Colonic locomotion

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Colonic locomotion

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Colonic locomotion

Proefschrift

ter verkrijging van de graad van doctor aan de Technische Universiteit Delft,

op gezag van de Rector Magnificus prof. dr. ir. J.T. Fokkema, voorzitter van het College voor Promoties,

in het openbaar te verdedigen op maandag 18 september 2006 om 12.30 uur door Dimitra DODOU

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Samenstelling promotiecommissie: Rector Magnificus, voorzitter

Prof. dr. ir. P.A. Wieringa, Technische Universiteit Delft, promotor Prof. dr. C-M Lehr, Universität des Saarlandes, Duitsland

Prof. dr. M.O. Schurr, Steinbeis-Hochschule Berlin, Duitsland Prof. dr. P. Fockens, Universiteit van Amsterdam

Prof. dr. ir. A. van Keulen, Technische Universiteit Delft Dr. ir. H.E.N. Bersee, Technische Universiteit Delft Dr. ir. P. Breedveld, Technische Universiteit Delft, adviseur Prof. dr. ir. J. Dankelman, Technische Universiteit Delft, reservelid

Dr. ir. P. Breedveld heeft als begeleider in belangrijke mate aan de totstandkoming van het proefschrift bijgedragen.

Title Colonic locomotion. PhD-thesis, Delft University of Technology, Delft, The Netherlands, September 2006

Author Dimitra Dodou

Cover design Dimitra Dodou, Paul Breedveld

Copyright Dimitra Dodou, Delft, The Netherlands, 2006 Print Optima Grafische Communicatie

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Summary

In 2005, about one million new cases of colonic cancer were diagnosed worldwide and the incidence is rising. The good news is that, if diagnosed early, colonic cancer is highly treatable. The most effective screening method for colonic cancer is colonoscopy. However, colonoscopy cannot be easily embraced by the population because of the related high pain intensity. The need to reconsider the colonoscopic procedure so that pain will be eliminated induces research into alternatives for colonoscopic investigation.

Robotic devices that move through the colonic tube by pulling themselves forward are a possible alternative. The main challenge for the successful development of such devices is their locomotion method along the slippery and deformable colon. The present research focuses on devices which require manipulating the friction with the colonic surface and regularly switching between high static friction to grip and low dynamic friction to slide. While sliding with low dynamic friction along the slippery colon is not an issue, generating high static friction and safe grip without at the same time causing pain or damage is a challenge to be encountered.

During the last decade, a number of robotic devices that attempt moving through the colonic tube by pulling themselves forward have been developed. Usually, the devices neglect the lubricating mucus layer that covers the colonic surface and grip by applying forces to the colonic wall per se. This study introduces a different method to increase as well as to manipulate friction along the colonic surface.

We introduce the idea to consider the mucus as an operational layer and attach the device to it. To achieve that, a layer with adhesive-to-the-mucus properties is interposed and sticks the device to the mucus layer. Sticking to a surface covered with a lubricant is a challenge, since most adhesives usually function on clean surfaces. How to stick to the slippery colonic wall is therefore the first question to be answered. We found out that the presence of mucus can paradoxically be turned into an advantage for sticking, if we consider interposing a layer of mucoadhesives between the device and the colonic wall. Mucoadhesives are polymers broadly applied in drug delivery. Not only they preserve their adhesiveness in the presence of mucus, but in fact they adhere to it. Although applying mucoadhesives as a means for colonic locomotion diverges significantly from their use in drug delivery, the simplicity of the idea to increase static friction by means of sticking is appealing and deserves further investigation.

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that the colonoscopic device should accomplish the examination as quick as possible differentiates our selection criteria from those in the case of drug delivery: a mucoadhesive suitable for colonic locomotion should respond and stick to the mucus instantly. This means that the mucoadhesive should in this case achieve adhesion only by means of physical and not by chemical bonds. In this study, the nature of the bonds was in consequence the main criterion when selecting the most suitable mucoadhesive to be experimentally tested.

A number of 2-D in vitro experiments were carried out to examine the frictional behaviour of mucoadhesives on the colonic surface. The mucoadhesive was interposed between a rigid plate and a porcine colonic segment that had been opened and stabilized with the inner surface up on a fixed basis. Friction was measured by means of a tensile testing machine.

The experiments showed that mucoadhesives can generate high static friction with the colonic surface, particularly when they are applied on the colonic surface in a film form, since films are not only adhesive to mucus but cohesive as well. Interestingly, the applied load does not play a significant role in the generated static friction. In other words, the static friction of mucoadhesive films appears to be adhesion-controlled within a range of (macroscopic) forces that is usually considered as load-controlled.

In contrast with Coulomb friction, the static friction of mucoadhesive films increases with the area of the film. Further experiments showed that not only the film area, but also the film geometry plays an important role in the generated friction. Strikingly, when reducing the area by opening holes within the film structure, static friction can be significantly increased. We hypothesised that such behaviour can be attributed to the film borderline that contributes to friction because of film sinkage into the soft colonic tissue. A film with holes includes a longer borderline leading consequently to higher static friction. Microscopic observations of the film borderline while the film was being sheared along the colonic tissue verified the hypothesis about the active role of the film borderline. A theoretical model was developed to express and predict the frictional behaviour of mucoadhesive films as a function of their geometric characteristics. The role of geometry in the generating static friction offers new outlets to friction manipulation and provides new options for the design of the device. By altering the film geometry, we can manipulate the level of the generated friction, and switch between high and low friction values, according to the demands of the device. Moreover, choosing geometries which can achieve high static friction despite their compact size can lead to a decrease of the overall size of the device.

In a series of additional 3-D experiments, mucoadhesive films were fixed around the perimeter of 3-D rigid U-shaped tubes and their static friction was measured inside the colonic tube. The results are equivalent with the 2-\D measurements along an opened colonic segment. The theoretical model was expanded so that it is able to predict the static friction of such 3-D film structures as well. An experimental fit indicated the feasibility of the model to estimate the frictional behaviour of a device that moves through the colonic tube.

