Advantages and disadvantages of intraoperative endoscopy.
\r\n\tThis book will mainly cover work related to: (i) cells mechanosensing and mechanotransduction mechanisms (ii) computational and experimental techniques in mechanobiology, (iii) mathematical mechanobiological models of bone remodeling, (iv) bone mechano-transduction, (v) innovative tools for mechanobiology and the role of medical imaging in this field and (vi) any other proposals related to innovations, clinical application and perspectives of mechanobiology.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"0a38ccecc83b50d8b015a6dd2533049d",bookSignature:"Prof. Abdelwahed Barkaoui",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10255.jpg",keywords:"Nuclear Mechanotransduction, Mechanosensitivity, Fluids Mechanics, Multiscale Mechanobiology, Modeling Cellular Mechanics, Finite Elements Method, Bone Remodeling, Mechanics Stimulus, Multi-scale Modeling, Mechanobiology Tools, Cell Imaging, Cell-Substrate Interactions",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"July 2nd 2020",dateEndSecondStepPublish:"July 23rd 2020",dateEndThirdStepPublish:"September 21st 2020",dateEndFourthStepPublish:"December 10th 2020",dateEndFifthStepPublish:"February 8th 2021",remainingDaysToSecondStep:"9 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Assistant director of LERMA laboratory, head of mechanical discipline at ECINE and coordinator of the ECINE study program accreditation committee, a member of the editorial board of several international scientific journals, also a member of the American Society of Mechanical (ASME) Engineers European Society of Biomechanics (ESB) and the International Society of Biomechanics (ISB).",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"320631",title:"Dr.",name:"Abdelwahed",middleName:null,surname:"Barkaoui",slug:"abdelwahed-barkaoui",fullName:"Abdelwahed Barkaoui",profilePictureURL:"https://mts.intechopen.com/storage/users/320631/images/system/320631.jpg",biography:"Abdelwahed Barkaoui is an associate professor of Mechanical Engineering at International University of Rabat. He obtained his University habilitation from university of Tunis El Manar-Tunisia in 2017 and his PhD from university of Orleans-France 2012. He has a master's degree in mechanics obtained from the INSA of Lyon-France. He held a position of director of the department of sciences and techniques of engineers and was a Member of the Scientific Advisory Board of the Preparatory Institute for Engineering Studies of El Manar. Currently, Dr. Barkaoui is an assistant director of LERMA laboratory, head of mechanical discipline at ECINE and coordinator of the ECINE study program accreditation committee. His research mainly concerns problems in biomechanics, mechanobiology and biomedical engineering. He is a member of the editorial board of several international scientific journals as Series on biomechanics (2019-), Frontiers in Bioengineering and Biotechnology “biomechanics” (2017-), The Open Biomedical Engineering (2019-), EC Orthopedics (2017-) and Reviewer for several international journals known in the field of biomechanics and mechanics (Scientific Reports (nuture.com), Engineering Fracture Mechanics, Biomechanics and Modeling in Mechanobiology, etc). He is also a member of the American Society of Mechanical (ASME) Engineers European Society of Biomechanics (ESB) and the International Society of Biomechanics (ISB). He has published more than 60 papers in international journals, books, and conferences.",institutionString:"International University of Rabat",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"International University of Rabat",institutionURL:null,country:{name:"Morocco"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"11",title:"Engineering",slug:"engineering"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"280415",firstName:"Josip",lastName:"Knapic",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/280415/images/8050_n.jpg",email:"josip@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copy-editing and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"872",title:"Organic Pollutants Ten Years After the Stockholm Convention",subtitle:"Environmental and Analytical Update",isOpenForSubmission:!1,hash:"f01dc7077e1d23f3d8f5454985cafa0a",slug:"organic-pollutants-ten-years-after-the-stockholm-convention-environmental-and-analytical-update",bookSignature:"Tomasz Puzyn and Aleksandra Mostrag-Szlichtyng",coverURL:"https://cdn.intechopen.com/books/images_new/872.jpg",editedByType:"Edited by",editors:[{id:"84887",title:"Dr.",name:"Tomasz",surname:"Puzyn",slug:"tomasz-puzyn",fullName:"Tomasz Puzyn"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"18247",title:"Associated Adeno Virus Vector for Producing Induced Pluripotent Stem Cells (IPS) for Human Somatic Cells",doi:"10.5772/22823",slug:"associated-adeno-virus-vector-for-producing-induced-pluripotent-stem-cells-ips-for-human-somatic-cel",body:'The discovery that adult somatic cells could be induced to become pluripotent stem cells with apparently all the properties of human embryonic stem cells ( hESCs ), independently by S.Yamanaka et al ( Takahashi et al l 2007 ) and by J. Thompson et al ( Yu et al 2009) was greeted with amazement and in some quarters with relief. The breakthrough, first reported in mice by S Yamanaka in Japan did not receive much notice, but the revelation that adult human cells could be reversed into an embryonic like state was astounding because it was so simple. It was greeted with relief where the progress of hECS was blocked at the federal level because producing hECS raised ethical concerns and political consequences. Yet four years later, although we have discovered much about iPS cells, they are far from being the ideal solution that they seemed to promise.
When human iPS cells were first published they appeared to have so many advantages over hECs. Foremost was the lack of an embryo being involved which meant they could not be logically banned or targeted as unethical (although some tried). Second the science behind making them was astonishingly simple. It only required delivery of four transcription factors found in embryos to reverse years of life as an adult cell back to an embryonic like cell. The record for number of years as an adult cell was set by Eggan et al ( Dimos et al 2008 ), who induced the skin cells of an 82 year old lady back to iPScells.
iPS cells offer the advantages of avoiding the religious or ethical considerations that plague the use of embryonic stem cells. They also could provide autologous transplantation, for repair and regeneration of tissue without rejection. If the donor cells retain the mutation or mutations that caused the patient’s disease state, it is possible to correct those mutations before implantation by homologous recombination. Even if they can not be corrected, those mutations are open to study in lineages derived from the iPS cells. A further advantage of studying iPS cells is access to testing new drugs in those diseased human cells. At present the barriers to adopting iPS in the clinic are the limitations of methods to produce the cells.
iPS technology is expected to move health sciences forward in unique ways for diagnosis, drug screening, toxicity, repair of mutations and treatment of human diseases. iPS cells produced from an individual are embryonic-like stem cells and they can be regrown into any of the 200 somatic cell types. iPS cell have many similarities with ESC cells including the cell morphology, surface antigens, gene expression, telomerase activity, and the epigenetic status. iPS cells have been produced by delivering transcription factors by different types of viral vectors including retroviruses (Takahasi et al 2007), lentiviruses (Chang C-W et al 2009), adenoviruses (Stadtfield et al 2008), plasmid transfections (Jia et al 2010), transposons (Woltjen et al 2009 ), mRNA or recombinant proteins (Warren et al 2010).
