bioeng 111606 lecture

8/13/2019 BioEng 111606 Lecture

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BIOCOMPATIBILITY & TISSUE DAMAGEBIOCOMPATIBILITY & TISSUE DAMAGE

CHAPTER 4 (LECTURE 2):

MEDICAL PHYSICS AND BIOMEDICAL ENGINEERINGMEDICAL PHYSICS AND BIOMEDICAL ENGINEERING

BIOMATERIALS BIOCOMPATIBILITY TISSUE DAMAGE BIOCOMPATIBILITY BIOMATERIALS

4.3 & 4.4: BIOCOMPATIBILITY4.3 & 4.4: BIOCOMPATIBILITY

BIOMATERIALTISSUE/BIOLOGICALENVIRONMENT

Biomaterial effects induce a tissue response

The tissue response generates a biomaterial effect

The cycle continues until equilibrium is reached or the the

biomaterial is removed


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Mechanisms for biomaterial/tissue interactionMechanisms for biomaterial/tissue interaction

Material releases toxic substance

e.g.unpolymerized monomer of bone cement

Material non-toxic but resorbable

e.g.suture material

Material non-toxic but stimulates inflammation or enhances

infection

any material being resorbed

Mechanical trauma

Non-toxic and non-absorbable

encapsulated

Highly interactive material bonds to tissues


4.3. MATERIAL RESPONSE TO THE BIOLOGICAL4.3. MATERIAL RESPONSE TO THE BIOLOGICAL

ENVIRONMENT:ENVIRONMENT:

BIOMATERIAL TISSUE/BIOLOGICALENVIRONMENT

7.4Arterial blood

7.1Venous blood

7.0Interstitial fluid

6.8Intracellular fluid

4.6-6.0Urine

1.0Gastric contents

pHpHTissue componentTissue component


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Effect of host on biomaterial:Effect of host on biomaterial:

Physical mechanical effects:

Abrasive wear

Fatigue

Stress-corrosion cracking

Corrosion

Degeneration and dissolution

Biological effects:

Absorption of substances from tissues

Enzymatic degradation

Calcification


Copper

Stainless steel

Titanium

Stainless steel, passivated

Silver

Nickel

Low-ally steelZinc

Magnesium

4.3.1. Metals: may fail due to:4.3.1. Metals: may fail due to:

Corrosion

Fracture

Wear

Yielding

Loosening

Infection

Table 4.3. Galvanic series of metals and alloys in sea water.

BEST

WORST


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4.3.2. Polymers4.3.2. Polymers

Non-biodegradable

Biodegradable

Polyethylene oxide/polyethylene tetraphalate (PEO/PET)

Polyglycolic acid (PGA) and polylactic acid (PLA)

Polylysine and poly(glutamic acid)

Applications:

adhesives

sutures

drug carriers

scaffolds


4.3.2. Ceramics4.3.2. Ceramics

Three types of bioceramics:

Nearly inert (e.g. alumina, pyrolitic carbon)

Totally resorbable (e.g. calcium phosphate)

Controlled surface activity, bind to tissues (e.g.

bioglass)


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Local effects

Systemic effects

Examples:

Local tissue response Immunological effects

Carcinogenicity

Biomechanical compatibility

4.4. TISSUE RESPONSE TO THE BIOMATERIAL:4.4. TISSUE RESPONSE TO THE BIOMATERIAL:

BIOMATERIAL TISSUE/BIOLOGICALENVIRONMENT


Blood material interactions

protein adsorption

coagulation

fibrinolysis

platelet activation

complement activation

leukocyte adhesion

hemolysis

Toxicity

Modification of normal healing

encapsulation

foreign body reaction

Infection

Carcinogenicity


Local host reaction:Local host reaction:


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effect of implant shape

effect of surface finish

role of surface porosity in tissue ingrowth

Osteoblasts adhered better to the rougher surface of the nanophase

version than the conventional sample.