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During its locomotion along the colon, the device should undergo a number of repeatable stick-unstick cycles. In other words, to make more than one step, the device should be able to restick to the colon. Both air and water unstick the device from the colonic surface, by changing the properties of the film irreversibly so that a new film should be used to stick the device on the next spot. Using a new film for each step can be achieved by including a film refreshment mechanism in the device, able to provide a new film each time the device requires sticking to the colon. To keep the design of the device simple, however, the changes of the film properties would be preferably reversible, so that one film could repeatedly switch between the states of stick-unstick-slide. To realise reversible film behaviour, the use of mucoadhesive polymers the properties of which can be altered according to environmental parameters (e.g. light) is promising and deserves future investigation.

Although the research focuses on colonic locomotion, it seems feasible to expand and apply the idea of increasing and manipulating friction by means of adhesive forces when gripping or handling soft, sensitive, or vulnerable objects. The artifice is to increase the adhesive forces up to a level that friction starts being controlled by adhesion, but without exceeding a ceiling of forces beyond which the adhesive falls into the area of permanent joints.

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Contents in brief

1 Introduction 1

2 Mucoadhesives and colonic locomotion 17

3 Friction manipulation and colonic locomotion 45 4 Friction of mucoadhesive films: the role of area 65 5 Friction of mucoadhesive films: the role of load 83 6 Friction of mucoadhesive films: the role of geometry 97 7 Stick, unstick, restick sticky films in the colon 123 8 Friction of mucoadhesive films: performance in the 3-D world 141 9 Discussion, conclusions, and future directions 157

Epilogue 167

Appendix A Dynamic friction of mucoadhesive films 169

Appendix B Statistics in the colon 171

Appendix C The importance of having a long borderline when gripping on

the colonic surface 175

Appendix D Derivation of equations for friction of various geometries 181

Appendix E In quest of the optimal geometry 187

Appendix F Friction of arbitrary shapes and factor analysis for friction 197

References 209

Samenvatting 233

Acknowledgments 237

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Chapter 1 Introduction

The last thing one discovers in composing a work is what to put first. T. S. Eliot

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1.1 Essentials of colonoscopy

Colonoscopy, an endoscopic examination of the large intestine, should change radically in the near future. Colorectal cancer has become the most common form of cancer in Europe (yearly about 9000 people in the Netherlands are diagnosed with colon cancer, leading to a high mortality rate of approximately 4500 patients) and the incidence is rising. The good news is that this form of cancer develops relatively slowly and is highly treatable if diagnosed early. For this reason, the European Health Ministers have adopted preventive screening for the most at-risk age group as a priority. 1-3_{According to the European Code}

Against Cancer, 4_{colonoscopy screening is more effective than other screening methods,}

with the apparent advantage that visualising the entire colon can lead to the identification of 95% of the patients with tumours. But in order to be accepted by the public, a screening method should not only be highly sensitive, but also comfortable and safe. With a perforation rate of 0.2% 5,6_{and high pain intensity}7_{(see Note [1.1]), colonoscopy cannot be}

easily embraced by the population.

In the anatomy of the digestive system (Figure 1.1), the colon is the part between the cecum and the rectum. Approximately 1.5 m long, the colon is mainly responsible for storing waste, reclaiming water, maintaining the water balance, and absorbing vitamins.

Figure 1.1: Anatomy of the digestive system.

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cable that can be connected to a light source and a camera. A biopsy channel is provided in order to insert instruments for simple interventions. Connections for suction and water are provided as well. Colonoscopy was first performed in 1969 by Shinya and Wolff opening a new era in the diagnosis and treatment of colonic disease. 8_{Colonoscopy is originated from}

the relative upper gastrointestinal endoscopic techniques. Colonoscopes are in fact similar in design with gastroscopes (i.e. an endoscope for visually examining the stomach), only longer. 9(a)

Figure 1.2: Conventional colonoscope with thickness of 1 cm and length of 1.5 m. The motion of the colonoscope

tip (left) can be controlled by a handgrip with control knobs (right).

The difference between gastroscopy and colonoscopy is that, oppositely to the straight upper part of the gastrointestinal tract, the 3-D structure of the colon includes a number of angles and loops. Pushing the colonoscope through the colon is therefore almost impossible without buckling that leads to painful stretching of the colonic tissue and the supporting ligaments. Mastering the technique is the result of a long learning curve (see Note [1.3]). It can be stated that the complications during a colonoscopy are mainly related to the difficulties to be encountered when moving a compliant colonoscope along the compliant colon and can be reduced only if there is a different way to perform colonoscopy.

The need to reconsider the colonoscopic procedure so that pain will be eliminated induced research into alternatives for colonoscopic investigation. At the Delft University of Technology (DUT), a research project is being carried out on the development of new methods of colonic locomotion to be implemented in a device that will be able to move along the colon and realise a colonoscopy. Figure 1.3 illustrates with a tree structure the research choices of the DUT project as well as the position of this thesis within the project. The reasons behind the choices within the DUT project are elaborated in § 1.2.

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Figure 1.3: Tree structure of the research at the Delft University of Technology on colonic locomotion. Project

choices are highlighted blue.

Indirect friction increase (radial pushing or pulling)

(§ 1.2.4) Colonic locomotion RESEARCH FIEL D Invasive (§ 1.2.1) Non-invasive (§ 1.2.1) Wired (§ 1.2.2) Non-wired (§ 1.2.2)

Clamping & sliding (§ 1.2.3) Rolling (§ 1.2.3) Pulling from ahead (§ 1.2.3)

Direct friction increase (no radial pushing or pulling)

(this thesis) Peristaltic-propelled device (§ 1.2.3) Self- propelling device (§ 1.2.3) Pushing from behind (§ 1.2.3) Device Device Mucoadhesive Mucus Epithelium PROPULS ION MET HOD GRIPPI NG MET HOD SAFET Y REQUIR E M E NT Device Device Mu cus Epithelium G r r e a p s Pushing from behind & pulling

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1.2.1 Examination technique: Invasive or non-invasive

Investigating the colon by means of a colonoscope is an invasive technique in the sense that the colonoscope makes the examination from inside the body. Despite the disadvantages of pain, discomfort, complications and risks, an invasive method offers the advantage that therapeutic actions can be performed and biopsies of eventual abnormalities can be taken.

