Rejection mechanisms of the corneal xenotransplantation in various animal models.
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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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All authors, who supported the excellent work showed in every chapter of this book, are placed at the frontier of knowledge on this subject, thus, this book will be obligated reference to issue upon its publication. Finally, this book has been published in an attempt to present a written forum for researchers and teachers interested in the subject, having a current picture in this field of research about these interesting and intriguing toxins.",isbn:null,printIsbn:"978-953-307-395-8",pdfIsbn:"978-953-51-4422-9",doi:"10.5772/896",price:139,priceEur:155,priceUsd:179,slug:"aflatoxins-biochemistry-and-molecular-biology",numberOfPages:480,isOpenForSubmission:!1,isInWos:1,hash:"b7f7359995dc5ee04e12df282495f77e",bookSignature:"Ramón Gerardo Guevara-González",publishedDate:"October 5th 2011",coverURL:"https://cdn.intechopen.com/books/images_new/372.jpg",numberOfDownloads:91643,numberOfWosCitations:173,numberOfCrossrefCitations:47,numberOfDimensionsCitations:211,hasAltmetrics:0,numberOfTotalCitations:431,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 17th 2010",dateEndSecondStepPublish:"December 15th 2010",dateEndThirdStepPublish:"April 21st 2011",dateEndFourthStepPublish:"May 21st 2011",dateEndFifthStepPublish:"July 20th 2011",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,8,9",editedByType:"Edited by",kuFlag:!1,editors:[{id:"62559",title:"Dr.",name:"Ramon G.",middleName:null,surname:"Guevara-Gonzalez",slug:"ramon-g.-guevara-gonzalez",fullName:"Ramon G. 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Blindness is a devastating situation with an estimated 39 million cases worldwide, and one of the common causes is corneal blindness [1]. Corneal transplantation is the standard treatment for the corneal blindness. According to “Cost‐benefit analysis of corneal transplant,” which had been reported by Eye Bank Association of America and the Lewin group in 2013, the net lifetime benefit from the transplantation was estimated at $118,000, whereas the medical cost of the transplant was $16,500 [2]. However, supply of the donor cornea cannot meet the demand in developing countries, and in near future, the number of the eligible cornea will be reduced in the aged societies of the developed countries [1, 3, 4]. Another reason to seek a substitute for allograft is that ethical concerns about organ trafficking [2, 5]. The lack of human donors and the ethical concerns regarding the human organ trafficking drive the need to explore alternative treatments such as corneal xenotransplantation and bioengineered corneas [2, 6–12]. When a survey was conducted through a telephonic interview to assess how corneal xenotransplantation will be perceived by the society, 42.4% of the individuals in the wait‐list for corneal allotransplantation expressed favorable views on corneal xenotransplantation [13].
Cornea is considered applicable as a xenograft, because the eye is regarded as an immune‐privileged site. Surprisingly, Dr. Kissam was the first one who conducted pig‐to‐human corneal xenotransplantation in 1844, although the pig cornea did not survive [14]. Current progress in genetically engineered (GE) pigs and development in gene editing made by clustered regularly interspaced short palindromic repeats (CRISPR)‐Cas9 technology have made xenotransplantation a possible option for human application [15–21]. Recent advances in corneal xenotransplantation through the success in primate studies and the establishment of international regulatory guidelines have brought us a step closer to apply xenograft in clinical trials [22–25]. In fact, clinical trial of lamellar corneal transplantation using a decellularized porcine graft had been already conducted in human subjects in China to treat fungal ulcers [26].
This chapter reviews the current knowledge of immunological and physiological barriers of corneal xenotransplantation, recent progress of corneal xenotransplantation in animal studies, and updates of regulatory guidelines in order to conduct clinical trials of corneal xenotransplantation.
A cornea is an avascular and transparent collagenous tissue with a critical role in vision by transmitting and refracting a light in order to focus the light on the macula. Adult human cornea measures 11–12 mm horizontally and 9–11 mm vertically [27]. It is approximately 500–550 μm thick in the center and 700 μm thick in the periphery [27]. The refractive power of the cornea is 40–44 diopters [27].
The cornea consists of three different cellular layers and two interfaces; the epithelial cell layer, Bowman’s layer (interface), the stroma containing keratocytes (fibroblasts), Descemet’s membrane (interface), and the endothelial cell layer (Figure 1) [27]. The thickness of the corneal epithelial layer is approximately 50 μm. Stem cells of the epithelium reside in the limbus, which is located in the peripheral junction between the cornea and the conjunctiva [27]. The stroma constitutes the largest portion, accounting for more than 90% of the total corneal thickness [27]. The uniform arrangement and continuous slow turn‐over of the collagen fibers by keratocytes are essential for corneal transparency [27]. A single layer of corneal endothelial cells covers the posterior surface of Descemet’s membrane, and it keeps the cornea transparent by actively pumping out the water from the stroma using Na+‐ and K+‐dependent ATPase against imbibition pressure [27].
Normal anatomy of the cornea and schematic figures of the different types of the keratoplasties. (A) Normal histology of a rabbit cornea in hematoxylin and eosin staining. (B) Schematic figure of a normal cornea which consists of three different cellular layers and two interfaces. (C) Penetrating keratoplasty (PK); a procedure of full thickness replacement of the cornea. (D) Anterior lamellar keratoplasty (ALK); a procedure of partial thickness replacement of the anterior cornea. (E) Deep anterior lamellar keratoplasty (DALK); a procedure of almost the full thickness of stromal layers except Descemet’s membrane. (F) Endothelial keratoplasty (EK); a procedure of replacement of the corneal endothelium including Descemet’s membrane or posterior stroma.
The cornea is one of the few tissues in the body that enjoy immune‐privileged status by passively ignoring or actively modulating immunological reactions [28, 29]. Normal and healthy cornea is devoid of vessels and lymphatic channels, thereby shielding it from immune‐mediated attacks by preventing transport of antigens and antigen‐presenting cells and thus attenuating the access of immune cells to the graft [28, 29]. Weak or absence of expression of major histocompatibility complex (MHC) class I and II antigens on the corneal cells is also related to the immune privilege of the cornea [29]. In addition, the cornea expresses various cell membrane‐bound or soluble immunomodulatory molecules such as Fas ligand (FasL, CD95L), complement regulatory proteins (CRPs), tumor necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL), programmed death‐ligand 1 (PD‐L1), and MHC‐Ib that are capable of suppressing immune cells [29]. Interestingly, eye has a unique immune suppression mechanism called anterior chamber‐associated immune deviation (ACAID) [29]. In corneal transplantation, the donor allografts are directly contacted with the AC to induce ACAID, a distinctive systemic immune response to alloantigen [28]. ACAID is an active process that induces antigen‐specific CD4+ and CD8+ T regulatory cells (Tregs) capable of suppressing cellular immune responses and protecting a graft from immune rejection in transplantation [29]. However, any infectious or inflammatory events may break down the immunological privilege of the cornea.
The history of corneal transplantation using allografts and xenografts dates back to more than two centuries [3]. Penetrating keratoplasty (PK), a procedure of full thickness replacement of the cornea, has been used as the dominant procedure worldwide [3]. It is a successful method for most causes of corneal blindness. Lamellar transplantation surgery, that selectively replaces only diseased layers of the cornea, consists of anterior lamellar keratoplasty (ALK) and deep anterior lamellar keratoplasty (DALK) [3]. ALK usually replaces partial thickness of the anterior stromal layers and it may induce interface haze between the graft and the recipient corneal stroma. DALK replaces almost the full thickness of stromal layers except Descemet’s membrane and endothelial cell layer without inducing interface haze. Both procedures can be applied to patients who have a corneal opacity with an intact endothelial cell layer, and they can eliminate the risk of endothelial rejection [3]. Endothelial keratoplasty (EK) can selectively replace the corneal endothelium in patients with endothelial disease. Rejection risk in PK is higher rather than that in ALK/DLAK or EK [3]. Different types of keratoplasties are schematically shown in Figure 1.
Although an eye is an immune‐privileged site, the innate, humoral, and cellular immune responses are involved in corneal allograft rejection. These immune reactions also happen in corneal xenograft rejection associated with pig antigens. Galactose-alpha-1,3-galactose (e.g. αGal) to which human natural Ig M antibodies are reactive is constantly expressed on porcine cells. This is a critical obstacle to overcome hyperacute xenogeneic rejection in most organ transplantation [30]. Therefore, the distribution of porcine antigens (e.g., αGal, non‐Gal) in the cornea has been investigated. It has been found that wild type (WT) porcine cornea expresses αGal mostly in the anterior stromal keratocytes in immunohistochemical or immunofluorescent staining [31, 32]. In vitro culture, αGal expression appears on both WT porcine endothelial cells and keratocytes [32]. Based on mass spectrometry, sialylated N‐glycans have been identified from both WT porcine corneal endothelial cells and keratocytes [33]. As non‐Gal antigens, N‐glycolylneuraminic acid (NeuGc) as well as N‐acetyl sialic acid (NeuAc) are also identified in both WT corneal endothelial cells and keratocytes [33]. Since α1,3‐galactosyltransferase gene‐knockout (GTKO) pigs that do not express the Gal epitopes have been made [15, 34], the feasibility of GTKO pigs is investigated for the corneal xenograft. In immunofluorescent staining, strong expression of NeuGc has been found in all layers of both WT and GTKO pig corneas [35]. That is to say, both αGal and non‐Gal epitopes are widely expressed in WT cornea, whereas antigenic epitopes such as non‐Gal are still expressed in GTKO cornea.
