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BMS354 Tissue engineering > Part 1 > Flashcards

Part 1 Flashcards

1
Q

What is regenerative medicine?

A

Umbrella term for tissue engineering and cell therapy- incorporates research on self healing

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2
Q

Tissue engineering?

A

Uses biomaterials- design tissues and ECM/scaffold

Biological substitutes to restore, maintain or improve tissue functions

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3
Q

Cell therapy?

A

Take cells and manipulate and place back into patient, sometimes cells transplanted or need support

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4
Q

Major causes of organ failure

A

Injury
disease
ageing

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5
Q

Current treatments for organ failure

A
  • Surgical reconstruction- suture
    Limitations= surgical complications, morbidity at the donor sites

-mechanical devices- pace maker, hip replacement, dialysis machine
limitations= only mechanical support, do not grow with the tissues (children)

-transplantation- of organs or tissues
Limitations= immunosuppressants, transplantation rejection

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6
Q

What is the transplantation crisis?

A

Three people die each day in the UK because a suitable organ can not be found
Problem with supply verses demand

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7
Q

Problem with some donors

A

Died from encephalitis
NOT kidney failure
Both got same donor, got the same disease as the donor that died- didn’t screen for it before

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8
Q

New releases in medicine

A

NHS blood and transplant statement about inquest into deaths of 2 transplant recipients after kidney transplant from the same donor

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9
Q

New Solutions for treatments for treatments of organ failure
Why is it needed?

A
  • donor tissues and organs are in short supple

- we want to minimise immune system response

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10
Q

Historical perspective of tissue engineering

A

Made in 1987
1990s research accelerates and industry begins to emerge. Stem cells started- derivation of pluripotent embryonic stem cells

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11
Q

How do we build a tissue?

A

Cells in tissues and interlinked with ECM component
ECM- protein fibres- elastin, collagen, reticular and ground substitutes
Resident cells- mesenchymal cells, macrophages, adipocyte, fibroblast

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12
Q

What are the building blocks of tissue engineering?

A
  • cells
  • biomaterial scaffolds
  • Bioactive molecules
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13
Q

the first Tissue engineering cartilage

A

Plastic and reconstructive surgery

  • total reconstructive of ear is difficult
  • elevated the feasibility of growing tissue engineered cartilage in the shape of a human ear
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14
Q

How did they make a cartilage in the shape of a human ear?

A
  • A plaster mould of a ear of a 3 year old child was cast from an impression of he ear- used as a SCAFFFOLD for seeding cells
  • Cartilage CELLS from a calf were seeded onto scaffold
  • After 12 weeks the constructs were explanted sectioned and stained
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15
Q

What were the drawbacks of early years in TE

A
  • Skin coverage is missing
  • bovine chondrocytes were used
  • Scaffolds had to be reinforced for mechanical stability
  • Implications on the growth rate of the artificial ear
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16
Q

Misconceptions of human ear tissue engineering

A

Not a genetically engineered mouse with a human ear on its back
- caught lots of media attention
- false
not human ear on back but calf

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17
Q

3D bioprinting system to produce human scale

A

doctors 3D print of living body parts
Since then the field has moved on
show ears have been 3D printed and the structures are more relevant

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18
Q

Steps of Red medicine and tissue engineering

A

Step 1-Research 1-5 years= Laboratory testing to establish cellular biology, scaffold engineering and action to provide proof of contact
Step 2- Development 3-5 years= preclinical and clinical testing to determine safety efficacy and production
Step 3- regulatory 3-5 years= Regulatory review of results in small and large populations
Step 4- commercial= product registration

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19
Q

General principles in tissue organisation

A

You know how this happens in nature - regeneration
in vitro= make tissues from scratch, need to know how function and their organization
Structure and components existing in cells and ECM

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20
Q

Wound heeling facts

A

30 days after injury new skin formed
injure protective barrier to body
open wound- incidence- no visible scar

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21
Q

Phase 1 of wound heeling

A
  1. Inflammatory phase- primary objective is to stop bleeding
    - clear out dead cells
    - stop injection- phagocytosis
    - Redness, swelling, clotting
    1 dilate promoting connection
    2 increase viscosity allowing blood to flow more slowly near the site of clotting
    3 leukocytes/WBC phagocytes go inflamed tissue engulfing bacteria
    4 GF production results in fibroblasts
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22
Q

