Obstructions of the Fallopian tube represent one of the most common reasons for an unfulfilled desire to have children. Microstent technology opens up new therapeutic possibilities to restore the natural lumen of the Fallopian tube within a single treatment. Within the current work we developed a self-expandable biodegradable microstent for gynecological applications. Based on a novel microstent design, prototypes were manufactured from poly-L-lactide tubing by means of fs-laser cutting. Microstent prototypes were characterized morphologically by means of scanning electron microscopy and biaxial laser scanning. As manufactured, a microstents outside diameter of about 2.3 mm and a strut thickness/width of about 114 µm/103 µm was measured. Mechanical characterization of microstents included bending as well as crimping and release behavior. After crimping to a minimum diameter of 0.8 mm and consecutive release, a microstent recovery to a diameter of 1.8 mm was found. Therefore, proof-of-concept for the self-expandable microstent could be successfully provided. © 2020 by Walter de Gruyter Berlin/Boston 2020

Bock, Andrea

Borowski, Finja

Brandt-Wunderlich, Christoph

Chichkov, Boris

Dierke, Ariane

Einenkel, Rebekka

Grabow, Niels

Großmann, Swen

Hinze, Ulf

Keiler, Jonas

Matschegewski, Claudia

Pilz, Nico

Reister, Paul

Rosam, Paula

Schmitz, Klaus-Peter

Schümann, Kerstin

Siewert, Stefan

Stiehm, Michael

Wree, Andreas

Zygmunt, Marek

English

Institutionelles Repositorium der Leibniz Universität Hannover

 Open Access. © 2020 Ariane Dierke, published by De Gruyter.  This work is licensed under the Creative Commons Attribution 4.0 License. Ariane Dierke*, Finja Borowski, Swen Großmann, Christoph Brandt-Wunderlich, Claudia Matschegewski, Paula Rosam, Nico Pilz, Paul Reister, Rebekka Einenkel, Ulf Hinze, Jonas Keiler, Michael Stiehm, Kerstin Schümann, Andrea Bock, Boris Chichkov,  Niels Grabow, Andreas Wree, Marek Zygmunt, Klaus-Peter Schmitz and Stefan Siewert Development of a biodegradable microstent for minimally invasive treatment of Fallopian tube occlusions  Abstract: Obstructions of the Fallopian tube represent one of the most common reasons for an unfulfilled desire to have children. Microstent technology opens up new therapeutic possibilities to restore the natural lumen of the Fallopian tube within a single treatment. Within the current work we developed a self-expandable biodegradable microstent for gynecological applications. Based on a novel microstent design, prototypes were manufactured from poly-L-lactide tubing by means of fs-laser cutting. Microstent prototypes were characterized morphologically by means of scanning electron microscopy and biaxial laser scanning. As manufactured, a microstents outside diameter of about 2.3 mm and a strut thickness / width of about 114 µm / 103 µm was measured. Mechanical characterization of microstents included bending as well as crimping and release behavior. After crimping to a minimum diameter of 0.8 mm and consecutive release, a microstent recovery to a diameter of 1.8 mm was found. Therefore, proof-of-concept for the self-expandable microstent could be successfully provided.  Keywords: Biodegradable microstent, Fallopian tube occlusion, enabling pregnancy, fertility treatment. https://doi.org/10.1515/cdbme-2020-30191 Introduction In about 35% of cases, female sterility arises from obstruc-tions of the Fallopian tube, particularly proximal tube occlu-sions (PTO) [1]. The Fallopian tube as a hormone-dependent valve is responsible for transport of the ovum. Therefore, an intact mobility of the fimbrial funnel as well as complete patency is crucial. The proximal end of the Fallopian tube is formed by longitudinal folds of the mucous membrane with a small lumen. Tubal disorders are commonly related to congenital anomalies, acute or chronic inflammatory diseases, endometriosis and other pathologies resulting in partial or total PTO [2]. We developed a therapy concept based on a biodegradable self-expandable microstent (Fig. 1). Figure 1: Concept of a biodegradable self-expandable microstent for minimally invasive treatment of Fallopian tube occlusions:  catheterization (A) and subsequent microstent release (B, C).  