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A pilot study on a new anchoring mechanism for surgical applications based on mucoadhesives

A pilot study on a new anchoring mechanism for surgical applications based on mucoadhesives
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   Minimally Invasive Therapy  . 2011;20:3  –  13 ORIGINAL ARTICLE A pilot study on a new anchoring mechanism for surgical applications based on mucoadhesives SELENE TOGNARELLI 1 , VIRGINIA PENSABENE 1,2 , SARA CONDINO 3 ,PIETRO VALDASTRI 1 , ARIANNA MENCIASSI 1 , ALBERTO AREZZO 4 , PAOLO DARIO 1,2 1 CRIM Lab, Scuola Superiore Sant  ’  Anna, Pisa, Italy,  2 Italian Institute of Technology (IIT), Center for  MicroBioRobotics IIT@SSSA, Pontedera, Italy,  3 ENDOCAS Center for Computer Assisted Surgery, University of Pisa,Pisa, Italy, and   4 Centre of Minimally Invasive Surgery, University of Torino, Italy  Abstract In order to minimize the invasiveness of laparoscopic surgery, different techniques are emerging from research to clinicalpractice. Whether the incision is performed on the outside  –   as in Single Port Laparoscopy (SPL)  –   or on the inside  –   as inNatural Ori fi ce Transluminal Endoscopic Surgery (NOTES)  –   of the patient ’ s body, inserting and operating all theinstruments from a single access site seems to be the next challenge in surgery. Magnetic guidance has been recently proposed for controlling surgical tools deployed from a single access. However, the exponential drop of magnetic  fi eld withdistance makes this solution suitable only for the upper side of the abdominal cavity in nonobese patients. In the present paperwe introduce a polymeric anchoring mechanism to lock surgical assistive tools inside the gastric cavity, based on the use of mucoadhesive  fi lms. Mucoadhesive properties of four formulations, with different chemical components and concentration,are evaluated by using both  in vitro  and  ex vivo  test benches on porcine stomach samples. Hydration of mucoadhesive  fi lms by contact with the aqueous mucous layer is analyzed by means of   in vitro  swelling tests, whereas optimal preloading conditionsand adhesion performances, in terms of detachment force, supported weight and size are investigated  ex vivo.  Mucoadhesion isobserved with all the four formulations. For a contact area of 113 mm 2 , the maximum normal and shear detachment forceswithstood by the adhesive  fi lm are 2,6 N and 1 N respectively. These values grow up to 12,14 N and 4,5 N when the contactarea increases to 706 mm 2 .Lifetime of the bonding onthe inner side of the stomach wallwas around two hours. Mucoadhesiveanchoring represents a fully biocompatible and safe approach to deploy multiple assistive surgical tools on mucosal tissues by minimizing the number of access ports. This technique has been quantitatively assessed  ex vivo  for anchoring on the inner wallof the gastric cavity or in gastroscopic surgery. By properly varying the chemical formulation, this approach can be extended toother cavities of the human body. Key words:  Mucoadhesive  fi lms, anchoring system, minimally invasive surgery, single port laparoscopy, natural ori   fi cestransluminal surgery  Introduction Laparoscopy has revolutionized the methods used by surgeons in traditional procedures, producing impor-tant advantages in terms of decreased postoperativepain, improved cosmetics and reduced hospitaliza-tion. Recently, there has been an impetus in thesurgical community to further reduce the invasivenessof laparoscopic surgery, designing and developingnew instrumentation and technologies. To achievethis goal, surgeons proposed to limit the number of abdominal incisions (Single Port Laparoscopy   –   SPL or LaparoEndoscopic Single-Site surgery   –   LESS (1))or to eliminate them completely (Natural Ori fi ceTransluminal Endoscopic Surgery   –   NOTES (2)).However, by reducing the number of trocars/incisions,and thus introducing the current endoscopes andinstruments together at a single site, several technicalrestrictions arise. Among these, the most critical issuesare a limited triangulation, poor ergonomics, limited Correspondence: S. Tognarelli, CRIM Lab, Scuola Superiore Sant  Anna, Piazza Martino della Libertà, 33-56127 Pisa, Italy.E-mail: selene.tognarelli@mail.crim.sssup.itISSN 1364-5706 print/ISSN 1365-2931 online    2011 Informa HealthcareDOI: 10.3109/13645706.2010.496955    M   i  n   i  m   I  n  v  a  s   i  v  e   T   h  e  r   A   l   l   i  e   d   T  e  c   h  n  o   l   D  o  w  n   l  o  a   d  e   d   f  r  o  m   i  n   f  o  r  m  a   h  e  a   l   t   h  c  a  r  e .  