College 1 – “An introduction to Tissue Engineering” – 22nd of November 2012

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College 1 – 29th of November 2012

Design Phyilosophy

Different components

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

  • Facilitate integration

  • Contribute to final events

Manufacturing Processes

  • 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

  1. 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
On Micro-level:

  • Chemical pathway (ionflows)

  • Mechanical ques

What enable the cells to respond?
The conditions they are in.
Artificial Tissue Development of Cells

  • Availability

  • Source

  • Protein expression level (screen the cells)

  • Response to physiological stimuli
     Mechanical history
    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

  • function

Of Biomaterials

  • Immunoprotection

  • Biocompatibility

  • Mechanical stability
     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

  • Safety characterisation
    – novel biomaterials

  • Biological complexity
    – 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

  • Guidance and Standards

  • 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).

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