Traumatic Brain Injury: Linking Macro- to Micro-Biomechanics

Traumatic Brain Injury (TBI) is unique from any other neurological disorder or disease in that it is induced by a physical event. Supra-threshold traumatic loading may cause structural damage ranging from overt tissue disruption to extremely subtle, subcellular damage. Such physical damage may directly precipitate secondary pathophysiology in addition to providing the context in which negative intracellular cascades unfold. This underscores the need to accurately represent tissue- and cellular-level injury biomechanics to fully describe clinical TBI as well as to develop and validate experimental models.

Our Approach: To understand Mechanisms and Consequences Of Neural Cellular “Pathological Mechanosensation” in TBI

We determine injury tolerance criteria based on acute biophysical disruptions and evolving neurodegeneration

We apply a multi-level approach including in vitro (2-D/3-D cell culture) and in vivo (rodent and porcine) models

Multi Level analysis

Goal: understand cell/tissue biomechanics to establish links between physical and physiological consequences of TBI

3-D In Vitro Model of TBIin vitro

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Movies

Volumetric reconstruction of a 3-D neuronal-astrocytic co-culture

Volumetric reconstruction of a 3-D neuronal-astrocytic co-culture after injury

Caption: Cell death and network degeneration following high strain rate deformation.

In Vivo Model of TBI

alterations in membranes

Accordingly, a major objective of the Cullen Lab is to link macro- to micro- brain injury biomechanics with acute cellular damage and evolving neuropathology across various experimental models of TBI. We have developed a unique experimental framework to establish the relationships between defined cell- and tissue-level biomechanical inputs and acute structural/biophysical alterations that may be responsible for neural cell death or persistent dysfunction. Attention to the injury biomechanics is important for establishing links between the physical and physiological consequences of TBI, thus facilitating the development of targeted medical therapeutics to address the predominantly afflicted cell populations based on the mechanisms of injury. 