It appears that any cell type in the body can be reprogrammed. It was first achieved in skin cells for easy availability. This meant that autologous stem cells could be grown from iPS cells. Autologous transplantation using human iPS cells would not be rejected by graft versus host problems. Even if the donor cells a contain mutation that cause the disease reprogramming can be carried out in mutated cells to study diseases and to correct the mutations ex vivo by homologous recombination. IPS cells are produced to be as close to human ESCs as possible to have the advantages of pluripotency that hESCs have. However hESCs could only be transplanted allogenically into adults and rejection would always be a problem.
Despite the euphoria and literally thousands of studies, there are nagging problems with making iPS cells work in the way that was hoped. One of the reasons is that iPS cells, just like hEScs, go through a stage of producing teratomas. Several studies have found that mice produced from iPS cells are more prone to cancer. The original method for producing iPScells was by a retrovirus to deliver the four transcritption factors. Retroviruses are notorious for random insertion in the genome and being oncogenic. In Yamanka’s study the method included c-Myc as a transcription factor that incrcreased cell growth. However the same property is the property that makes c-Myc an oncogene and therefore another prime suspect in causing cancer. Thompson’s group avoided using c-Myc but also used a retrovirus and instead of c-Myc used LIN 28 as a transcription factor (Yu et al 2009). Eventually Yamanaka’s group dispensed with c-Myc but lost efficiency. Only Oct4 and Sox2 seemed to be absolutely necessary. The other factors could be varied, with Nanog substituting for c-Myc. To avoid the dangers of retroviruses various alternatives for non-integrating delivery have been tried. Adeno-virus was used successfully. But Adenovirus while not being carcinogenic has other problems. In 1999 it was prematurely used in a Phase I gene therapy trial and caused the death of one of the participants, Jesse Gelsinger. Adenovirus produces many proteins and these induce immune reactions. It was an immune reaction to adenovirus in Jessie Gelsinger’s body that made adenovirus totally unacceptable for human use (Marshall 1999). There is an alternative however, Adeno-Associated Virus (AAV). Despite its name, AAV is unrelated to Adeno-virus, and is proving to be a very safe and reliable vector for gene delivery. Gene therapy with rAAV for restoring sight to patients blind since birth or early childhood (Leber congenital amaurosis) has proven that in humans rAAV is very safe (Maguire et all 2008).
Therefore we tested if AAV could be used to induce IPS in adult cells. Eventually there will come a time when iPS will be tested for therapeutic use in treating humans. Although there are now virus free methods of making iPS we do not know which method will have the greatest efficiency, safety, reproducibility or efficacy. Therefore having several different ways of producing iPS is still a viable quest, and here we show how AAV can be used to produce iPS cells.
We generated iPS from with four transcription factors: Oct3/4, Sox2, Klf4 and c-Myc by recombinant adeno-associated viral (rAAV) transduction.
The parvovirus adeno-associated virus (AAV) has single-stranded genome of approximately 4.7 kb carrying capacity. Recombinant AAV (rAAV) in which the two open reading frames of AAV, designated
Vector: pTR-UF3 (an adeno-associated virus (AAV)-based plasmid vector) pTR-UF3 (a kind gift of Nicholas Muzyczka) contains the humanized green fluorescent protein (hGFP) gene under control of cytomegalovirus (CMV) promoter through the polio virus type 1 internal ribosomal entry site (IRES). A 1.4 kb fragment, which contains Oct3/4 (1134 bp), was extracted from pMXs-Oct3/4 (a kind gift from Shinya Yamanaka’s Lab) by BstxI restriction enzyme digestion. The 1.4 kb fragment was inserted into the unique
Vector: pTR-UF11 (an adeno-associated virus (AAV)-based plasmid vector) pTR-UF11 (a kind gift of Nicholas Muzyczka) is derived from pSM620 [2] in which the internal sequences have been replaced by a green fluorescent protein (GFP) gene under the control of a chicken β-actin -cytomegalovirus promoter and a
Vector: pTR-UF11 (an adeno-associated virus (AAV)-based plasmid vector). The transcription factor of Klf4 was amplified by PCR (Forward Primer: GTG GTA CGG GAA ATC ACA AG and Reverse Primer: TTA AAA GTG CCT CTT CAT GTG) from the template of pMXs-Kfl4 (a kind gift from Shinya Yamanaka’s Lab). The 1.5 kb PCR product consists of Klf4 factor (1425 bp). The AAV-derived plasmid, which consists of Klf4 gene, was made by digesting pTR-UF11 with XbaI and SacI, blunting with large klenow fragment and ligating together with the above 1.5 kb PCR products, forming pTR-Klf4.
Vector: pTR-UF11 (an adeno-associated virus (AAV)-based plasmid vector). A 1.56 kb fragment, which contains c-Myc (1320 bp), was extracted from pMXs-c-Myc (a kind gift from Shinya Yamanaka’s Lab) by BstxI restriction enzyme digestion. The AAV-derived plasmid, which consists of c-Myc gene, was made by digesting pTR-UF11 with XbaI and SacI, blunting with large klenow fragment and ligating together with the above 1.56 kb fragment, forming pTR-c-Myc. The maps of rAAV vectors (pTR-UF3 and pTR-UF11) and the rAAV plasmids with defined factor (pTR-Oct3/4-GFP, pTR-Sox2-Neo, pTR-Klf4 and pTR-c-Myc, respectively) are summarized in Figure 1.
The procedures for rAAV production, including harvesting the cells (HEK 293), extraction by freezing and thawing purification by iodixanol heparin affinity chromatography as a second step in purification following the iodixanol gradient, are used regularly in our lab and published by Zolotukhin et al (1999)\n\t\t\t\t\t\tPhillips et al (2010 ). The maps for constructing AAV with Oct3/4, Sox2, and Klf-4 and c-myc are shown in Figure 1.
AAV-based plasmid with transcription factor of Oct3/4: A 1.4 kb fragment, which contains Oct3/4 (1134 bp), was extracted from pMXs-Oct3/4 (a gift from Shinya Yamanaka’s Lab) by BstxI restriction enzyme digestion (1a). The 1.4 kb fragment was inserted into the unique
The specific primers were designed to confirm the purified virus (rAAV) that contains the inserted defined factor (Myc, Klf4, Oct 4 and Sox2, respectively) as follows:
The “Universal” Forward Primer:
5’-GTG GTA CGG GAA ATC ACA AG-3’ (The primer was designed according the sequences from the backbone of rAAV plasmid vector beyond the full length of the defined factors)
The Reverse Primers:
Oct3/4
Reverse primer: 5’-AGATGGTGGTCTGGCTGAAC-3’
(Accession: M34381 Oct3/4: 581-562)
Sox2
Reverse primer: 5’-CTCCGGGAAGCGTGTACTTA-3’
(Accession: NM_011443 oct3/4: 805-786)
KLF4Reverse primer: 5’- GGAAGACGAGGATGAAGCTG-3’
(Accession: BC010301 Klf4: 862-843)
c-Myc
Reverse primer: 5’- ATCGCAGATGAAGCTCTGGT-3’
(Accession: NM_010849 Myc: 983-964)
One µl of viral DNA from the purified virus was amplified by Polymerase Chain Reaction (PCR) in 25 µl reaction volume by above universal forward primer paired with the specific reverse primer of Myc, Klf4, Oct 3/4 and Sox2, respectively. The amplification was performed in the following conditions: 4 minutes at 94oC; 15 cycles of 30 seconds at 94oC, 30 seconds at 58oC (annealing), 1 minute at 72oC and a final extension period of 10 minutes at 72oC in iCycler Thermal Cycler (Bio-Bad).