In vitro study has shown that IgG antibody binding affinities to the cornea or the T cell responses of GTKO pigs are weaker than those of WT pig corneas [35, 36]. NeuGc is a major target of human antibodies, but not a target of nonhuman primate (NHP) antibodies [37, 38]. The absence of αGal or NeuGc on porcine peripheral blood mononuclear cells or corneal cells can significantly decrease human antibody binding significantly in vitro [39, 40]. However, when immune reactions are compared between GTKO/hCD46 and GTKO/hCD46/NeuGc KO pigs, the strength of the human T‐cell proliferative response to GTKO/hCD46/NeuGc KO pig cells is similar to that to GTKO/hCD46 pig cells. The absence of NeuGc expression on GTKO/hCD46 pig cells does not diminish human platelet aggregation or decreases the instant blood‐mediated inflammatory reaction (IBMIR) to pig cells [41]. In an NHP study, GT KO/CD46 pig corneas are not associated with prolongation of the graft survival or a reduced antibody response compared with WT pig corneas [42]. Taken together, it remains doubtful whether the absence of αGal or NeuGc expression on cornea of the GE pigs might have an advantage over WT cornea in in vivo xenotransplantation.
Major histocompatibility complex (MHC) antigens play important roles in corneal allotransplantation [43–45]. Therefore, MHC antigens might have roles in corneal xenotransplantation as in other organ xenotransplantations [46, 47]. In fact, human antiporcine T cell response and binding property of IgG HLA‐specific antibodies to pig lymphocytes are similar to an allogeneic responses with both direct and indirect pathways of recognition in the human antiporcine MHC class II responses being functionally intact [48–50]. In DNA microarray, MHC‐A has been expressed in both WT porcine corneal keratocytes and endothelial cells [51]. Genetically‐engineered Class I MHC knockout pigs have reduced levels of CD4−CD8+ T cells in peripheral blood [52]. Modulation of swine MHC by transferring human HLA DPw0401 can reduce human‐to‐pig cellular response, in vitro [53]. Human dominant‐negative class II transactivator (CIITA‐DN) transgenic pigs that can suppress swine leukocyte antigen (SLA) class II expression have been found to have reduced human T cell response, in vitro [54]. Although MHC‐related immune response is evidently important in xenotransplantation, in vitro and in vivo immune responses against porcine MHCs in corneal xenotransplantation have not been published yet.
An unmodified cellular porcine cornea is defined as a xenotransplant medicinal product, while a decellularized porcine cornea is defined as a medical device [25]. As a medical device, porcine decellularized cornea can be produced in various ways to reduce immunogenicity [55–58]. Decellularized porcine cornea has an advantage on the survival of the graft by reducing immune responses in different animal models as well as in human clinical study [23, 26, 56, 57, 59, 60].
In corneal allotransplantation, a CD4+ T cell‐mediated reaction is primarily involved in graft rejection [8, 61–63], while CD8+ T cell‐ and complement‐mediated reactions are partially involved in allograft rejection [64–67].
Rejection mechanisms of corneal xenotransplantation have been investigated using various animal models (Table 1) [8, 23, 24, 42, 68–76]. The main rejection mechanism seems to be different depending on the animal model used. Unlike xenotransplantation of the vascular organs, hyperacute rejection (minutes to hours) is not presented in all corneal xenotransplantation models [4, 8].
Models | Median survival (days) | Proposed rejection mechanism |
---|---|---|
Lewis rat‐to‐guinea pig [68] | 8 | IgM and IgG xenoantibody |
Guinea pig‐to‐rat [69] | 7 | T cell, neutrophil, macrophage, Ig G |
Guinea pig‐to‐mouse [70, 71] | 9–16 | CD4+ T cell, complement, MHC class II |
Lewis rat‐to‐mouse [72] | 9.4 | CD4+ T cell, antibody |
Pig‐to‐mouse [73, 74] | 9.0–9.4 | CD4+ T cell, macrophage, complement |
Pig‐to‐GTKO mouse [75] | 9.0 | IgG αGal antibody, CD4+ and CD8+ T cell, macrophage |
WT pig‐to‐NHP [23, 24] | 26*–189.8** | CD4+ or CD8+ T cell, macrophage, B cell, IgG/IgM antibody, complement |
GTKO/CD46 pig‐to‐ NHP [42] | 104 | CD3+ T cell, non‐Gal pig antibody |
hCTLA4‐Ig pig‐to‐NHP [76] | 70.3 | Macrophage, CD3+CD4+ T cell, CD79+ B cell |
Rejection mechanisms of the corneal xenotransplantation in various animal models.
GTKO, α1,3‐galactosyltransferase gene‐knockout; WT, wild type; NHP, nonhuman primate; CD46, membrane cofactor protein (MCP).
*Survival of full‐thickness keratoplasty (PKP).
**Survival of anterior lamellar keratoplasty (ALK).
In Lewis rat‐to‐guinea pig corneal transplantation, the mean survival time of corneal xenografts has been reported to be 8 days with IgM and IgG xenoantibody production after pre‐sensitization [68]. In Guinea pig‐to‐rat model, the mean survival time of corneal xenografts is reported to be 7 days with a IgG deposition and infiltration of T cells, neutrophils, and macrophages in the graft [69]. In guinea pig‐to‐mouse corneal xenotransplantation, the median survival time is 9–16 days in wild types, whereas the survival time is extended in mice deficient in the CD4, C3, or MHC class II gene, suggesting that CD4+ T cells, complement, and host antigen‐presenting cells might contribute to graft rejection [70, 71]. In Lewis rat‐to‐mice corneal xenotransplantation, survival time (mean survival time of 44.1 days) of xenograft is found to be longer after treatment with antiCD4 antibody compared to that of the control (mean survival of 9.4 days). However, xenografts treated with antiCD4 antibody are rapidly rejected by antibody‐containing serum (mean survival of 21.5 days) [72]. In pig‐to‐mouse corneal xenotransplantation, median survival time is 9.0 days with macrophages and CD4+ T cells being found in rejected grafts in WT mice, and the survival time is extended in severe combined immunodeficiency (SCID) mice [73]. Natural killer (NK) cells are not involved in the xenogeneic rejection in this model [73]. In pig‐to‐mouse corneal xenotransplantation, complement depletion has prolonged the survival of xenograft, showing deposition of IgG and IgM in rejected grafts [74]. In pig‐to‐GTKO mouse corneal xenotransplantation, gradual increase of IgG αGal antibody is evident suggesting that αGal might affect the long‐term survival of pig corneal xenografts through antibody‐mediated reactions [75].
In pig‐to‐nonhuman primate (NHP) corneal xenotransplantation, grafts are not hyperacutely rejected, regardless of pig genotypes [7]. In WT pig‐to‐NHP corneal xenotransplantation, infiltrations of CD4+ or CD8+ T cells, macrophages, and B cells and deposits IgG/IgM and C3c have been observed in rejected grafts [23, 24]. It indicates that both the cellular and humoral responses are involved in WT corneal xenograft rejection of NHP models as in allograft rejection. In GT KO/CD46 (human complementary regulatory protein) pig‐to‐NHP corneal xenotransplantation, CD3+ T lymphocytes still infiltrate in the graft accompanied by increased non‐Gal pig antibodies in the blood [42]. Cell infiltration in rejected hCTLA4Ig transgenic grafts is mainly composed of macrophages with CD3+, CD4+ T, and CD79+ B cells to a lesser extent than those in WT types of grafts [76]. It indicates that T cell‐ and antibody‐mediated reactions cannot be exempted even in GE pig grafts.
To restore a vision in corneal xenotransplantation as a functional success, anatomical (e.g., diameter, thickness, and tensile strength), physiological (e.g., cellular behaviors), and optical (e.g., refractive power for light to focus on the retina) properties of the substitute cornea should be similar to those of a human cornea. In this regard, WT or GTKO pig cornea is considered as a potential alternative to human cornea (Table 2) [4, 7, 77–86].
Parameters and breed of the pig | Pig | Human | Mean pig age (months) |
---|---|---|---|
Central corneal thickness (μm) | |||
GE pig (Revivicor, Blacksburg, VA) | 659 [78] | 536 [80] | 1.5 |
WT Danish Landrace pig (Lars Jonsson Lynge, Denmark) | 666 [81] | 3.5 | |
WT pig (Wally Whippo, Enon Valley, PA) | 775 [78] | 5–10 | |
WT SNU miniature pig (Seoul, Korea) | 833 [77] | 42 | |
Yorkshire pig (Seoul, Korea) | 867 [82] | 4 | |
GE pig (Revivicor, Blacksburg, VA) | 868 [78] | 15 | |
Sus scrofa domestica | 877 [83] | 6–8 | |
GE pig (Revivicor, Blacksburg, VA) | 914 [78] | 20–25 | |
WT pig (Wally Whippo, Enon Valley, PA) | 995 [78] | 42 | |
Tensile strength (MPa) [84] | 3.70 | 3.81 | NA |
Stress‐relaxation pattern*; P (×100) [84] | 64.6a | 85.6 | NA |
Stress‐relaxation pattern*; K (−) [84] | 0.0553a | 0.0165 | NA |
Corneal power (Diopter) | 40.2 [82, 83] | 43.7 [85] | 4–8 |
Endothelial cell density (/mm2) | |||
WT pig (Wally Whippo, Enon Valley, PA) | 3094 [78] | 2720 [86] | 5–10 |
GE pig (Revivicor, Blacksburg, VA) | 3022 [78] | 15 | |
WT SNU miniature pig (Seoul, Korea) | 2625 [77] | 42 | |
WT pig (Wally Whippo, Enon Valley, PA) | 2130 [78] | 42 | |
GE pig (Revivicor, Blacksburg, VA) | 1714 [78] | 20–25 |
Anatomical, physiological, and optical properties of the pig cornea compared to those of adult human cornea.
The data present average of the parameters.
WT, Wild‐type; GE; genetically engineered; NA, not available data.
*P is the value of G (t) at the end of the stress‐relaxation test; K is the slope of fitted G (t)‐ln t line.
ap < 0.01 compared with Stress‐relaxation pattern in human.