c  o  m   b  y   I   B   I   C   i  r  c  u   l  a   t   i  o  n  -   A  s   h   l  e  y   P  u   b   l   i  c  a   t   i  o  n  s   L   t   d  o  n   0   1   /   1   2   /   1   1   F  o  r  p  e  r  s  o  n  a   l  u  s  e  o  n   l  y .  visual axis and  fi eld of view, and internal and externalcollision of instruments (2). In the case of SPL orNOTES, using a single trocar or a  fl exible endoscopeto deploy Assistive Internal Surgical Instruments(AISI) can overcome some of these hurdles.For laparoscopic interventions, miniature magneti-cally guided devices that  fi t entirely inside the abdo-men were presented in (3,4). They consist of instruments which are introduced through a singletrocarintotheabdominalcavityandarethenstabilizedon the peritoneum by external handheld magnets.Trans-abdominal magnetic anchoring and guidancesystems (MAGS) for minimally invasive surgery weredemonstrated in laparoscopic procedures on animals(2), introducing a camera and two tissue retractorsthrough a standard 12 mm trocar port. The maximumweight of a single AISI was 45 g, which was fully supported by the transabdominal magnetic link.From a technical standpoint, the most advancedsystem exploiting magnetic  fi xation and positioningconsists in a peritoneum-mounted imaging robot, asreported by Oleynikov et al. (5). It is a stationary outertube of 21 mm in diameter, with a rotating inner tubethat houses the lens, a camera board, and three micro-motors, for a total weight of 75 g (6). An improvedprototypeofthisroboticcamera,12mmindiameter,isdescribed by Canes and coworkers (7).However, relying on magnetic  fi eld for deviceanchoring and stabilization introduces a set of limita-tionsstillfarfrombeingsolved.Thecouplingstrengthdecreases exponentially with respect to the distancebetween the two magnets, thus limiting potentialapplications to the upper side of the abdominal cavity.Additionally, obese patients may not bene fi t from thisapproach due to the thick fat layer that acts as a spacerin between the external and the internal magnet.Furthermore, the operating area must not be crowdedwith magnets in order to prevent magnet-magnetinterference and operator-magnet collisions. Thisissue typically limits the use of MAGS to one ortwo units maximum. When several units are usedinside the abdominal cavity, two of them may occa-sionally come too close to each other and link together. If this happens, the procedure must beimmediately converted to open surgery to retrievethe MAGS (3). Finally, as for magnetic resonanceimaging (MRI), magnetic technology would be abso-lutely contraindicated for peacemaker holders, andharmful for patients with known metal foreign bodiesor implanted metal orthopedic prostheses (8).In order to overcome these limitations, while stillmaintaining the concept of introducing multiple toolsfrom a single access, we propose a polymeric anchor-ing mechanism based on biocompatible polymericbioadhesive  fi lms. This approach can be used to  fi xsurgical assistive or diagnostic instrumentation to theinner wall of human cavities. Within the present study,we aim to achieve a proof of concept of the proposedstrategy for the inner gastric cavity. AISI deployed inthe stomach may be useful in the therapy of gastriccancer(9),in supporting funduplicationprocedures totreatgastroesophagealre fl uxdisease(GERD)(10)andfor bariatric surgery (11). Additionally, novel techni-ques, such as natural ori fi ces transgastric surgery (12),may bene fi t from the use of purposely developed AISIattached to the inner gastric wall. Another interestingemerging technology where the proposed adhesionstrategy can play a fundamental role is endoluminalrobotic surgery. Harada et al.(13)deployed a modularrobot via oral access in the gastric cavity to performsurgical operations. In this case the feet of the robotjust push against the stomach wall, thus a stableadhesion is not guaranteed. Applying a  fi lm of mucoadhesive at the anchoring sites would improvestability of operation. Other devices reported in liter-ature that may bene fi t from the work presented in thispaper range from deployable pH or obscure bleedingsensors (14,15), currently anchored to the lumen wallby surgical clips, to physiological transducers that canbe used to monitor the status of a tissue during asurgical operation (16).A bioadhesive can be de fi ned as a synthetic orbiological material capable of adhering onto a biolog-ical substrate or tissue (17). Bioadhesion is governedby several mechanisms, including swelling of the poly-mer and binding between  fi lm and tissue, by attractivemolecular connections, Van der Waals, hydrogen andionic bonds. The adhesive formulation can be mod-i fi ed in order to enable the