Bio Compatibility Performance

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BiocompatibilityPerformance

Materials and Coatings



Kardium Confidential 2009

ISO 10993 -1

•

2 Terms and definitions• For the purposes of this document, the following terms and definitions apply.

• 2.1

• medical device

• any instrument, apparatus, appliance, material or other article, includingsoftware, whether used alone or in

• combination, intended by the manufacturer to be used for human beingssolely or principally for the purpose of:

• diagnosis, prevention, monitoring, treatment or alleviation of disease;

• diagnosis, monitoring, treatment, alleviation of or compensation for aninjury or handicap;

•

investigation, replacement or modification of the anatomy or of aphysiological process;

• control of conception;

• and which does not achieve its principal intended action in or on the humanbody by pharmacological,

• immunological or metabolic means, but which may be assisted in its function

by such means

• NOTE 1 Devices are different from dru s and their biolo ical evaluation




General Principles forBiological Evaluation

• 3.2 In the selection of materials to be used in device manufacture,the first consideration should be fitness for purpose with regard tocharacteristics and properties of the material, which includechemical, toxicological, physical, electrical, morphological andmechanical properties.

• 3.3 The following should be considered for their relevance to theoverall biological evaluation of the device:

• a) the material(s) of manufacture;

• b) intended additives, process contaminants and residues;

• c) leachable substances;

• d) degradation products;

• e) other components and their interactions in the final product;

• f) the properties and characteristics of the final product.

• NOTE If appropriate, identification and quantification of extractablechemical entities of the final product should precede biological

evaluation .




Categorization of MedicalDevices

•

Nature of Contact

• Duration of contact




Nature of contact

• Non Contact Devices (Not part of ISO10993)

•

Surface Contacting Devices (Skin,mucosal membranes, breached orcompromised surfaces).

•

External Communicating Devices.• Implant Devices.

l C i i




External CommunicatingDevices

• a) blood path, indirect: devices that contact the blood path at onepoint and serve as a conduit for entry into the vascular system;examples include solution administration sets, extension sets,

transfer sets and blood administration sets;

• b) tissue/bone/dentin: devices that contact tissue, bone orpulp/dentin systems; examples include laparoscopes, arthroscopes,draining systems, dental cements, dental filling materials and skinstaples;

• c) circulating blood: devices that contact circulating blood;examples include intravascular catheters, temporary pacemakerelectrodes, oxygenators, extracorporal oxygenator tubing andaccessories, dialysers, dialysis tubing and accessories,

haemoadsorbents and immunoadsorbents.




Duration of Contact

• a) Limited exposure (A): devices whosesingle or multiple use or contact is likely tobe up to 24 h;

• b) Prolonged exposure (B): devices whosesingle, multiple or long-term use orcontact is likely to exceed 24 h but not 30

days;

• c) Permanent contact (C): devices whosesingle, multiple or long-term use orcontact exceeds 30 days.




Canopus Device (Summary)

• It is an External CommunicatingDevice.

• It is in Contact with Circulating Blood.

• It is a Device with Limited Exposure(< 24 h)




Testing (General)

• Testing shall be performed on the finalproduct, or on representative samplestaken from the final product or from

materials processed in the same manneras the final product.• The existing information based on the

literature, experience and non-clinical

tests;• The protection of humans is the primary

goal of this document, a secondary goalbeing to ensure animal welfare and to

minimize the number and exposure of test




Testing (Detail)




Supplementary Test




ISO Standards

• ISO 10993 -4 Haemocompatibility.

• ISO 10993 -5 In Vitro Cytotoxicity.

• ISO 10993 -10 Sensitization &Irritation.

• ISO 10993 -11 Systematic Toxicity.




More ISO Standards

• ISO 10993 - 2 Animal Welfare.• ISO 10993 - 7 Ethylene Oxide

Sterilization.• ISO 10993 -12 Sample Preparations.• ISO 10993 -13 Degradation Products

from Polymers.• ISO 10993 -15 Degradation from

Metals and

Alloys.