As an alternative to colonoscopy, an X-ray examination can be used to detect abnormalities in the colon (Figure 1.4). During the examination, barium sulphate (a radiopaque contrast medium) is rectally instilled into the colon to increase the contrast in the X-ray images. An X-ray examination can be considered advantageous compared to colonoscopy in terms of having no risk of colonic wall perforation. However, during an X-ray examination, small polyps and sometimes even small cancers can be missed. Moreover, biopsy and polyp removal cannot be carried out during the examination and a follow-up colonoscopy is required.

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Figure 1.4: X-ray examination. (i) Equipment. (ii) Image of the colon.

Virtual colonoscopy (VC) is a non-invasive technique that combines 2-D and 3-D scans of the colon from computer tomography (CT) or magnetic resonance imaging (MRI) (Figure 1.5). During the procedure the patient lies on an examination table that moves through a scanner to produce a series of 2-D cross-sections along the length of the colon. Virtual reality software is used to reconstruct axial and multiplanar surface-rendered images as well as simulated endoluminal volume-rendered images of the colon. 10-14_{VC has been}

reported to have a sensitivity of 75% and a specificity of 90% in detecting colorectal cancer and polyps of 10 mm in size. 15-17_{Because VC can identify polyps on the proximal side of}

folds as readily as on the distal side, its potential sensitivity may be superior to that of conventional colonoscopy. 9(b)_{VC can be considered advantageous as it gives better}

imaging by using 15% less radiation dose than an X-ray examination. Most importantly, it provides clearer and more detailed images. Moreover, because it is comfortable and safe, it can be easily acceptable by the public. 10-12_{However, VC carries the disadvantages of every}

non-invasive technique: in case that abnormalities show up, a follow-up colonoscopy is required.

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Figure 1.5: Virtual colonoscopy. (i) Examination table and scanner. (ii) Volume-rendered image of the colon. 1.2.2 Safety requirement: Wired or non-wired

The recently developed wireless camera pill creates hope that pain during a colonoscopic examination can be a problem of the past (Figure 1.6). Swallowing the capsule is reported to be ‘easier than swallowing an aspirin’ and its size in not larger than that of a large vitamin pill. The capsule endoscope is propelled by the peristalsis through the gastrointestinal tract and takes images of the gastrointestinal wall by using a miniature camera and a short focal length lens. 18 _{The camera takes two images per second. The}

images are radio-transmitted on a portable recorder attached to a belt. The patient continues with regular activities while the capsule travels along the gastrointestinal tract. After the exam, the patient returns to the doctor’s office where the recorded images are rendered into a digital movie. A serious disadvantage of this technique is that the capsule is transported by the digestive system, taking thus pictures randomly. It can therefore not visualise the entire intestinal wall or look behind folds that are often present in the intestinal anatomy. There is therefore an increased risk that abnormalities are missed. Recently, researchers proposed a stopping mechanism that enables the capsule to anchor itself in one position. 19

The mechanism seems promising but it is not evaluated yet. The doctor teleoperates the capsule to stop at the spot where biopsy, drug delivery or detailed imaging is required. However, the camera pill cannot produce clear images of large digestive organs, such as the stomach and the colon and is thus only used for investigation of the small intestine.

A wire or tube connecting the device to the exterior of the patient is a lifeline for retracting the device out of the patient in case that the device fails. For safety reasons, it was therefore decided to focus the DUT project on a wired device. Additionally, it should be noted that a non-wired device should bring on board light source, power supply, even water and air tanks. If the device has to be able to take biopsies or delivery drugs, the carrying load increases further. In other words, autonomy works against size of a small colonoscopic device. If the device is connected to the exterior of the patient with a working channel, energy and light source, air and water flow, tools and drugs can be provided from the outside, so that the size, weight, complexity, and costs of the device are reduced. 1.2.3 Propulsion method: pushing from behind or pulling from ahead

Self-propelling or peristaltic-propelled

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at the outside of the device. One pair is used for moving the device forward, whereas the other pair moves the device backward. When the electrodes activate the colonic wall, the device is transported by the peristaltic wall contractions that are induced at the position of the electrodes. The main disadvantage of peristaltic-propelled devices is the device is transported in the same way as a bolus of food and can therefore not be controlled.

Self-propelling concerns the design of a motorised locomotion mechanism. A self-propelling device does not activate peristaltic waves but it should be able to often move against them. The DUT project focuses mainly on self-propelling devices of which the locomotion mechanisms are inspired by locomotion principles found in nature.

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Figure 1.6: The camera pill. (i) The interior of the capsule. 1. Optical dome, 2. Lens holder, 3. Lens, 4.

Illuminating LEDs (Light Emitting Diode), 5. Miniature camera 6. Battery, 7. Transmitter of images to aerials that are attached to the body of the patient, 8. Antenna. (ii) Image taken by the miniature camera.

Figure 1.7: Peristaltic-propelled device. 1. Contractile colonic tissue; 2. Forward direction of motion; 3. Body of

the device; 4. Electrodes for electro stimulation to create forward motion; 5. Electrodes for electro stimulation to create backward motion; 6. Flexible tube containing working channel for instruments, air channels and wires for electronics; 7. Nose of the device with exit hole for instruments and window for camera view. 20

Pushing from behind or pulling from ahead

A self-propelling device can be either pushed from behind, or pulled from ahead, or both. As already discussed in §1.1, steering a tube from behind when moving through the colonic loops and angles is often not trouble-free. Shape-memory mechanisms, however, are able to avoid buckling while being pushed from behind. In shape-memory mechanisms, the shape of the colonoscope is actively controlled while advancing through the colon. The first active shape memory mechanism 21_{consisted of a number of articulated segments with}

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magnets are replaced by two or more tension wires connecting vertebra-type rings. The main disadvantage of active shape-memory mechanisms is their high complexity as well as the large number of electromagnets or tension wires that are required to avoid buckling when negotiating through sharp curves.

