Biocompatibility Performance

Click to edit Master subtitle style Materials and Coatings

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, including software, whether used alone or in combination, intended by the manufacturer to be used for human beings solely or principally for the purpose of: diagnosis, prevention, monitoring, treatment or alleviation of disease; diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap; investigation, replacement or modification of the anatomy or of a physiological process; control of conception; and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means Kardium Confidential 2009 NOTE 1 Devices are different from drugs, and their biological evaluation

General Principles for Biological Evaluation

3.2 In the selection of materials to be used in device manufacture, the first consideration should be fitness for purpose with regard to characteristics and properties of the material, which include chemical, toxicological, physical, electrical, morphological and mechanical properties. 3.3 The following should be considered for their relevance to the overall 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 extractable chemical entities of the final product should precede biological Kardium Confidential 2009 evaluation .

Categorization of Medical Devices

Nature of Contact Duration of contact

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Nature of contact

Non Contact Devices (Not part of ISO 10993) Surface Contacting Devices (Skin, mucosal membranes, breached or compromised surfaces). External Communicating Devices. Implant Devices.
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External Communicating Devices

a) blood path, indirect: devices that contact the blood path at one point 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 or pulp/dentin systems; examples include laparoscopes, arthroscopes, draining systems, dental cements, dental filling materials and skin staples; c) circulating blood: devices that contact circulating blood; examples include intravascular catheters, temporary pacemaker electrodes, oxygenators, extracorporal oxygenator tubing and accessories, dialysers, dialysis tubing and accessories, haemoadsorbents and immunoadsorbents. Kardium Confidential 2009

Duration of Contact

a) Limited exposure (A): devices whose single or multiple use or contact is likely to be up to 24 h; b) Prolonged exposure (B): devices whose single, multiple or long-term use or contact is likely to exceed 24 h but not 30 days; c) Permanent contact (C): devices whose single, multiple or long-term use or Kardium Confidential 2009 contact exceeds 30 days.

Canopus Device (Summary)

It is an External Communicating Device. It is in Contact with Circulating Blood. It is a Device with Limited Exposure (< 24 h)
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Testing (General)

Testing shall be performed on the final product, or on representative samples taken from the final product or from materials processed in the same manner as 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 goal being to ensure animal welfare and to minimize the Kardium Confidentialand exposure of test number 2009

Testing (Detail)

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Testing (Detail)

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Supplementary Test

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ISO Standards

ISO 10993 -4 ISO 10993 -5

Haemocompatibility. In Vitro Cytotoxicity.

ISO 10993 -10 Sensitization & Irritation. ISO 10993 -11 Systematic Toxicity.
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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.
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ISO 10993 -5

This part of ISO 10993 describes test methods to assess the in vitro cytotoxicity of medical devices. These methods specify the incubation of cultured cells either directly or through diffusion a) with extracts of a device, and/or b) in contact with a device. These methods are designed to determine the biological response of mammalian cells in vitro using appropriate biological Kardium Confidential 2009 parameters.

ISO 10993 -10

This part of ISO 10993 describes the procedure for the assessment of medical devices and their constituent materials with regard to their potential to produce irritation and delayed-type hypersensitivity. 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. Kardium Confidential 2009

ISO 10993 -11

This part of ISO 10993 specifies requirements and gives guidance on procedures to be followed in the evaluation of the potential for medical device materials to cause adverse systemic reactions. Systemic toxicity Toxicity that is not limited to adverse effects at the site 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

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ISO 10993 -4
This part of ISO 10993 provides general requirements for evaluating the interactions of medical devices with blood. It describes: a) a classification of medical and dental devices that are intended for use in contact with blood, based on the intended use 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 according to specific categories, together with the principles and scientific basis of these tests. Detailed requirements for testing cannot be specified because of limitations in the knowledge and precision of tests For interactions of Kardium Confidential 2009 devices with blood. This part of ISO 10993 describes biological evaluation in general terms and

Skip testing ????

