CHANGES IN VOCAL FOLD TENSION DUE TO VARIATION
OF STIMULATION OF THE LARYNGEAL NERVE
Eric Goodyer, Bio-Informatics Research Group, De Montfort University
in collaboration with
Dr Dinesh Chhetri, UCLA School of Medicine, Division of Head and Neck Surgery
This Overseas Travel Grant proposal results from an invitation to establish collaborative research with Dr Dinesh Chhetri of the UCLA School of Medicine, Division of Head
and Neck Surgery. Dr Chhetri is part of an internationally recognised team in the field of vocal fold pathology, which includes Professor Gerald Berke and Associate Professor
Dave Berry. Dr Chhetri is investigating treatment for vocal fold paralysis, involving the reinervation of the vocalis muscle in cases of severe dysphonia [18,19,20]. Dr Chhetri
has requested our assistance for a study to quantify the change in vocal fold tissue tension resultant from nerve stimulation; to be carried out in-vivo using a canine model. If
successful then this would enhance our understanding of the interaction between the level of stimulation of the recurrent laryngeal nerve (RLN) and the resultant tension in the
vocal fold cover. Eric Goodyer of DMU and Dave Berry of UCLA are both named consultants to the Wisconsin Tissue Engineering research programme. We propose to carry
out a short pilot study to determine if it is feasible to use either the Laryngeal Tensiometer (LT) or the Linear Skin Rheometer (LR) to obtain in-vivo data from an anaesthetised
dog. A further study will be carried out at a later date following analysis of the data, and adjustments to the methods and equipment as required.
PART 1 - PREVIOUS RESEARCH TRACK RECORD
THE CENTRE FOR COMPUTATIONAL INTELLIGENCE AT DMU
Eric Goodyer is an active member of the CCI research group, which is researching fuzzy logic, bio-health informatics, neural networks, mobile robotics and creative
computing. The CCI was rated 4 in RAE 2002 and is actively engaged in research with UK and overseas partners. The Faculty has a specialist administrative structure to
support all research activity.
ERIC GOODYER
Eric Goodyer has been engaged in research and development since the completion of his MSc by exam and dissertation in 1977 at the Department of Electronics & Electrical
Engineering, UMIST. He joined the Scientific Instruments Research Association (Sira), as a Research Officer and was appointed head of his R&D group in 1982. Much of this
early work was commercially confidential restricting his ability to publish; however active involvement with various IEE and similar professional groups was encouraged.
Section 9 lists conference proceedings that relate to his early interest in instrumentation, particularly in the field of novel sensors and low power techniques [1,2,3,4,5]
He joined DeMontfort University in 1994, whilst maintaining strong links with industry; much of his work from 1994 was also of a confidential nature. Following an invitation
to join a collaborative team at Harvard Medical School investigating tissue engineering, he took the opportunity to undertake research in the true academic sense. Since 2003
he has secured grants totalling over £360k, and has published joint papers with international collaborators from Germany, Stockholm and the USA. His last two EPSRC grants
were rated as ‘Tending to Outstanding’.
RECENT RELEAVANT RESEARCH
Bio-Mechanical Properties of the Stratum Corneum
A specific area of the Group’s research is the visco-elastic measurement of human tissue. As a result of a long-standing research partnership with Procter & Gamble (in the UK
and the USA) a range of specialist and novel and methodologies have been developed that have enabled a series of bio-mechanical studies to be undertaken in Europe and the
USA [6,7,8,9]. Research undertaken with Unilever has resulted in the launch of a new product range, and our methodologies were used to support a recent patent application
[10]. The inclusion of a chapter on the LSR in a recent publication by the CRC Press, ‘Bioengineering of the Skin’ [11], as well as a study on bio-mechanical measurement
methodologies [12] has resulted in further interest in the technique. The Group remains in contact with Procter & Gamble, Unilever and other skin care companies, as well as
collaborating with colleagues in De Montfort's Health & Life Sciences Faculty, who are also researching the biomechanics of skin.
Bio-Mechanical Properties of The vocal fold
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The Group’s research into the properties of the vocal fold has been undertaken through a series of international collaborations, as summarised below.
