14.1 Neural tissue engineering principles

Neural tissue engineering tackles the complex task of rebuilding the brain and nervous system. It's a tricky field, dealing with intricate networks of neurons and glial cells, plus the challenge of crossing the blood-brain barrier to deliver treatments.

Scientists use special materials like hydrogels and nanofibers to mimic the brain's structure. They also add growth factors and tweak signaling pathways to help neurons grow and connect. It's all about recreating the delicate balance of the nervous system.

Neural tissue structure and function

Cellular components and their roles

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• Neural tissue is composed of two main cell types: neurons and glial cells
  • Neurons are responsible for transmitting electrical and chemical signals
  • Glial cells provide support, protection, and maintenance for neurons
• Neurons consist of a cell body (soma), dendrites, and an axon
  • The soma contains the nucleus and organelles
  • Dendrites receive signals from other neurons
  • The axon conducts electrical impulses away from the soma to other neurons or effector cells
• Glial cells include astrocytes, oligodendrocytes, and microglia
  • Astrocytes provide structural support, regulate neurotransmitter levels, and maintain the blood-brain barrier
  • Oligodendrocytes produce myelin sheaths that insulate axons and enhance signal transmission
  • Microglia are the immune cells of the central nervous system, responsible for clearing debris and responding to injury or infection

Extracellular matrix and neurotransmitters

• The extracellular matrix (ECM) in neural tissue is composed of proteins, glycoproteins, and proteoglycans
  • ECM components provide structural support, regulate cell adhesion and migration, and influence cell differentiation and survival
  • Examples of ECM proteins include laminin, fibronectin, and collagen
• Neurotransmitters are chemical messengers released by neurons to transmit signals across synapses
  • The main neurotransmitters include glutamate, GABA, dopamine, serotonin, and acetylcholine
  • Each neurotransmitter has specific functions in neural communication and modulation
  • For example, glutamate is the primary excitatory neurotransmitter, while GABA is the main inhibitory neurotransmitter

Challenges in neural tissue engineering

Complexity of neural tissue structure and organization

• One of the main challenges in neural tissue engineering is the complex structure and organization of neural tissue, which is difficult to replicate in vitro
  • This includes the intricate network of neurons and glial cells, the specific ECM composition, and the precise spatial arrangement of cells and ECM components
  • Replicating the 3D architecture and connectivity of neural circuits is a significant challenge
• Neural tissue has limited regenerative capacity, particularly in the central nervous system
  • This is due to the presence of inhibitory factors and the formation of glial scars that hinder axonal regrowth and regeneration
  • Examples of inhibitory factors include Nogo, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgp)

Blood-brain barrier and delivery of therapeutic agents

• The blood-brain barrier poses a challenge for delivering therapeutic agents and biomaterials to the brain
  • It selectively restricts the passage of substances from the bloodstream to the neural tissue
  • This barrier is formed by tight junctions between endothelial cells, astrocyte endfeet, and pericytes
• Strategies to overcome the blood-brain barrier include:
  • Modifying the properties of therapeutic agents to enhance their permeability (e.g., using nanoparticles or lipid-based carriers)
  • Temporarily disrupting the blood-brain barrier using focused ultrasound or osmotic agents (e.g., mannitol)
  • Exploiting receptor-mediated transcytosis to transport molecules across the barrier (e.g., using transferrin or insulin receptors)

Biomaterials for neural regeneration

Hydrogels and electrospun nanofiber scaffolds

• Hydrogels are widely used as scaffolds for neural tissue engineering due to their biocompatibility, tunable mechanical properties, and ability to encapsulate cells and bioactive molecules
  • Hydrogels can be based on natural polymers (e.g., collagen, hyaluronic acid, and alginate) or synthetic polymers (e.g., polyethylene glycol and poly(lactic-co-glycolic acid))
  • They provide a 3D environment that supports cell adhesion, proliferation, and differentiation
• Electrospun nanofiber scaffolds mimic the fibrous structure of the native ECM and promote cell alignment and neurite outgrowth
  • These scaffolds are made from polymers like poly(lactic acid), poly(caprolactone), and their copolymers
  • The high surface area-to-volume ratio of nanofibers enhances cell-matrix interactions and facilitates the delivery of bioactive molecules

Conductive and ECM-derived biomaterials

• Conductive biomaterials, such as polypyrrole, polyaniline, and carbon nanotubes, can be incorporated into scaffolds to enhance electrical signaling and stimulate neural cell growth and differentiation
  • These materials can facilitate the transmission of electrical impulses and promote the formation of functional neural networks
  • Conductive scaffolds can also be used for electrical stimulation to guide axonal growth and regeneration
• Decellularized ECM-derived materials, obtained from neural tissue or other sources, provide a more biomimetic microenvironment for neural cell growth and differentiation
  • These materials retain native ECM components and bioactive factors that support neural cell adhesion, survival, and differentiation
  • Examples include decellularized brain or spinal cord ECM, which can be processed into hydrogels or scaffolds
• Self-assembling peptide hydrogels, composed of short peptide sequences that form nanofibrous networks, can be designed to mimic specific ECM properties and support neural cell growth and differentiation
  • These peptides can be functionalized with bioactive motifs (e.g., RGD or IKVAV) to promote cell adhesion and neurite outgrowth
  • The mechanical and biochemical properties of self-assembling peptide hydrogels can be tailored by modifying the peptide sequence or concentration

Growth factors in neural engineering

Neurotrophic factors and retinoic acid

• Neurotrophic factors, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF), promote neuronal survival, differentiation, and axonal growth
  • Incorporating these factors into scaffolds or delivering them locally can enhance neural tissue regeneration
  • For example, NGF promotes the survival and growth of sensory and sympathetic neurons, while BDNF supports the survival and differentiation of various neuronal populations
• Retinoic acid, a derivative of vitamin A, plays a crucial role in neural development and differentiation
  • It can be used to direct the differentiation of stem cells into specific neural lineages and promote axonal outgrowth
  • Retinoic acid signaling is involved in the patterning of the neural tube and the specification of motor neurons and interneurons

Developmental signaling pathways and matrix remodeling

• Wnt proteins are involved in various aspects of neural development, including cell fate determination, axon guidance, and synapse formation
  • Modulating Wnt signaling pathways can influence neural cell differentiation and regeneration
  • For example, Wnt3a promotes the proliferation and differentiation of neural stem cells, while Wnt5a regulates axon guidance and branching
• Sonic hedgehog (Shh) is a morphogen that regulates neural patterning and differentiation during development
  • Incorporating Shh or its agonists into neural tissue engineering strategies can promote the generation of specific neural cell types and guide axonal growth
  • Shh signaling is critical for the development of ventral neural tube structures, such as motor neurons and interneurons
• Notch signaling is involved in neural stem cell maintenance, cell fate determination, and neuronal differentiation
  • Manipulating Notch signaling can be used to control the balance between neural stem cell self-renewal and differentiation in engineered neural tissues
  • Inhibition of Notch signaling promotes neuronal differentiation, while activation of Notch signaling maintains neural stem cell populations
• Matrix metalloproteinases (MMPs) are enzymes that remodel the ECM and play important roles in neural development, plasticity, and regeneration
  • Regulating MMP activity in engineered neural tissues can influence cell migration, axonal growth, and synapse formation
  • For example, MMP-2 and MMP-9 are involved in the degradation of inhibitory ECM components, such as chondroitin sulfate proteoglycans, which facilitates axonal regeneration after injury