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BMS354 Tissue engineering > Part 4 > Flashcards

Part 4 Flashcards

1
Q

Biocompatability of TE construct

A
  1. biomaterials and scaffold immune response

2. cells- immune reponse

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2
Q

Biomaterial tissue interactions

A

1, effect of biomaterials on body

  • changes to wound healing
  • toxicity
  • infection
  • tumorigenity
  • embolism
  1. Effect of body on biomaterial
    - calcification
    - enzymatic degradation
    - abrasion
    - corrosion
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3
Q

Healing process

A

Inflammatory- proliferative- remodelling

outcome of wound response depends on tissue impacted

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4
Q

Foreign body reponse

A
  1. pro inflammatory- non specific serum protein absorption, immune cell infiltration, macrophage classical activation
  2. anti-inflammatory- macrophage alternative activation, macrophage fusion and fibrous encapsulation
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5
Q

Macrophage mediated phagocytosis

A
  1. recognition
  2. adhesion
  3. phagocytosis
  4. digestion
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6
Q

Giant macrophage engulfed

A
  1. recognition
  2. cell fusion/ adhesion
  3. engulfment and digestion
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7
Q

Extracellular degradation

A
  1. recognition
  2. cell fusion and adhesion
  3. ec degradation
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8
Q

How does the body responds?

A

Difficult to predict
depend on material
macrophages release of messengers- foreign body granulation- scar formation- PVDF optimal integration of implant- retained flexibility

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9
Q

Fibrous Encapsulation

A

Tissue response to implanted biomaterials
Abundant deposition of extracellular matrix
Isolation of biomaterial from the local tissue environment

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10
Q

Effects of Fibrous Encapsulation on TE device

A

Forms a Diffusion barrier

Stops Vascularization

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11
Q

Device-related infections

A 
Implant infections are relatively common
Initially localized to the implant site
Bacterial biofilm
Staphylococci
Clinical examples
Biofilm-resistant materials
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12
Q

Bacterial biofilms

A

Communities of bacteria grown on surfaces of abiotic materials and host tissues
The bacteria embed themselves in a matrix “EXTRACELLULAR POLYMERIC SUBSTANCE”
Ancient adaptation
Coordinated behaviour
Enhanced survival at the population level

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13
Q

Stages of biofilm development

A
  1. attachment
  2. cell-cell adhesion
  3. proliferation
  4. maturation
  5. dispersion
  6. planktonic bacteria
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14
Q

Biofilm formation by Staphylococci

A

Staphylococci are particularly prone to creating biofilms
Multidrug-resistant methicillin-resistant -strains
S. aureus (MRSA)
S. epidermis (MRSE)

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15
Q

Examples of biofilm infections

A

Surgical repair materials (staples, sutures, mashes)

Orthopedic prosthetic joint infections

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16
Q

The race to the surface

A

Interactions with biomaterials, host cells/proteins
- floating bacteria and host cells/ proteins

Continual cell layer

  • no place for bacteria adhesion
  • floating bacteria
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17
Q

Cells do not interact directly with materials

A

A layer of protein (from growth media or plasma) adheres to the surface
Protein adsorption is affected by the surface properties of the material

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18
Q

Bacterial with bacteria repelling proteins

A

No reaction with bacterial binding proteins
Bacteria repelling proteins
Anti-adhesive coating- metal/ polymer surface

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19
Q

Toxicity and tumorigenity

Systemic and remote effects

A

By-products of physical/chemical wear can enter the blood stream and cause side effects in other parts of the body
Example: metal-on-metal hip replacements; releasing cobalt and chromium in the blood

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20
Q

Thromboembolic complications

A

Exposure of blood to an artificial material can cause thrombosis, embolization and consumption of platelets and plasma coagulation factors

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21
Q

Stent thrombosis

A

A rare but serious complication
Clinical consequences: death (20-48% cases) or myocardial infarction (60-70% cases)
Clinical approach to controlling thrombosis is the use of anticoagulant drugs

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22
Q

Tumours associated with implants

A

Orthopedic implant-related osteosarcoma
not enough cases to establish relationship
dont know if its a direct cause

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23
Q

Tumours associated with implants

A
  • Potential tumorogenicity of some biomaterials demonstrated in animal models
  • Neoplasms associated with therapeutic implants in humans are rare
  • Difficult to prove causal relationship in some cases
  • Mechanisms not clearly understood
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24
Q

Biocompatability of TE construct

A

Cells- immune response

  1. HUMORAL IMMUNITY: mediated by soluble antibodies produced by B lymphocytes
  2. CELLULAR IMMUNITY: mediated by T lymphocytes
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25
Q