 Collaboration with University Medical Centre Hamburg-Eppendorf (UKE)
Prof. Markus Hess, Head of the Department of Phoniatrics and Pediatric Audiology at UKE, is widely accepted as a leader in the field of quantitative laryngology. His
invitation to the Group to provide facilities for further research using human tissue represented a superb opportunity to both further our research programme, and to gain
valuable insight from a major figure in this field. With EPSRC support (GR/S85849/01) a collaboration was entered into with Markus Hess and his team. Over the last two
years unique measurements of the elastic properties of excised human vocal folds have been obtained [13,14,15]. We have also started to obtain in-vivo results from volunteer
patients; and these results have been published [16]. The IGR relating to this collaboration was deemed to be 'Tending to Outstanding'. The importance of this partnership is
that it has brought together the engineering skills of DMU with the life science skills at UKE. The result is a strong, and dedicated multi-disciplinary team that is investigating
the fundamental science and phenomena that is proving essential to the development of tissue engineering therapies by DMU’s other international collaborators.
 Collaboration with Harvard Medical School at Massachusetts Eye & Ear Infirmary (MEEI)
The Harvard group, which includes laryngeal surgeons, voice scientists and engineers, is currently engaged in a major programme to apply tissue engineering to repair/replace
damaged vocal folds in patients who have voice disorders. A key part of the tissue engineering process is to ensure that the implant matches the visco-elastic properties of the
natural vocal fold. With EPSRC support (GR/S23346/01) the joint research team successfully developed methodologies to map the bio-mechanical properties of the vocal fold.
Trials of the LSR using animal larynxes and a human larynx obtained from pathology were a success. Measurements were obtained from the delicate vocal fold epithelium as
well as surrounding tissue. From these results the first iso-contour maps showing the variation of elasticity with respect to position were generated and published [13,14]. The
team were able to detect artificially stiffened tissue, which suggests that it could be used to quantify and map areas where vocal fold properties have been changed by implants
or by pathology. Changes in pliability after tissue augmentation implant were measured with respect to time, opening the possibility to 'tune' the pliability of the vocal fold
during the implant procedure. These were the first direct measurements ever made of the mechanical properties of the superficial layer of the human vocal fold in an intact
larynx. The IGR relating to this collaboration was deemed to be 'Tending to Outstanding'.
 Collaboration with Huddinge University Hospital, Stockholm
Prof. Stellan Hertegard of Huddinge University Hospital, Stockholm has been researching the effectiveness of different tissue augmentation techniques. The most recent
collaboration quantified the effectiveness of hyaluronic implants in a rabbit model. They were split into 4 groups, one set were undamaged, one set had their vocal folds scarred,
the 3rd set had their vocal folds scarred and then augmented using Hyaluronic Acid implants, and the 4th group were similarly treated but with a control implant. The larynxes
were excised and measured using an Instron and a specially modified LSR. From this data it is possible to derive a range of elastic properties. The results indicate that
augmenting scarred tissue with hyaluronic acid implants can restore the elasticity of a damaged larynx back to near normal. These results were announced in New York last
year, and have been published [16,17]. A new research programme, begun in 2005, is quantifying the effectiveness of stem-cell implants into damaged vocal folds. Early results
indicate that stem-cell implants into scarred vocal folds does restore the elasticity – further stem-cell studies are planned to further this research programme.
 Collaboration with Wisconsin University Hospital, Madison USA
A large team, under the leadership of Dr Diane Bless, is planning to investigate new techniques to restore scarred vocal fold tissue employing a range of tissue engineering
techniques. Early this year the team successfully characterised a range of vocal folds, mainly canine, but also human and rat. The team was able to generate a series of surface
maps that show the variation of the elastic properties of the vocal fold, and were able to use these surface maps to contrast the difference between healthy and scarred tissue. A
major NIH grant to further this work has been applied for, primarily to investigate tissue engineering techniques and therapies. Our methodologies, alongside others, will be
used to quantify the effectiveness of these new therapies.
