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Keywords:

  • cord blood banking;
  • cord blood;
  • historical perspective

Summary

  1. Top of page
  2. Summary
  3. Recruitment and informed consent
  4. Cord blood collection
  5. Processing
  6. Testing
  7. Registration of CBU
  8. Testing at reservation, selection and issue
  9. Optimal size of a CBB
  10. Regulations
  11. New emerging CBBs
  12. Related and autologous/private CBB
  13. Future challenges
  14. Conclusions
  15. Acknowledgements
  16. References

Umbilical cord blood (UCB) contains stem and progenitor cells capable of restoring haematopoietic and immunological function in vivo. UCB is currently used as an alternative source of haematopoietic stem cells for transplantation in patients suffering from haematological malignancies, bone marrow failures and inherited metabolic disorders. In order to facilitate transplantation, large repositories of frozen cord blood units (CBUs) from altruistic donations have been established in many parts of the world and to date there are more than 300 000 units stored worldwide. These products have been banked under stringent quality conditions, in order to ensure their safety and efficacy.

The development and evolution of the policies and procedures currently in use in cord blood banking have been largely influenced by the clinical results of cord blood transplantation. This review aims to provide a historical overview of the various developments in the field of cord blood banking from its inception, highlighting the relevant aspects in their collection, banking and release that are known to influence the clinical outcome of these transplants.

The original observations that umbilical cord blood (UCB) contained cells capable of reproducing haematopoiesis in vitro and that these cells could be cryopreserved (Knudtzon, 1974; Fauser & Messner, 1978; Prindull et al, 1978; Broxmeyer et al, 1989, 1992), paved the way for the use of these cells in the clinical setting. The first attempt to transplant UCB was reported in 1972 (Ende & Ende, 1972), but the first successful UCB transplant was performed in 1988 by Elianne Gluckman and her team in Paris, in a patient with Fanconi anaemia, using cord blood from a human leucocyte antigen (HLA)-identical sibling (Gluckman et al, 1989); the patient is still alive and well. This success led to the establishment by Rubinstein in New York of the first unrelated cord blood bank (CBB) from voluntary donors in 1991 (Rubinstein et al, 1994). The first two unrelated UCB transplants, using units from this bank, were then performed in 1993 and the first large series reporting the clinical outcome of unrelated cord blood transplants was published in 1996 (Kurtzberg et al, 1996).

These results led to the realisation that, in order to facilitate cord blood transplantation, large numbers of well characterised and high quality CBUs, which could be readily available, would be required worldwide. A number of investigators began to develop procedures for collecting, storing and releasing CBUs for transplantation for potential related and unrelated recipients. At present there are 54 public unrelated CBBs in different parts of the world with over 300 000 units frozen, hence immediately available for transplantation. These CBBs have enabled the performance of over 10 000 unrelated cord blood transplants in children and adults with both malignant and non-malignant diseases, including acute and chronic leukaemia, bone marrow failure, immunodeficiencies and inherited metabolic disorders (Rocha et al, 2000; Laughlin et al, 2001, 2004; Wagner et al, 2002; Rocha et al, 2004; Prasad et al, 2008; Brunstein et al, 2007; Eapen et al, 2007; Barker et al, 2001).

Following the establishment of numerous CBBs, it was soon realised that networks at both national and international levels would be required to share the information kept in each CBB; this led to the foundation of NETCORD in 1998 (http://www.netcord.org). NETCORD’s main remit was to establish an international registry of CBUs and to develop procedures and quality standards for the safe exchange and clinical use of banked units. These efforts culminated with the establishment of the NetCord-Foundation for the Accreditation of Cellular Therapy (FACT) International Standards for Accreditation of Cord Blood Collection, Processing, Testing, Banking, Selection and Release in 2000 with the last version published in 2006 (http://www.factwebsite.org).

At present, there are 18 CBBs accredited with NetCord-FACT and more than 40 are now in the process of applying for accreditation. The American Association of Blood Banks (AABB) has now also developed standards and an accreditation scheme but these operate primarily in the USA. Most of the CBBs in the rest of the world are NetCord-FACT accredited or aiming at such accreditation.

In addition to the establishment of the Registry, development of standards and promoting the clinical use of cord blood, NETCORD was also instrumental in promoting the use of cord blood and in creating a registry for the validation and evaluation of the transplanted CBUs. This registry, Eurocord, was established in 1999 and is responsible for collecting and analysing all clinical outcome data on cord blood transplantation on behalf of the European Group for Blood and Marrow Transplantation (EBMT) (Gluckman et al, 1997). Eurocord and the American registry CIBMTR (Center for International Blood and Marrow Transplant Research) have recently agreed to share information and analyses, in order to avoid duplication of the reported data.

