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1. Prosaposin maintains lipid homeostasis in dopamine neurons and counteracts experimental parkinsonism in rodents

Author

Yachao He, Ibrahim Kaya, Reza Shariatgorji, Johan Lundkvist, Lars U. Wahlberg, Anna Nilsson, Dejan Mamula, Jan Kehr, Justyna Zareba-Paslawska, Henrik Biverstål, Karima Chergui, Xiaoqun Zhang, Per E. Andren, and Per Svenningsson

Subjects
Science
Abstract

Abstract Prosaposin (PSAP) modulates glycosphingolipid metabolism and variants have been linked to Parkinson’s disease (PD). Here, we find altered PSAP levels in the plasma, CSF and post-mortem brain of PD patients. Altered plasma and CSF PSAP levels correlate with PD-related motor impairments. Dopaminergic PSAP-deficient (cPSAPDAT) mice display hypolocomotion and depression/anxiety-like symptoms with mildly impaired dopaminergic neurotransmission, while serotonergic PSAP-deficient (cPSAPSERT) mice behave normally. Spatial lipidomics revealed an accumulation of highly unsaturated and shortened lipids and reduction of sphingolipids throughout the brains of cPSAPDAT mice. The overexpression of α-synuclein via AAV lead to more severe dopaminergic degeneration and higher p-Ser129 α-synuclein levels in cPSAPDAT mice compared to WT mice. Overexpression of PSAP via AAV and encapsulated cell biodelivery protected against 6-OHDA and α-synuclein toxicity in wild-type rodents. Thus, these findings suggest PSAP may maintain dopaminergic lipid homeostasis, which is dysregulated in PD, and counteract experimental parkinsonism.

Published
2023
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2. Feasibility and therapeutical potential of local intracerebral encapsulated cell biodelivery of BDNF to App NL−G−F knock-in Alzheimer mice

Author

Simone Tambaro, Sumonto Mitra, Ruchi Gera, Bengt Linderoth, Lars U. Wahlberg, Taher Darreh-Shori, Homira Behbahani, Per Nilsson, and Maria Eriksdotter

Subjects
Encapsulated cell biodelivery (ECB), Brain-derived neurotrophic factor (BDNF), Alzheimer’s disease (AD), App NL−G−F knock-in mice, Therapy, Drug delivery, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Alzheimer’s disease (AD) is an age-related disease characterized by altered cognition, neuroinflammation, and neurodegeneration against which there is presently no effective cure. Brain-derived neurotrophic factor (BDNF) is a key neurotrophin involved in the learning and memory process, with a crucial role in synaptic plasticity and neuronal survival. Several findings support that a reduced BDNF expression in the human brain is associated with AD pathogenesis. BDNF has been proposed as a potential therapy for AD, but BDNF has low brain penetration. In this study, we used an innovative encapsulated cell biodelivery (ECB) device, containing genetically modified cells capable of releasing BDNF and characterized its feasibility and therapeutic effects in the novel App knock-in AD mouse model (App NL−G−F ). Methods ECB’s containing human ARPE-19 cells genetically modified to release BDNF (ECB-BDNF devices) were stereotactically implanted bilaterally into hippocampus of 3-month-old App NL−G−F mice. The stability of BDNF release and its effect on AD pathology were evaluated after 1, 2-, and 4-months post-implantation by immunohistochemical and biochemical analyses. Exploratory and memory performance using elevated plus maze (EPM) and Y-maze test were performed in the 4-months treatment group. Immunological reaction towards ECB-BDNF devices were studied under ex vivo and in vivo settings. Results The surgery and the ECB-BDNF implants were well tolerated without any signs of unwanted side effects or weight loss. ECB-BDNF devices did not induce host-mediated immune response under ex vivo set-up but showed reduced immune cell attachment when explanted 4-months post-implantation. Elevated BDNF staining around ECB-BDNF device proximity was detected after 1, 2, and 4 months treatment, but the retrieved devices showed variable BDNF release. A reduction of amyloid-β (Aβ) plaque deposition was observed around ECB-BDNF device proximity after 2-months of BDNF delivery. Conclusions The result of this study supports the use of ECB device as a promising drug-delivery approach to locally administer BBB-impermeable factors for treating neurodegenerative conditions like AD. Optimization of the mouse-sized devices to reduce variability of BDNF release is needed to employ the ECB platform in future pre-clinical research and therapy development studies.

Published
2023
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3. The cholinergic system in subtypes of Alzheimer’s disease: an in vivo longitudinal MRI study

Author

Alejandra Machado, Daniel Ferreira, Michel J. Grothe, Helga Eyjolfsdottir, Per M. Almqvist, Lena Cavallin, Göran Lind, Bengt Linderoth, Åke Seiger, Stefan Teipel, Lars U. Wahlberg, Lars-Olof Wahlund, Eric Westman, Maria Eriksdotter, and for the Alzheimer’s Disease Neuroimaging Initiative

Subjects
Basal forebrain, Alzheimer’s disease, Heterogeneity, Subtypes, Structural MRI, Nerve growth factor, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background The heterogeneity within Alzheimer’s disease (AD) seriously challenges the development of disease-modifying treatments. We investigated volume of the basal forebrain, hippocampus, and precuneus in atrophy subtypes of AD and explored the relevance of subtype stratification in a small clinical trial on encapsulated cell biodelivery (ECB) of nerve growth factor (NGF) to the basal forebrain. Methods Structural MRI data was collected for 90 amyloid-positive patients and 69 amyloid-negative healthy controls at baseline, 6-, 12-, and 24-month follow-up. The effect of the NGF treatment was investigated in 10 biopsy-verified AD patients with structural MRI data at baseline and at 6- or 12-month follow-up. Patients were classified as typical, limbic-predominant, hippocampal-sparing, or minimal atrophy AD, using a validated visual assessment method. Volumetric analyses were performed using a region-of-interest approach. Results All AD subtypes showed reduced basal forebrain volume as compared with the healthy controls. The limbic-predominant subtype showed the fastest basal forebrain atrophy rate, whereas the minimal atrophy subtype did not show any significant volume decline over time. Atrophy rates of the hippocampus and precuneus also differed across subtypes. Our preliminary data from the small NGF cohort suggest that the NGF treatment seemed to slow the rate of atrophy in the precuneus and hippocampus in some hippocampal-sparing AD patients and in one typical AD patient. Conclusions The cholinergic system is differentially affected in distinct atrophy subtypes of AD. Larger studies in the future should confirm that this differential involvement of the cholinergic system may contribute to subtype-specific response to cholinergic treatment. Our preliminary findings suggest that future clinical trials should target specific subtypes of AD, or at least report treatment effects stratified by subtype. Trial registration ClinicalTrials.gov identifier: NCT01163825 . Registered 14 July 2010.

