Test 4 Flashcards
Heart Pathway
Superior vena cava > right atrium > tricuspid valve > right ventricle > pulmonary valve > pulmonary artery > lungs > pulmonary veins > left atrium > mitral valve > left ventricle > aortic valve > aorta
Current Cardiac Regenerative Therapies
1) Multipotent stem cells
2) Pluripotent stem cells
3) Non-cell strategies
Cardiac Multipotent Stem Cells
Benefits: vascularization, immunoprivileged, improved cardiac function
Limitations: low cardiomyogenic potential, poor cell engraftment, limited proliferation potential
Cardiac Pluripotent Stem Cells
Benefits: high cardiomyogenic potential, good cell engraftment, unlimited proliferation
Limitations: slow, electrical instability, teratoma formation
Cardiac Non-Cell Strategies
- Stimulation of endogenous cardiac repair (growth factors)
- Direct reprogramming of fibroblasts into functional cardiomyocytes
- Tissue Engineering
- Exosomes derived from stem cells
Main Targets for Tissue Engineering in Heart
1) Blood vessels
2) Heart muscle - myocardium
3) Heart valves
4 Potential Cardiac TE Cells
1) Multipotent Adult Germline Stem Cells
2) Endothelial Progenitor Stem Cells
3) Very Small Embryonic-like Stem Cells
4) Endogenous Cardiac Stem Cells
FGF Biomolecule
-promotes proliferation and differentiation
of endothelial cells, smooth muscle cells, fibroblasts
Ang1, Ang2 Biomolecules
-stabilize blood vessels
PDGF, PDGFR Biomolecules
-recruit smooth muscle cells
VE-Cadherin, CD31 Biomolecule
-promote endothelial junction
Ehprin Biomolecule
-formation of veins and arteries
Plasminogen activator inhibit -1 Biomolecule
-stabilizes nearby vessels
TE Product Requirements: Biocompatibility
- Minimize inflammatory/immunological response
- Growth and healing capabilities
- Tissue strength, stiffness, cellularity, composition, should be simillar to native tissue
TE Product Requirements: Functionality
- Appropriate mechanical and hemodynamic functionality
- Must be durable
TE Product Requirements: Blood Vessels
-Must be able to withstand high-pressure fluid
dynamics, turbulence
TE Product Requirements: Valves
-Must be able to operate in a very dynamic and severe
environment
-Open and close at 1 Hz, exposed to
mechanical stresses, high-pressure fluid dynamics,
turbulence, etc
TE Product Requirements: Myocardium Patch
- High vascularity is critical
- Mechanical and electrical anisotropy
3 Cardiac Biomaterials
1) Biodegradable polymers (PGA)
2) Hydrogels (collagen, fibrin, alginate)
3) Decellularized tissue (collagen, elastin, fibronecting)
Valve Replacement
1) Valves have complex architecture
2) TEHVs require complex molds
3) Cellularize with myofibroblasts to obtain a
functional valve
4 Limitations of Mechanical valves
1) Infections
2) Thromboembolism
3) Cannot grow
4) No self-repair capability
Limitation of Tissue-Engineered Valves
-Calcification of tissue
3 Main Approaches to Biological Heart Valves
1) Cell seeding of biodegradable valve matrices
2) Cell seeding of decellularized allograft or xenograft valves
3) Promote repopulation and adaptive remodeling of decellularized allograft valves
Bypass Vascular Grafts
- Walls cellularized with smooth muscle cells
- Lumen cellularized with endothelial cells
- Typical use is for coronary bypass surgery
Arteries and Veins
-Arteries carry oxygenated blood from the heart to the body (expect the
pulmonary artery)
-Veins carry deoxygenated blood used by the body back to the heart (except the pulmonary vein)
Myocardium Patch
- Tissue-engineered cardiac patches can be used to treat acute myocardial infarction
- Augment contractile function
- Promote revascularization
Myocardial Infarction
- Heart Attack
- Decrease in oxygen supply to part of heart, causes necrosis
Cell-Based cardiac pump
- Hollow structure with cardiac cells
- Contract in sync with host heart
- Proposed for chronic heart failure
Emphysema
Gradual damage of lung tissue, specifically thinning and destruction of the alveoli or air sacs
Lung Transplant Patient Survival
-Survival depends on many factors, including the
pre-transplant diagnosis, recipient age, weight
and overall health, type of transplant, various
donor characteristics and other factors.
