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BMS 109 > TE2 > Flashcards

TE2 Flashcards

1
Q

Mortality difference from skin injuries?

A

1942 -1952: the mortality rate of the age group: 15-44 years with 60% skin injury was 100%

1998 – 2003: the mortality rate of the same age group was 41%

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2
Q

What was the first organ to be fabricated?

A

Skin

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3
Q

Three layers of the skin?

A

Epidermis (outer)
Dermis (middle)
Hypodermis (inner)

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4
Q

Erpidermis contents?

A 
Stratisfied layer of cells.Thin layer that protects body from environment. Waterproof, no blood vessels. 
Cells: 
Keratinocytes
Melanocytes
Merkel cells
langerhans
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5
Q

Thickness of skin?

A

Eyelids 0.5mm to hands feet 1.5mm

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6
Q

What are keratinocytes?

A

Secretes keratin. Adds stiffness and waterproof barrier In epidermis.

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7
Q

What are melanocytes?

A

melanin secretion which protects the skin from UV. In epidermis.

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8
Q

What are Merkel cells?

A

Are mechanoreceptors. Close to endosensory neurons to signal to. In epidermis

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9
Q

What are langerhan cells?

A

dendritic antigen presenting cells for immunity. In epidermis

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10
Q

Dermis contents?

A

contains blood vessels. hair follices, subcutaneous, sweat glands. Fibroblasts.

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11
Q

Fibroblasts secrete? Function?

A

Wound healing. Collagen, elastin, glycosaminoglycans.

Dermis.

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12
Q

Hypodermis characteristics?

A

internal insulator, protects organs, stores fat for energy source. (thermal insulator and shock absorber). Network of adipose cells and collagen.

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13
Q

Cell cycle in epidermis?

A

cells move up as they differentiate. The basal (deep layer) is the only place where the cells are mitotic/ proliferate,and they gradually rise ,until dead at the top layer. Skin epidermis constantly renewed.

The basal layer also makes EXCM proteins- secrete the basement membrane which separates the epidermis and dermis.

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14
Q

What separates the dermis and epidermis?

A

The basal layer also makes EXCM proteins- secrete the basement membrane which separates the epidermis and dermis.

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15
Q

Clinical need for skin replacement? (5)

A

Burns, chronic wounds, surgery, genetic disorders, acute trauma

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16
Q

If injury only epidermis?

A

Redness and minor pain (erythmia), no scarring, no need for surgical treatment e.g. sunburn, surface scrape

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17
Q

if superficial partial thickness wound?

A

epidermis and superficial dermis. Wet and weeping wound, red to pink then blisters. Very painful exposure to sensory nerve. Heals spontaneously

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18
Q

if partial thickness wound?

A

Greater dermal damage, fewer skin appendages remaining.

Moist, white, red, then pink wound. Scarring is more pronounced.

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19
Q

Full thickness wound?

A

complete destruction of epithelium. Dry, leathery rigid wound, no sponteous healing- needs treatment.

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20
Q

Treatment of major skin injuries?

A

An early exision of a dry scab (ESCHAR) remove denatured proteins, which triggers inflammation as it creates a microbe breeding ground.
Early wound closure and skin grafts inserted over. (of varying amounts of dermis and epidermis)

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21
Q

Types of skin grafts?

A

split thickness- epidermis + only part of dermis.

full thickness- epidermis and all of dermis

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22
Q

What is used to remove the graft? Methods?

A

Dermatome used- gold standard is autologous. If not enough skin is taken ncan mesh the skin so it spans the gap.

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23
Q

What is ‘graft take’

A

When the skin is cut off the blood supply is stopped, but when inserted into new skin area the skin needs to reconnect to the vascular beds below within 2-3 days to keep the cells alive.
revascularisation=’taking’

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24
Q

How is the wound bed prepared for a skin graft?