attachment onto the wetmembrane layers covering human organs, such as theperitoneum, ortothemucosal layerliningonthe innersurface of the gastrointestinal tract. In this latter case,we usually refer to mucoadhesion.This  “ mucoadhesion ”  is allowed by natural orsynthetic hydrophilic macromolecules with high den-sity of hydrogen bond-forming groups. They can beembedded in  fi lms or platelets in order to developcontrolled drug carriers, able to locally release che-micals in the gastrointestinal area (18). In the work of Dodou et al. (19,20), mucoadhesives were studied forgenerating high static friction between a colonoscopicdevice and the colonic wall.Here we present a new application of these adhesivepolymers to  fi x AISI, such as miniature cameras, orimaging and lighting robots (8) to the inner wall of thegastric cavity. The mucoadhesive properties wereinitially investigated by using small prototyping mod-ules with a diameter of 12 mm that can be introducedinto the stomach by   fl exible endoscopy through theoral access (21). Bearing in mind potential extension4  S. Tognarelli et al.    M   i  n   i  m   I  n  v  a  s   i  v  e   T   h  e  r   A   l   l   i  e   d   T  e  c   h  n  o   l   D  o  w  n   l  o  a   d  e   d   f  r  o  m   i  n   f  o  r  m  a   h  e  a   l   t   h  c  a  r  e .  c  o  m   b  y   I   B   I   C   i  r  c  u   l  a   t   i  o  n  -   A  s   h   l  e  y   P  u   b   l   i  c  a   t   i  o  n  s   L   t   d  o  n   0   1   /   1   2   /   1   1   F  o  r  p  e  r  s  o  n  a   l  u  s  e  o  n   l  y .  of the proposed technique to other human cavities, itis worthy to mention that the same modules arecompatible with standard trocar for laparoscopicaccess, while SPL and LESS would allow the deploy-ment of modules up to 35 mm in diameter (22).In this paper, we analyze the adhesive propertiesof four different mucoadhesive chemical formulationsand compare their performance by   in vitro  and  ex vivo tests. A purposely developed test bench is presented inorder to evaluate both the preload force and the timerequired for an ef  fi cient anchoring. The adhesionstrength of these biocompatible mucoadhesive  fi lmsis measured, presenting the detachment forces anddebonding time that each formulation can afford.Finally, different dimensions for the mucoadhesivemodules are tested in order to de fi ne a guideline forthe design of a new generation of   “ mucoadhesiveassistive internal surgical instruments ” . All the ex vivo  tests of this pilot study were performed onthe inner surface of the gastric cavity. Suggestionsregarding how to approach different districts of thehuman body are outlined in the conclusions. Material and methods Adhesive properties of polymeric  fi lms with humanmucous have already been investigated (19,23). Forour intended purpose, the mucoadhesive  fi lm shouldbe designed considering that the physiological condi-tions change drastically in different human cavities,and in particular in the gastrointestinal tract regardingpH, tissue morphology and thickness of mucous layer(19). In the present pilot study, four different kindsof mucoadhesive  fi lms were prepared by varying themethod and formulation described by Dodou et al.(19), aiming to achieve adhesion on the inner side of the stomach. These were then compared with twosessions of   in vitro  and  ex vivo  tests.  Mucoadhesive  fi lms preparation A 0.3% w/w and a 1% w/w mucoadhesive hydrogelswere prepared by slowly sifting Carbopol CP 971PNF (agift by Noveon Inc., Cleveland, OH, USA) intodeionized water using a speed mixer. After that, theentire quantity of dry polymer was added. Stirringthen continued for 15 additional minutes at moderatespeed (600 rpm) to prevent air entrapment into thedispersion. Afterwards,  < 1 ml of triethanolamine(TEA 33729, purchased from Sigma Aldrich,St. Louis, MO, USA) was added under mild stirring(500 rpm) in order to neutralize the dispersion(pH 6,9  –  7,2). In this way, hydrogels were obtained.A 10% w/w polyvinylpyrrolidon (PVP, by Sigma-Aldrich), a 3% w/w polypropylene glycol (PPG)and a 2% w/w polyetilenglycol (PEG) aqueous solu-tions were prepared under stirring at 800 rpm for15 minutes each. Finally, a 1% Pluronic PF127(MW 12,600, Sigma Aldrich) aqueous solution wasprepared and stirred for 15 minutes. At this stage of the procedure, two different hydrogel dispersionswere prepared. The  fi rst one was obtained by mixingthe 0,3% w/w Carbopol hydrogel with the PVP solu-tion, PF127, and PEG or PPG aqueous solutions,while the second one was obtained by mixing the 1%w/w Carbopol hydrogel, with PVP, PF127, PPG orPEG solutions. Both dispersions were mixed understirring at 800 rpm