micro to macro

Contact Information

D. Kacy Cullen, Ph.D
105E Hayden Hall, 3320 Smith Walk
Philadelphia, PA 19104
dkacy@mail.med.upenn.edu

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News and Events

  • Dr. John O’Donnell, a postdoctoral fellow in the Cullen Lab, was awarded a prestigious NRSA (F32) Training Fellowship through the NIH. His project is titled “Modeling Disorders of Consciousness”. Way to go John!
  • The Cullen Lab and collaborators had a poster selected as one of the "Blue Ribbon Highlights" at the International Congress of Parkinson's Disease and Movement Disorders in Vancouver, Canada. The poster was titled “Tissue Engineered Nigrostriatal Pathway for Treatment of Parkinson’s Disease”. A write-up about the project in Neurology Today can be found here.
  • Dr. Cullen and collaborators received a major 4-year Merit Review Award from the Department of Veterans Affairs to advance their project “Transplantable Micro-Tissue Engineered Neural Networks to Restore the Nigrostriatal Pathway in Parkinson's Disease”. This exciting project applies cutting-edge tissue engineering and regenerative medicine techniques to build the full nigrostriatal pathway in vitro using human induced pluripotent stem cells, with efficacy testing of these human-scale constructs in a large animal model of Parkinson’s disease. Success of this project over the next several years will enable clinical trials based on precision medicine– rebuilding complex brain networks using a patients own cells and implanting these fully preformed constructs to replace vulnerable pathways lost due to neurodegenerative disease. The co-investigators on this project are Dr. Isaac Chen, Dr. John Wolf, and Dr. John Duda. Way to go team!
  • Dr. Cullen was promoted to Associate Professor at the University of Pennsylvania. Congratulations Dr. Cullen!
  • Congratulations to Laura Struzyna, a Bioengineering Doctoral Candidate in the Cullen Lab, whose winning entry for Penn's "Art in Science" competition was featured on the NIH Director's Blog! https://directorsblog.nih.gov/2016/12/15/snapshots-of-life-wired-for-nerve-regeneration/#more-7232
  • The Cullen Lab and collaborators at Penn (Drs. Isaac Chen, Douglas Smith, and John Wolf) and Rutgers University (Drs. Joachim Kohn and Hilton Kaplan) were awarded a 3-year, $2.1 million dollar grant from the U.S. Dept. of Defense on "Tissue Engineering Strategies to Maintain Distal Target Efficacy and Promote Full Functional Recovery Following Major Peripheral Nerve Injury".
  • The Cullen Lab and collaborators had two abstracts selected as “Hot Topics” (top 2% of submissions) for presentation in a platform session at the World Parkinson’s Congress meeting in Portland, OR. Carolyn Keating, a Neuroscience doctoral candidate, presented "Diffuse Brain Injury in Swine Causes Plasmalemmal Dysruption and α-Synuclein Over-Expression in the Substantia Nigra". Dr. John Duda presented "Can Living Micro-Tissue Engineered Axonal Tracts Reconstruct the Nigrostriatal Pathway in PD?"
  • Dr. Cullen had the honor of being selected as one of "3 People to Watch in Neuroscience in 2016" by STAT News (Health, Medicine, and Biotech publication): https://www.statnews.com/2015/12/23/three-to-watch-brain-science/.
  • Congratulations to Laura Struzyna, a Bioengineering Doctoral Candidate in the Cullen Lab, who won second place in the Perelman School of Medicine 2016 "Art in Science" Competition. The winning image is shown here.
  • Penn and the Journal of Neural Engineering put out a press release for our most recent manuscript describing the Cullen Lab's novel micro-tissue engineered neural networks to restore brain circuitry. Link: http://www.uphs.upenn.edu/news/News_Releases/2016/01/cullen/
  • Carla Winter, and undergraduate researcher in the Cullen Lab for the past 3 years, was selected as a George J. Mitchell Scholar (one of only 12 in the U.S.): http://www.upenn.edu/pennnews/news/penn-students-phillip-cohen-and-carla-winter-named-george-j-mitchell-scholarsThis is very prestigious and well-deserved honor. Way to go Carla!
  • Dr. Cullen had the honor of giving a TED-style talk at Penn’s Annual Neuroscience Public Lecture Series on Neuroengineering: Where Biology Meets Technology. Dr. Cullen discussed the lab’s pioneering work on "Restoring Nervous System Structure and Function With Tissue Engineered 'Living Scaffolds'” (YouTube video: https://www.youtube.com/watch?v=Cl98Eb36lD4).
  • The Cullen Lab and collaborators Dr. John Wolf, Dr. Misha Serruya, Dr. Brain Litt, Dr. Reuben Kraft and Dr. Isaac Chen were awarded a 3-year, $2 million dollar cooperative agreement (U01) from the NIH to further pioneer "Biological 'Living Electrodes' Using Tissue Engineered Axonal Tracts to Probe and Modulate the CNS".
  • The Cullen Lab received a 2-year grant from the U.S. Dept. of Defense to advance "Novel Tissue-Engineered Nerve Grafts for Repair of Currently Untreatable Peripheral Nerve Injury".
  • Bioengineering Ph.D. Candidate, Kritika Katiyar, was selected for a prestigious NRSA F31 Graduate Research Fellowship through the National Institutes of Health based on her proposal for "Molecular Mediators of Axon-Facilitated Axon Regeneration."
  • Dayo Adewole, a Bioengineering Ph.D. student in the Cullen Lab, was awarded a 3-year Graduate Research Fellowship through the National Science Foundation to develop next-generation neuroprosthetic interfaces. Way to go Dayo!
  • The Cullen Lab and collaborators Dr. John Duda, Dr. Isaac Chen, and Dr. John Wolf were awarded a 2-year grant from the Michael J. Fox Foundation for the project "Restoring the Nigrostriatal Pathway with Living Micro-Tissue Engineered Axonal Tracts".

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