One µl of viral DNA from the purified virus of UF3-Oct3/4-GFP was amplified as above by the forward primer 5’-CAG CGG AGA GGG TGA AGG TG-3’ (Accession: U50963 GFP: 87-106) and the reverse primer 5’-CAG GGC AGA CTG GGT GGA CA-3’ (Accession: U50963 GFP: 621-602)
Amplification products (10 µl) were analyzed on 1% agarose stained with ethidium bromide. The results were shown in the Figure 2.
Two human somatic cell types were used: IMR-90 a fetal skin fibroblast and HEP G2 liver cells were used to induce iPS. Before the transduction we tested a normal and a starving protocol, as described below.
The IMR-90 cells were purchased from American Type Culture Collection (ATCC, Catalog No. CCL-186) and they are diploid human cells that are being extensively characterized by the ENCODE Consortium and have published DNA fingerprints that allow confirmation of the origin of reprogrammed clones. IMR-90 cells also proliferate robustly for more than 20 passages before undergoing senescence, but grow slowly in human ES cell culture conditions (Yu, J 2009).
PCR results with AAV delivery of defined factors for reprogramming. Lane 1: pUF11-C-Myc (check C-Myc) (417bp). Lane 2: pUF11-KLF4 (check KLF4) (429bp). Lane 3: pUF3-Oct3/4-IRES-GFP (check Oct3/4) (583bp). Lane 4: pUF3-Oct3/4-IRES-GFP (check GFP) (535bp). Lane 5: pUF11-Sox2 (check Sox2) (433bp). Lane 6: 100 bp DNA Ladder. Lane 7: Positive control: pUF11consists of GFP (535bp). Lane 8: Negative control
A vector constructed with adeno-associated virus (AAV)-based plasmid vector (pUF11) containing green fluorescent protein (GFP) with 535bp (Phillips et al., 2010) was transduced in the cells. Cells were plated in 6 wells plates (5x 104 cells/well) and were cultured in Minimum Essential Medium (MEM Engle) supplemented with 10% heat-inactivated fetal bovine serum (10% FBS), 0.1 mM non-essential amino acids, and 1.0 mM sodium pyruvate. The cells were cultured by 24hs at 37oC, 5% CO2. One day later, when cells were approximately 70-80% confluent, the cells were washed twice with PBS and transduced with adeno-associated virus (AAV)-GFP vector with medium (MEM Engle) without FBS and antibiotic with MOI 50, 100, 250, 500 and 1000. Cells were incubated at 37oC, 5% CO2 for 24hs. The medium was change to MEM Engle 10% FBS. The medium was change every day. Ten days after the transduction the number fluorescent cells per well were quantified with confocal microscopy. Figure 3, the figure shows two green fluorescent cells isolated and analyzed by Confocal Microscopy (Leica Microsystems-TCS SP5) indicating successful AAV-GFP transduction. The GFP positive cells/field is shown Figure 4.
AAV-GFP transduction. The figure shows two green fluorescent cells isolated and analyzed by Confocal Microscopy (Leica Microsystems-TCS SP5) indicating successful AAV-GFP transduction.
To starving protocol the cells were plated in 6 wells plates (5x 104 cells/well) and were cultured in Minimum Essential Medium (MEM Engle) supplemented with 10% heat-inactivated fetal bovine serum (10% FBS), 0.1 mM non-essential amino acids, and 1.0 mM sodium pyruvate. The cells were cultured by 24hs at 37oC, 5% CO2. One day later, when cells were approximately 70-80% confluent, the cells were washed twice with PBS and incubated with medium without serum for 48 hs. After, the cells were transduced with adeno-associated virus (AAV)-GFP vector with medium (MEM Engle) without FBS and antibiotic with MOI 100, 1000 and 5000 and compared to normal protocol. Cells were incubated at 37oC, 5% CO2 for 24hs and the medium (MEM Engle) with FBS 20% for 24 hs. The medium was changed to MEM Engle 10% FBS. The medium was change every day. Ten days after the transduction the number fluorescent cells per well were quantified with Confocal microscopy. The Figure 5 shows that the transduction efficiency was most efficient with the normal protocol than the starving protocol.
To improve the transduction efficiency we tested the 4 factors together as well separately.
Using the normal protocol the cells were cultured by 24hs at 37oC, 5% CO2. One day later, the cells were transduced with adeno-associated virus (AAV)-Oct 3/4-GFP vector for 24hs. Two days later, the cells were transduced with c-myc. Three days later, the cells were transduced with Sox2 plus Klf-4 with medium (MEM Engle) without FBS with MOI 10, 100 and MOI 1000.
Also, using the normal protocol the cells were transduced with adeno-associated virus (AAV)-Oct 3/4-GFP vector plus Sox2, Klf-4 and c-myc with medium (MEM Engle) without FBS with MOI 10, 100 and 1000. After 24 hs the medium was changed to MEM Engle 10% FBS. The medium was change every day. Ten days after the transduction the number fluorescent cells per well were quantified with confocal microscopy. The Table 1 shows that the positive GFP cells were not different when the transduction was done with the 4 factors together as separately as well.
AAV-GFP vector transduction. The green fluorescent cells indicate the GFP expression analyzed by Confocal Microscopy (x250) inIMR-90 cells. The figure shows on the left the GFP positive cells/ field and dark field, and on the right the merge cells. A vector pUF11 (an adeno-associated virus (AAV)-based plasmid vector) consisting GFP (535bp) was transduced in human fetal fibroblasts with MOI 50, 100, 250, 500 and 1000.
The cells were cultured by 24hs at 37oC, 5% CO2. When cells were approximately 70-80% confluent, the cells were washed PBS and transduced with adeno-associated virus (AAV)-GFP vector. A vector pUF11 (an adeno-associated virus (AAV)-based plasmid vector) consisting GFP (535bp) was transduced in human fetal fibroblasts with MOI 100, 1000 and 5000. Ten days after the transduction the number fluorescent cells per well were quantified with confocal microscopy. A. Show that the transduction efficiency with the normal protocol B. Show the transduction efficiency with the starving protocol. The figure shows that the transduction efficiency was most efficient with the normal protocol than starving protocol.
Transduction of 4 factors together or separately as well, 10 days after the IMR-90 cells transduction. The results are expressed by GFP positive cells per well.