Fallopian tubeuterusovaryguiding catheter (yellow) formicro delivery catheter (blue)A B C______ *Corresponding author: Ariane Dierke: Institute for ImplantTechnology and Biomaterials e.V., Friedrich- Barnewitz-Str. 4, 18119 Rostock-Warnemünde, Germany,  e-mail: ariane.dierke@uni-rostock.de Finja Borowski, Swen Großmann, Christoph Brandt-Wunderlich, Claudia Matschegewski, Paula Rosam,  Michael Stiehm, Andrea Bock, Klaus-Peter Schmitz,  Stefan Siewert: Institute for ImplantTechnology and  Biomaterials e.V., 18119 Rostock-Warnemünde, Germany Nico Pilz, Paul Reister, Kerstin Schümann, Niels Grabow, Klaus-Peter Schmitz: Institute for Biomedical Engineering, Rostock University Medical Center, 18119 Rostock- Warnemünde, Germany Rebekka Einenkel, Marek Zygmunt: Department of  Obstetrics and Gynecology, University Medicine Greifswald, 17475 Greifswald, Germany  Ulf Hinze, Boris Chichkov: Institute of Quantum Optics,  Leibniz University Hannover, 30167 Hannover, Germany Jonas Keiler, Andreas Wree: Department of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany DE GRUYTER Current Directions in Biomedical Engineering 2020;6(3): 20203019 Development of a biodegradable microstent for minimally invasive treatment of Fallopian tube occlusions — 2  Current treatment options include in vitro fertilisation (IVF) or minimally invasive transcervical catheterisation of the Fallopian tube as an alternative to the more risky surgery. Success rates of conventional treatment options range between only 20% to 50% for a subsequent pregnancy [3]. Therefore, our biodegradable self-expandable micro-stent for minimally invasive treatment of Fallopian tube occlusions represents a promising treatment option. The implant device should restore the patency of the Fallopian tube by overcoming the external stenosis (e.g. due to fibrosis) and restore the tubal valve function. Within the current study, feasibility of the microstent concept was analyzed. 2 Materials and methods 2.1 Microstent design General requirements of the microstent include biocompa-tibility and degradation within a time frame of approximately two years. For a minimized influence of the device on the Fallopian tube epithelium, the stent structure should be designed as flexible as possible with a low surface coverage of less than 15%. Microstent design was developed using 3D-CAD (computer-aided design) software Creo Parametric 5.0 (PTC Inc., USA), considering anatomical boundary con-ditions as well as manufacturing-relevant aspects (Tab. 1).  Table 1: Geometrical parameters of self-expanding microstent. Stent length  l Inside diameter /  outside diameter  di / do Wall thickness t Strut  width  ws 20.0 mm 2.0 mm / 2.2 mm 100 μm 100 μm Figure 2 shows the open-cell design of the microstent. The device is composed of 12 meander ring segments, each ls = 1.7 mm and u = 6.6 mm wide in longitudinal and circumferential direction. Eight meanders are arranged over the circumference, per ring segment respectively. Longitudinally, the meander ring segments were joint by four connector elements, respectively. The microstent design (Fig. 2 ) represents the ex-panded state and offers extensive reserves for diameter re-duction. To avoid plastic deformations during the crimping process, the design was optimized with regard to minimized strain amplitudes. The corresponding finite-element analyses were not described within the current work. In the expanded state, minor surface coverage of 13% was achieved. Figure 2: Two-dimensional representation of the microstent  design (A) and the corresponding 3D-CAD model in the expanded state, which represents the microstent configuration as manufactured (B). 