 New Collaborations
We have recently been asked to join a team based at the Department of Ophthalmology, Guy's and St. Thomas' NHS Foundation trust to assist in a programme to investigate the
elastic properties of the human cornea. An initial study will start next month. We are also developing a new partnership with Queen’s Medical Centre (QMC) Nottingham, to
investigate the dynamics of the mucosal in-vivo using optical techniques.
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PART 2: DESCRIPTION OF THE PROPOSED RESEARCH AND ITS CONTEXT
1. INTRODUCTION
With the support of the EPSRC (GR/S85849/01, GR/S23346/01, EP/D025591/1) the DMU research team has been enabled to collaborate with 4 international partners, working
in the field of vocal fold bio-mechanics and tissue engineering. The end objective of this work is to assist and promote the development of new and novel tissue repair
techniques. To date this has focused on the use of implants, such as hyaluronic acid, to restore vocal fold pliability. Tissue Engineering is an exciting and challenging alternative
therapy that must be researched in more depth. Recent stem cell research [23] has indicated that it is possible to stimulate the self-regeneration of scarred vocal fold tissue.
DMU are actively assisting the investigations into stem-cell therapy being carried out at the Karolinska Institute. The DMU team has also been invited to assist in a $1.8M 5year NIH funded programme at Wisconsin University Hospital. This programme will be examining the use of genetic transfection to control, stimulate and suppress tissue
regeneration, as well as the use of mesh scaffolds and growth factors to manage new tissue regeneration. The DMU input has been essential to tissue repair researchers worldwide, resulting in the formulation of leading edge precision instrumentation that has been used to measure the extremely low forces exerted by the delicate vocal fold tissues.
No such similar techniques or methodologies are available from other sources that directly quantify vocal fold mechanical behaviour.
Our methodologies are used to characterise the biomechnical properties of healthy tissue, and to quantify the effectiveness of tissue augmentation and repair procedures. We
have now been approached by other research groups investigating other pathologies. One example being a pilot study recently carried out at St Thomas and Bart’s Hospital,
who are investigating the eye disease of corneal keratoconus. This disease is the result of weakness in the cornea that results in a malformed structure that causes optical
aberrations. The researchers are investigating a possible cure using cross-linked collagen augmentation to the mid-cornea region. DMU’s role is to deploy our point-specific
elasticity measuring methodology to map the variation of tissue stiffness across the surface of the cornea, before and after treatment with the collagen implant.
2. RESEARCH CONTEXT
 Characterisation of the Vocal Fold using Excised Tissue
This proposal is an essential extension of our preceding structured and coherent research ethos. The key objective is to evaluate and promote the use of new and novel tissue
repair techniques, such as hyaluronic acid augmentation, and tissue engineering including stem cell stimulated self-regeneration. The original research at Harvard Medical
School and UKE, using animal tissue and a limited set of freshly excised human larynxes, enabled us to develop and refine the methodologies that we are now successfully
deploying to support more fundamental research and to support tissue engineering programmes. Our results represent the first published material [13,14,15] that shows the
variation of elasticity over the surface of the human vocal fold. Detailed mappings have been obtained from both animal and human excised tissue. Figure 1 shows iso-contour
maps obtained at Harvard, and the experimental set-up used by Wisconsin University Hospital to verify our methodologies.
Figure 1 Iso-Contour Map from Harvard (left)
Supporting Experimental Set-up from Wisconsin (right)
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To capitalise on these achievements we are now part way through a large-scale study obtaining data from 50 excised larynxes and volunteer patients. This affords the
opportunity to generate the mathematical models that will ultimately enable objective assessment of the effectiveness of tissue repair surgery. Our interim results will be
presented to AQL 2006 in Groningen. Figure 2 shows a pair of graphs with our latest results, obtained by two different methods, one employing a direct shear stress/strain
analysis; the other employing an indentometer. These methods are referred to as ‘The Shear Model’ and ‘The Indentometer Model’. Note the similarity of the data sets, yielding
shear modulus ranges of typically between 500 and 2500 Pascal, with male larynxes tending to be stiffer than female, and a trend to increased stiffness with age.