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Decision tree for testing

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Haemocopatibility tests

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Minimun Test

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Amendtment 1 to ISO 10993-4

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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) or platelet membrane receptors). Light microscopy and ESM. Imaging techniques (ultrasound, CT, MRI etc).
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Haemolysis

The main event after haemolysis is the release of hemoglobin. This is regarded as an especially significant screening test because if this test is properly performed, an elevated plasma hemoglobin level indicates haemolysis and reflects erythrocyte membrane fragility in contact with materials and devices.
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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 with changes to elastic and permeability properties): Chemicals Toxins pH
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Mechanical Haemolysis
Mechanical forces Pressure The erythrocyte membrane is a semi permeable membrane. A pressure differential will occur when two solutions of different concentrations are separated by such a membrane. Osmotic pressure occurs when the membrane is impermeable to passive solute movement. These pressure differentials can cause erythrocyte swelling and cell membrane rupture with release of free hemoglobin. Vo = Red Blood Cell Volume in Isotonic Solution Kardium Confidential 2009 V = Volume of a Red Blood Cell in a non Isotonic

Osmotic pressure

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Mechanical Haemolysis

Rheology It is an emulsion Non- Newtonian behavior

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Duration of blood contact and Surface area

The chance to thrombus formation and embolization of the formed thrombi during manipulation of the device is proportional to the contact time between the device and the blood. Devices with large surface areas may cause the destruction or consumption of circulating blood cells and proteins near the surface of the device lowering their
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Surface Roughness Example

A rough surface has a higher affinity for platelet attachment and cause microturbulence at the surface. Anionic or cationic charge on the surface can influence plasma protein adhesion

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Surface chemistry Example

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Blood Flow Dynamics

The device can affect the dynamics of flow at or near the device surface In areas of turbulence, platelets can be forced to the surface of the device causing activation and aggregation In general, the more complex the device geometry, the greater the chance of turbulence, stagnant regions and haemo-incompatibility
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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 platelets and a little of fibrin
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Intrinsic Coagulation Path

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Extrinsic Coagulation Path

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Coagulation Factors

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Thus, heparin is not itself an inhibitor; instead, it acts as a catalyst by converting AT (Antithrombin) from a slow into a highly potent anti coagulant, without being consumed in the inhibitory process. This catalytic action is fundamental to the creation of a stable non thrombogenic surface, as the immobilized heparin is not exhausted or consumed in contact with blood, but maintains its catalytic activity.

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Priming to Cover material Surface and to attach Heparin Molecules

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Heparin Coating

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Artificial Blood Vessel

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Complement (immune) System

Another host defense against artificial materials and invading microorganisms is the complement system. Complement is activated by essentially any material, but is under strict control by regulating factors on the cells of the host organism(self). As foreign (non-self) materials lack this regulatory function, complement has the capacity to discriminate between self and nonself. Thus, the presence of any artificial surfaces in the blood circulation will cause some degree of complement activation. The principal outcome of this activation is an inflammatory reaction, which is beneficial in the defense against infectious agents but mayKardium Confidential a serious complication represent 2009

MSD Biomedical

ComfortCoat Hydrophilic coating Excellent lubricity: reduces the stiction and the friction forces and minimizes patient discomfort and tissue damage Superior durability: better adhesion to the surface of the medical device and cohesion of the polymer matrix Adhesion to many substrates: e.g.
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MSD Biomedical

ComfortCoat Hemocompatible Antimicrobial 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
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MSD Biomedical

VitroStealth non-fouling coating Excellent non-biofouling properties result in reduction in protein adsorption, nucleic acid adsorption, bacterial and cellular adhesion Crosslinking leads to extremely low levels of extractables and leachables
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DSM Biomedical

BioSpan Segmented Poliurethane Able to withstand millions of flex cycles. Often chosen for cardiac assist devices that must survive over 40 millions cycles per year.

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MSD Biomedical BioSpan Segmented Polyurethane

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Biocoat

HYDAK Advantages Exceptionally hydrophilic Lubricious when wet, preventing trauma and tissue abrasion 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-bacterialKardium Confidential 2009 surfaces

Biocoat

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Biocoat

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Parylene Deposition Process Vacuum Vapor Deposition

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Parylene Electrical Properties

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Parylene Mechanical Properties

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Parylene

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Parylene
Pinhole free barrier to protect against body fluids as well as moisture, chemicals and common gases

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Parylene

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