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J Mater Sci: Mater Med (2010) 21:1979–1987 Author's personal copy
In vivo study of ethyl-2-cyanoacrylate applied in direct contactwith nerves regenerating in a novel nerve-guide A. Merolli • S. Marceddu • L. Rocchi •F. Catalano Received: 1 January 2010 / Accepted: 22 February 2010 / Published online: 19 March 2010Ó Springer Science+Business Media, LLC 2010 Stitch suture is still the most recommended method to hold a nerve-guide in place but stitch suture is awell known cause of local inflammatory response. Glues of The gold standard in treating nerve gap-injuries is the several kinds have been proposed as an alternative but they autograft []. Unfortunately, there are several limitations are not easy to apply in a real surgical setting. In 2006 and complications associated with autografts: (a) harvesting authors developed a new concept of nerve-guide termed a donor nerve graft may have significant co-morbidity ‘‘NeuroBox'' which is double-halved, not-degradable and ]; (b) the donor nerve is, often, a smaller sensitive nerve rigid, and allows the use of cyanoacrylic glues. In this which limits, from the beginning, a full recovery when a study, Authors analyzed histologically the nerve-glue bigger and more important motor nerve requires the treat- interface. Wistar rats were used as animal model. In group ment; (c) there is an increasing difficulty in proposing an 1, animals were implanted a NeuroBox to promote the autograft to patients who neither accept the sacrifice of their regeneration of an experimentally produced 4 mm gap in nerves and its associated morbidity nor the lack of a guar- the sciatic nerve. In group 2, the gap was left without repair anteed positive outcome (in the worst case, they will per- (‘‘sham-operated'' group). Group 3 was assembled by ceive two lesions instead of one); (d) the two stitch sutures harvesting 10 contralateral intact nerves to document the securing the autograft (one proximal and one distal) may be normal anatomy. Semi-thin sections for visible light the site of an unfavourable fibroblastic proliferation microscopy and ultra-thin sections for Transmission Elec- An alternative to autograft is the allograft but it may tron Microscopy were analyzed. Results showed that bring the even greater problem of a life-long immunosup- application of ethyl-2-cyanoacrylate directly to the epi- pressive therapy []. A new class of commercial allografts neurium produced no significative insult to the underlining are now commercially available as non-immunogenic to nerve fibers nor impaired nerve regeneration. No regener- the host, since they are so highly processed that only the ation occurred in the ‘‘sham-operated'' group.
Laminin-laden structure of the original nerve fasciclesremains []; this treatment assimilate them to multichan-neled artificial nerve guides.
Artificial nerve guides (or conduits) have been intro- duced into clinical practice more than 20 years ago; theyare cylindrical conduits inside which a regenerating nervestump may find protection and guidance An overview A. Merolli (&)  L. Rocchi  F. Catalano of the clinical outcome showed that they perform at least as Orthopaedics and Hand Surgery Unit, The Catholic University good as autografts in peripheral nerve injuries where gaps School of Medicine in Rome, Complesso ‘‘Columbus'',via Moscati 31, 00168 Rome, Italy are not-longer-than 20 mm; in this situation they bring the advantage of avoiding donor site sacrifice and morbidityand provide an easier and quicker surgical technique , Nowadays there are several degradable nerve guides in National Research Council, ISPA-CNR, via dei Mille 48,07100 Sassari, Italy clinical use ] made of: poly-glycolic-acid (‘‘Neurotube''


J Mater Sci: Mater Med (2010) 21:1979–1987 Author's personal copy
Synovis USA); poly-lactic-acid (‘‘Neurolac'' Ascension apply in a real surgical setting, where the presence of blood USA—Polyganics NL); treated bovine collagen (‘‘Neur- and other fluids is highly variable and little manageable.
agen'' Integra USA; ‘‘Neuroflex'' and ‘‘Neuromatrix'' In 2006 authors developed, and tested in vivo, a new Stryker—Collagen Matrix USA); a proprietary hydrogel concept of nerve-guide termed ‘‘NeuroBox'' (patent WO/ non-degradable in vivo (‘‘SaluBridge'' SaluMedica USA).