To test the delivery of the 4 factors transcription genes during hole the pluripotency induction time, the cells were transducted using the normal protocol with adeno-associated virus (AAV)-Oct 3/4-GFP vector plus Sox2, Klf-4 with and without c-myc with medium (MEM Engle) without FBS and antibiotic with MOI 1000 (Experiment 1 and Experiment 2) (Figure 6). After 24hs was added 1ml/well medium 30% serum for 6hs. The medium was changed MEMEngle 10% + P/S and changed each 2 or 3 days. Twenty and 40 days after transduction the RNA was extracted with Trizol to quantify the GFP, Oct3/4, Sox-2, Klf-4 and c-Myc by RT-PCR, using the primers described above. Several different groups were tested to confirm effectiveness samples as showed by RT-PCR of agarose gel samples in the Figure 6.
Experiment 1: 20 days after transduction:
Control cells,
Oct 3/4-GFP,
Oct 3/4-GFP + Sox-2 + Klf-4 with c-Myc,
Oct 3/4-GFP + Sox-2 + Klf-4 without c-Myc.
Experiment 2: 40 days after transduction
Control cells,
Oct 3/4-GFP,
Oct 3/4-GFP + Sox-2 + Klf-4 with c-Myc,
Oct 3/4-GFP + Sox-2 + Klf-4 without c-Myc.
The figure 6 shows that the 4 factors are expressed for up 40 days.
RT- PCR results showing transcription factor gene expression after 20 days and 40 days transduction with AAV. All of the 4 markers are visible although Oct3/4 was weakly expressed. Sequences by RT-PCR of agarose gel samples from each experimental test group. Experiment 1: 20 days after transduction: a) Control: GFP b) With c-Myc c) Without c-Myc. Experiment 2: 40 days after transduction a) Control: GFP, b) With c-Myc c) Without c-Myc. Positive control. Ladder 100, Negative Control 1st reaction, Negative Control 2nd reaction: The cells were transduced with and without c-Myc. 1.3X106 cells; 70% confluence; 4 P; MOI 1000.
Heptocyte Cells: HepG2 Cell line was derived from the hepatocellular carcinoma cell line (ATCC - Hep G2/2.2.1); adherent; epithelial; from a 15 year old male Caucasian.
For human hepatocytes cells, 6 days after rAAV-GFP (Figure 7 A and B) and rAAV-Oct 3/4-GFP (Figure 7 C and D) (MOI-100) transduction, the GFP positive cells were observed by Confocal microscopy and total RNA was extracted with Trizol and the GFP and Oct 3/4 gene expression were determined by RT-PCR (Figure 7 E and F). Microscopically the rAAV-GFP could be clearly seen expressed in the cells, however rAAV-Oct 3/4-GFP was not observed.
Human Hepatocytes Cells, 6 days after transduction. Upper Panel: A. Confocal microscopy rAAV-GFP (MOI-100) and B. DAPI. C. rAAV-Oct3/4-GFP (MOI-100) and D. DAPI. Lower Panel: E. RT-PCR for GFP and F. Oct3/4-GFP. 1- Control; 2- GFP MOI 10; 3-GFP MOI 100; 4- Oct 3/4 - GFP MOI 10; 5-Oct 3/4 - GFP MOI 100; 6- Negative Control; 7- Positive Control; and 8- Ladder.
Since the question was: can we make iPScells with rAAV-GFP instead of retroviruses, lentivirus or adeno-virus we started with the same four transcription genes used by Yamanka who kindly provided them to us.
The IMR-90 a fetal skin fibroblast and HEP G2 liver cells were plated 1.3X106 cells with 70% confluence the cells transduced with Oct3/4, Sox-2 and Klf-4 with c-Myc and without c-Myc, MOI 1000. Before transduction the medium was changed to medium without serum and antibiotic for 24hs.The transduction was done with 4 factors together. After 24hs 30% serum was added 1ml/well for 6hs. The medium was changed to MEMEngle 10% + P/S for 3 days. The medium was changed to hESC medium 4 days after the transduction (Knockout DMEM supplemented with 15% knockout serum replacement, L-glutamine, nonessential amino acids, β-mercaptoethanol and penicillin/streptomycin). For the generation of iPS with rAAV transduction the cells were not cultured in MEFs or with chemicals treatment. The medium was changed every day. iPS colonies were picked between 20-30 days post transduction based on colony morphology. To HEP G2 liver cells 15 days after the transduction the cells were passage and re-transduced.
The medium was changed every day until the colonies become big enough to be picked out. Colonies should first become visible approximately a week after the transduction. They become large enough to be picked out around day 20. The reprogrammed clones were selected by morphological criteria (compact colonies, high nucleous to cytoplasm ratio and proeminent nucleoli) as showed Figure 8.
iPS cells from IMR-90 fibroblast cells. Upper Panel: iPS cells confocal microscopy image. Before transduction (IMR-90), iPS cells with 4 factors (with c-Myc), and iPS cells with 3 factors (without c-Myc). Lower Panel: iPS cells without c-Myc. Confocal image with bright field (A), fluorescence (B), merge (C).
Picking out the colonies: aliquot 20 µl of 0.25% trypsin/1 mM EDTA per well of 96-well plate. The medium was removed from the dish, and added 10 ml of PBS. Aspirate PBS, and added 5 ml of PBS. Pick colonies from the dish using a Pipetman set at 2 µl, and transfer it into the 96-well trypsin plate. We picked out as many colonies as we can within 15 min. Cells was incubated another 15 min in trypsin at 37oC to dissociate cells in the colonies. 180 µl of ES medium was added to each well, and pipetted up and down to break up the colony to single cells. The cell suspension was transferred into the well of 24-well plates with medium without feeder cells, and 300 µl ES medium added. The cells were incubated in 37oC, 5% CO2 until the cells reach 80-90% confluence. At this point they were passaged into 6-well plates.
To demonstrate these cells possess characterists of embryonic stem cells, we stained them for AP activity using a kit (CHEMICON®s Alkaline Phosphatase Detection) and the expression of membrane markers, Cell surface Stage-Specific Embrionic Antigens (SSEA-4) and Keratan sulphate-associated antigens (TRA-1-60 and TRA-1-81) using a kit (CHEMICON®s ES Cell Marker Samples) and the transcription factor Oct-4.
Alkaline Phosphatase staining was used as a marker for embryonic-like stem cells.The AP was quantified 20 days after treatment with hESC medium. Figure 8 shows the AP to HEP G2 liver cells and Figure 9 show the iPS cells membrane markers from Human hepatocyte cells (HEP G2).
iPS from Human hepatocyte cells (HepG2).Upper and down panels (A) Confocal bright-field, (B) alkaline phosphatase positive and (C) Hepatocytes cells transduced with 4 factors, 30 days after transduction. Upper, bright-field and down, GFP positive iPS (Oct-3/4 positive).
