Biomaterials - IIBME 379/385, CHE 379, Spring 2003 (Schmidt)

Goals:By the end of this lecture, you should be able to:• List and describe some of the common natural materials

used in TE• Describe how cells interact with the surrounding ECM• Describe how these interactions can be modulated• Define "biomimetic"• Define "Vroman effect"• Describe the biological responses to implanted materials• Describe common methods to assess biocompatibility

Outline:I. Natural Materials in Tissue EngineeringII. Cell Interactions with MaterialsIII. Controlling Cell Interactions - "Biomimetic" MaterialsIV. Analysis of Material Biocompatibility

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I. Natural Materials in Tissue Engineering

Last time, we focused predominantly on synthetic materials.Examples of some of the common synthetic polymers used in tissueengineering include: PLA, PGA, and PLGA.

Natural Materials are playing a larger role in TE applications.

Examples of Natural Materials include:

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II. Cell Interactions with Materials

SURFACE vs. BULK properties

Surface Properties governed by:

Interactions:

FunctionBioactivity

StructureSupportShape

Material ECM

Cell

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Cell Interactions/Cell Adhesion Modulate:

How do cells interact with their environment?

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Integrins are the main class of receptors that mediate bindingof cells to the ECM (e.g., fibronectin, laminin, collagen)...

Example of Cell Shape Changes and Binding:

• Cell shape changes induced via binding of adrenaline, thrombin, orADP to their respective G-Protein Coupled Receptors (GPCRs).

• Activation of the cell surface platelet-specific integrin αIIb β3 alsooccurs.

• Only activated cell surface αIIb β3 binds to fibrinogen, fibronectin,and von Willebrand factor, leading to adherence to the vessel walland formation of a platelet plug.

> In tissue engineering applications, cell adhesion andmigration are critical for tissue formation <

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III. Controlling Cell Interactions - "Biomimetic" Materials

Upon implantation, all materials are coated by serum proteins(e.g., fibronectin, vitronectin), and are eventually encapsulatedin fibrous tissue, as described in Section IV of these notes.

Thus, many techniques are geared at reducing non-specificadhesion "programming in" only specific cell adhesion sitesfor interaction.

Biomimetic materials are thus defined as:

This can be controlled through:

Other ways to control cell shape and adhesion:

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Geometry can be used to monitor cell migration...

PNAS 98:5992-5996, 2001

Cell shape can be used to control cell viability...

Science 276:1425-1428, 1997

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Cell shape and viability/function continued....

Science 276:1425-1428, 1997

20:40=20 µm circles separated by 40 µm5:10= 5 µm circles separated by 10 µm3:6= 3 µm circles separated by 6 µm

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Definitions for types of cell migration behavior:

Haptotaxis:

Chemotaxis:

Chemoaffinity:

Many migration assays and models exist to study migrationbehavior of cells on various materials.

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IV. Analysis of Material Biocompatibility

Tissue Response to MaterialsKey Cells Involved in Tissue Response:

Blood Cells (identified using a blood smear) are key players.

Blood cells consist of white blood cells (leukocytes) and red bloodcells. Granulocytes (eosinophils, basophils, neutrophils), monocytes(macrophages), and lymphocytes together comprise white cells.

Red blood cells are biconcave discs that lack a nucleus and carryhemoglobin which is responsible for oxygen transport.

What are the functions of neutrophils (polymorphonuclear leukocytesor PMNs), macrophages, and lymphocytes?

Platelets are cell fragments involved in clotting mechanisms toprevent excessive bleeding when tissue is injured.

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Response to a Material Implant:

Consider what happens to the biomaterial upon implantation into avascularized tissue of an animal or patient.

Answer the following:

What is the first event that occurs?

Define the Vroman Effect.

How can the event above be controlled? Give some examples ofhow this can be minimized or modulated.

What other factors may affect this event?

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Now let's consider the broader host response to the implantedbiomaterial.

Define and distinguish the following responses. What factors and/orcells are important in each case?

Acute Inflammation:

Chronic Inflammation:

Granulation Tissue:

Foreign Body Reaction:

Fibrosis and Fibrous Encapsulation:

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Inflammation:

The four signs associated with an inflammatory response:

1) Red (rubor) appearance at the injury site due to the presenceof RBCs just under the skin.

2) The site becomes swollen (tumor) due to the fluid that camewith the blood .

3) Site is warm (calor), which is the result of the warm bloodgoing to a cooler tissue site.

4) Painful (dolor) due to impingement on and damage to localnerve networks.

Healing in the presence of a biomaterial:

Define biocompatibility?

When a material is not biocompatible, the inflammatory responsecontinues as a chronic inflammatory response and progresses to giantcells and granulomas. The host tries to neutralize the foreign object(implant).

Formation of the fibrous capsule is an indication that the material isbiocompatible and will occur as an early step in healing.

Infection:

Presence of infection will prevent the resolution of inflammation, andan undesired chronic inflammatory response will occur.

What would happen if bacteria are involved during the process ofwound healing?

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Immune response:

A specific antigen-antibody based immune response will occur if cellsfrom another species or patient are implanted.

Allergic reactions are specific immune responses against non-biological entities. These reactions are not desired and can havedetrimental side effects (and must be considered in device design).

Why are degradation products from the materials of an implant animportant concern?

Biocompatibility testing:

An essential question to consider when a biomaterial is used in abiological system is: "will this material stimulate the appropriatebiological response for the intended use?".

Sterilization is crucial to the use of the material in vivo. (see Handout)

In vitro tests are common tests performed using tissue or cellcultures. In vivo tests to assess possible chronic inflammation arealso common.

Tests are designed for cytotoxicity, stimulation of immune response,irritation to tissues, provocation of chronic inflammation, effects onblood and blood components, and effects on genetic factors includingmutations and tumor formation.

In implantation of a nerve guidance channel composed of a polymerbased material, what are some of the biocompatibility tests involved?Provide some broad and specific tests.