These problems could be solved if the self-propelling device was pulled from ahead instead of being pushed from behind so that no shape memory is needed. It is not by chance that a significant number of currently developing colonoscopic devices follow this principle. 24-26_{However, a device that is pulled from ahead should make use of the friction}

with the colonic wall for its locomotion. Interestingly, replacing pushing with pulling inverts the friction requirements. While pushing a conventional colonoscope requires minimal friction, a device pulled from ahead should be able to regularly generate high friction and grip to the colonic wall. With such devices the challenge is shifted from manoeuvring loops to friction generation for gripping safely, atraumatically and painlessly.

A combination of pushing from behind and pulling from ahead is also possible. A Donut Colonoscope that is currently developed within the DUT project bases its locomotion in a combination of pushing and pulling. 27,28_{The principles of this locomotion mechanism are}

described in the next section.

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Figure 1.8: Shape-memory mechanism. (i) Partially cut through image of the distal end of a shape memory

controlled instrument carrier for endoscopic procedures in unsupported cavities. (ii) Detail of nested elements with electromagnets. (iii) Train of nested elements. 2A. Concave top plane of nested element; 26a. Electromagnet on concave plane of nested element; 26b. Electromagnet on convex plane of nested element. 21

To roll or to clamp-and-slide

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As an alternative for incremental clamping and sliding, locomotion can be realised by means of wheels or caterpillars that roll along the colonic wall. A self-propelling colonoscope using rolling endless belts was patented in 1996 by Takada 29_{(Figure 1.9). The}

belts are in frictional contact with the colonic wall and act like caterpillars running over the exterior of a colonoscopic tube. Guiding hooks prevent the belts of becoming loose during their rolling motion. Kim et al. patented in 2003 a car-like micro robot for colonoscopy (Figure 1.10). 30_{Shape memory alloy actuators control steering, whereas electric motors}

actuate the wheels of the device. Two passive steering wheels are placed at the front so that the device follows the curves of the colon. Sensors measure the pressure exerted to the colonic wall from the passive steering wheels and then control the active steering mechanism.

Figure 1.9: Self-propelling colonoscope with rolling endless belts (i) Cross sectional view of a belt driven

self-propelling colonoscope, (ii) Side view of the distal part of the flexible tube with endless belts, and (iii) Cross sectional view of the distal part of the flexible tube with endless belts. 1. Scope tip; 2. Bending section; 3. Flexible section; 4. Control housing; 5. Connecting tube; 6. Glass fibre light source; 7. Endless belt; 8. Guiding hook; 9. Guiding tube; 10. Guiding hole; 11. Video CCD; 12. Inside area of flexible section. 29

Figure 1.10: Micro robot for colonoscopy 1. Passive steering wheels; 2. Supporting units; 3. Colonic wall; 4.

Wheels of proximal part; 5. Active steering linear actuators; 6. Fixing linear actuators; 7. Wheels of distal part; 8. Camera and light source. 30

The main disadvantage of using rolling elements is that their contact area with the colonic wall is limited to a small part of the periphery of the device. Moreover, the rolling elements in the systems above are separated by gaps, which introduce a risk of damage or perforation of the colonic wall when tissue is stuck inside these gaps. Additionally, it is questionable whether conventional materials like those used for the rolling elements in the systems above can prevent accidental slip from the colonic wall.

A method to get rid of the gaps between the rolling elements is to surround the device by one flexible donut-shaped wheel. Based on this idea, a rolling colonoscopic device (the

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Donut Colonoscope) is currently being developed within the DUT project 27,28_(Figure

1.11). The patented locomotion system consists of three independently driven stents into a donut shape with adjustable diameter. The stents are driven by cables. The diameter of the donut is adjustable so that the device can adapt to variations in the diameter of the colon. The wires of the stents cut through the slippery layer that covers the colonic wall, facilitating direct contact between the stent and the wall.

Figure 1.11: The Donut Colonoscope developed within the DUT project.

Rolling is advantageously continuous, not incremental like clamping-and-sliding. The only requirement is that the friction between the wheels or caterpillars and the colonic wall is continuously high to generate sufficient grip for the locomotion. It should be noted, however, that, considering the large variations in the surface properties even along the same colon, friction manipulation may be of need for rolling locomotion as well to adjust the level of friction and ensure grip. The fact that all design concepts discussed throughout the thesis concern clamp-and-slide locomotion is therefore mainly driven by the intention to investigate the possibilities for friction manipulation and not only friction increase. The proposed friction manipulation methods can be adjusted so that they become applicable in rolling locomotion as well.

1.2.4 Gripping method: indirect or direct friction increase

By nature, the colonic environment facilitates slipping rather than gripping: the colonic wall is slippery and highly deformable in radial direction. In the literature 24-26_{, there are a}

number of colonoscopic devices that attempt moving by pushing the colonic wall outward. Most of those devices imitate the locomotion of an inchworm by using inflatable, radial segments (Figure 1.12). 31_{Locomotion consists of increments in which some segments}

were inflated, allowing clamping to the colonic wall, while the other segments are deflated and slide. Although effective when moving in industrial pipes, such a locomotion method cannot be promising for moving through the deformable colonic tube. If a colonoscopic device exerts forces in radial direction, the colonic wall will at first be pushed unavailingly outward and will start generating resistant force only after having being stretched up to the point that it causes pain to the patient.

If pushing the colonic tube outward is not an option, pulling the colonic wall inward with respect to the device may offer a possibility to increase friction. Following this reasoning, scientists developed a clamp-and-sliding method in which the inflatable segments were replaced by suction pads (Figure 1.13). 32_{The colonic wall was in that case not pushed}

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Figure 1.12: Motion of an inchworm mechanism. 1. Proximal inflatable radial segment; 2. Bellows; 3. Controllabe

angling mechanism; 4. Distal inflatable radial segment; 5. Atraumatic tip. 31

Figure 1.13: Sucking (left) and grasping (right) self-propelling devices. [left: Reprinted with permission from

Comput Aided Surg, 4, P Dario, MC Carrozza and A Pietrabissa, Development and in vitro testing of a miniature robotic system for computer assisted colonoscopy, 1-14, Copyright 1999 John Wiley & Sons, Inc.; right: Reprinted with permissision from IEEE Transactions on Biomedical Engineering, 49, L Phee, D Accoto, A Menciassi, C Stefanini, MC Carrozza and P Dario, Analysis and development of locomotion devices for the gastrointestinal tract, 613-616, © 2002 IEEE.]

