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BBC investigation exposes dangerous teeth-whitening industry - BBC News

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A BBC investigation finds kits on sale containing more than 500 times the legal limit of bleach.

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Association of body weight with efficacy and safety outcomes in phase III randomized controlled trials of direct oral anticoagulants: a systematic review and meta-analysis - PubMed

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Essentials The association of body weight and patient-important outcomes remains unknown. Phase III randomized controlled trials of direct oral anticoagulants (DOACs) were searched. Risk of outcomes varying among body weight subgroups is not attributable to anticoagulant type. Dose adjustment of DOA …

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Management of Dental Patients Taking Anticoagulants or Antiplatelet Drugs
Published March 2022 (2nd Edition) Introductory video for the 2022 edition of the guidance:
Downloads

Full Guidance (PDF) provides comprehensive background information, recommendations and practical advice.

Quick Reference Guide (PDF) summarises the main recommendations and clinical practice advice from the full guidance using treatment planning flowcharts.

Also available via the SDCEP Dental Companion app.

Supporting tools

A number of supporting tools are included with the full guidance to help the dental team implement the guidance recommendations. These are available for download:

Post-Treatment Advice for Dental Patients (PDF) - advice sheet to which individual post-treatment instructions and local emergency contact details can be added. If providing to a patient digitally, save the document by printing to pdf after adding any specific instructions, to prevent further modification.

Pre-Dental Treatment Instructions - DOACs (PDF) - fillable sheet for providing and recording individual pre-treatment instructions for dental patients taking a direct oral anticoagulant (DOAC). If providing to a patient digitally, save the document by printing to pdf after adding patient details and specific instructions, to prevent further modification.

Pre-Dental Treatment Instructions - Warfarin (PDF) - fillable sheet for providing and recording individual pre-treatment instructions for dental patients taking warfarin or another vitamin K antagonist. If providing to a patient digitally, save the document by printing to pdf after adding patient details and specific instructions, to prevent further modification.

About this guidance

The second edition of Management of Dental Patients Taking Anticoagulants or Antiplatelet Drugs aims to provide clear and practical advice to enable the dental team to manage and treat this patient group. The guidance presents advice to inform the assessment of bleeding risk and decision making for treatment planning. Specific recommendations for managing dental treatment for patients taking the various types of medication, including direct oral anticoagulants, warfarin and other vitamin K antagonists, low molecular weight heparins and antiplatelet drugs, are provided.

Advice points to support sustainable oral health are included as a result of consideration of the potential environmental impact of the recommendations and clinical advice in this guidance.

While the guidance is aimed primarily at dental professionals, aspects of the guidance will also be of relevance to medical professionals including those who prescribe or dispense anticoagulants and antiplatelet drugs.

NICE has accredited the process used by the Scottish Dental Clinical Effectiveness Programme to produce its Management of Dental Patients Taking Anticoagulants or Antiplatelet Drugs guidance. Accreditation is valid for 5 years from 15 March 2021. More information on accreditation can be viewed at www.nice.org.uk/accreditation. Further information about NICE accreditation of SDCEP guidance can be viewed at NICE Accreditation.

The College of General Dentistry and the dental faculties of the Royal Colleges have endorsed the second edition of this guidance as a source of reliable, high quality professional advice that promotes the provision of safe and effective oral health care for patients.

Guidance development

The second edition of this guidance is based on a full review of the content and current evidence, and the opinion of dental and medical experts, experienced practitioners and patients. The Guidance Development Group (GDG) for this guidance update comprised individuals from a range of branches of the dental and medical professions, including oral surgery, oral medicine, special care dentistry, restorative dentistry, general dental practice, dental therapy, cardiology, haematology, pharmacy, and general medical practice, and two patient representatives. Details of the GDG members are provided in the full guidance document.

The updated guidance has been subject to external peer review prior to finalising for publication and SDCEP acknowledges the important contribution of all those who commented during this stage.

The methodology used for the development of this guidance, including details of the evidence search strategy, evidence summaries, considered judgements and information about conflict of interests can be found in the webpage, or by contacting the SDCEP office ( Management of Dental Patients Taking Anticoagulants or Antiplatelet Drugs Guidance Methodology 2022 (PDF). Further information is available at the SDCEP guidance development process scottishdental.cep@nes.scot.nhs.uk).

During the development process, potential barriers to the implementation of this guidance were identified. A Guidance Implementation Summary (PDF) of information about these is provided. For further details visit the TRiaDS website.

Review and updating

For this guidance, a review of the topic will take place five years after publication and, if this has changed significantly, the guidance will be updated accordingly.

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scottish dental clinical effectiveness programme - sdcep

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Published March 2022 (2nd Edition) Introductory video for the 2022 edition of the guidance: Full Guidance (PDF) provides comprehensive background information, recommendations and practical advice. Quick Reference Guide (PDF) summarises the main recommendations and clinical practice advice from the full guidance using treatment planning flowcharts. Also available via the SDCEP Dental Companion app.

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If you're employed by an organisation that we regulate and you have concerns about the care being provided by your employer, we want you to tell us. Your information is very important in helping us form a picture of how well the service you work for cares for all the people who use it.

People who raise concerns about the care provided by their employer are sometimes called 'whistleblowers'. In law, whistleblowers are people who raise their concerns in a certain way and may receive protection in any employment dispute.

All organisations that provide care must have whistleblowing procedures and must make them available to their employees. Follow your employer's procedures if you have any concerns about care.

We don't have any powers to protect you from action taken against you by your employer. However, if you're involved in an employment tribunal in the future, the fact that you told us about your concerns may help you to claim for unfair dismissal.

How to raise concerns about poor care you've seen

Before contacting us, you may want to:

speak to your line manager or a senior member of staff about your concerns.

read your employer's whistleblowing policy which will give you information on what to do next.

If you do not feel like you can talk to someone in your organisation, read our quick guide to whistleblowing or guidance for workers which gives helpful advice on speaking out about poor care and what protection you will have from the law.
Whistleblowing: Quick guide to raising a concern with CQC
We have also produced a document explaining to providers of services why they should have a whistleblowing policy and the benefits of encouraging workers to raise concerns.
Whistleblowing: Guidance for providers Tell us about your concerns now
Other ways to contact us

If you can't use our online form, you can also email us or use the details on our contact us page.

