Johnathan Lyon | Duke University (original) (raw)

Papers by Johnathan Lyon

Science Advances, 2022

Patients with glioblastoma (GBM) have limited options and require novel approaches to treatment. ... more Patients with glioblastoma (GBM) have limited options and require novel approaches to treatment. Here, we studied and deployed nonfreezing "cytostatic" hypothermia to stunt GBM growth. This growth-halting method contrasts with ablative, cryogenic hypothermia that kills both neoplastic and infiltrated healthy tissue. We investigated degrees of hypothermia in vitro and identified a cytostatic window of 20°to 25°C. For some lines, 18 hours/day of cytostatic hypothermia was sufficient to halt division in vitro. Next, we fabricated an experimental tool to test local cytostatic hypothermia in two rodent GBM models. Hypothermia more than doubled median survival, and all rats that successfully received cytostatic hypothermia survived their study period. Unlike targeted therapeutics that are successful in preclinical models but fail in clinical trials, cytostatic hypothermia leverages fundamental physics that influences biology broadly. It is a previously unexplored approach that could provide an additional option to patients with GBM by halting tumor growth.

Biomaterials, 2020

Traumatic Brain Injury (TBI) triggers multiple biochemical and cellular processes that exacerbate... more Traumatic Brain Injury (TBI) triggers multiple biochemical and cellular processes that exacerbate brain tissue damage during secondary injury. Therapies that prevent or limit the evolution of secondary injury could significantly reduce the neurological deficits associated with TBI. Mesenchymal stem cell (MSC) transplantation after TBI can ameliorate neurological deficits by modulating inflammation and enhancing the expression of neurotrophic factors. However, transplanted MSCs can be actively rejected by the host immune response, such as the response mediated by cytotoxic CD8+ T cells, which thereby limiting their therapeutic efficacy. Here, we designed an agarose hydrogel that releases Fas ligand (FasL), a protein that can induce apoptosis in cytotoxic CD8+ T cells. We studied the immunosuppressive effect of this hydrogel near the allogeneic MSC transplantation site and its impact on the survival of transplanted MSCs in the injured brain. Agarose-FasL hydrogels locally reduced the host cytotoxic CD8+ T cell population and enhanced the survival of allogeneic MSCs transplanted near the injury site. Furthermore, the expression of crucial neurotrophic factors was elevated in the injury penumbra, suggesting an enhanced MSC-therapeutic effect. These results suggest that the development of immunosuppressive hydrogels for stem cell delivery can enhance the benefits of stem cell therapy for TBI.

Neural Engineering, 2020

Tissue engineering is the use of engineering methods to replace, replicate, or improve biological... more Tissue engineering is the use of engineering methods to replace, replicate, or improve biological tissues. Neural tissue engineering involves the integrated use of biomaterials, cellular engineering, and drug delivery technologies with the purpose of protecting, repairing, or regenerating cells and tissues of the nervous system. Through the introduction of biochemical, topographic, immunomodulatory, and other types of cues, tissues can be therapeutically controlled to direct growth and tissue function in order to overcome biological constraints on tissue repair and regeneration. These strategies can be applied when injury or disease occurs in the brain, spinal cord, for damaged peripheral nerves, or to improve chronic functionality of implantable neural interfaces. In this chapter, we present an overview of neural tissue engineering using examples of therapeutic systems including nerve conduits, implantable hydrogels, delivery of neurotrophic factors and stem cells, genetic approaches to tissue engineering, immunomodulation, and electrical stimulation.

Journal of Neuroinflammation, 2020

Background: Appropriately modulating inflammation after traumatic brain injury (TBI) may prevent ... more Background: Appropriately modulating inflammation after traumatic brain injury (TBI) may prevent disabilities for the millions of those inflicted annually. In TBI, cellular mediators of inflammation, including macrophages and microglia, possess a range of phenotypes relevant for an immunomodulatory therapeutic approach. It is thought that early phenotypic modulation of these cells will have a cascading healing effect. In fact, an anti-inflammatory, "M2-like" macrophage phenotype after TBI has been associated with neurogenesis, axonal regeneration, and improved white matter integrity (WMI). There already exist clinical trials seeking an M2-like bias through mesenchymal stem/stromal cells (MSCs). However, MSCs do not endogenously synthesize key signals that induce robust M2-like phenotypes such as interleukin-4 (IL-4).