The field of cord blood banking is now well established and has evolved substantially since it was first described. Its evolution has been greatly influenced by the clinical results and by a number of regulatory issues which are now in place (Brunstein & Wagner, 2006).

This review will describe some of the various steps involved in the establishment of a CBB programme (Fig 1), with particular reference to the banking of unrelated CBUs and will attempt to highlight the changes that have taken place in the evolution of the procedures involved, starting from the recruitment of the potential donor (the mother) to the final issue of the CBU for transplantation.

image

Figure 1.  Principal elements of cord blood banking.

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Recruitment and informed consent

  1. Top of page
  2. Summary
  3. Recruitment and informed consent
  4. Cord blood collection
  5. Processing
  6. Testing
  7. Registration of CBU
  8. Testing at reservation, selection and issue
  9. Optimal size of a CBB
  10. Regulations
  11. New emerging CBBs
  12. Related and autologous/private CBB
  13. Future challenges
  14. Conclusions
  15. Acknowledgements
  16. References

Cord blood banking is a very complex and expensive procedure and it is therefore crucial to try to maximise the resources and efficiency of the programme. As a result, at the beginning, most CBBs in Europe were only taking consent from those mothers from whom a successful collection had been obtained. However, in Europe and following the implementation of the European Union Tissues and Cells Directive (EUTCD) 2004/23/EC in April 2006, stating that ‘procurement of human tissues or cells shall be authorised only after all mandatory consent or authorisation requirements have been met’, all CBUs collected need to have a signed consent obtained prior to delivery. In our programme, consent is now obtained when the mothers attend their hospital at around 30 weeks of pregnancy or via a ‘mini consent’ form completed before the mother is in established labour. The introduction of the ‘mini consent’ form has not only helped to implement the EUTCD, but it has also increased the efficiency of the collection by decreasing the wastage of CBUs discarded due to the lack of consent (Kidane et al, 2007).

An important aspect of the consent process is to provide detailed and clear information about the tests required, the intended use of the unit, particularly in relation to the altruistic nature of the donation, and about the potential use of the clinically unsuitable units for research and development. This means, that for mothers who do not speak the language of the country where they are giving birth, all relevant information, including the process of obtaining consent should be performed in their own language.

With respect to the collection sites, it is important to select maternity units not only with high numbers of deliveries but also with an ethnically mixed population of potential donor mothers, in order to expand the HLA profile of the units banked.

Cord blood collection

  1. Top of page
  2. Summary
  3. Recruitment and informed consent
  4. Cord blood collection
  5. Processing
  6. Testing
  7. Registration of CBU
  8. Testing at reservation, selection and issue
  9. Optimal size of a CBB
  10. Regulations
  11. New emerging CBBs
  12. Related and autologous/private CBB
  13. Future challenges
  14. Conclusions
  15. Acknowledgements
  16. References

The collections of UCB from full term deliveries can be performed in utero or ex utero (Lasky et al, 2002). In utero collections are performed by a trained member of the delivery team during the third stage of labour before the placenta is delivered. Alternatively, the UCB can be collected by trained staff ex utero from the freshly delivered placenta, following full term normal delivery or caesarean section. This is carried out by suspending the placenta, cannulating the vein and allowing the blood to drain by gravity into a specially designed UCB collection bag (Armitage et al, 1999a).

In ex utero collections the risk to the mother or infant is minimal, but the risk of microbial contamination could be higher. Initial studies had indicated that in utero collections yielded larger volumes [and total nucleated cell (TNC) doses] than ex utero collections, but more recent studies have shown that, if appropriately trained staff are involved in the collection there is no significant difference in the volume, or indeed in the contamination rate, with either of these two methods (Lasky et al, 2002).

The safety of mother and child are paramount and, because of the possibility of early clamping and the diversion of the attention from the mother and newborn to the UCB collection, both the UK Royal College of Obstetricians and Gynaecologists (2006) and the Royal College of Midwives have recommended that all UCB collections should be made ex utero. In Europe, the collection of UCB can only be performed in sites that comply with the regulatory requirement of the EUTCD, i.e. licenced, so-called fixed sites.

