Standards or guidance related to cord blood and umbilical cord-derived cells.
\\n\\n
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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Benno Meyer-Rochow",authors:[{id:"60506",title:"Dr.",name:"Benno",middleName:null,surname:"Meyer-Rochow",fullName:"Benno Meyer-Rochow",slug:"benno-meyer-rochow"},{id:"60742",title:"Dr.",name:"Juhani",middleName:null,surname:"Itämies",fullName:"Juhani Itämies",slug:"juhani-itamies"},{id:"60743",title:"Dr.",name:"Reima",middleName:null,surname:"Leinonen",fullName:"Reima Leinonen",slug:"reima-leinonen"}]},{id:"19847",title:"Effects and Consequences of Global Climate Change in the Carpathian Basin",slug:"effects-and-consequences-of-global-climate-change-in-the-carpathian-basin",signatures:"János Rakonczai",authors:[{id:"58870",title:"Dr.",name:"János",middleName:null,surname:"Rakonczai",fullName:"János Rakonczai",slug:"janos-rakonczai"}]},{id:"19848",title:"Climate Change Impact on Quiver Trees in Arid Namibia and South Africa",slug:"climate-change-impact-on-quiver-trees-in-arid-namibia-and-south-africa",signatures:"Danni Guo, Renkuan Guo, Yanhong Cui, Guy F. Midgley, Res Altwegg and Christien Thiart",authors:[{id:"29391",title:"Dr.",name:"Danni",middleName:null,surname:"Guo",fullName:"Danni Guo",slug:"danni-guo"},{id:"41826",title:"Prof.",name:"Christien",middleName:null,surname:"Thiart",fullName:"Christien Thiart",slug:"christien-thiart"},{id:"54850",title:"Prof.",name:"Renkuan",middleName:null,surname:"Guo",fullName:"Renkuan Guo",slug:"renkuan-guo"},{id:"84247",title:"Mr.",name:"Yanhong",middleName:null,surname:"Cui",fullName:"Yanhong Cui",slug:"yanhong-cui"},{id:"106355",title:"Dr.",name:"Guy F.",middleName:null,surname:"Midgley",fullName:"Guy F. Midgley",slug:"guy-f.-midgley"},{id:"106360",title:"Dr.",name:"Res",middleName:null,surname:"Altwegg",fullName:"Res Altwegg",slug:"res-altwegg"}]},{id:"19849",title:"Changes in the Composition of a Theoretical Freshwater Ecosystem Under Disturbances",slug:"changes-in-the-composition-of-a-theoretical-freshwater-ecosystem-under-disturbances",signatures:"Ágota Drégelyi-Kiss and Levente Hufnagel",authors:[{id:"10864",title:"Dr.",name:"Levente",middleName:null,surname:"Hufnagel",fullName:"Levente Hufnagel",slug:"levente-hufnagel"},{id:"50135",title:"PhD.",name:"Agota",middleName:null,surname:"Dregelyi-Kiss",fullName:"Agota Dregelyi-Kiss",slug:"agota-dregelyi-kiss"}]},{id:"19850",title:"The Use and Misuse of Climatic Gradients for Evaluating Climate Impact on Dryland Ecosystems - an Example for the Solution of Conceptual Problems",slug:"the-use-and-misuse-of-climatic-gradients-for-evaluating-climate-impact-on-dryland-ecosystems-an-exam",signatures:"Marcelo Sternberg, Claus Holzapfel, Katja Tielbörger, Pariente Sarah, Jaime Kigel, Hanoch Lavee, Aliza Fleischer, Florian Jeltsch and Martin Köchy",authors:[{id:"50610",title:"Dr.",name:"Marcelo",middleName:null,surname:"Sternberg",fullName:"Marcelo Sternberg",slug:"marcelo-sternberg"}]},{id:"19851",title:"Climate-Driven Change of the Stand Age Structure in the Polar Ural Mountains",slug:"climate-driven-change-of-the-stand-age-structure-in-the-polar-ural-mountains",signatures:"Valeriy Mazepa, Stepan Shiyatov and Nadezhda Devi",authors:[{id:"61313",title:"Prof.",name:"Valeriy",middleName:null,surname:"Mazepa",fullName:"Valeriy Mazepa",slug:"valeriy-mazepa"},{id:"61314",title:"Prof.",name:"Stepan",middleName:null,surname:"Shiyatov",fullName:"Stepan Shiyatov",slug:"stepan-shiyatov"},{id:"61315",title:"Dr.",name:"Nadezhda",middleName:"Mikhailovna",surname:"Devi",fullName:"Nadezhda Devi",slug:"nadezhda-devi"}]},{id:"19852",title:"Mountains Under Climate and Global Change Conditions – Research Results in the Alps",slug:"mountains-under-climate-and-global-change-conditions-research-results-in-the-alps",signatures:"Oliver Bender, Axel Borsdorf, Andrea Fischer and Johann Stötter",authors:[{id:"58222",title:"Prof.",name:"Axel",middleName:null,surname:"Borsdorf",fullName:"Axel Borsdorf",slug:"axel-borsdorf"},{id:"61016",title:"Dr.",name:"Andrea",middleName:null,surname:"Fischer",fullName:"Andrea Fischer",slug:"andrea-fischer"},{id:"61017",title:"Dr.",name:"Oliver",middleName:null,surname:"Bender",fullName:"Oliver Bender",slug:"oliver-bender"},{id:"61018",title:"Dr.",name:"Johann",middleName:null,surname:"Stötter",fullName:"Johann Stötter",slug:"johann-stotter"}]},{id:"19853",title:"Are Debris Floods and Debris Avalanches Responding Univocally to Recent Climatic Change – A Case Study in the French Alps",slug:"are-debris-floods-and-debris-avalanches-responding-univocally-to-recent-climatic-change-a-case-study",signatures:"V. Jomelli, I. Pavlova, M. Utasse, M. Chenet, D. Grancher, D. Brunstein and F. Leone",authors:[{id:"54409",title:"Dr.",name:"Vincent",middleName:null,surname:"Jomelli",fullName:"Vincent Jomelli",slug:"vincent-jomelli"},{id:"55563",title:"Mrs.",name:"Irina",middleName:null,surname:"Pavlova",fullName:"Irina Pavlova",slug:"irina-pavlova"},{id:"55564",title:"Mrs.",name:"Delphine",middleName:null,surname:"Grancher",fullName:"Delphine Grancher",slug:"delphine-grancher"},{id:"55565",title:"Dr.",name:"Daniel",middleName:null,surname:"Brunstein",fullName:"Daniel Brunstein",slug:"daniel-brunstein"},{id:"92700",title:"Mrs.",name:"Marina",middleName:null,surname:"Utasse",fullName:"Marina Utasse",slug:"marina-utasse"},{id:"92701",title:"Dr.",name:"Marie",middleName:null,surname:"Chenet",fullName:"Marie Chenet",slug:"marie-chenet"},{id:"92702",title:"Prof.",name:"Frederic",middleName:null,surname:"Leone",fullName:"Frederic Leone",slug:"frederic-leone"}]},{id:"19854",title:"Glaciers Shrinking in Nepal Himalaya",slug:"glaciers-shrinking-in-nepal-himalaya",signatures:"Samjwal R. Bajracharya, Sudan B. Maharjan and Finu Shrestha",authors:[{id:"62372",title:"MSc.",name:"Samjwal",middleName:null,surname:"Bajracharya",fullName:"Samjwal Bajracharya",slug:"samjwal-bajracharya"},{id:"62373",title:"MSc",name:"Sudan",middleName:null,surname:"Maharjan",fullName:"Sudan Maharjan",slug:"sudan-maharjan"},{id:"136280",title:"Dr.",name:"Finu",middleName:null,surname:"Shrestha",fullName:"Finu Shrestha",slug:"finu-shrestha"}]},{id:"19855",title:"Subglacial and Proglacial Ecosystem Responses to Climate Change",slug:"subglacial-and-proglacial-ecosystem-responses-to-climate-change",signatures:"Jacob C. Yde, Teresa G. Bárcena and Kai W. Finster",authors:[{id:"56255",title:"Dr.",name:"Jacob",middleName:"C.",surname:"Yde",fullName:"Jacob Yde",slug:"jacob-yde"},{id:"61613",title:"Dr.",name:"Kai W.",middleName:null,surname:"Finster",fullName:"Kai W. Finster",slug:"kai-w.-finster"},{id:"61614",title:"Dr.",name:"Teresa G.",middleName:null,surname:"Bárcena",fullName:"Teresa G. Bárcena",slug:"teresa-g.-barcena"}]},{id:"19856",title:"Why Do We Expect Glacier Melting to Increase Under Global Warming?",slug:"why-do-we-expect-glacier-melting-to-increase-under-global-warming-",signatures:"Roger J. Braithwaite",authors:[{id:"62829",title:"Dr",name:"Roger",middleName:"James",surname:"Braithwaite",fullName:"Roger Braithwaite",slug:"roger-braithwaite"}]},{id:"19857",title:"Estimation of the Sea Level Rise by 2100 Resulting from Changes in the Surface Mass Balance of the Greenland Ice Sheet",slug:"estimation-of-the-sea-level-rise-by-2100-resulting-from-changes-in-the-surface-mass-balance-of-the-g",signatures:"Xavier Fettweis, Alexandre Belleflamme, Michel Erpicum, Bruno Franco and Samuel Nicolay",authors:[{id:"11546",title:"Prof.",name:"Samuel",middleName:null,surname:"Nicolay",fullName:"Samuel Nicolay",slug:"samuel-nicolay"},{id:"12687",title:"Dr.",name:"Xavier",middleName:null,surname:"Fettweis",fullName:"Xavier Fettweis",slug:"xavier-fettweis"},{id:"12688",title:"Prof.",name:"Michel",middleName:null,surname:"Erpicum",fullName:"Michel Erpicum",slug:"michel-erpicum"},{id:"61470",title:"MSc",name:"Alexandre",middleName:null,surname:"Belleflamme",fullName:"Alexandre Belleflamme",slug:"alexandre-belleflamme"},{id:"61471",title:"Mr.",name:"Bruno",middleName:null,surname:"Franco",fullName:"Bruno Franco",slug:"bruno-franco"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"71407",title:"Umbilical Cord Blood and Cord Tissue Bank as a Source for Allogeneic Use",doi:"10.5772/intechopen.91649",slug:"umbilical-cord-blood-and-cord-tissue-bank-as-a-source-for-allogeneic-use",body:'Umbilical cord blood (CB) has been utilized as a source of hematopoietic stem cells for three decades. It could potentially also serve as the optimum source of immune cells, such as mononuclear cells (MNC), regulatory T cells, NK cells, and mesenchymal stromal cells (MSCs) with or without genetic modifications, for immunotherapy and neurogenic regeneration in some cases. In addition, UB could be prepared as readily available products [1].