-90% of those who pass away from complications from their lung transplant do so because
of acute cellular rejections.
-In first year, bacterial infection leading cause of mortality
Three Eye Layers
1) Sclera - fibrous tunic
2) Choroid - vascular tunic
3) Retina - nervous tunic
Retina
- Sensory layer, innermost
- Contains photoreceptors
- Fovea centralis (macula lutae): center of retina, sharpest vision
- Blind spot where optic nerve leaves the eye
Rods
- Ability to see grey tones
- Sensitive to light
- Excited in dim light
- Provide peripheral vision
- LOW RES
Cones
- Found in central areas
- Need bright light to be excited
- 3 types respond to either green, red, blue
Vitreous chamber
- Posterior segment
- Large chamber behind lens
- Filled with clear gel: vitreous humor
- Transmits light
- Supports back of lens
- Holds layers of retina in place
Anterior chamber
•Smaller chamber between lens and cornea
• Filled with aqueous humor
• Nourishes lens and cornea (90 minutes!)
• Focuses incoming light
• Held in place by ligaments attached to ciliary
body.
Choroid Coat
- Vascular, nutritive layer
- Contains melanin (prevents light from scattering inside the eye)
- Anterior portion contains ciliary body and iris
Ciliary body
- Processes that secrete aqueous humor
- Muscle changes shape of lens to adapt near/far vision
Iris
- Made of pigmented smooth muscle
- Controls size of the pupil by dilation and constriction
Sclera
- Fibrous tunic
- Dense white fibrous connective tissue
- Contains sclera, cornea, conjunctiva
Sclera
- White of the eye
- Gives eye shape
- Protects inside of eye
Cornea
- Transparent epithelium protects front of eye
- Where light enters
Conjunctiva
Clear mucous membrane that covers sclera
Lens
- Posterior to pupil and iris
- Avascular transparent structure
- Consists of crystallin protein arranged in layers
- Attaches to ciliary body by ligaments that fine tune focusing of light on retina
Eye Protection
- Eyebrows
- Eyelids
- Eyelashes
- Conjunctiva
- Meibomian glands (oily lubricant)
- Lacrimal apparatus (tears, antibodies and antibacterial agents)
Refraction
- Both cornea and lens refract light rays
- To focus light, lens must change shape
Myopia
- Nearsightedness
- Only close objects can be seen
- Requires concave (negative) lenses
- Light rays focused in front of retina
Hyperopia
- Farsightedness
- Only distant objects can be seen clearly
- Convex (positive) leens
- Light rays focused behind retina
Astigmatism
- Two focal planes
- Horizontal and vertical light rays have different focal points
Retinal Detachment
-As we age, shrinkage of the vitreous body (humor) may lead to a detachment of the
retina from the choroid
-A retinal detachment is considered a medical emergency and needs immediate repair
before vision loss becomes permanent
Macular Degeneration
- Loss of vision in the center of the visual field (the macula)
- Damage to retina
- Major cause for visual impairment in older adults
- Impossible to recognize faces
Cataracts
- Opaque defect in cornea or lens
- Caused by injury, medication, diabetes
Conjunctivitis
- Inflammation of the conjunctival membrane, covers part of anterior eye
- Caused most frequently by viral infections (pink eye) and allergy.