A

graft needs to adhere to the wound bed- the graft needs a thin layer of CT to ‘take’ not directly to the bone. Needs no infection, bleeding or movement.

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25
Q

When is there a need for skin allografts?

A

If not enough tissue available from the patient or geentic disease e.e.g use cadaveric skin for temporary prevention of fluid loss or wound contamination. Can be obtained from a non-profit skin banks.

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26
Q

Advantage and disadvantages for skin allografts?

A

+ Can be obtained from a non-profit skin banks.

  • Pathogen transmission
  • immune rejection
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27
Q

Advantages and disadvatages to skin autograft?

A
  • limited availability of skin grafts
  • Pain and scarring in the donor area
    -further pain for patient
    + No immune reaction, rejection etc
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28
Q

Ideal qualities for skin grafts?

A
  • Leave no scars
  • readily available off the shelf for acute injuries
  • no immune response
  • cover and protect the wound
  • enhance the healing
  • lessen the pain
29
Q

The most simple epidermal substitute?

A
  • Skin biopsy from patient
  • Isolate keratinocytes with enzyme treatment,
  • Expand in culture x5000.
  • colonies merge into cultured eputhelial sheets.
  • Added back to wound to form epidermal layer.
30
Q

varied ‘taking’ of keratinocyte skin grafts?

A

15-85% taking. If the keratinocytes differentiate too far that they don’t express integrins- wont adhere to dermis so they need the right differentiation stage.

31
Q

MySkin method?

A

Create a subconfluent population, in the hope to keep the keratinocytes in the right differentiation state. (autologous keratinocytes).
Synthetic silicone delivery membrane

32
Q

MySkin trial? Aim

A

To compare the rate of healing of diabetic neuropathic ulcers using cultured autologous keratinocytes delivered on chemically defined transfer discs (Myskin™) (active treatment) versus healing obtained with cell-free discs (placebo).

33
Q

MySkin trial? method

A

16 patients with a total of 21 ulcers resistant to conventional therapy received active or placebo treatments weekly for 6 weeks. All patients then received active treatments for a maximum of 12 treatments where required.

34
Q

MySkin trial? results

A

Of 21, 10 ulcers healed and 8 improved, with 2 failing to respond (one ulcer was lost due to autoamputation).
Only 12 eligable for analysis as completed the treatment. 5 in the placebo group and 7 in the active group. Of these, five ulcers healed completely and seven were reduced by more than 50%. Complete healing took a median of ten active applications.

35
Q

MySkin trial? conclusions

A

Conclusions: Repeated regular applications of the patient’s keratinocytes, delivered on the carrier dressing, initiated wound healing in ulcers resistant to conventional therapy, with 18 out of 21 ulcers responding. The healing observed did not appear attributable to patient recruitment or the cell-free carrier dressing but to the delivery of the cultured cells. Only kertinocytes- no other epidermal appendages.

Treatment of 80% chronic wounds but needs readding.

36
Q

How are epidermal substitutes applied?

A

sprayed on the wound

37
Q

Dermal substitues structure?

A

Acellular- facilitate wound heeling, These substitutes are colonised and vascualrised by underlaying cells.

38
Q

Integra Dermal regeneration template structure?

A

2 layers:
-The dermal layer e.g. bovine type I collagen, shark chondroitin-6-sulfate. Xenogenic. This allows ingrowth of cells from the wound bed.

  • Psudoepidermal layer on top (epidermal replacement)-silicone replacement to stop heat loss and fluid loss- temporary layer.
  • Collagen-chondroitin matrix
39
Q

Integra Dermal regeneration template life cycle?

A

Once the dermal substitute has ‘taken’ the silicone can be removed and replaced byb cells- epidermal substitute.
Cells infiltrate and vascularised and remodel scaffold.

40
Q

AlloDerm structure?

A

Preserved by freeze drying.

Decellurised human matrix with seeded cells in.

41
Q

Alloderm burn study aims?

