BME 201 Final

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What is cell therapy? How does it work?

Cell therapy encompasses the technologies that deal with replacing dysfunctional or damaged cells with fully functional and healthy new cells. Blood transfusion is an example in which blood from a healthy donor of the same blood type as the patient (healthy & functional blood cells) are introduced into the donor.

What are the advantages of peripheral blood stem cell transplantation as compared to bone marrow stem cell transplantation?

• Peripheral blood stem cell sourcing is less painful (no giant needles stuck into your bone)

• Faster recovery time for hematopoietic cells and the immune system (allogenic → from member of the same species)

• Faster recovery time for blood count (autologous → self)

• Some medical conditions prevent people from receiving bone marrow stem cell transplants but allow peripheral blood stem cell transplants

(T/F) Bone marrow stem cells can be collected from the peripheral blood stream.

True, bone marrow stem cells can be collected by chemically-induced migration of stem cells into the blood and then collection from the blood. 

(T/F) Stem cells are type of cells that can self-renew and differentiate into different cell lineages. Progenitor cells can also differentiate into different cell lineages. Thus, they can self-renew as well.

False. Progenitor cells have a limited number of divisions, they can only self renew up to a certain point.

Primary Cells

cells taken directly from a culture

Cell Lines

cells taken from a culture of a culture and beyond - not directly from the tissue

Stem cells can divide into…

2 stem cells or 2 progenitors cell or 1 stem cell and 1 progenitor cell

Asymmetric Division

Each daughter cell has a different fate. Most common one stem cell one progenitor.

Environmental asymmetry

Daughter cell determined by the environment

Divisional asymmetry

Internal asymmetry, fate of daughter cells is determined at time of division

Red marrow

• more prevalent in younger organisms

• turns to yellow with age

• stem cells for blood & platelets

Yellow marrow function

stores fat

Disadvantages of Peripheral blood stem cells

• lower concentration (10 blood donations from 10 people for one marrow transplant vs. one donation for bone marrow stem cells)

  • use growth factors to combat this (expensive)

• Fewer stem cells

Hematopoietic Stem Cells

• produce blood

• need VERY specific signal proteins

• need stromal cells to live/not differentiate

Stem Cell Therapy Challenges

immune rejection & cancer challenges

Osteoclast

Large multinuclear cell that breaks down bone tissue and helps remodel and heal damage to bones

Osteoblast

Bone forming cells, synthesize and secrete new bone matrix

Osteogenic cells

Give rise to Osteoblast & Osteoclasts

Respond to trauma, reform & remodel bone

Bioreactor

3D environment for rapid and orderly development of functional 3D tissue structures

Bioreactor Functions

1. Make in vitro environment similar to the body

2. Establish proper and uniform concentrations of cells within a 3D scaffold

3. Control culture conditions (temp, pH, osmolality, O2, nutrients, metabolites, growth factors)

4. Provide physiologically relevant physical signals (intersitial flow, stress, pressure, compression)

Formula for cell differentiation

(change in cell population over time) + (rate of cell differentiation)*(change in population from differentiation state) = (# of cells)*[rate of cell proliferation - rate of cell death]

Formula for cell growth

1. specific growth rate = ln(2) / (time of doubling)

   1. also applicable to decay rate and half life

2. (change in cell population over time) = (specific growth rate)*(number of cell in the population)

Half Life & Nuclei Amount Formulas

1. (Final Amount) / (Initial Amount) = e^[(-decay rate)*(time)] = decimal % remaining

2. Amount at time t = (initial amount)*e^[(decay rate)*t)]

Concentration Formulas

Higher dissociation constant → ________ concentration.

Higher

If the concentration is equal to the dissociation constant then ___% of the signals are bonded to their receptors.

50

Equilibrium for bound and unbound recepter-ligand formula

Dissociation constant for receiving receptors = ???????
[G]*[R] / [G:R]

Convection

Pressure differences → transport of molecules IN blood

Diffusion

concentration gradients → OUT blood into tissue

endothelial cell migration & proliferation

How does one prevent their implant from being destroyed by the immune system?

Make its pores too small for antigens and immune system components to go through but big enough for insulin and glucose

What does pore structure determine?

• Size

• Distribution

• Continuity of individual pores

Biodegradable implants are open devices meaning…

All molecules and cell transport can go through them

Toxic biomaterial

Tissue around biomaterial dies

Nontoxic reabsorbable biomaterial

Biomaterial is eventually replaced by the surrounding tissues

Nontoxic inactive biomaterial

A thin non-adherent fibrous capsule forms around the biomaterial

Nontoxic bioactive biomaterial

An interfacial bond forms between the biomaterial and the tissue connecting them

Stress formula

stress = force / cross sectional area

Strain formula

Strain = [(deformed length - original length)/(original length)] x 100%

Brittle

high young’s modulus, completely breaks (bone)

Ductile

tougher, low yield strength (tendon)

Stress vs. Strain graph gives you the…

Ultimate tensile strength, yield strength/stress, and fracture/failure point

Tensile biomechanical test

Stretch until failure

Flexure biomechanical test

Bend until failure

Nanoindentation biomechanical test

Use an atomic force microscope to map nanoscale stiffness

Cyclic fatigue biomechanical test

Inflict cyclic stress below the ultimate tensile strength and measure endurance

Theranostic

combination of therapeutic and diagnostic functions

Challenges to Cell Therapy

• Identifying usable cells for cell therapies

• Cells must “learn” to function with bodily tissue

• Immune rejection

• Cancer

What components does an MRI use?

