low-frequency electrical stimulation has been shown to enhance nerve recovery outcomes both in model organisms and in patients. Electrical stimulation mimics the calcium ion wave that propagates along a nerve at the time of injury, and hastens the axons’ ability to bridge the injury site and start the regeneration process. Our lab’s prior studies have also found that local treatment with Botox enhances nerve recovery in injured rodents, and increases in vitro neurite regrowth in cultured motor neurons. This project combines these treatments in an effort to optimize a therapeutic regimen more effective than either treatment would be alone, utilizing rodent models of nerve injury and a new bioresorbable implanted electrode to deliver both electric stimulation and drug therapy.

Project: Precision neurotrauma medicine with patient-derived iPSC-neurons to determine patient specific factors affecting clinical outcomes (Belle Carnell Regenerative Neurorehabilitation Fund)

Lead lab members: Ally Togliatti, Dr. Colin Franz

1. Neurological trauma to the central and peripheral nervous system, such as traumatic brain injury, spinal cord injury, or peripheral nerve injury, can leave a patient with debilitating symptoms and permanently altered functionality. Rehabilitation outcomes among this subset of patients vary dramatically, even among those with similar injuries. This variance presents an opportunity for therapeutic innovation: if the mechanisms of injury or repair in patients with good long-term outcomes were understood, it might be possible to reproduce them in other patients who currently endure poor outcomes. Therefore, this research project entails the deep clinical phenotyping and generation of thousands of unique induced pluripotent stem cell (iPSC) lines from neurotrauma patients who fall within the top or bottom quartile of inpatient rehabilitation outcomes based on ongoing chart review. The data uncovered in this study will allow us to better understand the individual patient factors affecting the recovery process after neurotrauma and hopefully empower us to predict and influence rehabilitation outcomes.

Project: Using bioactive graphene scaffolds for reconstructive tissue engineering

Lead lab members: Dr. Sue Jordan, Yasmine Bouricha, Dr. Colin Franz

The use of large-scale 3D-printed graphene-based scaffolds can help in the recovery of function in patients with volumetric muscle loss (VML) and denervation injury following a motor vehicle collision or a military blast injury. Volumetric muscle loss is permanent under most circumstances, as the lost muscle cannot be recovered by the resident stem cells, called muscle-derived stem/progenitor cellss (MDSPC). Patients with volumetric muscle loss often show a decrease in limb function, often with concurrent injury to nerves as well. This project, performed in collaboration between Dr. Sue Jordan and Dr Colin Franz, involves the small-scale co-culture of muscle cells and motor neurons on 3D-printed graphene scaffolds with the goal to grow mature, innervated muscle fiber that is responsive to neural signals and that can be ultimately used on a larger scale in patient treatment to replace volumetric muscle loss and re-introduce lost limb functionality.