Some CBBs in the USA have been collecting CBUs in distant non-fixed sites, by providing the appropriate kit and instructions. The current revised version of the NetCord-FACT Standards allows for such collections to take place (http://www.factwebsite.org). It is unlikely that this practice will be implemented in the majority of European CBBs, not only because of the EUTCD requirements, but also due to the long established practice of using their own trained collection staff.

Acceptable values for volume and TNC content of the UCB units to be banked are established by each CBB programme to ensure that they meet the requirements of the transplant centres. As a result of the published data demonstrating the relevance of the TNC infused per kg of body weight in the clinical outcome of these transplants, the minimum cut-off volume and TNC count of the banked units have increased throughout the years (Gluckman et al, 1997, 2004; Rubinstein et al, 1998; Wagner et al, 2002; Ballen, 2005). Most CBBs nowadays tend to bank units with a TNC count above 100 × 107 per unit.

The National Health Service Cord Blood Bank (NHS-CBB), formerly known as the London Cord Blood Bank, was set up in 1996 with the aim of enriching the international haematopoietic stem cell (HSC) donor pool with units from ethnic minorities.

This strategy has had two important effects. Given that, in ethnic minority mothers, the volume and TNC content of the units collected are smaller (Ballen et al, 2004; Ellis et al, 2007), the minimum cut off volume accepted for banking is 40 ml or a TNC count above 40 × 107 per unit. This means that the bank contains a high proportion of units with a low TNC content but also a high proportion of units from ethnic minorities and ethnically mixed genetic background, expressing unique HLA haplotypes (Navarrete et al, 1998; Armitage et al, 1999b; Brown et al, 2000; Davey et al, 2004) (see Table I). This is of great benefit to ethnic minority patients in that nearly 36% of the units issued from the bank for transplantation are from ethnic minority donors.

Table I.   Ethnic distribution of cord blood and bone marrow donors registered with the British Bone Marrow Registry (BBMR).
Ethnic originCord blood units (n = 9814) (%)Bone marrow donors (n = 243 491) (%)
  1. Updated from Davey et al (2004).

European Caucasoid60·294·9
Non-European Caucasoid20·01·7
Black6·81·2
Oriental0·90·3
Other1·70·7
Mixed10·41·2

It is likely that as more successful results are seen with double cord blood transplantation, the use of units with low TNC counts (Barker et al, 2001, 2005; Bradstock et al, 2008), particularly those from ethnic minorities expressing unique HLA haplotypes, will increase. So far, approximately 50% of the units issued from the NHS-CBB programme have been for patients receiving double cord blood transplants.

Processing

  1. Top of page
  2. Summary
  3. Recruitment and informed consent
  4. Cord blood collection
  5. Processing
  6. Testing
  7. Registration of CBU
  8. Testing at reservation, selection and issue
  9. Optimal size of a CBB
  10. Regulations
  11. New emerging CBBs
  12. Related and autologous/private CBB
  13. Future challenges
  14. Conclusions
  15. Acknowledgements
  16. References

In the initial years of cord blood banking it was not clear whether the time interval between collection and processing affected the quality of the stem cells (Shlebak et al, 1999). Nevertheless, the current NetCord-FACT Standards indicate that all CBUs should be processed within 24 h of collection in either a closed system or in an environmentally controlled clean room.

Most of the initially stored units were frozen without any manipulation but it soon became clear that the long-term storage of large numbers of frozen units would create a space issue. This was addressed by trying to reduce the volume of the CBU prior to storage and a number of volume reduction methods were introduced, the majority of which deplete the unit of red cells and plasma, leaving the buffy coats in a standard volume, whilst maintaining the quality and quantity of the stem cells collected (Rubinstein et al, 1994; Armitage et al, 1999a) (Fig 2A, B).

image

Figure 2.  Cord blood processing. (A) Sepax 540 volume reduction system; automated cell separation; (100 ml[RIGHTWARDS ARROW]21 ml); ISBT 128 compatible & traceablility. (B) 10% DMSO Cryoprotectant; 50% DMSO diluted in Dextran 40; freezing bags two compartments; outer metal canister. (C) BioArchive System; Automated, controlled rate, liquid nitrogen freezer for cryopreservation and storage.

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An important consideration with any volume reduction method is the preservation of a maximum number of TNCs and CD34+ cells in the stored buffy coat layer (Regidor et al, 1999; Rogers et al, 2001).