Your privacy

The information you give us will be dealt with in confidence and you can raise concerns anonymously.

If you provide us with your contact details, we may use this information to:

respond to you - if you have asked us to

contact you - if we need further details.

We will treat your personal information in confidence but there may be times when we need to share it with others. This includes when:

we believe a vulnerable person is at risk of harm

a serious crime has been committed

another organisation needs to take action to ensure the safety and quality of care.

You can find out more about our approach to confidentiality in our Privacy statement.

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Report a concern if you are a member of staff

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If you're employed by an organisation that we regulate and you have concerns about the care being provided by your employer, we want you to tell us. Your information is very important in helping us form a picture of how well the service you work for cares for all the people who use it.

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Thrombosis UK, Formerly Lifeblood: The Thrombosis Charity has a mission to provide support to all those living with and affected by thrombosis

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Selection Criteria for Dental Radiography – College of General Dentistry

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Guidance on the Ionising Radiation (Medical Exposure) Regulations 2017 for employers and health professionals who carry out medical radiological procedures.

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Ionising Radiation (Medical Exposure) Regulations 2017: guidance

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Guidance on the Ionising Radiation (Medical Exposure) Regulations 2017 for employers and health professionals who carry out medical radiological procedures.

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Referring patients to the Royal Liverpool Dental Hospital

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Referring patients to the Royal Liverpool Dental Hospital

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Royal Liverpool and Broadgreen University Hospitals Trust

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The hospital caters for a variety of dental health needs including surgeries for dental extractions, minor oral surgery and designated clinics for the treatment of medically compromised patients and patients with latex allergy. In addition there is a general anaesthetic extractions surgery and recovery area and operating facilities for day case patients requiring treatment under general anaesthesia or intravenous sedation.

The Liverpool University Dental Hospital is a teaching hospital and as such we are able to accept a limited number of patients suitable for treatment by undergraduate and postgraduate students, junior hospital staff and specialist trainees.

Specialists or consultants also treat patients who fall within certain priority groups. Restorative waiting times for student treatment are variable and often show seasonal fluctuations relating to undergraduate timetables, student intake and examinations.
There are a limited number of staff hygienists, who only see priority cases.

In order to be referred for treatment you must be referred by your dentist or by the attending dentist who has dealt with your emergency treatment.

See below for referral guideline documents, which lay out the criteria for being accepted for treatment. These include some documents for use by professionals:

Liverpool University Dental Hospital Referral Guidelines

Dental Referral Proforma

Periodontal Protocol

Form for referring a patient for treatment by a dental student

See below for information for TMJ patients including:

TMJ Patient Information Leaflet

TMJ Exercises

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The hospital caters for a variety of dental health needs including surgeries for dental extractions, minor oral surgery and designated clinics for the treatment of medically compromised patients and patients with latex allergy. In addition there is a general anaesthetic extractions surgery and recovery area and operating facilities for day case patients requiring treatment under general anaesthesia or intravenous sedation.

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Sickle cell is a disorder of the haemoglobin in the red blood cells.

Haemoglobin is the substance in red blood cells that is responsible for the colour of the cell and for carrying oxygen around the body.

People with sickle cell disorder are born with the condition, it is not contagious. It can only be inherited from both parents each having passed on the gene for sickle cell.

The main symptoms of sickle cell disorder are anaemia and episodes of severe pain. The pain occurs when the cells change shape after oxygen has been released. The red blood cells then stick together, causing blockages in the small blood vessels.

These painful episodes are referred to as sickle cell crisis. They are treated with strong painkillers such as morphine to control the pain.

People with sickle cell are at risk of complications stroke, acute chest syndrome, blindness, bone damage and priapism (a persistent, painful erection of the penis).

Over time people with sickle cell can experience damage to organs such as the liver, kidney, lungs, heart and spleen. Death can also result from complications of the disorder. Treatment of sickle cell mostly focuses on preventing and treating complications.

The only possible cure for the disorder is bone marrow transplant but this is only possible for a limited number of affected individuals who have a suitable donor. A medicine called Hydroxyurea, can significantly reduce the number of painful crises.

1 SCD is inherited from both parents; sickle cell trait is inherited from one parent.

2 SCD can affect anyone, although it predominantly affects people from African and Caribbean backgrounds.

3 1 in 76 babies born in the UK carry sickle cell trait.

4 Approximately 15,000 people in the UK have sickle cell disorder.

5 Approximately 350 babies with SCD are born in the UK every year.

6 A simple blood test will tell whether you have sickle cell trait or the disorder

7 Children with SCD are at increased risk for stroke, the risk is highest between the ages of 2 and 16.

8 Episodes of pain may occur in sickle cell disorder and are generally referred to as a crisis

The Sickle Cell Trait

You are born with sickle cell trait. It is inherited when only one of your parents has passed on the sickle gene, and will never develop into sickle cell disorder.

You do not have symptoms from sickle cell trait, so it is a good idea to have a blood test to see if you have sickle cell trait.

If you have the trait, the majority of red cells in the blood are normal round shaped cells. Some sickle shaped cells may be present under certain conditions.

Sickle cell trait is found in 1 in 4 West Africans and 1 in 10 Afro-Caribbeans, and is also found in people who originate from the Mediterranean, Asia and the Middle East. It is less common in white European's, although with the ever growing diversity of the population this will change.

Most people who have sickle cell trait are healthy. However, anaesthetics can cause problems. If you have sickle cell trait Always notify your dentist or doctor before treatment commences to be on the safe side.

There is a small chance that you may experience pain at high altitudes (generally above 10,000 feet), including long-haul flying in unpressurised planes and mountain climbing. It is important you say you have sickle cell trait before undertaking such activities as you may need to breathe oxygen. Extreme exercise may also precipitate problems and if you are a professional athlete you should have a training programme that takes account of this.

The trait is not an illness, but if you are planning to have children, then certain factors have to be considered.

If your partner does not have sickle cell trait, then any children you have will not have sickle cell disorder, but they could have the trait (50% chance).

