College 1 – 29th of November 2012
Cells (optional) + ECM (may) + Scaffold (usually) + Signals (e.g. biomedical, biomechanical, bio-electrical) = Tissue Engineered Biological Substitute
Construct = physiologically build
Intelligent Scaffolds (Multifactorial Delivery Vehicles)
Hold or attract cells
Influence cell development
Reserve space for regeneration
Biodegradable scaffold will give after some time more space for new cells.
Inhibit inflammatory events
Breakdown into active factors (e.g. stimulate cell growth)
Encapsulate morphogens, cytokines and MMPs
MMPs break down proteins
Contribute to final events
Tested cells from working cell banks
Automatic injection into tissue bioreactors
Computerised system to monitor growth conditions including pH, CO2 and glucose utilisation (sensors)
Tissues are frozen (for transport)
Quality control for matrix properties and cell viability (tests)
Processed in bioreactors until clinical use
In the U.S.A. tissue engineering started in the biochemical departments. In the U.K. the biochemical departments are busy in the oil industry.
Cellular Signal Transduction
Chemical pathway (ionflows)
What enable the cells to respond?
The conditions they are in.
Artificial Tissue Development of Cells
Protein expression level (screen the cells)
Response to physiological stimuli
e.g. Isolated cells in cartilage which is frequently loaded, will respond differently than cells in cartilage which is not frequently loaded.
Long term maintenance of
At least initially, to match the environment.
Often collagen scaffolds are used in tissue engineering:
Making collagen is difficult
How do you know if new collagen is made by the cells?
Use a different type of collagen in the produced tissue than the cells will make. You can use Western Blotting to know which is which.
Usually radio-isotopes are used to know is there are any new cells.
TE Medical Products Require Innovative Regulatory Strategies
– novel biomaterials
– biological components lead to product variability and testing complexity
How to establish such a test protocol?
FDA Multi-centre review
combination products require Inter-centre review
need for cell/tissue standardised characterisation methods, reference materials and guidance
Tissue is a dynamic material
LIFE Intitiative - Objectives
Objectives - to produce an unlimited supply of human vital organs (heart, kidney ,liver) for transplantation.
Because there is a large unmet medical need. A new organ is cheaper for the society than the treatment in the last six months of their life. There are ethical issues associated with limited resources (how do you determine who gets the organ?).
The fatigue is an important issue for the engineered tissue.
Exam: Write the milestones within a 10 year program of an organ and what are the expected spin-offs of the research?
Example of the heart - Milestones
Functional heart available for pre-clinical testing - year 10
Thrombogenicity control - year 9
minimize the risk for trombose
Components human testing - year 8
Immune/Inflammatory control - year 7
Components small animal testing - year 6
Prototype cell and scaffold strategies - year 5
Flexible scaffolds with required stiffness/strength throughout degradation period - year 3
Human cardiomyocytes in large numbers from various sources - year 2
Examples of the heart - Selected Spin-Offs
Animal models for human diseases - year 10
Endothelial seeding of vascular grafts
Vascular networks (capillary beds) and conduits
Paediatric cardiac valves
Cardiac patches for repair of damaged tissues - year 5
In vitro model for conduction based diseases
Degradable materials for other TE applications
Cardiac cells for injection and in situ repair
In vivo culture of cardiac myocytes - diagnostic and drug testing
You have to produce some ECM in the scaffold before the implementation otherwise it cannot bear any load.
You want the scaffold to evoke cells to come to the scaffold and start producing ECM (e.g. hyaluronan does that).