It is well-known that human mesenchymal stromal cells (MSCs) can be harvested from various tissues that include the bone marrow (BM) [2], cord blood (CB) [3], adipose tissue [4], placenta [5], and umbilical cord (UC) [6]. Recently, clinical trials using MSCs for various diseases have been conducted, and some of them were approved. The BM is considered the traditional source of MSCs, and the characteristics and applications of BM-derived MSCs (BM-MSCs) have been studied in detail. However, the harvesting of these cells is associated with an invasive procedure, and it may cause hemorrhage, infection, and chronic pain. In addition, BM-MSCs exhibit accelerated senescence as the donors’ age [7].
On the other hand, both CB and UC are routinely discarded as medical waste. The harvesting of CB and UC-derived MSCs (UC-MSCs) is therefore noninvasive and painless. The CB drawn from the UC and placenta is well-known as the source of hematopoietic stem cells for CB transplantations. However, in this article, we focus on the CB as the source for immune cells and regenerative medicine, such as regulatory T cells (Treg), NK cells, MSCs, and so on. The UC is the conduit between the developing embryo and placenta and consists of two umbilical arteries and one umbilical vein buried in the Wharton’s jelly. UC-MSCs have the abilities of multipotency and self-renewal properties comparable or superior to MSCs derived from other tissues in some papers. For this reason, several private CB banks have begun to collect CB and UC. We have thus established the cord blood/cord bank, “IMSUT CORD”, as a new type of biobank, to supply both frozen UC tissues and master cells for research and clinical uses.
In this chapter, we will introduce the overall flow from collection to shipment as taking the example of IMSUT CORD and discuss several issues that need to be resolved in unrelated allogeneic off-the-shelf stable supply system at present.
There are many public and private CB banks in the world, in which procedures are nearly standardized intended for hematopoietic stem cell transplantation (HSCT) as shown in Section 5. The procedures include informed consent acquisition from the mother, collection of CB, processing, storage, to shipment, which have been already established. In the case of UC bank for unrelated allogeneic uses, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) which issued ICH Q5A as the regulation of materials for biological products requires the second blood test from the baby’s mother, to deny viral infection in window period at delivery. Figure 1 shows the overall process of banking in the mother’s side. We deal with both CB and UC. In the CB and UC collection hospitals, the purpose, overall process, private information policy, the right to withdrawal, 6-month health check, and second blood test for the mother to confirm the negative study of infection are explained to the mother, and she gives written consent as the guardian of the baby. In addition to obtaining informed consent, questionnaires about medical history, genetic history of the baby donor’s family, and history for the mother’s communicable disease risk behavior are conducted to survey their health. The CB and UC are then collected, and the mother’s blood is tested for infections. These documentations and tests in CB bank can be referred to UC banking as well, although additional safety tests for UC banking shall be required strictly. UC-MSCs from one donor can be delivered and administered to many patients. Especially when the CB and UC passed the safety and some quality tests at clinical grade, the mother is asked to receive the blood test to make sure that all infection tests are negative in 6 months after delivery. These second tests are demanded by the Pharmaceuticals and Medical Devised Agency (PMDA) like the FDA and EMA, because it should be proven that the donor’s mother and baby were not in the window period of viral infections at delivery. On the other hand, bacterial contamination is also taken care because the baby and placenta with UC come out from nonsterile vagina. We collect UC in the case of a scheduled cesarean section to reduce the possibility of contamination due to the exposure to the vaginal bacterial/fungal flora.
Overall flow from informed consent acquisition to shipment.
CB and UC are then transported from the collection hospitals to the CB/UC bank under controlled and validated temperature. CB is transported at validated temperature range (2–25°C) to protect cell viability, and the UC is cooled at 2–10°C in our facility.
Among the processing methods to obtain nucleated cells from CB for hematopoietic stem cell transplantation, the hydroxyethyl starch (HES) centrifugation method (HES method) is the most efficient and common. The HES method originated from the New York Blood Center CB bank [8]. Recently, automated CB processing SEPAX® (GE Healthcare Life Sciences) [9] and AutoXpress Platform® (Cesca Therapeutics, Inc.) [10] have been developed. For CB cryopreservation, DMSO and Dextran 40 together with CB-plasma are used worldwide [8].
On the other hand, no processing method of fresh or frozen CB not for hematopoietic stem cell transplantation has been settled as standard. The use of mononuclear cells (MNCs) obtained by the Ficoll-Paque centrifugation method (Ficoll method) or cell sorting with antibody-conjugated magnetic beads might be a new candidate for further processing and culture method. CB processed by HES method resulted in whole nucleated cells including neutrophils, monocytes, lymphocytes, and nucleated red blood cells with some amount of red blood cells (RBC). The recovery rate of hematopoietic stem cells and mononuclear cells processed by HES method is superior to those by Ficoll method. That is why HES method is introduced by CB banks in the world [8]. However, neutrophils in the nucleated cells and residual RBC may cause the aggregation resulting in the difficulty of further processing, when the frozen and thawed cells are diluted with large volume of isotonic solutions such as medium. Only frozen-thawed CB nucleated cells can be diluted with dextran and albumin/saline solution [8]. On the other hand, frozen-thawed MNCs processed by Ficoll method does not require such a special solution and can be diluted with medium and PBS, although the recovery rate of MNCs from the fresh CB by Ficoll method is less than that by HES methods.
MSCs derived from fresh CB are difficult to expand. Only one company, Medipost Co., Ltd., in Korea, has succeeded in expanding CB-derived MSCs. Their product, Cartistem®, has been approved by the Ministry of Food and Drug Safety in Korea for the treatment of osteoarthritis [11].