A major anatomical barrier in corneal xenotransplantation is the difference in corneal thickness between the human recipient and the pig donor. Pig corneal thickness and endothelial cell density are dependent on the age and the breed as shown in Table 2 [7, 77–79, 81–83]. Pig central corneas are thicker (659–995 μm) than human central corneas (average; 536 μm). The donor thickness should be in the range so that peripheral edges of the cornea between donor and recipient can be appropriately approximated. Unlike human cornea with center to peripheral thickness difference by 150–250 μm, there is no significant difference in the thickness between central (666 μm) and peripheral locations (657–714 μm) of pig cornea [81]. Consequently, a pig cornea whose central thickness is thicker than in human is considered applicable in human in surgical aspect. However, no paper has documented that pig corneal graft with a central thickness of more than 950–1000 μm is capable of being transplanted up to date. Tensile strength of the pig cornea is similar to that of the human cornea which is operable for corneal transplantation, although stress‐relaxation of the pig cornea is significantly lower than that of the human cornea [4, 84]. Differences in stress‐relaxation do not affect the long‐term mechanical maintenance of the graft in NHP studies. Optical power of the pig cornea has been found to be comparable to that of the human cornea [82, 83, 85].
The cornea can maintain transparency by functionally intact corneal endothelial cells. Therefore, endothelial density and proliferative potential in the endothelial cells of the pig cornea should be similar to those of human cornea. The proliferative potentials of pig and human endothelial cells are similar to each other [77, 79]. Endothelial cell density of the pig cornea is decreased depending on age, as similar to that of aged human [77–79, 86]. However, the age‐dependent decrease of endothelial cell density in GE pigs (1714.0 ± 19.2 mm−2 in 20–25 months old) is higher than that in WT pigs (2130.2 ± 193.7 mm−2 in 42 months old) [78]. Considering that more than 2200 mm−2 ofthe endothelial cell density is preferred for a donation, the age of the pig as a donor should be limited in accordance with endothelial cell density. The age limitation of GE pigs might be different from that of WT pigs. Unlike type‐dependent differences of endothelial cell density (WT versus GE), the preservation time‐dependent decrease of endothelial cell density in WT pig cornea is not different from that in human cornea [77]. The preservation time‐dependent decrease of endothelial cell density in GE pig cornea is not reported.
Survival of a corneal allograft or xenograft is affected by immunologic reaction, graft size, the presence of corneal endothelial cells, and the hierarchical discordancy between the donor and the recipient [87–92]. Therefore, we should compare the survival time of xenografts depending on the various animal models in consideration with the aforementioned risk factors.
Reported results on the survival time of different types of the pig grafts in various animal models are shown in Tables 3 and 4. Outcome for small and medium sized animal models is shown in Table 3. Decellularized graft survives longer than fresh grafts, and anterior lamellar partial thickness graft without including the endothelial cell layer survives longer than posterior lamellar or full thickness graft that includes the endothelial cell layer (Table 3) [56, 57, 60, 73, 93–95].
Type of pig donor | Recipient | Graft size (mm) | Graft thickness | Median survival (days) |
---|---|---|---|---|
Fresh | C57BL/6 mice | 3.0 | Posterior lamellae+ | 9.0 [73] |
Fresh | BALB/C mice | 3.0 | Posterior lamellae+ | 9.0 [73] |
Fresh | Sprague‐Dawley rats | 6.0 | Posterior lamellae+ | 9.3 [93] |
Fresh | Sprague Dawley rats | 2.0 | Anterior lamellae | 14.0 [94] |
Decellularizedς | Sprague Dawley rats | 2.0 | Anterior lamellae | 28.0 [94] |
Fresh | Rabbits | 7.0 | Anterior lamellae | 29.1 [95] |
Fresh | Rabbits | 7.0 | Full thickness | 16.8 [95] |
Decellularized* | Rabbits | 8.0 | Anterior lamellae | >180 [57] |
Decellularizedξξ | Rabbits | 6.3 | Anterior lamellae | 84 [60] |
Decellularized** | Rabbits | 10.0 | Anterior lamellae | 365 [56] |
The median survival time of various types of the pig grafts in small‐ or medium‐sized animal models.
+Posterior lamellae that includes endothelial cell layer (Anterior lamellae does not include endothelial cell layer).
ςLyophilized graft.
*Treated with hypertonic saline.
ξξTreated with 200 U/ml phospholipase A2 and 0.5% sodium deoxycholate.
**Treated with sodium dodecyl sulfate.
Type | Donor pig | Recipient (number) | Immunosuppression | Survival (days) | Reported year |
---|---|---|---|---|---|
ALK | WT | Cynomolgus (n = 6) | None | >30+, >30+, >30+, 75, 165, 180 | 2003 [31] |
ALK | WT | Rhesus (n = 4) | None | >90, >90, >90, >90 | 2007 [22] |
ALK | WT | Rhesus (n = 5) | None | 180, 15, 180, 180, 180 | 2011 [97] |
ALK | WT | Rhesus (n = 4) | Local and systemic steroid | >398, >194, 24.5, 24.5 | 2011 [23] |
ALK | WT | Macaca fascicularis (n = 4) | Local steroid | 9, 70, 21, 21 | 2014 [76] |
DALK | WT | Rhesus (n = 5) | Steroid+antiCD40 antibody | >389, >382, >236, >201, >61 | 2017 [99] |
ALK* | WT | Rhesus (n = 5) | None | 180, 180, 180, 180, 180 | 2011 [97] |
ALK* | WT | Rhesus (n = 5) | Local steroid | 180, 180, 180, 180, 180 | 2011 [97] |
ALK* | WT | Rhesus (n = 5) | Local and systemic steroid | >391, >265, >208, >195, 28 | 2011 [23] |
ALK | hCTLA4‐Ig transgenic | Macaca fascicularis (n = 4) | Local steroid | 21, 50, 90, 120 | 2014 [76] |
ALK | GTKO/hCD39/hCD55/hCD59/FT | Macaca fascicularis (n = 2) | Local steroid | 9,34 | 2014 [76] |
PKP | WT | Rhesus (n = 4) | Local steroid | 129, 276, 182, 144 | 2007 [22] |
PKP | WT | Rhesus (n = 6) | Cyclophosphamide+BMT | 32, 42, 40, 34, 38, 30 | 2013 [98] |
PKP | WT | Rhesus (n = 6) | Cyclophosphamide | 12, 18, 16, 20, 20, 20 | 2013 [98] |
PKP | WT | Rhesus (n = 3) | Local and systemic steroid | 21, 28, 29 | 2015 [24] |
PKP | WT | Rhesus (n = 4) | Local and systemic steroid + antiCD154 antibody | >933, >243, 318, >192 | 2015 [24] |
PKP | WT | Rhesus (n = 4) | Local steroid | 157, 28, 92, 33 | 2017 [42] |
PKP | GTKO/CD46 | Rhesus (n = 4) | Local steroid | 128, 57, 47, 171 | 2017 [42] |
Current progress on clinical efficacies in pig‐to‐NHP corneal xenotransplantation from 2003 to 2017.
ALK, anterior lamellar keratoplasty (partial thickness); BMT, bone marrow transplantation; DALK, deep anterior lamellar keratoplasty; FT, fucosyl transferase; GTKO, α1,3‐galactosyltransferase gene‐knockout; hCTLA4‐Ig, human cytoxic T‐lymphocyte‐associated antigen4‐immunoglobulin; hCD39, human ectonucleoside triphosphate diphosphohydrolase‐1; CD46, membrane cofactor protein (MCP); hCD55, human complement decay‐accelerating factor; hCD59, human MAC‐inhibitory protein; PKP, penetrating keratoplasty (full thickness).
+Sacrificed at 1 month for histology.
*Decellularized cornea.
Current progress on clinical efficacies in pig‐to‐NHP corneal xenotransplantation from 2003 to 2017 is shown in Table 4 [7, 22–24, 31, 42, 76, 96–99]. Some studies have presented encouraging outcomes in lamellar or full‐thickness corneal xenotransplantation with or without immunosuppressants. The survival time varies depending on the breed of the donor and recipients, immunosuppressive protocols, and types of the corneal grafts. Processed acellular corneas can prolong the survival time of ALK. With steroid treatment, partial thickness corneal transplantation that does not include endothelial cell layer (ALK) shows better survival than full thickness corneal transplantation (PKP). GE pigs in ALK or PKP do not show significant increase of the survival time compared to the control. With antiCD154 treatment, PKP using WT Seoul National University (SNU) miniature pig has demonstrated the longest survival time in the NHP model. Taken together, corneal xenotransplantation using fresh pig graft still requires stronger immunosuppressant than steroid alone, regardless of the type of donor pig (WT or GE).
In 2013, the first consensus on guidelines for clinical trials of corneal xenotransplantation has been established in Korea [87]. Thereafter, international consensus statement on conditions for undertaking clinical trials of xenocorneal transplantation has been finally published in International Xenotransplantation Society (IXA) in 2014 [25]. IXA consensus statements on conditions for clinical trials of corneal xenotransplantation include the followings; (1) ethical requirement, (2) quality control of source pigs, (3) quality control of pig corneal products, (4) preclinical efficacy and safety data that are required to justify a clinical trial, (5) strategies to prevent porcine endogenous virus transmission (PERV) transmission, and (6) patient selection and informed consent.
Key ethical requirements for clinical trials of corneal xenotransplantation are essentially identical to those required in other areas of clinical trials. These guidelines adhere to the basic ethical principles for clinical trials of islet xenotransplantation established by the Ethics Committee of the IXA and the Changsha Communique of the World Health Organization [25, 100]. Regulatory guidelines for pig sources and strategies to prevent porcine endogenous virus transmission (PERV) are basically the same as those for clinical trials of islet xenotransplantation [101–103].