Published
2020
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4. Long-term, stable, targeted biodelivery and efficacy of GDNF from encapsulated cells in the rat and Goettingen miniature pig brain

Author

Lars U. Wahlberg, Dwaine F. Emerich, Jeffrey H. Kordower, William Bell, Tracie Fradet, and Giovanna Paolone

Subjects
Encapsulation, GDNF, Neuroprotection, Neuroregeneration, Therapeutics. Pharmacology, RM1-950
Abstract

Delivering glial cell line-derived neurotrophic factor (GDNF) to the brain is a potential treatment for Parkinson's Disease (PD). Here we use an implantable encapsulated cell technology that uses modified human clonal ARPE-19 ​cells to deliver of GDNF to the brain. In vivo studies demonstrated sustained delivery of GDNF to the rat striatum over 6 months. Anatomical benefits and behavioral efficacy were shown in 6-OHDA lesioned rats where nigral dopaminergic neurons were preserved in neuroprotection studies and dopaminergic fibers were restored in neurorecovery studies. When larger, clinical-sized devices were implanted for 3 months into the putamen of Göttingen minipigs, GDNF was widely distributed throughout the putamen and caudate producing a significant upregulation of tyrosine hydroxylase immunohistochemistry. These results are the first to provide clear evidence that implantation of encapsulated GDNF-secreting cells deliver efficacious and biologically relevant amounts of GDNF in a sustained and targeted manner that is scalable to treat the large putamen in patients with Parkinson's disease.

Published
2020
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5. Where Dopaminergic and Cholinergic Systems Interact: A Gateway for Tuning Neurodegenerative Disorders

Author

Marianne Amalric, Tommy Pattij, Ioannis Sotiropoulos, Joana M. Silva, Nuno Sousa, Samira Ztaou, Cristiano Chiamulera, Lars U. Wahlberg, Dwaine F. Emerich, and Giovanna Paolone

Subjects
acetylcholine, dopamine, Alzheimer’s and Parkinson’s disease, impulse control, encapsulated cell-based system, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Historically, many investigations into neurodegenerative diseases have focused on alterations in specific neuronal populations such as, for example, the loss of midbrain dopaminergic neurons in Parkinson’s disease (PD) and loss of cholinergic transmission in Alzheimer’s disease (AD). However, it has become increasingly clear that mammalian brain activities, from executive and motor functioning to memory and emotional responses, are strictly regulated by the integrity of multiple interdependent neuronal circuits. Among subcortical structures, the dopaminergic nigrostriatal and mesolimbic pathways as well as cholinergic innervation from basal forebrain and brainstem, play pivotal roles in orchestrating cognitive and non-cognitive symptoms in PD and AD. Understanding the functional interactions of these circuits and the consequent neurological changes that occur during degeneration provides new opportunities to understand the fundamental inter-workings of the human brain as well as develop new potential treatments for patients with dysfunctional neuronal circuits. Here, excerpted from a session of the European Behavioral Pharmacology Society meeting (Braga, Portugal, August 2019), we provide an update on our recent work in behavioral and cellular neuroscience that primarily focuses on interactions between cholinergic and dopaminergic systems in PD models, as well as stress in AD. These brief discussions include descriptions of (1) striatal cholinergic interneurons (CINs) and PD, (2) dopaminergic and cholinergic modulation of impulse control, and (3) the use of an implantable cell-based system for drug delivery directly the into brain and (4) the mechanisms through which day life stress, a risk factor for AD, damage protein and RNA homeostasis leading to AD neuronal malfunction.

Published
2021
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6. Seizure-Suppressant and Neuroprotective Effects of Encapsulated BDNF-Producing Cells in a Rat Model of Temporal Lobe Epilepsy

Author

Chiara Falcicchia, Giovanna Paolone, Dwaine F. Emerich, Francesca Lovisari, William J. Bell, Tracie Fradet, Lars U. Wahlberg, and Michele Simonato

Subjects
Genetics, QH426-470, Cytology, QH573-671
Abstract

Brain-derived neurotrophic factor (BDNF) may represent a therapeutic for chronic epilepsy, but evaluating its potential is complicated by difficulties in its delivery to the brain. Here, we describe the effects on epileptic seizures of encapsulated cell biodelivery (ECB) devices filled with genetically modified human cells engineered to release BDNF. These devices, implanted into the hippocampus of pilocarpine-treated rats, highly decreased the frequency of spontaneous seizures by more than 80%. These benefits were associated with improved cognitive performance, as epileptic rats treated with BDNF performed significantly better on a novel object recognition test. Importantly, long-term BDNF delivery did not alter normal behaviors such as general activity or sleep/wake patterns. Detailed immunohistochemical analyses revealed that the neurological benefits of BDNF were associated with several anatomical changes, including reduction in degenerating cells and normalization of hippocampal volume, neuronal counts (including parvalbumin-positive interneurons), and neurogenesis. In conclusion, the present data suggest that BDNF, when continuously released in the epileptic hippocampus, reduces the frequency of generalized seizures, improves cognitive performance, and reverts many histological alterations associated with chronic epilepsy. Thus, ECB device-mediated long-term supplementation of BDNF in the epileptic tissue may represent a valid therapeutic strategy against epilepsy and some of its co-morbidities. Keywords: BDNF, ECB devices, hippocampus, epilepsy, neurogenesis, cell encapsulation