There are diverse procedures and culture methods for the isolation of MSCs from the various compartments of UC, such as Wharton’s jelly, veins, arteries, UC lining membrane, subamnion, and perivascular regions [12]. The isolation methods of MSCs from the Wharton’s jelly, vein, and arteries of UC are reported previously, although the marked differences were not found as far as the 10% fetal bovine serum (FBS) and α minimum essential medium (MEM) [13]. There are several papers to obtain MSCs from whole UC versus Wharton’s jelly [14] or different parts of the same UC [15], but we suggest that to process from whole UC seems sufficient and simple for further processing [15]. Despite the wide range of isolation and culture procedures, the different groups seem to agree on the cryopreservation of UC tissue [16] and explant method [17] followed by the harvest of migrating cells from tissue. However, large-scale culture methods remain to be determined. Figure 2 shows the example of scheme of CB and UC collection and process and shipping to clinical use.
IMSUT CORD scheme of CB and UC from collection to shipping for clinical use.
It is known that the UC tissue can be frozen in a cryoprotectant. This possibility of cryopreservation is the advantages of UC tissue for both clinical and research uses. The reasons of the advantages are:
UC tissue processing can be started after the donor’s health and infection statuses are confirmed well. This leads to initial cost-effectiveness because unnecessary works using inappropriate materials are eliminated. In addition, we can thaw a small amount of the UC to survey, before culturing MSCs in a large scale.
Storage of the tissues of origin allows us to keep traceability and to check the quality as the biological resources at a later date.
When new reagents or techniques were developed in the future, we can isolate novel cells from the cryopreserved UC tissues.
If the donor, the baby, has diseases that can be treated with autologous cells, including iPS cells or gene-modified cells, or autologous UC-MSCs, the cryopreserved UC tissues would be the appropriate source.
Several animal serum-free cryoprotectants containing 5–10% dimethyl sulfoxide (DMSO) are available. Whether the use of serum originating from animals, such as fetal bovine serum (FBS), is required, is critical, because it adds the risk of the transmission of zoonotic infections, immunological reactions, and additional regulatory issues [18]. There are several reports of cryopreservation of the UC tissue, using serum-free and xenogeneic animal-free (xeno-free) cryoprotectants. Ennis et al. introduced CryoStor CS10® (BioLife Solutions Inc., WA) for isolating human UC perivascular cells (HUPVCs). However, they did not show the comparative test results to those of fresh UC [19]. Roy et al. reported the cryopreservation of the UC tissue in 10% DMSO and 0.2 M sucrose solution, but the cumulative cell yield derived from the frozen-thawed UC-MSCs in their solution was inferior to that of fresh UC-MSCs [20]. We previously reported the cryopreservation of UC tissue, with no impact on viability, using a serum- and animal origin-free cryoprotectant, STEM-CELLBANKER® [16]. We demonstrated that cells derived from UC cryopreserved in this manner retained the phenotypic characteristics of MSCs, including the immunosuppressive activity in allogeneic mixed lymphocyte reactions, as well as differentiation potential. As shown in Figure 2, with the cryopreservation of UC tissue, UC processing might be altered.
There are two major approaches after frozen-thawed UC tissue: explant and enzymatic digestion methods. Frozen-thawed UC tissue is manually minced into small fragments approximately 1–2 mm3 in size. Mincing is preferred to using a surgical scalpel or the use of an autologous mixer. These fragments are aligned and seeded regularly on a tissue culture-treated dish. After the tissue fragments attach to the bottom of the dish, culture media is added, slowly and gently in order not to detach the fragments [21, 22, 23, 24]. Media is then refreshed every 3–7 days for 2–4 weeks until the fibroblast-like adherent cells reach 80–90% confluence. Subsequently, adherent cells and tissue fragments are rinsed once with PBS, detached using trypsin, and washed with media. The culture is then filtered to remove tissue fragments. The disadvantage in the explant method is that tissue fragments often float in media, resulting in the poor recovery of cells. To protect the exfoliation of tissue fragments from the bottom of the culture dish, we introduced stainless steel mesh (Cellamigo®; Tsubakimoto Chain Co.) shown in Figure 2, No. 8. In this manner, we can plate source tissue more quickly and harvest more MSCs. In addition, the incubation time required to reach 80–90% confluence is reduced [17].
In the enzymatic digestion method, UC is minced into small pieces and immersed in the media containing enzymes such as collagenase, or a combination of collagenase and hyaluronidase with or without trypsin [21, 24, 25, 26]. The cells dissociated by the enzymes are then cultured until they reach full confluence. However, the digestion method is costly and time-consuming and may result in decreased cell viability due to lytic activity and varying sensitivity of the cells to collagenase. In addition, the initial harvested cells include more of the other types of cells compared with that harvested using the explant method.
It is critical to consider how much we can expand the UC-MSCs to allow allogeneic “off-the-shelf” industrial availability, because the proliferation of adherent cells needs a large surface area. The conventional method uses multilayered flasks, and the cells are cultured in incubators installed in cleanrooms. These multilayer flasks can consistently support the expansion of UC-MSCs, and the state of cell confluence can be examined under the microscope. However, this method requires the considerable involvement of operators because the processes of seeding, refreshment, passage, and harvest require individual and manual works. Several companies have introduced the spinner bioreactor with a microcarrier made of plastic, dextran, denatured collagen-coated beads, and other components. The bioreactor system may reduce the number of operators required and may allow to reduce the clean levels of facility since it is a closed system. On the contrary, several critical problems of the bioreactor system exist. The cost of equipment is high and it is difficult to evaluate cell proliferation environment such as pH, lactate, and so on. When some microcarriers are torn off by spinner, or undigested microcarriers are residual in the final products, we have no ideas to remove the residual microcarriers completely. Recently, a plastic bag bioreactor system with a microcarrier in gentle locking was reported [27]. The most critical problem is that the cells produced by the flask-based culture method may be different from those by bioreactors. Harvesting cells on a large scale is still not easy. Recently, filter-based cell concentration and washing systems were introduced (
The academic culture level such as IMSUT CORD is at small to middle scale. Only the company may have the ability to expand the cells at extra-large scale and maintain to control and supply the cell product for clinic constantly.
Master and product cells of UC-MSCs for clinical use are usually required for long-term cryopreservation, together with records on the donor infant and the mother. There are several cryoprotectants for long-term cryopreservation. The most popular cryoprotectant consists of 5–10% dimethyl sulfoxide with human albumin. Recently, serum-free cryoprotectants, described in Section 4.1, have been commercialized and are thought to be more ideal compared to those containing human-derived serum. In addition to cryoprotectants, it is important to build an adequate record preservation system. Those who manage the long-term cryopreservation should preserve the records that include the documentation relating to the collection including donors, processing, results of quality tests, and instruments directly related to the products. The kinds of records and the length to be preserved are in accordance with the bank policies and standards and the corresponding domestic laws and regulations. It is necessary to discuss how long we should or we can cryopreserve CB and UC tissue, UC master cells, and product cells, in the technical and ethical aspects. In the technical aspect, the cell-preserving vessel to accommodate the cell suspension for long-term freezing should be durable in a liquid nitrogen. In the ethical aspect, we do not expect whether the babies can recapture their ownership of CB and UC even though their mother waived the ownership of them, when they grow up to be adult.
The Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy proposed the minimal criteria for defining human MSCs [28, 29]. First, MSCs must be plastic-adherent when maintained in standard culture conditions. Second, MSC must express CD105, CD73, and CD90 but not CD45, CD34, CD14 or CD11b, CD79α or CD19, and HLA-DR surface molecules. Third, MSCs must differentiate into adipocytes, chondroblasts, and osteoblasts in vitro [30, 31, 32]. Immunosuppressive effects have now become the most popular property of MSCs for potential clinical use [12]. Defect in HLA-class II expression with negative CD80 and CD86in UC-MSCs even in the presence of inflammatory cytokines such as IFN-γ can theoretically rescue them from immune recognition by CD4+ T cells [33]. MSCs can also inhibit proliferation of and cytokine secretion by immune cells, as well as alter subtypes of macrophage from M1 to M2 in vitro [34, 35, 36, 37]. This immunomodulation is linked mainly to soluble factors such as indoleamine 2,3-dioxygenase (IDO), PGE2, and HLA-G5 [38], hepatocyte growth factor, and transforming growth factor-β1 released from MSCs [39]. Further quality tests are dependent on clinical applications and characteristics of MSCs.