Guidelines for corneal‐specific issues have been intensively discussed on the procurement of porcine corneal products, preclinical efficacy, and safety data to justify initiation of a clinical trial, and inclusion criteria of the subjects. In order to be enrolled, the subject must meet the following criteria; (1) must be diagnosed with legal blindness as defined by the American Medical Association and the United States Congress as best corrected visual acuity of 20/200 or less in the better eye, (2) must be diagnosed with a corneal blindness that can be only cured with a corneal transplantation, (3) must not have timely access to receive corneal allotransplantation, (4) must be over the legal age, (5) must not be pregnant, must not plan to become pregnant, and must not be breast feeding, and (6) should be highly compliant. Keratoconus should be excluded due to the excellent allograft survival and younger age of the subject. Guideline for visual acuity can be exempted in a subject who requires an emergency operation for actual or impending corneal perforation. Regarding adequate procurement of the corneal xeno‐product, the guidelines of the European Eye Bank Association (EEBA) on the preparation of human corneal tissue should be adopted under provision that laboratory tests have confirmed that biological properties of the preserved pig cornea based on EEBA guidelines are comparable to those of the preserved human cornea. To prove preclinical efficacy, NHP data that the pig cornea xenograft should survive for more than 6 months in five of eight consecutive NHPs are required (ideally for 12 months in one or two successful cases). Compared to the 5‐year survival rate (70–80%) of the islet allotransplantation, mean 5‐year survival rate of corneal allotransplantation among the various corneal diseases is similar to each other (70–80%) [104–106]. Therefore, the same preclinical efficacy that has been accepted for islet xenotransplantation can be applied to corneal xenotransplantation with provisional condition that patient who is diagnosed as keratoconus must be excluded.
In 2016, the IXA consensus statement on conditions for undertaking clinical trials of porcine islet products has been revised for the first time [107–114]. New or under‐appreciated topics have been discussed and updated regarding regulatory framework, genetic modification of the source pig, recipient monitoring for preventing disease transmission, patient selection, porcine islet product manufacturing, and quality control of source pigs. To undertake clinical trials of corneal xenotransplantation, under‐appreciated topics as follows should also be addressed and revised [2]. (1) In source pigs, PERV‐C negative donor pigs should be considered preferable, and donor pig selection criteria should be primarily based on low PERV expression levels and the lack of infectivity. (2) Clinical trial protocols using GE pig products also need to be assessed on a case‐by‐case basis. (3) For preclinical efficacy in corneal xenotransplantation, the finding that survival in four of six (or five of eight) consecutive NHP experiments may be sufficient to indicate potential success of a clinical trial that is similar to those in islet xenotransplantation. (4) Clinically relevant microorganisms should be included in pig screening programs. (5) When microorganisms are confirmed to be absent in the donor pig by sensitive microbiological examination, recipients need not to be monitored. (6) Life‐long surveillance for PERV should be adjusted based on the clinical sign and the laboratory test if the subjects do not show any suspicious sign of PERV infection by sensitive laboratory examination for 2 years. In a clinical trial of islet cell xenotransplantation using microencapsulated pig islets, PERV DNA and PERV RNA are not detected in peripheral blood up to 113 weeks by real‐time RT‐PCR [115]. In this clinical trial, the subjects were followed‐up for two years. If the risk of PERV transmission is proved to be negligent, follow‐up time should be adjusted accordingly. Given that substantial scientific progress has been made in islet xenotransplantation and cornea field, the international consensus statement on corneal xenotransplantation is expected to be updated regarding these under‐appreciated issues.
Due to progresses made in immunosuppressive protocols, the availability of GE pigs, and appropriate guidelines for clinical trials, corneal xenotransplantation using pig cornea might be a feasible option to solve the shortage of donor corneas in the future. Decellularized porcine graft also appears to be efficient in a clinical trial. Results of recent experiments of the corneal xenotransplantation in NHP models using cellularized pig grafts are encouraging, and it helps us decide whether we should keep developing xeno‐related products of cornea. With better understanding on the antigenicity of pig cornea and the rejection mechanism involved in corneal xenotransplantation, optimized and standardized immunosuppression should be established before conducting a human clinical trial. As for fresh corneal grafts from GE pigs, the further experiments need to be performed to verify their efficacies as substitutes for human corneas.
This study was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health & Welfare, Republic of Korea (Project No. HI13C0954).
The temporal bone is a dense complex bone that constitutes the lower lateral aspect of the skull and has complex anatomy because of the three-dimensional relationships between neurovascular structures. The petrous portion of the temporal bone has a role as the partition between the middle and posterior cranial fossae. It articulates with the occipital bone (occipitomastoid suture) posteriorly, the parietal bone (squamous suture) superiorly, the sphenoid bone (spheno-squamosal suture) and the zygomatic bone (arcus zygomaticus) anteriorly, and the mandible (temporomandibular joint) inferiorly [1, 2]. It contains multiple intrinsic channels, along with the internal carotid artery (ICA), cranial nerves, and sigmoid sinus (SS), all within intricate spatial architecture. Owing to a complex web of foramina and neurovascular structures of the temporal bone, the lateral skull base is a technically difficult region for surgeons. Because the middle and inner ear structures of hearing and equilibrium are preserved in the temporal bone, a surgical dissection of it requires thorough understanding of three-dimensional (3D) map of the topographic anatomy to avoid iatrogenic risks. The relationship between the surface landmarks and expected internal structures and the segmentation of the temporal structures by using key surgical lines and spaces allow a better understanding of its anatomic architecture. Each temporal bone consists of five distinct osseous segments including the squamous, tympanic, petrous, mastoid, and styloid portions [3, 4].
The anterosuperior part of the temporal bone is a large flattened scale-like plate that forms the lateral boundary of the middle cranial fossa. It has three borders and two surfaces [1].
Superiorly, it overlaps the sculpted squamous margin of the middle third of the parietal bone and constructs the squamosal suture. Posteriorly, it forms the occipitomastoid suture with the squamous part of the occipital bone. Also, there is an angle, parietal notch, between the squamous and mastoid portions of the temporal bone (Figure 1). Antero-inferiorly, its thick serrated margin takes part in pterion formation and articulates with the greater wing of the sphenoid bone to form the spheno-squamosal suture. Inferiorly, it fuses and forms the petro-squamous suture with the superior surface of the petrous portion by extending medially as tegmen tympany [5, 6].
The surface landmarks on the squamous portion: 1, temporal fossa; 2, supra-meatal crest; 3, temporal line; 4, external acoustic meatus; 5, supra-meatal triangle (Macewen’s triangle); 6, middle temporal artery; 7, squamo-mastoid suture; 8, mandibular fossa (glenoid fossa); 9, articular eminence; 10, zygomatic process; 11, petrotympanic fissure (Glaserian fissure); 12, mastoid foramen; 13, parietal notch; 14, mastoid process; 15, mastoid notch (digastric fossa); 16, occipital sulcus; 17, tympano-mastoid suture; 18, vaginal process; 19, styloid process.
External surface, the greater part of the temporal fossa, provides origin to the temporalis muscle and is limited below by the curved line, the temporal line, that lies from the supra-meatal crest to the mastoid cortex posteriorly. Below this line, just above and behind the external acoustic meatus (EAM), the supra-meatal triangle (Macewen’s triangle) contains the supra-meatal spine, spine of Henle and the cribriform area (Figure 1). Also, the squamo-mastoid suture is located approximately 1 cm below the temporal line [5, 6, 7]. On this smooth surface, there is a sulcus for the middle temporal artery, which is the medial branch of the superficial temporal artery (STA). Antero-inferiorly, the zygomatic process projects by two roots: the upper border of the posterior root forms the supra-meatal crest and the lower border forms a laterally based projection, known as post-glenoid tubercle or process (PGP). Inferiorly, the concavity along the surface of the anterior root is called the glenoid fossa (GF), which is bounded by the articular eminence (ArE) anteriorly and the PGP posteriorly [5, 6, 7].
Internal surface is rough and concave in shape, and the anterior and posterior divisions of middle meningeal artery (MMA) run in a groove on this surface that defines the boundary of middle cranial fossa with impressions for the gyri of the temporal lobe. Inferiorly, it forms the petro-squamosal suture with the anterior surface of the petrous part [5, 6].
The Macewen’s triangle, a surgical surface marking for the mastoid antrum (MA), is formed between the temporal line superiorly, the posterosuperior wall of the EAM antero-inferiorly, and the opening of the mastoid emissary vein or sinodural angle posteriorly (Figure 1). The temporal line corresponds to the tegmen tympani (TT), which is a bony plate below the middle cranial fossa dura and over the mastoid air cells. The mastoid cortex posterior to the spine of Henle is a guide to the lateral wall of the MA and located 15 mm deep to it in adults but in new born about 2 mm [5, 6, 8]. The cribriform area in Macewen’s triangle is perforated by numerous small holes that serve as a passage for the vessels of the mucosa of the antrum. The dissection along the margins of this triangle is safer because the vital neurovascular structures are absent. Peris-Celda et al. reported that the temporal line is supratentorial and infratentorial in 93% and 7% of the cases, respectively [9]. During retro-auricular mastoidectomy, the MA may be exposured by drilling the cribriform area and provides a safer surgical approach to the tympanic cavity. The tympanic portion and the styloid process may show variations depending on the shape and the position of the spine of Henle. The MA is located in the same line of the spine of Henle at about 10 years; then the MA is enlarged and placed 1 cm behind it [6, 9].
The MMA lies underneath the pterion which is a common junction between the temporal, parietal, frontal, and sphenoid bones. The fracture of this weakest bony part may result in an epidural bleeding. Between the temporal muscle and fascia, the STA and the superficial temporal vein (STV) courses in close proximity with the zygomaticotemporal (ZTN) and the auriculotemporal (ATN) nerves, branches of the trigeminal nerve (TN). Because of a vessel running superficial to the nerve (80% STA), the underlying nerve may be compressed and results in temporal migraine headache. Lee et al. reported that the intersection (compression) point among the ATN, STA, and STV was at an average of 40 mm superior and 10 mm anterior to the tragus, which is a significant surface landmark at the most anterosuperior point of the EAM. The applications of surgical decompression of the ATN in these compression points improve migraine headache [10].