Phase 2 of wound heeling

A

proliferative phase

  • new tissue formation
  • disorganised tissue
  • focus moves to building new tissue to fill wound space, fibroblasts secrete collagen and cause angiogenesis
  • form granulation tissue which is a scaffold for tissue scar, soft so bleeds easily and is leaky
  • epithelization= regeneration, migration and organization of the epithelial cells at the wound edge
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23
Q

Phase 3 of wound heeling

A

Remodelling phase

  • remodelling new collective tissue
  • can take a while
  • collagen forms final scar tissue- may achieve 70/80% if normal tensile strength by 3 months
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24
Q

The healing process steps

A
  1. cut blood vessels bleed onto wound
  2. blood clot forms and leukocytes clean the wound
  3. blood vessels regenerate and granulation of tissue form
  4. epithelization regenerates and scar tissue forms
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25
Q

What does the outcome of injury depend on?

A
  1. how long
  2. type of tissue damaged
  3. amount of damage
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26
Q

Injury pathway

A
  1. mild, superficial injury= regeneration

2. severe injury= scar formation

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27
Q

Injury- cellular and vascular response

A
  1. Stimulus removed acute injury either:
    - Cell death, intact tissue framework- Regeneration restitution of normal structure
    - Cell death, framework of tissue damaged- repair scar formation
  2. Persistent tissue damage- fibrosis, tissue scar
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28
Q

What is acute injury

A

Intact matrix

Some loss of cell but will regenerate

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29
Q

Cells + matrix=

A

Scar

Deposition of connective tissue, proliferation of residual cells within

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30
Q

Pulmonary fibrosis

A

Results of infection in lungs
persistent
connective tissue scar
lead to lung organ failure

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31
Q

Fibrous encapsulation

A

Hip replacement

  • body sees foreign object in the body it will try to protect by laying down collagen
  • deposit ECM- get fibrous encapsulation
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32
Q

Granulation tissue

A

formation of scar
soft so bleeds easily
new tissue forms 3/4 days post wound healing process and called this as looks granular

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33
Q

Sources of cells

A
  1. autologous- patients own cells
  2. allogenic- cells from same species
  3. xenogeneic- different species
  4. syngeneic or isogenic- genetically isolated
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34
Q

What are autologous cells?

A

Tissue matching not required
no graft and host response
engraftment faster
Disease transmission not needed

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35
Q

What are allogenic cells?

A

Tissue matching required
host response needed
slower engraftment
Disease transmission possible

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36
Q

Cell types for tissue engineering

A

differentiated mature cells
mixture of differentiated cells
stem cells

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37
Q

Advantages of stem cells

A

Adult= multipotent, derive different cell types, get from patient
Embryonic= kept in culture for long periods
induced pluripotent stem cells= halogenate (differentiate into any cell types)

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38
Q

Disadvantages of stem cells

A

Adult= get from patient so depends on which patient is suffering from (genetic) hard to multiply
Embryonic and IPS= hard to get specific cell type as so many trivial, done in vitro

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39
Q

Differential cells

A 
Advantages 
- already functional 
Disadvantages 
- specific 
- already permanently differentiated 
- limited proliferation
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40
Q

How does adult stem cells work?

A

Biopsy from bone marrow or adult tissue

bone marrow derived mass

41
Q

How does embryonic cells work?

A

Egg and sperm
fertilisation
inner cell mass human biopsy
embryonic stem cell colony

42
Q

How does induced pluripotent stem cells work?

A

Adult somatic cells
lentiviral delivered + transcription factors
IPSC colony

43
Q

Example of differentiated cell types

A

Fibroblasts, keratinocytes, osteoblasts, endothelial cells, chondrocytes, preadipocytes, adipocytes

44
Q

Steps of culturing cells

A
  1. Growth medium contains necessary components- GF, nutrients, glucose
  2. laminar hood- Stops infection
  3. incubator- 37 degrees, not sealed as need gas exchange, stop evacuation using solution at bottom of incubator
45
Q

What is GMP

A

Good manufacturing practise
Ensures that medicinal products are consistently produced and controlled to the quality standards appropriate to their intended use

46
Q

Outcomes of GMP

A
  • control environment
  • everything documented
  • correct regulation
47
Q

Importance of studying cells- material interaction

A

In tissue engineering, cells are in contact with biomaterials
Use of materials in TE requires understanding of cells with materials
Most cells require attachment to a solid surface

48
Q

What does the ECM do?