Vocal Fold Shear Modulus (shear model)
Vocal Fold Shear Modulus (indentometer model)
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Figure 2 Variation of Shear Modulus with Respect to Age
These results are highly novel, as there is very little published literature that details work carried out with human tissue. Our methodologies are unique in that they use intact
larynxes and are capable of relating the data obtained to a specific anatomical position and direction of stress. The results are similar to those obtained by other methods, such as
parallel plate rheometry; as detailed in our publications. Wisconsin University Hospital has independently verified our methods; and they have now submitted supporting results
for publication. Wisconsin successfully generated contour maps, showing the variation of elasticity across the surface of the vocal fold of canine, human and rat samples. The
rat was particularly challenging in view of the extremely small structures that the collaborating team were trying to attach to; however it was achieved, and it was shown
possible to distinguish between healthy and scarred tissue.
 Characterisation of Vocal Fold using in-vivo Data
Towards the end of 2004 a new measurement apparatus, designed by DMU, was successfully deployed that allowed quantification of the bio-mechanical properties of healthy
and diseased vocal folds, in-vivo, with volunteer patients at UKE. The most recent comparable published work was that by Tran QT, Berke GS, Gerratt BR, Kreiman J, in 1993
[22]. Their work was groundbreaking, but relied on a cumbersome apparatus that would be difficult to reconstruct. In contrast the DMU apparatus has been designed to clamp
on to a standard laryngoscope, such that it can be used repeatably in the operating theatre. The laryngeal tensiometer is clamped to a standard size C laryngoscope (figure 3). A
load cell, similar to that used by the LSR system, is rigidly clamped to the laryngoscope. A probe is inserted down the laryngoscope, and is attached to the vocal fold. A sprung
hand grip arrangement allows the surgeon to displace the probe by 1mm, which on release provides a smooth displacement during which time the change in force is logged. A
detailed description of the design and methodology can be found in our most recent publication [14]. The graph (figure 3) shows a series of readings taken from a larynx. Each
step represents a compression change in the handgrip, and release. The data is noisy, but the noise threshold is well below the force difference that we are trying to measure.
Similar data is obtained from the LSR, and a good signal can be recovered using digital signal processing techniques; these will be added to future versions of this instrument.
The paper details results obtained from two volunteer female patients of similar age. Elasticity measurements were obtained from healthy tissues from both, and were found to
be similar and in line with findings from excised tissue. In addition we measured the elasticity in the region of a large polyp, which resulted in a reading showing far lower
stiffness than that for healthy tissue; this is the result that is to be expected. Since then we have obtained data from 8 volunteer patients, yielding values of shear modulus for
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healthy tissue from between 673 Pascal to 2143 Pascal. This range is similar to that obtained from the excised tissue, and in recent work published by R Chan and presented by
J McGlashan. Chan obtained his data from excised vocal fold covers; McGlashan used an optical in-vivo technique to derive modulus from measurements of the mucosal wave
velocity.
Figure 3 The In-Vivo Laryngeal Tensiometer and Typical Data Trace
 Tissue Engineering Studies
The results of our research to date demonstrate that the key milestone of obtaining meaningful data from both excised larynxes and from volunteer patients in-vivo has been
achieved. These data, and our methodologies are now in demand by other teams investigating tissue engineering therapies. To date we have assisted Harvard [13] and
Karolinska [17,18] to quantify the effectiveness of hyaluronic acid tissue augmentation, as well as completing a recent study with Karolinska that examined stem-cell therapy.
We have now been invited to participate in a major NIH funded 5-year research programme based at Wisconsin University. The EPSRC have partially funded our involvement,
and a study has begun to assess the viability of using ultrasonics to measure tissue properties in-vivo. Data obtained by this promising methodology is being compared to that
obtained using our existing electro-mechanical apparatus and similar equipment. If successful then it will give us another tool that will be able to obtain data in a non-invasive
manner in-vivo.
UCLA has requested our assistance for a study to quantify the change in vocal fold tissue tension resultant from nerve stimulation. This will be carried out in-vivo using a
canine model. If successful then this would enhance our understanding of the interaction between the level of stimulation of the recurrent laryngeal nerve (RLN) and the
resultant tension in the vocal fold cover. We propose to carry out a short pilot study, based on four trips to UCLA, to determine if it is feasible to use either the Laryngeal
Tensiometer (LT) or the Linear Skin Rheometer (LR) to obtain in-vivo data from an anaesthetised dog.