The safety tests required differ according to the risks of clinical applications. For example, the tests of CB banking for hematopoietic stem cell transplantation are different from those of UC-MSCs. Donor-recipient relation of the former is one-to-one, and the risk is limited to one patient. On the other hand, that relationship of the latter, as UC-MSCs master cells and product cells, is one-to-many, so hundreds of patients may suffer health injuries by one donor. Thus, the vials of UC-MSCs are tested thoroughly at a designated time not only known viruses but also unknown viruses. Those tests should follow the local, national or international applicable laws and regulations. More precise safety tests for CB and UC shall be described elsewhere for the respective products for clinical application.
There are international standards/guidance for CB collection, banking, and release of hematopoietic stem cell transplantation, such as the Foundation for the Accreditation of Cellular Therapy (FACT)/NETCORD [40], American association of Blood Banks (AABB), US Food and Drug Administration (FDA) shown in Table 1, and local standards or regulations under the applicable laws in respective countries. A CB/UC bank, facility, or individual should implement if the standard of practice in the community or applicable law establish additional requirements. International standards/guidance for biobanking process for UC collection, processing, culture, and release has not been settled, but collection and banking protocols can follow the CB banking standards and good tissue practice. Each CB/UC bank, facility, and individual should analyze its practices and procedures to determine whether additional standards apply. Compliance with the standards is not an exclusive means of complying with the standard of care in the industry or community or with local, national, or international laws or regulations [40]. Allogeneic public CB banks requested US FDA accreditation with FACT/NETCORD or AABB in the USA, while the CB banks in Europe (EU) required FACT/NetCord with additional requirements like FACT/JACIE standards, when it is requested by the respective national regulation affairs. There are many private or private-public combined CB banks in the world, which tend to follow the AABB standards and have the inspection and accreditation (
Items | Accreditation organization | Standards or guidance titles |
---|---|---|
Cord blood (CB) processing for hematopoietic stem cell transplantation | FACT/NETCORD FACT/JACIE | International Standards for Cord Blood Collection, Banking, and Release for Administration International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration |
FDA in the USA | Guidance for Industry: Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications Guidance for Industry and FDA Staff: Investigational New Drug Applications for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic and Immunologic Reconstitution in Patients with Disorders Affecting the Hematopoietic System | |
AABB | Standards for Cellular Therapy Services | |
Umbilical cord-derived cells including mesenchymal stromal cells (UC-MSCs)/somatic cell or other derivative cells CB not intended for hematopoietic stem cell transplantation | FACT | Common standards for Cellular Therapies |
FDA in the USA | Good Tissue Practice 21CFR 1271.210 Current Good Tissue Practice (CGTP) and Additional Requirements for Manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products Guidance for FDA Reviewers and Sponsors Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs) | |
AABB | Standards for Cellular Therapy Services | |
EMA in EU | Tissues and Cells Directives: Guideline on human cell-based medicinal products (EMEA/CHMP/410896/2006) for ATMP | |
PMDA (Japan) | Good Gene, Cellular, and Tissue-based Products Manufacturing Practice (GCTP) | |
Quality management system | ISO | ISO9001 ISO/TC276 (Draft) |
Standards or guidance related to cord blood and umbilical cord-derived cells.
Foundation for the Accreditation of Cellular Therapy, FACT; US Food and Drug Administration, FDA; American Association of Blood Banks, AABB; advanced therapy medicinal products, Pharmaceutical and medical devices agency (PMDA). This table does not include the law defined in each country. These standards, guidance, guidelines, and practices are not intended to apply all cell therapies using CB and UC. The CB/UC bank carefully chooses and implements them for your intended products under the applicable law.
The number of clinical trials using CB and UC-MSCs in the fields of immune cell therapies and regenerative medicine has been increasing. On the other hand, CB as a source of hematopoietic stem cell transplantation is less used recently, because the cell number is limited, the engraftment of HSC is delayed, and HLA haplo-identical HSCT is induced and controlled. These clinical trials are aimed uses that include severe acute graft-versus-host disease (GVHD) treatment, rapid engraftment of HSCT, and the prevention of severe acute GVHD. Clinical trials using CB- and UC-MSCs are summarized in Tables 2 and 3, respectively. We started a sponsor-investigator clinical trial using UC-derived MSCs for patients with treatment-resistant severe acute GVHD supported by the research fund of the Japan Agency for Medical Research and Development (AMED). Consistent supply is the critical key to conduct clinical trials and for marketing. For the stable supply of frozen CB and UC, or UC-derived MSCs, we have established a CB and UC bank, named IMSUT CORD, in our institute. This bank also provides CB and UC-MSCs for immunotherapy and regenerative medicine products to hospitals and pharmaceutical companies shown in Figure 2. The bank also provides frozen CB, frozen UC, master cells, and the cells after master cells as an intermediate products requiring further processing or more culture in the companies.
Authors | Cell type | Disease | Patients number | Age (range) year | Route and procedure of administration | Cell number/kg or body | Results | Adverse events |
---|---|---|---|---|---|---|---|---|
Brunstein et al. [79] | CB-NC-derived Treg (CB from The New York Blood Center) | Grade II–IV acute GVHD | Treg: 11 | 61 (45–68) | IV | 3–100 × 106 Treg/kg | aGVHD: Treg group 9%, control 45% cGVHD: Treg 0%, control 14% | No dose-limiting infusion adverse events |
Control: 22 | 60 (34–69) | — | ||||||
Kellner et al. [80] | Fucosylated or non-fucosylated UCB-Tregs | HSCT | 5 | IV (−1 day of HSCT) | 1 × 106/kg | No infusion reactions | ||
Zhu et al. [81] | CB-MNC | Chronic complete spinal cord injury | 8 in Hong Kong | 42.6 ± 2.7 | IT (dorsal entry zone) | 1.6–3.2 × 106 | Walk 10 m, 15/20 pts. (p = 0.001), no necessity of assistance for bladder management, 12/20 (p = 0.001) and bowel management (p = 0.002) | 1 neuropathic pain;1 subarachnoid hematoma and pneumocephalus due to cerebrospinal loss;1 arachnoid hemorrhage I HK group, |
Phase I–II | 20 in Kunming | 36.9 ± 2.4 | 68 AEs including postoperative wound swelling; 9 pain Overall 5 severe AE in 28 patients | |||||
Shah et al. [82] | CB-MNC-derived NK cells (CB from MD Anderson Cord Blood Bank) | Multiple myeloma undergoing autologous PBSCT | 12 | 48–70 | 5 × 106, 1 × 107, 5 × 107 and 1 × 108 CB-NK cells/kg | 10 achieved VGPR (8 near CR) as the best response | No infusional toxicities and no GVHD | |
Lv et al. [83] | CB-MSC + UC-MSCs | Autism | 14 CB-MNC9 CB-MNC and UC-MSCs14 no cells therapy | CB-MNC: 7.08 (3.29–12.01) CB-MNC + UC-MSCs: 6.51 (3.98–9.83)Control: 5.02 (3.51–10.02) | IV | Proximately 2 × 106/kg CB-MNCs1 × 106/kg of UC-MSCs 4 times in 5–7 day | Improvement of CARS, ABC scores, and CGI evaluation at 24 weeks in CB-MNCs with UC-MSCs | No treatment-related and no severe adverse effects |
Dolstra et al. [84] | CB-CD34-derived NK cells (CB from Cord Blood Bank Nijmegen) | AML in old patients | 10 | 68–76 | IV | 3 and 30 × 106/kg | NK cell maturation in vivo, MRD become negative in 2/4 with MRD before IV | No GVHD, no toxicity |
Park et al. [85] | CB-derived MSCs | Rheumatoid arthritis | 9 | 57.4 ± 10.0 | IV | 2.5 × 107, 5 × 107, or 1 × 108 | DAS2/-ESR decreased, inflammatory cytokine levels are reduced | No DLT, no major toxicity |
Laskowitz et al. [86] | CB-NC (CB from Carolinas Cord Blood Bank or MD Anderson Cord Blood Bank) | Cerebral stroke | 10 | 65.5 (45–79) | IV on 3–9 days poststroke | Cell dose 1.54 (0.84–3.34) × 107/kg, CD34+ 2.03 (0.10–6.80) × 105/kg | All improved by at least one grade in Modified Rankin Score | AE tolerated no serious AE |
Huang et al. [87] | CB-MSCs | Cerebral palsy (age: 3–12) | 27 (CB-MSCs) | CB-MSCs: 7 (3–12) | IV | 27:4 CB-MSCs IV at 5 × 107 with basic rehabilitation treatment | Significant improved of GMFM-88 evaluation | No serious AE |
27 (control) | Control: 7 (3–12) | |||||||
Kim et al. [88] | CB-MSCs | Moderate-to-severe atopic dermatitis | 34 (7 in phase I, 27 in phase IIa) | 29.07 ± 2.03 (n = 14) | SC | 2.5 × 107 | Improved atopic dermatitis scores, pruritus score, serum IgE and eosinophil number | No serious AE |
28.08 ± 1.07 (n = 11) | 5.0 × 107 |
Clinical trials using allogeneic cord blood.