If you and your partner both have the trait, there is a 25% chance that any child conceived may have sickle cell disorder and 50% chance they will have the trait.

What to do next?

If you want to know your sickle cell status you can ask your GP for a blood test.

In some parts of the country there are also local sickle cell centres that can arrange a blood test for you.

You may have been screened for sickle cell disease. Screening is offered .

To all newborn babies as part of the newborn bloodspot (heelprick test) when your baby is five days old. The key reason for offering newborn screening for sickle cell disease is because babies with sickle cell disease are vulnerable to serious infections. By identifying babies early in life , they can be prescribed penicillin and be referred for specialist care, so that they stay healthy.

Newborn screening also detects babies who have the trait (also known as a carrier) for sickle cell disease.

To all pregnant women early in pregnancy (ideally by ten weeks) . Antenatal screening identifies parents to be who have the trait (also known as a carrier). If the mother is identified with the trait, the baby's father is offered a screening test.

There are several treatments available to help manage sickle cell (HbSS) and prevent or treat its symptoms. Your GP, hospital doctor or specialist nurse will recommend appropriate treatments for you or your child. Their recommendations may include:

Penicillin (or erythromycin in the case of allergy) is prescribed to all infants from the age of 3 months to prevent overwhelming pneumococcal sepsis. [1,2] Other infections, for example chest infection or osteomyelitis (infection of the bone) are treated with the appropriate antibiotic.

All infants should receive immunisations according to the universal schedule. In addition, those with sickle cell disease should receive extra vaccinations against Meningitis (Men ACWY) and Pneumococcus (PPV). The latter is given 5 yearly throughout life.

Mild to moderate painful episodes may be managed with over-the-counter painkillers like ibuprofen and paracetamol which should be taken regularly until the episode is over. It is sometimes necessary to go to hospital for severe pain as stronger painkillers such as opiates may be needed.

Blood transfusions are used in the management of sickle cell disease in different ways. In the case of a sudden drop in haemoglobin, such as acute splenic sequestration or aplasia due to parvovirus infection, a simple top-up of non-sickle cell blood is given. In acute emergencies, such as stroke or acute chest syndrome, an exchange blood transfusion is needed to reduce the amount of sickle cells in the blood. Regular, usually monthly, blood transfusions are indicated in the long-term management of stroke or if there is no response to other medications such as hydroxycarbamide (see below). Blood transfusions come from donated blood, which is collected, carefully tested for infections such as hepatitis and HIV, and then closely matched to the recipient to prevent reactions.

Also known as hydroxyurea, hydroxycarbamide increases the amount of foetal haemoglobin (HbF) in the blood and reduces the frequency of painful episodes and acute chest syndrome.[3] It is important to remember that hydroxycarbamide must be taken every day for it to work well and regular blood tests are necessary both to monitor benefits and possible side effects. It is now recommended that hydroxycarbamide should be discussed with parents of all children with sickle cell disease from the age of 9 months in order to prevent the onset of long-term complications., improve quality of life and maintain healthy growth.[4] However, while conversations should start from the age of 9 months, hydroxycarbamide is only licensed for use in children over the age of 2 years.

The mortality in childhood sickle cell disease has fallen from 10% in the 1980's to <1% now. This is almost entirely due to new-born screening, early registration into care and penicillin prophylaxis. Advice and support to parents is also crucial in insuring early recognition of symptoms and good access to medical care. The morbidity from stroke has reduced significantly with the introduction of routine transcranial Doppler screening from the age of 2 years. The adoption of the British Society of Haematology guideline to discuss with parents the early use of hydroxycarbamide and starting treatment from the age of 2 years, should improve quality of life further and prevent long- term complications before they develop.

For further information about the treatment and management of sickle cell, speak to a healthcare professional.

The following standards and guidelines are also available

Standards for the Clinical care of Adults with Sickle cell disease in the UK https://www.sicklecellsociety.org/wp-content/uploads/2018/05/Standards-for-the-Clinical-Care-of-Adults-with-Sickle-Cell-in-the-UK-2018.pdf Sickle Cell Disease in Childhood: Standards and recommendations for Clinical Care https://www.sicklecellsociety.org/wp-content/uploads/2019/11/SCD-in-Childhood_Final-version-1.pdf

1. Prevention of infection 1 Oligbu G, Collins S, Sheppard C, et al. Risk of invasive pneumococcal disease in children with sickle cell disease in England: a national observational cohort study, 2010-2015. Arch Dis Child 2018; 103: 643-7.

2. Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. N Engl J Med 1986; 314: 1593-9.

3. Rees DC. The rationale for using hydroxycarbamide in the treatment of sickle cell disease. Haematologica. 2011 Apr;96(4):488-91.

4. Qureshi A, Kaya B, Pancham S, et al. Guidelines for the use of hydroxycarbamide in children and adults with sickle cell disease: A British Society for Haematology Guideline. Br J Haematol 2018; 181: 460-75.

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Haemoglobin is the substance in red blood cells that is responsible for the colour of the cell and for carrying oxygen around the body. People with sickle cell disorder are born with the condition, it is not contagious. It can only be inherited from both parents each having passed on the gene for sickle cell.

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Quality assurance

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Our reports tell you what we think about the quality of care.

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Please send product news information and images to Adrian O'Dowd at adrian.odowd@nature.com, Product news is provided as a service to readers using text and images from the manufacturer, supplier or distributor and does not imply endorsement by the BDJ. Normal and prudent research should be exercised before purchase or use of any product mentioned.

The subject of platelet-rich plasma, also known as PRP can be confusing.

Over the years, since Drs Arun Garg and Robert Marx first placed patients' own blood in a centrifuge to bring plasma to the top, fibrin to the middle and erythrocytes to the bottom, commercial forces and a lack of industry standardisation has led to myriad nomenclatures, including, but not limited to PRF, i-PRF, A-PRF etc. However, they are all the same product.

Garg is an internationally-recognised dental educator and surgeon who, for more than 20 years, served as a full-time professor of surgery in the division of oral and maxillofacial surgery and as director of residency training at the University of Miami, Leonard M. Miller School of Medicine.

He is considered the world's pre-eminent authority on bone biology, bone harvesting and bone grafting for dental implant surgery. Alongside Dr Marx, he pioneered the use of platelet-rich plasma (PRP).

