Publications by authors named "D Kacy Cullen"

665 Publications

Neuroimmune Interactions and Immunoengineering Strategies in Peripheral Nerve Repair.

Prog Neurobiol 2021 Sep 4:102172. Epub 2021 Sep 4.

Center for Brain Injury & Repair, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, 19104, United States; Center for Neurotrauma, Neurodegeneration and Restoration, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, 19104, United States; Axonova Medical, LLC, Philadelphia, PA, 19104, United States; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, United States. Electronic address:

Peripheral nerve injuries result in disrupted cellular communication between the central nervous system and somatic distal end targets. The peripheral nervous system is capable of independent and extensive regeneration; however, meaningful target muscle reinnervation and functional recovery remain limited and may result in chronic neuropathic pain and diminished quality of life. Macrophages, the primary innate immune cells of the body, are critical contributors to regeneration of the injured peripheral nervous system. However, in some clinical scenarios, macrophages may fail to provide adequate support with optimal timing, duration, and location. Here, we review the history of immunosuppressive and immunomodulatory strategies to treat nerve injuries. Thereafter, we enumerate the ways in which macrophages contribute to successful nerve regeneration. We argue that implementing macrophage-based immunomodulatory therapies is a promising treatment strategy for nerve injuries across a wide range of clinical presentations.
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http://dx.doi.org/10.1016/j.pneurobio.2021.102172DOI Listing
September 2021

Perioperative Stroke: Comment.

Anesthesiology 2021 10;135(4):761-762

Harvard Medical School at Massachusetts General Hospital, Boston, Massachusetts; and St. Elizabeth's Medical Center and Tufts University School of Medicine, Boston, Massachusetts.

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http://dx.doi.org/10.1097/ALN.0000000000003919DOI Listing
October 2021

Biopreservation of living tissue engineered nerve grafts.

J Tissue Eng 2021 Jan-Dec;12:20417314211032488. Epub 2021 Aug 11.

Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA.

Tissue engineered nerve grafts (TENGs) built from living neurons and aligned axon tracts offer a revolutionary new approach as "living scaffolds" to bridge major peripheral nerve defects. Clinical application, however, necessitates sufficient shelf-life to allow for shipping from manufacturing facility to clinic as well as storage until use. Here, hypothermic storage in commercially available hibernation media is explored as a potential biopreservation strategy for TENGs. After up to 28 days of refrigeration at 4℃, TENGs maintain viability and structure . Following transplantation into 1 cm rat sciatic defects, biopreserved TENGs routinely survive and persist for at least 2 weeks and recapitulate pro-regenerative mechanisms of fresh TENGs, including the ability to recruit regenerating host tissue into the graft and extend neurites beyond the margins of the graft. The protocols and timelines established here serve as important foundational work for the manufacturing, storage, and translation of other neuron-based tissue engineered therapeutics.
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http://dx.doi.org/10.1177/20417314211032488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361542PMC
August 2021

Restoring lost nigrostriatal fibers in Parkinson's disease based on clinically-inspired design criteria.

Brain Res Bull 2021 Oct 28;175:168-185. Epub 2021 Jul 28.

Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, United States; Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael Crescenz Veterans Affairs Medical Center, Philadelphia, PA, United States. Electronic address:

Parkinson's disease is a neurodegenerative disease affecting around 10 million people worldwide. The death of dopaminergic neurons in the substantia nigra and the axonal fibers that constitute the nigrostriatal pathway leads to a loss of dopamine in the striatum that causes the motor symptoms of this disease. Traditional treatments have focused on reducing symptoms, while therapies with human fetal or stem cell-derived neurons have centered on implanting these cells in the striatum to restore its innervation. An alternative approach is pathway reconstruction, which aims to rebuild the entire structure of neurons and axonal fibers of the nigrostriatal pathway in a way that matches its anatomy and physiology. This type of repair could be more capable of reestablishing the signaling mechanisms that ensure proper dopamine release in the striatum and regulation of other motor circuit regions in the brain. In this manuscript, we conduct a review of the literature related to pathway reconstruction as a treatment for Parkinson's disease, delve into the limitations of these studies, and propose the requisite design criteria to achieve this goal at a human scale. We then present our tissue engineering-based platform to fabricate hydrogel-encased dopaminergic axon tracts in vitro for later implantation into the brain to replace and reconstruct the pathway. These tissue-engineered nigrostriatal pathways (TE-NSPs) can be characterized and optimized for cell number and phenotype, axon growth lengths and rates, and the capacity for synaptic connectivity and dopamine release. We then show original data of advances in creating these constructs matching clinical design criteria using human iPSC-derived dopaminergic neurons and a hyaluronic acid hydrogel. We conclude with a discussion of future steps that are needed to further optimize human-scale TE-NSPs and translate them into clinical products.
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http://dx.doi.org/10.1016/j.brainresbull.2021.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404430PMC
October 2021
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