- Also result from bacterial infections and many other irritants
Glaucoma
- Blockage to aqueous humor flow
- Increase of pressure inside eye
- Can lead to degeneration of eye function
Diabetic retinopathy
- most common cause of vision loss among people with diabetes
- swelling of macula
Cornea Tissue Engineering
Cells: mucosal epithelial cells, limbal stem cells
Tissues: amniotic membrane
Lens Tissue Engineering
Currently, cataracts removed surgically and replaced with artificial intraocular lense
PCO
-Posterior capsule opacification
-lens epithelial cells remaining after cataract
surgery have grown on the capsule causing it to
become hazy and opaque
Retina Tissue Engineering
Cells: retinal pigment epithelium, ESC, iPSC
Biomaterial: thinner than 50 um, porous, biodegradable, correct Young’s modulus
Biomaterial Examples: PLGA, PLLA, PGS, PCL
Two Approaches for Bionic Eye
1) Artificial Silicon Retina - ASR
2) Multi-unit Artificial Retina Chipset
ASR
- Artificial Silicon Retina
- Microscopic silicon chip
- Contains solar cells called microphotodiodes
- Convert light energy from images into electrical impulses
- Powered solely by incident light
MARC
- Multi-unit Artificial retina chipset
- uses CCD camera input and laser beam to transmit image into chip present in retina
Neuroglia in PNS
Satellite cells:
- surround neuron cell bodies
- Regulate O2 and Co2 nutrient and neurotransmitter levels
Schwann cells:
- surround axons, myelination of axon
- Participate in repair process after injury
Neuroglia in CNS
Oligodendrocytes:
-myelinate CNS axxons
Astrocytes:
-Maintain blood-barrier
Microglia:
-remove cell waste
Ependymal cells:
- line ventricals/spinal cord
- make cerebrospinal fluid
Dendrites
Conduct impulses towards the cell body
Soma
Control center of neuron
Axon
- Conduct impulses away from cell body
- Only one axon per neuron
- Trigger zone: site where action potentials are generated
Sensory neurons
- afferent = conduct signals to CNS
- specialize to detect stimuli
Interneurons
- within CNS
- interconnect incoming sensory pathways to outgoing motor pathways
Motor neurons
-efferent = from CNS to muscles/effectors
Myelination in CNS
- By oligodendrocytes (myelinate multiple axons)
- Myelin sheath: insulating layer around a nerve fiber
- Newer layers of myelin must be pushed under the older ones
Myelination in PNS
- By Schwann cell (myelinate only one axon)
- Assists in nerve fiber regeneration
White Matter
- Aggregation of myelinated axons from many neurons
- Brain and spinal cord
Grey Matter
- Lacks myelin
- Formed from neuronal cell bodies and dendrites
PNS Division
- Somatic
- Autonomic
- Enteric
Cranial Nerves
- On: olfactory
- Old: optic
- Olympus: oculomotor
- Towering: trochlear
- Top: trigeminal
- A: abducens
- Fin: facial
- And: auditory
- German: glossopharyngeal
- Viewed: vagus
- Some: skeletal/accessory
- Hop” hypoglossal
Spinal Nerves (PNS)
-31 pairs of left-right spinal nerves
Rate of nerve signal travel depends on 2 factors
1) Fiber diameter
2) Presence or absence of myelin
Graded (Local) potential
- Used for short-distance communication only
- Do not travel down axon
- Depolarize the cell
Action potential
- Allow for communication over long distances within the body
- Requires threshold stimulus to fire
- Trigger zone is where action potential is generated
Resting membrane potential
- Created using ion gradients and a variety of ion channels
- Creates net negative charge inside cell
- 70 mV
Action Potential Graph
1) Local potential rises: Na+ ion arrive at axon hillock, depolarizing membrane
2) Threshold: potential reaches -55 mV, voltage-gated Na+ channels open
3) Neuron fires: membrane depolarizes, producing a spike as it passes past 0 mV, K+ gates slowly open
4) Peak: usually around +35 mVV
5) Repolarization K+ leaves neuron to drop membrane back to RMP
6) Hyperpolarization: K+ gates stay open long enough to drop 1-2 mV below RMP
7) Return to RMP
Local Potentials vs Action Potentials
Local Potential: reversible, decremental, graded
Action Potential: irreversible, nondecremental, not graded
Synaptic Transmission
- action potential causes voltage-gated Ca 2+ channel to open in synaptic end bulb
- Causes a release of neurotransmitter across synaptic cleft to bind to postsynaptic ligand-gated channels
Regeneration of PNS Nerve Fiber
Can occur if:
- neuron soma is intact
- some neurolemma of Schwann cell remains
- Nerve growth factors
Steps of PNS Nerve Fiber Regeneration
1) Fiber is cut: macrophages clean up debris
2) Degeneration of schwann cell and axon
3) Regeneration: form regeneration tube, require NGFs