ISO 10993 -5

• This part of ISO 10993 describes testmethods to assess the in vitro cytotoxicityof medical devices.

•

These methods specify the incubation of cultured cells either directly or throughdiffusion

a) with extracts of a device, and/or

b) in contact with a device.• These methods are designed to determine

the biological response of mammaliancells in vitro using appropriate biologicalparameters.




ISO 10993 -10

• This part of ISO 10993 describes theprocedure for the assessment of medicaldevices and their constituent materials

with regard to their potential to produceirritation and delayed-typehypersensitivity.

This part of ISO 10993 includes

a) pretest considerations,b) details of the test procedures, and

c) key factors for the interpretation of

the results.




ISO 10993 -11

• This part of ISO 10993 specifies requirements andgives guidance on procedures to be followed in theevaluation of the potential for medical devicematerials to cause adverse systemic reactions.

• Systemic toxicity

Toxicity that is not limited to adverse effects at thesite of contact between the body and the device

• Acute systemic toxicity

Adverse effects occurring at any time after single,multiple or continuous exposures of a test sample

within 24 h




ISO 10993 -4

• This part of ISO 10993 provides general requirements forevaluating the interactions of medical devices with blood.It describes:

a) a classification of medical and dental devices that areintended for use in contact with blood, based on the intendeduse and duration of contact as defined in ISO 10993-1,

b) the fundamental principles governing the evaluation of the interaction of devices with blood,

c) the rationale for structured selection of tests accordingto specific categories, together with the principles andscientific basis of these tests.

• Detailed requirements for testing cannot be specifiedbecause of limitations in the knowledge and precision of tests

•

For interactions of devices with blood. This part of ISO10993 describes biological evaluation in general terms and




Skip testing ????




Decision tree for testing




Haemocopatibility tests




Minimun Test

Amendtment 1 to ISO




Amendtment 1 to ISO10993-4




Thrombosis Metrics

• Percentage of occlusion.

• Flow reduction.

• Gravimetric analysis.

•

Pressure drop across device.• Retrieval and examination of device.

• Autopsy of distal organs.

• Antibody binding. (measuring the amount of

labeled antibody specific for fibrin(ogen) orplatelet membrane receptors).

• Light microscopy and ESM.

• Imaging techniques (ultrasound, CT, MRI etc).




Haemolysis

• The main event after haemolysis isthe release of hemoglobin.

•

This is regarded as an especiallysignificant screening test because if this test is properly performed, anelevated plasma hemoglobin level

indicates haemolysis and reflectserythrocyte membrane fragility incontact with materials and devices.




Haemolysis Causes• Mechanical Forces:

– Osmotic Pressure. – Material Properties:

• Surface Morphology• Surface Chemistry and Energy• Cell Wall interaction• Air Entrainment

– Rheology• Shear Forces• Friction• Flow Stability

• Biological Factors (Changes to the membrane structure withchanges to elastic and permeability properties):

– Chemicals

– Toxins

– pH




Mechanical Haemolysis

•

Mechanical forces — PressureThe erythrocyte membrane is a semi permeable

membrane. A pressure differential will occur whentwo solutions of

different concentrations are separated by such amembrane. Osmotic pressure occurs when themembrane is

impermeable to passive solute movement. Thesepressure differentials can cause erythrocyte swelling

and cell

membrane rupture with release of freehemoglobin.

Vo = Red Blood Cell Volume in Isotonic Solution

V = Volume of a Red Blood Cell in a non Isotonic




Osmotic pressure




Mechanical Haemolysis

• Rheology

• It is an emulsion

• Non- Newtonian behavior

Duration of blood contact




Duration of blood contactand Surface area

• The chance to thrombus formationand embolization of the formedthrombi during manipulation of the

device is proportional to the contacttime between the device and theblood.

•

Devices with large surface areas maycause the destruction orconsumption of circulating bloodcells and proteins near the surface of the device lowerin their




Surface Roughness Example

A rough surface has ahigher affinity forplatelet attachmentand cause micro-

turbulence at thesurface.

