Neural Tissue Engineering

What is tissue engineering?

Applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function

Using natural and synthetic materials and cells

Goal is to mimc native tissue function

Why tissue engineering?

Artificial prosthese and mechanical devices save and improve lives but are prone to mechanical failure

Mechanical devices rarely integrate with host tissue and can trigger adverse tissue responses

Autologous grafting is effective but leaves significant donor site morbidity

What is a biomaterial?

A material intended to interface with biological systems to evaluate, treat, augment, or replace any tissue, organ, or function in the body

Tissue engineering paradigm

1. Cell isolation

2. Cell proliferation

3. Scaffold

4. Construct

5. Tissue generations

6. Transplantation

Translational Glycomatierals and Neural repair Laboratory

Brain ECM: stem cell maintenance and brain repair + progression of invasive brain tumors

Neuronal Networks

Structural Connectivity

Communication dynamics

Functional connectivity

What are key components of the ECM of the brain?

proteoglycans

Protein glycosylation

sulfated glycosaminoglyans attached to proteoglycans

Sulfaction code

essential for molecular recognition and multivalent growth factor binding and signaling

chondroitin sulfate proteoglycans in the brain ECM

TBI Spectrum

~223,000 TBI-related hospitalizations and 64,000 death in the US

Mild TBI

Children and Adolescents

Risk Factors: Learning and memory impairments

Moderate TBI

Amateur and professional athletes playing soccer, football and other contact sports

Older adults

Risk Factors: long-term learning, memory and behavioral dysfunction

Severe TBI

Closed-head or penetrating head trauma resulting from MVC, GSW, blast related injuries

Risk factors: permanent paralysis, significant life-long moter and sensory dysfunction, death

Pathophysiology of severe TBI

Primary Injury: Severe/penetrating brain damge

Secondary Injury: Edema, BBB Breach, Membrane Permeability, Excitotoxiity, Inflammation, Cell Death, Significant Volume Loss

Controlled cortical impact injury

How they induce mouse tbi

eCS Matrix implants

enhance angiogenesis ad regional cerebral blood flow

The reach and grasp circuit

Volumetric mapping of the reach-to-grasp function using Arc (Activity-related cytoskeleton-associated protein)

CCI-Suction ablation (SA) TBI model

CCI followed by Suction ablation, replaced with neurodegenerative disk and brain glue

sTBI causes

ECM and glycoaminoglycan remodeling

Steps to administering brain glue

1. brain-mimetic eCS matrix impantation

2. recruitment of endogenous NSCs and neurotrophic factors

3. ECM and Vascular Repair

4. Functional recovery

What can reduce the use of animals in research?

New Approach Methodologies (NAMs)

• Like lung-on-a-chip

3D Neuron On Chip

Neruon-on-Chip Device

Human iPSC - Prefrontal Cortex Neurons in Geltrex with 3D printed positive mold

Conclusions

1. Injury induces biphasic neuronal response and the temporal release of inflammatory cytokines that are associated with tau release and neuronal function changes

2. Injury induces acute tau hyperphosphorylation and extracellular release

3. Injury induces long-term intracellular accumulation of AT8+, NFT+ tau