Immunoisolation as a TE strategy for treatment of Type I Diabetes

A

Type I Diabetes – autoimmune disease
Loss of insulin-producing islet cells of the pancreas
“The Edmonton Protocol” – successful islet transplantation from cadavers
Need for immunosupression

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26
Q

Immunoisolation

A

Does not use immunosupression

Uses selectively permeable membranes

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27
Q

Different approaches for immunoisolation

A
  1. Macroencapsulation
  2. microencapsulation
  3. ultra-thin coating

Immunoisolating membranes size decreases
Diffusion of nutrients increases

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28
Q

Development of stem cell-derived islet replacement therapies

A

Use encapsulation
allow insulin secretion
stops immune system from destroying them
*lots of companies trying to make this a viable approach

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29
Q

Other approaches

A

Hypothyroidism
Genetically engineered cells to secrete neurtropic or angiogenic factors
Enhancing tumor specific cellular immunity

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30
Q

Food news

A

Vegetarian meat aimed t replacing the real thing

lab grown meat

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31
Q

Why engineering of food?

A

2006 69% increase to 2050
required increase in food calories 9.6 billion by 2050
Meat= most valuable livestock products
- all essential aa, bioavailable minerals and bitamins
- more people eating plant based

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32
Q

Agriculture has impact on environment 2010

A

70% water consumption
24% greenhouse gas emissions
37% earth landmarks

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33
Q

Current meat production is not sustainable

A

maturing complex organisms

using them for basic muscle and fat

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34
Q

Cultured meat concept

A

Growing animal parts for food production separate 1932 Churchill
not much else change

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35
Q

Meat production on spaceships

A

2002 benjaminson et al
culture skeletal muscle of fish
2013- lab grown burger , not good in terms of taste and texture NOT the point could be viable approach to lab grown food

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36
Q

Building blocks

A

Cells, biomaterials/ scaffolds, bioactive molecules, bioreactor
skeletal muscles

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37
Q

What do you need to know to culture meat

A
  1. Skeletal muscle structure- muscle cells- myofiber= grouped into muscle fibres, long dividing cells dont degenerate normally
  2. Satelite cells regenerate muscle upon injury
    - satelite cells= Pax 7/3 myf5
    - myoblasts= MyF5, Pax7/3
    - myotubes= MyoD, myogen
    - de novo fibres
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38
Q

Satelite cells, culture expand

A

Satelite cells - isolate+ culture - proliferative phase - differentiation phase

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39
Q

What other cell types fir cultured meat

A

Embryonic stem cells

source= some animals

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40
Q

Properties of biomaterials/ scaffolds for TE meat process

A

Edible, non toxic, non-allergenic biomaterial, supportive of full differentiation

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41
Q

Source of allernative cells for cultured meat production

A

Embryonic or induced pluirpotent stem cells
- unlimited proliferation
- need for differentiation optimisation
Alternative adult stem cells

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42
Q

Scaffolds and bioreactors for cultured meats

A
  1. Stem cells
  2. Animal free growth serum + myoblast proliferate + porous collagen microspheres
  3. Myoblasts form myotubes on collagen microspheres
    • bioreactors
  5. Myotubes differentiate into myofibres
  6. meat products
43
Q

Maturation of muscle tissue

A

Anchorage
mechanical stimulation
electrical stimulation

44
Q

Alternative fabrication strategies

A

Currently fabrication strategies- no hgihly organised structure
3D printing muscle tissue- high cell viability after the printing process

45
Q

Technical challenges of food TE

A

Lab grown meat gets rare funding boost
all research lies with conventional companies
- academic research lags behind
- copyright this protocol= difficult to build research
not completely transparent, protect

46
Q

Specifics of food TE

A

Scale
Efficacy
customer acceptancy

47
Q

Scale

A

Global meat production= 293 million tons/ years
1 bioreactor per 10 million
culture media

48
Q

Efficacy

A

Optimise scale up

optimize differentiation

49
Q

Customer acceptancy

A

no benefits so why would they do it?

would you eat a chicken if grown in a lab?