2008/029373) which is double-halved, not-degradable and Several other experimental guides have been proposed and rigid, and does not require the use of any stitch to be tested in vitro and in vivo [, ].
sutured to the nerve stump, allowing the use of cyanoac- From the biomaterial point of view, there are three rylic glues instead. The device proved to allow a successful structural districts in a nerve guide, namely: (a) the outer nerve regeneration in vivo [ structure, which is basically the tube inside which the nerve In this study, Authors analyzed histologically the nerve- stumps are accommodated; (b) the inner structure, which is glue interface in vivo. Their hypothesis is that the little how the tube is filled; (c) the suture, which is the site where invasiveness in applying ethyl-2-cyanoacrylate directly to a mechanical force is being applied to the guide and where the epineurium (which is allowed by the peculiar design of a mechanical and biological insult is being received by the the device) is instrumental to the absence of any signifi- nerve stump.
cative insult to the underlining nerve fibers (which was Stitch suture is still the most recommended method to observed) and this contributed significantly to the suc- hold the guide in place but stitch suture is a well known cessful nerve regeneration that had taken place.
cause of local inflammatory response (Fig. Gluesof several kinds have been proposed as an alternative[but, unfortunately, they have proved not easy to 2 Materials and methods Twenty-two male Wistar rats, weighing about 300 g, wereused as animal model. Three groups of samples werestudied. In group 1 (G1), 15 animals were implanted aNeuroBox double-halved stitch-less nerve-guide to pro-mote the regeneration of an experimentally produced 4 mmgap in the sciatic nerve. In group 2 (G2), 7 animals had the4 mm gap left without repair (‘‘sham-operated'' group).
Group 3 (G3) was assembled by harvesting 10 contralateralintact nerves (6 from G1 and 4 from G2) and this group ofsamples documented the normal anatomy of the sciaticnerve in the experimental model.
The NeuroBox was micro-machined from a solid block of poly-methyl-methacrylate (PMMA) (Repsol, Madrid,Spain) using computer-aided manufacturing (CAM) tech-niques, at the Institute of Bioengineering of Catalunia.
Devices were degreased by sonication in a mix of distilledwater and ethyl alcohol (50–50%) and sterilized by low-temperature (STERRAD Sterilization Systems, Johnson & Johnson,USA). In the NeuroBox the traditional cylindrical nerveguide is replaced by a box of two-halves into which threemain compartments are recognizable: (1) a lodgement forthe neural stump (one proximal and one distal); (2) acompartment for the acrylic glue (one proximal and onedistal); (3) a flat ‘‘regeneration chamber'', where elongatingaxons from the proximal stump are invited to spread(Fig. b).
Ethyl-2-cyanoacrylate (Loctite, Henkel, Germany) was Fig. 1 a A transverse section showing two heads of an epineural knot employed as cyanoacrylic glue. The dedicated glue- (S), where a great number of hyperhemic capillaries and hemosiderin compartment of the NeuroBox promotes the polymeriza- deposits can be seen (H&E; bar = 10 lm). b Schematic drawing of a tion of the glue with just the minimum amount which is NeuroBox device: the volume for the acrylic glue (G) and the flat‘‘regeneration chamber'' (R) are labelled needed for its wetting. Neural stumps are gently accommodated


J Mater Sci: Mater Med (2010) 21:1979–1987 Author's personal copy
within their compartments, in the bottom half of the guide, Table 1 Implant and retrieval scheme just prior the end of the polymerization process. The acrylic glue conforms to the stumps. The top-half wasgently positioned so to close the device symmetrically (by wetting, with the glue, the dedicated top-half glue- compartments). However, the NeuroBox guide cannot be considered completely sealed but, on the contrary, some empty space remains at both entrances and fluids and cells may access the regeneration chamber.
Adequate measures were taken to minimize pain or Implantation scheme for G1 (NeuroBox), G2 (sham operated group) discomfort to the animals and experiments were conducted and G3 (intact contralateral nerve) in accordance with ECC D86/609 and with the approval ofthe National Committee for Animal Experimentation.