for 15 minutes.The produced dispersions were processed undervacuum at room temperature to remove the entrappedair and they were kept overnight at 4  C to completehydration. The dispersions were returned to roomtemperature and poured into polystyrene Petri dishes.Next, the produced samples were dried in an oven at38  C for 24 h. After demoulding, the  fi nal thicknesswas 0,2 mm in all cases.Table I shows, for each sample (S1, S2, S3, S4), thechemical elements andtheirconcentration (%w/w) inthe  fi nal formulations. In vitro swelling study  In general, mucoadhesion occurs in three stages, i.e.wetting, penetration and mechanical interlockingbetween polymer and mucous membrane (24  –  26).However, as most adhesion phenomena, the mucoad-hesion process is still under debate in the scienti fi ccommunity, thus a single uni fi ed theory is not yetavailable (27).Hydration of mucoadhesive  fi lms by contact withthe aqueous mucous layer is a prerequisite for satis-factory mucoadhesion (28) and can be evaluated by measuring the water absorption capability of thepolymer. Table I. Chemical details for the four mucoadhesive formulations(S1, S2, S3, S4).  FormulationsIngredients  S1 S2 S3 S4 Carbopol   0,3% 0,3% 1% 1% PPG   3% _ 3% _  PVP   10% 10% 10% 10% PEG   _ 2% _ 2% PF127   1% 1% 1% 1%  Anchoring mechanism for surgical applications based on mucoadhesives  5    M   i  n   i  m   I  n  v  a  s   i  v  e   T   h  e  r   A   l   l   i  e   d   T  e  c   h  n  o   l   D  o  w  n   l  o  a   d  e   d   f  r  o  m   i  n   f  o  r  m  a   h  e  a   l   t   h  c  a  r  e .  c  o  m   b  y   I   B   I   C   i  r  c  u   l  a   t   i  o  n  -   A  s   h   l  e  y   P  u   b   l   i  c  a   t   i  o  n  s   L   t   d  o  n   0   1   /   1   2   /   1   1   F  o  r  p  e  r  s  o  n  a   l  u  s  e  o  n   l  y .  The hydration behavior of the four polymeric for-mulations is determined by following the proceduredescribed by Efentakis et al. (29). Brie fl y, fragments of each fi lm, with an area of 95 mm 2 , werecut and 0,1 mlofdeionizedwaterwasaddedontothesurface.At fi xedtimeintervals(1,2,5,10and15minutes)theexcessof water on the surface of swollen  fi lms was absorbedusing blotting paper, and the samples were weighted.The hydration percentages of the polymeric  fi lmswere calculated according to the following equation(17): Swelling Index W W W  h d d  =− where  W  d   and  W  h  represent the weight of the driedand hydrated polymeric  fi lms, respectively.Tests were repeated ten times for each sample and foreach time interval and the  fi nal data were expressed asaverage value  ±  standard deviation (S.D.). Ex vivo mucoadhesion tests A  fi rst set of experiments was carried out with apurposely developed setup, for the determination of preload force and time required for an ef  fi cientanchoring of AISI with mucoadhesion strategy andthe evaluation of the normal and shear detachmentforces and time that the mucoadhesive  fi lm can stand.In particular, the preload conditions can in fl uence thepenetration and mechanical interlocking betweenpolymeric  fi lm and mucous membrane.A second set of experiments was performed by using in part the same test bench for evaluating therelationship between the mucoadhesion and thedimension and weight of a generic AISI providedby mucoadhesive  fi lm. Ex vivo  experiments were carried out using freshly excised porcine stomach tissue gathered from theslaughterhouse on the days of the trials. Gastric speci-mens were gently cleaned in order to remove diges-tion debris, while preserving the mucous layer thatprotects the epithelial tissue.The stomach model was selected because it pre-sents a high quantity of mucous, which can be main-tained in  ex vivo  conditions. More interestingly, thephysiological conditions inside the stomach are theworst for the mucoadhesive  fi lm lifetime, because of the acid pH values (e.g. two to three  in vivo  condi-tions) (30). This means that if the  fi lms work properly in these conditions, they can perform even better inother sections of the gastrointestinal tract, where thepH is more neutral.In all these tests, before starting the experiments,the pH value on the mucosal surface was measured by a pocket-sized pH-meter with replaceable electrode(Hanna Instruments, Padova, Italy).  