3. AIMS AND OBJECTIVES
The aim of the proposed research is to quantify the relationship between stimulation of the recurrent laryngeal nerve (RLN) and the resultant change is tension of the vocal fold
cover, and to quantify the change in vocal fold tension with respect to time. To achieve this the key objective is to adapt the vocal fold tissue measuring apparatus to enable it to
be used for in-vivo studies in a canine model.
4. PROGRAMME AND METHODOLOGY
4.1 METHODOLOGY
UCLA have extensive experience of vocal fold research in a canine model. This study will be performed in accordance with the PHS Policy on Humane Care and Use of
Laboratory Animals, the NIH Guide for the Care and Use of Laboratory Animals, and the Animal Welfare Act (7 U.S.C. et. Seq.). The protocol will be submitted for approval
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by the Institutional Animal Care and Use Committee of the University of California, Los Angeles, and will also be submitted for approval to De Montfort University’s Ethical
Approval body.
Instrumentation
Both the LT and the LSR devices could be of value for this project. The LT has been deployed successfully in the OR environment to obtain in-vivo data from humans, and
deployed in Stockholm in a rabbit model. The gape of canines is large enough to insert the LT probe, which will then be attached to the mid-membranous part of the vocal fold.
The LSR probe should also be capable of such an attachment; but with more difficulty due to the bulk of instrument’s measuring head. We are sure of successful attachment
with the LT, and have a reasonable confidence of success with the LSR.
Both instruments can be attached using a needle, or the methylcellulose based adhesive successfully used with humans, or with suction. Both devices operate in a similar
manner, the LT applies a known displacement and measures force, and the LSR applies a known force and measures displacement. The applied stress is in the transverse
direction to the axis of the Vocal Process to the Anterior Commisure. Use of an adhesive or suction ensures that the direct stress is applied only to the epithelium, and careful
control of the needle penetration depth ensures that the direct stress is only applied to lamina propria and epithelium. Our previous published work demonstrates that this is
achievable, and that the stress mainly occurs in the vocal fold cover. Force can be resolved to 10 micrograms, and displacement to 1 micron.
From this data we can derive a measure of the stiffness of the vocal fold cover in terms of force applied per distance displacement. It is possible to derive an absolute estimate
of the value for shear modulus using established mathematical procedures, and applying the correct geometric model. However our primary interest is to measure the change in
stiffness due to RLN stimulation, therefore quantifying the relative change that is adequate for this study.
At least 5 readings will be taken from the same point, using different levels of stimulation. From this data the relative change in stiffness with respect to stimulation will be
determined. We will also take the opportunity to determine whether or not the tension changes with time, due to relaxation of the bio-mechanical process. This will be achieved
by taking a series of readings at known time intervals after the application of the nerve stimulus.
The above procedures are identical to our published and validated methodologies for obtain shear modulus data for the vocal fold cover. They all rely on the subject or
specimen being still, and the stress being applied by the measuring instrument.
The In-vivo Canine Model
Mongrel dogs (approximately 25 kg each) will be used. Each dog will be anaesthetised with intramuscular acepromazine (0.1 – 0.5 mg/kg), then intravenous sodium
pentobarbital (Nembutal) (30 mg/kg) to maintain a level of corneal anaesthesia. Throughout the procedure, general anaesthesia will be achieved using halothane. Maintenance
intravenous fluid will be given at 2 ml/kg/hr. Core temperature will be monitored with a rectal probe, and a heating pad will be used to maintain a homeostatic temperature. The
vocal folds will be visualised prior to operation to verify normal anatomy. Intravenous dexamethasone will be given periodically to decrease nerve and vocal cord swelling.