The first semi-automated system for volume reduction, the OptiPress was introduced in 1999. At present most CBUs are reduced to a standard volume of 21 ml prior to freezing, using automated systems such as SEPAX 540 (Biosafe SA, Eysins, Switzerland) or the AutoXpress. Through the introduction of two new filters, one for the hydroxyethyl starch/anticoagulant (complete with a small sample bulb to allow for re-sampling) and a second to add the dimethyl sulphoxide (DMSO), the SEPAX 540 system remains sterile and is referred to as ‘closed’ (Armitage, 2006). This means that processing of these units can be undertaken in a Grade C room, under a laminar flow cabinet. The AutoXpress is also considered a closed system and can be used in a Grade C room.

Another important additional advantage of volume reduction is that it reduces the amount of DMSO contained in the unit, a fact particularly beneficial for units that will be infused to small children. Initially, due to the large volume of DMSO, cord blood cells had to be washed prior to infusion, especially in the case of small children. Nowadays, washing is not required for volume-reduced units.

Long term viability of the frozen cells was also of concern but it is now known that the standard cryopreservation protocols of freezing the cells in 10% DMSO in controlled rate freezers and storage below −135°C give an average of 80% recovery of nucleated cells and >90% recovery of progenitor cells, as measured by stem cell surrogate markers, CD34+ cells and colony forming unit (CFU) assays (Mugishima et al, 1999).

In the beginning, all units were frozen using manually controlled rate freezing and placed directly in liquid nitrogen storage tanks. These days, the freezing of buffy coats can be performed using manually or automated (Bioarchive; ThermoGenesis Corp., Rancho Cordova, CA, USA) controlled rate freezer equipment. The automated system provides a platform to freeze and store cells at the same time, minimising exposure to temperature changes and also allows the electronic identification of the archived units. Thus when a unit is required for issue, it can be automatically retrieved, through a periscope, without exposing the other units to temperature changes (Fig 2C).

However, both the automated and the manual systems are perfectly adequate, provided the temperatures are regularly monitored and the process is fully evaluated and quality controlled.

In order to maximise the volume of cells stored, all the ‘waste’ components produced during the processing of the units are utilised for testing and archiving. Archiving of samples is crucial, in order to be able to perform additional tests in future when a unit is selected for transplantation. At the NHS-CBB, a blood film is prepared from the fresh cord blood to perform an initial haematological screening of the unit. In addition, a small piece of cord tissue is collected and frozen as a source of DNA for future testing, if required.

Testing

  1. Top of page
  2. Summary
  3. Recruitment and informed consent
  4. Cord blood collection
  5. Processing
  6. Testing
  7. Registration of CBU
  8. Testing at reservation, selection and issue
  9. Optimal size of a CBB
  10. Regulations
  11. New emerging CBBs
  12. Related and autologous/private CBB
  13. Future challenges
  14. Conclusions
  15. Acknowledgements
  16. References

Current practice indicates that, whereas some tests need to be performed upfront for banking (before or after processing) and registration purposes, either in the mothers or the CBUs, others can (and some must) be performed once the unit has either been reserved or selected for transplantation (Table II). Amongst the tests required at banking are those performed on the mother’s blood, which, in the UK, are the same as those required for blood donors. With the shortening of the window period of infectivity by the introduction of nucleic acid testing for human immunodeficiency virus (HIV)/hepatitis B virus (HBV)/hepatitis C virus (HCV), it should be possible to eliminate the need for a second 6 month follow-up sample from the mother to retest for infectious disease markers. This requirement was one of the important reasons why significant numbers of units had to be discarded, in spite of their compliance with the banking requirements. Also and mostly depending on the country of origin of the mother-donors, additional screening, such as tests for Malaria, Chagas’ disease and, more recently, West Nile Virus and severe acute respiratory syndrome, are required to comply with regulations in each country. The CBU is also tested for these markers, once reserved or selected for transplantation.

Table II.   Cord blood unit and maternal sample testing.
BankingReservation/issue
  1. HIV, human immunodeficiency virus; HCV, hepatitis C virus; HBV, hepatitis B virus; HBs-Ag, hepatitis B surface antigen; Ab, antibody; PCR, polymerase chain reaction; HTLV1, Human T cell lymphotropic virus type 1; TPHA, Treponema pallidum haemagglutination assay; CMV, cytomegalovirus; HLA, human leucocyte antigen; FBC, full blood count; TNC, total nucleated cells; MNC, mononuclear cells; nRCC, nucleated red cell count; NAT, nucleic acid test; CFU, colony-forming unit.

