Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Blond McIndoe Research Foundation Queen Victoria Hospital

East Grinstead

West Sussex

Dr. Yella Martin

Postdoctoral Fellow

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Blond McIndoe Research Foundation

• Founded in 1961

• BMRF is an independent research institute

• We work closely with surgeons at the Burns unit at Queen Victoria

Hospital to identify/address clinical needs

• Translational unit with focus on:

– Skin

– Fat/adipose tissue

– Cornea

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Blond McIndoe Research Foundation

Tissue Regeneration and Repair

Tissue Engineering

Overview of Research Projects

Upcoming Projects

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Tissue Regeneration

What is the difference between repair and regeneration?

Repair is the adaptation to loss of tissue and leaves

behind scar tissue.

Regeneration restores the missing organ mass and

re-establishes structure and function.

Mason, et al. (2008)

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Skin

• Skin provides the protective barrier to the environment

– Water retention

– Prevention of infection

• Skin can self-repair to a certain extent

but it cannot fully regenerate

• Wound healing has three stages:

– Inflammation

– Proliferation

– Tissue remodelling

Gurtner, et al. (2008)

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Skin

• Skin provides the protective barrier to the environment

– Water retention

– Prevention of infection

• Skin can self-repair to a certain extent

but it cannot fully regenerate

• Wound healing has three stages:

– Inflammation

– Proliferation

– Tissue remodelling

Gurtner, et al. (2008)

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Skin

• Skin provides the protective barrier to the environment

– Water retention

– Prevention of infection

• Skin can self-repair to a certain extent

but it cannot fully regenerate

• Wound healing has three stages:

– Inflammation

– Proliferation

– Tissue remodelling

Gurtner, et al. (2008)

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Skin

• Skin provides the protective barrier to the environment

– Water retention

– Prevention of infection

• Skin can self-repair to a certain extent

but it cannot fully regenerate

• Wound healing has three stages:

– Inflammation

– Proliferation

– Tissue remodelling

Gurtner, et al. (2008)

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Skin

• Skin provides the protective barrier to the environment

– Water retention

– Prevention of infection

• Skin can self-repair to a certain extent

but it cannot fully regenerate

• Wound healing has three stages:

– Inflammation

– Proliferation

– Tissue remodelling

• Small superficial wounds can heal without scarring

• Larger, deeper wounds heal with scarring and

may require surgical intervention

• Chronic wounds require specialist care

Gurtner, et al. (2008)

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Skin

• Scarring can significantly affect appearance and function

• Current treatment options:

– Dressings

– Skin graft

– Meshed skin graft

– Artificial skin replacements

– Autologous/allogeneic cell therapy

Skin graft Meshed skin graft Dermal replacement Autologous cell therapy

Skin graft mesher

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Fat/adipose tissue

• White adipose tissue stores lipids

• Adipose-derived stem cells have the ability to regenerate adipocytes

• When entire fat pads are missing, adipose tissue cannot regenerate:

– Burn injuries

– Trauma, such as explosions or traffic accidents

– Tumour resection

• Soft tissue loss can have a significant affect on

appearance and function at the affected site

• Current treatment options:

– Tissue transplants (flaps)

– Synthetic implants

– Injection of autologous adipose cells (lipoaspirate)

Gesta, et al. (2007)

Mauer, et al. (2010)

Choi, et al. (2010)

Mariman, et al (2011)

Pre-adipocyte Adipocyte

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Tissue Engineering

Tissue engineering is an interdisciplinary

field that applies the principles of

engineering and the life sciences toward the

development of biological substitutes that

restore, maintain, or improve tissue function.

Langer and Vacanti (1993)

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Regenerative Medicine/Tissue Engineering

Regenerative medicine/tissue engineering research includes the

following areas:

– Development of novel biomaterials/scaffolds

– Identification of optimal cell sources

– Biomolecules

– Engineering Methods and Design

– Functional assessment of regenerated/engineered tissues

– Informatics as applied to tissue engineering

National Institute for Biomedical Imaging and Engineering (2004)

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Blond McIndoe Research Foundation Projects

Skin Treatment of burns

Improve healing

Reduce scarring

Fat/soft tissue Replacement and regeneration of missing tissue contours

Eye Regeneration of the limbus and the cornea

Skin cancer Detection

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Skin: Massive burns leave little viable skin for grafting

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Sprayed keratinocytes

or

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Cells delivered in suspension

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Improvement of skin cell culture for patients

• Current practice: keratinocytes are grown in the presence of lethally

irradiated mouse dermal cells.