Thomas J. Webster et al., Expert Rev. Medical Devices 1(1), 2004


Infection usually require reoperation

May result in amputation, osteomyelitis, or death

Vascular prostheses infections result in death

25-50% of the time

Intravenous catheters, periotoneal dialysis, and

urologic devices frequently become infected or

cause secondary infections

Total artificial heart causes 100% infection after 90

days

Artificial organs at a critical crossroads due to

infection

ImplantImplant--associated infection:associated infection:


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Implants reduce number of bacteria required to begininfection

Implants and dead tissue provide framework for

microorganisms to proliferate

Infection caused by adherence to surface by bacteria

Bacteria and tissue may compete for surface space

Bacteria on surface kill tissues and are resistant to

antibodies and defense mechanisms

Bacteria within biofilms are sometimes resistant to

antibiotic levels ~ 1,000 fold higher than those

required to kill their planktonic counterparts

Bacteria prefer surfaces, tissues do not

Thus, potential for infection very high

ImplantImplant--associated infection (continue):associated infection (continue):


Features of implant-associated infections

Biomaterial or damaged tissue

Adhesive colonization

Resistance to host defense and antibiotics

Specific materials, organisms, host location

Transformation of nonpathogens to virulent form by

biomaterial

Infection persistence

Polymicrobiality

Tissue integration at biomaterial surface

Tissue cell damage or necrosis



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Implant-associated infection mechanisms

Bacteria adhere to surface through a variety of interactions

Rough surfaces, grains, and other discontinuities increase

adherence

Form a biofilm 2 to hundreds of bacteria thick

Forms a 3-D structure that holds bacteria

Groups of bacteria have better survival than individuals

Varied species may interact

Damage by wear, corrosion, toxins, etc provide an interface

bacteria may exploit

Biomaterials may disrupt natural microbe preventatives (free

iron or other nutrients) Infection may then spread as bolus, etc.

Host defense may be exhausted by prolonged inflammation

Response to biomaterial may reduce efficacy of macrophages



Orthopaedic device-related infections remain one of the

most common and potentially problematic

complications faced by the more than 750,000 U.S.

patients who receive orthopaedic procedures for joint

replacements annually.

Infection rates are 7-9% for elbow replacements and 1-2%

for hip replacements. Patients with open fractures

clearly show a significantly higher risk of infection.

These infections are caused by relatively common

biofilm-forming bacterial pathogens (e.g. S. aureus, S.

epidermidis, P. aeruginosa, and E. coli).

ImplantImplant--associated infectionassociated infection orthopaedicsorthopaedics::


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Antibiotics, systemic or in situ

Precolonization by healthy tissues

Peptides and sugars on surface to encourage tissue adhesion and

discourage pathogen adhesion

Coating surface to direct biological activity

Genetic modification of local tissue adhesion

Better understanding of surface phenomenon and structure

ImplantImplant--associated infection prevention strategies:associated infection prevention strategies:


Approaches to attach to

various (biomedical) devicesmonolayerformation

Self-assembly ofpolypeptide

multilayernanocoatingsStabilization cross-linking

Molecular

recognition

DNA/gene

protein/peptide

cell

drug

SURFACE MODIFICATION & MULTI-FUNCTIONALIZATION

BASED ON

POLYPEPTIDE DESIGN & ELECTROSTATIC SELF-ASSEMBLY

Substrate

BIOENGINEERING NANOCOATINGS FOR IMPLANT-

ASSOCIATED INFECTION PREVENTION


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Drug loading & release:

Antibiotics (e.g. cefazolin, gentomycin) Antimicrobial polypeptides (e.g. Histatin 5)

Cytokines (e.g. IL-12)

Multi-drug loading

Growth factors: (e.g. BMP, TGF-1, IGF-I) RGD peptides

competing for spaceBacterial cell

Osteoblast cell

Fig. Plot of drug concentration vs.

time for different release systems.