Maternal sampleMaternal sample
 HIV (Ab + PCR), HCV (Ab), HBV, (HBsAg + anti-Hbcore + PCR), HTLV1 + 2 Ab, TPHA, CMV IgG, ±Malaria Ab, ±Chagas Ab HLA type
 HIV, HCV, HBV, NAT
Cord blood sampleCord blood sample
 ABO/Rh Confirmatory HLA  typing (high resolution)
 Bacteriology; post processing Microbiology
 HLA-A, -B, -DR (DNA typing)  Anti-HBc, HBsAg
 FBC: pre and post processing  Anti-HTLV, anti-HIV,   anti-HCV
 CD34/viability: post processing  TPHA
 TNC/MNC: pre and post processing  HIV, HBV and   HCV NAT
 nRCC: pre and post processing  CMV IgG + CMV PCR
 Blood film screening  Others as required
 Haemoglobinopathy report Blood film examination
 Medical review and quality checked Bleedline
   HLA typing
  CFU assay
  CD34 count + viability
 Congenital Malformation  Registry
 Medical review and  results checked

With the introduction of volume reduction, it is now necessary to perform a full blood count TNC, nucleated red cell and CD34 counts before and after processing, in order to assess the effect of the manipulation on the viability and quality of the unit prior to its long term storage.

The need for CD34 testing arose following the description by some transplant centres that CD34 was a better correlate for engraftment than the TNC dose (Wagner et al, 2002; Moscardóet al, 2009). However, not all banked units have had CD34 counts performed at banking, which is largely due to the fact that up until recently there was not a standardised test for the identification of CD34+ cells and it was therefore difficult to compare results from different centres. Today this test has become more standardised and it is now also possible to assess simultaneously both the percentage and viability of CD34+ cells.

The finally processed unit is also tested for both aerobic and anaerobic cultures to assess the presence of bacterial and/or fungal cross-contamination from the birth canal or systemic sepsis in the donor-mother or infant. Initially, lightly contaminated units were kept in the bank provided an antibiotic sensitivity test was performed and the results communicated to the transplant centre if required. However, the current NetCord-FACT Standards mandate that bacterially contaminated unrelated units should be discarded. CBUs collected for directed use, either related or autologous, can still be banked provided the above mentioned tests are performed.

All CBUs are ABO/Rh and HLA typed at the time of banking. The first two editions of the NetCord-FACT Standards did not specify the techniques required for HLA typing, therefore, there are numerous banked units that have been registered with serologically defined HLA types. However, current standards indicate that all HLA typing should be carried out using DNA-based molecular techniques. This HLA typing information is then used for registering the cord blood donations with the relevant cord blood or bone marrow registries.

Registration of CBU

  1. Top of page
  2. Summary
  3. Recruitment and informed consent
  4. Cord blood collection
  5. Processing
  6. Testing
  7. Registration of CBU
  8. Testing at reservation, selection and issue
  9. Optimal size of a CBB
  10. Regulations
  11. New emerging CBBs
  12. Related and autologous/private CBB
  13. Future challenges
  14. Conclusions
  15. Acknowledgements
  16. References

Over the years, it has become clear that, on completion of processing and testing, all the information regarding the mother and the CBU must be reviewed by a medical officer to assess the suitability of the unit for inclusion into the bank. Once the units are medically released, they can be listed for searches with both the national and international registries. All CBUs are registered under a unique identifier with the following information: HLA type, volume of collected cord blood and TNCC of the final product. The issue as to whether the CD34 count should be included at registration is currently under discussion.

At present there are two international registries: NETCORD, which lists only CBUs, and Bone Marrow Donors Worldwide (BMDW), which contains both bone marrow donors and CBUs (http://www.bmdw.org). There are approximately 200 000 CBUs in NETCORD and 350 000 registered with BMDW. Most CBUs registered with NETCORD are also in BMDW.

Some of the first CBBs that were established operated as independent registries. However, today the vast majority of CBBs work through their national registries due to the fact that most transplant centres prefer a combined search report, listing all available, suitably matched bone marrow donors and CBUs at the same time (Hurley et al, 2003; Heemskerk et al, 2005).

The current NetCord-FACT Standards indicate that all registry aspects of the CBB programmes need to operate under the guidelines of World Marrow Donor Association (WMDA) (http://www.worldmarrow.org) and that these registries should be WMDA accredited or in the process of accreditation. Transplant centres initiate a search for CBUs in the same way as for bone marrow donors and once a transplant centre receives a match report, it contacts the relevant cord blood bank directly.