Figure 10 show the AP to IMR-90 fibroblast cells and Figure 11 show the iPS cells membrane markers from Human fibroblast cells (IMR-90). The iPS cells shows morphology such as compact colonies, high nucleus to cytoplasm ratio and prominent nucleoli. The testing for markers of human embryonic stem cells in the AAV induced iPS cells was positive.
iPS from Human hepatocyte cells (HepG2). iPS cells membrane markers: the transcription factor Oct-4; Keratan sulphate-associated antigens (TRA-1-60 and TRA-1-81) and Cell surface Stage-Specific Embrionic Antigens (SSEA-4).
iPS from Fibroblast Human Cells (IMR-90). A. Control cells, B. Alkaline phosphatase positive.
iPS from Fibroblast Human Cells (IMR-90). iPS cells membrane markers: the transcription factor Oct-4; Keratan sulphate-associated antigens (TRA-1-60 and TRA-1-81) and Cell surface Stage-Specific Embrionic Antigens (SSEA-4).
In the present paper we report the application of AAV serotype 2 as a vector for producing human iPS cells from adult somatic liver and cells. We delivered the transcription factors: Oct 4, Sox2, c-Myc and Klf4 that were originally used by S. Yamanaka et al (Takahashi et al 2007). We are well aware that this set of factors is not the optimal choice except for Oct4 and Sox2. Many other factors can replace cMyc and Klf4. However for the demonstration that AAV is an appropriate vector for reprogramming adult cells to iPS cells, we chose to work with the factors that have consistently been used for efficient conversion of differentiated somatic cells. In future studies with AAV we plan to test replacement factors. While more in vivo tests are necessary, this report establishes a feasible new method for producing iPS cells with AAV
rAAV has not previously been used as the viral vector for delivery of transgenes to induce pluripotent cells. AAV has several advantages over other viral vectors. Unlike retroviruses (and wild type AAV), rAAV does not integrate into the chromosomes. Therefore it does not raise concerns about insertional mutagenesis. This is confirmed by the safe and stable experience in several human trials with rAAV(Maguire et al, 2008). Originally retroviruses were the vectors of choice for delivery of transcription factors (Takahashi et al 2007). However, they are unsuitable for human use because of oncogenic risks from insertional mutagenesis. Lentivirus has a large carrying capacity, but it is a retrovirus. As the virus type for HIV the public might be concerned about its use in iPS cells for autologous transplantation. The adenovirus has been tested as a non-integrating virus. The results were positive but not efficient (Stadtfield et al, 2008). Using adenovirus as a vector is appealing for its ease of production and use, although such studies overlook that the adenovirus is not a viable vector for humans. The adenovirus caused fatal effects in the failed gene therapy trial at University of Pennsylvania in 1999 (Marshall, 1999). Thus even though these vectors might be better developed and even though they may serve the purpose of making iPS cells, they carry a negative public image for human use. The leading viral vector in several successful clinical trials recently has been the recombinant adenoassociated virus vector (rAAV). Experience with rAAV in humans is safe, stable, producible in high titers (1012 infectious particles per ml) and non-immunogenic (Maguire et al 2008). In this paper we propose that rAAV is an advantageous vector for producing human iPS cells for therapeutic transplantion.
However only a few papers in the literature have explored AAV and iPS and those reports used AAV for specialized purposes. Khan et al (2010) showed that AAV can selectively target mutations and correct mutations in iPS cells by homologous recombination. They used AAV in specifically generated human iPS cells with two different gene mutations (HPRT1 and HMBA1) responsible for the Lesch-Nyan syndrome. They studied fibroblasts and mesenchymal cells as the adult cell sources that had been reprogrammed with Oct4, Sox2 Lin28 NANOG as the transgenes. Reprogramming was conventional with a lentivirus. The successful correction of a mutation in the iPS cells extends the usefulness of AAV beyond making iPS cells to making iPS cells better. If autologous adult somatic cells have a mutation that can be corrected by gene targeting with AAV, they become available for therapeutic purposes. Targeting with AAV was achieved without cytotoxicity (Khan et al 2010). A similar paper report from Mitsui et al (2009), who received iPS cells directly from S Yamanaka, tested AAV targeting of HPRT1.
Very recently (as we go to press) a new development in iPS production has indicated that a single microRNA may be able to effect the whole reprogramming process without resorting to transcription factors for delivery. (Anoke-Danso et al April 7, 2011). This new concept would be another use for AAV because AAV is excellent for delivery of miRNA (Qiao et al 2011). It is too soon to tell which method will ultimately make iPScell a successful alternative to embryonic stem cells or not.
In conclusion, several different types of vectors and delivery systems have been used to reprogram adult somatic cells to iPS cells but none have become predominantly useful. Here we show that rAAV is successful in delivering transcription factors to adult fibroblasts and hepatic cells and reprogramming them to iPS cells. rAAV is efficient and effective. We used low MOIs. Each of the 4 transcription factor was delivered in a separate rAAV plasmid so that in future applications the transgenes can be easily varied. There was no evidence of cytotoxicity and the iPS cells were stable. The iPS cell showed the accepted in vitro characteristics of being inducible Pluripotent Stem Cells, including cell morphology, alkaline phoshphatase positive staining, and SSEA1 positive staining. Doxocyclin was not required, making it simpler to use than the doxocyclin lentivirus method. While more in vivo tests are necessary, this report establishes a feasible new method for producing iPS cells with AAV. Other studies indicate AAV will be having the added advantage of being used for accurate targeting of mutations in iPS so that the mutations can be corrected by homologous recombination. With these advantages the use of AAV can move the technology of iPS closer to therapeutic use in human patients.
Oliveira EM was the recipient of a CNPq-PDE Fellowship (No.200994/2007-7) and from Dr MI Phillips Grant in USA. E. M. Oliveira holds scholarships from CNPq, Brazil. Dr. MI Phillips was supported by grant from NIH 1 R01 HL 077602.
Traditionally, intraoperative endoscopy (IOE) was the only means for the visualization of small bowel mucosal lesions not accessible to upper gastrointestinal endoscopy and colonoscopy. However, with the advances in abdominal imaging and the advent of capsule endoscopy (CE), the use of IOE diminished. A comparative study of CE and IOE found the sensitivity and specificity of CE to be 95% and 75%, respectively [1]. Hence, most guidelines recommend CE for detection of suspected small bowel lesions in patients with obscure gastrointestinal (GI) bleed. However, the main disadvantage of CE was inability to perform therapeutic procedures. Subsequently, the device assisted enteroscopy (DAE), namely, spiral endoscopy, double balloon enteroscopy (DBE) and single balloon enteroscopy (SBE) was developed which has brought paradigm shift in the treatment of small bowel mucosal diseases. DAE allows visualization, biopsy and removal of the small bowel mucosal lesions.
However, IOE is still an indispensable tool for the evaluation and treatment of small bowel diseases in special situations and institutions with lack of DAE facilities. The reported success rate of IOE to achieve complete enteroscopy ranges between 57–100% in different series [1, 2, 3, 4, 5, 6, 7, 8, 9, 10]. The advantages and disadvantages of IOE have been summarized in Table 1.