Published
2018
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7. Amyloid-Beta Peptides and Activated Astroglia Impairs Proliferation of Nerve Growth Factor Releasing Cells In Vitro: Implication for Encapsulated Cell Biodelivery-Mediated AD Therapy

Author

Sumonto Mitra, Silvia Turchetto, Winant Van Os, Lars U. Wahlberg, Bengt Linderoth, Homira Behbahani, and Maria Eriksdotter

Subjects
Alzheimer’s disease (AD), astrocytes, amyloid beta (Aβ), encapsulated cell biodelivery (ECB), nerve growth factor (NGF), drug delivery strategy optimization, Cytology, QH573-671
Abstract

Alzheimer’s disease (AD) treatment is constrained due to the inability of peripherally administered therapeutic molecules to cross the blood–brain barrier. Encapsulated cell biodelivery (ECB) devices, a tissue-targeted approach for local drug release, was previously optimized for human mature nerve growth factor (hmNGF) delivery in AD patients but was found to have reduced hmNGF release over time. To understand the reason behind reduced ECB efficacy, we exposed hmNGF-releasing cells (NGC0211) in vitro to human cerebrospinal fluid (CSF) obtained from Subjective Cognitive Impairment (SCI), Lewy Body Dementia (LBD), and AD patients. Subsequently, we exposed NGC0211 cells directly to AD-related factors like amyloid-β peptides (Aβ40/42) or activated astrocyte-conditioned medium (Aβ40/42/IL-1β/TNFα-treated) and evaluated biochemical stress markers, cell death indicators, cell proliferation marker (Ki67), and hmNGF release. We found that all patients’ CSF significantly reduced hmNGF release from NGC0211 cells in vitro. Aβ40/42, inflammatory molecules, and activated astrocytes significantly affected NGC0211 cell proliferation without altering hmNGF release or other parameters important for essential functions of the NGC0211 cells. Long-term constant cell proliferation within the ECB device is critically important to maintain a steady cell population needed for stable mNGF release. These data show hampered proliferation of NGC0211 cells, which may lead to a decline of the NGC0211 cell population in ECBs, thereby reducing hmNGF release. Our study highlights the need for future studies to strengthen ECB-mediated long-term drug delivery approaches.

Published
2021
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8. Widespread Striatal Delivery of GDNF from Encapsulated Cells Prevents the Anatomical and Functional Consequences of Excitotoxicity

Author

Dwaine F. Emerich, Jeffrey H. Kordower, Yaping Chu, Chris Thanos, Briannan Bintz, Giovanna Paolone, and Lars U. Wahlberg

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Methods. Human ARPE-19 cells engineered to secrete high levels of the glial cell line-derived neurotrophic factor (GDNF) were encapsulated into hollow fiber membranes. The devices were implanted into the rat striatum 1 week prior to striatal quinolinic acid injections. Animals were evaluated using a battery of validated motor tests, and histology was performed to determine the extent of GDNF diffusion and associated prevention of neuronal cell loss and behavioral deficits. Results. Encapsulated cell-based delivery of GDNF produced widespread distribution of GDNF throughout the entire implanted striatum. Stereological estimates of striatal neuron number and volume of lesion size revealed that GDNF delivery resulted in near complete neuroprotection. Conclusions. Delivery of neurotrophic molecules such as GDNF using encapsulated cells has reached a technological point where clinical evaluation is justified. Because GDNF has been effective in animal models of Parkinson’s disease, stroke, epilepsy, and Huntington’s disease, among other debilitating neurodegenerative diseases, encapsulated cell-based delivery of GDNF might represent one innovative means of slowing the neural degeneration seen in a myriad of currently untreatable neurological diseases.

Published
2019
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9. Lentiviral delivery of Meteorin protects striatal neurons against excitotoxicity and reverses motor deficits in the quinolinic acid rat model

Author

Jesper Roland Jørgensen, Dwaine F. Emerich, Chris Thanos, Lachlan H. Thompson, Malene Torp, Briannan Bintz, Lone Fjord-Larsen, Teit E. Johansen, and Lars U. Wahlberg

Subjects
Neuroprotection, Excitotoxicity, Neurotrophic factor, Huntington's Disease, Gene therapy, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Meteorin is a newly discovered secreted protein involved in both glial and neuronal cell differentiation, as well as in cerebral angiogenesis during development; but effects in the adult nervous system are unknown. The growth factor-like properties and expression of Meteorin during the development of the nervous system raises the possibility that it might possess important neuroprotective or regenerative capabilities. This report is the first demonstration that Meteorin has potent neuroprotective effects in vivo. Lentiviral-mediated striatal delivery of Meteorin to rats two weeks prior to injections of quinolinic acid (QA) dramatically reduced the loss of striatal neurons. The cellular protection afforded by Meteorin was associated with normalization of neurological performance on spontaneous forelimb placing and cylinder behavioral tests and a complete protection against QA-induced weight loss. These benefits were comparable in magnitude to those obtained with lentiviral-mediated delivery of ciliary neurotrophic factor (CNTF), a protein with known neuroprotective properties in the same model system. In naive animals, endogenous levels of both Meteorin and CNTF were increased in glial cells in response to QA lesion indicating that Meteorin may exert its protective effects as part of the reactive gliosis cascade in the injured brain. In summary, these data demonstrate that Meteorin strongly protects striatal neurons and deserves additional evaluation as a novel therapeutic for the treatment of neurological disorders with an excitotoxic component such as Huntington's Disease.