AE, adverse event; AML, acute myeloid leukemia; CB, cord blood; UC, umbilical cord; MSCs, mesenchymal stromal cells; MNCs, mononuclear cells; NK cells, natural killer cells; Treg, regulatory T cells; GVHD, graft-versus-host disease; PBSCT, peripheral blood stem cell transplantation; IV, intravenous injection; SC, subcutaneous injection.
Authors | Disease | Patients number | Age (range) year | Route and procedure of administration | Cell number/kg or body | Frequency interval | Results | Adverse events |
---|---|---|---|---|---|---|---|---|
Engraftment facilitation and graft-versus-host disease (GVHD) in hematopoietic stem cell transplantation | ||||||||
Wu et al. [41] | Severe steroid-resistant aGVHD | 2 | Pt 1:4 | IV | Pt 1: 3.3, 7.2, 8.0 × 106/kg | 3 | Improved | No |
Pt 2:6 | IV | Pt 2: 4.1 × 106/kg | 1 | |||||
Si et al. [42] | Severe aplastic anemia | 37 | 5 | IV (7–10 days after HSCT) | 1 × 106/kg | 1 | aGVHD II–IV; 17 of 37 (45.9%) | No |
(0.75–11.58) | cGVHD, 7 of 37 (18.9%) | |||||||
Wu et al. [43] | Refractory/relapsed hematologic malignancy | 50 | 26 (9–58) | IV (4 h before haploidentical HSCT) | 5 × 105/kg | 1 | aGVHD II–IV, 12 of 50 (24.0%) cGVHD, 17 of 45 (37.7%) (3 extended) | No |
Wu et al. [44] | Severe AA | 21 | 18 (4–31) | IV (4 h before HSCT) | 5 × 105/kg | 1 | aGVHD II-IV;12 of 21 (57.1%) 3 of 9 extended cGVHD | No |
Fu et al. [45] | Refractory severe AA | 5 | 15.2 (9–22) | IV (2 days after PBSCT) | 1 × 106/kg | 1 | No severe aGVHD or cGVHD | No |
Gao et al. [46] | Prophylaxis of chronic GVHD after HLA-haploidentical stem cell transplantation | 62 | Age < 8, 15 pts.; 18–40, 39; >40, 8 | IV | 3 × 107 cells | Until cGVHD occurred, leukemia relapsed, or 4 cycles | cGVHD at 2 yr.: MSCs group 27.4%, control 49.0% (P = .021). Severe lung cGVHD: MSCs group 0, control 7 (P = .047) | No |
Zhu et al. [47] | High-risk acute leukemia | 25 | 11.2 (4–17) | IV (before haploidentical HSCT) | Median 1.14 × 106/kg (1.03–1.39 × 106/kg) | 4 (over 7 days intervals) | aGVHDI, 8 of 25 (32.0%) cytomegalovirus viremia, 23 of 25 (92.0%) | No |
Pan et al. [48] | Extensive bone marrow necrosis of a chronic myeloid leukemia patient | 1 | 10 | iBM | iBM: 2 × 107/kg | 1 | BM recovered | No |
IV | IV: 2 pp. × 106/kg | |||||||
Neurogenic injuries | ||||||||
Wang et al. [49] | Traumatic brain injury | 20 | 27.5 (5–48) | Intrathecal (IT) | 1 × 107 | 4 (5–7 days intervals) | Motor functional recovery after 6 months | No |
Jin et al. [50] | Hereditary spinocerebellar ataxia | 16 | 39.9 (21–56) | IV + intrathecal | IV; 4 × 107 | 4 (over 7 days interval) | Motor functional recovery after 6 months | No |
IT; 2 × 107 cells | ||||||||
Wang et al. [51] | Cerebral palsy | 16 (8 twins) | 6.29 (3–12) | IT | 1–1.5 × 107 cells | 4 (3–5 days intervals) | Motor functional recovery after 1 and 6 months | No |
Diabetes mellitus | ||||||||
Guan et al. [52] | DM (type 2) | 6 | 40.5 (27–51) | IV | 1 × 106/kg | 2 (2 weeks interval) | Insulin-independent for 25–43 Mo, 3 dose reduction of insulin, others | No |
Hu et al. [53] | DM (type 1) | 15 | 17.6 | IV | 2.6 ± 1.2 × 107/kg | 2 (4 weeks interval) | HbA1c and C-peptide improvement in MSCs group | No |
Cai et al. [54] | DM (type 1) | 21 | 18–29 (5–28) at onset | Supraselective pancreatic artery cannulation | 1.1 × 106/kg, with autologous BM-MNC | 1 | Moderate improvement of metabolic measures | 1 transient abdominal pain |
Kong et al. [55] | DM (type 2) | 18 | IV | 1 × 106/kg | Day 0 and until Day 90 if effective | FBS reduced plasma C-peptide and regulatory T cells increased | 4/18: slight fever | |
Heart and angioplasty | ||||||||
Cai et al. [56] | Avascular necrosis of the femoral head | 30 | 41.6 (19–63) | Femoral head artery (co transplant with autologous BM) | Autologous BM-BM-MNCs, 60.7 ± 11.5 × 106/kg UC-MSCs, 1 × 106/kg | 1 | Improved | No |
Can et al. [57] | Myocardial ischemia | 39 | 30–80 | Intracoronary | 2 × 107/kg | 1 | Ongoing | No |
Zhao et al. [58] | Severe systolic heart failure | 30 | 52.9 (20–79) | Intracoronary | Unknown | 1 | Cardiac remodeling and function improved with reduced mortality rate | No |
Li et al. [59] | Coronary chronic total occlusion | 15 | Unknown | Intracoronary | 3 × 106/4 × 106/5 × 106/kg | 1 | Infarcted size reduced with improved left ventricular EF | No |
Musialek et al. [60] | Acute myocardial infarction | 10 | 55.6 (32–65) | Intracoronary | 3 × 107/body | 1 | Feasible and procedural safe as off-the-shelf cellular therapy | Transient fever (38.9°C) |
Bartolucci [61] | Heart failure | 15 | 57.33 ± 10.05 | IV | 1 × 106 cells/kg | 1 | Significant improvements in LVEF, NYHA functional class, Minnesota Living with Heart Failure Questionnaire | No |
Liver | ||||||||
Xue et al. [62] | Decompensated liver cirrhosis | 50 | Unknown | Intrahepatic artery | 3 × 107/body | 1 | Increase of serum albumin | No |
Wang et al. [63] | Primary biliary cirrhosis | 7 | 49 (33–58) | IV | 5 × 105/kg at 4 weeks interval | 3 | ALP and γ-GTP | No |
Shi et al. [64] | Prevention of acute liver allograft rejection | 14 (13, single dose, 1 multiple dose) | 57 ± 12 | IV | 1 × 106 cells | Single (13 pts), 3 times every 4w (1 pt) | Decreases of ALT, AST, T-BIL Histologic improvements, MSCs 6, control 0. | No |
Liang et al. [65] | Liver cirrhosis caused by autoimmune diseases | 23 (2 CB-MSC, 1 BM MSC) | 53.4 (35–70) | IV | 1 × 106 cells/kg | 1 | Not statistically significant improvement | 2, fever; 3, mild fidgetiness, suffered from insomnia |
Zhang et al. [66] | Ischemic-type biliary lesions following liver transplantation | 12 | 47.3 ± 10.1 | IV | 1 × 106 cells/kg | 6 (1, 2, 4, 8, 12, 16 weeks) | Significantly decreased need for interventional therapies. 1-, 2-yr graft survival rates: MSCs group (100%, 83.3%), control group (72.9%, 68.6%) | No |
Xu et al. [67] | Hepatitis B virus-related acute-on-chronic liver failure | 30:UC-MSC | UC-MSC: 40.67 ± 9.89 | IV | 105 cells/kg | UC-MSC, once a week, 4 times | No significant improvement of short-term prognosis | Fever, UC-MSC 11 pts., PE + UC-MSC 6 pts |
20, UC-MSC + plasma exchange | UC-MSC/plasma exchange, 42.00 ± 6.55 | IV | UC-MSC/PE: first 2 UC-MSC: 2nd day after 1st, 3rd PE treatments | |||||
Gastrointestinal tract | ||||||||
Zhang et al. [68] | Crohn’s disease | 41 | 32.7 (20–41) | IV | 1 × 106 cells/kg | Once a week, four times | Decreases of CDAI, HBI, corticosteroid dosage | Fever 4, upper respiratory tract infection, 7 |
