Capillary Bed Bioreactor: Improved Estimation Of Dermal Bioavailability
Lead Research Organisation:
University of Bath
Department Name: Chemical Engineering
Abstract
Historically, animal testing has been used to support risk assessment for a variety of toxicological endpoints related to
cosmetic ingredients, including the local lymph node assay (LLNA) to assess the sensitization potential and potency of a
chemical. However, in recent years, there has been a continuous drive to reduce the level of animal testing undertaken to
support risk assessments for new cosmetic products, and a move towards a mechanistic understanding of human
exposure. Consequently, the development of mechanistic/biologically relevant in vitro, in chemico or in silico models for
predicting the sensitising potential and/or potency of new chemicals is necessary to generate data leading to increased
confidence in predictions of in vivo scenarios. The chemical and biological events driving the induction of human skin
sensitisation are now well understood and companies such as Unilever use this information in non-animal models to test
the safety of new compounds. Discs of ex vivo skin (from cosmetic surgery procedures) are mounted in diffusion cells and
the permeation of a test item through the skin is monitored over time. While this has proved to be an adequate model, it
does not truly represent living skin. At present, little is known regarding chemical clearance via dermal capillaries, and this
is a gap in our mechanistic understanding of the bioavailability of a topically applied chemical in the elicitation of skin
sensitisation. The proposed capillary bed bioreactor (CBB) better replicates the in vivo environment of the skin and its
blood supply by providing a bed of pseudovascularisation in the form of hollow fibre membranes. Therefore it should more
accurately predict permeation of chemicals through the skin, and provide data that more closely resembles that of the in
vivo scenario. The new bioreactor will be more physiologically accurate than the current model and can therefore
potentially refine inputs to our mechanistic models for skin sensitisation, to give us more accurate predictions of adverse
outcomes. This in turn will give greater confidence in our ability to risk assess new ingredients in the future without the
requirement for animal testing.
cosmetic ingredients, including the local lymph node assay (LLNA) to assess the sensitization potential and potency of a
chemical. However, in recent years, there has been a continuous drive to reduce the level of animal testing undertaken to
support risk assessments for new cosmetic products, and a move towards a mechanistic understanding of human
exposure. Consequently, the development of mechanistic/biologically relevant in vitro, in chemico or in silico models for
predicting the sensitising potential and/or potency of new chemicals is necessary to generate data leading to increased
confidence in predictions of in vivo scenarios. The chemical and biological events driving the induction of human skin
sensitisation are now well understood and companies such as Unilever use this information in non-animal models to test
the safety of new compounds. Discs of ex vivo skin (from cosmetic surgery procedures) are mounted in diffusion cells and
the permeation of a test item through the skin is monitored over time. While this has proved to be an adequate model, it
does not truly represent living skin. At present, little is known regarding chemical clearance via dermal capillaries, and this
is a gap in our mechanistic understanding of the bioavailability of a topically applied chemical in the elicitation of skin
sensitisation. The proposed capillary bed bioreactor (CBB) better replicates the in vivo environment of the skin and its
blood supply by providing a bed of pseudovascularisation in the form of hollow fibre membranes. Therefore it should more
accurately predict permeation of chemicals through the skin, and provide data that more closely resembles that of the in
vivo scenario. The new bioreactor will be more physiologically accurate than the current model and can therefore
potentially refine inputs to our mechanistic models for skin sensitisation, to give us more accurate predictions of adverse
outcomes. This in turn will give greater confidence in our ability to risk assess new ingredients in the future without the
requirement for animal testing.
Planned Impact
The ultimate impact of the capillary bed bioreactor will be on the customers who use the products being tested who will get
better value for money and results due to more effective products. The novel bioreactor technology will provide Unilever
with competitive advantage through improved human relevant estimation of dermal bioavailability and better
parameterisation of models for human toxicity (e.g. skin sensitisation). It's manufacture will create new business
opportunity and freedom to operate in the UK and global marketplace. Broader applications of the novel bioreactor design
beyond this project will give a competitive edge in the medical technology market for UK Plc.; its manufacture will create
new industry and jobs. Researchers (academic and industrial) around the world will benefit from more accurate IVIVE data
from the models and the knock-on effect of this, e.g. from new compounds for exploitation to papers in higher impact
journals.