Testing at reservation, selection and issue

  1. Top of page
  2. Summary
  3. Recruitment and informed consent
  4. Cord blood collection
  5. Processing
  6. Testing
  7. Registration of CBU
  8. Testing at reservation, selection and issue
  9. Optimal size of a CBB
  10. Regulations
  11. New emerging CBBs
  12. Related and autologous/private CBB
  13. Future challenges
  14. Conclusions
  15. Acknowledgements
  16. References

When a CBU is reserved or selected for transplantation, a number of additional tests are performed at the request of the transplant centres. The type and resolution of tests required at this point have changed over the years as a result of the clinical outcome analyses. For instance, the range of required tests for infectious disease markers is expanding and now includes Epstein Barr virus (EBV), human herpes virus (HHV)-6, -7 and -8 and toxoplasmosis.

The request for CFU assays to assess the functionality of the CB cells, is still controversial and many transplant centres are prepared to go ahead with the transplant in the absence of these results. Due to the high cost of CFU assays and since these results can take up to 14 d, most CBBs perform this test at the stage of reservation of the unit. High resolution HLA typing is also performed prior to the issue of the unit. Screening of the selected CBU for abnormal haemoglobins has become an additional requirement prior to the issue of the unit.

Optimal size of a CBB

  1. Top of page
  2. Summary
  3. Recruitment and informed consent
  4. Cord blood collection
  5. Processing
  6. Testing
  7. Registration of CBU
  8. Testing at reservation, selection and issue
  9. Optimal size of a CBB
  10. Regulations
  11. New emerging CBBs
  12. Related and autologous/private CBB
  13. Future challenges
  14. Conclusions
  15. Acknowledgements
  16. References

Haematopoietic stem cell transplantation is currently an optional form of treatment for a broader category of patients and its activity has increased steadily in the past years. At present, approximately only 30% of patients can find an HLA identical donor from within the family. With the reduction in family size more and more patients now need to search for a well-matched HLA type unrelated donor in the established donor registries. Discussions around cost efficiency and optimal size of these registries, including CBBs, required to provide donors for the majority (80%) of patients in need of an unrelated donor, have been ongoing since bone marrow donor registries were first established (Kollman et al, 2004; Katz-Benichou, 2007; Howard et al, 2008). The probability of finding an HLA matched unrelated donor depends not only on the degree (i.e. 6/6 or 10/10 loci) and resolution (medium versus high) of the HLA matching required but also on the ethnic background and compatibility of the patient (Beatty et al, 2000) and the pool of donors to be searched. Since the vast majority of donors currently available in the international registries are of European Caucasoid ethnic background, the probability of finding a 6/6 (or a 10/10) HLA-matched donor for patients from an ethnic minority background is significantly reduced (Dew et al, 2008; Meyer-Monard et al, 2008; Querol et al, 2009).

In the CBB setting, the assumption that a higher degree of HLA mismatches can be tolerated (Kleen et al, 2005), and that UCB transplantation could be performed with as little as 3/6 HLA loci matching between the recipient and the CBU, these reports led to the proposition that the required size of UCB inventory could be smaller than that of a bone marrow registry and that most patients could find at least one 4/6 matched donor from the current global CBU inventory. Several studies have now confirmed that the outcomes of cord blood transplantation between 4/6 and 5/6 matched donors and recipients seem to be comparable to those seen between fully matched adult donors (Eapen et al, 2007; Sauter & Barker, 2008; Takahashi et al, 2009). However, the exact impact of HLA mismatches is beginning to emerge and it may be different in malignant versus non-malignant diseases. Therefore, the question as to whether a smaller number of banked CBUs would suffice, still requires evaluation (Howard et al, 2008).

Regulations

  1. Top of page
  2. Summary
  3. Recruitment and informed consent
  4. Cord blood collection
  5. Processing
  6. Testing
  7. Registration of CBU
  8. Testing at reservation, selection and issue
  9. Optimal size of a CBB
  10. Regulations
  11. New emerging CBBs
  12. Related and autologous/private CBB
  13. Future challenges
  14. Conclusions
  15. Acknowledgements
  16. References

As CBB activity involves the import and export of a cellular product across different countries, it needs to operate within a highly regulated environment in order to ensure that the donations provided for transplantation are safe and meet the highest of quality standards. The regulatory aspects covering the activity of CBB have increased significantly in recent years.