The anterior articular part of the GF is formed by a gentle sloped area of the squamous portion, which facilitates the movement of the temporomandibular joint (TMJ) during wide mouth opening. At the lateral aspect of the ArE, a small bony ridge, articular tubercle (AT), serves as an attachment for the lateral collateral ligament. The PGP inhibits backward displacement of mandibular head and participates to the superior wall of the EAM [8]. The posterior nonarticular part of the GP is formed by the tympanic portion and the squamo-tympanic suture intervenes between them. The inferior edge of the TT (petrous part) divides this suture into two: a petro-squamosal fissure in front and a petrotympanic fissure (Glaserian fissure) behind (Figure 1). The chorda tympani nerve, a branch of the facial nerve, exits the temporal bone through the Glaserian fissure and joins the lingual nerve as the parasympathetic input to start the submandibular and sublingual gland secretions [2, 4, 5].
The articulation between the GF and the condyle of the mandible is called TMJ, which plays an essential role in speech, respiration, swallowing, and specially mastication. Because the TMJ is in close proximity with the MMA, some surgical landmarks around the TMJ and foramen spinosum (FS) play a critical role in surgical approaches. Miller et al. reported that researchers measured the distances from the zygomatic root (first projection of the zygomatic arch = PGP) to some surgical landmarks such as the arcuate eminence (AE), the head of the malleus (HM) under the TT, and the FS to identify the location of the internal auditory meatus (IAM) or the superior semicircular canal (SSC). Also, they described the superior petrosal triangle as a consistent triangle between the zygomatic root, the FR, and the HM to localize the bony tegmen over the tympanic cavity [11]. Baur et al. offered simply identifiable reference landmarks including the AE, the most lateral aspect of the Glaserian fissure and the FS and measured the distances between them to predict the location of the MMA [12]. According to these researchers, the internal landmarks including the HM and Bill’s bar (the vertical crest in the fundus of the internal auditory canal) are in a single plane with the zygomatic root [11].
After the ArE forming the anterior limit of the GF, the anterior root continues in front as a bony ridge that forms the posterior boundary of the infratemporal fossa, which is a small triangular area transmitting the neurovascular structures between the pterygopalatine fossa and temporal fossa. Then, a serrated anterior end of the zygomatic process passes straight forward and articulates with the temporal process of the zygomatic bone and completes the zygomatic arch. The temporal fascia inserts to this arch and the temporal line superiorly and also the masseter muscle origins from the arch inferiorly. The lateral temporomandibular ligament attaches to the AT, and the GF is covered with an articular disc to construct the synovial TMJ with the condyle of the mandible [5, 6, 7].
Anteriorly, the small part of squamous portion takes part in the infratemporal fossa formation with the zygomatic bone and the greater wing of the sphenoid bone. Below the zygomatic bone, the branches of the first and second mandibular parts of the MA with veins and the pterygoid plexus of veins, the mandibular and lingual nerves pass through the infratemporal fossa. During the infratemporal fossa approaching for surgical removal of tumors localized in the orbit, the maxillary and sphenoid sinuses, the detailed anatomical knowledge of these neurovascular structures is needed. Depending on the position of the infratemporal fossa below the floor of the middle cranial fossa and posterior to the maxilla, it is in close proximity with the parapharyngeal and masticator spaces. The parapharyngeal carotid artery enters the carotid canal (CC) behind the FS and foramen ovale. During transpterygoid infratemporal fossa approach, the positions of these surgical landmarks can be used to prevent ICA injury [13].
Ossification of the squamous portion starts intramembranously from one center around the zygomatic process at the 2nd month. At birth it fuses with the other membranous bone, tympanic portion. Normally, at birth the temporal bone consists of three parts; the petrous, squamous, and the tympanic [1].
The mastoid portion forms the pneumatized thick posterior part of the temporal bone. It fuses with the squamous portion antero-superiorly and the tympanic portion anteriorly and the petrous portion anteromedially. It has three borders and two surfaces [5, 6].
Posteriorly, it articulates with the squamous part of the occipital bone between lateral angle and the jugular process and constructs the occipitomastoid suture. Inferiorly, the mastoid process extends as a rough and conical shaped projection and filled with mastoid cells variable in shape and size. Anteriorly, it associates with the tympanic portions of the temporal bone to form the tympano-mastoid suture, and the inferior auricular branch of the vagus nerve (Arnold’s nerve) exits through this suture [5, 14, 15].
Near the squamo-mastoid suture, the occipital belly of occipito-frontalis and auricularis posterior muscles attach on the external surface that is perforated by numerous small foramina. At the posterior border of the mastoid portion or the occipitomastoid suture, the largest one, mastoid foramen is located and transmits an emissary vein connecting the SS with the posterior auricular vein and a branch of occipital artery to the dura mater (Figure 1). The mastoid process serves for the attachment of the sternocleidomastoid, splenius capitis, and longissimus capitis muscles and shows variations in shape and size with respect to sex. The posterior belly of the digastric muscle is originated from the mastoid notch (digastric fossa), which is a depression on the inferomedial margin of the mastoid process (Figure 1). More medial to the notch lies a sulcus, the occipital sulcus, forming a groove for the occipital artery [4, 6].
The internal surface includes a well-defined and curved sigmoid sulcus lying along its junction with the posterior surface of petrous part and lodges the SS, partially the transverse sinus, which are separated from mastoid air cells by a thin plate of bone. The mastoid foramen transmitting the mastoid emissary vein may be open to this sulcus. The SS begins as the continuation of the transverse sinus and lies downward in a S-shaped groove and opens into the superior jugular bulb. There is a sinodural angle between the dura plates of the SS and middle and posterior cranial fossae [2, 5, 9, 16].
The mastoid process shows tree types of pneumatization patterns including pneumatic (full air cell), sclerotic (solid mass of bone), and mixed (air cells and bone marrow) types. Especially, in the anterosuperior part of the mastoid process, there is an irregular cavity that is larger than other mastoid cells and called MA, which corresponds to the cribriform area. It is covered with the mucous membrane of the tympanic cavity and communicates anteriorly with the epitympanic recess of the middle ear via the aditus ad antrum. The tegmen antri, a roof of the MA, separates it from the middle cranial fossa. During embryonic period, the squamous and petrous portions fused each other and forms the petro-squamous suture. In adults, it forms a thin bony septum, the Körner’s septum, by extending into the mastoid process [1, 4, 6, 9, 17]. Körner’s septum divides the mastoid air cells in the mastoid process into a deep petrous part medially and a superficial squamous part laterally. The petro-squamosal sinus or the mastoid emissary vein may infrequently be observed along this septum. During mastoidectomy or transmastoid approaches, awareness of this crucial landmark and its variations is essential to avoid iatrogenic complications. The squamous part starts to develop at 8th week, whereas the petrous part develops later at 6th months during embryogenesis, and each part opens into the MA separately [1]. Also, the mastoid cells are separated by bony plates from the adjacent structures such as the posterior wall of the EAM anteriorly, tegmen plate superiorly, SS posteriorly, digastric ridge inferiorly, and the lateral semicircular canal (LSC) or solid triangle medially. The solid triangle is a compact bony angle between three SCs. During the mastoidectomy, all the air cells around this septum and adjacent bony structures should be removed without damaging the bony plates. To avoid iatrogenic injury to the adjacent structures, the MA must be open superiorly toward TT. The tympano-mastoid suture at the posterior wall of the MA is surface marking of the course of the vertical portion of the facial nerve (FN) [9, 16, 18]. Peris-Celda et al. reported that the parietal notch corresponds to the posterior petrosal point and the SS (the transverse-SS junction) in 66 and 34% of the cases, respectively [9].
Ossification of the mastoid portion is endochondral which is identical to the petrous and styloid portions. At birth, the mastoid process is absent, and the MA is invisible and covered by a thin bony plate that is extension of the squamous portion. At the first year, the mastoid process becomes prominent and the petro-squamous suture arises. The antrum can be seen obviously at about the fifth year. During puberty, the thickness of the process increases, and it becomes pneumatic that is lined by mucous membrane. In adults, the mastoid process may not contain air cells in 20% cases [1, 2, 17].
An annular shaped part of the temporal bone forms the tympano-mastoid suture posteriorly and the squamo-tympanic suture superiorly (Figure 1). Medially, it fuses with the petrous portion, whereas a free lateral part of it constructs the major part of the EAM and also serves an attachment for the cartilaginous part of the external auditory canal (EAC). Its inferior margin is free, and it has two parts on the lateral surface; posterosuperior part forms the EAM, and anteroinferior part limits the mandibular fossa posteriorly [5, 19].
Medially, just above the GF, this suture is subdivided by a thin tegmen part of the petrous portion into two: the petrotympanic fissure posteriorly and the petro-squamosal fissure anteriorly. Lateral part of this upper margin fuses with the back of the PGP to form the nonarticular part of the GF. Inferiorly, the lateral part of the margin gives an attachment for the deep part of the parotid fascia and forms the vaginal process, which wraps the root of the styloid process laterally [2, 4].
Laterally, external surface is bounded by the cartilaginous part of the EAC which extends from the auricle to the tympanic membrane. The EAC is an S-shaped tube, about 2.5 cm in long, that is composed of the lateral third cartilaginous part and the medial two-thirds osseous part [14, 15, 18]. The tympanic part constructs the anterior wall and floor and the lower part of posterior wall of the EAM, whereas the squamous part forms the superior and upper part of the posterior wall of it (Figure 1). The tympanic part grows from the tympanic ring, which is open U-shaped possessing two edge anterior and posterior. The anterior edge forms the tympano-squamous fissure within the anterosuperior part of the EAM and the petrotympanic fissure within the middle ear, whereas the posterior edge forms the tympano-mastoid fissure within the posteroinferior part of the EAM near the stylomastoid foramen (SMF) [2, 4, 19].