2.2 Manufacturing of microstent-prototypes Poly(L-lactide) (PLLA, Resomer L210, Evonik Health Care GmbH, Germany) was used as base material. PLLA represents an absorbable thermoplastic polymer which is widely used in biomedical applications and offers favourable mechanical properties in the field of stent technology, such as a high elastic modulus of 1,200 MPa ≤ E ≤ 2,700 MPa, a tensile strength of 28 MPa ≤ σm ≤ 50 MPa and an elongation at break of εB = 6%. Absorption rates of 1.5 to 5 years are described in the literature [4]. For the manufacturing of tubular semifinished products, a solution of 4 g PLLA in 400 ml chloroform (Carl Roth GmbH + Co. KG, Germany) was prepared. The dipping process is carried out using a self-developed dipping robot. During repeated immersion in the solution, the dipping mandrels (dm = 2.0 mm) are rotated by 180° per dipping repetition, thus achieving a homogeneous distribution of tubing wall thickness. Measurement of the tubing outside diameter was conducted by means of a biaxial laser system (ODAC 32 XY, ZUMBACH Electronic AG, Switzerland). Manufacturing of microstent prototypes was conducted using a 780 nm fs-laser (Spectra-Physics, Santa Clara, USA) in combination with a positioning system (Aerotech Laserturn 5, Aerotech, Inc., USA). A laser pulse of 50 fs and a repetition rate of 1 kHz with a pulse energy of up to 3.5 mJ was used. Scanning electron microscopy (SEM, Quattro S, Thermo Fisher Scientific Inc., USA) was used to evaluate surface and edge quality of the microstent prototypes. Imaging was conducted in low vacuum mode without sample l = 20.0 mmu= 6.6 mm ≙d o= 2.1 mmlS = 1.7 mmABDevelopment of a biodegradable microstent for minimally invasive treatment of Fallopian tube occlusions — 3  preparation by means of conductive layers at a pressure of 50 Pa and an acceleration voltage of 5 kV. Microstent outside diameter was measured optically by means of the biaxial laser system in increments of 0.02 mm along the longitudinal axis.  2.3 In vitro testing of microstent prototypes For mechanical characterization of microstent prototypes, bending stiffness and radial force were investigated at 37 °C. For determination of the bending stiffness EI, the microstent prototypes were clamped on the one side and the free end was deflected laterally for u = 300 µm. A clamping length of lc = 9 mm was used. Bending reaction force Fb on five circumferential positions was measured using an integrated load cell (PW4MC3/300G-1, Hottinger Baldwin Mess-technik, Germany). For each circumferential position three force values were recorded and averaged. Bending stiffness was calculated according to formula 1. 𝐸𝐼 =𝐹𝑏∙𝑙𝑐33∙𝑢   (1) Radial force Fr as a function of diameter d was measured in accordance with DIN EN ISO 2539-2 using the Blockwise Radial Force Tester TTR 2 in combination with an iris diaphragm (J-Crimp Station RJU124, Blockwise Engineering LLC, USA). Crimping was conducted subsequently in increments of 0.1 mm to minimum crimping diameters ranging from dc = 2.2 mm to 0.8 mm. 3 Results 3.1 Manufacturing of microstent prototypes Tubular semifinished products with reproducible wall thickness of t = (97.2 ± 6.0) µm (n = 8) were manufactured. Further processing resulted in two microstent prototypes. As manufactured, a microstent outside diameter of do = (2.35 ± 0.08) mm and do = (2.28 ± 0.06) mm with a minor variation along the longitudinal axis was measured for prototype #1 and #2, respectively. Strut width and wall thickness of approximately ws = 114 μm and t = 103 µm were determined at different measuring points using SEM. An exemplary macro and a SEM image of microstent prototype #2 are shown in Fig. 3.  Figure 3: Exemplary macro (A) and SEM image (B) of microstent prototype #2.  3.2 In vitro testing of microstent prototypes The maximum bending reaction force Fb at maximum lateral deflection of u = 300 µm and the bending stiffness EI as results of the bending tests are summarized in Tab. 2.  Table 2: Results of bending tests with two microstent prototypes: maximum bending reaction force Fb at maximum lateral deflection of u = 300 µm and bending stiffness EI based on five circumferential measurement positions (n = 3), respectively. microstent prototype Fb [N] EI [Nmm²] #1 5.40 ± 0.57  1.09 ± 0.19  #2 5.30 ± 0.63  1.07 ± 0.25   Radial force measurements were conducted using prototype #1. Figure 4 depicts the relation of radial force Fr and diameter d, exemplary for minimum crimping diameters of dc = 2.0 mm, 1.5 mm and 1.0 mm.  Figure 4: Radial force Fr as a function of diameter d for minimum crimping diameters dc = 2.0 mm, 1.5 mm and 1.0 mm; Characterization of microstent prototype #1. 