50
Q

Examples of companies producing tissue engineered meat

A
  • memphysis
  • FM
  • cleanmeat
  • Alephform
51
Q

Public sentiment is everything

A

Abraham lincoln 1858

  1. tastes and texture
  2. ethics and attitudes
52
Q

Benefits

A
  1. Healthier meat- adding vitamins, reduce fat, increase levels of conjugated inoleric acid
  2. create new products
  3. control over texture and flavour
53
Q

Method for making in vitro meat

A

Skeletal meat- isolate- muscle sc- essential cues- expand- essential cues niche for differentiation- maturate towards functional myofibers- essential cues 3D model system- culture in bioreactors= in vitro meat

54
Q

Other animal product substituted for TE

A

lab grown leather and fat

55
Q

Method for making TE leather

A
  1. take small sample
  2. isolate/ culture
  3. deposit cells in sheets and induce collagen
  4. layer sheets and continue culture
  5. fuse layers to form hide
  6. tan hide using fewer chemicals
  7. finish and dye
  8. fashion into finished designer items
56
Q

Regulatory framework: a historical perspective

A

‘Elixir Sulfanilamide’ incident (1937)
The Nuremberg Code (1946)
The Softenon (thalidomide) incident (1956)
The Declaration of Helsinki (1964)
A statement of ethical principles for medical research

57
Q

Conventional drug developement

A

Discovery
preclinical study
clinical trials 1,2,3
authorization

58
Q

Regulatory agencies

A

European Medicines Agency (EMA) [EU]
Food and Drug Administration (FDA) [USA]
Ministry of Health, Labour and Welfare [Japan]

59
Q

What are the different phases for

A
  1. healthy volunteers
  2. people with disease
  3. largest group- risk benefit ratio
60
Q

Legislation framework

A

Advanced therapies- have their own
guidelines- ATMP (advanced tissue medicincal product) advanced product that is either gene therapy, somatic cell therapy or TE product

61
Q

Concerns related to the use of cells

A 
Survival 
Interaction
Evolving functionality
Migration
- no standard
62
Q

Regulatory requirements

A

preclinical test- each TE method different
disease
The diversity and inherent properties of TE products require a case-by-case consideration
An overarching set of general considerations

63
Q

Overarching regulatory requirements

A
  1. The establishment of manufacturing process and controls
  2. Preclinical safety and efficacy studies in clinically relevant models
  3. Clinical trials on human participants
64
Q

Manufactoring and scalability

A

Product consistency
product stability
- functional= cells can change over time
producible process- people trained in same way

65
Q

Preclinical studies

A 
Testing in animal models 
expectations from proclincal data 
consider
- safety 
- functionality/engraftment 
-immune response
66
Q

Animal models

A

No default species
chosen based on scientific reasoning
NEED to understand limitations

67
Q

Phase 1 trial- Age related macular degradation

A

Embryonic stem cells use to device retinal pigment epithelium patch
quality control required for each step of manufacture- eg medium for cells see appearance and viability of cells

68
Q

Design preclincial studies for hESC-RPE derived cells

A

Main concern= tumors- dont expect too much proliferation but could end up with teratoma
ensure no remaining stem cells to give rise to tumours

69
Q

Model of choice for preclinical hESC-RPE derived cells

A

Mice
Demonstrate safety of teratoma
immunocomprimised and can ensure no rejection

70
Q

What did they use for clinical studies on eyes?

A

had to transplant 100s into human eye
Used pigs as same size eye
Similar

71
Q

Exploratory trial

A

Phase 1 not appropriate as not stages of TE method often include surgery
not appropriate to perform surgery on healthy volunteers
Use small study with small group of patients
primary concern= safety

72
Q

What does the exploratory trial do?

A

Evaluates feasibility of treatment in humans but may not be statistically significant

  • starting doses based on realistic possibility of therapeutic benefit
  • threshold dose- max dose not limited by potential toxicity
73
Q

Defining comparator

A

The currently accepted treatment – but this may not always be available or proven to work better
A device performance can be surgeon-dependant!- skills of surgeon dictate success

74
Q

Randomization

A

Each participant has the same chance of receiving treatment
standardized and independent of investigator
issues/solutions for TE products
blinding a trial impossible these pretty much

75
Q

Follow up/ patient care

A

Important for determining the efficacy
Either one person follows up all patients or all care givers should be appropriately trained
The trial should be designed to minimize the effect of the procedure on patient care

76
Q

Risk- benefit

A

Hospital Exemption
ATMPs exempted from the centralized marketing authorization procedure
Individual case studies

77
Q

Healthcare industry

A

translation of therapies to patient
user vs payer in healthcare industry-you as the consumer decide to buy product based on own opinions
in this case doctor decides this and patients doesnt directly pay
goverment biggest payer/inserter- heavy influence in politics

78
Q

Valley of death

A

The gap between discoveries in the lab and therapeutic leads that enter clinical trials

Academic research – early phases of therapeutic development
make breakthrough
Big Pharma- make investments= no guaranteed promise of success

79
Q

GO GO TE

A

Integrin dermal regeneration template
trancyte, dermograft (advanced tissue science)
- named for TE by this company but company went bankrupt- company founded in 87
- 40 patients praise from the doctors
- substitutes for skin wounds produced but no profit made

80
Q

Case study for skin replacement in burn victims

A

Large market- 100,000 per year
25,000 require skin replacement
- treatment for skin ulcers= potential profits in the billions
- got approval for dermograft for FDA 1991

81
Q

Why didnt it work

A

Unanticipated delays
price dropped dramatically
manufacture challenging

82
Q

How did they try to pay it off?