1.3 Approach

The aim of this thesis is to find a method that provides high friction inside the colon without pushing the colonic wall outward or pulling it inward. Pushing the colonic wall outward or pulling it inward by means of suction or grasping increases friction indirectly, i.e. by affecting the normal forces and wavers between insufficient grip and tissue damage. We aim increasing friction directly, i.e. by means of adhesion so that the device sticks to the colonic wall. Sticking to a surface covered with a lubricant is a challenge, since most adhesives require clean surfaces. Sticking to the slippery colonic wall is therefore the first challenge to be encountered; the lubricating mucus that covers the colonic wall cannot be neglected. It seems, however, that the presence of mucus can paradoxically be an advantage for sticking, if we interpose a layer of mucoadhesives between the device and the colonic wall. Mucoadhesives are polymers broadly applied in drug delivery. Not only they adhere in the presence of mucus, but in fact they adhere to it. Although applying mucoadhesives as a means for colonic locomotion diverges significantly from their use in drug delivery, the simplicity of the idea to stick to the colonic wall is appealing and deserves further investigation. All methods of friction increase and manipulation that are investigated in the framework of this study are therefore related to mucoadhesives.

1.4 Aim

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choices, but the complete lack of information about their frictional characteristics urges revisiting mucoadhesives from an engineer’s point of view.

This study therefore aims to

• Test experimentally the frictional performance of mucoadhesives that seem to be favourable for colonic locomotion.

• Identify the fundamentals lying behind the frictional behaviour of mucoadhesives.

• Check the feasibility of mucoadhesives for use in a self-propelling device.

• Indicate eventual preferences and limitations derived by the use of mucoadhesives for colonic locomotion.

1.5 Thesis outline & reader’s guide

The thesis consists of nine chapters and six appendices. Chapters 2-8 have been kept intact in their form as journal articles. This may lead sometimes to repetitions in the introductory part or the methodology, but makes the chapters fairly self-contained so that they can be read in random order. Since these articles were created while the study was still afoot, revisiting them after a more global picture of the findings had been constructed would be useful in order to place them within the general scientific framework and offer a holistic view. For this reason, each of Chapters 2-7 ends with a reflection, which was not included in the primary article. The reflection contains an implied criticism, a careful (re)consideration (or contemplation if one prefers) of the aspects discussed in the chapter. The scope is to bring all particular aspects elaborated in each article as a unity up to a common generalised integrative ideological level so that their consistency will be communicated. After each chapter, a number of notes are provided, referred to by numbers between square brackets. These notes aim to provide supplementary background information that would improve but not interrupt the readability of the text.

1.5.1 What this thesis does not contain

This study focuses on the fundamentals of colonic locomotion. Developing an intestine inspection and intervention device is out of the scope of the study. Design aspects discussed regularly throughout the thesis are in a conceptual level with only the scope to connect the findings with their primary application. There is in fact an implicit, bi-directional interaction between this fundamental study and the design of the device in a multiple manner. At the same time, however, the two domains are kept free to involve and expand themselves independently, so that their results will be eventually not only co(r)-related but also multipurpose and diversely applicable.

1.5.2 What this thesis does contain

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aspects being visited regularly throughout this thesis. Figure 1.14 illustrates how those three aspects are reticulated among chapters and appendices. By reading the picture clockwise, it appears that the study starts with conceptual solutions, which are later tested experimentally and re(de)fined. The further the experiments evolve, the more a tendency to gain insight into the fundamental principles and the underlying theory becomes imperative. Additional experiments were carried out in a later stage to verify the theory and reconnect the work to its conceptual basis in terms of design.

Figure 1.14: Pictorial representation of the contents of Chapters 2-9 and Appendices A-F.

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Notes

[1.1] Pain and discomfort during colonoscopy. The main problem for patients undergoing colonoscopy is pain. Redelmeier and co-workers 34_{tested whether a memory failure observed in}

psychological experiments could be applied in a clinical setting to lessen patients’ memories of the pain of an unpleasant medical procedure, such as a colonoscopy. Patients undergoing colonoscopy recorded the intensity and duration of pain on an analogue scale in real-time and retrospectively and their pain memory was evaluated (Figure 1.15). Redelmeier et al. concluded that patients’ judgments of total pain were strongly correlated with the peak intensity of pain and with the intensity of pain recorded during the last 3 minutes of the procedure. 7 For that reason, a non-pharmacological method for changing patients’ memory of colonoscopy has been tested: with some patients, a short interval was added at the end of the procedure during which the tip of the colonoscope remained in the rectum. As theorised, patients who underwent the extended procedure experienced the final moments as less painful, rated the entire experience as less unpleasant, and ranked the procedure as less aversive. 34

Figure 1.15: Real-time recordings of the intensity of pain of a patient undergoing colonoscopy. The patient

recorded the intensity of pain each minute. The pain is visualised on an analogue scale. ‘0’ stands for ‘no pain’ and ‘10’ stands for ‘extreme pain’. 34

[1.2] Instrumentation. The colonoscope used conventionally consists of a control head and a flexible tube with a manoeuvrable tip. The head is connected to a light source via an umbilical cord, through which pass other tubes transmitting air, water and suction. The suction channel is used for the passage of diagnostic tolls, such as biopsy forceps, and therapeutic devices. During the colonoscopic procedure, the colonoscope tube enters into the rectum, and drives into the colon till reaching the cecum.

[1.3] Anatomical difficulties in completing colonoscopy. A colonoscopy is complete when the colonoscope reaches the cecum. The trained endoscopist should be able to reach the cecum in 95% of cases. 35,36_{However, there are anatomical characteristics that hinder completion.}35,37_Examinations

are much more difficult in younger patients than in older patients, because the mesocolon, the double membrane that supports and stabilises the position of the colon, in youth is relatively “tight” and intolerant for being stretched. In slender women, the colon is relatively longer and folded into a smaller abdominal cavity and in tall, obese men, having a long, mobile mesentery and a long colon, the colonoscope may get “hung up” near the hepatic flexure such that, despite of all the efforts to straighten the instrument, there might not be enough remaining colonoscope length to complete the examination. Similar results concern the patients’ experience with colonoscopy. 38_{Men may have a}

better colonoscopic experience than women. Older males may tolerate colonoscopy better than female patients and may require less sedation. In addition, men who drink alcohol may tolerate the procedure less than other patients.

