An international research team led by UCL, Great Ormond Street Hospital, and KU Leuven is using 3D-printing and nanodiamonds to design treatments that could help babies repair their damaged lungs while still in the womb.
The new research is published in the Blue Journal (American Journal of Respiratory and Critical Care Medicine).
Congenital Diaphragmatic Hernia (CDH) is a devastating disease affecting one in 3,000 newborns. CDH means that the diaphragm (the muscle between the abdomen and the chest) has not fully developed. As a result, organs that are supposed to sit within the abdomen can easily move into the chest cavity and crush fragile growing lungs, meaning the baby doesn't have space to develop fully formed lungs. In the severest form, and when left untreated, less than 25% of babies born with CDH will survive after birth.
Current treatment can involve delicate surgery during pregnancy to insert a surgical balloon into the baby's windpipe, to stimulate the lungs to grow (known as fetoscopic tracheal occlusion or FETO). This improves survival to 50% but a better treatment is needed urgently.
Vascular endothelial growth factor (VEGF) is a growth hormone which supports lung development in pregnancy but is significantly lower in the lungs of babies with CDH.
To deliver more VEGF to the baby's lungs in a safe, controlled and sustained way, the teams attached VEGF to a microscopic delivery system made from nanodiamonds - carbon nanoparticles smaller than the thickness of a human hair. The work was developed in large part at the Zayed Centre for Research and benefitted from around a quarter of a million pounds from GOSH Charity.
To test the effectiveness of the VEGF delivery system, the team developed lab-grown human 'mini lungs' with key features of CDH and worked with different animal models of the condition. Through a number of comparisons, the team were able to show that giving the VEGF delivery system at the same time as FETO led to the healthiest lungs.
Modelling congenital diaphragmatic hernia
To mimic the disease and compression of the lungs seen in CDH for humans, the teams used 3D-printing directly around human lung tissue grown in the lab at the Zayed Centre for Research. These lab-grown mini-lungs were underdeveloped when compressed by the 3D printing, simulating the condition, and therefore good models for the condition and testing the VEGF delivery system.
Co-lead author, Dr Stavros Loukogeorgakis a surgeon from Great Ormond Street Hospital and Associate Professor of Paediatric Surgery at UCL Great Ormond Street Institute of Child Health said: "Nanodiamonds, 3D printing and growth hormones in the womb all sounds a bit 'science fiction' we know, but this research is really showing us what is possible. As the saying goes: 'diamonds are forever', so we now want to create a delivery system that would break down as the baby grows. This isn't an insurmountable problem, and we could be in a place to offer this to the first families in as little as five years."
Professor Paolo De Coppi, surgeon at GOSH and NIHR Professor of Paediatric Surgery at UCL Great Ormond Street Institute of Child Health, said: "VEGF is a powerful mediator of growth in our bodies and can help us to create new blood vessels and muscle, but uncontrolled or in large doses it can contribute to disease. The use of a delivery system like the nanodiamonds was crucial for us to test if VEGF could do what we want it to do, where we want it, in a controlled manner. By working with multidisciplinary, international teams, we've been able to use various and diverse models that we wouldn't be able to do if we worked alone - collaboration is key."
Professor Jan Deprest, fetal surgeon at UCLH and KU Leuven (Belgium), Professor of Obstetrics and Gynaecology said: "This study shows two essential things. First, this new treatment is likely to boost the effect of the surgery before birth we can offer today. Second, that we can mimic the condition with miniaturized lungs derived from the unborn baby in the laboratory, so that we can test before birth drugs that could save its life after birth. This collaboration once again shows how important international collaboration is, in particular in rare diseases."
Families affected by CDH
CDH effects around 1 in 3,000 births and Great Ormond Street Hospital will treat around one child a month for this condition. Through a multidisciplinary service between GOSH and UCLH, families are currently offered appointments, counselling and the balloon procedure (FETO) when appropriate.
Amelia's story
Amelia was just a few days old when she was transferred to GOSH for lifesaving surgery for CDH. Her condition was identified on an ultrasound scan while mum Georgia was pregnant.
Georgia Turner, 26 years old from Croydon in south London, said: "My pregnancy and birth was a complete whirlwind after Amelia was diagnosed with CDH. It wasn't something I'd heard of before and then I realised how serious it was. I had extra scans and treatment at my local hospital, and the team hoped Amelia's condition would only be moderate.
"Unfortunately, after Amelia was born, the clinical team told me how serious her condition was as her bowel and stomach had moved into her chest. She was taken to GOSH and put on a machine to support her breathing and heart. The team thought she might need to be on it for a few weeks, but she was off within a couple of days. She's such a little fighter!"
Amelia spent four months recovering on the neonatal unit at GOSH and then a further three months at her local hospital, before returning home with mum Georgia.
Now a cheeky 16-month-old, Amelia was making great progress until her CDH reoccurred. A rare side effect that can sometimes unfortunately happen to up to 20% children with the condition. After confirming her CDH relapse on an x-ray, Amelia was brought back to GOSH for specialist surgery.
Georgia continued: "Now she's a lot bigger and stronger she coped well with the second CDH surgery. She only needed support with her breathing for one night on the intensive care unit and by morning she was chatting with the staff! She's bounced back really quickly which is great to see.
"I didn't have any big warning signs from Amelia that her CDH had relapsed which was really worrying. New research like this is great to see how experts are trying to make the treatment for CDH more successful for all children, and less invasive. Hopefully better treatments will also prevent relapse cases like Amelia."
The National Institute for Health and Care Research (NIHR) supported this work though the NIHR GOSH Biomedical Research Centre and an NIHR Fellowship to one of the lead authors, and the research was supported by BREATH Consortium for Lung Regeneration Longfonds and CDH-UK (The Congenital Diaphragmatic Hernia Charity), supporting families through research, information, emotional and practical support.