Hu et al. [69] | Ulcerative colitis | 34 | 42.9 ± 23.1 | IV then IA | 0.5 × 106 cells/kg | 2, 7 days | Decreases of median Mayo score, histology score. Improvement of IBDQ scores | No |
Skin | ||||||||
Hashemi et al. [70] | Chronic skin ulcer | 5 | 30–60 | Covered by acellular amniotic membrane seeded with WJSCs | About 2 × 106 cells were seeded | Epithelial surface of acellular amniotic membrane | Significantly decreased wound healing time, wound size. Significantly declined wound size after 6, 9 days | Not stated |
Kidney | ||||||||
Sun et al. [71] | Prevention of delayed graft function and acute rejection in renal transplantation | 21 | 41.0 ± 11.5 | IV | 2 × 106 cells/kg (before transplantation), 5 × 106 (during surgery) | ← | No significant improvement | No |
Deng et al. [72] | Lupus nephritis | 12 MSC, 6 placebo | 29 ± 10 | IV | 1 × 108 cells | 2 times 1 wk. interval | Not statistically significant improvement | 1: leucopenia, pneumonia, subcutaneous abscess, 1: severe pneumonia |
Autoimmune diseases | ||||||||
Wang et al. [73] | Active and refractory SLE | 40 | 17–54 | IV | 1 × 106 cells/kg on day 0 and 7 | 2 | MCR (13 of 40, 32.5%), PCR (11 of 40, 27.5%) during 12 months, although several patients relapse after 6 months | No |
Wang et al. [74] | RA | 136 | 46.1 | IV | 4 × 107 cells, 2nd in 3 months later | 1 (n = 112) | Decreases of serum TNF-α, IL-6, increase of regulatory T cells. Significant remission for 3–6 months | Mild fever (<38.5°C) without treatment at injection, 6 patients |
2 (n = 24) | ||||||||
Riordan et al. [75] | Multiple sclerosis | 20 | 41.2 (24–55) | IV | 2 × 107 UC-MSC | 7 (1–4 days) | Significant improvements of various symptoms. Inactive lesions by MRI in 15/18 patients. (83.3%) after 1 year | Headache, fatigue |
Others | ||||||||
He et al. [76] | Severe sepsis | 15 (3 cohorts) | 56 (25–72) | IV | 1 × 106 cells/kg | 1 | System clinical outcomes are not changed | No |
2 × 106 cells/kg | ||||||||
3 × 106 cells/kg | ||||||||
Cao et al. [77] | Recurrent intrauterine adhesions | 27 | 35.1 ± 3.8 (27–42) | Loaded onto a collagen scaffold | 1 × 107 | 1 | Pregnant, 10 of 26 patients | No |
Clinical trials using allogeneic umbilical cord-derived mesenchymal stromal cells.
aGVHD, acute graft-versus-host disease; cGVHD, chronic GVHD; HSCT, hematopoietic stem cell transplantation; AA, aplastic anemia; BM, bone marrow; IT, intrathecal injection; AE, adverse event; AML, acute myeloid leukemia; CB, cord blood; UC, umbilical cord; BM, bone marrow; PE, plasma exchange; RA, rheumatoid arthritis; MSCs, mesenchymal stromal cells; DM, diabetes mellitus; FBS, fast blood sugar; ES, ejection fraction; IV, intravenous injection; SC, subcutaneous injection; DM, diabetes mellitus.
The following are also the major points for managing CB and UC banking.
First, to build an adequate quality management system to serve the resource of cell therapy products, we have introduced the concept of the ISO 9001 and obtained its certification, and as a result, we introduced the concept of PDCA cycle. Second, involvements of various kinds of specialists must be considered. There are many procedures, such as collection, obtaining informed consent, application to ethics review committee, and document management. Third, health check and infection test of the donor’s mother are required to ensure that no infection is detected after window period of infections. In this process, both traceability and personal information protection must be satisfied. Fourth, we respect the right of decision to donate, rejection, or withdrawal. Donor’s mother should be explained the policy of the bank that the consented withdrawal time is set at the initiation of processing for clinical use. Although the CB and UC belong to the baby, we obtain informed consent from the donor’s mother as guardianship and ownership are asked to be transferred to the bank. Fifth, there is also the issue of how long the UC tissue and UC-MSCs can be cryopreserved. For example, in the Japanese public CB bank for HSCT, the CB is cryopreserved for 10 years as a clinical grade of HSC source. After this period, they are used for basic research or preclinical studies or discarded if they are not used for research. A cryopreservation period of 10 years for UC and UC-MSCs may be the first threshold to be checked. In addition, we disclose the information in website for the mothers who have not been explained about the new researches or new clinical trials at the first IC acquisition. Lastly, because unlike CB, the UC is a tissue considered as a part of the perinatal appendage, we must follow the tissue transport and medical disposal/waste regulations under the applicable laws or local rules and ethical standards.
Recently, there are an increasing number of private CB banks, which have initiated to serve the cryopreservation of UC, i.e., private CB and UC bank. Using private autologous CB, clinical trials for cerebral palsy caused by hypoxic ischemic encephalopathy (HIE) reported their efficacy [78], although the collection of CB is difficult for the baby in such a severe situation of delivery, resulting in the limited application entry. Recently, we obtained the proof of concept that the UC-MSCs attenuated the neurogenic and functional damage caused by intraventricular hemorrhage (IVH) in newborn model mice. Duke University implemented the clinical trial using allogeneic UC tissue-derived cells for the patients with HIE. Allogeneic off-the-shelf UC-MSCs are a promising source; however, we do not know the adverse events such as HLA antibody induction caused by long-term repeated injections of allogeneic cells. Therefore, autologous use of CB and UC is still challenged to be discussed continuously.
Although several problems still remain to be dissolved, operation of adequate CB and UC bank should be considered as the provider of cell source for regenerative and immune cell therapy, because of their prominent characteristics and convenient and noninvasive collection.
This study was supported by Grants-in-Aids for Scientific Research from the Japan Agency for Medical Research and Development (AMED) (19be0504001h0002). We thank Kamisato A. PhD. for ethical support. We specially thank Takahashi A. MT, Ms. Hori A., Yamamoto Y. MT., Mr. Miharu Y. MT, Ms. Izawa, and MS. Nagaya N., for processing and quality management. We also thank the staff of NTT Medical Center Hospital and Yamaguchi Hospital, Tokyo, for their assistance with the collection of UC and CB.
