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Microcellular injection moulding for an oesophageal implant [Elektronische Ressource] / Hongbin Wu

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139 Pages
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Lehrstuhl für Medizintechnik Technische Universität München Microcellular Injection Moulding for an Oesophageal Implant Hongbin Wu Vollständiger Abdruck der von der Fakultät für Maschinenwesen der Technischen Universität München zur Erlangung des akademischen Grades eines Doktor-Ingenieurs genehmigten Dissertation. Vorsitzender: Univ.-Prof. Dr.-Ing. Michael F. Zäh Prüfer der Dissertation: 1. Univ.-Prof. Dr. med., Dr.-Ing. habil. Erich Wintermantel 2. Univ.-Prof. Dr.-Ing. Horst Baier Die Dissertation wurde am 10.08.2009 bei der Technischen Universität München eingereicht und durch die Fakultät für Maschinenwesen am 02.11.2009 angenommen Dedication I Dedication This dissertation is dedicated to my immediate family, my wife Jingjing Cong, my parents Lide Wu and Ailing Li. None of this would have been possible without their love and patience. They have been a constant source of love, concern, support and strength all these years. I would like to express my heart-felt gratitude to them. Abstract II Abstract This study introduces a method for producing a ring shaped polymer implant, which is to be placed around the sphincter of the oesophagus in order to reduce the amount of gastric juices reflux in the oesophagus. This idea of having a polymeric sleeve around the oesophagus has previously been applied by other authors, however not successfully due to migration of the implant along the oesophagus.

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Published 01 January 2009
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Lehrstuhl für Medizintechnik
Technische Universität München


Microcellular Injection Moulding
for an Oesophageal Implant



Hongbin Wu



Vollständiger Abdruck der von der Fakultät für Maschinenwesen der Technischen
Universität München zur Erlangung des akademischen Grades eines
Doktor-Ingenieurs
genehmigten Dissertation.

Vorsitzender: Univ.-Prof. Dr.-Ing. Michael F. Zäh
Prüfer der Dissertation: 1. Univ.-Prof. Dr. med., Dr.-Ing. habil. Erich Wintermantel
2. Univ.-Prof. Dr.-Ing. Horst Baier

