Electrospun coaxial hyaluronan-based non-woven fleeces for opthalmic drug release

Abstracts – BMT 2021 – Hannover, 5 – 7 October • DOI 10.1515/bmt-2021-6010
   Biomed. Eng.-Biomed. Tech. 2021; 66(s1): S52–S56 • © by Walter de Gruyter • Berlin • Boston                       S52

Electrospun coaxial hyaluronan-based non-woven fleeces for opthal-
mic drug release
Torsten Walter, tw@innovent-jena.de, Ralf Wyrwa, rw1@innovent-jena.de, Matthias Schnabelrauch, ms@innovent-
jena.de
INNOVENT e.V., Biomaterials Department, Jena, Germany

Introduction
Coaxial electrospinning is a versatile method to create ultrathin core-shell-fibers consisting of different materials. It al-
lows the incorporation of materials not considered to be electrospinnable into the inner phase of polymeric fibers, such
as low molecular weight polymers or drugs. In this study we incorporate hyaluronan, a linear, highly biocompatible
glycosaminoglycan (GAG) and component of the extracellular matrix, and the beta blocker timolol into a polylactide
shell to generate novel drug delivery systems (DDS) for glaucoma treatment in ophthalmology.

Methods
High molecular weight, and e. g. via thiol-ene-click chemistry crosslinkable hyaluronans of lower molecular weight
were used as core material for coaxial fibers. Timolol maleate was added to the core spinning solutions. Using poly(L-
lactide-co-DL-lactide) shell solutions and a coaxial spinneret in the commercial E-Spintronic (E. Huber, Gernlinden,
Germany) non-woven fleeces were generated. Drug release profiles wer monitored via release studies in phosphate
buffered saline (PBS, pH = 7.4) at 37 °C. Quantification of released timolol was performed UV/VIS spectroscopically.

Results
Drug loaded electrospun non-woven fleeces with coaxial fiber diameters between 0.5 and 2 µm could be generated in a
stable electrospinning process. Depending on the inner phase compostion and timol maleate concentration low to mod-
erate burst releases and a long-lasting drug release period up to 37 days were observed. Obviously, the polylactide
sheath fiber acts as a diffusion barrier enabling a retarded release of water soluble timolol maleate over a desired longer
time period.

Conclusion
Novel electrospun coaxial fiber DDS could be successfully generated. They show promising controllable release pro-
files making them potential candidates for future applications in glaucoma therapy superior to existing medication like
eye drops to be administered daily.

Abstracts – BMT 2021 – Hannover, 5 – 7 October • DOI 10.1515/bmt-2021-6010
   Biomed. Eng.-Biomed. Tech. 2021; 66(s1): S52–S56 • © by Walter de Gruyter • Berlin • Boston                   S53

A hydrogel based quasistationary test system for in vitro dexame-
thasone release studies for middle ear drug delivery systems
Thomas Eickner, Institute for Biomedical Engineering University Medical Center Rostock, University of Rostock, Ros-
tock, Germany, thomas.eickner@uni-rostock.de
Michael Teske, Institute for Biomedical Engineering University Medical Center Rostock, University of Rostock, Ros-
tock, Germany, michael.teske@uni-rostock.de
Natalia Rekowska, Institute for Biomedical Engineering University Medical Center Rostock, University of Rostock,
Rostock, Germany, natalia.rekowska@uni-rostock.de
Volkmar Senz, Institute for Biomedical Engineering University Medical Center Rostock, University of Rostock, Ros-
tock, Germany, volkmar.senz@uni-rostock.de,
Klaus-Peter Schmitz, Institute for Biomedical Engineering, University Medical Center Rostock, and Institute for Im-
plantTechnology and Biomaterials e.V, Warnemünde, Germany, schmitz@iib-ev.de
Niels Grabow, Institute for Biomedical Engineering University Medical Center Rostock, University of Rostock, Ros-
tock, Germany, niels.grabow@uni-rostock.de

Introduction
For the investigation of in vitro drug release, methods have been used in which samples of drug delivery systems are
immersed in release medium. The medium is used to measure drug concentration via chromatography or photometry.
These systems are suitable to simulate drug release in tissues that are filled with liquids. When considering predomi-
nantly humid regions, e.g. the middle ear, reproducible in vitro determination of drug release becomes particularly chal-
lenging. In this study the development of a system, that allows adjustment in size, volume, sampling at regular intervals
and determining the drug concentration is reported.

Methods
Samples were produced by mixing PEGDA700 with dexamethasone as drug. The mixture was filled into silicone molds
and polymerized by UV-light. For building the release test system an alginate hydrogel was used and placed in glass
vials. Saline was used as release medium and injected under the hydrogel. The position of the hydrogel was adjusted to
slightly contact the medium surface. Samples were then placed on top of the hydrogel. The determination of drug con-
centration in the release medium was performed by HPLC-measurements.