Published
2011
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10. Tuneable Recombinant Spider Silk Protein Hydrogels for Drug Release and 3D Cell Culture

Author

Tina Arndt, Urmimala Chatterjee, Olga Shilkova, Juanita Francis, Johan Lundkvist, Daniel Johansson, Benjamin Schmuck, Gabriele Greco, Åsa Ekblad Nordberg, Yan Li, Lars U Wahlberg, Maud Langton, Jan Johansson, Cecilia Götherström, and Anna Rising

Subjects
Biomaterials, Electrochemistry, Condensed Matter Physics, Electronic, Optical and Magnetic Materials
Published
2023
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11. Amyloid-beta peptides and activated astroglia impairs proliferation of nerve growth factor releasing cells in vitro

Author

Sumonto, Mitra, Silvia, Turchetto, Winant, Van Os, Lars U, Wahlberg, Bengt, Linderoth, Homira, Behbahani, and Maria, Eriksdotter

Subjects
Lewy Body Disease, Amyloid beta-Peptides, QH301-705.5, astrocytes, Alzheimer’s disease (AD), encapsulated cell biodelivery (ECB), drug delivery strategy optimization, Cells, Immobilized, Article, nerve growth factor (NGF), Cell Line, Alzheimer Disease, Stress, Physiological, inflammation, Culture Media, Conditioned, amyloid beta (Aβ), Nerve Growth Factor, Humans, Cognitive Dysfunction, Biology (General), Peptides, Cell Proliferation
Abstract

Alzheimer’s disease (AD) treatment is constrained due to the inability of peripherally administered therapeutic molecules to cross the blood–brain barrier. Encapsulated cell biodelivery (ECB) devices, a tissue-targeted approach for local drug release, was previously optimized for human mature nerve growth factor (hmNGF) delivery in AD patients but was found to have reduced hmNGF release over time. To understand the reason behind reduced ECB efficacy, we exposed hmNGF-releasing cells (NGC0211) in vitro to human cerebrospinal fluid (CSF) obtained from Subjective Cognitive Impairment (SCI), Lewy Body Dementia (LBD), and AD patients. Subsequently, we exposed NGC0211 cells directly to AD-related factors like amyloid-β peptides (Aβ40/42) or activated astrocyte-conditioned medium (Aβ40/42/IL-1β/TNFα-treated) and evaluated biochemical stress markers, cell death indicators, cell proliferation marker (Ki67), and hmNGF release. We found that all patients’ CSF significantly reduced hmNGF release from NGC0211 cells in vitro. Aβ40/42, inflammatory molecules, and activated astrocytes significantly affected NGC0211 cell proliferation without altering hmNGF release or other parameters important for essential functions of the NGC0211 cells. Long-term constant cell proliferation within the ECB device is critically important to maintain a steady cell population needed for stable mNGF release. These data show hampered proliferation of NGC0211 cells, which may lead to a decline of the NGC0211 cell population in ECBs, thereby reducing hmNGF release. Our study highlights the need for future studies to strengthen ECB-mediated long-term drug delivery approaches.

Published
2021

12. List of contributors

Author

Masashi Abe, Jon D. Ahlstrom, Julie Albon, Julie Allickson, Graça Almeida-Porada, Richard A. Altschuler, Daniel G. Anderson, Nasim Annabi, Judith Arcidiacono, Nureddin Ashammakhi, Anthony Atala, Kyriacos A. Athanasiou, Hani A. Awad, Stephen F Badylak, Gowri Balachander, Wayne Balkan, Jennifer J. Bara, Michael P. Barry, Harihara Baskaran, Matthew L. Bedell, Donald Andrew Belcher, David B. Berry, Hina Bhat, Zuhaib F. Bhat, Sangeeta N. Bhatia, Catherine Clare Blackburn, Anna Blocki, Kevin M. Blum, Matthew A. Bochenek, Lawrence J. Bonassar, Joseph V. Bonventre, Mimi R. Borrelli, Robby D. Bowles, Amy D. Bradshaw, Andres M. Bratt-Leal, Christopher K. Breuer, Luke Brewster, Eric M. Brey, Priscilla S. Briquez, J.A. Buckwalter, Karen J.L. Burg, Timothy C. Burg, Batzaya Byambaa, Prafulla K. Chandra, Amanda X. Chen, Fa-Ming Chen, Shaochen Chen, Julian Chesterman, Arnav Chhabra, Seow Khoon Chong, Richard A.F. Clark, Muriel A. Cleary, M. Coleman, George Cotsarelis, Ronald G. Crystal, Gislin Dagnelie, Mohammad Ali Darabi, Jeffrey M. Davidson, Joseph Davidson, Paolo De Coppi, Derfogail Delcassian, Paul de Vos, Anthony Dominijanni, Ryan Donahue, Allison P. Drain, Craig L. Duvall, Jenna L. Dziki, Abdelmotagaly Elgalad, George Eng, Vincent Falanga, Niloofar Farhang, Lino Ferreira, Donald W. Fink, Heather E. Fleming, Peter Fong, Mark R. Frey, Denise Gay, Sharon Gerecht, Charles A. Gersbach, D.M.R. Gibbs, Simran Gidwani, Shaimar R. González Morales, Ritu Goyal, Maria B. Grant, Andrea Gray, Howard P. Greisler, Tracy C. Grikscheit, Karl Grosh, Farshid Guilak, Jason L. Guo, Yingli Han, Joshua M. Hare, Ammar Mansoor Hassanbhai, Konstantinos Hatzistergos, David C. Hay, Xiao-Tao He, Timothy Henderson, Darren Hickerson, Darren H.M. Hickerson, Abdelkrim Hmadcha, Camila Hochman-Mendez, Chao Huang, Jeffrey A. Hubbell, Joern Huelsmann, Jun Tae Huh, Joshua G. Hunsberger, Leanne E. Iannucci, Haruhisa Inoue, John Jackson, Yangzi Jiang, Vladimir V. Kalinichenko, J.M. Kanczler, Jeffrey M. Karp, F. Kurtis Kasper, Ali Khademhosseini, Ji Hyun Kim, Erin A. Kimbrel, Irina Klimanskaya, Joachim Kohn, Sunil Kumar, Themis R. Kyriakides, Spencer P. Lake, Johnny Lam, Robert Langer, Robert Lanza, Timothy S. Leach, Benjamin W. Lee, Iris Lee, Sang Jin Lee, David Li, Linheng Li, Qian Liu, Alexander V. Ljubimov, Chi Lo, Michael T. Longaker, Javier López-Beas, Jeanne F. Loring, Ying Luo, Ben D. MacArthur, Nicolas N. Madigan, Henning Madry, Renata S. Magalhaes, Nancy Ruth Manley, Jonathan Mansbridge, Jeremy J. Mao, K.M. Marshall, J.A. Martin, M. Martins-Green, Kathryn M. Maselli, Mark W. Maxfield, Kyle W. McCracken, James Melville, Antonios G. Mikos, José del R. Millán, Maria Mirotsou, Daniel T. Montoro, Matthew P. Murphy, Sean V. Murphy, Michael Musillo, Padmalosini Muthukumaran, Adam M. Navara, Christopher E. Nelson, Laura E. Niklason, Craig Scott Nowell, Regis J. O’Keefe, Kathy E. O’Neill, Richard O.C. Oreffo, Ophir Ortiz, Andre Francis Palmer, Serafeim Perdikis, M. Petreaca, Maksim V. Plikus, Christopher D. Porada, Mark Post, Aleš Prokop, Raj K. Puri, Pengxu Qian, Milica Radisic, Micha Sam Brickman Raredon, Ellen Rothman Richie, Paul Rouse, Hooman Sadri-Ardekani, W. Mark Saltzman, Luiz C. Sampaio, Christopher R. Schlieve, Su-Hua Sha, Paul T. Sharpe, V. Prasad Shastri, Yanhong Shi, Thomas Shupe, Dario Sirabella, Aleksander Skardal, J.M.W. Slack, Stephen R. Sloan, Shay Soker, Bernat Soria, Bárbara Soria-Juan, Frank E. Stockdale, Josh Stover, Thomas Stransky, H. Christiaan Stronks, Patrick S. Stumpf, Kyung Eun Sung, Daniel Swarr, Dagmara Szkolnicka, Jun Takahashi, D.K.O. Tang, Winson Tang, Doris A. Taylor, Yao Teng, Swee Hin Teoh, Anthony J. Smith, Elsa Treffeisen, Rocky S. Tuan, Joseph P. Vacanti, Cor van der Weele, Matthew Vincent, Gordana Vunjak-Novakovic, Lars U. Wahlberg, Derrick C. Wan, Anne Wang, Dan Wang, Qiwei Wang, Yanling Wang, Yu-li Wang, Zhanwen Wang, Valerie M. Weaver, J.A. Wells, Jean F. Welter, Feng Wen, Jake Weston, Jeffrey A. Whitsett, James K. Williams, Anthony J. Windebank, Mark Eu-Kien Wong, Stefan Worgall, Iwen Wu, Rui-Xin Wu, Virginia Y. Xie, Malcolm Xing, Kenneth M. Yamada, Shinya Yamanaka, James J. Yoo, Simon Young, Claire Yu, Hanry Yu, Yifan Yuan, William Zacharias, Jason Zakko, Ai Zhang, Yuanyuan Zhang, Zheng Zhang, Chunfeng Zhao, Yimu Zhao, and Laurie Zoloth