Anaesthesia was induced by 75 mg/kg ketamine chlorhy- tight. The sciatic nerve was cut proximally to its trifurca- drate (KETAVET 100, Farmaceutici Gellini, Aprilia, Italy) tion and a gap of 4 mm in length ensued. Surgical opera- and 0.5 mg/kg medetomidine chlorhydrate (DOMITOR, tion required the assistance of optical magnification (Zeiss Farmos Orion Corporation, Espoo, Finland) with intra- OP MI 1, Carl Zeiss, Jena, Germany).
muscular injection on the right tight. A 30 mg/kg methyl- Animals were sacrificed under deep anaesthesia, in an predinisolone (SOLU-MEDROL, Pharmacia & Up John atmosphere saturated with CO2; retrievals followed the NV/SA, Puurs, Belgium) was administered prior to surgery.
timing shown in Table . At retrieval, the nerve is simply A curvilinear transverse incision with superior convex- dislodged from the guide. Macroscopic examination of the ity was performed to gain a smooth access to the intra- operated site was performed. Retrieved nerves were fixed muscular interstice to expose the sciatic nerve, in the left in buffered formaline; post-fixed in osmium tetroxide and Fig. 2 a Intact sciatic nerve of a Wistar rat shows that the epineurium (V); a distinct perineurium (P) surrounds the nerve fascicle (toluidine (E) is a wide bumping protective coat wrapped around the nerve blue; bar = 100 lm). c Transverse section of an intact sciatic nerve: fascicles (F), with main vascular trunks and their collateral sinusoidal the perineurium (P), with its peculiar lamellar arrangement of roughly branches embedded in (bar = 0.5 mm). b Transverse section of an 7–8 concentric layers, surrounds the nerve fascicle (epineurium is intact sciatic nerve: the epineurium (E) is made of loose areolar labelled with E) (H&E; bar = 10 lm) connective tissue and adipose tissue, with embedded epineural vessels


J Mater Sci: Mater Med (2010) 21:1979–1987 Author's personal copy
dehydrated in serial passages of acetone, then embedded inaraldite. Semi-thin sections were stained for visible lightmicroscopy (Nikon SMZ 800); ultra-thin sections were cutfor Transmission Electron Microscopy (TEM) (Zeiss EM109T). Images were processed by a commercial software(‘‘PhotoDeLuxe'', Adobe).
Five zones were mapped in a retrieved nerve. (1) The Proximal End (PE), 5 mm proximal to the surgical tran-section. (2) The Proximal Glueing Region (PGR), 1 mm inlength and about 1 mm proximal to the surgical transection(this is the proximal area embraced and locked by thepolymerized acrylate glue). (3) The Regenerate (R). (4)The Distal Glueing Region (DGR), 1 mm in length andabout 1 mm distal to the surgical transection (this is thedistal area embraced and locked by the polymerizedacrylate glue). (5) The Distal End (DE), 5 mm distal to thesurgical transection.
Ethyl-2-cyanoacrylate was applied in direct contact withthe epineural sheath. In the rat, as controls show, Epineu-rium is a wide bumping protective coat wrapped around thenerve fascicle(s) (Fig. a), made of loose areolar connec-tive tissue and adipose tissue, with embedded main vas-cular trunks and their collateral sinusoidal branches(epineural vessels) (Fig. b). A distinct perineurium, with apeculiar lamellar arrangement of roughly 7–8 concentriclayers, surrounds the nerve fibers (Fig. c).
Authors did not find any image of adverse early inflammatory response or tissue necrosis. No glue appearedinside the epineurium or inside the nerve bundles, in sec-tions taken at the glueing regions or anywhere else, at anytime.
When 6 animals in G1 were sacrificed in an early stage (2 after 3 days; 2 after 1 week; 2 after 2 weeks; as shownin Table no finding was suggestive of any impairment ofnerve fibers at the level of the glueing regions (Fig. In Fig. 3 After 3 days, no morphological alteration of nerve fibers was this stage, the regenerate consists mostly of an assembled found at the level of the glueing regions, both in unstained sections jelly structure of fibrin, blood cells, Schwann's cells and (a) and in immuno-stained sections (b; green = axons; red = Schwann's cells) (courtesy of the Institute of Bioengineering of In G1 nerve regeneration occurred after 1 months and it was observed in 9/9 cases (3 after 1 month; 3 after2 months; 3 after 3 months; as shown in Table ). The Epineural sheath which was in direct contact with ethyl- retrieved nerve was about 4 mm longer than the contra- 2-cyanoacrylate in the proximal and distal glueing regions lateral intact nerve. There were no signs of any massive (PGR and DGR) showed no major microscopic alterations and adverse intraneural fibroblastic proliferation; large and nor they were found in the underlining nerve fibers; a clear small myelinated fibers were identified and also several fascicular structure, well demarcated from the surrounding non-myelinated axons; fine blood vessels were well rep- epineurium, was preserved (Fig. ).