In the UK, the ‘Code of Practice for Tissue Banks’ covers all establishments providing tissues and cells of human origin for therapeutic use. It forms the basis for the Department of Health accreditation scheme to which all CBBs within the UK are required to be licenced, with inspections carried out by the Medicines and Healthcare products Regulatory Agency (MHRA). The EUTCD implemented in 2006 requires all member states to have inspection and accreditation systems in place, ensuring that all banks providing these services comply with an agreed set of standards. In the UK this is regulated by the Human Tissue Authority (HTA), set up in 2004 and implemented in April 2006.

Internationally, the majority of CBBs work to accreditation by the NetCord-FACT Standards. These standards also state that all laboratories supporting CBB activities need to have the relevant additional accreditations in place, e.g. European Federation for Immunogenetics or American Society for Histocompatibility and Immunogenetics for the HLA aspects and WMDA for the registry aspects. The Food & Drug Administration (FDA) is the regulatory authority in the USA. It should be noted that clinical transplantation aspects of cord blood cells are covered by the FACT-JACIE (Joint Accreditation Committee-ISCT & EBMT) Standards and not by the NetCord-FACT Standards.

New emerging CBBs

  1. Top of page
  2. Summary
  3. Recruitment and informed consent
  4. Cord blood collection
  5. Processing
  6. Testing
  7. Registration of CBU
  8. Testing at reservation, selection and issue
  9. Optimal size of a CBB
  10. Regulations
  11. New emerging CBBs
  12. Related and autologous/private CBB
  13. Future challenges
  14. Conclusions
  15. Acknowledgements
  16. References

A number of public CBBs have now emerged in countries where not only the family size is small but also where bone marrow donor registries are small or non-existent. Countries such as Japan (Kodera, 2008), Singapore and China are now investing in developing CBBs (Meijer et al, 2009). More than 4000 UCB transplants, i.e. most of the HSC transplant activity in Japan today, is carried out using CBUs stored in the Japanese Cord Blood Bank Network (JCBBN) where there are more than 30 000 units stored (Nagamura-Inoue et al, 2008). The situation in China is similar and at present there are at least six established CBBs with four more being planned. The number of CBUs banked in China is uncertain and figures between 25 000 and 250 000 have been reported.

In other countries, such as Mexico, public cord blood banking has become very successful and cost-efficient (Novelo-Garza et al, 2008). There, in spite of the existence of a bone marrow donor registry, requirements cannot be covered locally with adult donors and the cost of importing a bone marrow donor harvest is too high, compared with the local availability and provision of a CBU.

Related and autologous/private CBB

  1. Top of page
  2. Summary
  3. Recruitment and informed consent
  4. Cord blood collection
  5. Processing
  6. Testing
  7. Registration of CBU
  8. Testing at reservation, selection and issue
  9. Optimal size of a CBB
  10. Regulations
  11. New emerging CBBs
  12. Related and autologous/private CBB
  13. Future challenges
  14. Conclusions
  15. Acknowledgements
  16. References

Cord blood banking procedures were developed primarily for the collection and banking of unrelated CBUs. The banking of directed CBUs, either related or autologous, requires different considerations. In the directed related setting, the cord blood is collected from the sibling of a patient with a disease that can potentially be treated with a cord blood transplant. These collections have to be performed at the request of the physician treating the patient, with the agreement of the obstetrician looking after the mother (Reed et al, 2003; Smythe et al, 2007). In these cases, considerations such as minimum volume collected, volume reduction or exclusion due to microbial contamination do not apply. An increasing dilemma though, is that in many cases (approximately 70%), the collected CBUs are not fully HLA-matched with the patient and it is unlikely that those units will ever be used for the intended patient; they will have to be kept frozen indefinitely unless clear policies regarding their disposal are put in place. So far, most of the banked related units used have been fully HLA-matched for patients with haemoglobinopathies (Smythe et al, 2007). In fact, in some places, related cord blood transplantation is the first line of treatment for patients with thalassaemia major (Locatelli et al, 2003).

In future, with the possibility of prenatal genetic diagnosis (PGD), it will be possible to collect units selected only from HLA-identical siblings, as has already proved possible (Grewal et al, 2003).