Published
2020
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13. Brain implants

Author

Lars U. Wahlberg

Subjects
medicine.medical_specialty, education.field_of_study, business.industry, Population, Dentistry, Disease, Biology, Regenerative medicine, Brain implant, Health care, Medicine, Bone regeneration, Intensive care medicine, education, business, Stem cell biology, health care economics and organizations
Abstract

As the U.S. population ages, skeletal-tissue injury and loss from trauma or disease exact a burgeoning socioeconomic burden on the health care system. Recent data place U.S. health care expenditures at over $1.8 trillion (). Skeletal-related injuries and diseases represent a significant portion of this cost. According to 2003 data from the U.S. Health Cost and Utilization Project, there were approximately 1 million hospital admissions for appendicular skeletal fractures in the United States, with an aggregate cost of over $26 billion. Costs for skull and facial fractures contributed an additional $1.3 billion. Of all fractures, approximately 10% are complicated with impaired healing. Thus, regenerative medicine offers an exciting option for addressing the reconstruction of osseous defects. With the culmination of developments in materials science, bioengineering, stem cell biology, and molecular biology, the potential of tissue engineering to accelerate bone regeneration becomes a distinct possibility.

Published
2020
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16. Cholinergic profiles in the Goettingen miniature pig (Sus scrofa domesticus) brain

Author

Laura J, Mahady, Sylvia E, Perez, Dwaine F, Emerich, Lars U, Wahlberg, and Elliott J, Mufson

Subjects
nervous system, Swine, Models, Animal, Animals, Brain, Swine, Miniature, Female, Receptors, Nerve Growth Factor, Immunohistochemistry, Article, Choline O-Acetyltransferase
Abstract

Central cholinergic structures within the brain of the even-toed hoofed Goettingen miniature domestic pig (Sus scrofa domesticus) were evaluated by immunohistochemical visualization of choline acetyltransferase (ChAT) and the low-affinity neurotrophin receptor, p75NTR. ChAT immunoreactive (-ir) perikarya were seen in the olfactory tubercle, striatum, medial septal nucleus, vertical and horizontal limbs of the diagonal band of Broca and the nucleus basalis of Meynert, medial habenular nucleus, zona incerta, neurosecretory arcuate nucleus, cranial motor nuclei III and IV, Edinger-Westphal nucleus, parabigeminal nucleus, pedunculopontine nucleus and laterodorsal tegmental nucleus. Cholinergic ChAT-ir neurons were also found within transitional cortical areas (insular, cingulate, and piriform cortices) and hippocampus proper. ChAT-ir fibers were seen throughout the dentate gyrus and hippocampus, in the mediodorsal, laterodorsal, anteroventral and parateanial thalamic nuclei, the fasciculus retroflexus of Meynert, basolateral and basomedial amygdaloid nuclei, anterior pretectal and interpeduncular nuclei, as well as select laminae of the superior colliculus. Double immunofluorescence demonstrated that virtually all ChAT-ir basal forebrain neurons were also p75NTR positive. The present findings indicate that the central cholinergic system in the miniature pig is similar to other mammalian species. Therefore, the miniature pig may be an appropriate animal model for preclinical studies of neurodegenerative diseases where the cholinergic system is compromised.