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He was born in 1969 in Naama, Algeria. He received his BS degree in 1993, the MS degree in 1997, the PhD degree in 2007 from the Electrical Engineering Institute of Djilali Liabes University of Sidi Bel Abbes (ALGERIA). He is an active member of IRECOM (Interaction Réseaux Electriques - COnvertisseurs Machines) Laboratory and IEEE senior member. He is an editor member for many international journals (IJET, RSE, MER, IJECE, etc.), he serves as a reviewer in international journals (IJAC, ECPS, COMPEL, etc.). He serves as member in technical committee (TPC) and reviewer in international conferences (CHUSER 2011, SHUSER 2012, PECON 2012, SAI 2013, SCSE2013, SDM2014, SEB2014, PEMC2014, PEAM2014, SEB (2014, 2015), ICRERA (2015, 2016, 2017, 2018,-2019), etc.). His current research interest includes power electronics, control of electrical machines, artificial intelligence and Renewable energies.",institutionString:"University of Béchar",institution:{name:"University of Béchar",country:{name:"Algeria"}}},{id:"99749",title:"Dr.",name:"Abdel Hafid",middleName:null,surname:"Essadki",slug:"abdel-hafid-essadki",fullName:"Abdel Hafid Essadki",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"École Nationale Supérieure de Technologie",country:{name:"Algeria"}}},{id:"101208",title:"Prof.",name:"Abdel Karim",middleName:"Mohamad",surname:"El Hemaly",slug:"abdel-karim-el-hemaly",fullName:"Abdel Karim El Hemaly",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/101208/images/733_n.jpg",biography:"OBGYN.net Editorial Advisor Urogynecology.\nAbdel Karim M. A. El-Hemaly, MRCOG, FRCS � Egypt.\n \nAbdel Karim M. A. El-Hemaly\nProfessor OB/GYN & Urogynecology\nFaculty of medicine, Al-Azhar University \nPersonal Information: \nMarried with two children\nWife: Professor Laila A. Moussa MD.\nSons: Mohamad A. M. El-Hemaly Jr. MD. Died March 25-2007\nMostafa A. M. El-Hemaly, Computer Scientist working at Microsoft Seatle, USA. \nQualifications: \n1.\tM.B.-Bch Cairo Univ. June 1963. \n2.\tDiploma Ob./Gyn. Cairo Univ. April 1966. \n3.\tDiploma Surgery Cairo Univ. Oct. 1966. \n4.\tMRCOG London Feb. 1975. \n5.\tF.R.C.S. Glasgow June 1976. \n6.\tPopulation Study Johns Hopkins 1981. \n7.\tGyn. Oncology Johns Hopkins 1983. \n8.\tAdvanced Laparoscopic Surgery, with Prof. Paulson, Alexandria, Virginia USA 1993. \nSocieties & Associations: \n1.\t Member of the Royal College of Ob./Gyn. London. \n2.\tFellow of the Royal College of Surgeons Glasgow UK. \n3.\tMember of the advisory board on urogyn. FIGO. \n4.\tMember of the New York Academy of Sciences. \n5.\tMember of the American Association for the Advancement of Science. \n6.\tFeatured in �Who is Who in the World� from the 16th edition to the 20th edition. \n7.\tFeatured in �Who is Who in Science and Engineering� in the 7th edition. \n8.\tMember of the Egyptian Fertility & Sterility Society. \n9.\tMember of the Egyptian Society of Ob./Gyn. \n10.\tMember of the Egyptian Society of Urogyn. \n\nScientific Publications & Communications:\n1- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Asim Kurjak, Ahmad G. Serour, Laila A. S. Mousa, Amr M. Zaied, Khalid Z. El Sheikha. \nImaging the Internal Urethral Sphincter and the Vagina in Normal Women and Women Suffering from Stress Urinary Incontinence and Vaginal Prolapse. Gynaecologia Et Perinatologia, Vol18, No 4; 169-286 October-December 2009.\n2- Abdel Karim M. El Hemaly*, Laila A. S. Mousa Ibrahim M. Kandil, Fatma S. El Sokkary, Ahmad G. Serour, Hossam Hussein.\nFecal Incontinence, A Novel Concept: The Role of the internal Anal sphincter (IAS) in defecation and fecal incontinence. Gynaecologia Et Perinatologia, Vol19, No 2; 79-85 April -June 2010.\n3- Abdel Karim M. El Hemaly*, Laila A. S. Mousa Ibrahim M. Kandil, Fatma S. El Sokkary, Ahmad G. Serour, Hossam Hussein.\nSurgical Treatment of Stress Urinary Incontinence, Fecal Incontinence and Vaginal Prolapse By A Novel Operation \n"Urethro-Ano-Vaginoplasty"\n Gynaecologia Et Perinatologia, Vol19, No 3; 129-188 July-September 2010.\n4- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Laila A. S. Mousa and Mohamad A.K.M.El Hemaly.\nUrethro-vaginoplasty, an innovated operation for the treatment of: Stress Urinary Incontinence (SUI), Detursor Overactivity (DO), Mixed Urinary Incontinence and Anterior Vaginal Wall Descent. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/ urethro-vaginoplasty_01\n\n5- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamed M. Radwan.\n Urethro-raphy a new technique for surgical management of Stress Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/\nnew-tech-urethro\n\n6- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamad A. Rizk, Nabil Abdel Maksoud H., Mohamad M. Radwan, Khalid Z. El Shieka, Mohamad A. K. M. El Hemaly, and Ahmad T. El Saban.\nUrethro-raphy The New Operation for the treatment of stress urinary incontinence, SUI, detrusor instability, DI, and mixed-type of urinary incontinence; short and long term results. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=urogyn/articles/\nurethroraphy-09280\n\n7-Abdel Karim M. El Hemaly, Ibrahim M Kandil, and Bahaa E. El Mohamady. Menopause, and Voiding troubles. \nhttp://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly03/el-hemaly03-ss\n\n8-El Hemaly AKMA, Mousa L.A. Micturition and Urinary\tContinence. Int J Gynecol Obstet 1996; 42: 291-2. \n\n9-Abdel Karim M. El Hemaly.\n Urinary incontinence in gynecology, a review article.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/abs-urinary_incotinence_gyn_ehemaly \n\n10-El Hemaly AKMA. Nocturnal Enuresis: Pathogenesis and Treatment. \nInt Urogynecol J Pelvic Floor Dysfunct 1998;9: 129-31.\n \n11-El Hemaly AKMA, Mousa L.A.E. Stress Urinary Incontinence, a New Concept. Eur J Obstet Gynecol Reprod Biol 1996; 68: 129-35. \n\n12- El Hemaly AKMA, Kandil I. M. Stress Urinary Incontinence SUI facts and fiction. Is SUI a puzzle?! http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly/el-hemaly-ss\n\n13-Abdel Karim El Hemaly, Nabil Abdel Maksoud, Laila A. Mousa, Ibrahim M. Kandil, Asem Anwar, M.A.K El Hemaly and Bahaa E. El Mohamady. \nEvidence based Facts on the Pathogenesis and Management of SUI. http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly02/el-hemaly02-ss\n\n14- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Mohamad A. Rizk and Mohamad A.K.M.El Hemaly.\n Urethro-plasty, a Novel Operation based on a New Concept, for the Treatment of Stress Urinary Incontinence, S.U.I., Detrusor Instability, D.I., and Mixed-type of Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/urethro-plasty_01\n\n15-Ibrahim M. Kandil, Abdel Karim M. El Hemaly, Mohamad M. Radwan: Ultrasonic Assessment of the Internal Urethral Sphincter in Stress Urinary Incontinence. The Internet Journal of Gynecology and Obstetrics. 2003. Volume 2 Number 1. \n\n\n16-Abdel Karim M. El Hemaly. Nocturnal Enureses: A Novel Concept on its pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecolgy/?page=articles/nocturnal_enuresis\n\n17- Abdel Karim M. El Hemaly. Nocturnal Enureses: An Update on the pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecology/?page=/ENHLIDH/PUBD/FEATURES/\nPresentations/ Nocturnal_Enuresis/nocturnal_enuresis\n\n18-Maternal Mortality in Egypt, a cry for help and attention. The Second International Conference of the African Society of Organization & Gestosis, 1998, 3rd Annual International Conference of Ob/Gyn Department � Sohag Faculty of Medicine University. Feb. 11-13. Luxor, Egypt. \n19-Postmenopausal Osteprosis. The 2nd annual conference of Health Insurance Organization on Family Planning and its role in primary health care. Zagaziz, Egypt, February 26-27, 1997, Center of Complementary Services for Maternity and childhood care. \n20-Laparoscopic Assisted vaginal hysterectomy. 