Looking to set the record straight on PRP and speaking about its evolution, Garg said: 'I could play the same game and introduce 5th generation PRP but that would be disingenuous.

'The truth is, PRP is PRP whatever way you look at it, and PRF, i-PRF and so on are all PRP too! The only difference between the 1990s when Robert and I created this by-product of patients' own blood and now is that we have kept up with changing technology. All autologous blood concentrates are the same, irrespective of what another user may call it.'

Teaming up with Garg to make sense of the confusion is the prestigious publisher Quintessence, hosting his blog on autologous blood concentrates on its website.

If you would like to know more about how PRP misconceptions have developed over the years, to learn the truth behind the abbreviations and to buy Garg's book on the topic, please visit http://www.quintpub.net/news/2018/08/autologous-blood-concentrates-making-sense-of-all-the-hype/#.W9a-6zGYSUn.

About this article

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Please send product news information and images to Adrian O'Dowd at adrian.odowd@nature.com, Product news is provided as a service to readers using text and images from the manufacturer, supplier or distributor and does not imply endorsement by the BDJ. Normal and prudent research should be exercised before purchase or use of any product mentioned.

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NHS England is responsible for commissioning high quality primary care services for the population of England. NHS England's commissioning policy is to move towards more place based, clinically led commissioning and is sharing or delegating commissioning of primary medical care services to CCGs.

In addition to commissioning primary care services. NHS England has responsibility for commissioning of all dental services including specialist, community and out of hours dental services.

The following documents form part of a suite of policies and procedures to support commissioning and contract management of primary care.

These policies and procedures support quality and consistency of commissioning and eliminate duplication of effort in the management of the four primary care contractor groups

All policies and procedures have been designed to support the principle of proportionality. By applying these policies and procedures, commissioners should be able to respond to local issues within a national framework.

Primary care professional bodies, representatives of patients and the public and other stakeholders were involved in the production of these documents.

The policies are underpinned by five key principles;

To support the continuous improvement of primary care

To maintain the right balance between operating in a consistent fashion, maintaining appropriate local flexibility

Clear alignment with NHS England commissioning policy and NHS England business plan.

Compliance with legislation

To support a reasonable, proportionate and consistent approach across the four primary care contractor groups.

This suite of documents will be refined in light of feedback from users. Please send your feedback to england.primarycareops@nhs.net clearly stating in the subject header "Policy feedback: policy name".

Dental policies

NHS England has published a set of 37 interim commissioning policies for non-specialised services which will be subject to public consultation next year.

Please see below to access additional policies:

Letter from the UK's four Chief Dental Officers to clarify the way forward for the consideration of the findings of the Intercollegiate Advisory Committee for Sedation in Dentistry (IACSD): Standards for Conscious Sedation in the Provision of Dental Care Report. The extant DH guidance is the minimum standard to be achieved pending further joint direction from the four CDOs.

Guidance provided by the Chief Dental Officer-England in conjunction with the NHS Patient Group Directions Website Board, Department of Health and the Medicines and Healthcare products Regulatory Agency to provide clarification to the dental care profession on the legalities of NHS England commissioned services buying patient group directions (PGDs) from online registered dental practitioners.

Improved signposting around dental complaints will help patients and providers

A new dental complaints joint statement is set to help patients, providers and other health organisations involved in this area of work.

Produced by the Regulation of Dental Services Programme Board (NHS England, the NHS Business Services Authority, the Department of Health, the Care Quality Commission, the General Dental Council and Healthwatch England), it will help ensure there is a shared understanding of the correct route for complaints among regulators, commissioners and providers.

Previously the dental complaints system has been seen as complex and confusing, experienced overlap and revealed a lack of consistency across organisations.

A report on the work of the Regulation of Dental Services Programme Board is now available.

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NHS England is responsible for commissioning high quality primary care services for the population of England. NHS England's commissioning policy is to move towards more place based, clinically led commissioning and is sharing or delegating commissioning of primary medical care services to CCGs. In addition to commissioning primary care services.

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The Cosmetic Products ((Safety) Amendment) Regulations 2012 (implementing Directive 2011/84 EU which amends Directive 76/768/EEC) came into force on 31 October 2012. This means:

Toothwhitening products containing or releasing between 0.1% and 6% hydrogen peroxide cannot be used on any person under 18 years of age except where such use is intended wholly for the purpose of treating or preventing disease.

Toothwhitening products containing or releasing less than 0.1% of hydrogen peroxide, including mouth rinse, tooth paste and tooth whitening or bleaching products are safe and will continue to be freely available on the market.

Tooth whitening products containing or releasing between 0.1% - 6% of hydrogen peroxide should be used as follows:

an appropriate clinical examination is to be carried out in order to ensure that there are not risk factors or any other oral pathology concerns;

exposure to these products should be limited to ensure that the products are only used as intended in terms of frequency and duration of application;

the products should not be directly available to the consumer, only through a dentist, dental hygienist or dental therapist.

Tooth whitening products containing or releasing between 0.1% to 6% hydrogen peroxide can ONLY be sold to dental practitioners.

For each cycle of use, the first use can ONLY be carried out by dental practitioners or under their direct supervision if an equivalent level of safety is ensured.

After the first cycle of use, the product may be provided by the dental practitioner to the consumer to complete the first cycle of use.

Concentrations exceeding 6% of hydrogen peroxide present or released in oral products, including tooth whitening or bleaching products, remain prohibited UNLESS wholly for the purpose of the treatment or prevention of disease.

It is a criminal offence to act in breach of the Regulations.

GDC registrants need indemnity for any treatment which they provide.

The GDC does not bring criminal prosecutions of bring criminal prosecutions of breaches of the regulations as this role is undertaken by Trading Standards. However, the GDC is concerned with the fitness to practise of its members. It takes the view that if a practitioner has committed a criminal offence, that must be relevant to any assessment of that practitioner's fitness to practise irrespective of whether there has been a prosecution. Therefore, if we receive information or a complaint that a registrant is using a product for cosmetic purposes in excess of the 6%, they may face fitness to practise proceedings and can expect to have the matter referred to the relevant Trading Standards department.

