Many children are affected by congenital cardiovascular diseases and congenital heart defects are the leading cause of death in neonates. Almost one percent of children are affected by some sort of congenital heart defect and almost twenty-give percent of these patients require surgery.

Many congenital hear defects involve issues with arteries or veins and can result in a disruption of blood flow throughout the heart, so may require a bypass for the blockage or the replacement of a defective vein/artery.

Some patients get varying forms of transplants. Autografts, or the use of tissue from elsewhere in the patient, can be limited due to availability and quality of that tissue for transplant. Allografts, or tissue from a human donor, is limited due to a lack of donors and are immunogenic. Xenografts, or tissue from another species, is also immunogenic and may not necessarily be an effective replacement depending on the tissue.

Therefore, there is a need for the creation of therapies that do not require transplantation of tissue. One potential treatment are synthetic grafts made out of materials like PTFE (polytetrafluoroethylene) that exhibit adequate mechanical strength, but are non-biodegradable and exhibit poor integration of endothelial cells. Smaller diameter grafts are also likely to develop thrombosis (blood clots), stenosis, and become infected. An additional challenge experienced in pediatric and neonatal patient populations is the inability of synthetic graft materials to grow with the patient, making them a non-ideal solution for treating some of these congenital heart defects¹.

The paper “Tissue engineered vascular grafts for pediatric cardiac surgery” discusses the results of a clinical trial by their group on tissue engineered vascular grafts (TEVG) for children with congenital heart defects. TEVG were made from biodegradable polymers, PCL and PLLA mixed with PGA or PLA that were seeded with cells. Follow-up data from a clinical trail conducted from 2001-2004 is presented on patients who received these TEVG. These biodegradable TEVGs in patients ranging from one year to young adulthood resulted in no graft-related mortality. Additionally, at 4 years post-implantation, there was no significant evidence of graft rupture, aneurysms, or calcification.

Image: An example of a tissue engineered vascular graft for implantation.

Many of the implanted TEVGs also demonstrated growth with the child. 6 of 25 patients had vessel narrowing of which 4 had balloon angioplasty and 1 had a stent insertion. The team is currently investigating causes of graft stenosis and ways to prevent this. However, the majority of the treated patients exhibit TEVG growth and remodeling, marking an improvement over synthetic grafts, at least in terms of applicability to pediatric and neonatal patients.

Image: TEVG 13 years after implantation with appearance similar to that of the native veins.

Based on properties of TEVGs that we expect, there may also be a decreased inflammatory or immunogenic response and a decreased risk of dilation, although this was not explicitly discussed or analyzed within the paper.

This paper is a good start towards providing evidence that TEVGs may be an improvement over other current clinical treatments. Since this is done with a relatively small sample size as a Phase One clinical trail in pediatric patients, further expansion of the sample size is needed. Adverse effects may occur at lower frequencies that are not observed with a  small sample size.

Additionally, given the success of this group in treating pediatric patients, a similar study for neonates should be conducted. Children as young as one year were included in this clinical trial and the majority of patients were under the age of five. Therefore, given its success in very young children, this technology as currently created may hold great promise in treating neonates.

Another interesting direction to investigate is whether faster TEVG remodeling and cellular integration from the patient would occur if particular ECM molecules were added in varying ratios. Collagen, elastin, and gelatin are all common ECM components and have been used for TEVGs as a “collagen gel approach.” Integrating some of these molecules into this TEVG in varying ratios could result in better biocompatibility and decreased adverse events.

References:

Shoji, T. et. al. Tissue engineered vascular grafts for pediatric cardiac surgery. Translational Pediatrics (2018). 7(2): 188-195.

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.

Bulk metallic glasses (BMGs) are amorphous metallic alloys with high strength and a low elastic modulus. BMGs have high wear resistance, are resistant to corrosion, and are biocompatible which makes them good potential materials for medical device implants. BMGs with micropatterning also exhibit a reduced foreign body response compared to flat BMGs or some other traditional materials¹.

BMGs also exhibit improved endothelial cell adhesion as compared to a nickel-titanium metal¹, which may make them good candidates for vascular stents. Additionally, the biocompatibility and relative bio-inertness of many BMGs may allow BMG stents to be implanted with a reduced foreign body response and reduced immunogenicity.

Image 1: Improved endothelial cell adhesion in BMGs as compared to Nitinol, a common material for stents.

Stents can be inserted within the body to open clogged or restricted blood vessels such as arteries or the aorta. Stents are typically made of metal. Stents are typically deployed in two ways: either inflated with a balloon catheter through a procedure known as balloon angioplasty or through the use of a self-expanding stent where no balloon is required. Self-expanding stents are advantageous as they can be easier deployed around bends in arteries or the aorta. However, some current problems with stents are the need for patients to take antiplatelet agents to prevent clotting around the vessel and blockage/occlusion⁵. Due to the reduced foreign body response seen with BMGs, it is possible that BMGs may mitigate some of the current problems with stent immunogenicity and vessel blockage/occlusion.