A 
Provides structural support 
mechanical properties 
provides bioactive cues for cells 
scaffold for tissue renewal 
Act as the reservoir of GF and potentiates their actions
49
Q

Components of ECM

A

Collagen
glycosymonaglycons
Fibronectin

50
Q

Composition varies depending on tissues

A

Muscle= high tensile strength

  1. fibrous structural proteins- high tensile strength
  2. water hydrated gels- resilience
  3. adhesive glycoproteins - connect cells to ECM
51
Q

Structural proteins collagen

A

80/90% collagen 1,2,3
Polypeptides chains- twist helices, helical structures
High abundance of 3 aa- proline, hydroxyproline + glycine

52
Q

Proteoglycans

A

Composed of glycosaminoglycan chains linked to a specific protein core
very hydrophilic- form highly hydrated compressive gel
lubricated, resistant, found in joints

53
Q

Adhesive molecules

A

Fibronectin
Attach cell to ecm
Stress activated mechanical pathway
Cell adhesion to ECM/biomaterials

54
Q

What are integrins?

A

heterodimers made up of 19a + 8b subunits
Which subunits depends on what is recognised- composition determines specifically
extracellular, transmembrane and intracellular domain
most integrins recognise several ECM proteins

55
Q

What is conformational integrin activation

A

Inactive (bent)

  • active (extended)= intrinsic ligand, inside out- ligand in short cytoplasmic
  • active (clustered)= extrinsic ligand, outside in
56
Q

What does activated integrin activate

A

Activates the FA complex

  • talin kindlin
  • vinculin
  • a-actinin
  • FAK cos Src paxillin
  • ILK

The goes onto assembly of the actin cytoskeleton, activation of signalling pathway

57
Q

What is the major signalling pathways integrins use?

A

Focal adhesion kinase

  • integrins a and b
  • activates FAK
58
Q

Mechanotransduction

A

process by which external mechanical stimuli are transmitted into the nucleus
Modulate biomaterials to determine cell fates

Contains

  • ecm- Laminin fibres, collagen fibronectin
  • binds integrins
  • cytoskeleton meditated signals- cytoplasmic signal transduction
  • proliferation, differentiation, protein synthesis, attachment, migration, shape change
59
Q

What is EBSC?

A

derived retinal pigment epithelium patch in age related macular degeneration (replace missing cells from eye)

  • widely publicised
  • Phase 1 clinical trial
  • used biomaterials, synthetic basement membrane
60
Q

What are biomaterials?

A

Non viable materials used in a medical device intended to interact with biological systems
Used to develop scaffolds

61
Q

NIH definition of a biomaterial

A

National institute of health
Any substance or combination of substances synthetic or natural in origin, which can be used for any period of time, as a whole or part of a system which treats, augments or replaces tissues, organs or function of the body

62
Q

What is the historical perspective on Biomaterials

A

examine eyes of spit fighter plane pilots- had splinters in eyes from cockpit but did not produce an immune response

  • catalax= clouding of lens
  • could be used as a synthetic substance implanted in body without immune response
63
Q

What is biocompatibility of materials

A

Ability of materials to perform with an appropriate host response in a specific application

64
Q

Examples of appropriate host response

A

resistance to blood clotting
resistance to bacterial colonization
normal healing

65
Q

What is the evolution of biometerials?

A

1st generation- bio inertness- do not interact with body fluid or tissues
2nd generation- bioactivity
3rd generation- function tissue

66
Q

Bioglass

A

Started bioactivity

  • exceptional material as it binds with bone
  • when implanted into rats implants bound to bone and became as one, can be hit and wont come apart
  • don’t respond to mechanical ques of body= non functional
67
Q

What are polymers?

A

poly= many
meros= parts
- large molecules made up of chains or rings of linked monomeric links
mw- 200,000 Da

68
Q

Different structures of a polymer?

A

Linear
branched
network- different polymers linked together

69
Q

What is a car tire made up of?

A

Polymers linked together with sulfur and carbon black to give its colour

70
Q

Repeat units in polymers

A

Polyethene, polyproline, polyvinylchloride
repeated units
single bonds between C atoms

71
Q

Different types of polymers

A
  1. Homopolymer- Only one repeated functional group
  2. Block copolymer
  3. alternating copolymer
  4. graft copolymer
  5. random copolymer
72
Q

What is mixing of polymers?