Each animal will be placed supine, the neck prepped, and a midline incision from the hyoid bone to the sternal notch made. The sternocleidomastoid and strap muscles are
exposed and retracted laterally to expose the larynx and trachea. Neck exploration is then performed to locate both recurrent laryngeal nerves (RLN) and superior laryngeal
nerves (SLN) at their entrance into the larynx. Both RLN will be isolated 5 cm inferior to the larynx. Custom designed rubber electrodes (monopolar, flexible, conductive
neopreme with silicone, and silicone insulation KE45) will be applied to the isolated nerves at the most proximal point dissected. Electrical isolation of the two nerves will be
confirmed by direct visualization of the vocal folds during phonation. The RLN will be stimulated by a constant current nerve stimulator (WR Medical Electronics Co. Model
2SLH, St. Paul, Minnesota). These nerves will be stimulated at 80 Hz with 0-3.0 mA for 1.5 msec pulse duration to achieve adduction.
4.2 WORK PROGRAMME
Work Package 1: Apparatus Construction
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The laryngeal measuring apparatus will be adapted based on our initial understanding of the experimental requirements, and transported to UCLA.
Work Package 2: Data Acquisition (feasibility study)
An initial visit and study will be carried out to ensure the feasibility of using the data acquisition apparatus. Despite our confidence of success there may be improvements that
can be identified. This will be a two-way process, as this will be the first opportunity that the UCLA team will have to deploy the laryngeal apparatus. This will allow us to
modify the study protocols if required, and to identify other studies that will be enabled due to access to DMU’s expertise.
Work Package 3: Data Analysis (feasibility study)
The outcome of this work package will be a set of data that relates vocal fold cover tension to applied stimulation current. These results will be analysed in the light of existing
knowledge, and mathematical models either in the form of equations or graphs will be prepared to describe our new findings.
The experimental setup will be reviewed, and recommendations for changes will be noted and acted upon.
Subject to the quality of the initial results a journal paper will be prepared for peer review. The feedback from the peer review process will become part of the design review.
Work Package 4: Review and redesign of Experimental Procedures
The DMU team will revise the apparatus and methodologies as a result of a study of the results and feedback. The UCLA team will review the experimental setup based on the
initial results.
Work Package 5: Data Acquisition and Analysis (main study)
Over a period of 1 year more data will be acquired using the revised methodologies derived from the design review. As a minimum we will seek to obtain sufficient data to
correlate vocal fold cover tension with stimulation current. As a target each group of 5 readings will offer a Correlation Coefficient of better than 80%, which is considered to
be a reasonable target for an in-vivo study.
As well as modelling the relationship between stimulation and tension, we will also derive estimates for the change in tissue modulus. It is known that that there is a relationship
between the velocity of the mucosal wave (produced during phonation) and tissue modulus and density. It should therefore be possible to relate the wave velocity back to the
nerve stimulation current.
RELEVANCE TO BENEFICIARIES
Vocal fold paresis is a debilitating disease, resulting in partial or total loss of voice. Reinervation therapy has been demonstrated to be of value in many cases, and UCLA are
leaders in developing this treatment. Success and partial success results in an immediate enhancement of the quality of life of the patient. This study will enable us to gain a
greater understanding of how the therapy works, and will therefore result in an improved procedure in the operating theatre.
DISSEMINATION AND EXPLOITATION
There is potential for dissemination by various means. To date DMU have successfully disseminated our work in 3 European Journals, Folia Phoniatrica, The European
Archives of OtoRhinoLaryngology and Acta OtoLaryngologica. The work of the UCLA team is well published in a range of US based journals including The Laryngoscope.
The results of this work will be presented on both sides of the Atlantic as appropriate. The main European Conference opportunity will be the Pan European Voice Conference,
to be held in Groningen in 2007; at which we may be able to make an initial announcement. UCLA will subsequently be able to present the full findings at one of the major
Laryngological Conferences to be held in the USA in 2008.
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Any IPR resulting from the proposed research will be protected through established mechanisms at DMU. A collaboration agreement will be drawn up with UCLA prior to the
start of the project.
It is our intention to continue with this partnership in the future. UCLA are currently preparing a grant application to support this initial study and further work into tissue repair
techniques. Liaison will be enhanced as both Dave Berry and Eric Goodyer are named consultants to the Wisconsin University Hospital based 5 year programme into tissue
engineering.