Image 2: Left – Balloon expandable stent. Right – self-expandable stent. These are two common methods of deploying stents in humans, using either a shape memory alloy like nitinol that can be self-expanding, or a metal stent that can be inflated using a balloon.

Thus, BMGs may make good biomaterial candidates for fetal stents. Fetal stenting has been performed with some success in clinical trials. Fetal atrial septal stenting with traditional metal-based stent materials resulted in an improved outcome over no treatment². Fetuses were treated for hypoplastic left heart syndrome. The treatment was only successful in only two of four treated fetuses, which, although an improvement over the current lack of treatments, is not ideal. The two fetuses with unsuccessful treatments developed stenosis of their stents in utero and died after birth. The four untreated fetuses all died after birth.

Image 3: Left – illustration of a healthy aorta. Right – illustration of a restricted aorta that might benefit from the use of a stent.

BMGs may reduce the rate of stent stenosis due to their reduced foreign body response. Therefore, they may represent an important improvement for fetal stent technology.

Future work should be done in the study of BMGs for stenting. First, work should be done in model organisms, such as sheep or pigs. Work in a large-animal model may be easier than a small animal rodent model due to the technical difficulties of delivering a stent in utero. Stenosis of stents composed of nitinol and BMG in treated animals should be compared. The efficacy of stent treatment in reducing infant mortality and/or in utero demise should also be evaluated. Eventually, a clinical trial evaluating these factors should be performed. Hopefully, stents composed of BMG could be used in utero to reduce fetal and neonatal demise.

References:

Ayomiposi Loye. Bulk metallic glasses for biomedical applications. In class lecture.

Charturvedi, R.R., et. al. Fetal stenting of the atrial septum: technique and initial results in cardiac lesions with left atrial hypertension. Int J Cardiol. (2013). 168(3):2029-36.

Kumar, G.P., et. al. Deployment of a bulk metallic glass-based self-expandable stent in a patient-specific descending aorta. ACS Biomater. Sci. Eng. (2016). 2(11): 1951-1958.

Meagher, P., et. al. Bulk metallic glasses for implantable medical devices and surgical tools. Advanced Materials. (2016) 28:27.

“What is a stent?”. American Heart Association.

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

In vitro cultivation of embryos increases their exposure to reactive oxygen species (ROS). This increased exposure can lead to oxidative stress and apoptosis. Melatonin, when added to embryo culture, has been shown to convey a protective effect, resulting in fewer embryo deaths and increased development and hatching rates.

Image 1: Photo of 2-cell embryos in culture.

During development, mammalian embryos are surrounded by the zona pellucida, a glycoprotein coat designed to protect the embryo and prevent early implantation. However, the zona pellucida is quite porous and can be penetrated by macromolecules such as antibodies, enzymes, and even small viruses. As the embryo develops, at the blastocyst stage, it bursts through the zona pellucida and hatches. Therefore, hatching at the appropriate developmental stage is seen as a sign of a healthy embryo that would be ready to implant into the uterine wall if it were in vivo. Thus, improving hatching rates within culture likely correlates with improving embryo health, which could be helpful if trying to, for example, improve implantation rates of healthy embryos within a context like in vitro fertilization (IVF).

Image 2: An SEM image of the outer surface of the zona pellucida. Reproduced from [2].

The authors of the study “Effects of two types of melatonin-loaded nanocapsules with distinct supramolecular structures: polymeric (NC) and lipid-core nanocapsules (LNC) on bovine embryo culture model” delivered melatonin within embryo culture through their nanocapsules to attempt to improve embryo development and hatching.

Reactive oxygen species, through interactions with DNA, proteins, and lipids in the developing embryos can cause alterations to the mitochondria of developing embryos, arrest of development, and reduce the likelihood of embryonic development to the blastocyst stage and subsequent hatching from the zona pellucida [1]. Melatonin has been shown to reduce the formation and effects of harmful free-radicals within embryos [1]. However, melatonin is only slightly soluble in an aqueous solution, like an embryo culture medium [1], reducing its half-life and bioavailability.

One method to overcome delivery challenges, especially those associated with poorly soluble, hydrophobic and/or low stability drugs it to encapsulate them into nanoparticles or nanomaterials.

The authors of the paper therefore encapsulated melatonin into both polymeric and lipid-core nanocapsules to try to overcome this delivery challenge. The study’s polymeric nanocapsules contain a polymeric film surrounding a liquid core and are composed of capric/caprylic triglycerides. The lipid-core nanocapsules contain a mixture of sorbitan monostearate, capric/caprylic triglycerides, and poly(ε-caprolactone) and are stabilized by micelles. The sorbitan monostearate is within the lipid core and interacts with the melatonin loaded into the nanocapsule. As a result, the lipid-core nanocapsule had significantly (40x) more loading of drug than the polymeric nanocapsule.

Image 3: (Left): chemical structure of poly(ε-caprolactone) and (Right): chemical structure of capric/caprylic triglyceride.