Advantages of IOE | Disadvantages of IOE |
---|---|
Complete bowel examination is possible in same sitting | Anesthesia and laparotomy related complications |
The procedure is safe as it is performed under direct vision | Enterotomy related complications |
Allows peritoneal, mesentery and omental examination and biopsy, if required | Availability of the endoscopy equipments and endoscopist at the time of surgery |
Allows definitive treatment of the disease in the same sitting | Inability to negotiate the endoscope in case of dense bowel adhesions |
Minimizes the number of procedures and enterotomies in patients with multiple lesions like PJS | Inability to visualize the mucosa in case of massive bleeding |
Advantages and disadvantages of intraoperative endoscopy.
In the current era, despite the widespread use of DAE, IOE plays an important in the management of various GI disorders. In a 10-year study by Kopacova et al., the authors performed IOE in 41 patients with the commonest indication being obscure gastrointestinal bleeding followed by Peutz-Jeghers syndrome (PJS) [6]. The indications of IOE in the present scenario are as follows:
Obscure gastrointestinal bleeding – It is recurrent or persistent bleeding from the unknown source in the GI tract that could not be identified on conventional endoscopy, colonoscopy and barium studies or enteroclysis [11]. Small bowel lesions account for 45–75% cases of obscure gastrointestinal bleed [11, 12]. In such cases, extensive investigations including enterography using computed tomography (CT) or magnetic resonance imaging (MRI), CE, DBE and RBC scan can often help in identifying the lesion (Figure 1). However, sometimes it is not possible to identify the site and cause of GI bleed in such patients despite exhaustive work-up. IOE is very helpful in detecting the mucosal lesions within the small bowel of patients with GI bleed (Figure 2). In a recent series of 67 patients with GI bleed, CE, colonoscopy, upper gastrointestinal endoscopy and DBE was performed in 96%, 87%, 87% and 73% cases respectively [10]. Despite these preoperative investigations, IOE was performed in 40% patients with the diagnostic yield of 76% [10].
PJS – It is characterized by presence of multiple hamartomatous polyps throughout the GI tract, mucocutaneous pigmentation and an increased risk of GI cancers. These polyps are predominantly located in the small and can lead to several problems including recurrent abdominal pain, GI bleed, intussusception, bowel obstruction and perforation. As per the recommended guidelines, polyps more than 1 cm should be excised to prevent future complications [13]. Previously, these patients required surgical excision with or without IOE. But with the availability of DAE, many of these polyps can be removed endoscopically (Figure 3). Nevertheless, surgery and IOE is required in many cases for complete exploration of small bowel and resection of large or malignant polyps (Figure 4). In a recent study of 27 patients with PJS, the success rate of enteroscopy was 76% [14]. IOE was required in 4 patients which improved the complete treatment rate to 92%. IOE has also been shown to facilitate polyp resection, reduce the number of laparotomies [6] and extensive bowel resection [15].
Familial adenomatous polyposis (FAP) – It is an autosomal dominant disorder characterized by development of premalignant adenomatous polyps in the colon. Moreover, these patients are at the risk of development of duodenal polyposis, duodenal cancer, jejunal and ileal polyps [16]. Most of these can be visualized using conventional upper gastrointestinal endoscopy and colonoscopy. CE and DAE are useful for the visualization of jejunal and ileal polyps. However, in FAP patients with history of abdominal surgery such as pancreatoduodenectomy for duodenal cancer or total proctocolectomy for colorectal cancer, diagnostic and/or therapeutic DAE can be difficult. In such cases, IOE can be used to achieve complete clearance [16].
Crohn’s disease (CD) – It is an inflammatory bowel disease predominantly affecting the small intestine. The transmural inflammation leads to the development of deep ulcers causing GI bleeding and small bowel strictures causing intestinal obstruction. In presence of strictures, CE is contraindicated due to the risk of impaction. DAE also has its limitation in passing across the tight strictures making complete small bowel examination difficult. IOE helps in examining the mucosal side of the involved bowel segments to determine the disease activity. Previous studies involving CD patients have reported that IOE can identify new lesions not seen on preoperative examination [17].
Computed tomography - a 53-year-old lady presented with anemia, weight loss and recurrent abdominal pain for one year. On computed tomography, she was found to have thickening in the mid segment of the ileum (arrow) with proximal dilated bowel loops containing feculent material (A: Axial section, B – Coronal section).
Intraoperative enteroscopy via enterotomy of the patient with ileal thickening on computed tomography showing normal mucosal folds (A, B, C), a suspected vascular lesion (arrow, D), a small mucosal lesion (arrow, E) which was biopsied (F). No ileal stricture or significant mucosal disease was identified.
Peutz-Jeghers syndrome – The follow-up gastroscopy of the patient with Peutz-Jeghers syndrome one year after intraoperative enteroscopy and polyp excision showing multiple small polyps throughout the stomach (A). Few pedunculated polyps were present in the large bowel (B, C) which were excised endoscopically (D).
Peutz-Jeghers syndrome – A 29-year-man presented with recurrent abdominal pain. On evaluation, he was found to have multiple polyps throughout the small and large intestine causing intussusception. At surgery, intraoperative enteroscopy via oral and anal route was performed and small polyps amenable to endoscopic resection were excised. Two large polyps, one in the transverse colon (A) and another in the proximal jejunum (B) were marked by endoscopy and excised surgically.
Patients not responding to medical therapy or those who develop persistent GI bleeding or intestinal obstruction require surgical intervention. At surgery, multiple segments of small bowel with skip areas are often involved. The extent and type of surgery in such cases is difficult to ascertain. IOE allows complete small bowel examination and helps in surgical planning. In such cases, surgical intervention is most often performed for tight strictures (<15 mm diameter), stricture with active ulcer and bleeding ulcer [18].
IOE is also useful in CD patients undergoing emergency surgery for intestinal obstruction or perforation without prior endoscopic examination. In such cases, complete small bowel evaluation along with ileocecal junction is important to prevent postoperative complications and avoid repeated surgeries.
Bowel obstruction or perforation – Sometimes, patients presenting with small bowel obstruction or perforation without prior endoscopic evaluation may require IOE for appropriate surgical treatment. One such situation is the presence of multiple strictures on preoperative CT. Similar to CD, patients with multiple strictures due to other causes such as tuberculosis requiring emergency surgery for intestinal obstruction or perforation can undergo IOE in the same sitting if feasible to allow complete small bowel examination and avoid multiple surgeries (Figure 5). Another clinical situation is difficulty in identification of the cause of bowel obstruction. In one of our previously reported cases, a patient of moderately severe acute gallstone pancreatitis developed colonic obstruction in the follow up [19]. On CT abdomen, there was a resolving peripancreatic collection surrounding the transverse colon with grossly dilated ascending colon and small bowel loops. In order to rule out mucosal disease, IOE via enterotomy route was performed (Figure 6). As there was no mucosal disease, side-to-side ileo-transverse colonic anastomosis was performed without colonic resection [19].