Worldwide, many private CBBs are collecting and storing UCB for eventual autologous or family use. Although there are more than 1 million of these units stored in these private CBBs, an insignificant number have been transplanted, mostly with unknown outcomes (Thornley et al, 2009). Furthermore, the scientific and clinical arguments for the banking of these units are not universally accepted. In addition there are a number of ethical issues associated with this practice which have been extensively reviewed (Lind, 1994; Burgio & Locatelli, 1997; Sugarman et al, 1997; Kim et al, 2004; Kurtzberg et al, 2005; Brand et al, 2008).

In order to safeguard the eventual recipients of these units and the families paying for these collections, NetCord-FACT have developed and published standards applying to CBBs involved in the collection of these CBUs.

Future challenges

  1. Top of page
  2. Summary
  3. Recruitment and informed consent
  4. Cord blood collection
  5. Processing
  6. Testing
  7. Registration of CBU
  8. Testing at reservation, selection and issue
  9. Optimal size of a CBB
  10. Regulations
  11. New emerging CBBs
  12. Related and autologous/private CBB
  13. Future challenges
  14. Conclusions
  15. Acknowledgements
  16. References

As cord blood transplantation continues to increase and new clinical protocols are introduced and more data becomes available (Barker et al, 2003; Eapen et al, 2007), other factors related to the quality and the efficacy of CBUs may appear. In addition, and in spite of the relative success of cord blood transplantation, there are still important challenges to overcome that may require changes to our current practices. One of these challenges is to explore means of increasing the TNC content of the banked units in order to improve engraftment. The early attempts at ex vivo expansion of the cord blood stem cells have not been very successful, as it appears that the majority of the protocols described so far have led to the expansion of mainly mature progenitors (McNiece et al, 2000; Jaroscak et al, 2003; Robinson et al, 2005). Some investigators have now attempted the infusion of UCB intra bone (Frassoni et al, 2008) or in conjunction with CD34+ or third party bone marrow-derived mesenchymal stem cells, with or without CD34+ cells, with limited improvement in engraftment rates (Fernández et al, 2003; Kim et al, 2004; Gonzalo-Daganzo et al, 2009). Another challenge is to try to improve the immune reconstitution on the CBT patients in order to reduce infections and/or viral reactivation (Parody et al, 2006; van Burik & Brunstein, 2007).

It is likely that, in future, some of the immunotherapy protocols currently in use for bone marrow transplantation, such as expansion of viral specific T cell or natural killer cells could be applied to cord blood transplantation.

Conclusions

  1. Top of page
  2. Summary
  3. Recruitment and informed consent
  4. Cord blood collection
  5. Processing
  6. Testing
  7. Registration of CBU
  8. Testing at reservation, selection and issue
  9. Optimal size of a CBB
  10. Regulations
  11. New emerging CBBs
  12. Related and autologous/private CBB
  13. Future challenges
  14. Conclusions
  15. Acknowledgements
  16. References

Cord blood banking, which involves the collection, processing, testing, banking, registration, selection and release of frozen CBUs is a highly complex and specialised field. Since its inception, it has undergone a significant evolution driven primarily by the clinical results obtained with the use of the banked units. On the other hand, despite the initial scepticism of many transplant physicians, the success of cord blood transplantation that we see today has been made possible by the establishment and development of good quality, highly regulated CBBs in many parts of the world. Also, if the new experimental protocols for the expansion of haematopoietic stem cells and/or immune effectors prove to be successful, further development of the procedures currently used in the banking of UCB will be required.

Acknowledgements

  1. Top of page
  2. Summary
  3. Recruitment and informed consent
  4. Cord blood collection
  5. Processing
  6. Testing
  7. Registration of CBU
  8. Testing at reservation, selection and issue
  9. Optimal size of a CBB
  10. Regulations
  11. New emerging CBBs
  12. Related and autologous/private CBB
  13. Future challenges
  14. Conclusions
  15. Acknowledgements
  16. References

We would like to acknowledge all collection and processing staff at the NHS-CBB and the H&I Laboratory at the NHSBT Colindale Centre for their contribution to the NHS-CBB programme. We would also like to thank Dr Fiona Regan for her advice on all medical aspects and Mrs Sue Armitage for her input in establishing the NHS-CBB programme. Our special thanks also to Denny Williams for making this manuscript possible.

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  2. Summary
  3. Recruitment and informed consent
  4. Cord blood collection
  5. Processing
  6. Testing
  7. Registration of CBU
  8. Testing at reservation, selection and issue
  9. Optimal size of a CBB
  10. Regulations
  11. New emerging CBBs
  12. Related and autologous/private CBB
  13. Future challenges
  14. Conclusions
  15. Acknowledgements
  16. References
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