resented (confirming what already reported ]). A fibrous More in details, in the PGR the normal structure of capsule was found around the guide but not inside the the nerve was preserved, with myelinated large diameter regeneration chamber (Fig. fibers and smaller non-myelinated fibers and intraneural


J Mater Sci: Mater Med (2010) 21:1979–1987 Author's personal copy
Fig. 4 a A transverse section of the nerve regenerated inside the a sharp blade (SB) and the transparent wall of the regeneration NeuroBox (toluidine blue; bar = 10 lm). b A tiny intraneural chamber showed tiny blood vessels in the regenerated nerve capillary in the regenerated nerve (TEM; bar = 1 lm). c A thick fibrous capsule (FC) was found around the nerve-guide; it was cut by vascularization. TEM showed smaller fibers, with thin transection with negligible or absent gap, prescribes the myelin sheath, which represent newly regenerating axons; joining of the two nerve-stumps by an end-to-end suture there are also larger fibers with disruption myelin figures, (neurorraphy) ] and it is widely accepted that the stumps as expected in degenerating axons proximal to a lesion must not be sutured under tensional stress ] otherwise (Fig. b). In DGR, tiny myelinated and non myelinated the development of a fibroblastic and myofibroblastic fibers represent axons that entered the distal stump; there proliferation will be greatly favoured. The latter phenom- is, also, the presence of Schwann's cells digesting the enon will impair and eventually stop any axonal regener- myelin of axons which underwent Wallerian degeneration ation []. However the use of stitches (both degradable or not degradable) represent a significative local inflammatory On the contrary, no regeneration was observed in G2, stimulus [, ] even without tensioning the stumps and is where the gap was left un-treated (3 after 1 month; 4 after able to provoke enough fibrosis to impair nerve regener- 2 months; as shown in Table ).
One should not assume the fibroblastic and myofibrob- lastic proliferation to be un-avoidable, just because of our present inability to abandon the use of stitches. Researchon ‘‘stitch-less'' techniques in any surgery associated with There are several proposals in the literature about the best artificial nerve guides seems instrumental, in our opinion, solution to adopt for each of the three districts which to the successful development of the guides themselves and constitute an artificial nerve guide [but the suture dis- glues seem to most straightforward option.
trict, in our opinion, has received minor attention until The present knowledge on nerve-glues is, however, now. This district is the mechanical interface between the limited. In the past, cyano-acrylic glues, and ethyl-2- guide and the nerve and is a crucial point both biologically cyanoacrylate in particular, have been associated with and surgically; established surgical treatment, in acute Asthma [] and Allergic Contact Dermatitis –



J Mater Sci: Mater Med (2010) 21:1979–1987 Author's personal copy
Fig. 5 A clear fascicular structure of the nerve was preserved in the of glue were found (a and b: toluidine blue; bar = 0.1 mm) (c and d: proximal glueing region (a, c) and in the distal glueing region (b, d), H&E; bar = 10 lm) were well demarcated from the surrounding epineurium; no particles Fig. 6 a Transmission electron microscopy of the proximal glueing to a lesion (bar = 10 lm). c The distal glueing region shows tiny region with myelinated and non-myelinated fibers (bar = 1 lm) myelinated and non myelinated fibers as well; Schwann's cells are representing newly regenerating axons; b there are also fibers with digesting the myelin of axons which underwent Wallerian degener- disruption myelin figures, as expected in degenerating axons proximal ation (bar = 10 lm) J Mater Sci: Mater Med (2010) 21:1979–1987 Author's personal copy
Furthermore, ethyl-2-cyanoacrylate has been correlated Discussing the experimental design, it must be said that with neuropathy in sporadic cases in which, it must be the limited number of implanted guides was dictated noted, other factors were possibly involved and great mostly by the high costs associated with their production, quantity and/or prolonged exposure were reported [– while the short length of the treated gap was chosen to As a group of rapidly polymerizing adhesives, cyano- simplify the experiment aimed primarily at testing the acrylates have found surgical applications as skin-wound adequacy of the new concept of the ‘‘stitch-less'' guide.