Water, radio waves, magnets

How does a T1 MRI work?

p+ atoms line up with a magnetic field and then fall back down to a normal energy state releasing a photon equivalent to the change in energy state which can be measured

How does a T2 MRI work?

Spin of H2O - differences in brightness, brighter

X-Rays

Good for bones, cannot do soft tissue, shadow images, fractures

Roentgen

Measure of radiation quantity and effect on surrounding objects (radioactive exposure)

Curie

disintegrations per unit time (radioactive activity)

How would you get consistent drug level release within the body?

pH sensitive biodegradable pill with a pressure expansion through chemical reaction to stick out a “needle” to stick into intestine lining

CAR-T

Modified T-cells for cancer recognition and treatment

How long does bone marrow take to regenerate?

2-3 days

Allogenic

From a donor to a patient → some immune rejection

Human Leukocyte Antigens (HLA)

immune system genetic markers, chromosome 6

Artificial Skin Grafts

Transplant dermal fibroblasts

Pancreatic Beta-Islet Cell Therapy

Langerhans transplant, isolate islets from donor, inject with long needle, requires immunosurpressants, needs hollow fiber bioreactor

Cartilage

Chordrocyte transplantation, no direct blood supply

Serum is made of…

blood plasma without clotting factors (fibronectin)

Skeletal muscle

Long strong fibers, precursor myoblast fusion

Heart/Cardiac muscle

shorter, stronger fibers

Metals as a biomaterial

• high strength

• fracture resistance, elastic

• Electrically and thermally conductive

• Corrodes

Stent

metal mesh scaffold used to expand arteries, inserted with a balloon, lasts for 2-6 years

Materials for hip replacement

Titanium or cobalt-chrome

Thermoplastic

Linear or branched polymer, PGLA, degreaded through hydrolysis, can heat/melt/mold/recycle

Thermosetting

Crosslinked polymers, heat degrades

Poly-A tribisn

Pressure → liquidity, bioink

ECM is secreted by the ______ which require a vascular system lined with ______ cells.

Fibroblasts, endothelial

Endothelial cells control…

Passage of materials and white blood cells in the vascular system

Mechanoreceptors

Endothelial have, allows for development of blood vessels in regards to stress

Angiogenesis

Formation of new capillaries that sprout from existing small vessels, VEGF (vascular endothelial growth factor)

HIF-1

Hypoxia-inducible factor, low oxygen → VEGF

How does one suppress HLA genes?

Target Beta-2-microblobulin with silencing RNA using lentiviral vectors or CRISPR CAS-9

Islet cell transplant process

Collangenase enzymes into donor organ to isolate islets, purify, Ficoll to separate beta islets, xrays and ultrasounds to place catheter and insert the islet cells

Deep Cartilage Defects Treatment

Insert outside developed chondrocyte (produce cartilage)

Types of White Blood Cells

1. Neutrophils - phagocytose and destroy bacteria

2. Eosinophils - destroy large parasites and modulate allergic inflammatory response

3. Basophils - release histamine (allergic reaction)

4. Monocytes - become tissue macrophages, digest invading microorganism

5. Lymphocytes - B cells (make antibodies) T cells (kill infected cells)

Platelets

Cells circulating in blood that are part of primary hemostasis → blood clots

Albumin

made in liver, bonds small molecules for transport through blood, maintains osmotic pressure of blood

Globulins

• Alpha - thyroxine and retinol

• Beta - iron transporting (tranferrin)

• Gamma - antibodies

Skeletal muscle cells

large, muscle fibers

Heart muscle cells

orderly actin and myosin, striated

Smooth muscle cells

no striation, propel food, raising hair

Myoepithelials

no striation, in epithelial, from ectoderm, expel shit from glands, eye’s iris muscle

Osteoporosis

Rate of bone absorption > rate of bone formation

Osteocytes

have secreted bone tissue surrounding, regulate calcium

Bone-lining cells

along surface of adult bones, regulate calcium and phosphate into and out of the bone matrix

Hyperplasia

Cell replication → increasing number of cells keeping the same size

Hypertrophy

DNA synthesis without cytokinesis

more volume, bigger cells, same number

Cyclin-dependent kinases

Drive the cell cycle

S phase

DNA synthesis, 10-12 hours, half of cell cycle time

M phase

mitosis, chromosomes segregate, less than an hour, nuclear and cell division

Cytokines

small growth factors, chemically stable with long half lives

Chemokines

Small cytokines, induce cell migration

Secretion?????????? (4 of ln 12)