The internal surface fuses with the petrous portion and forms the tympanic sulcus for the lodgement of the tympanic membrane, which forms an angle about 55° with the floor of the EAM and separates the external and middle ear (ME). At the upper part, the tympanic sulcus does not fuse each other by forming the greater and lesser tympanic spines and a notch called Rivinus between them. This notch is closed by the pars flaccida of the tympanic membrane. The notch of Rivinus corresponds to the junction between the squamous and tympanic portions [1, 4, 14, 20].
Ossification starts from the four centers around the tympanic ring at the end of the embryonic period (8th week) via intramembranous ossification of the EAM. The tympanic ring at first is nearly straight and then turns into horseshoe shape (annular) and then, the open arms extending upwards terminate in a notch for the location of the tympanic membrane between them. After birth, the upper segment of the tympanic bone grows rapidly but because of the gradual development of the lower segment, a deep notch (tympanic foramen) is left in the anterior part of the bony EAM. Normally, the tympanic ring fuses until the age of 5 year but a dehiscence may persist (range 4.6−22.7%) at the anteroinferior aspect of the EAM, called foramen of Huschke (foramen tympanicum). This fusion defect is not a true foramen, but it may cause a connection between the EAM and the posteromedial part of the TMJ and results in TMJ herniation and the secretion of the parotid gland and also the dissemination of tumor and infections into the EAM [1, 14, 19, 20]. Anteriorly, the EAM may communicate with the retromandibular part of the parotid gland via the fissures of Santorini within the anterior cartilage. Peris-Celda et al. reported that the SSC dehiscence can be observed approximately 1.5 cm posterior to the middle point of the EAM in 86% of the cases [9]. In newborn, the tympanic membrane is infiltrated with air and the tympanic ring forms a bony plate, which may cause the development of a cleft, the auricular fissure, posteriorly and a cleft, the tympano-squamous fissure, anteriorly [19, 20].
The petrous portion is a dense pyramid-shaped bone and composed of the labyrinth of the internal ear, the tympanic cavity of the middle ear and a bony part of the auditory Eustachian tube (ET), and canals for the passage of the ICA and the FN. It is ossified from the otic capsule by forming a 45° angle with the horizontal axis. It has a base, an apex, and three surfaces and three borders [3, 4, 21].
Superiorly, the petrous ridge is the longest border and a boundary between the posterior part of the middle cranial fossa (the anterior surface of the petrous part) and the anterior part of the posterior cranial fossa (the posterior surface of the petrous part). It contains a groove that lodges the superior petrosal sinus (SPS) and the lateral margin of tentorium cerebelli attaches to this margin (Figure 2). Posteriorly, the medial part of the posterior margin articulates with the basilar part of occipital bone along the petro-clival fissure and forms a groove that lodges the inferior petrosal sinus (IPS) that extends from the posteroinferior part of the cavernous sinus to the internal jugular vein (IJV). The lateral part of the posterior margin is free and limits the jugular foramen (JF) supero-laterally and has a triangular notch for the lodgement of the inferior ganglion of the glossopharyngeal nerve (Jacobson’s nerve = GPN). Anterolateral border is formed by the ET extending from the anteroinferior wall of the tympanic cavity to the nasopharynx [3, 4, 9].
The surface landmarks on the anterior surface of the petrous portion: a, petrous ridge (sulcus of the superior petrosal sinus); b, arcuate eminence; c, tegmen tympani; d, sulcus of the lesser petrosal nerve; e, sulcus of the greater petrosal nerve; f, trigeminal impression; g, petrous apex; ıocc, internal opening of carotid canal.
The base is integrated with the inner surface of the squamous and mastoid portions, whereas the apex forms the posterolateral margin of the foramen lacerum (FL) and faces the Meckel’s cave medially. There is a fibrocartilage connection between the apex and the clivus. The internal opening of the carotid canal (IOCC) is observed at the apex for the intracranial entry of the ICA. At the anterolateral part of the FL, the petro-sphenoid ligament connects the tip of the apex to the dorsum sellae of the sphenoid and the abducent nerve lies below this ligament and enters the cavernous sinus adjoining the ICA [1, 7, 16].
Anterior surface describes a triangular area, between the linear lines as follows: a horizontal line that starts from the preauricular burrhole in front of the tragus to petrous apex at the FL and passes through the FS anteriorly, the petrous ridge posteriorly and the petro-squamous suture, which lies along the junction of the petrous pyramid with the vertical part of the squamous portion laterally [3, 16, 22]. It consists of some marking landmarks (Figure 2).
The anteromedial two-third of the musculotubal canal is cartilaginous, whereas the posterolateral third is bony. The bony part consists of two small canals that are separated by a thin bony septum at the lateral part the petrous portion. The tensor tympani muscle passes through the superior semicanal, whereas the inferior semicanal forms the bony portion of the ET. The tensor tympani muscle originates from the greater wing of the sphenoid and inserts into the upper part of the medial surface of the handle of malleus after making a bend around the processus cochleariformis in the tympanic cavity [4, 6]. The ET lies between the tympanic orifice and the isthmus, which has the smallest diameter at the intersection point of the petrous and squamous parts of the temporal bone just behind the sphenoid spine. Brown et al. reported that the ET is subdivided by genu within the membranocartilaginous part into two portions; posterior horizontal ET between the genu and the anterior attachment of the tympanic membrane ridge, whereas the anterior vertical ET lies from the genu to the nasopharyngeal orifice and opens into the nasopharynx. During endoscopic eustachian tube obliteration, the ET is cannulated to treat refractory CSF rhinorrhea by identifying three anatomic parameters: the ET length, isthmus diameter, and genu location. According to a new surgical classification, the cartilaginous portion of the ET is divided into the petrous, lacerum, pterygoid, and nasopharyngeal parts. The bony part attaches to the ET sulcus or sulcus tuba, which is contiguous to the FL medially. The FL is located in the incomplete confluence of the union of the body and the lingular process of the greater sphenoid wing anteriorly, the clivus of the occipital bone medially and the petrous apex posteriorly and covered with the fibrocartilaginous tissue that separates the ET from the ICA [23].
The internal opening of the CC is located near the FL for the passage of the ICA, which is freed at the petrous apex into the cavernous sinus (Figure 2). It is localized medial to the ET, below the greater superficial petrosal nerve (GSPN), a branch of the FN and the trigeminal ganglion [1, 3, 4]. The petrous segment of the ICA within the CC has four anatomic parts, called vertical, posterior genu, horizontal, and anterior genu. During endoscopic endonasal surgery, the junctional part of the ET at the sphenoid spine and FS is crucial landmark to identify and protect the petrous segment of the ICA [13]. The anatomical and surgical relationships between the ET and the petrous segment of the ICA are as follows:
The first curve, posterior genu is located at the level of the bulging basal turn of the cochlea within the bend of the CC. Laterally, the bony part of the ET and the tendon of the tensor tympani muscle; posterolaterally, the promontory and posterosuperiorly, geniculate ganglion are paramount landmarks for the posterior genu of the ICA. The V3 lying anteromedially to the FS and the parapharyngeal segment of the ICA, which passes posteroinferiorly to the sphenoid spine, are critical landmarks. Posterolaterally, the petroclival fissure cartilage is an important landmark to separate the pharyngobasilar fascia from the anterior genu of ICA.
The second turn of the ICA, anterior genu, above the fibrous tissue of the FL is in close proximity to the lacerum segment of the cartilaginous ET laterally and continues as the paraclival ICA in the carotid groove. During the endoscopic approach, the Vidian artery and nerve (VN) are critical landmarks for the second curve of the ICA.
For safe manipulation of the horizontal part of the ICA, the GSPN can be used as surgical landmark. Above the anterolateral margin of the FL the union of the GSPN and the deep petrosal branch of the carotid neural plexus forms the VN which is located anteroinferiorly and lateral to the second turn of the ICA. Malignancies that involve the petrous apex or the carotid artery require the extended endoscopic endonasl approach (EEA). During this procedure, the medial and lateral optico–carotid recesses in the cavernous sinus and the vidian canal (VC) are vital surgical landmarks, which allow to identify the position of the ICA for safe surgical resection near the ICA [13].
At the apex above the CC, a shallow fossa called trigeminal impression (Figure 2) is located for the lodgement of the sensory ganglion of the TN (semilunar ganglion or Gasser’s ganglion) that is covered by a pouch-shaped dura mater called Meckel’s cave [3]. Vascular compression and arachnoid adherence of the TN branches result in trigeminal neuralgia. During endoscopic vascular decompression and Meckel’s cave approaches, the VC, the bone between V2 and the VC and the pneumatization of the sphenoid sinus form a safe route to access and to decompress Gasser’s ganglion with branches, the cranial nerves (III, IV, VI), and the petrous ICA [13, 23].
Behind the trigeminal impression, the roof of the IAM is indicated as a shallow fossa, then it continues with the AE, which is a surgical landmark for the middle fossa approach and located at the junction of the posterior third and the anterior two-thirds of the petrous portion (Figure 2). It is a valuable guide to signify the SSC and the roof of the vestibule up to 93% of the temporal bones [19, 22].
The TT is a thin bony layer covering all of the anterior surface (Figure 2). It forms the roof of the mucosal line including from behind to forward the MA, tympanic cavity and ET which are lined with mucosa. Also, its lateral edge turns downward to subdivide the squamo-tympanic fissure into two parts [1, 3].
On the TT, a bony roof of the geniculate ganglion, there are two foramina, which continue as a small groove adjoining anteromedially; the medial one starts from the hiatus of the facial canal and lodges the GSPN, a branch of the FN and the petrosal branch of the MMA, whereas the lateral one lodges the lesser superficial petrosal nerve, a branch of GPN (Figure 2) [3, 9, 16, 22].