Foreign body (FB) removal – Most of the cases of non-impacted FB ingestion can be managed conservatively. Sharp FB ingestion require endoscopic removal if feasible. Few cases with impacted FB in the small bowel not accessible to endoscopic removal or those who develop complications such as intestinal perforation require surgery.
Intraoperative enteroscopy via enterotomy of a patient with multiple small bowel strictures on computed tomography showing a narrow stricture in the proximal ileum (A). Rest of the small bowel showed mild mucosal edema at few places with no obvious strictures (B, C, D).
Intraoperative enteroscopy via enterotomy of a patient with resolving acute pancreatitis and colonic obstruction showing mucosal edema at the site of obstruction (A, B) with grossly dilated colon loaded with feculent material (C).
Some cases with multiple FB ingestion located at different locations may require IOE to remove all the foreign bodies with minimum enterotomies. IOE can also help in such cases to confirm complete clearance during the operation [20].
Failure of DAE to identify or treat the lesion – Often, complete small bowel examination is not possible with DAE. The reasons for failure of DAE include previous laparotomies, bowel adhesions, anatomical variations, etc. [21]. In such cases, IOE is useful in achieving complete bowel evaluation and treatment if required in the same sitting.
Abdominal surgery required for other reasons – In some situations such as CD with symptomatic gallstone disease or FAP with periampullary carcinoma, if the patient is planned for abdominal surgery, then IOE can be performed in the same sitting instead of DAE.
Identification of the site of disease during surgery – In the era of DAE, most of the small bowel lesions requiring surgical excision are marked with India ink. However, in some cases were the ink is not visible or cases were the mucosal lesions were detected on CE such as ectopic pancreatic tissue, arteriovenous fistula, and hemangioma, IOE is useful for intraoperative localization.
Lack of DAE facility – DAE is available at most centers in developed countries. However, in low income countries or in limited resource setting, IOE is a safe and effective alternative to DAE. It allows diagnosis and treatment of the small bowel diseases in the same sitting.
IOE is mainly performed via conventional laparotomy. However, it can be performed by mini-laparotomy [22, 23] or laparoscopy [24, 25, 26, 27]. IOE can be performed by gastroscope, colonoscope, pediatric scope or balloon enteroscope depending upon the probable site of the lesions, the indication for IOE and the availability of the equipments. In rare circumstances, IOE can be performed using a laparoscope [28]. IOE can be conducted through oral route, anal route and through an enterotomy site (Figure 7). The choice of the preferred route for IOE depends upon the location of the lesion.
Schematic presentation of different routes for intraoperative enteroscopy: (A) Transoral route, (B) transanal route and (C) enteroscopy via enterotomy.
The patients are admitted before the procedure. All routine investigations including cardiorespiratory work up are done to rule out any contraindication for surgery. The day before the procedure the standard bowel preparation (the same as for colonoscopy) with either polyethylene glycol or sodium phosphate is given [29]. The patients are asked to fast for 6 hours before the surgery.
All the endoscopes and the accessories are sterilized before the procedure. The endoscopist has to scrub like any other member of the operating team. The part of the endoscope to be inserted in the operating field is covered with a plastic sleeve routinely used for laparoscopic procedures. This will help in maintaining the sterility of the procedure. The procedure is performed under general anesthesia.
Transoral endoscopy can be performed with the patient in supine or left lateral position [30]. Prior to the insertion of the endoscope, a nasogastric tube is placed to decompress the stomach. Subsequently, the nasogastric tube is removed and the gastroscope is inserted.
Like the routine endoscopy, the gastroscope is passed in to the duodenum (Figure 7A). If the intraoperative endoscopy is pre-planned, then the endoscope can be passed as far as possible into the duodenum before the abdominal incision to take benefit of the tamponade effect of the abdominal wall.
During the passage of the endoscope, a loop tends to form along the greater curvature of the stomach and the ‘C’ of the duodenum. Once, the endoscope has reached the jejunum, the assistant surgeon can place the right hand along the greater curvature of the stomach and the left hand over the second part of the duodenum to straighten the endoscope. This will help in going further deep in to the small bowel via the oral route.
Deeper passage of the scope in to the jejunum is performed with the help of the operating team. Mobile small bowel and mesentery is necessary to facilitate smooth passage of the scope and avoid bowel injury. Hence, if adhesions are present then adhesiolysis should be performed by the operative team before initiating IOE.
For the examination of the small bowel beyond the proximal jejunum, the operating surgeon straightens the bowel loops as the endoscopist gently pushes the endoscope in to the jejunum. Subsequently, about 40–50 cm of small bowel is telescoped on to the shaft of the endoscope by the operating surgeon.
Advancement of the endoscope through the small bowel must be smooth, slow, gentle and under direct vision to avoid mucosal trauma by the endoscope and avoid excessive tension on the mesentery.
The mucosa is thoroughly examined during the insertion and withdrawal of the endoscope. Any lesion if detected is biopsied or excised endoscopically using the standard techniques. Bleeding from the endoscopic excision site can be controlled by endoscopic techniques or transmural sutures by the operating team.
If the lesion is big and requires surgical excision, then the site of the lesion must be marked with a simple suture by the operating team.
In most cases, it is possible to examine the whole small bowel via oral route using the standard-length colonoscope. But if not possible, then the terminal ileum can be examined in a retrograde fashion via transanal route.
The distal most point up to which the scope reaches in the small bowel is marked with a simple suture by the surgical team.
Throughout the procedure, the operating room lights are dimmed so that the endoscopy team is able to clearly visualize the bowel mucosa and the location of the endoscope. The abnormal vascular lesions can be better identified by transillumination.
During withdrawal, after inspecting the mucosa, the air is aspirated by the endoscopist and the surgeon occludes the intestinal lumen with his index and middle fingers to avoid re-insufflation.
After completion of the endoscopy, the lesions at the marked sites are excised surgically by multiple enterotomies or segmental bowel resection depending upon the intraoperative findings.
This is the least preferred route for IOE due to limited maneuverability.
The procedure can be performed in lithotomy or left lateral position.
The steps are similar to that of colonoscopy (Figure 7B). In case of difficulty in negotiating the scope across the colonic flexures, the operating surgeons can guide the scope.
Small lesions can be excised or biopsied endoscopically while large lesions can be marked with simple suture for subsequent surgical excision.
After reaching the ileocecal region, the surgeon slowly pushes the ileal loops over the scope for the mucosal examination. However, evaluation of the small bowel beyond terminal ileum via anal route is difficult.
In such cases, if there is a large colonic lesion requiring surgical excision, a colotomy can be made near the site of resection and the colonoscope can be advanced through it to facilitate further small bowel examination.
After appropriate adhesiolysis, whole of the small bowel is freed.
A circular purse-string suture is taken at a suitable point (usually the mid portion) of the small intestine on the anti-mesenteric side [6]. A small enterotomy is made at the center of the purse string suture just sufficient enough to allow the passage of the endoscope.