Die Dissertation wurde am 10.08.2009 bei der Technischen Universität München
eingereicht und durch die Fakultät für Maschinenwesen am 02.11.2009
angenommen Dedication I
Dedication
This dissertation is dedicated to my immediate family, my wife Jingjing Cong, my parents
Lide Wu and Ailing Li. None of this would have been possible without their love and
patience. They have been a constant source of love, concern, support and strength all these
years. I would like to express my heart-felt gratitude to them.
Abstract II
Abstract
This study introduces a method for producing a ring shaped polymer implant, which is to be
placed around the sphincter of the oesophagus in order to reduce the amount of gastric juices
reflux in the oesophagus. This idea of having a polymeric sleeve around the oesophagus has
previously been applied by other authors, however not successfully due to migration of the
implant along the oesophagus. The implant in this study consists of a porous inner side, in
which tissue can grow in and by this prevent migration of the implant.
®An industrial microcellular injection molding process, named MuCell , was used to produce
implants with a porous structure. As raw material a thermoplastic polyurethane was selected.
Two molds were designed for the process study and for producing the implants. The process
parameters affecting the pore structure, pore distribution and pore size, were analyzed in
detail to ensure a suitable pore morphology for cell ingrowth. Key processing parameters for
®the pore size, morphology and porosity were identified. The MuCell process was utilized
successfully in this study to produce a medical implant for treating reflux diseases with an
optimal pore structure for cell ingrowth.
Biocompatibility tests have proven that the implants need to be treated by surface treatments
in order to improve their biocompatibility. Two surface treatment methods, plasma activation
and TiO -coating, were performed to enhance cell adhesion and proliferation on the implant 2
surface. After surface treatments biocompatibility of implants was seen to be increased. In
vitro tests showed that the plasma activation and TiO -coating had similar effects, but in vivo 2
tests revealed the plasma activation as being more effective. Cell and tissue ingrowth into the
porous structure of the implants were observed. The implants following the named treatments
were classified as biocompatible, thus suitable for surgical implantation.
Zusammenfassung III
Zusammenfassung
In dieser Arbeit wurde ein neues Implantat für die Behandlung der Reflux-Krankheit
®entwickelt. Eine Methode, die als MuCell bekannt ist, wurde in dieser Arbeit verwendet, um
ein poröses Implantat herzustellen. Das Implantat sollte um die Speiseröhre der Patienten, die
an der gastroäsophagealen Reflux-Krankheit leiden, durch einen minimal-invasiven Eingriff
gelegt werden, um damit passiv den Speiseröhren-Schließmuskel zu unterstützen. Im
Vorversuch anderer Autoren wurde ein ähnliches Implantat um die Speiseröhre implantiert,
jedoch ohne ausreichende Fixation durch Einwachsen von Gewebe. Es ist Ziel dieser Arbeit,
eine optimale Porenstruktur zu erzeugen, die ein Einwachsen von Gewebe erlaubt und eine
dauerhafte Fixierung ermöglicht.
Es ist gelungen, die gewünschte poröse Struktur und Prototypen des Implantates durch ein
mikrozelluläres Spritzgießverfahren herzustellen. Thermoplastische Polyurethane wurden als
Rohstoff verwendet. Die Porenmorphologie sowie Porengröße und Porosität des Implantates
als Funktion der Veränderung der Prozess-Parameter wurden in dieser Arbeit ausführlich
untersucht. Einige Kernparameter, die als die wichtigsten im Schaumspritzgießverfahren
hinsichtlich des Einflusses auf die Porenmorphologie waren, wurden festgelegt. Das
®MuCell -Verfahren wurde in dieser Studie erfolgreich für ein medizinisches Implantat zur
Behandlung der Reflux-Krankheit eingesetzt.
Durch Versuche zur Biokompatibilität wurde bewiesen, dass, um die Biokompatibilität des
Implantates zu verbessern, die Implantate mit Oberflächenbehandlungsmethoden behandelt
werden müssen. Zwei Methoden, Plasmaaktivierung und TiO -Beschichtung, wurden zur 2
Verbesserung der Zell-Adhäsion und -Proliferation auf der Oberfläche des Implantates
angewendet. Nach der Oberflächenbehandlung war die Biokompatibilität der Implantate
deutlich erhöht. Plasmaaktivierung und TiO -Beschichtung zeigten im in-vitro Test eine 2
vergleichbare Wirkung. Jedoch zeigte sich im in-vivo-Test, dass die Plasmaaktivierung eine
deutlichere Verbesserung der Biokompatibilität bewirkt. Zell- und Gewebeeinwachsverhalten
in die poröse Struktur des Implantats wurden beobachtet und die Implantate wurden als
biokompatibel nach der Herstellung und Behandlung klassifiziert. Mit dem vorliegenden
Verhalten wurde ein chirurgisch einsetzbares neues Implantat erfolgreich entwickelt.
Acknowledgement IV
Acknowledgement
The research work has been carried out during the period of 2006-2009 at the Department and
Chair for Medical Engineering, TU München, Garching b. München, Germany. The writing
of this dissertation has been one of the most significant academic challenges I have ever had
to face. Without the support, patience and guidance of the following people, this study would
not have been completed.
First of all I would like to express my sincere gratitude to my supervisor Prof. Dr. med.
Dr.-ing. habil Erich Wintermantel for giving me the opportunity to work in this Department,
for this interesting theme. His wisdom, knowledge and commitment to the highest standards
inspired and motivated me.
My first and second referee, Prof. Dr.-Ing. Michael F. Zäh and Prof. Dr.-Ing. Horst Baier,
deserve my most sincere thanks for all the support, productive inputs during the entire project
and especially for contributing their expertise to this work.
I would also like to thank my project partner Mr. Henning Schlicht from Medi-Globe GmbH.
He has proven great help in mold construction and mechanics during the entire period of the
project. The clinical partner, Mr. Armin Schneider from the MITI group, Klinikum rechts der
Isar, deserves severe gratitude for the performing in vivo tests of the implants.
Dr. Havard J. Haugen deserves my thanks for his insightful comments and constructive
criticisms at different stages of my research. As former staff of this Department he is deeply
involved in this project through out the whole period. His help in micro-CT measurements let
this dissertation become more valuable.
My thanks go out to all fellows and staff members of the Department. Particularly, I would
like to acknowledge Dr. Markus Eblenkamp, Dr. Hector Perea, Mr. Erhard Krampe for their
valuable discussions that helped me understand my research area better. I am indebted to my
assistant, Mrs. Ilse Schunn, for her excellent work in chemical and biological experiments. I
am also thankful to Mr. Uli Ebner and his staff members in Mechanical System and Technical
Lab for their maintaining all the machines so efficiently.
Furthermore, I would like to thank Mrs. Susanne Schnell from IMETUM (Central Institute of
Medical Engineering) for her kind instructions in the materials lab.
Also, I would like to acknowledge all students, without whom this dissertation would have
been impossible. Their motivation and hard working mentality gave me great inspiration.
Their names: Mr. Lei Song, Mr. Shen Qu, Ms. Lena Haas.
Acknowledgement V
All of the above and many others have contributed substantially in one way or another to this
thesis. I express my deepest gratitude and appreciation to all of them.
Table of contents VI
Table of contents
1  Introduction ..................................................................................................................... 9 
1.1  Gastro-oesophageal reflux disease (GORD) ........................................................... 9 
1.1.1  Description of GORD ........................................................................................ 9 
1.1.2  Causes and symptoms of GORD ................................................................... 10 