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General Dental Council - Put patients' interests first- FAQ

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The Cosmetic Products ((Safety) Amendment) Regulations 2012 (implementing Directive 2011/84 EU which amends Directive 76/768/EEC) came into force on 31 October 2012. This means: Toothwhitening products containing or releasing between 0.1% and 6% hydrogen peroxide cannot be used on any person under 18 years of age except where such use is intended wholly for the purpose of treating or preventing disease.

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Mohammed Junayed Uddin Hamza

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Press release

The proportion of people engaging in multiple unhealthy lifestyle behaviours has fallen significantly according to a new report on the clustering of unhealthy behaviours over time from The King's Fund.

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Clustering of unhealthy behaviours over time

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Press release The proportion of people engaging in multiple unhealthy lifestyle behaviours has fallen significantly according to a new report on the clustering of unhealthy behaviours over time from The King's Fund.

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Abstract

Patients with inherited anemia and hemoglobinopathies (such as sickle cell disease and β-thalassemia) are treated with red blood cell (RBC) transfusions to alleviate their symptoms. Some of these patients may have rare blood group types or go on to develop alloimmune reactions, which can make it difficult to source compatible blood in the donor population. Laboratory-grown RBC represent a particularly attractive alternative which could satisfy an unmet clinical need. The challenge, however, is to produce - from a limited number of stem cells - the 2x1012 RBC required for a standard adult therapeutic dose. Encouraging progress has been made in RBC production from adult stem cells under good manufacturing practice. In 2011, the Douay group conducted a successful proof-of-principle mini-transfusion of autologous manufactured RBC in a single volunteer. In the UK, a trial is planned to assess whether manufactured RBC are equivalent to RBC produced naturally in donors, by testing an allogeneic mini-dose of laboratory-grown manufactured RBC in multiple volunteers. This review discusses recent progress in the erythroid culture field as well as opportunities for further scaling up of manufactured RBC production for transfusion practice.

Introduction

Red blood cell (RBC) transfusions are the mainstay treatment for anemic patients and are given routinely in hospitals around the world. Depending on the clinical presentation, blood transfusions are likely to be administered to improve the patients' quality of life and are administered either intermittently when needed, or for extended periods, as in the case of 50-90% of patients suffering from myelodysplastic syndromes and for transfusion-dependent patients with inherited anemia and hemoglobinopathies (such as sickle cell disease and β-thalassemia). Chronic RBC transfusions introduce secondary complications which contribute to morbidity, due mainly to transfusion-induced iron overload and erythrocyte alloimmunization. It is particularly challenging for blood services to source RBC compatible for multiply alloimmunized patients with chronic transfusion-dependent anemia or rare blood types.

Breakthroughs in the field of erythropoiesis research have led to the development of reproducible protocols that can yield large numbers of cultured human reticulocytes, often referred to as laboratory-grown or cultured red blood cells (cRBC). In addition to being an excellent model system for exploring human erythropoiesis in health and disease, this work has laid the foundations for the interest in producing human cRBC for transfusion purposes or as a vehicle for red cell-based therapeutics. The production of cRBC from stem cells or other cellular sources (see below) may one day fill the unmet clinical need for transfusion-dependent patients, but only if the challenge of growing enough clinical grade RBC can be met.

The term "manufactured RBC" (mRBC) refers to clinical grade cRBC grown under good manufacturing practises (GMP). Both cRBC and mRBC are in fact nascent RBC, known as reticulocytes5-7 and they are referred to only as mRBC within this manuscript from now on to avoid confusion. One added benefit of mRBC, compared to standard donor-derived RBC, is that they are a homogeneous population of immature RBC that should last the normal 120-day lifetime in the circulation. This regenerative medicine product is anticipated to reduce transfusion frequency and the associated iron overload.6 Support for this idea comes from studies showing that transfusion of young RBC (also called neocytes) is beneficial to patients with inherited anemias, reducing iron overload and increasing the interval between transfusions.8-12

mRBC have been tested in immunocompromised mice models5,6,13 and non-human primates.13 Importantly, a proof-of-principle mini-transfusion of autologous mRBC has been conducted in a single volunteer, illustrating that mRBC can survive in the circulation and are safe for use in humans.5 The benefit of mRBC in allogeneic transfusions across multiple recipients still needs to be demonstrated before moving to patients. The commercial company Rubius Therapeutics has a business model built around producing novel mRBC for therapeutics. To date, Rubius has conducted one injection of mRBC engineered for treatment of phenylketonuria in a single patient (Rubius press release 12 th March 2020 ¹⁴), but no further specific information was released. In the UK, the National Health Service Blood and Transplant (England's Blood Service) is intending to conduct a single-center, randomized, allogeneic, controlled, phase I, cross-over trial denominated RESTORE (Recovery and Survival of Stem Cell Originated Red Cells (ISRCTN:42886452 and EudraCT: 2017-002178-38). This healthy volunteer trial has faced significant delays, most recently due to the COVID-19 pandemic but will, it is hoped, be carried out in the near future to assess the recovery and survival of a mini-dose of mRBC derived from CD34⁺ cells isolated from adult blood donors versus the standard RBC from the same donor.

Laboratory-grown RBC offer the greatest potential in terms of sourcing rare blood groups for sickle cell and thalassemia patients with alloimmunity. It must be acknowledged however, that these patients also present the greatest challenge in terms of requirements for blood. Adult patients require multiple units of blood per month.15 Realistically, the first therapeutic use of mRBC is likely to take place in a pediatric setting or for red cell-based therapeutics, such as enzyme replacement therapies, as both these applications require smaller numbers of mRBC. There is also a need to determine the number of mRBC that represents a therapeutic dose. For adult patients, one unit of standard RBC is estimated to consist of approximately 2x10 ¹² RBC which raises the hemoglobin of an average adult by 1 g/dL. For pediatric patients, doses are more variable as they depend on the weight of the patient but are lower than an adult dose. It should be noted that a proportion (5-10%) of standard RBC are lost within the first 24 hours after transfusion16 and this increases to 25% or more with blood storage time. Therefore, the actual number of RBC required to treat anemia is likely to be lower if the majority of the cells are nascent.