A

Mixing not chemically mixed

73
Q

Hydrogels

A

Crosslinked polymer networks that are insoluble but swell in aqueous medicine
offer an environment that resembles the highly hydrated state of natural tissue

74
Q

Basic classes of biomaterials

A
  1. Natural- nature
  2. synthetic- made in lab
  3. semi-synthetic- combo
75
Q

Different types of natural polymers

A
  1. protein based natural polymer
    - collagen (25% of body weight), silk (high strength weight ratio), gelatin (formed from collagen), fibrin (blood clot component), elastin and soybean
  2. polysaccharide
    - chitosan- extraskeleton of nuclei
    - alginates- bacteria
    - hyaluronan- umbilical cord cartilage and skin
    - chondroitin sulfate- cartilage
76
Q

How do we obtain materials?

A
  1. Extraction
  2. Purification
  3. concentration
77
Q

What are synthetic polymers for scaffolds?

A
  • polylatic acid
  • polyglycolic acid
  • poly (lactic to glycolic acid)
78
Q

What are semi synthetic polymers?

A

Hybride molecules made by incorporation of biologically active macromolecules onto the backbone of synthetic polymers
example= PEG (polyethene glycol)

79
Q

Benefits and disadvantages of natural

A

+ biofunctional, IDG domain, cheap

- mechanical stability, sourcing them, variation in branches

80
Q

Benefits and disadvantages of Synthetic

A

+ industrial scale, tailored to suit needs

- don’t know if they work, immune response, toxicity, biodegradability

81
Q

Properties of biomaterials

A 
physical= strength, elasticity, architecture 
Chemical = degradability, reabsorption, water content 
Biological= interactions with cells, release of biological active signals
82
Q

Degradable materials

A

Broken down overtime
use materials initially as scaffold and over time get replaces with scaffold in TE can be positive
break covalent bond
should produce non toxic biproducts

83
Q

Resorbable materials

A

Total elimination of the initial foreign material and its biproducts
can be metabolised and secreted from the body, no trace
*products can be degradable and not reabsorbable

84
Q

Properties of examples of biomaterials

A
  1. internal sutures= hold tissue together until heals and then degrade
  2. soft contact lenses= transparent, refractive and hold shape
  3. artificial hip joints= strong, not much wear and tear
85
Q

Bulk properties of materials

A

Strength, toughness, fatigue and stability

86
Q

How can mechanical properties of biomaterials influence how the cells can behave?

A

Stem cells placed onto 3 different types of materials with different stiffness
least stiff= blood/brain
medium= muscle
most= bone

87
Q

Bulk verses surface properties

A

designing materials that fulfil bulk and surface

88
Q

Suface modifications

A
  1. chemically/ physically alternating atoms/ molecules in the existing surface
  2. overcoating the existing surface with material that have different composition
  3. creating surface textures and patterns
89
Q

Considerations for surface modifications

A

thin surface modification
delamination resistance
surface analysis

90
Q

What do cells interact with?

A

Do not interact directly with materials
a layer of protein adheres to the surface
protein absorption is affected by the surface properties of the material
Recognise protein and form indirect link

91
Q

Non fouling surfaces

A

Resistant to absorption of protein or adhesion of cells

PEG and zwitterionic polymers

92
Q

How to make non fouling surfaces adhere?

A

Cell adhesion occurs through receptors in the cell membrane
RGD domain in fibronectin and vitronectin
Cellular response can vary with surface density of RGD

93
Q

How to functionalise surfaces

A
  1. fibronectin= naturally occurring biometic biomaterials
    - activation of fibronectin binding
  2. adhesion complex- attach biomolecules to polymer surface
  3. immobilisation of integrin binding peptides or entire protein
  4. if resistant of cell binding- use RGD domains
  5. intracellular signalling modulation of events
94
Q

Micrometer- scale chemical patterns

A

a) a prepolymer is poured on a structural master
b) the prepolymer is cured and the stamp peeled off the master
c) the stamp is cut into smaller pieces
d) the stamp is linked by soaking in ink solution
e) ink printed by contacting an inked stamp with a suitable surface
f) patterned substrate is obtained

95
Q

Study for cell: material interaction

A

new blood vessel formation- angiogenesis
Endothelial cell growth is critical
EC increases in speed area are accompanied by increase of cell proliferation

96
Q

Hypothesis for cell: material interaction

A

cell shape per SA controls cell fate of endothelial cells

97
Q

Approach

A

micropatterning of fibronectin islands
cells assume the shape of the islands
Extent of cell spreading is determined whether a cell underwent proliferation or apoptosis

98
Q

Conclusions

A

Same GF- genes- same ECM- different geometry- different fates
cells can filter the same set of chemicals input to produce different functional output

BMS354 Tissue engineering (5 decks)

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