Ceramics are a class of biomaterials with an ionic crystalline structure containing long-range order in their structures. Ceramics have a range of biomedical uses, notably in implants such as hip replacements and in biocompatible sensors. Ceramics can be bio-inert, bio-reactive, or somewhere in between. Ceramics also typically have a high modulus of elasticity, can withstand compressive loads, and have material properties that are highly controllable.

In obstetrics care, fetal heart monitoring is used to indicate fetal health and indicate a range of complications that can occur during pregnancy. In high-risk pregnancies, such as those typically monitored by maternal-fetal medicine doctors, ultrasound echocardiography is used to investigate the health of the fetus and fetal heart, which is too expensive to typically be used without some sort of indication¹. Fetal heart rate is typically monitored in all pregnancies by Doppler based cardiotocography but this method lack reliability (only 60%) and cannot be used for long-term monitoring¹. Recent developments have allowed for sensors that can be placed on the maternal abdomen to measure fetal heart rate, however, this requires specialized training as well as abrasion of the top layer of the epidermis to acquire a reliable signal. Even with these precautions, the technique is still very prone to noise interference from maternal sources and ambient electrical noise.

Image 1: A diagram of a fetal heart

Image 2: An example of fetal echocardiography

The paper “validation of beat by beat fetal heart signals acquired from four-channel fetal phonocardiogram with fetal electrocardiogram in healthy late pregnancy” discusses the use of ceramic sensors for fetal heart monitoring.

The ceramic sensors are placed within a harness that is placed upon the maternal abdomen. This can be comfortably left on the mother for long-term monitoring. Unlike the previously developed sensors for fetal heart monitoring using inexpensive abdominal sensors, this system could allow for long-term monitoring as well as lessened maternal discomfort. The sensors were validated by comparing the results from their measurements with those from fetal echocardiography, with a value of R=0.96, meaning that the results from these sensors compare highly with those of the well-validated fetal echocardiography method.

Image 3: A harness placed on the maternal abdomen for fetal heart monitoring in low-risk pregnancies.

The study uses biocompatible bio-inert ceramic sensors that contact the skin. Thus, their sensors could potentially be topically adhered for long-term monitoring, especially if the harness and sensor combination were made smaller. If these sensors were to be miniaturized for long-term and portable fetal heart monitoring, ceramics are a good materials class choice. Ceramics, unlike metals, can contact the body without causing inflammation. Metal particulates released from friction to the body can cause metallosis, tissue necrosis, and severe inflammation making metal a poor choice for a long-term biosensor. Depending on the polymer, an immune response can also occur. For example, poly(ethylene-glycol) under repeated exposure to the body can produce an immune response. In general, polymers in the body have a protein coating on their surface which determines how the body interacts with them. Depending on the composition of this protein coat, the material can be either degraded by the body or cause an immune response / foreign body response. Certain types of ceramics, such as alumina and zirconium, meanwhile appear to be bio-inert, causing no response in the body at all.

This study marks an improvement over previously existing technologies meant to monitor the fetal heart in low-risk pregnancies. The ceramic sensors mark no technological improvements over fetal echocardiography, however, fetal echocardiography is too expensive currently to be commonly used in low-risk pregnancies. Therefore, this study is an improvement over technologies currently used in monitoring low-risk pregnancies since it is safer for the fetus than Doppler based cardiotocography and more maternally biocompatible than previous maternal abdominal monitoring sensors. This technology would be further improved by making the harness and sensors smaller, making it more comfortable for the mother, especially if long-term monitoring were to be done.

Additionally, exploring an implantable bio-inert ceramic sensor for use in high-risk pregnancies would also be very interesting. This could provide portable long-term monitoring in pregnancies where severe fetal heart defects have been previously diagnosed. A bio-inert ceramic sensor could potentially allow for a sensor to monitor the fetal heart beat without a significant immune response. Furthermore, the rate of degradation of ceramics can be controlled through controlling grain size and compound composition, among other things. This could allow a sensor to potentially be implanted for up to 40 weeks without sensor degradation, at which point it could either be retrieved from the body or degraded in a biocompatible manner.