A

As a dermal replacement around joints to prevent contractile and scar tissue formation here

42
Q

Alloderm burn study methods?

A

Patients received AlloDerm graft selectively on joint areas. 31 patients returned to measuring range of motion of joints, the quality of grafted skin condition criteria of skin elasticity, scar thickness, trans-epidermal water loss, melanin and erythema level was measured in a total of 11 patients among them.

43
Q

Alloderm burn study results?

A

43.6%) showed no limitations, (21.8%) showed limitations below 10%,(29.1%) showed limitations between 10 and 19% and (5.5%) showed limitations over 20%.
Scar tissue thickness reduced from mean 2.5mm to 1.8mm after alloDerm treatment areas. Erythema and water loss (halved) was also reduced.

44
Q

Steps for putting on dermal and epidermal composite skin substitues?

A

First apply the dermal substitute into the wound bed and wait for cells and vascularature to infiltrate then place the epidermal substitute on (cells- keratinocytes).

45
Q

What are composite skin substitutes?

A

A composite skin substitute (graftskin) for surgical wounds that include both epidermis and dermis-synthetic human skin equivalent.
Most are based on allogenate skin cells (e.g. keratinocyes) put into a dermal skin scaffold.
Provide off the shelf products.
Can have temporary bioactive dressings.

46
Q

composite dermalsubstitute skin example?

A

OrCel

47
Q

OrCel structure?

A

Composite skin substitute consisting of cultured allogenic fibroblasts and keratinocytes obtailed from neonatal foreskin.
Fibroblasts are seeded into a bovine type 1 collagen sponge and keratinocytes are placed on top.
Cytokines and growth factors from the product promote host cell migration and wound healing. This is important as these are allogenic cells so will be recognised by the immune system, so need to be replaced as a long term solution.
But no appendages, melanocytes, mechanosensitive cells.

48
Q

Issue with wound heeling of the skin?

A

Contractile skin layed down which is stiff with little elasticity making movement very difficult

49
Q

Use of AlloDerm?

A

Full-thickness skin burns, alloplastic breast reconstruction, abdominal wall reconstruction, rhinoplasty, building gums before dental work.

50
Q

Limitations of current skin replacement strategies?

A
  • Average wait time 3-12 weeks after biopsy is taken. (isolate and expand keratinocytes, assemble scaffold etc) Not off the shelf.
  • currently composite skin substitutes only use keratinocytes and fibroblasts no appendages, or melanocytes etc.
  • ‘clincial success but economic failure’
51
Q

LOREAL and TE?

A

Have a spin factory where they test products on left over tissue from plastic surgery, now turned to 3D printing skin.

52
Q

EB skin briefly describe what happened?

A

Dying syrian refugee boy with genetic skin condition Epidermolysis bullosa EB had over 70% of his skin severely injured was admitted to a spanish hospital in 2015. His skin was regenerated using a one off compassionate transgenic stem cell treatment.

53
Q

What is EB? Causes..?

A

Epidermolysis bullosa is a gentic disorder which affects 1/50,000 births. It causes spontaneous skin blistering due to a faulty protein that impedes the epidermis attatching to the basement membrane.

Painful, life threatening, sepsis risk and skin cancer

54
Q

How do the epithelial cells attatch to the basment membrane and dermis?

A

EC: intermediate filaments binds to plectrin and adhesion molecules. These bind to integrin which spans across the EC to the BM.
BM: integrin binds to laminin, which connects to anchoring fibrils, and then to the dermis below the BM.

55
Q

Keratinocytes make?

A

-integrins- binds epithelial cells to Basement membrane (and to laminin and then fibrils below to dermis)

56
Q

Mutation in syrian refugee boy?

A

Had epidermolysis bullosa. Laminin 332 mutation in the splice site within intron 14 of LAMB3.

  • the laminin couldn’t interact with integrins, so the epithelial cells would come apart from the BM, causing skin blistering
57
Q

Why syrian refugee Epidermolysis bullosa boy couldn’t have autologous skin cells used?

