An 83-year-old woman has been implanted with the world’s first “3D printer-created jaw”. Using cutting-edge laser manufacturing techniques, doctors and metal experts were able to build up layers of titanium to form a custom metal jawbone to exactly fit her face. The metal jawbone was then inserted into her lower jaw, replacing a large section of bone that was destroyed by a chronic infection.

The technique of 3D printing has been used to build prototype products for some time, but in recent years scientists have begun experimenting with the medical possibilities offered by the process. In this case, a specialist metalwork company called Layerwise was able to translate 3D bone scans into a custom jaw. The company had previously used the process to make bone-shaped prostheses and dental implants. To make a full jawbone, the implant team had to overcome a number of challenges, such as how to encourage muscles to attach to the implant and how to incorporate the nerves necessary for normal movement of the jaw.

While 3D printing is still very much an experimental medical technique, scientists are even currently devising ways in which they might use it to produce whole organs, which are either “printed” by sandwiching layer after layer of living cells on top of each other or created by building scaffolds for cells to grow on.

Why did the woman need a new jaw?

The woman had a condition called osteomyelitis, a type of damaging bone infection usually caused by bacteria or, less often, by a fungal infection. It can occur when infections in nearby skin, muscle or tendons spread to a bone, or when an infection spreads from another part of the body through the blood stream. Depending on the nature of the infection and the health of the patient, osteomyelitis  can cause permanent damage to bones. The condition can be treated with antibiotics to get rid of the infection and prevent further damage, but sometimes surgery will be needed to remove dead bone tissue from around the site of the infection.

If a section of bone tissue is removed, surgeons can close the space by grafting in bone taken from elsewhere in the body or by inserting specialised filler materials that promote regrowth of the surrounding bone.

In this case, the patient had a progressive, chronic form of osteomyelitis which affected nearly her whole jawbone. This meant that she experienced permanent destructive changes which could not be treated by antibiotics alone. Because of the patient’s age, reconstructive surgery using conventional methods would have been risky. Therefore, her medical team decided to attempt to use a bespoke titanium-based implant to replace nearly her entire lower jaw.

What is 3D printing?

3D printing broadly encompasses a variety of different techniques. All the techniques involve using computers to knit together layers or particles of materials to form a new 3D structure. At present, doctors, scientist and technicians use 3D print technology to build implants out of metals, plastics and ceramics and are experimenting with making 3D structures using synthetic bone materials  and even living cells.

It can have several advantages over traditional manufacturing techniques, most notably the ability to create highly accurate bespoke structures such as dental implants. In the case of the new jaw implant, the process offers the option to create a structure that can perfectly fit the dimensions and contours of the patient’s face. Given the complexity involved, using an off-the-shelf implant is not practical.

To create the implant, the manufacturer Layerwise used a type of 3D printing called “selective laser melting”. During the process, heat-producing lasers are focussed on a bed of metal powder so that particles are precision-fused to form a 3D structure. This process is different to traditional metalwork, in which a shape is created by starting with a solid block and removing metal, similar to sculpting. Instead, the 3D printing process allows a shape to be built by adding tiny, intricate layers of particles, much like building a structure layer-by-layer from microscopic building blocks.

Has it been used medically before?

Doctors have previously used 3D-printed metal implants for dentistry and small bone prostheses, but this was the first time it was used to make a full jawbone. The benefit is that these custom-made prostheses can be modelled and shaped to fit the unique structure of someone’s surrounding bones. The surgeons revealed that surgery to implant the jaw took less than four hours and that the patient could speak and swallow again the day after surgery. This rapid recovery of function is encouraging.

It is likely that this technique will be investigated by other surgical groups, but the current reports relate only to the treatment of a single patient with chronic bone infection. It is not yet known whether it could be successful in wider facial reconstructive surgery, for example following trauma.

What might it be used for in the future?

While there are no guarantees that experimental lab techniques can be turned into usable treatments, medical 3D printing has been a hot topic in the news in recent years.

For example, in November 2011, BBC News reported that a team of scientists from Washington State University had used “a bone-like ceramic powder” to make a bone-like material that acts as a scaffold for new cells to grow. However, his experimental technique had not been used in people at the time of reporting.

Scientists are also looking at whether it is possible to use 3D printing to create important structures such as heart valves and even whole organs. A variety of systems is being tested in the lab, from creating 3D scaffolds for cells to populate to layering cells themselves.

Much of this cutting-edge technology is years away at the very least, but the possibilities are great and very exciting, as highlighted during a talk by Dr Anthony Atala at last March’s TED conference.