Adhesion performance and preload requirements The porcine stomach was opened longitudinally and fi xed, with the inner surface facing upwards on aDerlin plate (14,5    14 cm 2 ) by means of two rect-angular constrains (Figure 1A).The polymeric  fi lms were attached by cyanoacry-late adhesive to 12 mm diameter cylindrical rapid-prototyping modules.The  fi lm-covered module was placed in contactwith the gastric tissue and the preload force (5 and10 N) was applied on the sample for a fi xed time (one,three,  fi ve minutes) in order to ensure intimate con-tact between the tissue and the mucoadhesive sample.A digital load cell (Alluris, FMI210, Freiburg,Germany) with 0,01 N resolution and 0  –  50 Nmeasuring range was mounted on a servo-controlled linear slider (M-410CG, PI, Karlsruhe,Germany). The maximum stroke of the slider is100 mm, with an adjustable speed from 7  m m up to A.B. Figure 1. Experimental setup for preload application (A) and adhesive detachment force measurements (B). 6  S. Tognarelli et al.    M   i  n   i  m   I  n  v  a  s   i  v  e   T   h  e  r   A   l   l   i  e   d   T  e  c   h  n  o   l   D  o  w  n   l  o  a   d  e   d   f  r  o  m   i  n   f  o  r  m  a   h  e  a   l   t   h  c  a  r  e .  c  o  m   b  y   I   B   I   C   i  r  c  u   l  a   t   i  o  n  -   A  s   h   l  e  y   P  u   b   l   i  c  a   t   i  o  n  s   L   t   d  o  n   0   1   /   1   2   /   1   1   F  o  r  p  e  r  s  o  n  a   l  u  s  e  o  n   l  y .  1 mm/s. A proportional derivative (PD) controller wasimplemented in order to enable precise movement of the load cell during the measurements. As shownin Figure 1B, the load cell and the tissue holderwere  fi xed so that a normal force can be applied tothe  fi lm-covered module attached to the gastricspecimen.A continuous translational motion was imposedto the slider in the Y direction with a speed of 0,7 mm/s and the mucoadhesive detachment force(F D ) was determined for each chemical formulation.Each measurement was repeated ten times on dif-ferent areas of the gastric specimen. It is worthy tonote that all the tissue samples were extracted fromthe same animal and the morphological differencesbetween different gastric segments were assumed tobe negligible.The detachment force measurements for the fourmucoadhesive formulations were aimed to select thebest preload condition, in terms of force and time,and the best chemical formulation among the fourproposed.  Measurement of supported weight and size The mucoadhesive  fi lms were attached to cylindricalrapid-prototype modules and, based on the previoustestsession,theoptimalpreloadconditionwasapplied.AsrepresentedinFigure2, theDerlinsupport withthetissue was turned upside-down and a weight holderwastiedtothemodule.Thisallowedtovarythenormalpulling load (15, 20 and 25 g), working against themucoadhesive anchoring. The debonding time for thefour mucoadhesive formulations under three differentloading conditions was measured.Based on the results obtained so far, the bestperforming polymeric formulation was attached tocylindrical modules having different diameters (i.e.12, 15, 20 and 30 mm), as represented in Figure 3,and F D  was measured for each different module by using the same setup as described above. Preloadforce and time adopted in this experiment are thebest ones assessed during the previous test sessions.Each test was performed ten times to achieve statis-tical relevance. The  fi nal goal of this experiment is toverify that, given that the adhesion is essentially asurface phenomenon, the detachment force is pro-portional to the mucoadhesive contact area. Thiswould allow us to predict the required module diam-eter, given the AISI load.A similar test was performed to quantify the sheardetachment force as the module diameter increases.This experiment was performed with the same setupas described previously, properly modi fi ed in order toapply a tangential load on the mucoadhesive module,as represented in Figure 4.A continuous translational motion was imposed tothe slider tangentially to the tissue with a speed in arange of 0,7 mm/s and the shear detachment force(F S ) was determined. Also in this case, the bestperforming polymeric formulation was attached tocylindrical modules having different diameters (i.e.12, 15, 20 and 30 mm). The preload force and timeadopted in this experiment are the best ones assessedduring the previous test sessions. Figure 2. Experimental setup for debonding time measurement.  Anchoring mechanism for surgical applications based on mucoadhesives  7    M   i  n   i  m   I  n  v  a  s   i  v  e   T   h  e  r   A   l   l   i  e   d   T  e  c   h  n  o   l   D  o  w  n   l  o  a   d  e   d   f  r  o  m   i  n   f  o  r  m  a   h  e  a   l   t   h  c  a  r  e .  c  o  m   b  y   I   B   I   C   i  r  c  u   l  a   t   i  o  n  -   A  s   h   l  e  y   P  u   b   l   i  c  a   t   i  o  n  s   L   t   d  o  n   0   1   /   1   2   /   1   1   F  o  r  p  e  r  s  o  n  a   l  u  s  e  o  n   l  y .
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