Toxic level

Therapeutic level

Ineffective level Single dose

Prolonged

Time

Controlled

Drugconcentration

GOAL

BIOENGINEERING NANOCOATINGS FOR IMPLANT-

ASSOCIATED INFECTION PREVENTION


Toxicity distant from implant site

Causes

Chemical toxicity

Accumulation of wear products

Corrosion or degradation

Excess inflammation

Vasoactive products from complement

Immune response

Symptoms

General: swelling, itching, rashes, sneezing

Lungs: changed breathing patterns

Kidneys: changed urine excretion or pain

Joints: pain swelling, loss of function

GI tract: diarrhea or constipation

Systemic toxicity:Systemic toxicity:


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Bone interactions with bioceramics

Implant

Tissue response

Toxic: tissue dies

Inert: capsule forms

Bioactive: interfacial bond forms

Dissolves: replaced by tissue

Bioceramic Tissue attachment

Dense, nonporous, inert: bone grows into surface irregularities,

cementing

o Relative motion and capsule cause failure

Porous, inert: bone growth mechanically connects materials

(biological fixation)

o More stable, best as coating

Dense, nonporous, surface reactive: chemical bonding to bone

(bioactive fixation)o Active surface, bioglass, HA, and composites

Dense, nonporous, resorbable: slowly replaced by bone

o Must engineer strength, resorption rate, metabolites


Irritation

Produces mild to moderate pain or discomfort

(e.g. itching)

Usually surface phenomenon

Chemical or physical incompatibility

Inflammation

More severe response than irritation

Signals include redness, heat, swelling, pain

Defensive response

Occurs with all resorbable materials

Necrosis

Cell/tissue death

Undesirable biomaterial results:Undesirable biomaterial results:


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Pyrogenicity

Tendency to produce fever

IL-1 and tumor necrosis factor from activated

macrophages

Lipopolysaccharides from gram negative

bacterial cell walls

Some polymers (PE, PTFE) selectively absorb

endotoxin

Sensitization

Generally a delayed reaction

Immunologically mediated

Allergies a typical example

May require repeated exposure

Amines and metals significant

Undesirable biomaterial results (continue):Undesirable biomaterial results (continue):


Mutagenicity

Tendency to produce genetic mutation

Combination of dose and frequency of exposure

o plasticizers cause lethal mutation in mice

Carcinogenicity or tumorigenesis

Tendency to produce tumors or cancer

Related to dose, exposure and genetic susceptibility

Related to characteristics of materials

Solid state carcinogenesis in rodents

Undesirable biomaterial results (continue):Undesirable biomaterial results (continue):


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4.5.2. IN VIVO AND CLINICAL TRIALS

In vivo (Latin: (with)in the living) means that which takes place

inside an organism. In science, in vivo refers to

experimentation done in or on the living tissue of a whole, living

organism as opposed to a partial or dead one. Animal testing

and clinical trials are forms of in vivo research.

A fracture setup and an open fracture rat model of osteomyelitis.


Inn Vivo Tests:ivo Tests:Toxicity

Sensitization

Rabbit Pyrogen

USP Class Testing

Sub-Chronic/Chronic

Intracutaneous

Reactivity

Irritation Testing

Histology Examination

Etc.

InnVitro Tests:itro Tests:Cytotoxicity

Hemolysis

PT/PTT Testing

AMES Mutagenicity

Carcinogencity Testing

Etc.

Test animals:est animals:Rabbits

Mice/rat

Pig

People


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Voluntary standards, e.g. established by

interested organizations:

ASTM

ANSI

AAMI

ISO

Government standards

Vary from country to country

Generally not voluntary

Approval of government required formarketing device

In US, the FDAis responsible for regulating

medical devices

BIOMATERIAL REGULATION:BIOMATERIAL REGULATION:


WHAT ARE SOME OF THE CHALLENGES?WHAT ARE SOME OF THE CHALLENGES?

To more closely replicate complex tissue

architecture and arrangement in vitro

To better understand extracellular and

intracellular modulators of cell function

To develop novel materials and processing

techniques that are compatible with biological

interfaces

To find better strategies for infection prevention

and immune acceptance

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