Links To The Headlines

World's first 3D printer-created jaw fitted to 83-year-old. Daily Mail, February 7 2012

Transplant jaw made by 3D printer. BBC News, February 7 2012

3D printer builds new jaw bone for transplant. The Daily Telegraph, February 7 2012

“Diabetic mothers-to-be have high risk of giving birth to children with congenital abnormality,” The Guardian said today.

The news is based on UK research that compared the rates of birth defects in women with and without diabetes. It found that about 7% of pregnancies in women with diabetes were affected by birth defects that were not caused by problems with the number or structure of the chromosomes. This was 3.8 times higher than the rate in women without diabetes. The study also found that women who have worse control over their blood sugar around the time of conception were at greater risk.

It has been known for some time that diabetes in pregnancy is associated with a higher risk of various complications, and this large study provides further evidence on the link between diabetes and birth defects. UK medical guidance already addresses this risk, and recommends that from adolescence onwards, women with diabetes should be routinely given information on the importance of planning any future pregnancies and on getting specialist care and advice when they decide to have a baby. Women with very poor control of their diabetes are also advised not to become pregnant until their blood sugar control has improved.

Women with diabetes are likely to already be aware of these risks. However, this study provides another reminder that diabetic women who are thinking about becoming pregnant should discuss their options with their doctor first.

Where did the story come from?

The study was carried out by researchers from Newcastle University, the Regional Maternity Survey Office in Newcastle, and the South Tees NHS Trust. It was funded by Diabetes UK, the Department of Health, the Healthcare Quality Improvement Partnership, and the four primary care trusts in northeast England. The study was published in the peer-reviewed medical journal Diabetologica.

The Guardian provided good coverage of this story, and put it into context of what is already known about how a woman’s diabetes can affect her pregnancy. The shorter news article in The Independent covered the basics of the story, but could be taken to suggest that the study was the first to discover the risk. In fact, this risk has been known for some time.

What kind of research was this?

Pregnancies in women with diabetes are already known to be at increased risk of various complications, including stillbirth and birth abnormalities. This cohort study aimed to clarify the extent to which diabetes increases the risk of major birth defects, and how this risk is affected by other factors such as maternal age, smoking and socioeconomic status.

A cohort study is the best way to assess this type of question, which could not be answered by a randomised controlled trial. Clearly, women with diabetes differ from women without diabetes in terms of their medical condition, but the two groups may also vary in other ways. It is important that researchers take such differences into account during their analyses.

What did the research involve?

The researchers used data collected on approximately 401,000 pregnancies that occurred between 1996 and 2008. They looked at whether mothers had diabetes, and if their babies had birth defects. The researchers then looked at whether birth defects were more common in babies born to mothers with diabetes.

The researchers obtained their data from the north of England, collected by the Northern Diabetes in Pregnancy Survey (NorDIP) and the Northern Congenital Abnormality Survey (NorCAS). NorDIP contains data on pregnancies in women diagnosed with diabetes at least six months before conception. It does not include women with gestational diabetes (diabetes that only occurs in pregnancy).

The study excluded multiple pregnancies (twins or triplets) and included pregnancies where the baby died at or before 20 weeks of pregnancy, or where the pregnancy was terminated due to a foetal abnormality. It included all eligible births in the study region in the study period. Abnormalities were classified according to standard definitions, and could be recorded up to the age of 12 years. Some birth abnormalities are caused by problems with the number or structure of chromosomes (the structures in the cell that contain our DNA). These abnormalities were looked at separately.

The researchers looked at the effect of various diabetes-related factors including how well the woman’s blood sugar was controlled at around the time of conception, whether she had type 1 or type 2 diabetes, and diabetes complications diagnosed before pregnancy (such as kidney or eye problems). They also looked at the effect of maternal age at the time of delivery, gestational age at time of delivery, folic acid intake before conception, foetal gender, number of previous babies, pre-pregnancy care, and smoking during pregnancy. Any significant factors were taken into account in the analyses to determine the effect of the individual factors.

What were the basic results?

Among the 401,149 pregnancies, 1,677 were in women with pre-existing diabetes. Most of these women (78.4%) had type 1 diabetes. Overall, 9,488 pregnancies were affected by at least one major birth defect, and 129 of these were in women with diabetes.

In women with diabetes, 71.6 per 1,000 pregnancies were affected by non-chromosomal major birth defects. This was 3.8 times higher than the rate in women without diabetes. Women with diabetes did not have an increased risk of having a baby with birth defects caused by chromosomal abnormalities.

When looking at specific factors linked to the risk of birth defects, the researchers found that women who had worse blood sugar control at around the time of conception were at increased risk of having babies with birth defects. Blood sugar control is often calculated using a measure called HbA1c level. This represents the levels of haemoglobin in the blood with a sugar molecule attached.