Anionic or cationiccharge on the surface

can influence plasmaprotein adhesion




Surface chemistry Example




Blood Flow Dynamics

• The device can affect the dynamicsof flow at or near the device surface

• In areas of turbulence, platelets can

be forced to the surface of the devicecausing activation and aggregation

• In general, the more complex the

device geometry, the greater thechance of turbulence, stagnantregions and haemo-incompatibility




Blood flow dynamics

• Slow flow or stagnant systems(veins) produce “red thrombus” =red cells with lots of fibrin

• High flow systems (arteries) produce“white thrombus” = lots of plateletsand a little of fibrin




Intrinsic Coagulation Path




Extrinsic Coagulation Path




Coagulation Factors




• Thus, heparin is not itself an inhibitor;instead, it acts as a catalyst by convertingAT (Antithrombin) from a slow into a highlypotent anti coagulant, without beingconsumed in the inhibitory process.

This catalytic action is fundamental to the

creation of a stable non thrombogenicsurface, as the immobilized heparin is notexhausted or consumed in contact withblood, but maintains its catalytic activity.

Pr m ng to Cover mater a




Pr m ng to Cover mater aSurface and to attach

Heparin Molecules

i C i




Heparin Coating




A ifi i l Bl d V l




Artificial Blood Vessel

Complement (immune)




Complement (immune)System

• Another host defense against artificial materialsand invading microorganisms is the complementsystem. Complement is activated by essentiallyany material, but is under strict control by

regulating factors on the cells of the hostorganism(“self”). As foreign (“non-self”) materialslack this regulatory function, complement has thecapacity to discriminate between “self” and “non-self.” Thus, the presence of any artificial surfacesin the blood circulation will cause some degree of complement activation. The principal outcome of this activation is an inflammatory reaction, whichis beneficial in the defense against infectious

agents but may represent a serious complication

MSD Bi di l




MSD Biomedical

• ComfortCoat® Hydrophiliccoating

• Excellent lubricity: reduces the

stiction and the friction forces andminimizes patient discomfort andtissue damage

•

Superior durability: better adhesionto the surface of the medical deviceand cohesion of the polymer matrix

•

Adhesion to many substrates: e.g.

MSD Bi di l




MSD Biomedical

• ComfortCoat® HemocompatibleAntimicrobial coating

• Antimicrobial activity: demonstrated

activity against E.Coli and S Aureus• Hemocompatibility: positive results in

hemocompatibility and

thrombogenicity tests• Excellent lubricity and superior

durability: reduces stiction and

friction and thus reduces patient

MSD Bi di l




MSD Biomedical

• VitroStealth® non-foulingcoating

• Excellent non-biofouling propertiesresult in reduction in proteinadsorption, nucleic acid adsorption,

bacterial and cellular adhesion• Crosslinking leads to extremely low

levels of extractables and leachables

DSM Bi di l




DSM Biomedical

• BioSpan Segmented Poliurethane•

Able to withstand millions of flexcycles.• Often chosen for cardiac assist

devices that must survive over 40millions cycles per year.

MSD Biomedical




MSD Biomedical

BioSpan SegmentedPolyurethane

Bi t




Biocoat

• HYDAK Advantages• Exceptionally hydrophilic

• Lubricious when wet, preventing trauma and tissueabrasion

• Abrasion resistant

• Very thin, flexible coatings can be applied

• Biocompatible

•

Non-thrombogenic• Prevents adhesion of platelets, proteins, and

microorganisms

• Carrier for bioactive substances to make –

anti-bacterial surfaces

Bi t




Biocoat

Bi t




Biocoat

Parylene Deposition Process




Parylene Deposition ProcessVacuum Vapor Deposition

Parylene Electrical




Parylene ElectricalProperties

Parylene Mechanical




Parylene MechanicalProperties

Parylene




Parylene

Parylene




Parylene

Pinhole free barrier to protectagainst body fluids as well asmoisture, chemicals and commongases

Parylene



Parylene

Bio Compatibility Performance

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