The addition of melatonin significantly reduced the presence of ROS in 8 cell embryos (Image 2). The addition of melatonin-loaded lipid-core nanocapsules further reduced the presence of ROS. Melatonin-treatment also significantly improved hatching rates of embryos. This effect was slightly more pronounced for melatonin-loaded lipid-core nanocapsule treatment than melatonin alone.

Image 4: The presence of ROS in 8 cell embryos. Treatment with melatonin reduces the presence of ROS. Reproduced from citation [1].

Therefore, the addition of lipid-core nanocapsules represents an improvement over unmodified embryo culture (no melatonin) and embryo culture with the addition of free melatonin. Although it is unclear if the improvement in hatching rates would make a significant difference in an IVF setting or improve reimplantation rates, it seems probable that this could make a difference. Therefore, overall, this study seems like a success for its proposed application. To make this clinically translatable, however, more safety data would need to be presented (where does cell death occur due to dosing of the therapeutic?) and reimplantion studies, where treated embryos are reimplanted into surrogate mothers, should also be performed. This would give some evidence that the nanocapsule treatment is safe, at least within the model bovine system the study uses.

Furthermore, some rationale for the use of capric/caprylic triglycerides and poly(ε-caprolactone) would be helpful. Is there some sort of property to these polymers that makes them especially attractive for use in an embryo culture system? (i.e. do they interact with the zona pellucida in some manner, do they have a particularly attractive biocompatibility/safety profile, which may be especially important when dealing with an embryo, or do they have a degradation/release profile for melatonin that is especially applicable here?). Many FDA approved therapies involving nanoparticles/nanomaterials/microparticles use a poly(lactic-co-glycolic acid) (PLGA) or a poly(ethylene glycol) (PEG) based system due to their favorable biocompatibility profiles. As such, polymeric nanomaterial based therapies incorporating PLGA and/or PEG have become very commonplace, so some rationale for the choice of very different polymer systems would be interesting.

(Application of week’s lecture to study) Another interesting direction for this study to take would be to investigate bio-active polymer systems for delivery of melatonin.  As discussed in class, there are approximately three generations of nanoparticle/nanomaterials for delivery. The first generation, which this study falls into, uses a biocompatible polymer system that is developed into a particular shape like a sphere or a rod. A drug is typically encapsulated inside of the polymer. The second generation of particles have surface modifications to improve delivery. This may come in the form of a PEGylated particle to give the nanomaterial/nanoparticle a “stealth” factor that can reduce bioelimination and allow the particle to stay in circulation longer within the body. Or, it may come in the form of conjugating an antibody to the surface of the particle that gives the particle improved targeting/retention within a particular tissue type through preferentially interacting with a particular receptor. This could also come in the form of placing a ligand on the surface which allows the particle to bind to a particular tissue-type or receptor to a certain cell-type. The third emergent generation of particles are ones that interact with and respond to their environments. These particles are able to act upon biological cues and may only release their cargo in certain environments, thus improving delivery to a particular type of tissue or cell type, i.e. to a tumor. This study could therefore try to investigate a way to make a particle that releases once it interacts with the spongy, porous surface of the zona pellucida. As it is being taken up into the cell, it could specifically release its cargo. If the particle has a slow enough degradation rate, this could result in less melatonin being passively released to the media and depending upon diffusion to be taken up into an embryo, and more active release into the embryo. This could lead to lower doses being necessary and help to reduce any potential toxicity induced by over-treatment of melatonin.

Citations:

1. Komninou, et. al. Effects of two types of melatonin-loaded nanocapsules with distinct supramolecular structures: polymeric (NC) and lipid-core nanocapsules (LNC) on bovine embryo culture model. PLOS One (2016).
2. Familiari, et. al. Structural changes of the zona pellucida during fertilization and embryo development. Front Biosci (2008). 1;13:6730-6751.

This is my class blog for BENG 434: Biomaterials!

For weekly posts, please go to the posts section of the website!!!

This blog is focused on how biomaterials can be used in therapies for developing humans, namely embryos and fetuses, with maybe some therapies for neonates included. A variety of biomaterials have shown promise in treating a plethora of human diseases from brain cancer to hip implants to safe in vivo gene editing. However, due to some of the unique challenges involving fetal and embryonic therapies, research here has lagged behind adult and pediatric research. My blog hopes to highlight biomaterials being used to treat patients before their birth.

Many diseases can impact development and some of this organ damage can cause lifelong problems. For example, in a disease like cystic fibrosis, by the time a child is born, they already have multi-system organ damage. From birth, children with cystic fibrosis can experience pancreatic insufficiency, lung damage, and microcolon, which can require surgical intervention, among other problems. Therefore, there is a strong rationale to intervene before birth to perhaps treat a disease before organ damage can occur. This could substantially reduce the disease burden at birth and potentially allow for a healthy child.

This blog hopes to expose people to some of the exciting fetal and embryonic therapies incorporating biomaterials that are being explored currently.