Kaen et al. described the “VELPPHA” area indicating the posterior limit of the transpterygoid EEA. It is composed of the VC (V), the ET (E), the FL (L), the petroclival fissure (P), the pharyngobasilar fascia (PHA), and multiple cartilaginous fibers between them. The posterior opening of the VC, the posterior limit of surgical corridor in the transpterygoid approach, is located above the ET and below the petrous ICA. Behind the posterior margin of the medial pterygoid process, the superomedial border of the ET attaches to the cartilaginous fibers of the FL. The petroclival fissure is situated between the lateral border of the clivus (occipital bone) and the petrous part of the temporal bone and lodges the IPS. The horizontal segment of the petrous ICA turns upward at the medial border of the petrous apex to form the anterior genu of the ICA, and then it continues as the lacerum segment, second vertical segment of the ICA. So, the VC-ET junction is a safe and critical landmark for efficient localization of the lacerum segment of the ICA, as part of the transpterygoid extension of EEA [24].
Tayebi Meybodi et al. described the pterygoclival ligament as a thickened extension of the pharyngobasilar fascia from the pterygoid process to the anteromedial aspect of the lacerum segment of the ICA and reported that the course of the pterygoclival ligament consistently refers to the anteromedial aspect of the lacerum ICA. So, they suggested that the pterygoclival ligament can be used as a safe landmark in case of tumor invasion of the VN, and drilling along the medial aspect of this ligament is more reliable way compared with the VN to avoid the ICA injury during extended EEA. Also, they remarked that this ligament may localize in a venous compartment, which is in contact with the cavernous sinus superiorly and the pterygoid venous plexus posteroinferiorly [25].
The posterior surface, anterior wall of the posterior cranial fossa, is encircled by a venous triangle that is formed by the grooves for SS posteriorly and SPS at the petrous ridge and IPS at the junction of the pars lateralis of the occipital bone and the temporal bone anteroinferiorly. The SS drains into the bulb of the IJV, which exists from the JF together with the cranial nerves (IX-XI) [1, 6, 9].
The IAM is a short canal, about 1 cm long, and has a large orifice, which allows passage of the vestibulocochlear nerve below the FN, the superficial petrosal artery (a branch of the MMA) and the labyrinthine artery (branch of the basilar artery). The bottom (fundus) of the IAM is subdivided into unequal superior and inferior portions by a transverse falciform crest, and into the anterior and posterior portions by a vertical segment, Bill’s bar, respectively (Figure 3) [2, 15]. The localization of the nerves within the IAM is determined by a triangular shaped Bill’s bar as follows; posteriorly the superior and inferior vestibular nerves, anteroinferiorly the cochlear nerve, anterosuperiorly the FN and nervus intermedius pass through the foramina of the fundus (Figure 3) Mortazavi [1, 4, 6].
The aqueductus vestibuli is a bony canal which contains the saccus and ductus endolymphaticus. Its opening is an oblique slit behind the IAM (Figure 3). The endolymphatic sac is located at the lateral part of the posterior surface medial to the posterior SSC [2, 18].
The subarcuate fossa is an indistinct depression (large in new born) located behind the IAM (Figure 3) and transmits a small vein and the subarcuate artery, which is a branch of the meatal segment of the anterior inferior cerebellar artery [4, 5, 9, 14].
The surface landmarks on the posterior surface of the petrous portion: a, petrous ridge; b, arcuate eminence; h, internal acoustic meatus; ı, subarcuate fossa; j, aqueductus vestibuli; k, sigmoid sinus sulcus; m, sulcus of the middle meningeal artery; 12, mastoid foramen.
The inferior surface articulates with the basilar part of occipital bone medially, and the greater wing of the sphenoid bone anteriorly and forms an irregular external surface of the base of the skull. Below the apex, there is a quadrilateral area that serves as an attachment for the levator veli palatini muscle. The lateral part of this area merges with the posterior margin of the greater wing of sphenoid to form the sulcus tuba in front of the cartilaginous portion of the auditory tube [4, 5, 21]. It presents some anatomical landmarks as follows:
The external opening of the CC, which shows an inverted L-shape course, forms the entrance for the ICA, which is surrounded by a plexus of sympathetic nerves (Figure 4). The anterior margin of the horizontal segment of the CC is separated from the musculotubal canal by a thin layer of bone laterally [1, 5, 18].
The jugular fossa is a deep dome-shaped depression at the lateral wall of the JF and located behind the CC and below the floor of the tympanic cavity. It houses the superior bulb of the IJV and the mastoid canaliculus (Figure 4) for the entry of the Arnold’s nerve, which provides sensory innervation of the EAC and auricle [9, 15]. The jugular spine in the jugular notch of the occipital bone divides the JF into the pars nervosa (anterior) and pars venosa (posterior) [4, 5, 9]. Normally, the jugular bulb is located between the IJV and the horizontal course of the SS. Abnormalities of it (80% below the FN in the mastoid cavity) result in dehiscence of the adjacent structures such as: the mediolateral enlargement of the JB results in the vestibular aqueduct, PSC, and IAC dehiscence, whereas the anteroposterior enlargement of the JB may cause the FN dehiscence. Abnormal high riding JB shows both mediolateral and anteroposterior enlargement and results in dehiscence of the FN [26].
Between the jugular fossa and the CC, the inferior ganglion of the GPN is localized in a triangular depression, whereas the inferior tympanic canaliculus penetrates into wedge-shaped bony ridge and transmits the tympanic branch of the GPN and inferior tympanic artery. At the apex of this triangular depression, there is an external opening of the cochlear aqueduct (Figure 4), which connects the perilymphatic space to the subarachnoid space and transmits the cochlear vein [1, 5, 14].
Behind the CC the vaginal process which is the extension of the sharp lower border of the tympanic plate wraps the root of the styloid process (Figure 4). The lower border of that extension serves an attachment for the deep layer of parotid fascia [1, 3, 5, 6].
The surface landmarks on the inferior surface of the petrous portion: FM, fossa mandibularis; FS, foramen stylomastoideum; FJ, fossa jugularis; ET, eustachian tube; eocc, external opening of carotid canal; ıocc, internal opening of carotid canal; star: inferior tympanic canaliculus; arrowhead: cochlear aqueduct.
Internal structures in the petrous portion contain the ME and inner ear. The ME contains an air-filled tympanic cavity and the ossicular chain which is composed of the malleus, incus, and stapes [14]. The walls of the ME:
Lateral wall contains the tympanic membrane and the scutum pointed infero-medially from the squamous portion. The tympanic membrane has two parts; pars flaccida is located in a fibrocartilaginous ring called the tympanic sulcus and susceptible to perforations and pars tensa is situated in the notch of Rivinus above the lateral process of the malleus. At the medial surface of the membrane a depression called umbo is formed by attachment of the manubrium of the malleus.
Medial wall consists of the cochlear promontory, the FC, the oval and round windows. It is divided into three part by the bony ridges: the ponticulus superiorly and the subiculum inferiorly. The oval window (vestibular window) is located above the ponticulus whereas the round window (cochlear window) is below the subiculum, and the tympanic sinus between them is located medial to the FC. The vestibular window is closed by the base of the stapes. The facial recess lies below the lateral SSC and superolateral to the oval window.
Superior wall, the TT, which forms the roof of the ME.
Inferior wall is a bony roof of the IJV.
Anterior wall includes the anterior epitympanic recess superiorly, below it the tensor tympani muscle lies posteriorly and attaches to the neck of the malleus after turning laterally. The orifice of the ET and below it the CC is located inferiorly.
Posterior wall consists of the pyramidal eminence, epitympanum, and facial recess. The stapedius muscle passes through the pyramidal eminence and inserts to the head of the stapes [2, 5, 7, 14, 18].
The tympanic cavity is lined with the mucous membrane that extending into the MA posteriorly and the ET anteriorly. This cavity consists of three parts changing according to the level of the tympanic membrane; the epitympanum (superior to the level of the tympanic membrane), mesotympanum (at the level of the tympanic membrane), and hypotympanum (inferior to the level of the tympanic membrane). The hypotympanum has the orifice of the ET. At the lateral part of the epitympanum below the lateral malleal ligament there is the Prussak space which is bounded by the neck of the malleus medially and the pars flaccida and scutum laterally [2, 3, 5, 14].
Inner ear is comprised of the otic capsule (osseous labyrinth), which surrounds the membranous labyrinth and is divided into three parts from anterior to posterior including the cochlea, vestibule, and three SCs [14]. Cochlea is the spiral shaped bony labyrinth of the inner ear that looks like a snail shell making 2¾ turns about the modiolus and consists of the vestibular and the tympanic and the cochlear ducts, which are formed by an inner membranous partition. The vestibular duct (scala vestibuli) locates at the superior part of the cochlear canal and contains perilymph (rich in sodium ions) and is limited by the oval window, and is separated from the cochlear duct by Reissner’s membrane. The cochlear duct (scala media) locates at the middle part of the cochlear canal and contains endolymph (rich in potassium ions) and is separated from the tympanic duct by the basilar membrane, which has the Organ of Corti including the sensory hair cells. The stereocilia of these cells perceives the potential difference between the perilymph and the endolymph and converts that motion to electrical signals and finally hearing occurs. The tympanic duct (scala tympani) locates at the inferior part of the cochlear canal and contains perilymph as the vestibular duct and is limited by the round window [3, 5, 14, 15]. Vestibule contains the utricle and saccule. SSCs containing three semicircular ducts organized like three flower leafs that join the vestibule. They are located perpendicular to each other; the superior corresponds to the AE, the posterior is parallel to the posterior surface of the pyramid, and the lateral is perpendicular the mucosal plane and angled at 30°from the transverse plane [3, 15].
The FN passes through the anterosuperior part of the IAM and enters the fallopian canal (FC). It contains motor, sensory, and parasympathetic fibers and has six segments as follows:
Cisternal segment lies from the brain stem to the IAM. This part runs together with the cisternal part of vestibulocochlear nerve in same pia mater coverage.
Meatal segment is the smallest part of the FC and contains Bill’s bar as an important landmark.
