Spina bifida is a birth defect occurring when the neural tube fails to close properly. In the United States, about four in every thousand babies are affected by spina bifida. The most severe form of spina bifida, which if untreated, can result in severe disabilities, is known as myelomeningocele. With a myelomeningocele, neural tissue, cerebrospinal fluid (CSF), and tissue extends outside of the spinal cord in a membrane bound sac. This sac can burst due to the movements of the developing fetus and lead to mechanical injury to the nerves and tissue as well, leading to further nerve damage.
Image 1: Patient with spina bifida myelomeningocele. A membrane-bound sac filled with nerves, tissue, and CSF can be seen in the illustration.
Patients with myelomeningoceles often have paralysis in the lower extremities, bladder and bowel difficulties, Chiari ll malformations (brain tissue extending into the hole at the base of the skull where the top of the spinal cord is located), hydrocephalus, and intellectual impairments. Mothers with fetuses diagnosed with spina bifida either terminate the pregnancy, seek in utero intervention, or postnatal treatment. Of fetuses surviving to birth, about 10% die as neonates and less than half of those surviving will be able to function on their own in the future. Spina bifida is a devastating condition with a very high disease burden across the lifespan of the patient.
Myelomeningocele patients treated in utero to protect the spinal cord and close the myelomeningocele exhibit improved independence and general amelioration of symptoms. At 30 months, the number of myelomeningocele patients able to walk increased from 21% to 42% due to in utero intervention. However, patients undergoing fetal surgery also had an increased rate of premature labor and often exhibited other complications. Fetal surgery can also be dangerous for the mother.
Image 2: Fetal surgery to improve myelomeningocele outcomes. By protecting the myelomeningocele, the spinal cord was more protected and there was less damage to the nerves after surgery. Abnormalities in the brain such as Chiari II malformations and hydrocephalus were also improved.
Therefore, an intervention was sought that could protect the myelomeningocele to improve patient outcomes but that could avoid the risks of fetal surgery. Farrelly et. al. in “Alginate microparticles loaded with basic fibroblast growth factor induce tissue coverage in a rat model of myelomeningocele” seeks to address this using natural alginate particles.
Alginate is a natural polysaccharide present in algae and seaweed, and is typically obtained from brown seaweed. It has a structural role in cell walls. When eaten as a food (by a human, mouse, pig, etc.), some alginate is digested and most is eliminated in the feces. Alginate therefore functions as a good source of fiber when consumed as a food.
Image 3: Brown seaweed, an edible source of alginate.
Alginate is currently used or found in pharmaceuticals, cosmetics, textiles, in food additives and food, and medically for making dental impressions. Alginate is safe to consume and is highly biocompatible. It also exhibits low toxicity. Alginate is also highly biodegradable, making it a good candidate for use in drug delivery.
Alginate microparticles (MPs) were prepared that were loaded with basic fibroblast growth factor (bFGF). Alginate microparticles were found to be biodegradable and biocompatible. bFGF has been shown to encourage soft tissue growth over myelomeningocele defects in utero. Alginate bFGF loaded microparticles can be administered by injection to the amniotic fluid of a developing fetus.
In this study, alginate MPs were delivered by intraamniotic injection to rat fetuses using a glass micropipette. Rat fetuses were then imaged to determine if tissue covered the myelomeningocele defect. Histology was also performed. Alginate bFGF loaded MPs were found to allow for a tissue covering of the myelomeningocele to protect from further neural damage. About 30% of treated fetuses had significant covering that would likely improve outcomes at birth.
Image 4: Improved covering of the myelomeningocele with alginate MP treatment as compared to a control.
Although this study seems promising, further optimization of the alginate MP system needs to be done to improve the success rate of the treatment. This could be done through altering particle size, adding a surface modification, or increasing dosing. Toxicity of the alginate MPs should also be more rigorously investigated, i.e. looking fetal cytokines for evidence of an innate immune response. This study should also analyze safety and efficacy in animals treated in utero after birth. Symptoms of the disease should be tracked to adulthood so a comparison of the treatment efficacy with control rats can be done. Incidence of paralysis, lifespan, hydrocephalous, interventions after birth required, etc. should be reported for both the experimental and control groups.
Reference: Farrelly, J.S., et. al. Alginate microparticles loaded with basic fibroblast growth factor induce tissue coverage in a rat model of myelomeningocele. J Pediatric Surg (2018). S0022-3468.