• Replace mouse dermal cells with human dermal cells from same

patient: Jubin et al. (2011)

• Screen medium formulations to identify alternative methods for cell

expansion.

This will allow us to change current clinical practice and make

treatments safer for patients.

Current medium Human dermal cells New medium 1 New medium 2

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Sprayed keratinocytes

or

This technique has limitations as cells do not recover well

from being put into solution.

How can we overcome this?

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Microcarriers to improve wound healing

Microcarrier Covered with cells

Keratinocytes can be grown on small gelatin microcarriers and delivered

directly to the wound bed.

Martin, et al. (2011)

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Microcarriers to improve wound healing

Skin graft Microcarriers

Treatment of wounds with keratinocytes

on microcarriers resulted in skin repair

that was comparable to a skin graft.

Wounds contract as they heal, and scars can

form. Wounds treated with keratinocytes on

microcarriers contracted less than those

treated with skin grafts, p=0.05.

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Nanofibres to reduce scarring

Fibroblasts align along the orientation of the

nanofibres, cytoskeletal actin (red), focal

adhesions (green). By modulating the

behaviour of fibroblasts we hope to reduce

the amount of contraction that occurs during

healing.

Aligned Random

Fibroblasts

Contractures can form during wound

healing. They can be very painful and

restrict mobility. Contraction is thought to

occur by a combination of specialised

fibroblast cells and tensile forces across

the wound.

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

FAT/SOFT TISSUE: Reconstruction of soft contours

• Adipose/soft tissue can be lost due to:

– Burn injuries

– Trauma, such as explosions or traffic accidents

– Tumour resection

• Soft tissue loss can have a significant affect on appearance and function at the affected site

• Soft tissue injury before and after surgery

• Loss of contour is evident 1 year post surgery

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Use of adipose-derived stem cells (ADSCs)

ADSCs in culture ADSCs on microcarriers

a b

c d

(a, b) Microcarriers with ADSCs remained in the

tissue at 2 weeks after implantation. (c, d) GFP

(green) shows cells that were labelled prior to

transplantation, DAPI (blue) shows cell nuclei.

GFP DAPI

Excised fat or liposuction

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Soft tissue sponges

a b c

1cm 1cm 1cm

Porous soft sponges made from alginate/collagen seeded with ADSCs.

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Blond McIndoe Research Foundation Projects

Skin Treatment of burns

Improve healing

Reduce scarring

Fat/soft tissue Replacement and regeneration of missing tissue contours

Eye Regeneration of the limbus and the cornea

Skin cancer Detection

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Blond McIndoe Research Foundation Upcoming Projects

Skin Detection of infections in burn wounds – development of smart

dressings

Fat/soft tissue Modelling of early events that occur after transplantation – the role of

hypoxia

Eye Development of novel materials to deliver cells for corneal repair

Skin cancer Molecular mechanisms

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

Collaborations vital

Queen Victoria Hospital

University of Brighton

Brighton Sussex Medical School

University College London

Imperial College London

University of Bath/Frenchay Hospital Bristol

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240

BMRF Scientific Team

Professor Di Lawrence-Watt – Director of Research

Dr. Justin Sharpe – Head of Research

Postdoctoral Fellows:

– Dr. Yella Martin

PhD students:

– Elsie Fok, Saikat Ray

Research Assistants:

– Catherine Lenihan

Research technicians:

– Judy Roxburgh, Kasia Jubin, Trevor Eydman

Medical students 2011/12:

– Nicky Stevens, Sam Haddad, Manraj Phull, Tom Kilpatrick,

Kevin Lichtenstein

Blond McIndoe

Research Foundation

Registered Charity

Number: 1106240