REFERENCES
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2. Goodyer EN. Novel sensors for measuring fuel flow and level. Proceedings of the SPIE - The International Society for Optical Engineering , pages 150-4, 1989.
3. Goodyer EN. Application of CMOS Technology To Process Instrumentation: Some Case Studies. Software & Microsystems 3(3):75-77, June 1984.
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No.85), pages 1-5, 1983.
5. Goodyer EN. A microprocessor-based gas flow computer. Application of Microprocessors in Devices for Instrumentation and Automatic Control. pages 57-66, 1980.
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8. P.J. Matts. Sensitive Measurement of Stratum Corneum Mechanical Properties Using the Linear Skin Rheometer. Stratum Corneum IV, June 2004, Paris
9. K. P. Ananthapadmanabhan, David J. Moore, Kumar Subramanyan, Manoj Misra & Frank Meyer. Cleansing Without Compromise: The Impact Of Cleansers On The Skin
Barrier And The Technology Of Mild Cleansing Dermatologic Therapy, Volume 17 Issue s1 Page 16 - February 2004
10. Liquid Cleansing Composition Having Simultaneous Exfoliating And Moisturizing Properties. United States Patent Application 20040091446
11. Bioengineering of the Skin, Skin Biomechanics. Chapter 8 the Gas Bearing Electrodynamometer and the Linear Skin Rheometer. Published by CRC Press. ISBN 0-84937521-5
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13. Goodyer EN,Gunter H,Masaki A, Kobler J. Mapping the visco-elastic Properties of the Vocal Fold, AQL 2003, Hamburg.
14. Goodyer EN, Muller F, Bramer B, Chauhan D, Hess M. In Vivo Measurement of the Elastic Properties of the Human Vocal Fold. European Archives of Oto-RhinoLaryngology, 263(5):445-462, May 2006.
15. Goodyer EN, Hemmerich S, Müller F, Kobler JB, Hess M. The shear modulus of the human vocal fold, preliminary results from 20 larynxes. European Archives of OtoRhino-Laryngology. Online August 2006
16. M Hess, F Muller, J Kobler, S Zeitels, E Goodyer. Measurements of Vocal Fold Elasticity Using the Linear Skin Rheometer. Folia Phoniatrica, March 2006, vol 58, issue 3.
17. S Hertegård, Å Dahlqvist, E Goodyer, E Maurer. Viscoelasticity In Scarred Rabbit Vocal Folds After Hyaluronan Injection - short term results. AAO-HNSF/ARO Research
Forum during the 2004 Annual Meeting of the American Academy of Otolaryngology-Head and Neck Surgery Foundation, New York, New York, September 19-22, 2004.
18. Hertegård S, Dahlqvist Å, Goodyer E, Maurer. Viscoelastic Measurements After Vocal Fold Scarring In Rabbits– Short Term Results After Hyaluronan Injection. Acta
Oto-Laryngologica – July 2006
19. Chhetri, D.K., Mendelsohn, A.H., Blumin, J.H., Berke, G.S. Long-term follow-up results of selective laryngeal adductor denervation-reinervation surgery for adductor
spasmodic dysphonia.. The Laryngoscope. 116 (4), pp. 635-642.
20. Chhetri, D.K., Berke, G.S.. Treatment of adductor spasmodic dysphonia with selective laryngeal adductor denervation and reinervation surgery. Otolaryngologic Clinics of
North America 39 (1), pp. 101-109.
21. Chhetri, D.K., Blumin, J.H., Vinters, H.V., Berke, G.S. Histology of nerves and muscles in adductor spasmodic dysphonia. Annals of Otology, Rhinology and Laryngology
112 (4), pp. 334-341.
22. Tran QT, Berke GS, Gerratt BR, Kreiman J. Measurement of Young's modulus in the in vivo human vocal folds. Ann Otol Rhinol Laryngol. 1993 : 102, 584-91.
23. Regeneration Of The Vocal Fold Using Autologous Mesenchymal Stem Cells. Kanemaru S, Nakamura T, Omori K, Kojima H, Magrufov A, Hiratsuka Y, Hirano S, Ito J,
Shimizu Y. Ann Otol Rhino Laryng. 2003 Nov;112(11):915-20.
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