Published
2016

17. Contributors

Author

Mathew G. Angelos, Jacopo Baglieri, Carmen Bertoni, Laura Breda, Hildegard Büning, Lawrence Chan, Wenhao Chen, Laurence J.N. Cooper, Alisa Dong, Christopher H. Evans, Charles A. Gersbach, Steven C. Ghivizzani, Saar Gill, Joseph C. Glorioso, William F. Goins, Perry B. Hackett, H. Kirk Hammond, Manu Jain, Michael Kalos, Dan S. Kaufman, Fahad Kidwai, Christopher D. Kontos, Robert A. Kratzke, Robert E. MacLaren, Michelle E. McClements, Federico Mingozzi, Sarah B. Mueller, Jianfang Ning, Manish R. Patel, Michelle Prickett, Samuel D. Rabkin, Stefano Rivella, Paul D. Robbins, Michele Simonato, Timothy K. Starr, Tong Tang, Pratiksha I. Thakore, Jakub Tolar, Lars U. Wahlberg, Christopher E. Walsh, Jie Wu, Aini Xie, and Yisheng Yang

Published
2015
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18. List of Contributors

Author

Robby D. Bowles, Anthony J. (Tony) Smith, Jon D. Ahlstrom, Julie Albon, Peter G. Alexander, Richard A. Altschuler, Pedro Alvarez, A. Amendola, Rachael Anatol, Nasim Annabi, Piero Anversa, Judith Arcidiacono, Anthony Atala, Kyriacos A. Athanasiou, François A. Auger, Debra T. Auguste, Hani A. Awad, Stephen F. Badylak, Alexander M. Bailey, Michael P. Barry, Daniel Becker, Visar Belegu, Jonathan Bernhard, Timothy Bertram, Valérie Besnard, Z.F. Bhat, Hina Bhat, Sangeeta N. Bhatia, Sarindr Bhumiratana, Paolo Bianco, Catherine Clare Blackburn, Thomas Bollenbach, Lawrence A. Bonassar, Mike Boulton, Amy D. Bradshaw, Christopher K. Breuer, Luke Brewster, Eric M. Brey, Mairi Brittan, Bryan N. Brown, T. Brown, J.A. Buckwalter, Deborah Buffington, Karen J.L. Burg, Timothy C. Burg, Stéphane Chabaud, Thomas Ming Swi Chang, Yunchao Chang, Robert G. Chapman, Fa-Ming Chen, Una Chen, Elisa Cimetta, Richard A.F. Clark, Karen L. Clark, Muriel A. Cleary, Réjean Cloutier, Clark K. Colton, George Cotsarelis, Ronald G. Crystal, Gislin Dagnelie, Lino da Silva Ferreira, Jeffrey M. Davidson, Thomas F. Deuel, Natalie Direkze, Gregory R. Dressler, Charles N. Durfor, Craig L. Duvall, George Eng, George Engelmayr, Thomas Eschenhagen, Mark Eu-Kien Wong, Vincent Falanga, Katie Faria, Denise L. Faustman, Dario O. Fauza, Qiang Feng, Lino Ferreira, Donald W. Fink, William Fissell, Lisa E. Freed, Mark E. Furth, Denise Gay, Sharon Gerecht-Nir, Lucie Germain, Charles A. Gersbach, Francine Goulet, Ritu Goyal, Maria B. Grant, Howard P. Greisler, Farshid Guilak, Brendan A.C. Harley, David A. Hart, Abdelkrim Hmadcha, Steve J. Hodges, Heidi R. Hofer, Jeffrey O. Hollinger, Patricia Holobaugh, Jeffrey A. Hubbell, H. David Humes, Donald E. Ingber, Beau Inskeep, Xingyu Jiang, Jan Kajstura, Ravi S. Kane, Jeffrey M. Karp, F. Kurtis Kasper, Ali Khademhosseini, Sven Kili, Erin A. Kimbrel, Irina Klimanskaya, Joachim Kohn, Shaun M. Kunisaki, Themis R. Kyriakides, Eric Lagasse, Jean Lamontagne, Robert Langer, Robert Lanza, Shimon Lecht, Benjamin W. Lee, Chang H. Lee, Mark H. Lee, Peter I. Lelkes, Annarosa Leri, David W. Levine, Feng Li, Michael T. Longaker, Javier López, Shi-Jiang Lu, Ying Luo, Ben D. MacArthur, Nancy Ruth Manley, Rohan Manohar, Jonathan Mansbridge, Athanasios Mantalaris, Jeremy J. Mao, J.L. Marsh, David C. Martin, J.A. Martin, M. Martins-Green, Koichi Masuda, Mark W. Maxfield, Kathryn L. McCabe, John W. McDonald, Richard McFarland, Antonios G. Mikos, José del R. Millán, Josef M. Miller, Shari Mills, Kristen L. Moffat, Mark J. Mondrinos, Daniel T. Montoro, Malcolm A.S. Moore, Rebekah A. Neal, Robert M. Nerem, Shengyong Ng, Craig Scott Nowell, Haruko Obokata, Bjorn Reino Olsen, Richard O.C. Oreffo, Regis J. O’Keefe, Kathy O’Neill, Ophir Ortiz, Carolyn K. Pan, Vikas Pathak, M. Petreaca, Daniela Pezzolla, Maksim V. Plikus, Julia M. Polak, Mark Post, Sean Preston, Aleš Prokop, Milica Radisic, Egon Ranghini, Yehoash Raphael, A.H. Reddi, Herrmann Reichenspurner, Ellen Richie, Pamela Gehron Robey, Becky Robinson, Anabel Rojas, Shuvo Roy, Alan J. Russell, Rajiv Saigal, W. Mark Saltzman, Ali Samadikuchaksaraei, Athanassios Sambanis, Jochen Schacht, Stacey C. Schutte, Lyndsey Schutte, Steven D. Schwartz, Robert E. Schwartz, Lori A. Setton, Su-Hua Sha, Jing Shan, Paul T. Sharpe, Songtao Shi, Arun R. Shrivats, Franck Simon, Dario Sirabella, J.M.W. Slack, Bernat Soria, Patrick Spicer, Kelly R. Stevens, Frank E. Stockdale, H. Christiaan Stronks, Lorenz Studer, Shuichi Takayama, James A. Thomson, Jordan E. Trachtenberg, Elsa Treffeisen, Rocky S. Tuan, Charles A. Vacanti, Joseph P. Vacanti, Cor van der Weele, Matthew Vincent, Gordana Vunjak-Novakovic, Lars U. Wahlberg, Derrick C. Wan, Anne Wang, Angela J. Westover, George M. Whitesides, Jeffrey A. Whitsett, Steve Winitsky, Celia Witten, Stefan Worgall, Nicholas A. Wright, Ioannis V. Yannas, Simon Young, Junying Yu, Zheng Zhang, Wenfu Zheng, Wolfram Hubertus Zimmermann, and Laurie Zoloth