Reference: Khandoker, et. al. Validation of beat by beat fetal heart signals acquired from four-channel fetal phonocardiogram with fetal electrocardiogram in healthy late pregnancy. Scientific Reports (2018). 8:13635.

As we discussed in class, one way that cells recognize biomaterials is through the proteins that are coated on them. For nanoparticles, proteins surround the particle forming something called the protein corona. This allows cells to recognize and interact with the particle.

Image 1: Cartoon showing the formation of the protein corona of a nanoparticle.

“Nanotechnology for Maternal Foetal Medicine” discusses the importance of characterizing nanoparticles in the medium they will be used, i.e. amniotic fluid. Although many studies using nanoparticles show promise as fetal therapies, some essential safety questions remain unanswered, which hinders clinical translation. Nanoparticle stability and distribution within placental and fetal environments needs to be better characterized to overcome these hurdles. Many of these factors are influenced by the composition of the protein corona of nanoparticles, so a better understanding and improved characterization of the protein corona is essential for eventual translation to clinic.

The composition of the protein corona can be very important for nanoparticle biocompatibility and stability. Nanoparticle toxicity is influenced by protein corona composition¹. Furthermore, biodistribution of particles is highly influenced by the composition of the protein corona¹.

The composition of the protein corona alters what proteins cells are interacting with. This can modulate what cells will preferentially take up particles. For example, adsorption of immunoglobins or complement proteins to the nanoparticle’s surface can encourage phagocytosis by macrophages whereas particular ligands can encourage clathrin-mediated endocytosis by most cells in the body. Therefore, the protein corona influences how nanoparticles are seen and processed by the body, as well as can influence the efficacy of the drug dose inside the nanoparticle (i.e. if it is not being delivered to the correct cell type, it is likely not an efficacious treatment).

Nanoparticles can also be stabilized (or destabilized) by the protein corona. For example, a PLGA nanoparticle that is not very stable in saline may exhibit greater stability in blood¹. Therefore, testing the stability and release of a nanoparticle in the medium it will be applied to is important. The varying protein compositions may lead to differing protein coronas which can significantly influence nanoparticle behavior.

Therefore, if we want to use nanoparticles for fetal therapy, we need to understand how they will perform in the media they will be used in. If nanoparticles are being systemically injected to fetal circulation, then this is already known, since it is well researched how nanoparticles perform when injected systemically. However, little is known about the protein corona and nanoparticle stability in amniotic fluid. A PLGA nanoparticle may exhibit great stability in the blood, but, due to the different protein corona it will form, be very unstable in amniotic fluid.

Understanding the protein corona of nanoparticles in amniotic fluid is important as many fetal therapies may want to explore administration to the amniotic fluid. Maternal-fetal medicine doctors and fetal surgeons can access the amniotic cavity (for amniocentesis) safely with a very low risk of fetal loss as early as 13 weeks of gestation. At the 10^th to 11^th week of gestation, the fetus also begins to breathe and swallow amniotic fluid to help lung development. Therefore, a gene therapy designed to target a genetic disorder primarily affecting the respiratory or GI systems may want to take advantage of nanoparticle delivery through the amniotic fluid.

Image 2: Diagram describing process of amniocentesis.

“Nanotechnology for Maternal Foetal Medicine” makes an important point about the need for more research in the field of cell-biomaterial interactions, specifically looking at how the protein corona of nanoparticles influences behavior in different media. Since many potential fetal therapies may involve delivery to amniotic fluid, research in maternal-fetal medicine needs to gain a better understanding of nanoparticle protein coronas in amniotic fluid. If we want more nanoparticle-based therapies to make it to clinic, this could be essential.

Reference: Casals, et. al. “Nanotechnology for Maternal Foetal Medicine.” International Journal of Pediatrics and Neonatal Health (2018). 2:5, 57-66.

Image 1 reproduced from: Riviere, et. al. “Computational approaches and metrics required for formulating biologically realistic nanomaterial pharmacokinetic models.” Computational Science & Discovery (2013). 6(1):014005.

Image 2 reproduced from: “Amniocentesis.” Mayo Clinic. https://www.mayoclinic.org/tests-procedures/amniocentesis/about/pac-20392914