The healing power of placenta - human amniotic membrane

12 April 2016



As the rate of diabetes continues to rise, foot ulcers and chronic wounds that often accompany the condition remain a persistent problem. Doctors are now looking into a solution that is about 100 years old, which uses wound dressings made from human amniotic membrane – a tissue found in the placenta. Rod James investigates what this means for those suffering with diabetes.


As the rate of diabetes continues to rise, foot ulcers and chronic wounds that often accompany the condition remain a persistent problem. Doctors are now looking into a solution that is about 100 years old, which uses wound dressings made from human amniotic membrane - a tissue found in the placenta. Rod James investigates what this means for those suffering with diabetes.


The most important challenges the world faces are often the least glamorous or thrilling - and the least talked about. There is one healthcare threat in particular, with grave long-term implications, that certainly doesn't get the coverage it deserves: the rise of chronic disease.

The figures on diabetes are particularly alarming. The International Diabetes Federation estimates that 415 million people between the ages of 20 and 70 worldwide have diabetes (diagnosed or undiagnosed), and this figure is expected to grow to 642 million by 2040 - equivalent to around 10% of the world's population. A recent study by the California Center for Public Health Advocacy, which analysed data from the US Government's 'National Health and Nutrition Examination Survey', concluded that 9% of adults in California have diagnosed diabetes, while another 46% (around 13 million people) have undiagnosed or pre-diabetes.

As well as being a significant burden to those who contract the disease, this trend will put huge financial pressure on health services, which are already creaking under the weight of ageing populations. A paper published in Diabetic Medicine projected that the UK National Health Service's (NHS's) annual spending on diabetes will increase from £9.8 billion to £16.9 billion between 2012 and 2035, accounting for around 17% of the entire NHS budget.

Dealing with this problem involves, to a large extent, educating people - to eat more healthily, exercise more, stop smoking cigarettes and reduce alcohol intake - but this must happen in conjunction with new treatments.

A lot of research into such treatments is being driven by stem cell research. In February, for example, scientists from Harvard University extracted the stomachs from mice and grew them into mini organs capable of producing insulin. These organs continued to produce insulin after being transplanted back into the animals, suggesting a possible method of replacing the insulin-producing cells that are lost in diabetes. If this concept came to fruition, it would revolutionise treatment of the disease. However, you don't always have to look forward to move forward, as researchers of diabetes-related wound care are discovering.

Old tricks, reimagined

Common complications of diabetes are ulcers and wounds on the feet. High blood-glucose levels can lead to poor blood flow and the onset of neuropathy, which causes reduced nerve sensitivity, particularly in the body's extremities. As a result, wounds heal more slowly and are likely to worsen without the patient realising. In the US, diabetic foot lesions are responsible for more hospitalisations than any of the disease's other complications and, in some cases, can result in the need to amputate.

One of the biggest problems with using amniotic membrane in wound care is that general practitioners, and even people who specialise in wound care, don’t know about it.

Increasingly, wound-care researchers have been looking back to a technique first employed in 1910 at Johns Hopkins Hospital, Baltimore. The treatment involves the use of human amniotic membrane, a clingfilm-like substance that is actually the innermost layer of the human placenta. It is generally taken from patients who have had caesarean sections, due to the increased likelihood of the membrane being intact. This placental membrane is fecund with stem cells and proteins, which have been shown to accelerate the healing process when placed on a wound.

Back to the future

Collagens are the major structural component of the placental membrane structure: the placenta's tensile strength is due to large amounts of type I and III collagens, as well as small amounts of type V, VI and VII. The viscoelastic properties of the membrane are down to the presence of elastin, the same substance that allows skin to return to its normal shape after it has been pinched. Regenerative growth factors, along with a range of proteins, cytokines and peptides, help to promote tissue regeneration.

After being widely used for a few decades, the process was brought into question in the 1950s ,when people began to understand how viruses are transmitted through infection. It fell out of favour almost completely in the 1980s, with the onset of AIDS. But scientific developments over the past ten years have made the use of amniotic membrane much safer and it has made a gradual comeback, with ophthalmologists eager to adopt the treatment again.

"Ten years ago, when a technology called decellularisation - the ability to remove cells from tissue and still preserve the architecture of the structure - became available, the membrane started to be used again," says Dr Dusko Ilic, a physician and stem-cell-science professor at King's College London. "Why did it start in ophthalmology, not wound care? I don't know. But it is used in ophthalmology pretty widely - not in all countries, but in the UK. It is produced in one place in the country, but in small amounts."

