Biomaterial -Interaktion mellan levande vävnad och syntetiska material

Transcription

1 Biomaterial -Interaktion mellan levande vävnad och syntetiska material LTH EXTG005 HT2014 Lars Magnus Bjursten Cecilia Eriksson Linsmeier Kursmaterial finns att hämta här:

2 Kursmål Understand the special requirements imposed on biomaterials Interaction with biological environment Lack of serviceability Special requirements in various applications (vascular, orthopaedic, ophtalmic) The development path for a new medical device/ biomaterial/

3 Kurslitteratur Kompletterande läsning Buddy-Ratner/isbn /

4 Kurslitteratur Kompletterande läsning Buddy-Ratner/isbn /

5 Biomaterial A biomaterial is any matter, surface, or construct that interacts with biological systems. Material intended to interface with biological systems to evaluate, treat, augment or replace any tissue, organ or function of the body (ESB Consensus Conference II)

6 Biocompatibility 1. "The ability of a material to perform with an appropriate host response in a specific application", (this definition deals with materials and not with devices ESB Consensus Conference I). 2. "The quality of not having toxic or injurious effects on biological systems" 3. "Comparison of the tissue response produced through the close association of the implanted candidate material to its implant site within the host animal to that tissue response recognised and established as suitable with control materials" - ASTM 4. "Refers to the ability of a biomaterial to perform its desired function with respect to a medical therapy, without eliciting any undesirable local or systemic effects in the recipient or beneficiary of that therapy, but generating the most appropriate beneficial cellular or tissue response in that specific situation, and optimising the clinically relevant performance of that therapy" 5. "Biocompatibility is the capability of a prosthesis implanted in the body to exist in harmony with tissue without causing deleterious changes".

7 Medical device Europalagstiftning Medical device' means any instrument, apparatus, appliance, material or other article, whether used alone or in combination, including the software necessary for its proper application intended by the manufacturer to be used for human beings 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,

8 Medical device US legislation Medical machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory that is: Recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them Intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment or prevention of disease, in man or other animals Intended to affect the structure or any function of the body of man or other animals, and does not achieve any of its primary intended purposes through chemical action within or on the body of man or other animals and does not depend on metabolic action to achieve its primary intended purposes.

9 Use of Biomaterials Substitute for organ function To promote tissue regeneration Access devices Drug delivery Diagnostic procedures Biotechnology

10 Substitute for organ function Organs where the function is primarily related to cell function Liver, Muscle, Intestine, Nerve, Brain Organs where the function is related to the Extra Cellular Matrix (ECM) and the cells are primarily supporting the ECM Skeleton, ligament, tendon, tooth, intraocular lens Other functions Access device, drug delivery, diagnostics,some barriers, component in tissue engineering

11 Historisk utveckling av höftproteser Wear and poor anchorage 1920 Glass as sliding surface Fatigue and corrosion problems 1953 Acrylic used as bone cement 1956 Metal to metal 1958 Metal to Teflon, Metal to HMWPE 1970 Ceramic to HMWPE 2010 World market $4.7 billion

12 Historisk utveckling av Intraocular lenses Accidentally implanted fragments of canopy WWII (ICI Perspex PMMA) First implant Industry, Soft lenses million lenses

13 Development and testing of Medical Devices Idea Proof of principle Physiological principle Materials evaluation In vitro tests In vivo test Adaptation to a clinical device Human anatomy and physiology Clinical evaluation Risk/benefit Cut off point

14 Ethics How to develop Biomaterials? Use of animals? Clinical evaluation? Commercial aspects vs patient needs? How to regulate devices? Different devices for young and old? Exposure to litigation

15 Wound healing

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22 Cells in the Immune system Lymphocytes T-cell (helper, supressor...) B-cell (incl. plasma cell) Macrophages (Monocytes, dendritic cells) Basophils Eosinophils

23 Professional Phagocytes Main location Blood Bone marrow Bone tissue Gut and intestinal Peyer's patches Connective tissue Liver Lung Lymphoid tissue Variety of phenotypes neutrophils, monocytes macrophages, monocytes, sinusoidal cells, lining cells osteoclasts macrophages histiocytes, macrophages, monocytes, dendritic cells Kupffer cells, monocytes self-replicating macrophages, monocytes, mast cells, dendritic cells free and fixed macrophages and monocytes, dendritic cells Nervous tissue microglial cells (CD4 + ) Spleen Thymus Skin free and fixed macrophages, monocytes, sinusoidal cells free and fixed macrophages and monocytes resident Langerhans cells, other dendritic cells, conventional macrophages, mast cells