Published
2014
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19. Targeted delivery of nerve growth factor via encapsulated cell biodelivery in Alzheimer disease: a technology platform for restorative neurosurgery

Author

Lars U, Wahlberg, Göran, Lind, Per M, Almqvist, Philip, Kusk, Jens, Tornøe, Bengt, Juliusson, Michael, Söderman, Eva, Selldén, Åke, Seiger, Maria, Eriksdotter-Jönhagen, and Bengt, Linderoth

Subjects
Male, Drug-Related Side Effects and Adverse Reactions, Capsules, Diagonal Band of Broca, Neurosurgical Procedures, Cell Line, Cohort Studies, Stereotaxic Techniques, Drug Delivery Systems, Postoperative Complications, Prosencephalon, Alzheimer Disease, Suture Anchors, Image Interpretation, Computer-Assisted, Nerve Growth Factor, Humans, Aged, Aged, 80 and over, Drug Implants, Equipment Design, Middle Aged, Magnetic Resonance Imaging, Cholinergic Fibers, Basal Nucleus of Meynert, Female, Genetic Engineering, Tomography, X-Ray Computed
Abstract

The authors describe the first clinical trial with encapsulated cell biodelivery (ECB) implants that deliver nerve growth factor (NGF) to the cholinergic basal forebrain with the intention of halting the degeneration of cholinergic neurons and the associated cognitive decline in patients with Alzheimer disease (AD). The NsG0202 implant (NsGene A/S) consists of an NGF-producing, genetically engineered human cell line encapsulated behind a semipermeable hollow fiber membrane that allows the influx of nutrients and the efflux of NGF. The centimeter-long capsule is attached to an inert polymer tether that is used to guide the capsule to the target via stereotactic techniques and is anchored to the skull at the bur hole.Six patients with mild to moderate AD were included in this Phase Ib open-label safety study and were divided into 2 dose cohorts. The first cohort of 3 patients received single implants targeting the basal nucleus of Meynert (Ch4 region) bilaterally (2 implants per patient), and after a safety evaluation, a second cohort of 3 patients received bilateral implants (a total of 4 implants per patient) targeting both the Ch4 region and the vertical limb of the diagonal band of Broca (Ch2 region). Stereotactic implantation of the devices was successfully accomplished in all patients. Despite extensive brain atrophy, all targets could be reached without traversing sulci, the insula, or lateral ventricles.Postoperative CT scans allowed visualization of the barium-impregnated tethers, and fusion of the scans with stereotactic MR images scan was used to verify the intended positions of the implants. Follow-up MRI at 3 and 12 months postimplantation showed no evidence of inflammation or device displacement. At 12 months, implants were successfully retrieved, and low but persistent NGF secretion was detected in half of the patients.With refinement, the ECB technology is positioned to become an important therapeutic platform in restorative neurosurgery and, in combination with other therapeutic factors, may be relevant for the treatment of a variety of neurological disorders. Clinical trial registration no.: NCT01163825.

