UHV-Alginate as Matrix for Neurotrophic Factor Producing Cells—A Novel Biomaterial for Cochlear Implant Optimization to Preserve Inner Ear Neurons From Degeneration

Hütten, Mareike; Erhacrt, Friederike; Zimmermann, Heiko; Reich, Uta; Esser, Karl‐Heinz; Lenarz, Thomas; Scheper, Verena

doi:10.1097/mao.0b013e3182804949

Cited by 12 publications

(9 citation statements)

References 27 publications

(22 reference statements)

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“…Despite this, the supernatant including the cell‐delivered BDNF did have an equal or even better neuroprotective effect than the recombinant BDNF. A similar finding was observed when investigating the neuroprotective effect of BDNF overexpressed from genetically modified NIH3T3 fibroblasts (Hütten et al, ). There, fibroblasts produced BDNF in concentrations in the picogram range but the neuroprotective effect was significantly increased compared to the relevant control (recombinant human BDNF 50 ng/ml).…”

Section: Discussionsupporting

confidence: 82%

“…To enhance the therapeutic effect achievable with MSCs we here developed a lentivirally based system for BDNF‐overexpression and secretion by human mesenchymal stem cells (hMSCs). The transplantation of BDNF‐overexpressing hMSCs should be linked to a delivery system avoiding cell migration and allowing nutrition and growth factor diffusion such as encapsulated cell devices (Konerding et al, ; Wahlberg et al, ) or hydrogel entrapment (Hütten et al, ). For this purpose, it may be beneficial to differentiate the hMSC into chondrocytes: firstly, differentiated cells are less carcinogenic or tumorigenic, and secondly, chondrocytes are able to withstand hypoxic conditions and low nutrient supply.…”

Section: Introductionmentioning

confidence: 99%

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BDNF‐overexpressing human mesenchymal stem cells mediate increased neuronal protection in vitro

Scheper

Schwieger

Hamm

et al. 2019

J of Neuroscience Research

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The use of neurotrophic factors as therapeutic agents for neurodegenerative diseases is considered as an approach aimed at restoring and maintaining neuronal function in the peripheral and central nervous system. Since the neuroprotective effect is depending on chronic delivery of the neurotrophic factors a sustained application, e.g., via cell‐based delivery is necessary. Human mesenchymal stem cells (hMSCs) were lentivirally modified to overexpress brain‐derived neurotrophic factor (BDNF) and to express fluorescent marker genes for easy visualization. Since genetically modified cells should be site‐specifically retained (e.g., by encapsulation) in the patients to avoid adverse effects the cells were additionally differentiated to chondrocytes to hypothetically improve their vitality and survival in a delivery matrix. Different polycations for lentiviral transduction were investigated for their efficiency. The success of differentiation was determined by analysis of chondrocyte marker genes and the neuroprotective effect of BDNF‐overexpressing cells was exemplarily investigated on neurons of the peripheral auditory system. The genetically modified hMSCs overexpressed BDNF from under 1 to 125 ng ml−1 day−1 depending on the donor and transfection method. Using protamine sulfate the transfection efficacy was superior compared to the use of polybrene. The BDNF secreted by the MSCs was significantly neuroprotective in comparison to the relevant controls even though the produced mean concentrations were lower than the effective concentrations for recombinant industrially produced proteins described in literature. The presented system of BDNF‐overexpressing hMSCs is neuroprotective and is therefore considered as a promising method for sustained delivery of proteins in therapeutically relevant amounts to degenerating neuronal structures.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

BDNF‐overexpressing human mesenchymal stem cells mediate increased neuronal protection in vitro

Scheper

Schwieger

Hamm

et al. 2019

J of Neuroscience Research

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“…Using ultra-high viscous alginate (UHV-alginate) made of the brown algal species Lessonia nigrescens and Lessonia trabeculata , it has been shown that coating the CI with this alginate is possible (Schwieger et al, 2018). It has also been demonstrated that BDNF-overexpressing murine fibroblasts survive in the UHV-alginate and release BDNF at a concentration that is neuroprotective in vitro (Hütten et al, 2013). Since gaining approval for use in humans of murine fibroblasts as xenogeneic cells may be difficult, a human cell source may prove more beneficial.…”

Section: Introductionmentioning

confidence: 99%

Stem Cell Based Drug Delivery for Protection of Auditory Neurons in a Guinea Pig Model of Cochlear Implantation

Scheper

Hoffmann

Gepp

et al. 2019

Front. Cell. Neurosci.