Estimation of systemic exposure via the dermal route for the purposes of toxicological risk assessment is performed in
accordance with OECD Guideline 428. The chemical and biological events driving the induction of human skin sensitisation are now well understood, and have been mapped out as an 'adverse outcome pathway' in a recent OECD report, however
little is known regarding chemical clearance via dermal capillaries, and this is a gap in our mechanistic understanding of the
bioavailability of a topically applied chemical in the elicitation of skin sensitisation. The proposed capillary bed bioreactor
(CBB) better replicates the in vivo environment of the skin and its blood supply by providing a bed of pseudovascularisation
in the form of hollow fibre membranes. Therefore it should more accurately predict permeation of chemicals through the
skin, and provide data that more closely resembles that of the in vivo scenario. As such the CBB and the more accurate
data it provides will be of interest to regulators.
The public engagement activities will reach out to all of these groups, as well as children to enthuse the next generation of
engineers, scientists, medics and carers, and also to educate them about the need for a healthy lifestyle to prevent liver
and heart disease.
better value for money and results due to more effective products. The novel bioreactor technology will provide Unilever
with competitive advantage through improved human relevant estimation of dermal bioavailability and better
parameterisation of models for human toxicity (e.g. skin sensitisation). It's manufacture will create new business
opportunity and freedom to operate in the UK and global marketplace. Broader applications of the novel bioreactor design
beyond this project will give a competitive edge in the medical technology market for UK Plc.; its manufacture will create
new industry and jobs. Researchers (academic and industrial) around the world will benefit from more accurate IVIVE data
from the models and the knock-on effect of this, e.g. from new compounds for exploitation to papers in higher impact
journals.
Estimation of systemic exposure via the dermal route for the purposes of toxicological risk assessment is performed in
accordance with OECD Guideline 428. The chemical and biological events driving the induction of human skin sensitisation are now well understood, and have been mapped out as an 'adverse outcome pathway' in a recent OECD report, however
little is known regarding chemical clearance via dermal capillaries, and this is a gap in our mechanistic understanding of the
bioavailability of a topically applied chemical in the elicitation of skin sensitisation. The proposed capillary bed bioreactor
(CBB) better replicates the in vivo environment of the skin and its blood supply by providing a bed of pseudovascularisation
in the form of hollow fibre membranes. Therefore it should more accurately predict permeation of chemicals through the
skin, and provide data that more closely resembles that of the in vivo scenario. As such the CBB and the more accurate
data it provides will be of interest to regulators.
The public engagement activities will reach out to all of these groups, as well as children to enthuse the next generation of
engineers, scientists, medics and carers, and also to educate them about the need for a healthy lifestyle to prevent liver
and heart disease.
People |
ORCID iD |
| Marianne Ellis (Principal Investigator) |
Publications
Perez Esteban P
(2019)
Hollow-fiber membrane technology: Characterization and proposed use as a potential mimic of skin vascularization towards the development of a novel skin absorption in vitro model
in Biochemical Engineering Journal
| Description | Adding a capillary bed to a skin model alters the transport of compounds (caffeine) across the skin. This new model could provide a surrogate for capillary-based clearance in in vitro skin absorption studies to better replicate the transport in the skin. |
| Exploitation Route | Using the hollow fibres to replicate vasculature in other tissues, particularly lung which also has an air interface |
| Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
| Description | Adding a capillary bed to a skin model alters the transport of compounds (caffeine) across the skin. |
| First Year Of Impact | 2016 |
| Sector | Healthcare |
| Impact Types | Societal,Economic |
| Title | Dataset for Hollow-fiber membrane technology: Characterization and proposed use as a potential mimic of skin vascularization towards the development of a novel skin absorption in vitro model |
| Description | This dataset contains data collected using capillary bed bioreactor (CBB), a new method for pseudovascularisation of skin models. The data was collected by sampling the permeate that exited the fibres, and the amount of caffeine in the samples was measured using HPLC for the purpose of assessing permeability. By observing and analyzing the data we can conclude that the new bioreactor will be more physiologically accurate than the current model and can therefore potentially refine inputs to our mechanistic models for skin sensitisation, to give us more accurate predictions of adverse outcomes. The data is organised in an Excel spreadsheet with each tab relating to a specific figure in the paper. |
| Type Of Material | Database/Collection of data |
| Year Produced | 2019 |
| Provided To Others? | Yes |