Doctors generally try to keep HbA1c levels below 7%. In this study, each increase of 1% in HbA1c over 6.3% was associated with a 30% increase in the odds of birth defects (odds ratio [OR] 1.3, 95% confidence interval [CI] 1.2 to 1.4). Women who already had kidney problems as a result of their diabetes also had an increased risk of having babies with birth defects (OR 2.5, 95% CI 1.1 to 5.3).

Some other factors were associated with an increased risk of birth abnormalities when looked at in isolation, such as low intake of folic acid and lower socioeconomic status. However, once all other factors were taken into account, these were no longer statistically significant.

How did the researchers interpret the results?

The researchers concluded that the main modifiable factor associated with birth defects in women with diabetes is their blood sugar control at around the time of conception. They say that the association with diabetes-related kidney problems needs to be studied further.

Conclusion

This study supports the existence of an association between maternal diabetes and increased risk of birth abnormalities, and helps quantify the size of the association. The study’s strengths include its large size and ability to include the entire population in the study area. However, there are a number of points to note:

• The researchers took into account various factors that could influence the results. However, as with all studies of this type, it is possible that unknown or unmeasured factors, other than maternal diabetes, could have affected the risk of birth defects.
• From this study we cannot say what effect diabetes arising in pregnancy (gestational diabetes) might have on risk of birth defects, as these women were not included in this analysis.
• The study relied on registry-recorded data, and there may be some omissions or inaccuracies in this data. That said, the registries used standard systems for recording data that should increase the reliability of their records.

The link between maternal diabetes and an increased risk of birth defects is already established. Better blood sugar control can help reduce this risk, although it cannot eliminate the risk completely. The National Institute for Health and Clinical Excellence (NICE) recommends that women with diabetes who are trying to conceive should aim for an HbA1c of less than 6.1%, if this can be achieved safely. It also suggests that women with an HbA1c of over 10% should avoid becoming pregnant.

NICE also recommends that:

• Women with diabetes who are planning to become pregnant should be informed of the need to establish good blood sugar control before conception, and that maintaining it throughout pregnancy will reduce the risk of miscarriage, birth defects, stillbirth and neonatal death. They also say that it is important for healthcare providers to explain that these risks can be reduced, but not eliminated entirely.
• The importance of avoiding unplanned pregnancy should be an essential component of diabetes education from adolescence onwards for women with diabetes.
• Women with diabetes who are planning to become pregnant should be offered pre-conception care and advice before they stop using contraception.

This study supports the need for specialist information and planning for pregnancy in women with diabetes. Women with diabetes who are thinking about becoming pregnant should discuss this with their doctor if they have not already done so.

Links To The Headlines

Women with diabetes warned to take precautions when having a baby. The Guardian, February 6 2012

Diabetes lifts birth defect risk. The Independent, February 6 2012

Diabetes quadruples birth defects risk, say researchers. BBC News, February 6 2012

Mothers-to-be with diabetes ‘four times more likely to have baby with birth defects’. Daily Mail, February 6 2012

Links To Science

Bell R, Glinianaia SV, Tennant PWG et al. Peri-conception hyperglycaemia and nephropathy are associated with risk of congenital anomaly in women with pre-existing diabetes: a population-based cohort study. Diabetologia (awaiting publication)

A “single genetic mutation can double your risk of stroke”, the Daily Mail has reported. The newspaper added that scientists hope the discovery could lead to tailored treatments for the condition.

The news is based on research which looked for genetic variations that were more common in people who had had an ischaemic stroke than in people who had not had one. Ischaemic strokes occur when the blood flow to a part of the brain is blocked. They account for 80% of stroke cases. By testing the DNA of several thousand participants, the researchers identified a new genetic variant that was associated with increased risk of a type of ischaemic stroke called a “large vessel stroke”. In large vessel strokes, one or more of the arteries supplying blood to the brain become blocked. People can carry up to two copies of the variant, and the study’s authors estimated that each copy of the variant a person carried was associated with about a 42% increase in the odds of a large vessel stroke. However, it is not yet known whether this genetic variant raises the risk of a stroke, or if it is found near to another variant that is responsible for the increased risk.

This well-designed study has identified a new association between a genetic variation and strokes. However, the study cannot confirm whether the variation itself causes the increased risk of a stroke. This key issue will need to be clarified before these findings can contribute to the development of the new treatments that many newspapers optimistically predicted.

Where did the story come from?

The study was carried out by researchers from the University of Oxford, St George’s, University of London, and a number of other UK and international universities and research institutes. It was funded by The Wellcome Trust. The study was published in the peer-reviewed scientific journal Nature Genetics.