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Background: The success of a cochlear implant (CI), which is the standard therapy for patients suffering from severe to profound sensorineural hearing loss, depends on the number and excitability of spiral ganglion neurons (SGNs). Brain-derived neurotrophic factor (BDNF) has a protective effect on SGNs but should be applied chronically to guarantee their lifelong survival. Long-term administration of BDNF could be achieved using genetically modified mesenchymal stem cells (MSCs), but these cells should be protected – by ultra-high viscous (UHV-) alginate (‘alginate-MSCs’) – from the recipient immune system and from uncontrolled migration. Methods: Brain-derived neurotrophic factor-producing MSCs were encapsulated in UHV-alginate. Four experimental groups were investigated using guinea pigs as an animal model. Three of them were systemically deafened and (unilaterally) received one of the following: (I) a CI; (II) an alginate-MSC-coated CI; (III) an injection of alginate-embedded MSCs into the scala tympani followed by CI insertion and alginate polymerization. Group IV was normal hearing, with CI insertion in both ears and a unilateral injection of alginate-MSCs. Using acoustically evoked auditory brainstem response measurements, hearing thresholds were determined before implantation and before sacrificing the animals. Electrode impedance was measured weekly. Four weeks after implantation, the animals were sacrificed and the SGN density and degree of fibrosis were evaluated. Results: The MSCs survived being implanted for 4 weeks in vivo . Neither the alginate-MSC injection nor the coating affected electrode impedance or fibrosis. CI insertion with and without previous alginate injection in normal-hearing animals resulted in increased hearing thresholds within the high-frequency range. Low-frequency hearing loss was additionally observed in the alginate-injected and implanted cochleae, but not in those treated only with a CI. In deafened animals, the alginate-MSC coating of the CI significantly prevented SGN from degeneration, but the injection of alginate-MSCs did not. Conclusion: Brain-derived neurotrophic factor-producing MSCs encapsulated in UHV-alginate prevent SGNs from degeneration in the form of coating on the CI surface, but not in the form of an injection. No increase in fibrosis or impedance was detected. Further research and development aimed at verifying long-term mechanical and biological properties of coated electrodes in vitro and in vivo , in combination with chronic electrical stimulation, is needed before the current concept can be tested in clinical trials.

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“…Compared to other studies with cell-based drug delivery, 15,33,43,44,61,62 the tested MSCs have the great advantage of being an autologous source. MSCs can be obtained, modified, and encapsulated from patients before they undergo a cochlear implantation.…”

Section: Amount and Biological Effect Of Released Bdnfmentioning

confidence: 96%

“…30,31 Furthermore, a bidirectional transfer of small molecules is possible, leading to a supply with nutrients, growth factors, and oxygen. At the same time, waste products, CO 2 , and produced active molecules, such as insulin 32 or BDNF, 33 can be released. For biotechnological processes, alginate lyases allow the defined degradation of the liquid and gelled alginates.…”

Section: Introductionmentioning

confidence: 99%

Alginate-encapsulated brain-derived neurotrophic factor–overexpressing mesenchymal stem cells are a promising drug delivery system for protection of auditory neurons

et al. 2020

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The cochlear implant outcome is possibly improved by brain-derived neurotrophic factor treatment protecting spiral ganglion neurons. Implantation of genetically modified mesenchymal stem cells may enable the required long-term brain-derived neurotrophic factor administration. Encapsulation of mesenchymal stem cells in ultra-high viscous alginate may protect the mesenchymal stem cells from the recipient’s immune system and prevent their uncontrolled migration. Alginate stability and survival of mesenchymal stem cells in alginate were evaluated. Brain-derived neurotrophic factor production was measured and its protective effect was analyzed in dissociated rat spiral ganglion neuron co-culture. Since the cochlear implant is an active electrode, alginate–mesenchymal stem cell samples were electrically stimulated and alginate stability and mesenchymal stem cell survival were investigated. Stability of ultra-high viscous-alginate and alginate–mesenchymal stem cells was proven. Brain-derived neurotrophic factor production was detectable and spiral ganglion neuron survival, bipolar morphology, and neurite outgrowth were increased. Moderate electrical stimulation did not affect the mesenchymal stem cell survival and their viability was good within the investigated time frame. Local drug delivery by ultra-high viscous-alginate-encapsulated brain-derived neurotrophic factor–overexpressing mesenchymal stem cells is a promising strategy to improve the cochlear implant outcome.

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UHV-Alginate as Matrix for Neurotrophic Factor Producing Cells—A Novel Biomaterial for Cochlear Implant Optimization to Preserve Inner Ear Neurons From Degeneration

Abstract: This study demonstrates UHV-alginate to be a suitable scaffold for BDNF-producing fibroblasts. UHV-alginates are a promising biomaterial for cochlear implant biofunctionalization.

Cited by 12 publications

References 27 publications

BDNF‐overexpressing human mesenchymal stem cells mediate increased neuronal protection in vitro

BDNF‐overexpressing human mesenchymal stem cells mediate increased neuronal protection in vitro

Stem Cell Based Drug Delivery for Protection of Auditory Neurons in a Guinea Pig Model of Cochlear Implantation

Alginate-encapsulated brain-derived neurotrophic factor–overexpressing mesenchymal stem cells are a promising drug delivery system for protection of auditory neurons

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