Self-Assembling Peptide Nanofiber Scaffolds for Neurological Tissue Regeneration

 

Sebastián Aguirre, Thomas Bates, and Martín Reyes

Authors

Sebastian Aguirre is a rising junior at Cypress Woods High School in Houston, Tx. He is very passionate about STEM, specifically chemistry and engineering. In the future he hopes to attend a prestigious university and major in chemical or biochemical engineering. In his free time he enjoys rock climbing, doing community service, and is the president of his school’s Spanish Club.

Thomas Bates is a rising junior at San Marcos High School in Texas. He is very passionate about Gene Manipulation, and in Phage Therapy. These fields interest him particularly because he has a twin sister with Down Syndrome. He would like to be able to help people like her and other people with genetic disorders. He also has a personal interest in Phage Therapy; when he was seven his father died of Necrotizing Fasciitis commonly known as “Flesh-eating Bacteria” an antibiotic resistant bacteria. In the future he would like to be able to overcome antibiotic resistance in a number of the newly arising resistant bacterium. At school he enjoys participating on the varsity swim and varsity men’s choir.

Martin Reyes is a rising junior at Colegio Bolivarin Cali, Colombia. He is intrigued about the future of medicine and humanity. He enjoys playing the piano, designing houses, teaching, and learning skills and concepts for the sake of his own interest. Martin aspires to empower others to explore their passions even when the resources are scarce. He believes that anyone can find the creativity needed to do something productive out of nothing.

Introduction

Nanotechnology is an emerging field of study that has come to prominence in the past fifty years. Scientists have learned to manipulate matter at the nanoscale to accomplish what humans previously thought was impossible. Despite having applications in many different fields, nanotechnology has had a particularly profound influence in medicine because of its regenerative properties. One of the most significant is the possibility of stimulating nervous tissue reconstruction and curing degenerative brain diseases such as Alzheimer’s or Frontotemporal Dementia. Research in nanotechnology has allowed humans to engineer self-assembling peptide nanofiber scaffolds(SAPNS), nanosized (1nm=10​-9​m) biomaterials that can induce the regrowth of brain tissue. Here we will discuss how SAPNS could be the future of nervous tissue activation and other applications as shown by recent success in neurological models.

The Nervous System

The nervous system is a complex organ system composed of the brain, spinal cord, and peripheral nerves; all of which are comprised of neurons (Figure1). Neurons have a cell body from which dendrites branch out, increasing the surface area for signal reception. Another, longer extrusion branching out of the body is the axon, which is a long rod-like structure that transmits electrical impulses from the nucleus of the cell to the axon terminals. At the axon terminals, impulses coming from the nucleus facilitate the exocytosis of signaling molecules called neurotransmitters, which are taken up by other neurons or the targeted cells (Reece et al., 2014, pgs. 1062-1063).The primary purpose of nervous tissue is to transmit information of bodily functions from the brain to the body’s extremities. As a result, the body suffers greatly when faced with nervous tissue degeneration.