10th International Annual Congress Modern Trends in Reproductive Techniques 23-24 March 1995. Alexandria, Egypt. \n21-Immunological Studies in Pre-eclamptic Toxaemia. Proceedings of 10th Annual Ain Shams Medical Congress. Cairo, Egypt, March 6-10, 1987. \n22-Socio-demographic factorse affecting acceptability of the long-acting contraceptive injections in a rural Egyptian community. Journal of Biosocial Science 29:305, 1987. \n23-Plasma fibronectin levels hypertension during pregnancy. The Journal of the Egypt. Soc. of Ob./Gyn. 13:1, 17-21, Jan. 1987. \n24-Effect of smoking on pregnancy. Journal of Egypt. Soc. of Ob./Gyn. 12:3, 111-121, Sept 1986. \n25-Socio-demographic aspects of nausea and vomiting in early pregnancy. Journal of the Egypt. Soc. of Ob./Gyn. 12:3, 35-42, Sept. 1986. \n26-Effect of intrapartum oxygen inhalation on maternofetal blood gases and pH. Journal of the Egypt. Soc. of Ob./Gyn. 12:3, 57-64, Sept. 1986. \n27-The effect of severe pre-eclampsia on serum transaminases. The Egypt. J. Med. Sci. 7(2): 479-485, 1986. \n28-A study of placental immunoreceptors in pre-eclampsia. The Egypt. J. Med. Sci. 7(2): 211-216, 1986. \n29-Serum human placental lactogen (hpl) in normal, toxaemic and diabetic pregnant women, during pregnancy and its relation to the outcome of pregnancy. Journal of the Egypt. Soc. of Ob./Gyn. 12:2, 11-23, May 1986. \n30-Pregnancy specific B1 Glycoprotein and free estriol in the serum of normal, toxaemic and diabetic pregnant women during pregnancy and after delivery. Journal of the Egypt. Soc. of Ob./Gyn. 12:1, 63-70, Jan. 1986. Also was accepted and presented at Xith World Congress of Gynecology and Obstetrics, Berlin (West), September 15-20, 1985. \n31-Pregnancy and labor in women over the age of forty years. Accepted and presented at Al-Azhar International Medical Conference, Cairo 28-31 Dec. 1985. \n32-Effect of Copper T intra-uterine device on cervico-vaginal flora. Int. J. Gynaecol. Obstet. 23:2, 153-156, April 1985. \n33-Factors affecting the occurrence of post-Caesarean section febrile morbidity. Population Sciences, 6, 139-149, 1985. \n34-Pre-eclamptic toxaemia and its relation to H.L.A. system. Population Sciences, 6, 131-139, 1985. \n35-The menstrual pattern and occurrence of pregnancy one year after discontinuation of Depo-medroxy progesterone acetate as a postpartum contraceptive. Population Sciences, 6, 105-111, 1985. \n36-The menstrual pattern and side effects of Depo-medroxy progesterone acetate as postpartum contraceptive. Population Sciences, 6, 97-105, 1985. \n37-Actinomyces in the vaginas of women with and without intrauterine contraceptive devices. Population Sciences, 6, 77-85, 1985. \n38-Comparative efficacy of ibuprofen and etamsylate in the treatment of I.U.D. menorrhagia. Population Sciences, 6, 63-77, 1985. \n39-Changes in cervical mucus copper and zinc in women using I.U.D.�s. Population Sciences, 6, 35-41, 1985. \n40-Histochemical study of the endometrium of infertile women. Egypt. J. Histol. 8(1) 63-66, 1985. \n41-Genital flora in pre- and post-menopausal women. Egypt. J. Med. Sci. 4(2), 165-172, 1983. \n42-Evaluation of the vaginal rugae and thickness in 8 different groups. Journal of the Egypt. Soc. of Ob./Gyn. 9:2, 101-114, May 1983. \n43-The effect of menopausal status and conjugated oestrogen therapy on serum cholesterol, triglycerides and electrophoretic lipoprotein patterns. Al-Azhar Medical Journal, 12:2, 113-119, April 1983. \n44-Laparoscopic ventrosuspension: A New Technique. Int. J. Gynaecol. Obstet., 20, 129-31, 1982. \n45-The laparoscope: A useful diagnostic tool in general surgery. Al-Azhar Medical Journal, 11:4, 397-401, Oct. 1982. \n46-The value of the laparoscope in the diagnosis of polycystic ovary. Al-Azhar Medical Journal, 11:2, 153-159, April 1982. \n47-An anaesthetic approach to the management of eclampsia. Ain Shams Medical Journal, accepted for publication 1981. \n48-Laparoscopy on patients with previous lower abdominal surgery. Fertility management edited by E. Osman and M. Wahba 1981. \n49-Heart diseases with pregnancy. Population Sciences, 11, 121-130, 1981. \n50-A study of the biosocial factors affecting perinatal mortality in an Egyptian maternity hospital. Population Sciences, 6, 71-90, 1981. \n51-Pregnancy Wastage. Journal of the Egypt. Soc. of Ob./Gyn. 11:3, 57-67, Sept. 1980. \n52-Analysis of maternal deaths in Egyptian maternity hospitals. Population Sciences, 1, 59-65, 1979. \nArticles published on OBGYN.net: \n1- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Laila A. S. Mousa and Mohamad A.K.M.El Hemaly.\nUrethro-vaginoplasty, an innovated operation for the treatment of: Stress Urinary Incontinence (SUI), Detursor Overactivity (DO), Mixed Urinary Incontinence and Anterior Vaginal Wall Descent. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/ urethro-vaginoplasty_01\n\n2- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamed M. Radwan.\n Urethro-raphy a new technique for surgical management of Stress Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/\nnew-tech-urethro\n\n3- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamad A. Rizk, Nabil Abdel Maksoud H., Mohamad M. Radwan, Khalid Z. El Shieka, Mohamad A. K. M. El Hemaly, and Ahmad T. El Saban.\nUrethro-raphy The New Operation for the treatment of stress urinary incontinence, SUI, detrusor instability, DI, and mixed-type of urinary incontinence; short and long term results. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=urogyn/articles/\nurethroraphy-09280\n\n4-Abdel Karim M. El Hemaly, Ibrahim M Kandil, and Bahaa E. El Mohamady. Menopause, and Voiding troubles. \nhttp://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly03/el-hemaly03-ss\n\n5-El Hemaly AKMA, Mousa L.A. Micturition and Urinary\tContinence. Int J Gynecol Obstet 1996; 42: 291-2. \n\n6-Abdel Karim M. El Hemaly.\n Urinary incontinence in gynecology, a review article.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/abs-urinary_incotinence_gyn_ehemaly \n\n7-El Hemaly AKMA. Nocturnal Enuresis: Pathogenesis and Treatment. \nInt Urogynecol J Pelvic Floor Dysfunct 1998;9: 129-31.\n \n8-El Hemaly AKMA, Mousa L.A.E. Stress Urinary Incontinence, a New Concept. Eur J Obstet Gynecol Reprod Biol 1996; 68: 129-35. \n\n9- El Hemaly AKMA, Kandil I. M. Stress Urinary Incontinence SUI facts and fiction. Is SUI a puzzle?! http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly/el-hemaly-ss\n\n10-Abdel Karim El Hemaly, Nabil Abdel Maksoud, Laila A. Mousa, Ibrahim M. Kandil, Asem Anwar, M.A.K El Hemaly and Bahaa E. El Mohamady. \nEvidence based Facts on the Pathogenesis and Management of SUI. http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly02/el-hemaly02-ss\n\n11- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Mohamad A. Rizk and Mohamad A.K.M.El Hemaly.\n Urethro-plasty, a Novel Operation based on a New Concept, for the Treatment of Stress Urinary Incontinence, S.U.I., Detrusor Instability, D.I., and Mixed-type of Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/urethro-plasty_01\n\n12-Ibrahim M. Kandil, Abdel Karim M. El Hemaly, Mohamad M. Radwan: Ultrasonic Assessment of the Internal Urethral Sphincter in Stress Urinary Incontinence. The Internet Journal of Gynecology and Obstetrics. 2003. Volume 2 Number 1. \n\n13-Abdel Karim M. El Hemaly. Nocturnal Enureses: A Novel Concept on its pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecolgy/?page=articles/nocturnal_enuresis\n\n14- Abdel Karim M. El Hemaly. 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