Petrous (labyrinthine) segment forms first genu (geniculate ganglion) above the cochlea at the lateral wall of the ME and gives a branch named as GSPN. Then, it enters the tympanic cavity and forms an angle ranging from 19 to 107° with tympanic segment of the FC [7, 20]. Because of this segment is the narrowest part and lack of arterial anastomoses, it is susceptible to embolic attacks and vascular compression.
Tympanic segment (first part) starts from first genu and turns backwards to lie in a thin-walled bony canal that runs evenly between the lateral SSC superiorly and the oval window inferiorly and medial to the incus. A dehiscence of the bony canal is more common at this segment in average 41–75%.
Pyramidal segment (second part of the tympanic segment) forms second genu at the posterior wall of the ME above the pyramidal process. It forms an angle ranging from 95 to 125° with mastoid segment of the FC [7, 20].
In the mastoid or vertical segment, the FN gives the acoustic branch for the stapedius muscle, the chorda tympani, and sensitive branch for the auricular region. This segment is located 5.50 mm anteromedially to the SS and extends from the level of the LSC to the digastric ridge (~3.8 mm). Then it exits the temporal bone at the SMF and enters the parotid gland [14, 27].
According to the classical description, the FC has four segments: labyrinthine, tympanic, pyramidal, and mastoid, but the meatal segment is important from an anatomical and surgical perspective. The stylomastoid artery, a branch of the posterior auricular or the occipital arteries, supplies the inferior parts of the FC up to the second genu and anastomoses directly with the petrosal branch of the MMA, which supplies the geniculate ganglion. The FC pathologies are composed of agenesis, aplasia, narrowing, and osteopetrosis of the canal, which result in complete or incomplete facial paralysis. Bell’s palsy depending on the activation of a dormant herpes virus, is responsible for 50% of peripheral FN palsies. The FC dehiscence can be congenital or secondary to the surgical intervention or pathology of adjacent structures and results in cerebrospinal fluid (CSF) otorrhea. Several surgical approaches, including the translabyrinthine, transcochlear and retrosigmoid, are used to treat the FC pathologies [27].
Ossification of the petrous portion begins from the 14 centers that fuse to form otic capsule and is completed at birth. The petrous portion develops from the cartilaginous differentiation of the mesenchyme by endochondral ossification at the 16th week of gestation. The cementum layer in teeth roots and petrous portion of the temporal bone contain the optimal endogenous DNA substrate which can provide information to specify the geographic location for genomic analyses [28]. Damgaard et al. reported that the prevalence of the endogenous DNA contents in nonpetrous bones and teeth is ranged from 0.3 to 20.7%, while the levels for petrous bones ranges between 37.4 and 85.4% [29]. Due to the high density and resistance to harsher climatic conditions of the petrous bone, the otic capsule of the petrous bone preserves DNA substrate extremely well and has much higher endogenous DNA level than the teeth by 5.2-fold on average. So, it is currently acknowledged as the optimal substrates for ancient genomic research [28, 29].
Kawase’s triangle: Borghei-Razavi et al. evaluated the safety of this posteromedial middle fossa triangle for removal of the tumors locating or spreading into the cerebellopontine angle and petroclival area. Kawase’s triangle was identified between the GSPN laterally, the geniculate ganglion at the AE posteriorly, and ganglion gasserian at the trigeminal impression anteriorly. During anterior petrosectomy for accessing the posterior cranial fossa via middle fossa, the GSPN forms the lateral border of the surgical approach (Figure 5) [30].
The surgical triangles on the anterior surface: Kawase’s triangle: Post-med (posteromedial triangle) and Glasscock’s triangle: post-lat (posterolateral triangle). FS, foramen spinosum; GG, geniculate ganglion; TI, trigeminal impression.
Glasscock’s triangle, or the posterolateral middle fossa triangle, is identified between the TN (V3), the geniculate ganglion at the AE and FS (Figure 5). The margins of this triangle are formed by a line between where the GSPN crosses under V3 and the FS medially, a line between the FS and geniculate ganglion laterally, and GSPN describing the base [3, 5, 16].
Rhomboid area (Kawase triangle+postmeatal area) is situated between the GPN, petrous ridge, AE, and the posterior border of the V3. A large tumor located in the midline skull base or spreading into the infratemporal and petroclival region even the cavernous sinus can be removed by extended EEA through V2-V3 corridor to avoid complications including ICA injury, IPS bleeding, TN injury and CSF leak [31].
Trautmann’s triangle is bounded by the SPS superiorly, SS posteriorly, and solid angle which is formed by three SCs anteriorly (Figure 6). In this triangle, the retro-labyrinthine tract from the MA, the endolymphatic sac, and the vestibular aqueduct are located [5, 9].
The surgical triangles on the posterior surface: Trautmann’s triangle margins are formed between the superior petrosal sinus superiorly, the sigmoid sinus posteriorly, and the semicircular canals antero-inferiorly. Star: Citelli’s angle (sinodural angle) is formed between the dural plates of the middle fossa superiorly, the posterior fossa anteriorly and the sigmoid sinus posteriorly.
Donaldson’s line is a surgical line that is parallel to the LSC whereas it is vertical to the posterior SSC and divide it into superior and inferior portions. Below this line medial to the labyrinth the endolymphatic sac is situated. Citelli’s angle (sinodural angle); is bounded by the middle fossa dura plate (SPS) superiorly, posterior fossa dura plate (bony plate covering the MA) anteriorly and the SS posteriorly (Figure 6). During mastoidectomy the air cells in this triangle should be removed [1, 5, 6].
In clinical applications, for fully understanding of the tridimensional architecture of the petrous portion, a reference lines and angles can be defined on the anterior and posterior surfaces from a superior view.
Peris-Celda et al. reported that the EAM and the IAM are located in the same coronal plane on the anterior surface forming surgical triangle [9]. Tawfik-Helika et al. separated the pyramid into four compartments and described two segmentation method to provide better understanding of the distributions of these compartments. They identified four compartments based on their connections: mucosal, cutaneous, neural, and vascular [3, 21].
The mucosal compartment consists of an air filled and mucosa lined cavities from anterior to posterior: the ET, ME, and the MA (Figure 7). The mucosal line in an oblique anteromedial direction extends along these structures and is used for segmental description of this pyramid, and all major anatomical landmarks can be identified relative to this axis for surgical approaches [3, 9, 21].
(A) The margins of the anterior surface of the left petrous portion from a superior view are shown posteriorly by a (thick black) line along the PR, petrous ridge; anteriorly by a (dashed black) line lying from the preauricular burrhole to PA, petrous apex and passing through the FS, foramen spinosum; and laterally by a (dashed white) line along the petro-squamous suture. OC, optic canal; ACP, anterior clinoid process; FL, foramen lacerum; SOF, superior orbital fissure; FR, foramen rotundum; FO, foramen ovale; MMA, middle meningeal artery; IOCC, internal opening of carotid canal; GSPN, greater petrosal nerve; AE, arcuate eminence; TT, tegmen tympani; JF, jugular foramen; IAM, internal acoustic meatus; SSS, sulcus sigmoid sinus. (B) The segmentation of the left petrous pyramid into four compartments including mucosal, cutaneous, neural, and vascular is shown on the left petrous portion.
Extending the mucosal line posteriorly, the MA is separated into medial and lateral parts, whereas anteriorly, the bony portion of the ET is localized at the junction of the petrous and squamous parts and the cartilaginous part opens into the pharynx anteriorly. Medially the line passing through the sulcus of the GSPN and laterally a straight line lying between the foramen ovale and FS are parallel to this line (Figure 7) [3, 9, 21].
The cutaneous compartment is composed of the EAM, which is covered by the skin and separated from the ME by the tympanic membrane medially.
The neural compartment is composed of the otic capsule, which is located medial to ME and the mucosal line. In this bony container, the cochlea, vestibule, and SCs are located from anterior to posterior around the fundus of the IAM (Figure 7).
The vascular compartment is composed of the ICA. The axis passing through the horizontal part of the CC is parallel and medial to the mucosal line (Figure 7) [3]. Moreover, Tawfik-Helika et al. described X and V segmentation methods to advance and enhance education of the compartments.
The X method divides the petrous pyramid into four spaces by using two reference lines intersecting with each other at the ME; the mucosal line and the EAM-IAM line form the X letter (Figures 8 and 9). These four spaces around the ME and the contents in it are as follows:
The anteromedial space—the cochlea and the petrous apex including the ICA
The anterolateral space—the roof of the TMJ
The posterolateral space—the lateral part of the MA
The posteromedial space—the posterior labyrinth and the medial part of the MA
Schematic representations of the segmentation of the left petrous portion by using X and V methods.
Schematic representation of the external and internal landmarks on the left petrous portion. V, trigeminal nerve and branches (V1, V2, V3); TI, trigeminal impression; IOCC, internal opening of carotid canal; ET, Eustachian tube; GG, geniculate ganglion; ME, middle ear; MA; mastoid antrum; EAM, external acoustic meatus; TMJ, temporomandibular joint; SCCs, semicircular canals; IAM, internal acoustic meatus; VII, facial nerve; VIII, vestibulocochlear nerve; IX, glossopharyngeal nerve; X, vagus nerve; XI, accessory nerve.
The V method arranges five segments around the mucosal line (Figures 8 and 9) These five segments and the contents in it are as follows:
The petrous apex segment—the ICA medial to the ET
The otic capsule segment—the IAM, cochlea, vestibule and SCs
The mastoid segment—the angle around the MA
The EAM segment—the lateral part of the ME
The TMJ segment—the roof of the TMJ lateral to the ET [3].
Detailed description of the temporal anatomy pointing to relationships between internal and external landmarks and a holistic approach including X an V segmentation methods that break down the petrous pyramid into spaces and compartments can provide an easy way to understand and to use surgical applications. The compartmental approach can be helpful in the fields of education and radiological applications as well as surgery.
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