24 S. Gordon: Nat Rev Immunol. 3, Jan 2003, p23

25 The Macrophage Foreign Compound soluble particle surface Phagocytosis Immune response Cytokines Antigen processing Reactive Oxygen Intermediates (ROI) Metalloproteases Local Environment: Cells & Matrix Proteolytic enzymes Cell surface receptor activation

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29 Wound healing

30 Foreign body reaction

31 Foreign body reaction Tissue is organized parallel to the surface! Macrophages (Mø) are usually closest to the materials interface

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35 What can a cell detect? Surface chemistry! Non specific! Receptor specific! Surface structures! Particles! Shear stress

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38 Gold with covalently bound self assembling monolayers (Whiteside) -OH functionality -CH3 functionality gluthation

39 Foreign body capsule formation by modified surfaces Capsule thickness 30 days µm Gold OH- CH3- Gluthation

40 Surface ligands e.g. RGD e.g. Bone Sialoprotein

41 Bone sialo protein adsorbed on polystyrene Control: albumin

42 Ligand binding Cell binding e.g. RGD Matrix binding: e.g. Bone sialoprotein

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44 Surface geometry Polyethylene film Coarse side: 100 grit sandblasted glass imprint smoth side: air interface or smooth glass imprint

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46 If surface contact or substance release triggers adverse host response, then a smooth surface should induce least reaction

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48 Polymer degradation Copolymers of 1,5-dioxepan-2-one and L- or D,L-dilactide: In vivo degradation behaviour. Löfgren et al J.Biomater.Sci. Polymer Edn. 6, 411(1994)

49 In-vitro results rarely translate to in-vivo

50 ?

51 Cell death at the interface shown by i.v. injection of propidium iodide Rosengren et al: JBMR, , p. 918

52 The Macrophage Mr Hyde: Induction of Tissue Injury Dr Jekyll: Extracellular Matrix Remodelling and Resolution of Inflammation

53 Macrophage activation from Duffield JS: Clin Sci (Lond). 2003;104(1):27-38

54 Proposed negative feedback for inflammatory Mø populations entering the inflamed site Monocytes entering the inflamed tissue become classically activated and induce apoptotic death of other cells in the tissue. These newly apoptotic cells are phagocytosed by the killer Møs and this process brings about a switch in Mø function to a cell sharing many features with the alternatively activated Mø. from Duffield JS: Clin Sci (Lond). 2003;104(1):27-38

55 S. Gordon: Nat Rev Immunol. 3, Jan 2003, p23

56 S. Gordon: Nat Rev Immunol. 3, Jan 2003, p23

57 S. Gordon: Nat Rev Immunol. 3, Jan 2003, p23

58 S. Gordon: Nat Rev Immunol. 3, Jan 2003, p23

59 Cell death at the interface shown by i.v. injection of propidium iodide Rosengren et al: JBMR, , p. 918

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61 The Young Modulus is the gradient of the stress-strain graph for the region that obeys Hooke s Law Young modulus = tensile stress tensile strain = Fl Ae

62 Typical Young s moduli Aluminium oxide ceramics Stainless steel, CoCr alloys Titanium alloy PMMA Polyethylene Silicone elastomere Bone (cortical) Soft tissue muscle, tendons Cells 350 GPa 200 GPa 100 GPa 3 GPa 1 GPa 2 MPa 20 GPa 40 KPa KPa

63 Stress on tissue?

64 Klein-Nulend et.al: FASEB (1995) 9, 441

65 Shear at the interface Cell death Intracellular sensor/effector Alternate Mø activation circuits in macrophages? ECM remodelling/foreign body formation

66 Macrophage Activation by Biomaterials Soluble products from material Immunogenic materials ((Materials that become immunogenic by protein interaction)) Surface activation of cascade systems Mechanical shear at the interface!?

67 By applying magnets in a rotating magnetic field controlled oscillating shear can be applied

68 Exposure to (increased) controlled shear 5 x 10-6 Nm 1 w 2 hours daily 1 Hz Exposure with magnet Exposure without magnet

69 The thickness of the fibrotic capsule at implanted polyethylene spheres, different only in their size. Mathematical modeling suggests that mechanical factors are most important for the observed differences and release of substances from the different sized materials cannot explain the differences

70 Interfacial shear seems to be the single most important factor for host tissue response (?)

71 Implant 50 µm

72 Fluorescein (green) released from implant, cell nuclei (blue) Capillaries (red; CD31)

73 Meghdi Babakhanlou James Ko

74 Any substance or cytokine released at the interface will only have a limited reach before it is distributed systemically