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Chapter 2 Mucoadhesives and colonic locomotion

D. Dodou, P. Breedveld, and P. A. Wieringa

Published in European Journal of Pharmaceutics and Biopharmaceutics, 60 (2005) 1-16 under the title “Mucoadhesives in the gastrointestinal tract: revisiting the literature for

novel applications”

The majority of people engaged in interdisciplinary work lack a common identity. As a result, they often find themselves homeless, in a state of social and intellectual marginality. Wolfram Swoboda, Disciplines and Interdisciplinarity: A Historical Perspective, 1979

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Abstract

This article investigates applying mucoadhesives to manipulate friction and to achieve locomotion of an alternative colonoscopic device through the large intestine. Considering that such an application of mucoadhesives is new, the authors recognised the need to revisit the different aspects of mucoadhesion in the gastrointestinal tract on the basis of the literature and to re-evaluate them according to the requirements for intestinal locomotion. First, the material properties which are critical for the locomotion mechanism and specific categories of mucoadhesives characterised by those critical properties were identified. The next step was to examine the structural characteristics of those categories to specify which of the already synthesised mucoadhesives are promising candidates for friction manipulation. Then, the response of those mucoadhesives to a number of environmental stimuli was examined. At the end, two in vitro experiments were carried out to study the potential of mucoadhesives for intestinal locomotion. A comparative analysis of the role of mucoadhesives in drug delivery and in intestinal locomotion leads to the conclusion that the two applications can be approached to one extent with common principles, but crucial differences are present as well. 2.1 Introduction

In an effort to prevent colorectal cancer, a leading cause of death in Western civilisation, colonoscopic examinations are being carried out. The patient drinks a laxative fluid to empty the gastrointestinal tract, after which the endoscope is inserted into the rectum. The patient stays usually conscious to avoid the risk of complications caused by anaesthesia. Although the results of colonoscopic procedures are quite successful, the use of conventional flexible colonoscopes makes the examination unpleasant, since it frequently causes painful cramps to the patient. Additionally, although colonoscopy is regarded as a relatively safe procedure, it entails the risk of perforation of the intestinal wall. 1,2_{For this}

reason, a new intestine inspection and intervention device is being developed at TU Delft. The device will be inserted into the rectum and will be able to move forward and backward through the colon. Pre-treatment of the patient with commonly used sedatives which reduce the colonic motility can facilitate the locomotion of the device against the direction of the colonic peristaltic waves. The device will be connected with the outside world via a tube, so that it can be pulled back and removed when needed. The tip of the device will contain a camera with a light source and a biopsy channel that can be used to insert instruments for simple interventions.

The main challenge for the successful development of the intestine inspection and intervention device is its locomotion mechanism along the flaccid and slippery colonic wall. To achieve successful locomotion, the device should be able to manipulate the properties of the interface with the colonic surface. More precisely, the device should be able to generate high friction to ensure gripping and low friction to allow sliding. The device can grip on the colonic surface with high friction by interposing an adhesive interlayer between its body and the mucus layer [2.1]. Before initiating sliding, the device should be able to change the properties of the interposed adhesive interlayer, e.g. by decreasing its viscosity, thus allowing unsticking and sliding.

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adhere to the colonic mucus, but can also be easily attached to the surface of the device. Furthermore, films hydrate and thus interact quickly after contact with mucus. 4_This

parameter is significant for an intestine inspection and intervention device, since the device should be able to move through the colon relatively quickly to reduce the time needed for the medical investigation. The second step to implement the locomotion concept is to generate low friction in the presence of the mucoadhesive interlayer. A number of mucoadhesives have the ability to respond to external stimuli and to alter their material properties. Friction can be reduced and thus manipulated by controlling the behaviour of those environmental-sensitive mucoadhesives via alterations in the values of the external stimuli.

The device can consist of a number of cylinders with constant diameter connected together via extensors (Figure 2.1). Each cylinder is coated with a mucoadhesive film which plays the role of the adhesive interlayer. The friction manipulation for safe grip and atraumatic sliding is realised as follows: In each stage, all cylinders (blue), except one (green), grip with high friction, since they are covered with mucoadhesive films. The green cylinder should unstick and slide forward with low friction. For this reason, an external stimulus is applied and the mucoadhesive film responds by changing its rheological properties or by disrupting the bonds with the mucus. In this way, the green cylinder becomes unstuck and is free to slide. The required advancement is produced by elongating and compressing the extensors.

To apply mucoadhesives as a medium for friction manipulation and intestinal locomotion, we should first identify which group of already synthesised mucoadhesives can be used as the adhesive interlayer and which external stimuli can be applied to alter the properties of these mucoadhesives. In this framework, a literature survey on mucoadhesion and mucoadhesives in the gastrointestinal tract in general and particularly in the colonic region, has been carried out. The existing literature of mucoadhesives focuses mainly on the requirements for successful controlled drug delivery [2.2]. A new set of requirements for the use of mucoadhesives as a medium for friction manipulation has thus to be constituted. Considering that the set of requirements for intestinal locomotion is partly different from the set of requirements to deliver drugs, the authors recognised the need to revisit the different aspects of mucoadhesion in the gastrointestinal tract on the basis of the literature and to reconsider and re-evaluate these aspects according to the requirements for the locomotion mechanism. A comparative analysis of the role of mucoadhesives in drug delivery and in intestinal locomotion has been carried out as well. The aim was to determine to what extent a unified approach for both cases can be followed and to indicate in which points such a unified approach should be differentiated. After exploring which mucoadhesives and external stimuli seem to be the most promising candidates for friction manipulation, two in vitro experiments were carried out to study the potential of mucoadhesives for intestinal locomotion.

The reviewed information in this paper is systemised in four fundamental questions that are tightly interrelated:

1. What are the theories that describe the mechanism of mucoadhesion?

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Figure 2.1: Intestine inspection and intervention device with cylinders connected via extensors. All cylinders are

coated with mucoadhesive films. The blue cylinders grip with high friction, whereas the green cylinder slides with low friction. The yellow tube connects the device with the outside world.