1.1.3  Treatment for GORD ...................................................................................... 12 
1.1.4  Conclusion of current treatment methods ....................................................... 19 
1.2  A new implant for treating GORD ........................................................................... 19 
® 1.3  The MuCell Process, a useful foaming method .................................................... 21 
2  Aim of the study ............................................................................................................ 28 
3  Foaming Theory 29 
3.1  Background ............................................................................................................ 29 
®3.2  The foaming process with MuCell technology ...................................................... 30 
3.2.1  Creation of a single phase of polymer melt-gas-solution ................................ 31 
3.2.2  Cell nucleation ................................................................................................ 34 
3.2.3  Cell growth ...................................................................................................... 37 
3.2.4  Cell stabilization .............................................................................................. 41 
3.3  Model modification ................................................................................................. 43 
3.3.1  Rheology of mixture ........................................................................................ 43 
3.3.2  Macroscopic flow ............................................................................................ 44 
4  Materials and methods 46 
4.1  Experimental strategy 46 
4.2  Materials ................................................................................................................. 48 
4.3  Polymer processing ................................................................................................ 49 
4.3.1  Machinery ....................................................................................................... 49 
4.3.2  Blowing agent ................................................................................................. 50 
4.3.3  Implant design (i.e. mold design) .................................................................... 51 
4.4  Characterization of macro- and microstructures .................................................... 53 
4.4.1  Microscopy ..................................................................................................... 53 
4.4.2  Porosimetry .................................................................................................... 54 
4.4.3  Microcomputed tomography (MicroCT) .......................................................... 55 
4.4.4  Comparing of different measuring methods ................................................... 55 
4.5  Thermal and rheological analysis ........................................................................... 56 
4.6  Surface treatment of implants ................................................................................ 56 
4.6.1  Plasma treatment ........................................................................................... 57 
Table of contents VII
4.6.2  Titanium coating ............................................................................................. 57 
4.7  Chemical analysis .................................................................................................. 58 
4.8  Biocompatibility analysis (in vitro) .......................................................................... 58 
4.8.1  Cell types ........................................................................................................ 58 
4.8.2  Cell culturing ................................................................................................... 58 
4.8.3  Cytotoxicity test (in vitro) ................................................................................ 60 
4.8.4  Histological methods ...................................................................................... 61 
4.9  Animal tests (in vivo) .............................................................................................. 63 
4.9.1  Tests with rabbit ............................................................................................. 63 
4.9.2  Tests with mini pigs ........................................................................................ 64 
5  Polymer processing and pore morphology................................................................ 66 
5.1  Influence of the processing parameters on pore morphology ................................ 66 
5.1.1 the weight reduction and gas content ......................................... 66 
5.1.2  Influence of the injection speed ...................................................................... 72 
5.1.3 the plasticizing temperature ........................................................ 76 
5.1.4  Influence of the plasticizing pressure ............................................................. 79 
5.1.5 the mold temperature .................................................................. 82 
5.1.6  Standard deviation of measuring .................................................................... 86 
5.1.7  Short summary ............................................................................................... 87 
5.2  Influences of the mold design on pore morphology ............................................... 88 
®5.3  Benefits from MuCell technology .......................................................................... 90 
5.4  Summary ................................................................................................................ 93 
6  Biocompatibility of foamed implants 95 
6.1  Surface treatment, sterilization and its influences on the implants......................... 95 
6.1.1  Surface treatment and sterilization of implants ............................................... 95 
6.1.2  Chemical and physical changes of implants after surface treatments and
sterilization ...................................................................................................... 96 
6.2  In-vitro test ........................................................................................................... 102 
6.2.1  The influence of surface treatments ............................................................. 102 
6.2.2  Influence of γ-ray irradiation as sterilization method ..................................... 105 
6.3  In vivo test ............................................................................................................ 113 
7  Conclusions ................................................................................................................ 116 
7.1  Processing ........................................................................................................... 116 
7.2  Biological analysis ................................................................................................ 116 
7.3  Summary .............................................................................................................. 117 
8  Outlook ........................................................................................................................ 118 
Nomenclature ...................................................................................................................... 120 
Table of contents VIII
Greek letters ................................................................................................................... 122 
References ..................................................................................................................... 123 
Appendix A, Culture medium additives ....................................................................... 136 
Appendix B, Histological preparation .......................................................................... 137 