Uses and qualities

The placental membrane comes in two forms - cryopreserved and dehydrated - which each have different advantages. Ilic's team compared the commercially available varieties of each and published its findings in a paper called 'Human amniotic membrane grafts in therapy of chronic non-healing wounds' in the British Medical Bulletin in March 2016.

Cryopreserved membrane, it concluded, has stronger healing qualities, but it is more expensive to make and more complicated to handle, requiring cold storage along the supply chain. Most of the producers of human amniotic membrane, including the two largest players - MiMedx and Osiris - are based in the US, making the transportation of cryopreserved products to Europe difficult. Less effective, dehydrated varieties can be stored in normal medicine cabinets, however, and have a longer shelf life, making this the only viable option for widespread distribution.

"If you are aiming to send the membrane to hospitals and clinical centres that would be applying it directly to patients, like burn centres or wound-care centres, then cryopreserved is fine," Ilic says. "But if you are planning to manufacture and distribute to underdeveloped countries, or a place where you are not quite sure what the conditions are like, I would choose to work with the dry one.

"One of the biggest problems with using amniotic membrane in wound care is that general practitioners, and even people who specialise in wound care, don't know about it," he says.

Supporting evidence

Raising awareness for such things requires demonstrable evidence, which is gained through clinical trials. In April 2014, a team from Harvard University performed a study involving three patients with five lower-extremity diabetic ulcers between them. Amnioexcel, an amniotic membrane product developed by US-based tissue-regeneration company DermaSciences, was applied to the wounds.

The results were positive in all cases, with the team concluding that the product was "an attractive option for treating complex, chronic wounds because of its non-immunogenic, anti-inflammatory and antibacterial properties". It added: "The tissue also provides a matrix for cellular migration and proliferation, and a number of essential growth factors and cytokines."

Ongoing efforts

In France, at the Hôpitaux de Paris, researchers are recruiting for a clinical trial that Ilic hopes will be one of the most significant demonstrations of the effectiveness of placental membrane as a wound-care tool. The study will include patients suffering from recessive epidermolysis bullosa dystrophica, a disease caused by genetic defects in the COL7A1 gene, which leads to a lack of collagen VII in the skin. Symptoms include pain, superinfection, joint inflammation and joint contractures.

A minority of patients suffer from chronic ulcers, which can take more than three months to heal and can play a decisive role in the morbidity and mortality of the disease, according to the trial's organisers.

If the trial is successful, the practitioners who are treating the patients – who also work with chronic wounds – will see how it heals, and will start to use it in different diagnoses and different conditions.

The study will evaluate the efficacy of the amniotic membrane in treating such wounds compared with a standard dressing, over a 12-week period. Ilic's team is involved in recruiting for the trial and has secured the participation of members of the Dystrophic Epidermolysis Bullosa Research Association's Serbian and Croatian branches.

"If the trial is successful, the practitioners who are treating the patients - who also work with chronic wounds - will see how it heals, and will start to use it in different diagnoses and different conditions," Ilic says. "This is the best way to show to the people who work in wound care how the membrane works. If the results are good, and I believe they will be, the membrane can be exported to other countries."

A true solution?

It should be noted that Ilic has more than just an academic interest in the outcome. He and his co-authors are planning to form a company that would manufacture human amniotic membrane in line with EU directives from a manufacturing base in Serbia. The team has been in contact with a manufacturing partner in Belgrade that is experienced in handling the placental material, and has secured the participation of the obstetrics department of a medical school in the city, which will provide the raw materials.

By manufacturing in Serbia, Ilic hopes to bring down costs enough that amniotic membrane can become a realistic solution for countries and wound-care centres of different sizes and budgets. If the company materialises, it will take six to nine months to produce the membrane for clinical trials.

Slowly but surely in the US, insurers are beginning to reimburse policy holders for human-amniotic-membrane treatment, which is likely to lead to increased use. Europe will surely not be far behind.

Dr Dusko Ilic is a senior lecturer in stem cell science at King’s College London, coordinator of the cross-divisional postgraduate programme in stem cells and regenerative medicine, and head of the induced pluripotent stem cell core facility.
The amniotic membrane – the innermost layer of the placenta – is anti-inflammatory and antimicrobial; its regenerative growth factors make it ideal for use in tissue engineering and regeneration.


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