Scientific Reports, 2019

Treatment of neuroepithelial cancers remains a daunting clinical challenge, particularly due to a... more Treatment of neuroepithelial cancers remains a daunting clinical challenge, particularly due to an inability to address rampant invasion deep into eloquent regions of the brain. Given the lack of access, and the dispersed nature of brain tumor cells, we explore the possibility of electric fields inducing directed tumor cell migration. In this study we investigate the properties of populations of brain cancer undergoing electrotaxis, a phenomenon whereby cells are directed to migrate under control of an electrical field. We investigate two cell lines for glioblastoma and medulloblastoma (U87mg & DAOY, respectively), plated as spheroidal aggregates in Matrigel-filled electrotaxis channels, and report opposing electrotactic responses. to further understand electrotactic migration of tumor cells, we performed RNA-sequencing for pathway discovery to identify signaling that is differentially affected by the exposure of direct-current electrical fields. Further, using selective pharmacological inhibition assays, focused on the PI3K/mTOR/AKT signaling axis, we validate whether there is a causal relationship to electrotaxis and these mechanisms of action. We find that U87 mg electrotaxis is abolished under pharmacological inhibition of PI3Kγ, mTOR, AKT and ErbB2 signaling, whereas DAOY cell electrotaxis was not attenuated by these or other pathways evaluated.

Advanced Drug Delivery Reviews, 2017

Malignant brain tumors represent one of the most devastating forms of cancer with abject survival... more Malignant brain tumors represent one of the most devastating forms of cancer with abject survival rates that have not changed in the past 60 years. This is partly because the brain is a critical organ, and poses unique anatomical , physiological, and immunological barriers. The unique interplay of these barriers also provides an opportunity for creative engineering solutions. Cancer immunotherapy, a means of harnessing the host immune system for anti-tumor efficacy, is becoming a standard approach for treating many cancers. However, its use in brain tumors is not widespread. This review discusses the current approaches, and hurdles to these approaches in treating brain tumors, with a focus on immunotherapies. We identify critical barriers to immunoengineering brain tumor therapies and discuss possible solutions to these challenges.

Advanced Healthcare Materials, 2018

Brain tumors remain a great clinical challenge, in part due to their capacity to invade into eloq... more Brain tumors remain a great clinical challenge, in part due to their capacity to invade into eloquent, inoperable regions of the brain. In contrast, inflammation in the central nervous system (CNS) due to injuries activates microglia and astrocytes culminating in an astroglial scar that typically “walls‐off” the injury site. Here, the hypothesis is tested that targeting peritumoral cells surrounding tumors to activate them via an inflammatory stimulus that recapitulates the sequelae of a traumatic CNS injury, could generate an environment that would wall‐off and contain invasive tumors in the brain. Gold nanoparticles coated with inflammatory polypeptides to target stromal cells in close vicinity to glioblastoma (GBM) tumors, in order to activate these cells and stimulate stromal CNS inflammation, are engineered. It is reported that this approach significantly contains tumors in rodent models of GBM relative to control treatments (reduction in tumor volume by over 300% in comparison to controls), by the activation of the innate and adaptive immune response, and by triggering pathways related to cell clustering. Overall, this report outlines an approach to contain invasive tumors that can complement adjuvant interventions for invasive GBM such as radiation and chemotherapy.

Treatment of aggressive glioblastoma brain tumors is challenging, largely due to diffusion barrie... more Treatment of aggressive glioblastoma brain tumors is challenging, largely due to diffusion barriers preventing efficient drug dosing to tumors. To overcome these barriers, bacterial carriers that are actively motile and programmed to migrate and localize to tumor zones were designed. These carriers can induce apoptosis via hypoxia-controlled expression of a tumor suppressor protein p53 and a pro-apoptotic drug, Azurin. In a xenograft model of human glioblastoma in rats, bacterial carrier therapy conferred a significant survival benefit with 19% overall long-term survival of >100 days in treated animals relative to a median survival of 26 days in control untreated animals. Histological and proteomic analyses were performed to elucidate the safety and efficacy of these carriers, showing an absence of systemic toxicity and a restored neural environment in treated responders. In the treated non-responders, proteomic analysis revealed competing mechanisms of pro- apoptotic and drug-resistant activity. This bacterial carrier opens a versatile avenue to overcome diffusion barriers in glioblastoma by virtue of its active motility in extracellular space and can lead to tailored therapies via tumor-specific expression of tumoricidal proteins.

Abstract—In electroencephalogram (EEG) based brain-computer interfaces (BCI) systems, evoked pote... more Abstract—In electroencephalogram (EEG) based brain-computer interfaces (BCI) systems, evoked potentials provide a relatively accurate way of selecting between large numbers of classes. However, they rely on external stimuli. Mental imagery (eg motor imagery), on the other hand, does not require external stimulation and allows real-time control but the detection of induced EEG patterns can be error-prone. In this paper we propose a scalable, useradaptive BCI that combines the advantages of imagery and evoked potentials.