Brain Injuries and Degeneration
Tissue degeneration, as a result of brain trauma constitutes one of the primary challenges of the field of neuroscience. Once there is tissue loss in essential functional areas of the brain regeneration is impossible. This is primarily due to the fact that after the brain experiences trauma, there is irregular blood flow in the forms of cellular infiltration, ischemia, and plasma protein extravasation. Followed by tissue scarring in the brain, traumatic brain injuries (TBIs) cause the disappearance of the structural base, which is vital
for brain tissue regeneration. The first step for repairing this tissue includes filling the cavity with structural support to promote neuron regrowth (Leung, Wang, & Wu, 2012). Neurological surgeries are the primary cause of brain tissue degeneration in the form of a TBI. The difficulty faced when healing TBIs is attributed to the complexity of the wounds. As a result, research on possible ways of attenuating may contribute to eventually finding an
ideal solution. Research on stem cells, the current leading method of relieving TBIs, has shown that stem cells can differentiate into nervous tissue and heal nervous degeneration. However, stem cells have the risk of uncontrollable proliferation leading to the formation of teratoma, a type of germ cell tumor (Politis & Lindvall, 2012). Because of this, neurologists commonly perform a coaptation, in which the ends of an injury are sutured, to mitigate TBIs.  Nonetheless, this method is not very convenient since it can only soothe small
wounds, for it decreases blood flow and inhibits axonal regeneration. Another more promising way of restoring axons is by performing a nerve allograft, in which an organism receives a nerve transplant from a donor of the same species. The procedure creates a template for axonal regrowth; however, the efficacy of the system is limited to the body’s rejection of the transplant and the probability of the newly introduced cells to become cancerous (Sedaghati & Seifalian, 2015). Recent developments have brought a new form of therapy in the form of SAPNS, which work by providing framework for the brain tissue to regenerate. SAPNS and RADA16-I SAPNS are made of repeats of hydrophilic and hydrophobic amino acids assembled into a beta sheet structure with nonpolar and polar surfaces. The beta sheets self-assemble to
form a 3D nanofiber scaffold with pores 5-200 nm in diameter. The purpose of this type of structure is to resemble the natural extracellular matrix of cells. This increases biocompatibility within mammalian bodies since peptides are nontoxic and biodegradable, aspects that aid in modulating the way the body reacts to unknown substances, known as the foreign body reaction. When a biomaterial is inserted into body tissue, it is essential to keep in mind the physical characteristics of the specific tissue. Cells exert forces and respond to mechanical cues; therefore, the biomaterial that is introduced must mimic the mechanical properties of the tissue. This will reduce the inflammatory response as well as prolong the durability and maximize the efficiency of the biomaterial. Because the brain has minimal stiffness in comparison to other organs, it is crucial to decrease the stiffness of the SAPNS by introducing them in the form of a hydrogel. An animal model in vivo was performed on a hamster that had a brain injury, in which a form of SAPNS called RADA16-I were introduced in the form of a 1% RADA16-I hydrogel. When modeled, the nanofibers self-assembled into scaffolds that provided the axons with the
structural integrity for their reconstruction, which synchronically stopped internal bleeding. The model proved that the RADA16-I was able to weave axons together across previously injured areas that would not have regenerated otherwise.

Discussions for Future Applications
Along with embryonic stem cells, SAPNS have been used to promote neural cell connections in stroke patients (Kim, 2005). During a stroke, the brain experiences diminished blood flow, resulting in brain trauma and cell death. Prompting new neural connections through the use of SAPNS could be a therapeutic application could attenuate the cell death that sometimes occurs in a stroke. Frontotemporal Dementia could also benefit from this method as this disease occurs when the lobes shrink due to damage in the frontal
or temporal parts of the brain, affecting a person’s behavior and mobility. Another possible implementation of this technology is in the treatment of Alzheimer’s disease, a brain degenerative disease prominent in over 5.4 million Americans. Alzheimer’s is caused by the degeneration of nervous tissue, mainly in the parietal lobe, which controls verbal abilities; frontal lobe, which is where intelligence, judgment, and behavior are developed; and temporal lobe, which is in charge of memory (Alzheimer’s Association, 2016). SAPNS provide nanocellular bridges for the axons to grow across, allowing the brain tissue to regenerate and prevent future tissue loss. A possible non-neurological use of SAPNS is in the area of diabetic wound healing. Chronic diabetic wounds often result in neuropathy or neural damage. One way to overcome this neuropathy in the future would be to introduce a hydrogel with carbon nanotubes and SAPNS to the injured area. The scaffolds would help with healing the nervous degradation that happens in chronic diabetic wounds. Carbon nanotubes are cylindrical carbon molecules often used to strengthen materials due to their stiff mechanical properties. A thicker
hydrogel would be needed in this situation to mimic more closely the stiffness of the surrounding tissue to prevent rejection from the body. Conclusion
Peptide nanofiber scaffolds have already contributed major developments in our ability to treat TBIs yet are not perfect as the healing can leave scars in its wake (Leung & Wang, 2012). SAPNS have been incorporated into treating TBIs as they restore structural integrity, thus stimulating axonal regrowth. The relevance of this technology lies far beyond TBIs and could be applied to cure Alzheimer’s, Frontotemporal Dementia, or stroke victims. In the future, neurological degenerative diseases or injuries could be obsolete due to the
restorative abilities gained from the progressive research on nanobiomaterials and their pertinence in the field of medicine. In turn, this might increase the longevity and quality of human life worldwide. Much about nanobiomaterials and their applications is still unknown, but one thing that we can be sure of is that it will change the face of medicine forever.

Aknowledgements
This work would not have been possible without the help of Professor Dr. Jagannath Padmanabhan, and teaching assistants Danielle Nicklas and Chia-Ying Lee. Thanks to Professor Padmanabhan for all the work he did in giving us the tools and inspiring us to bring this article to life. We are very grateful for all the help Danielle Nicklas and Chia-Ying Lee provided in supporting us through the editorial process. Lastly, a special thanks to Stanford University for providing us with this opportunity through the Stanford Pre-Collegiate Studies program.

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