The endoscope is inserted through the enterotomy and the circular suture is tied around the scope over the bowel to prevent air leak during insufflation (Figure 7C).
First, the proximal part of the small intestine is examined due to lower bacterial load.
Enteroscopy should be performed slowly with gradual advancement of the scope and minimum insufflation to prevent bowel injury.
Endoscopic biopsy or excision is performed for the visualized mucosa lesions as appropriate. If surgical excision is required, then the site of lesion is marked by the operating surgeon with a simple suture.
During the inspection of the proximal half of the small bowel, the distal part if clamped and vice-versa to prevent over-inflation.
The endoscopic views during IOE are different from the routine endoscopic picture due to transillumination by the operating lights in the theater. However, the operating lights can be dimmed if required as per the endoscopist’s choice.
In order to avoid contamination of the operative field, some authors have described the use of laparoscopic port.
In this technique, a 12-mm or 15-mm bladeless laparoscopic port with or without balloon is inserted from the enterotomy site in to the bowel [31, 32, 33, 34].
The laparoscopic camera sleeve is fixed to the port with tape.
The endoscope is passed through the camera sleeve and port in to the bowel for enteroscopy.
This technique allows to maintain the sterility of the operative field.
In this technique, in order to avoid the laparotomy, the endoscope is passed through one of the 12- or 15-mm laparoscopic port [24, 25, 26].
IOE can be performed via oral [25, 27, 34], anal [35] or enterotomy route [24, 26].
The procedure for IOE via oral or anal route is same as described above except that the adhesiolysis and handling of the small bowel is performed laparoscopically. Additionally, the bowel insufflation has to be minimum to allow space for laparoscopic bowel manipulation [24].
For IOE through enterotomy, a small jejunotomy is made and the endoscope is passed through it in to the bowel.
Although the mobility of the scope is restricted compared to conventional IOE through laparotomy, it is possible to visualize the whole small intestine with careful manipulation of the small bowel loops.
After the withdrawal of the endoscope, the enterotomy wound is sutured laparoscopically.
However, this procedure is technically more demanding and time consuming. Both the laparoscopist and endoscopist need to be highly skilled and experienced.
DAE is possible in most of the cases. However, in some cases, DAE may be difficult due to previous laparotomy, or inability to reduce the forming loops during DAE leading to incomplete bowel examination.
In such cases, DAE can be performed under laparoscopic guidance. Laparoscopy can be undertaken by conventional 3-ports or SILS technique [21, 27].
In SILS technique, a SILS port is inserted at the umbilicus. A 10-mm laparoscope and two 5-mm non-traumatic graspers are inserted through the SILS port. Laparoscopic adhesiolysis is performed before starting enteroscopy.
Enteroscopy is performed using conventional flexible endoscope or DBE. Surgical manipulation of the bowel loops is done during enteroscopy if required.
The visualized lesions can be excised endoscopically or laparoscopically depending upon the location and size of the lesions and the available expertise.
In a recent study of 13 patients who underwent SILS enteroscopy, target pathology could be reached in all but one patient with PJS, in whom antegrade DBE failed to reach up to the target polyp and a small enterotomy was required to complete IOE and excise the polyp [21].
A review of 16 studies involving 468 patients by Voron T, et al. reported that the site of bleeding could be successfully identified in 371 patients (79.3%) [16]. The predominant lesions responsible for obscure GI bleed were vascular lesions (n = 227, 61%), benign ulcers (n = 70, 19%), tumors (n = 36, 10%) and diverticula (n = 15, 4%) [16]. The most common route of IOE was transoral followed by trans-enterotomy. A recent study by Manatsathit W, et al. also reported vascular lesions, ulcers and tumors to be the most common lesions detected on IOE [36].
The reported rates of diagnostic and therapeutic yield of IOE are 79.3% (58–100%) and 75.7% (48–94%), respectively [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 16, 36]. The diagnostic yield for obscure GI bleeding after non-diagnostic abdominal imaging has been reported to be 91–100% and after non-diagnostic VCE/DAE varies from 14.2% to 66.7% [1, 6, 9, 36]. Traditionally, the treatment of the lesions detected during IOE were performed surgically. But, with the advancement in the endoscopic techniques, the lesions are being increasingly tackled endoscopically as far as possible and surgical treatment is performed for the rest of the lesions especially in condition like PJS.
IOE via enterotomy converts clean surgery in to clean-contaminated surgery which increases the risk of infective complications. Another problem of IOE is excessive bowel handling which increases the risk of postoperative ileus. The reported complication rates of IOE vary between 1 and 50% [16, 36, 37]. According to a combined data of 10 studies involving 309 patients, the overall morbidity rate was 16.8% which included surgical and medical morbidities [37]. The complications were mainly related to general anesthesia, laparotomy and bowel surgery required for bowel lesions and not solely related to IOE. Prolonged postoperative ileus was one of the predominant surgical morbidity. Other morbidities included bowel obstruction, wound infection, intrabdominal collections/abscess, intra-abdominal bleeding, chest infection and cardiorespiratory failure [18, 37]. The complications directly related to IOE include mucosal laceration, bowel wall hematoma, mesenteric hematoma or bleeding due to excessive handling during IOE and rarely, bowel perforation [38].
The overall mortality rate of IOE from the combined data of 14 studies including 419 patients was 5% [37]. The main causes of death were multiorgan failure, septic shock, diffuse intravascular coagulopathy and hemorrhagic shock [37].
An important issue in patients with obscure GI bleed after any investigation or treatment is the development of recurrent GI bleed. The reported incidence of recurrent GI bleed ranges from 13–52% in different series [9, 36, 37]. It is important to note that differentiation between iatrogenic mucosal trauma from mucosal vascular lesions by IOE is difficult [39]. Secondly, vascular lesions can be evanescent, hence early IOE or at time of bleeding can make the detection of these lesions possible [40]. Other reasons for rebleeding could be appearance of new lesions due to same or different disease, incomplete endoscopic treatment of the existing lesions such as angiodysplasia, etc.
IOE involves lot of small bowel handling and manipulation to allow smooth passage of the endoscopy across the bowel loops. In cases of dense adhesions with shortened mesentery, IOE can be difficult and increase the risk of bowel injury. Another situation where IOE is difficult is in the presence of massive GI bleeding as the lumen is completely filled with blood and examination of the bowel mucosa is not possible [7].
With the increasing use of DAE, the need for IOE has reduced. However, it continues to be an extremely useful tool in patients with obscure GI bleed, multiple polyposis syndromes, multiple foreign bodies or bowel obstruction where DAE cannot be performed or has failed. Moreover, IOE has been found to reduce the need for repeated surgeries by allowing complete small bowel examination and treatment in the same sitting. Although IOE via laparotomy remains the gold standard, availability of advanced minimally invasive equipments have allowed IOE to be performed via multiport or single port laparoscopy.
The authors have no conflict of interest to declare.
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