Science Advances, 2022

Patients with glioblastoma (GBM) have limited options and require novel approaches to treatment. ... more Patients with glioblastoma (GBM) have limited options and require novel approaches to treatment. Here, we studied and deployed nonfreezing "cytostatic" hypothermia to stunt GBM growth. This growth-halting method contrasts with ablative, cryogenic hypothermia that kills both neoplastic and infiltrated healthy tissue. We investigated degrees of hypothermia in vitro and identified a cytostatic window of 20°to 25°C. For some lines, 18 hours/day of cytostatic hypothermia was sufficient to halt division in vitro. Next, we fabricated an experimental tool to test local cytostatic hypothermia in two rodent GBM models. Hypothermia more than doubled median survival, and all rats that successfully received cytostatic hypothermia survived their study period. Unlike targeted therapeutics that are successful in preclinical models but fail in clinical trials, cytostatic hypothermia leverages fundamental physics that influences biology broadly. It is a previously unexplored approach that could provide an additional option to patients with GBM by halting tumor growth.

Biomaterials, 2020

Traumatic Brain Injury (TBI) triggers multiple biochemical and cellular processes that exacerbate... more Traumatic Brain Injury (TBI) triggers multiple biochemical and cellular processes that exacerbate brain tissue damage during secondary injury. Therapies that prevent or limit the evolution of secondary injury could significantly reduce the neurological deficits associated with TBI. Mesenchymal stem cell (MSC) transplantation after TBI can ameliorate neurological deficits by modulating inflammation and enhancing the expression of neurotrophic factors. However, transplanted MSCs can be actively rejected by the host immune response, such as the response mediated by cytotoxic CD8+ T cells, which thereby limiting their therapeutic efficacy. Here, we designed an agarose hydrogel that releases Fas ligand (FasL), a protein that can induce apoptosis in cytotoxic CD8+ T cells. We studied the immunosuppressive effect of this hydrogel near the allogeneic MSC transplantation site and its impact on the survival of transplanted MSCs in the injured brain. Agarose-FasL hydrogels locally reduced the host cytotoxic CD8+ T cell population and enhanced the survival of allogeneic MSCs transplanted near the injury site. Furthermore, the expression of crucial neurotrophic factors was elevated in the injury penumbra, suggesting an enhanced MSC-therapeutic effect. These results suggest that the development of immunosuppressive hydrogels for stem cell delivery can enhance the benefits of stem cell therapy for TBI.

Neural Engineering, 2020

Tissue engineering is the use of engineering methods to replace, replicate, or improve biological... more Tissue engineering is the use of engineering methods to replace, replicate, or improve biological tissues. Neural tissue engineering involves the integrated use of biomaterials, cellular engineering, and drug delivery technologies with the purpose of protecting, repairing, or regenerating cells and tissues of the nervous system. Through the introduction of biochemical, topographic, immunomodulatory, and other types of cues, tissues can be therapeutically controlled to direct growth and tissue function in order to overcome biological constraints on tissue repair and regeneration. These strategies can be applied when injury or disease occurs in the brain, spinal cord, for damaged peripheral nerves, or to improve chronic functionality of implantable neural interfaces. In this chapter, we present an overview of neural tissue engineering using examples of therapeutic systems including nerve conduits, implantable hydrogels, delivery of neurotrophic factors and stem cells, genetic approaches to tissue engineering, immunomodulation, and electrical stimulation.

Journal of Neuroinflammation, 2020

Background: Appropriately modulating inflammation after traumatic brain injury (TBI) may prevent ... more Background: Appropriately modulating inflammation after traumatic brain injury (TBI) may prevent disabilities for the millions of those inflicted annually. In TBI, cellular mediators of inflammation, including macrophages and microglia, possess a range of phenotypes relevant for an immunomodulatory therapeutic approach. It is thought that early phenotypic modulation of these cells will have a cascading healing effect. In fact, an anti-inflammatory, "M2-like" macrophage phenotype after TBI has been associated with neurogenesis, axonal regeneration, and improved white matter integrity (WMI). There already exist clinical trials seeking an M2-like bias through mesenchymal stem/stromal cells (MSCs). However, MSCs do not endogenously synthesize key signals that induce robust M2-like phenotypes such as interleukin-4 (IL-4).