A

70% of skin was denuded.
Other areas blistered
Few areas were normal for taking autologous skin cells (keratinocytes)
All cells had the mutation in anyway.

58
Q

What gave the scientists the idea of treatment for syrian refugee EB? Why no developments since?

A

Epidermolysis bullosa- saw a publication 2006 nature- italian scientists had treated a small area of EB using stem cells, but was only a small area not whole body!

No developments as new stricter legistlation came in abut GMP (good manufacting practice)

59
Q

Options that had to be considered for methods of skin replacement in syrian refugee boy?

A

Epidermolysis Bullosa.
Repair or replace mutated gene? (replace skin cells)
Ex vivo( cell taken from patient and then put back) or in vivo (derive body)? Invivo
Vectors: viral or non viral? Viral

60
Q

Method of skin replacement in syrian refugee boy? (making of cells)

A
  1. Ex vivo- took biopsy, cultured (and then added back.)
    Keratinocytes cultured in feeder layers expanded.
  2. Retroviral vector expressing full length of LAMB3 cDNA Placed under viral promoter made. This didn’t correct the gene but just added correct version.
  3. Viral vector transfection with added correct gene into keratinocyes.
  4. pre-graft culture had NGS analysis- to see where the gene had inseted in genome (check not into oncogene/tumour supressor etc cancer problem, but if vital gene the cells will just die off
61
Q

Method of skin replacement in syrian refugee boy? (making of tissues)

A
  1. expand biopsy taken into epithelial sheets with transgenic keratinocytes.
  2. Cultured for 7 days in fibrin coated flasks (as opposed to cultured plastic which also tested)
  3. Transplanted onto patients skin in skin grafts.
  4. Follow ups
62
Q

follow ups for skin replacement in syrian refugee boy?

A

Immunofluorescent probes to test for tLAMB3.
Early none seen but after 4 months was present in those transduced epidermal cells.

Microscope of skin- no blisters seen. Immunoflurosecence for Laminin 332 after 4 months- .

Normal skin functionality and elasticity- not the same colour (no melanocytes)

Cancer checks (has GM cells- risk)

63
Q

EB syrian boy study- what next?

A

Not just using keratinocytes and fibroblasts, but add melanocytes, appendages (mechanoreceptors, hairs, sensory neurons) and immune cells.

Create both layers. Hard to create both epidermis(ectoderm) and dermis(mesoderm) from stem cells as different germ layers, v different signals for diferentiation needed.

64
Q

Bioengineering a 3D skin from iPS cells aim?

A

Aim: Induced pluripotent stem cells can be used to mimic the developmental patterning of skin and create the appendages.

65
Q

Bioengineering a 3D skin from iPS cells method?

A
  1. From the iPS cells, let them randomly differentiate into embryonic bodies.
  2. aggregate and implant these embyronic bodies under collagen in mice (CDB method: clustering depdent EB transplantation)
  3. See what develops under the bodies cues.
66
Q

Bioengineering a 3D skin from iPS cells results?

A
  • Hair grew: Colour of the donor not host. (wnt3b helped development of hair)
  • Also had additional skin structures like subcutaneous glans with epithelial connctions, fat, dermis, errector pilli muscles and nerve fibres.
  • Disadvantage- not very controlled, random differentiation.
67
Q

Other uses of Skin substitutes besides for wounds?

A
  • cosmetic testing (not on animals)
  • drug screening
  • cosmetic surgery
68
Q

Skin substitutes for disease study?

A

Psoriasis- can see chronic inflammatory skin disease causing red plaques on skin.
Keratinocyte hyperproliferation, immune cell infiltration and increased angiogenesis to skin.
See if any drugs can reduce this.
Or add differnt cytokines and see what causes the disease in vitro- then inhibit these etc.

BMS 109 (20 decks)

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