2. What material properties can be influenced to obtain effective mucoadhesion, according to these theories?

The aim of reviewing the material properties was to evaluate which of them play the most critical role in intestinal locomotion. The re-evaluation is required, considering that the critical material properties for the locomotion mechanism differ from the related properties for drug delivery.

3. What mucoadhesives have been developed according to these material properties? This question has to be answered, since the main goal of the literature search was to identify which group of already synthesised mucoadhesives can be used as the interlayer between the intestine inspection and intervention device and the colonic surface. The mucoadhesives were categorised in four basic groups according to the different types of bonds which can be developed with the mucus. It seems that the favourable mucoadhesives for intestinal locomotion can be different from the mucoadhesives which are favourable for drug delivery.

4. What factors influence the material properties of these mucoadhesives?

There are several ways to influence one or more material properties of the mucoadhesives. Intrinsic factors are structural characteristics that can be affected during

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the polymerisation process of a mucoadhesive. External factors are environmental stimuli that can be activated to alter the properties of a mucoadhesive. A comparative analysis of the factors and their preferable values for successful drug delivery or intestinal locomotion leads to the conclusion that, though common principles can be established for both applications, differences are present as well.

2.2 Drug delivery vs. intestinal locomotion: requirements of the mucoadhesive A mucoadhesive used in oral drug delivery should meet the following requirements: 5

• Adhesiveness with the mucus layer, to provide adequate contact.

• Ability to swell and allow drug release.

• Ability to prolong the residence time of the drug at the site of administration.

• Lack of interaction with the active drug, to allow the drug to be released and absorbed through the mucosal surface.

• Biocompatibility with the mucosal surface, to avoid cytotoxicity or other irreversible alterations of the mucosal surface.

• Biodegradability, to allow the physical clearance of the mucosal surface.

Table 2.1: Requirements that a mucoadhesive should meet for drug delivery and for intestinal locomotion. Drug Delivery Intestinal locomotion

Adhesiveness with the mucus layer Swelling and allowing drug release Prolonged residence time

Adhesiveness with the mucus layer Response to external stimuli

Quick mucus-mucoadhesive interaction Lack of interaction with the drug Cohesiveness

Biocompatibility Biodegradability

A mucoadhesive used as an interlayer between the colonic surface and an intestine inspection and intervention device should meet the following requirements:

• Adhesiveness with the mucus layer, to provide strength within the interlayer-mucus interface and thus high friction.

• Ability of the mucoadhesive to respond to alterations of the external stimuli.

• Quick interaction of the mucoadhesive with the mucus, to reduce the time needed for the medical investigation.

• Cohesiveness, to provide strength inside the interlayer.

• Biocompatibility with the mucosal surface, to avoid cytotoxicity or other irreversible alterations of the mucosal surface.

• Biodegradability, to allow the physical clearance of the mucosal surface.

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the loaded drug, whereas, the absence of drug in the case of intestinal locomotion recalls all the requirements concerning eventual interactions between the drug and the mucoadhesive. 2.3 Theories of mucoadhesion

A number of researchers worked out theories that explain the mechanisms with which mucoadhesives adhere to the mucus layer. The theories of mucoadhesion are based on the classical theories of metallic and polymer adhesion. There are four main theories that describe the possible mechanisms of mucoadhesion: the electronic, the adsorption, the wetting and the diffusion theory.

• The electronic theory 6,7_{assumes that transfer of electrons occurs between the mucus and}

the mucoadhesive due to differences in their electronic structures. The electron transfer between the mucus and the mucoadhesive leads to the formation of a double layer of electrical charges at the interface of the mucus and the mucoadhesive. This results in attraction forces inside the double layer.

• The adsorption theory 8-12_{concerns the attraction between the mucus and the}

mucoadhesive achieved via molecular bonding caused by secondary forces such as hydrogen and van der Waals bonds. The resulting attractive forces are considerably larger than the forces described by the electronic theory.

• The wetting theory 13-18_{correlates the surface tension of the mucus and the mucoadhesive}

with the ability of the mucoadhesive to swell and spread on the mucus layer and indicates that interfacial energy plays an important role in mucoadhesion. By calculating the interfacial energy from the individual spreading coefficients of the mucus and the mucoadhesive or by calculating a combined spreading coefficient, predictions about the mucoadhesive performance can be obtained. The wetting theory is significant, since spreading of the mucoadhesive over the mucus is a prerequisite for the validity of all the other theories.

• The diffusion theory 9,19-25_{concerns the interpenetration to a sufficient depth and physical}

entanglement of the protein and polymer chains of the mucus and the mucoadhesive, depending on their molecular weight, degree of cross-linking, chain length, flexibility and spatial conformation.

None of these theories gives a complete description of the mechanism of mucoadhesion. The total phenomenon of mucoadhesion is a combined result of all these theories. Some of the researchers prefer to divide the mucoadhesion process into sequential phases, each of which is associated to a different mucoadhesion mechanism: 3,26_{First, the polymer gets wet}

and swells (wetting theory). Then, non-covalent (physical) bonds are created within the mucus-polymer interface (electronic and adsorption theory). Then, the polymer and protein chains interpenetrate (diffusion theory) and entangle together, to form further non-covalent (physical) and covalent (chemical) bonds (electronic and adsorption theory).

2.4 Material properties of mucoadhesives

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and non-covalent) with the mucus layer and their spatial conformation due to the entanglement of chains. The creation of molecular bonds and the entanglement of chains lead to changes of the rheological behaviour of the mucoadhesives. The rheological properties of mucoadhesives can therefore be used as an indication of the extent of molecular bonding and spatial conformation. The cohesiveness of mucoadhesives contributes indirectly to their adhesive ability, since it concerns the internal strength of the mucoadhesive. All these properties are discussed below with regard to the requirements for successful drug delivery or intestinal locomotion. A re-evaluation is required, since the critical material properties appear to be different in these two applications.