Many excellent reviews have been written on mRBC and the prospect of using mRBC for transfusion.17-25 We therefore offer below a concise overview of the progress to date, highlighting the relevant issues and opportunities for optimizing and increasing the mRBC yield to an adult therapeutic dose.

Overview of the erythroid culture process

The recapitulation of erythropoiesis using primary hematopoietic stem and progenitor cells (HSPC) ex vivo requires specific combinations of cytokines and growth factors in order to first expand the HSPC, and then to direct lineage specification to ensure full differentiation to the reticulocyte stage (see Figure 1 ). Over the last 20 years, multiple laboratories have developed two-dimensional liquid culture systems that reproduce the process and stages of human erythropoiesis to generate reticulocytes. These include two to four stages, each characterized by the inclusion or omission of specific growth factors ( Table 1 ). The general consensus is for the inclusion of a primary stage favoring HSPC expansion with interleukin-3 and stem cell factor, a secondary erythroblast expansion stage including stem cell factor and erythropoietin, followed by a terminal differentiation stage with erythropoietin. Notably, holotransferrin is included throughout the culture period. Some laboratories further modify the initialstage culture media by including, for example, thrombopoietin and fms-like tyrosine kinase 3 (Flt-3) to enhance stem cell proliferation13 and may also include glucocorticoids to increase expansion prior to differentiation.26 The more recent culture protocols listed in Table 1 have been undertaken at considerably larger scale (i.e., at least 1 L), with some reports of successful generation of large numbers of reticulocytes. The challenge for the field is to increase the production even further to generate the equivalent of a therapeutically useful adult dose.

Starting material

The studies reporting the highest yields all use HSPC specifically isolated from cord blood, mobilized5 or standard peripheral blood ( Table 1 ). Another option is to use the whole peripheral blood mononuclear cell (PBMNC) component for production of mRBC, thereby omitting the expensive step of CD34⁺ isolation. As well as reducing costs, the use of PBMNC as the starting material under the correct culture conditions can contribute towards increasing the yield of mRBC. Indeed, PBMNC include all cells with erythroid lineage potential, some of which are CD34⁻ that can enhance culture yield.29 PBMNC also include CD14⁺ cells that might act as helper/feeder cells that can limit the cell death of erythroid progenitors during the first few days of culture when volumes are still small and cells are kept in static tissue culture flasks or dishes.

We highlight that there are other sources that are gaining traction, including immortalized pluripotent stem cells and immortalized cell lines, which can be used to differentiate to reticulocytes, but we will not discuss these here because these have not yet been grown at scale. These sustainable cellular sources have great potential for continual blood production once the technical challenges of growing them have been circumvented and are likely to comprise a second wave of blood products after stem cellderived mRBC.

Natural donor variation and yields

The genetic makeup of the donor-derived cellular starting material has long been recognized to have an impact on yield, which is problematic when trying to consistently produce a high number of mRBC using random donors.34 This variation could be due to the number of HSPC present per volume of blood, which is highly variable between donors, or down to subtle variations in genetic factors that influence how HSPC and erythroid progenitors proliferate, enucleate and/or respond to culture media composition. More work is therefore needed to explain the differences in yields observed between donors under standardized and reproducible culture conditions. The payoff from this painstaking work would be the identification of potential genetic variations that could be pre-screened for or utilized by genetically engineering alterations the starting material to benefit production.

Genome-wide association studies as well as identification of rare phenotypes linked to specific RBC traits might help to identify genetic variants suitable for reliably producing large numbers of mRBC. An example of such an approach was carried out by Sankaran's group.35 LNK/SH2B3 is an adaptor protein that negatively regulates hematopoietic cytokine signaling. Rare lost-of-function SH2B3 alleles have been associated with JAK2-mutationnegative erythrocytosis and a hypomorphic allele of SH2B3 (single nucleotide polymorphism rs3184504) was found to be significantly associated with high hemoglobin levels, packed cell volume and RBC count in vivo.38 Using shRNA knockdown in adult, mobilized, peripheral blood and cord blood CD34⁺ cells, Giani et al. 35 suppressed the expression of the LNK/SH2B3 protein and reported a 2- to 7-fold increase in yield of enucleated RBC in shRNA-treated cells compared to cells transduced with a control shRNA. More recently, a study of rare MAM-negative individuals by Thornton and colleagues39 showed that peripheral blood CD34⁺ cells from two MAM-negative individuals had a proliferation advantage in ex-vivo erythroid cultures, resulting in an average 5-fold increase in cell number compared to four age- and gender-matched MAM-positive controls. Whether the same observations concerning loss-of-function SH2B3 and MAM-negative cells hold true for large-scale cultures and across multiple donors still needs to be determined.

Beyond yield, the choice of donor can also affect the quality of the final mRBC product due to the donor's own RBC intrinsic characteristics - not just in terms of blood group which can be selected for, but also in terms of storage characteristics or even longevity in circulation once transfused. The planned RESTORE clinical trial may provide data on this as the survival time of transfused stem cell-derived mRBC in the circulation of the recipient will be directly compared to the survival time in circulation of the same donor's standard RBC.

Genetic manipulation and small molecules

A key challenge for the field is to prevent the attrition of the self-renewal capacity of HSPC and to maintain the expansion capacity of erythroid progenitors (burst-forming and colony-forming units-erythroid) for a longer period before terminal erythroid differentiation occurs. One way to do this is through the use of glucocorticoids (see below) which can potentially improve the asynchronicity of enucleation in cultures, and may then improve reticulocyte stability and filtration efficiency. Another way is to use culture manipulation to try and maintain stemness and proliferation potential. For example, there are small molecule inhibitors that are reported to enhance cord blood HSPC self-renewal, such as UM171 ⁴⁰ and the aryl hydrocarbon receptor agonist SR-1.41 There are also factors such as angiopoietin-like 5 and IGBFP242 and notch ligand.43 Although there is evidence that these small molecules or factors enhance HSPC expansion, there are no data yet to suggest that they can enhance the yield of reticulocytes when cultured on a large scale.

Figure 1.