Scientific Reports, 2019

Treatment of neuroepithelial cancers remains a daunting clinical challenge, particularly due to a... more Treatment of neuroepithelial cancers remains a daunting clinical challenge, particularly due to an inability to address rampant invasion deep into eloquent regions of the brain. Given the lack of access, and the dispersed nature of brain tumor cells, we explore the possibility of electric fields inducing directed tumor cell migration. In this study we investigate the properties of populations of brain cancer undergoing electrotaxis, a phenomenon whereby cells are directed to migrate under control of an electrical field. We investigate two cell lines for glioblastoma and medulloblastoma (U87mg & DAOY, respectively), plated as spheroidal aggregates in Matrigel-filled electrotaxis channels, and report opposing electrotactic responses. to further understand electrotactic migration of tumor cells, we performed RNA-sequencing for pathway discovery to identify signaling that is differentially affected by the exposure of direct-current electrical fields. Further, using selective pharmacological inhibition assays, focused on the PI3K/mTOR/AKT signaling axis, we validate whether there is a causal relationship to electrotaxis and these mechanisms of action. We find that U87 mg electrotaxis is abolished under pharmacological inhibition of PI3Kγ, mTOR, AKT and ErbB2 signaling, whereas DAOY cell electrotaxis was not attenuated by these or other pathways evaluated.

Advanced Drug Delivery Reviews, 2017

Malignant brain tumors represent one of the most devastating forms of cancer with abject survival... more Malignant brain tumors represent one of the most devastating forms of cancer with abject survival rates that have not changed in the past 60 years. This is partly because the brain is a critical organ, and poses unique anatomical , physiological, and immunological barriers. The unique interplay of these barriers also provides an opportunity for creative engineering solutions. Cancer immunotherapy, a means of harnessing the host immune system for anti-tumor efficacy, is becoming a standard approach for treating many cancers. However, its use in brain tumors is not widespread. This review discusses the current approaches, and hurdles to these approaches in treating brain tumors, with a focus on immunotherapies. We identify critical barriers to immunoengineering brain tumor therapies and discuss possible solutions to these challenges.

Advanced Healthcare Materials, 2018

Brain tumors remain a great clinical challenge, in part due to their capacity to invade into eloq... more Brain tumors remain a great clinical challenge, in part due to their capacity to invade into eloquent, inoperable regions of the brain. In contrast, inflammation in the central nervous system (CNS) due to injuries activates microglia and astrocytes culminating in an astroglial scar that typically “walls‐off” the injury site. Here, the hypothesis is tested that targeting peritumoral cells surrounding tumors to activate them via an inflammatory stimulus that recapitulates the sequelae of a traumatic CNS injury, could generate an environment that would wall‐off and contain invasive tumors in the brain. Gold nanoparticles coated with inflammatory polypeptides to target stromal cells in close vicinity to glioblastoma (GBM) tumors, in order to activate these cells and stimulate stromal CNS inflammation, are engineered. It is reported that this approach significantly contains tumors in rodent models of GBM relative to control treatments (reduction in tumor volume by over 300% in comparison to controls), by the activation of the innate and adaptive immune response, and by triggering pathways related to cell clustering. Overall, this report outlines an approach to contain invasive tumors that can complement adjuvant interventions for invasive GBM such as radiation and chemotherapy.

Treatment of aggressive glioblastoma brain tumors is challenging, largely due to diffusion barrie... more Treatment of aggressive glioblastoma brain tumors is challenging, largely due to diffusion barriers preventing efficient drug dosing to tumors. To overcome these barriers, bacterial carriers that are actively motile and programmed to migrate and localize to tumor zones were designed. These carriers can induce apoptosis via hypoxia-controlled expression of a tumor suppressor protein p53 and a pro-apoptotic drug, Azurin. In a xenograft model of human glioblastoma in rats, bacterial carrier therapy conferred a significant survival benefit with 19% overall long-term survival of >100 days in treated animals relative to a median survival of 26 days in control untreated animals. Histological and proteomic analyses were performed to elucidate the safety and efficacy of these carriers, showing an absence of systemic toxicity and a restored neural environment in treated responders. In the treated non-responders, proteomic analysis revealed competing mechanisms of pro- apoptotic and drug-resistant activity. This bacterial carrier opens a versatile avenue to overcome diffusion barriers in glioblastoma by virtue of its active motility in extracellular space and can lead to tailored therapies via tumor-specific expression of tumoricidal proteins.

Abstract—In electroencephalogram (EEG) based brain-computer interfaces (BCI) systems, evoked pote... more Abstract—In electroencephalogram (EEG) based brain-computer interfaces (BCI) systems, evoked potentials provide a relatively accurate way of selecting between large numbers of classes. However, they rely on external stimuli. Mental imagery (eg motor imagery), on the other hand, does not require external stimulation and allows real-time control but the detection of induced EEG patterns can be error-prone. In this paper we propose a scalable, useradaptive BCI that combines the advantages of imagery and evoked potentials.