1 Introduction 9
1 Introduction
1.1 Gastro-oesophageal reflux disease (GORD)
Gastro Oesophageal Reflux Disease (GORD) is a very common disease in Western Europe
and North America and plays a very important role in the development of esophageal
adenocarcinoma [108]. The definition of GORD is a longtime exposure of the oesophagus to
gastric components such as acid, pepsin and bile [18]. Some studies have shown that there
was an increasing incidence of adenocarcinomae of the esophageals and gastric cardia in the
past two decades [154,207]. Furthermore oesophageal carcinoma is one of the eight most
common cancers worldwide and growing rapidly in western Europe and North America
[22,44,110].
Over 40 % of the general population in America had at least weekly occurrences of heartburn
or regurgitation (symptoms of GORD) [52]. Drugs prescribed predominantly for GORD cost
the UK National Health Service a projected pound sterling 625 million in 2004, 7 % of the
primary care prescribing budget. The total cost to Swedish society of GORD in 1997 was
$424 million dollars, or $63 per adult [2,122]. In USA the annual direct cost for managing the
disease is estimated to be more than $9 billion dollars [169]. The people who have GORD
have a high possibility to get the cancer and because of the long-term treatment with drugs the
quality of life for these people has been decreased [88]. In summary there is a considerable
need for good therapeutic treatment with high economic impact.
1.1.1 Description of GORD
The Fig. 1.1 shows a physiological diagram of the stomach. The oesophagus, diaphragma,
lower oesophageal sphincter, stomach and duodenum compose the whole stomach system.
The lower oesophageal sphincter (LOS) is a specialized segment of the circular muscle layer
of the distal oesophagus and accounts for approximately 90 % of the basal pressure at the
oesophago-gastric junction [18]. The LOS functions as an anti-reflux barrier to protect the
oesophagus from the caustic gastric content [4,18].
The food passes through the oesophagus and into the stomach under the function of a
wavelike muscle contraction of the oesophageal wall. After the passage of the food, the LOS
can contract itself to prevent the reflux of gastric fluids. Besides the LOS, there are also other
additional barriers that contribute to the anti-reflux function. For example, the oesophagus has
a secondary peristalsis that is called as oesophageal clearance which may aid to push reflux
back into the stomach. Another mechanism is one of the components of the oesophagus is a
cell membrane, which can restrict the diffusion rate of hydrogen into the epithelium, therefore