2.4.1 Swelling

The ability of mucoadhesives to swell is a prerequisite for mucoadhesion, since it concerns wetting, uncoiling and spreading of the polymer over the mucus (wetting theory). This spreading process, controlled by the interfacial energies of the mucus and the mucoadhesive, allows intimate contact at the mucus-mucoadhesive interface, thus governing the formation of bonds. 17,18_{Overhydration, however, forms a slippery mucilage}

deteriorating mucoadhesion. 27_{Furthermore, swelling is a key-parameter for}

environment-sensitive drug delivery, 28_{where drug release can be achieved by a reversible volume}

change of an environmental-sensitive polymer with controlled swelling-deswelling ability.29 Swelling is a crucial parameter for intestinal locomotion as well, since intimate mucus-mucoadhesive contact is important and controlled swelling-deswelling ability can lead to on-off switching between high and low friction.

2.4.2 Molecular bonding

The presence of suitable molecular groups in the mucoadhesive leads to the formation of covalent bonds (e.g. disulfide bonds), as well as non-covalent bonds (e.g. ionic, hydrogen and van der Waals bonds) with the mucus layer. These molecular bonds contribute considerably to good adhesion, according to the electronic and the adsorption theory. Covalent bonds are stronger than non-covalent bonds and therefore lead to higher mucoadhesive forces. 30,31_{However, covalent bonds require time to be created, whereas}

non-covalent bonds are formed immediately as soon as the mucus and the mucoadhesive come in contact. The delay time which is required for covalent bonding does not play an impending role in drug delivery, in which maintaining the delivery system at a particular location for an extended period of time (~ 3 h in oral delivery 3,5_{) is advantageous. This is}

the reason why research in drug delivery focuses on the synthesis of mucoadhesives that form strong covalent bonds with the mucus, even if this formation requires time. In the case of an intestine inspection and intervention device, delay time is a crucial parameter, since the device should accomplish the medical investigation in a short time. It is thus preferable in that case to use mucoadhesives which interact with mucus only with non-covalent bonds that can be activated immediately after the two materials come in contact.

2.4.3 Spatial conformation

The interpenetration rate of the mucus-mucoadhesive chains depends on the diffusion coefficient and the chemical potential gradient of the interacting macromolecules. 32_The

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mucoadhesive network control the effective chain length which can penetrate into the mucus. 3_{In this way, spatial conformation is critical for the interpenetration of}

mucus-mucoadhesive chains. It should be noted, however, that spatial conformation is a time-dependent phenomenon, since the interpenetration of the mucus and mucoadhesive chains requires a certain amount of time. This is the reason why spatial conformation is not expected to contribute significantly to a short-time application such as the locomotion of a device through the colon.

2.4.4 Rheological properties

The chain entanglement and the molecular bonding which occur between the mucus and the mucoadhesive lead to changes in the rheological behaviour of the two materials. 33_Since

changes in the rheological properties reflect the degree of interaction between mucus and mucoadhesive, rheological methods constitute a common way to evaluate mucoadhesion. For instance, mucus-mucoadhesive systems with a high elastic component show good mucoadhesiveness. 34,35_{Moreover, a high viscosity and viscoelasticity of the system}

mucus-mucoadhesive indicates improved cohesiveness and resistance to deformation. 36_{A number}

of authors measured that the viscosity of the system mucus-mucoadhesive can be larger than the sum of the separate viscosities from the mucus and the mucoadhesive. This phenomenon is named “rheological synergism”. 32,36-38_{High rheological synergism}

indicates extensive chain entanglement (diffusion theory) and molecular bonding (adsorption theory) and thus good mucoadhesive ability. Therefore, rheological synergism refers to a state in which the interpenetration between mucoadhesive and mucus has been already achieved and is not simply an interfacial phenomenon. Although rheological synergism reflects satisfying mucoadhesion in drug delivery, it cannot be used as an indication for good mucoadhesion in the case of intestinal locomotion. However, the non-Newtonian character of both the mucus and the mucoadhesive (i.e. the alteration of rheology as a function of the applied shear rate and the time) can be employed in both cases of drug delivery and intestinal locomotion as a medium for controlled mucoadhesion in correlation with the parameters of time and pressure.

2.4.5 Cohesiveness

Mucoadhesives exhibit high adhesiveness at their interface with the mucus layer, but should exhibit sufficient cohesiveness as well, to prevent internal fracture of the mucoadhesive. Solid forms of mucoadhesives show in general satisfying cohesiveness. A number of solid mucoadhesive dosage forms for drug delivery in the gastrointestinal tract, such as tablets, micro- and nanoparticles, granules, pellets, and capsules, have been studied in vitro and in vivo. 39_{They showed satisfying mucoadhesive performance, even if in vitro/in vivo testing}

cannot always predict the mucoadhesive performance in humans. 40_{In the case of an}

intestine inspection and intervention device, the mucoadhesive can be transferred and administered on the spot and not via the oral route. In this case, the mucoadhesive can thus be applied even in forms which are not applicable in colonic drug delivery, such as films or patches. Another aspect of the correlation between cohesiveness and mucoadhesive ability is pointed out by Hägerström et al. 41_{who investigated the mucoadhesiveness of common}

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increased interaction at the interface disturbed the internal cohesive structure of the polymer network.

Figure 2.2 visualises the interrelation between the theories of mucoadhesion (red circles) and the material properties of mucoadhesives (blue circles). The overlapping areas between the circles indicate how and to what extent the mucoadhesive theories are connected to the material properties. As visualised in figure 2.2, first the mucoadhesive swells (wetting theory) and then molecular bonding (electronic and adsorption theories) occurs as the formation of non-covalent bonds within the mucus-mucoadhesive interface. Next spatial conformation (diffusion theory) is introduced to achieve interpenetration between the mucus and mucoadhesive. Then molecular bonding continues as the formation of new non-covalent and non-covalent bonds inside the mucus-mucoadhesive interface. The rheological properties are visualised as an overlapping circle, since they are an indication of the extent of covalent molecular bonding and spatial conformation.

Figure 2.2: Theories of mucoadhesion (red circles) and material properties of mucoadhesives (blue circles). The

overlapping areas between the circles of the material properties and the mucoadhesive theories indicate how and to what extent the former are connected to the latter.

2.5 Chemicals with mucoadhesive ability