sutures as well as hemostatic and embolizing agents [ Despite these limitations, a safe use of ethyl-2-cyanoac- In more recent literature promising results have been rylate in direct contact with a nerve regenerating inside the reported with cyanoacrylate molecules in nerve surgery, in NeuroBox was demonstrated and this maintains our com- mitment to refine a ‘‘stich-less'' surgical technique for 2-octyl-cyanoacrylate. These papers show that cyanoacrylic nerve repair. Any progress in nerve-guide surgery will lead, glues can be used in direct contact with the nerve –].
someday, to a significant reduction in nerve-autografts The actual use of cyanoacrylate glue in a true surgical requirement; this will mean lesser associated morbidity, setting may bear a lot of technical difficulties and this may shorter surgical time, minor complexity. In brief, a real explain, in part, early negative recommendations improvement for treating a large number of patients.
First: it is not easy to control the curing time of the glue,which should be not too fast, so giving the surgeon ade- The NeuroBox is an international patent of the Catholic University in Rome (WO/2008/029373).
quate time to accurately put the stumps in place, but (at thesame time) should be not too slow, to avoid the accidentalflow of part of the glue in front of the nerve stump(bringing the misfortunate consequence of sealing it and impairing the regeneration process). Second: to find asuitable method of delivering the glue in a real surgical 1. Sinis N, Schaller HE, Schulte-Eversum C, Lanaras T, Schlosshauer environment may be an additional problem; for example, B, Doser M, et al. Comparative neuro tissue engineering using tiny quantities required by a digital nerve suture could different nerve guide implants. Acta Neurochir Suppl. 2007; polymerize early inside a microscopic delivery tube, before 2. Rappaport WD, Valente J, Hunter G. Clinical utilization and reaching the stump. Third: in a real surgical setting, an complications of sural nerve biopsy. Am J Surg. 1993;166:252–6.
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32_RODRIGUEZ MARADIAGA_pp_484-495.QXD_Layout 1 07/02/13 16:06 Pagina 484 The Global Quest for Tranquillitas Ordinis. Pacem in Terris, Fifty Years Later Pontifical Academy of Social Sciences, Acta 18, 2013 www.pass.va/content/dam/scienzesociali/pdf/acta18/acta18-rodriguezmaradiaga.pdf Aproximación geopolítica a la justiciaen un mundo globalizado

Microsoft word - laboratory rotations researchtopics msc iandi - 100827

Researchmaster Infection & Immuntiy Laboratory rotations & Reaearch topics IMMUNOLOGY – LABROTATIONS & RESEARCH TOPICS Researchmaster Infection & Immuntiy Laboratory rotations & Reaearch topics Title: (Immuno)pathogenesis of chronic lymphocytic leukemia Workgroupleader: dr. A.W. Langerak T: 010-704 4089 E: a.langerak@erasmusmc.nl W: http://www.erasmusmc.nl/immunologie/onderzoek/moleculaireimmunologie/mid/?lang=en Background Chronic lymphocytic leukemia (CLL) is the most frequent type of leukemic proliferation in the Western world. CLL is found in adults and typically associated with age. The majority of CLL cases is of B-cell type, while a minority derives from T lymphocytes (also called T-cell large granular lymphocyte leukemia, T-LGL). Over the last years it has become increasingly clear that CLL is a heterogeneous disease, with a variable clinical course and differences in survival. CLL is an example of a multi-factorial disease, in which both genetic and micro-environmental factors contribute to leukemogenesis. Although in recent years many studies have focused on prognostic markers, there is still no complete picture of the factors that are involved in the (immuno)pathogenesis and that are determining for the prognosis.