Results
The developed system presented in this study allows for the release of dexamethasone without the samples being com-
pletely surrounded by medium. The hydrogel mediates the contact with the medium and hence the diffusion of the drug.
Release was monitored for 23 days. Drug concentration in the medium revealed to be reproducible.

Conclusion
The presented system was successfully designed and manufactured. The system is easy to build and therefore suitable to
monitor the drug release of dexamethasone from PEGDA700 derived polymer over a long period of time. Further chal-
lenges that remain to be considered are the low mechanical stability of the hydrogel,which results in the need for fre-
quent manufacturing during the handling of the system.

Abstracts – BMT 2021 – Hannover, 5 – 7 October • DOI 10.1515/bmt-2021-6010
   Biomed. Eng.-Biomed. Tech. 2021; 66(s1): S52–S56 • © by Walter de Gruyter • Berlin • Boston                     S54

Alginate Coating of Cochlear Implants for Local Drug Delivery
Verena Scheper, Department of Otolaryngology, Hannover Medical School, Hanover, Germany,
Cluster of Excellence ”Hearing4all”, Hannover, Germany, Scheper.Verena@mh-hannover.de
Thomas Lenarz, Department of Otolaryngology, Hannover Medical School, Hanover, Germany,
Cluster of Excellence ”Hearing4all”, Hannover, Germany, Lenarz.Thomas@mh-hannover.de
Jana Schwieger, Department of Otolaryngology, Hannover Medical School, Hanover, Germany,
Cluster of Excellence ”Hearing4all”, Hannover, Germany, Schwieger.Jana@mh-hannover.de

Introduction
Hydrogels may serve as drug delivery depot to improve the outcome of Cochlear Implants (CI) by local pharmacothera-
py. Additionally, as CI-coating, they may smoothen the electrode insertion process and by this positively influence the
postoperative inflammatory reactions.

Methods
Alginate was investigated for its electrode coating suitability, biocompatibility and bioefficacy for inner ear drug deliv-
ery in vitro and in vivo.

Results

Alginate, crosslinked using BaCl2 or CaCl2, is biocompatible for inner ear tissue in vitro. BaCl2-linked alginate re-
mained stable in artificial perilymph for 6 months, while CaCl2-linked alginate degraded after 3 months. When coating
an electrode dummy with alginate the insertion forces in an artificial cochlea model are reduced by 75% compared to an
uncoated control. Electrode impedances of active electrodes were not affected by the coating. Incorporation of dexame-
thasone sodium phosphate (DEX) in the gel was possible and the released DEX was measurable using HPLC-MS. Co-
culture of alginate-encapsulated brain-derived neurotrophic factor (BDNF) overexpressing mesenchymal stem cells
(BDNF-MSC) protected spiral ganglion neurons (SGN) from degeneration in vitro. The encapsulated, BDNF-MSC sig-
nificantly increased the number of mono- and bipolar SGN and their neurite regeneration but did not attract the neurites.
Subsequent in vivo testing showed that a coating of CI-electrodes with alginate encapsulated BDNF-MSC preserved
SGN from degeneration in a deafened guinea pig model.

Conclusion
Alginate is otocompatible and is a promising matrix for drug delivery and cell based therapies to the inner ear. It is pos-
sible to coat CI-electrodes using this gel whereby the impedances are not affected and insertion forces are tremendously
reduced. The released compounds can influence the inner ear cells by affecting fibrosis and preserving neurons from
degeneration. Further experiments are needed before being able to bring an alginate functionalized CI into the clinic but
the preclinical data are promising.

Abstracts – BMT 2021 – Hannover, 5 – 7 October • DOI 10.1515/bmt-2021-6010
   Biomed. Eng.-Biomed. Tech. 2021; 66(s1): S52–S56 • © by Walter de Gruyter • Berlin • Boston               S55

Die rechtliche Einordnung von Kombinationsprodukten
Peter Lotz M.C.J. (NYU), Rechtsanwalt und Attorney-At-Law (New York), MAYRFELD Rechtsanwälte & Attorneys-
At-Law, Frankfurt/Main, Deutschland, peter.lotz@mayrfeld.com

Einführung in Kombinationsprodukte
Als Kombinationsprodukte werden Therapeutika bezeichnet, die sowohl Merkmale eines Medizinprodukts als auch
Merkmale eines Arzneimittels aufweisen. Bei solchen Produkten ist oft fraglich, ob diese der Konformitätsbewertung
nach MDR oder einer Arzneimittelzulassung bedürfen. Die korrekte rechtliche Einordnung solcher Produkte hat nicht nur
signifikante wirtschaftliche, sondern auch regulatorische Konsequenzen. Aus diesem Grund ist es bereits im Entwick-
lungsstadium wichtig, eine korrekte rechtlichen Einordnung vorzunehmen, damit die Entwicklungsergebnisse im Rahmen
der Konformitätsbewertung oder Zulassung letztendlich verwertbar sind und der Rahmen der regulatorischen Anforde-
rungen pre-marketing wie auch post-marketing entsprechend eingeschätzt werden kann.