4) Regenerated fiber: fiber contacts target, soma shrinks to its original size
Engineered Nervous Tissue Cells: Schwann Cells
- Autologous Schwann Cells difficult to obtain in large numbers
- Allogeneic Schwann Cells involved in immunological rejections
Engineered Nervous Tissue Cells: Neural Crest Related Precursors
– From skin
– Differentiate into neurons and Schwann cells
Engineered Nervous Tissue Cells: Embryonic Stem cells
-Grown in spheroid
Engineered Nervous Tissue Cells: BMSCs, ASCs, iPS
-Differentiate into Schwann Cells
Engineered Nervous Tissue Biomaterials: Decellularized
– Autologous non-neural
– Allogeneic neural / non-neural
– Xenogeneic neural / non-neural
Engineered Nervous Tissue Biomaterials: Naturally derived polymers
– ECM proteins: collagen, laminin, fibrin, fibronectin, hyaluronan
– Polysaccharides: chitosan, alginate, agarose
– Proteins: silk, keratin
– FDA approved: NeuroGen
– CFDA (China’s FDA) approved: Chitosan based TENG
Engineered Nervous Tissue Biomaterials: Biodegradable Synthetic polymers
– poly(phospoesters), polyurethanes, electrically conducting polymers
– FDA / CE (European) commerically available:
• Neurotube: PGA
• Neurolac: PLC
Engineered Nervous Tissue Biological Factors: Growth Factors
– Nerve Growth Factor (NGF)
– Brain-Derived Neurotrophic Factor (BDNF)
– Neurotrophin-3 (NT-3)
– Glial Derived Neurotrophic Factor (GDNF)
– Ciliary Neurotrophic Factor (CNTF)
– Fibroblast Growth Factors (FGF)
Engineered Nervous Tissue Biological Factors: Growth Factors Release
– Adsorption of growth factors into scaffold during fabrication
– Entrapment of growth factor-loaded microspheres into scaffold
– Immobilization of factors onto scaffold
– Installation of osmotic mini-pump or injection device
– Gene Therapy
Engineered Nervous Tissue Electrical Factors: Electrical charges
-Stimulate cellular differentiation
– Neurite extension
– polyaniline, polypyrrole, polythiophene, and polyacetylene
– Graphene
Tay-Sachs Diseasee
- Degenerative disorder of the Myelin Sheath
- Hereditary disorder of infants of Eastern European Jewish ancestry
- Abnormal accumulation of glycolipid GM2 in myelin sheath disrupts conduction of nerve signals
Multiple Sclerosis
- Degenerative disorder of the Myelin Sheath
- Oligodendrocytes & myelin sheaths in the CNS deteriorate
- Myelin replaced by hardened scar tissue
- “Immue-mediated”
Amyotrophic Lateral Sclerosis
- Neruodegenerative Disease
- Nerve cells break down, which reduces functionality in the muscles they supply
Alzheimer’s Disease
-Neurodegenerative Disease
-Memory loss for recent events, moody, combative, lose ability to talk, walk & eat
-Show deficiencies of ACh & NGF
-Neurofibrillay tangles (microtubules): insoluble
twisted fibers found inside the brain’s nerve
cells. Cannot transport nutrients
-Formation of β-amyloid protein from breakdown product of PMs
Parkinson Disease
- Degeneration of dopamine-releasing neurons
- Progressive loss of motor function beginning in 50s or 60s: No recovery
Tissue Engineering for Neurodegenerative Diseases
- Blood Brain barrier model
- Drug Toxicity/Disease Modeling
- Neurodegeneration Model
- Neuromuscular Junction Model
- 3D Printed Nervous System on a chip
Brain Tumors
Arise from:
- Meninges
- Metastasis from non-neuronal tumors in other organs
- Glial cells (mitotically active)
Spinal Cord Injury
1) Less/no sensation
2) Can’t sweat
3) Less body hair
4) Can’t cough (respiratory failure #1 cause of death among SCI patients)
Scaffold Design for Nerve Repair
- Nerve Guidance Conduit/Channel (NGC); cylindrical tube with empty lumen
-After implantation, neural scaffold should act as a substrate for adhesion,
proliferation, migration, and function of neural cells
Biodegradable glass
repair facial / median
nerve in sheep
ZnO ceramic
neural scaffold for PNS
regeneration
Carbon nanostructures (nanotubes, nanofibers, graphene)
used as guides
Al2O3 nanostructures:
biocompatibility with
neural cells
Natural Materials for nerve repair
-PGA,PLA,PLGA -processed into foams and seeded
with Schwann cells
- cross-linked PEG hydrogels + growth factors to mimic
the ECM are under development
Advanced Therapies for Nerve Repair
-PLGA- Collagen conduits filled with collagen
fibres showed 80mm nerve defects to be treated in dogs.
-Not well controlled because of handmade
fabrication techniques and no scale up possible.
Ink-Jet printing of polymers
- -Precise delivery of polymer solutions.
- 3D structures with desired thickness, dimensions, incorporation of biomolecules possible
Nanostructures are the anwer
yes they are