Published
2012

20. CONTRIBUTORS

Author

Jon D. Ahlstrom, Richard A. Altschuler, A. Amendola, David J. Anderson, Piero Anversa, Anthony Atala, Kyriacos A. Athanasiou, François A. Auger, Debra T. Auguste, Claudia Bearzi, Daniel Becker, Francisco J. Bedoya, Eugene Bell, Timothy Bertram, Valérie Besnard, Christopher J. Bettinger, Sangeeta N. Bhatia, Paolo Bianco, Anne E. Bishop, C. Clare Blackburn, Michael P. Bohrer, Roberto Bolli, Lawrence J. Bonassar, Jeffrey T. Borenstein, Michael E. Boulton, Amy D. Bradshaw, Luke Brewster, Eric M. Brey, Mairi Brittan, T. Brown, Scott P. Bruder, Joseph A. Buckwalter, Christopher Cannizzaro, Yilin Cao, Lamont Cathey, Thomas M.S. Chang, Yunchao Chang, Robert G. Chapman, Alice A. Chen, Faye H. Chen, Una Chen, Richard A.F. Clark, Clark K. Colton, Stephen C. Cowin, Ronald Crystal, Gislin Dagnelie, Jeffrey M. Davidson, Thomas F. Deuel, Elizabeth Deweerd, Gregory R. Dressler, George C. Engelmayr, Carol A. Erickson, Thomas Eschenhagen, Vincent Falanga, Katie Faria, Denise L. Faustman, Dario O. Fauza, Lino da Silva Ferreira, Hanson K. Fong, Peter Fong, Lisa E. Freed, R.I. Freshney, Mark E. Furth, Jeffrey Geesin, Sharon Gerecht, Lucie Germain, Kaustabh Ghosh, William V. Giannobile, Francine Goulet, Maria B. Grant, Warren Grayson, Howard P. Greisler, Farshid Guilak, Craig Halberstadt, Brendan Harley, Kiki B. Hellman, Abdelkrim Hmadcha, Steve J. Hodges, Walter D. Holder, Chantal E. Holy, Toru Hosoda, Jeffrey A. Hubbell, H. David Humes, Donald E. Ingber, Ana Jaklenec, Hee-Sook Jun, Jan Kajstura, Ravi S. Kane, Jeffrey M. Karp, John Kay, Ali Khademhosseini, Salman R. Khetani, Joachim Kohn, Shaun M. Kunisaki, Matthew D. Kwan, Themis R. Kyriakides, Eric Lagasse, Robert Langer, Douglas A. Lauffenburger, Kuen Yong Lee, Annarosa Leri, David W. Levine, Amy S. Lewis, Wan-Ju Li, Wei Liu, Michael T. Longaker, Ying Luo, Michael J. Lysaght, Nancy Ruth Manley, Jonathan Mansbridge, J.L. Marsh, David C. Martin, J.A. Martin, Manuela Martins-Green, Koichi Masuda, Robert L. Mauck, John W. McDonald, Antonios G. Mikos, Josef M. Miller, David J. Mooney, Malcolm A.S. Moore, Matthew B. Murphy, Robert M. Nerem, William Nikovits, Craig Scott Nowell, Bojana Obradovic, Bjorn R. Olsen, James M. Pachence, Hyoungshin Park, Jason Park, M. Petreaca, Julia M. Polak, A. Robin Poole, Christopher S. Potten, Ales Prokop, Milica Radisic, Yehoash Raphael, A. Hari Reddi, Herrmann Reichenspurner, Ellen Richie, Pamela G. Robey, Marcello Rota, Jeffrey W. Ruberti, Alan J. Russell, E. Helene Sage, Rajiv Saigal, W. Mark Saltzman, Athanassios Sambanis, Jochen Schacht, Lori A. Setton, Upma Sharma, Paul T. Sharpe, Jonathan M.W. Slack, Anthony J. Smith, Martha J. Somerman, Lin Song, Bernat Soria, Frank E. Stockdale, Lorenz Studer, Shuichi Takayama, Juan R. Tejedo, Vickery Trinkaus-Randall, Alan Trounson, Rocky S. Tuan, Gregory H. Underhill, Konrad Urbanek, Charles A. Vacanti, Joseph Vacanti, F. Jerry Volenec, Gordana Vunjak-Novakovic, Lars U. Wahlberg, Derrick C. Wan, George M. Whitesides, Jeffrey A. Whitsett, James W. Wilson, Stefan Worgall, Mark E.K. Wong, Nicholas A. Wright, Ioannis V. Yannas, Ji-Won Yoon, Simon Young, Hai Zhang, Wenjie Zhang, Beth A. Zielinski, James D. Zieske, Wolfram-Hubertus Zimmermann, and Laurie Zoloth

Published
2007
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21. CONTRIBUTORS

Author

Patrick Aebischer, Richard A. Altschuler, Pascal Ambrosini, David J. Anderson, Anthony Atala, François A. Auger, Efstathios S. Avgoustiniatos, David W. Barnes, Eugene Bell, Marie C. Béné, John G. Bishop, T. Bohrer, Lawrence J. Bonassar, Amy D. Bradshaw, Kelvin G.M. Brockbank, Leon W. Browder, Scott P. Bruder, Mary Bartlett Bunge, Arnold I. Caplan, Thomas Ming Swi Chang, Robert G. Chapman, Una Chen, Richard A.F. Clark, Réjean Cloutier, Clark K. Colton, Joanne C. Cousins, Stephen C. Cowin, Gislin Dagnelie, Thomas F. Deuel, Charles N. Durfor, Brian E. Edwards, Carol A. Erickson, Gilbert C. Faure, Denise Faustman, Dario O. Fauza, Eric G. Fine, Lee G. Fradkin, Lisa E. Freed, Claudia Gaffey, John D. Gearhart, Lucie Germain, Francine Goulet, Howard P. Greisler, Alan J. Grodzinsky, Craig R. Halberstadt, Janet Hardin-Young, C. Hasse, Matthias Hebrok, Kiki B. Hellman, Walter D. Holder, Edward Hsu, Jeffrey A. Hubbell, Mark S. Humayun, H. David Humes, Donald E. Ingber, Hugo O. Jauregui, Roger D. Kamm, Ravi S. Kane, Jens O.M. Karlsson, Anne Kessinger, Byung-Soo Kim, Naomi Kleitman, Joachim Kohn, Hiroshi Kubota, Robert P. Lanza, Douglas A. Lauffenburger, Kuen Yong Lee, Peter I. Lelkes, Robert E. London, Jack W. Love, Thomas L. Luntz, Michael J. Lysaght, Jeffrey M. Macdonald, Manuela Martins-Green, Robert W. Massof, John M. McPherson, Douglas A. Melton, Antonios G. Mikos, Josef M. Miller, Neal A. Miller, David J. Mooney, Jennifer E. Morgan, Melvin L. Moss, Claudy Mullon, Christopher S. Muratore, Gail K. Naughton, Robert M. Nerem, Björn Reino Olsen, Gregory M. Organ, James M. Pachence, Nancy L. Parenteau, Terence A. Partridge, Jacques Penaud, A. Robin Poole, Denis Rancourt, Yehoash Raphael, A.H. Reddi, Lola M. Reid, J. Dezz Ropp, Robert N. Ross, M. Rothmund, R. Bruce Rutherford, E. Helene Sage, Jacqueline Sagen, W. Mark Saltzman, Gordon H. Sato, Jochen Schacht, Michael J. Shamblott, Graham Sharp, Albert K. Shung, Adam J. Singer, Barry A. Solomon, Ruth R. Solomon, Susan J. Sullivan, Shuichi Takayama, Jeffrey Teumer, Robert C. Thomson, Mehmet Toner, Vickery Trinkaus-Randall, Ross Tubo, Brian R. Unsworth, Charles A. Vacanti, Joseph P. Vacanti, Martin P. Vacanti, Robert F. Valentini, Gordana Vunjak-Novakovic, Lars U. Wahlberg, Taylor G. Wang, John F. Warner, George M. Whitesides, Jay M. Wilson, Haiyun Wu, Arron S.L. Xu, Lian Xue, Ioannis V. Yannas, Michael J. Yaszemski, Nan Zhang, Beth A. Zielinski, A. Zielke, and U. Zimmerman

Published
2000
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