Methode zur rechtlichen Einordnung
Wir werden zunächst im Rahmen einer rechtsmethodologischen Prüfung am Fall kurz die wesentlichen Merkmale zur
Einordnung von Medizinprodukten und Arzneimitteln beleuchten. Sodann sollen mit einem Blick auf die regulatorischen
Rahmenbedingungen die einzelnen Arten von Kombinationsprodukten identifiziert werden. Anhand von Beispielen sol-
len die unterschiedlichen regulatorischen Tatbestandsvoraussetzungen zur Einordnung von Kombinationsprodukten er-
läutert werden. Abschließend werden die unterschiedlichen Konsequenzen der entsprechenden Einordnung stichpunktar-
tig zusammengefasst.

Ziel
Der Vortrag soll einen Überblick über die rechtlichen Anforderungen und die methodologische Herangehensweise im
Rahmen der regulatorischen Einordnung von Kombinationsprodukten geben, um für die Notwendigkeit entsprechender
Weichenstellungen bereits im Entwicklungsstadium zu sensitivieren und die Strukturierung des notwendigen Dialogs mit
Behörden und Beratern zu erleichtern.

Abstracts – BMT 2021 – Hannover, 5 – 7 October • DOI 10.1515/bmt-2021-6010
   Biomed. Eng.-Biomed. Tech. 2021; 66(s1): S52–S56 • © by Walter de Gruyter • Berlin • Boston                     S56

Drug-eluting coating of extruded polymeric tubular microstructures
Olga Sahmel, Institute for Biomedical Engineering, Rostock University Medical Center, Rostock-Warnemünde, Ger-
many, olga.sahmel@uni-rostock.de
Stefan Siewert, Institute for ImplantTechnology and Biomaterials e.V., Rostock-Warnemünde, Germany, stef-
an.siewert@uni-rostock.de
Dalibor Bajer, Institute for Biomedical Engineering, Rostock University Medical Center, Rostock-Warnemünde, Ger-
many, dalibor.bajer@uni-rostock.de
Thomas Reske, Institute for ImplantTechnology and Biomaterials e.V., Rostock-Warnemünde, Germany, thom-
as.reske@uni-rostock.de
Daniela Arbeiter, Institute for Biomedical Engineering, Rostock University Medical Center, Rostock-Warnemünde,
daniela.arbeiter@uni-rostock.de
Christine Friederike Kreiner, KreCo Kreiner Consulting Gesellschaft für wissenschaftlich-technisches Projektmanage-
ment mbH, c.f.kreiner@t-online.de
Rudolf Guthoff, Department of Ophthalmology, University Medical Center Rostock, rudolf.guthoff@med.uni-
rostock.de
Klaus-Peter Schmitz, Institute for ImplantTechnology and Biomaterials e.V. and Institute for Biomedical Engineering,
Rostock University Medical Center, Rostock-Warnemünde, Germany, klaus-peter.schmitz@uni-rostock.de
Niels Grabow, Institute for Biomedical Engineering, Rostock University Medical Center, Rostock-Warnemünde, Ger-
many, niels.grabow@uni-rostock.de)

Introduction
In various biomedical applications, extrusion represents a common manufacturing process for polymeric semi-finished
products. Extrusion allows processing of a wide range of biomaterials, as well as different cross-sectional geometries.
The current study deals with manufacturing of polymeric microtubes by extrusion processing. Furthermore, feasibility
of a drug-eluting as it is used for a variety of medical devices, for example microstents for minimally invasive glaucoma
therapy, was assessed.

Methods
Semi-finished products based on biodegradable poly-L-lactide (PLLA) and a non-biodegradable polycarbonate-based
silicone elastomer (SIL) were manufactured by means of extrusion. Resveratrol served as an active ingredient. The drug
was tested in advance for 37°C temperature resistance using differential scanning calorimetry. Three different concen-
trations (10%, 15% and 30%) of resveratrol were applied by means of spray-coating. Drug release behavior was ana-
lyzed in vitro at 37°C.

Results
Drug stability at 37°C was confirmed. The in vitro drug release shows a correlation between the amount of active ingre-
dient and the release time. With a higher drug content, a faster release was observed. In addition, the release from SIL
was faster compared with PLLA. After 50 days, approximately 50-60% residual Resveratrol was found in the PLLA
extract.

Conclusion
Since extrusion is already a chloroform-free manufacturing process, it would also be worthwhile to test a chloroform-
free active ingredient coating in the near future. An alternative would be to dust the active ingredient onto the warm ex-
trudate immediately after it exits the die.