A

Fundraising occured builiding a facility which couldnt be paid off
overall
finiancial planning needs to be thorough
communication important
HIG risk investment

83
Q

What is the main aim?

A

How can product be developed and produced at an afforable price that still outweighs risk

84
Q

Bottleneck TE products

A 
Financial reward not garanteed 
case by case pathway
manufacture usually expensive 
complicated by biological nature of the products 
no unique business
85
Q

Risk in regenerative medicine revenues

A

906 reg medicine companies worldwide
13 billion raised
1028 clinical trials underway

86
Q

Spectrum of models

A

Modelling systems appropriately- physiological tolerance but experimentally not viable
increase complexity= decrease experimental tractability

87
Q

Drug attrition

A

Time from lab to market
~10 years
~2.6 billion
When clinical trial starts 5 drugs trialled from 5-1000 compound library

88
Q

What should models do

A

Accurately predict the outcome in patients

89
Q

Adverse reactions

A

4/1000 emergencies due to this
20% acute kidney
dying pipeline

90
Q

When are drugs withdrawn from market

A

When the risk outweight the benefits
VIOXX 2004
- major causes hepatoxicity (liver) and cardiotoxicity (heart)
- current model not sufficient- otherwise would predict outcome more accurately

91
Q

Details of model systems

A

In vivo= primary cells, transformed all lines, stem cells

In vivo= animal models- even primates dont read out human outcome

92
Q

Example of when model organism doesnt read out human outcome

A

PGN1412 immunotherapy leukemia
thought would revolutionise
6 patients died in phase 1 clinical trial caused by major organ killed
difference in aa between humans and primates

93
Q

ORGANOIDS

A

resembling an organ

  • organ on a chip
  • enough physiological relevence and reasonably experimentally tractable
94
Q

Stem cells prognosters aggregated into 3D ball and soluable cells

A

3D organoid produced through self organisation
huge field in stem cells atm
cells allowed to self organise to create stuctures- not in control of this
organs placed on chip to control this

95
Q

ON A CHIP

A

Device for culturing cells in continuously perfused micrometer sized chamber
incorporates minimal units that mimic tissue and organ level functions
microfabrication and microfluidics combine with cell culture methods

96
Q

Fabrication method

A
  • polymer mixed with crosslinking agent and poured onto mould
  • heated to solidify
  • placed on glass slide- see through microscope
  • puncture holes to cellular fluid through
    add dye for tracability
97
Q

Micro fluidics

A

Science underpinning small volume manipulation
fluid particles well organised
Follow laminar now normally
more control over fluid
means gradients can be created allowing case of analysis

98
Q

Typical components

A

Geometric confinement and patterning- control our cell placement/ interactions
environment control- movement
sensors tested to give physiological readouts

99
Q

Lung on a chip review

A

Human lungs gas exchange- large SA to vol ratio, alveolar epithelium in a singular layer- incontact with air and water
cyclical stretching is seen in aveolus and its epithelium#
Cells need mechanical stimualtion to mature properly

100
Q

How is aleveolar primary functional unit mimicked on a chip

A

Chip design

  • chip minature
  • multilayered- larger porous membrane upper layer
  • placed one side of porous membrane with alveolar epithelium
  • other side endothelium
  • air in top chamber and media representing blood in bottom layer- air liquid interspace achieved
  • can use different dyes to show different cell tyeps and cell viability
  • added air increased sufectant production
101
Q

How do they mimic cyclincal stretching

A

Using vaccum attached to outer chambers

102
Q

Modelling pulmonary inflammation

A 
Caused by pathogens, toxins or allegens 
pneuomia (acute) asthma (chronic)
- cytokines released by epithelium 
- TNF-a
- activation of endothelium- ICAM1
- leukocytes infiltrate the alveoli
103
Q

How would you modify the on the chip system for pulmonary inflammation?

A

TNF-a used to stimulate the cascade- add to endothelium

staining used to measures levels of ICAM1- expression upregulated in cells stimulated with TNFa

BMS354 Tissue engineering (5 decks)

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