1 mmBA1 mm-101230.5 1 1.5 2 2.5radial force [N]diameter [mm]1 dc = 2.0 mmdc = 1.5 mmdc = 1.0 mmDevelopment of a biodegradable microstent for minimally invasive treatment of Fallopian tube occlusions — 4  The maximum radial force increases from Fr = 0.32 N to 37.14 N with degreasing crimping diameter from dc = 2.2 mm to 0.8 mm (Fig. 5). Figure 5: Maximum radial force Fr as a function of minimum crimping diameter dc; Characterization of microstent prototype #1. Figure 6 illustrates the microstent diameter after crimping to various diameters and consecutive release. Due to plastic strain, the diameter after crimping and release decreases with decreasing crimping diameters. Nevertheless, after crimping to a diameter of dc = 0.8 mm and consecutive release, the microstent still recovers to 1.8 mm, corresponding to an acceptable diameter recovery of 77% compared with its diameter as manufactured.  Figure 6: Diameter of microstent prototype #1 after crimping to diameters from dc = 2.0 mm to 0.8 mm and consecutive release; diameter after crimping and release measured using biaxial laser device; mean value ± standard deviation of microstent diameter along the longitudinal axis; extrapolation for a further reduction of crimping diameter. 4 Discussion The current work represents an initial attempt to develop a self-expandable biodegradable microstent for minimally invasive treatment of Fallopian tube occlusions. The presented technologies are suitable for the manufacturing of microstent prototypes with reproducible quality.  The Microstent prototypes show low values for bending stiffness, comparable with commercially available biodegadable stents for vascular application such as BIOTRONIK Magmaris 3.0/20 (EI = 0.89 Nmm2), Abbott Absorb GT1 3.0/18 (EI = 4.20 Nmm2) or Elixir DESolve 3.0/18 (EI = 1.50 Nmm2) [5]. Commercially available drug-eluting stents for vascular application such as BIOTRONIK Orsiro 3.0/15 (EI = 8.8 Nmm²) are commonly by one order of magnitude stiffer [6].  The presented analyses of crimping and release behavior strongly indicate feasibility of a polymeric self-expandable microstent for gynecological applications in combination with a micro delivery catheter with an inner diameter of 0.8 mm. Further investigations are planned with regard to simulated use in an in vitro and ex vivo model.  Author Statement Research funding: Financial support by the Federal Ministry of Education and Research (BMBF) within RESPONSE "Partnership for Innovation in Implant Technology" is gratefully acknowledged. Conflict of interest: Authors state no conflict of interest. References [1] Diagnostic and therapy before assisted reproductive treat-ments. Guideline of the DGGG, OEGGG and SGGG (S2K-Level, AWMF Registry No. 015/085, 02/2019). www.awmf.org, assessed march 23, 2020 [2] Rohen JW, Lütjen-Drecoll E. Funktionelle Histologie. kurzgefaßtes Lehrbuch der Zytologie, Histologie und mikroskopischen Anatomie des Menschen nach funktionellen Gesichtspunkten. 4. Aufl. Stuttgart: F. K. Schattauer Verlagsgesellschaft mbH; 2000. [3] Allahbadia GN, Merchant R. Fallopian Tube Recanalization: Lessons Learnt and Future Challenges. Women’s Health 2010; Volume: 6; issue: 4; 531–549. [4] Martin DP, Williams SF. Medical applications of poly-4-hydroxybutyrate: a strong flexible absorbable biomaterial. Biochemical Engineering Journal. 2003;16(2)97–105. [5] Schmidt W, Behrens P, Brandt-Wunderlich C, Siewert S, Grabow N, Schmitz KP. In vitro performance investigation of bioresorbable scaffolds – Standardtests for vascular stents and beyond. Cardiovascular Revascularization Medicine. 2016;17(6)375–383. [6] Schmidt W, Lanzer P, Behrens P, Brandt-Wunderlich C, Öner A, Ince H, Schmitz KP, Grabow N. Direct comparison of coronary baremetal vs. drug‑eluting stents: same platform, different mechanics? European Journal of Medical Research; 2018;23(1):2.  0102030400.5 1 1.5 2 2.5maximum radial force [N]crimping diameter [mm]01230.5 1 1.5 2 2.5diameter after release [mm]crimping diameter [mm]

Development of a biodegradable microstent for minimally invasive treatment of Fallopian tube occlusions

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Development of a biodegradable microstent for minimally invasive treatment of Fallopian tube occlusions

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Institutionelles Repositorium der Leibniz Universität Hannover