Perhaps the most exciting advancement in erythroid progenitor manipulation is the recently reported overexpression of BMI1 in human HSPC, which gave a 10 ¹² fold increase of erythroblasts.44 Not only does the extensive expansion give the potential for higher yields (assuming the cells do not differentiate spontaneously when grown in large volumes), it also confers the opportunity for further genetic manipulation due to the extended time frame. Genetic manipulation in the form of YTHDF2 knockdown also generated a reported 14.3-fold increase in CD34⁺ frequency in the culture conditions used by a separate group of researchers.45 Alternatively, better biomimicry of the stem cell niche to recapitulate conditions ex vivo has the potential to maintain HSPC stemness for longer periods and therefore increase yield; however, these technologies still require further development.46-52 It will be very interesting to see if applications of these innovations can translate into higher yields for large-scale mRBC production.

Media composition and optimization

As well as exploiting cell-intrinsic properties, the base medium composition could be further developed and supplemented. Erythroid progenitors are generally cultured in Iscove modified Dulbecco medium (IMDM) and laboratories maintain consistency with suppliers whenever possible. There are many different IMDM commercially available, some better than others in terms of supporting the proliferation and enucleation of erythroid progenitors. Studies are needed to determine exactly what nutrients are required to support the highest proliferation rates of HSPC and erythroid progenitors in culture, particularly important when culturing at high cell densities. Interestingly Heshusius et al. supplemented their IMDM with nucleosides and a range of trace elements to make a more defined GMP-compliant medium.7 Zhang and colleagues13 added folic acid and selenium to their large-scale cultures of human cord blood CD34⁺ cells. An experimental approach, using parallel stirred tank micro-bioreactors, is needed to identify the definitive media and supplements to use for erythroid culture.

The lipid sources added to base media by different laboratories also vary significantly, with some groups favoring different amounts of plasma, serum (human or bovine) or serum-free conditions supplemented with animal, human or plant-derived lipid-rich reagents. For compliance with GMP, animal sources must eventually be substituted, which can have an impact on yields. In their recent report Heshuvius et al. also highlighted the importance of albumin purity for proliferation.7 Interestingly, Wilkinson et al. 53 showed that 0.1% human serum albumin can be replaced by 0.1% polyvinyl alcohol for cultures of human umbilical cord blood-derived CD34⁺ cells but as yet this observation has not been tested on a large scale.

Glucocorticoids

The importance of glucocorticoids in promoting stress erythropoiesis was originally discovered in avian and mice studies and glucocorticoids have been used to increase the yield of human mRBC.26,29,56,57 Three of the larger-scale erythroid culture protocols reported to date incorporate glucocorticoids, using either dexamethasone in serum-free conditions7 or hydrocortisone in the presence of 5% plasma5 or in serum-free conditions.27

Table 1.

Recent studies have highlighted both the importance of lipid metabolism during terminal erythroid differentiation58 and the fact that exposure to glucocorticoids can affect the lipid metabolism in cultured erythroid cells. For erythroid cells cultured in the presence of hydrocortisone, the defect in lipid metabolism and resulting fragility of mRBC can be counteracted by supplementing the medium with cholesterol- rich lipids.60 Interestingly though, addition of cholesterol- rich lipids slightly accelerated differentiation60 and Heshuvius et al. reported that the addition of plasma caused premature differentiation in the presence of dexamethasone. 7 The interplay between glucocorticoid exposure time and lipid metabolism needs further investigation to maximize yield without compromising mRBC quality.

Table 2.

Holotransferrin

The majority of current protocols use between 0.33 and 0.7 mg/mL holotransferrin isolated from human plasma,5-7 which represents the highest costing individual culture reagent. Holotransferrin is the natural carrier used to deliver iron to the developing erythroid cell by binding to CD71 and being internalized. It is then recycled by the cell and released back into the medium in its apo-form. A cheaper, plant-derived recombinant holotransferrin, optiferrin, is available but this is still expensive. Theoretically, the transferrin concentration could be reduced in culture media as long as iron is also supplemented to bind apo-transferrin, without causing cell toxicity or increasing the likelihood of bacterial growth. For example, Timmins and colleagues used 0.12 mg/mL holotransferrin in combination with 900 ng/mL ferrous sulfate and 90 ng/mL ferric nitrate.27 Olivier et al. used holotransferrin at a concentration of 0.05 mg/mL and 3 mM FeIII-EDTA in small scale immortalized pluripotent stem cell cultures, reportedly without affecting the yield of reticulocytes, but the potential impact on mean cell hemoglobin concentrations and viability during storage of the mRBC produced was not measured.61 Other iron supplements that could be tested include reagents that would deliver iron to erythroid cells in a CD71-independent manner. These include the small lipophilic molecule hinokitiol that can carry iron across the cell membrane into erythroid cells or alternatively, ferric carboxymaltose and iron sucrose, both already prescribed to patients suffering from iron deficiency.64

Bioreactors and growing erythroid cells at larger scale

The majority of erythroid cultures described in the literature are small and rely on the use of static tissue plastic flasks. For the reported larger scale cultures, a variety of culture vessels have been utilized. The original 2.5 mL packed mRBC produced under GMP conditions and tested in a single volunteer were cultured in static plastic flasks.5 Spinner flasks (of 1.5 L and 3 L volumes) have since been used successfully from day 7 onwards for constantly batch-fed cultures reaching a volume of ~28 L to produce 10 mL of packed filtered reticulocytes.6 Zhang et al. used rotating wall vessels to grow 2x10 ⁸ cells from cord blood CD34⁺.13 Most recently, Heshusius and colleagues used a 1 L gas-permeable, rapid expansion bioreactor (G-Rex; Wilsonwolf) which, as well as facilitating partial media replenishment, allowed 90% of the expansion medium to be removed and replaced by differentiation medium. Although the expansion was 10-fold lower in the G-Rex compared to static dishes, the enucleation rate was similar and by extrapolation the authors predicted that ~4.5 mL mRBC could be produced using this bioreactor.7 The cell numbers from these studies are encouraging but are still a long way from the prediction by Timmins et al.,27 who suggested it may be possible to produce 500 units from a single cord blood donation.