This study was covered by a number of newspapers. In general, the coverage of the research was good, although many news stories focused on its potential to lead to the development of screening tests and new treatments. However, there is no guarantee that this research will lead to such advances. If it does, they are likely to be some way off.

What kind of research was this?

This case-control study aimed to identify genetic factors that are associated with an increased risk of ischaemic strokes. Ischaemic strokes occur when there is a blockage of blood flow to part of the brain. This can deprive brain cells of vital oxygen and nutrients. Around 80% of strokes are ischaemic. The remainder are haemorrhagic strokes, caused by a blood vessel rupturing in or around the brain.

To find genetic variants associated with strokes, the researchers read the DNA sequences of a group of patients who had had an ischaemic stroke. They compared them to the sequences of a group of healthy people. Their theory was that genetic variations that were more common among the stroke group could potentially be linked to stroke risk. To verify whether the variants they initially identified in these groups were associated with strokes, the researchers tested if the same pattern was seen when another group of stroke patients were compared with another group of healthy individuals (controls). This is an accepted method that is used when performing genetic studies of this type.

Although this was a well-designed study, genetic studies like this one can only show that a particular genetic variant is associated with a disease. Further experiments are required to see if the variants identified have a role in causing strokes, or if they lie close to other genetic variants that have this effect. What these variants do still needs to be identified, so media claims that this research could lead to potential new treatments seem premature.

It is also important to remember that genetic, medical and lifestyle factors are likely to contribute to a person’s risk of a stroke. It should not be assumed that a person’s genetics mean that they will definitely have a stroke. Equally, people without high-risk genetics may still be at risk of a stroke risk because of lifestyle factors, such as smoking.

What did the research involve?

In the first phase of the study, researchers recruited 3,548 individuals who had had an ischaemic stroke (the cases) and 5,972 healthy individuals (the controls). The researchers looked for genetic variants that were more common in the stroke group. In a second phase, the researchers confirmed their findings in a new group of 5,859 cases and 6,281 controls.  The new genetic variation they identified was then re-confirmed in a further 735 cases and 28,583 controls.

What were the basic results?

The researchers identified genetic variants at three locations that have been associated with different subtypes of ischaemic stroke in previous studies (near the genes PITX2 and ZFHX3, and on the short arm of chromosome 9). In addition, they identified a genetic variant at a new position within the HDAC9 gene, which was associated with a subtype of ischaemic stroke called large vessel stroke. In large vessel strokes, one or more of the large arteries supplying blood to the brain become blocked. This variant in HDAC9 occurs on about 10% of chromosomes in people in the UK. Humans have two copies of each chromosome, and therefore we can carry up to two copies of this variant (one on each chromosome). The researchers calculated that each copy of the variant that a person possessed was associated with a 42% increase in the odds of having a large vessel stroke (odds ratio 1.42, 95% confidence interval 1.28 to 1.57 for each copy).

How did the researchers interpret the results?

The researchers concluded that they have “identified a new association with the HDAC9 gene region in large vessel stroke”. They also stated that “the mechanism by which variants in the HDAC9 region increase large vessel stroke risk is not immediately clear.”

Conclusion

In this study, researchers have identified a genetic variant in the HDAC9 gene that is associated with a subtype of ischaemic stroke called a large vessel stroke. Large vessel strokes occur when one or more of the arteries supplying blood to the brain become blocked.

In this type of study, the genetic variants identified as being associated with a condition are not necessarily the cause of the increase in risk. Instead, they may lie near another variant that is responsible for the effect. In order to unlock the role of the HDAC9 gene, researchers will now need to study it and the region surrounding it more closely, both to confirm whether the variation in this gene is responsible for the increase in stroke risk and, if so, how it has this effect.

Genetic, medical and lifestyle factors are likely to contribute to stroke risk. In addition, multiple genetic factors may potentially contribute to the risk. It’s important to note that although having higher-risk genetic variants increases the risk of having a stroke, it does not guarantee that a person will have one. Equally, people who do not have any associated variants can still be at risk of a stroke because of lifestyles factors such as smoking, drinking and their diet.

This well-designed study found an association between a new genetic variant and one type of stroke. As yet, it is not possible to say whether this finding will lead to the development of new treatments for large vessel strokes.

Links To The Headlines

New genetic discovery could boost treatment for stroke patients. The Independent, February 6 2012

Mutant gene clue to beat strokes. Daily Express, February 6 2012

Links To Science

The International Stroke Genetics Consortium (ISGC), the Wellcome Trust Case Control Consortium 2 (WTCCC2), Bellenguez C et al. Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nature Genetics, February 5 2012 (published online)