There are still many types of bioreactors to choose from and explore further for erythroid culture including: (i) continuous stirred tank bioreactors or spinner flasks which contain internal impellers; (ii) fluidized bed bioreactors in which cells are kept in suspension by the culture medium moving upwards; (iii) rocking heated platforms (wave-like bioreactors) onto which large disposable bags are attached; (iv) rotating wall vessel bioreactors also known as roller bottles and finally, (v) multi-layered static flasks. Whatever becomes the bioreactor of choice for erythroid cell culture, it will need to facilitate higher density culture, be scalable and incorporate automation. In the long term, this will make erythroid culture more cost-effective by: (i) reducing labor costs - cells would be cultured in a single container making the cultures easier to feed and less laborintensive, with the possibility of automated, remote feeding of media and/or specific depleted nutrients; (ii) reducing the footprint and space required for each batch production; (iii) easing scale up; and (iv) minimizing human error and batch-to-batch variation by carefully controlling different parameters (such as pH, agitation and oxygenation) for optimal culture conditions. One can eventually then imagine rooms filled with bioreactors manufacturing mRBC continuously at scale for clinical use.

The challenge for producing mRBC in any of the above types of bioreactors type lies in the variety of culture conditions required during this 3-week process. All cultures are initiated from a small number of HSPC or approximately 100x10 ⁶ PBMNC, seeded in a small volume of medium. The erythroid cells then proliferate reaching a fold expansion of >10 ⁵ and requiring low cell densities for optimum growth (2-8x10 ⁵ cells/mL) or medium replenishment (constant versus repeated batch feeding). Orthochromatic erythroblasts then enucleate and are relatively fragile during this process. Moreover, erythroid cultures are inherently asynchronous, a proportion of cells start enucleating while others are still proliferating; this is noticeable in the last week of culture. To maximize yield, culture conditions have to support cells at different stages of terminal differentiation and nascent reticulocytes must remain viable until the highest percentage enucleation is reached. A manufacturing process that uses a bioreactor efficiently, minimizing the transitions between different types of culture vessels during the 21 days of culture, producing a high yield of reticulocytes and automating feeding, still needs to be identified.

Once the final product is made (i.e., mRBC have been filtered and stored), new cultures have to be reinitiated using new donor-derived HSPC. This is where immortalized pluripotent stem cells or an immortalized cell line that enucleates efficiently would be a game-changer as stocks of the same cell phenotype could be maintained.

Reticulocyte filtration and storage

At the end of the procedure, large-scale erythroid cultures need to be volume reduced and filtered to separate the mRBC from the nucleated cells and expelled nuclei (also known as pyrenocytes). Currently, the filters used are dead-end leukoreduction filters routinely used by blood banks. These have been designed to filter whole blood, which typically consists of ~ 5x10 ⁹ RBC and only ~5x10 ⁶ nucleated cells per milliliter of blood. In comparison, the percentage enucleation for mRBC cultures is approximately 80% and the medium contains pyrenocytes as well as free DNA released by disintegrated nuclei. It is notable that very few studies on mRBC yield test the filterability of their final product or report the yield after filtration. This is a key parameter as the mRBC must be purified before clinical use and this process currently alters the yield by 30-50%. Strategies and more research are needed to improve reticulocyte recovery after filtration, which will lead to a dramatic increase in yield. There are open-ended filter technologies, such as tangential flow filtration systems or acoustic resonance cell filtration,65 which could potentially be used but are as yet untested. More experimental approaches include lab-on-a-chip microfluidic label-free reticulocyte-sorting methods.66 All these possibilities need testing and optimizing on a large culture scale which is expensive, therefore, highlighting filtration as a key area of research calling for innovation as well as commercial investment and collaboration.

Once filtered, the mRBC need to be stored whilst quality control tests are carried out and until they can be transfused into a patient. As reticulocytes, mRBC are more fragile than RBC and more optimal storage conditions need to be developed. An alternative approach is to promote maturation of cultured reticulocytes into bona fide erythrocytes, which is another area of active research.

Compliance with Good Manufacturing Practice and quality control

Finally, it should be remembered that the challenge for mRBC production is not only to deliver a manufacturing process that can produce enough mRBC at scale but to develop a process that is GMP-compliant. Often GMP compliance includes the use of clean rooms, highly trained staff specialized in GMP, using closed processes to minimize any risk of infection, robust batch manufacturing protocols, as well as specific manufacturing processing and quality release criteria which are not required in standard R&D laboratories. The challenges of GMP compliance on large-scale erythroid cultures for a transfusion product may have an impact on yield, add pressure to culture times and increase costs, so will need to be considered and planned for from the outset.

Summary

Technologies to revolutionize transfusion options for patients with anemia, in particular for those receiving regular life-long transfusions, are much needed. There is great potential for laboratory-grown mRBC to be used in transfusion practice once production is mastered at scale. In the meantime, these culture systems at smaller scale have proven to be brilliant tools for understanding human erythropoiesis and optimizing culture methodology. The efficient production of mRBC at scale is now essentially a biotechnological challenge that requires multidisciplinary efforts. We have highlighted some of the key areas, breakthroughs and challenges (summarized in Table 2 ), in which investment together with intensive research into further optimization of culture systems and use of bioreactors at scale are needed to make the clinical use of adult therapeutic doses of mRBC become a reality. Focused research and collaboration between academics, blood banks, commercial entities and new spinouts, especially around the use of RBC-based therapeutics, will no doubt help to drive the development and efficiency of mRBC production under GMP conditions into the clinic.

Funding Statement

Funding: SP, CES and the work in AMT's laboratory is funded in part by a National Institute for Health Research Blood and Transplant Research Unit (IS-BTU-1214-10032) in red blood cell products (University of Bristol) and NHSBT R&D grants(WP15-05; WP15-04). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

References

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22. Severn CE, Toye AM. The challenge of growing enough reticulocytes for transfusion. ISBT Sci Ser. 2018;13(1):80-86. [ Google Scholar]

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Towards manufactured red blood cells for the treatment of inherited anemia

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Patients with inherited anemia and hemoglobinopathies (such as sickle cell disease and β-thalassemia) are treated with red blood cell (RBC) transfusions to alleviate their symptoms. Some of these patients may have rare blood group types or go on to develop alloimmune reactions, which can make it difficult to source compatible blood in the donor population.