Key Concepts in the Use of Biomaterials

BMEN 344 – BIOLOGICAL INTERACTIONS AND TESTING KEY CONCEPTS IN THE USE OF BIOMATERIALS IN SURGERY AND MEDICAL DEVICES Learning Objectives

 Appreciate the importance of biological testing for medical devices and the present- day requirement to demonstrate safety and efficacy  Possess a baseline knowledge of cell and molecular biology that is important for understanding biological interactions and testing  Appreciate that medical devices must contend with the body’s protective and reparative responses  Be able to describe, in general terms, the sequence of events after a biomaterial is placed in a biological milieu and what cells are responding to when they encounter an implanted biomaterial

2 Poll Question

Imagine that your grandmother suffers from cataracts, and over the holidays you learned that her doctor wants to perform surgery and implant a new intraocular lens that he and some colleagues have developed. Do you think this is a good idea?

www.socrative.com BMEN344 3 Monet’s Water Lily Pond, a painting of the pond and bridge before any visual symptoms (1899) The Japanese Bridge at Giverny (1918-1924) 4 Marmor. Arch Ophthalmol. 2006;124(12):1764-1769. Biomaterials History: The Era of the Physician-Hero

 Newly developed high-performance materials (especially polymers) became readily available after the World Wars  Government regulatory activity was minimal, and today’s protections for human subjects were non-existent  Materials originally manufactured for airplanes, automobiles, clocks, and radios were taken “off the shelf” by innovative physicians and applied to medical problems  Silicones, polyurethanes, Teflon, nylon, methacrylates, titanium, and stainless steel

5 Biomaterials History: The Era of the Physician-Hero

Sir Harold Ridley developed intraocular lenses after observing that plastic shards healed in place with no further reaction

6 Biomaterials History: The Era of the Physician-Hero  Willem Kolff devised the first dialysis machine from a Maytag washing machine in the 1960s  Belding Scribner and Wayne Quinton developed an arteriovenous shunt to enable chronic dialysis

https://ohiomemory.org/digital/collection/p267401coll36/id/24024/ 7 Leonard et al. Blood Purif 2011;31:92–95. Biomaterials History: The Era of the Physician-Hero

Published in 1956

Deterling and Bhonslay. AMA Arch 8 Surg. 1956;72(1):76-91 Biomaterials History: Taking Action to Protect Patients

 In 1969 President Nixon called for “certain minimum standards” for medical devices and declared that “the government should be given additional authority to require premarketing clearance in certain cases [of medical devices].”  In 1970 The Cooper Report was released (Medical Devices: A Legislative Plan”) and reported that more than 700 deaths and 10,000 injuries were associated with medical devices  512 deaths and injuries were attributed to heart valves  89 deaths and 186 injuries were tied to heart pacemakers  10 deaths and 8,000 injuries were attributed to intrauterine devices 9 Biomaterials History: Taking Action to Protect Patients

10 Biomaterials History: Taking Action to Protect Patients

 While the Cooper Committee recommendations were being debated in Congress during 1972 and 1973  Pacemaker failures were reported  In 1975, hearings took place on problems that had been reported with the Dalkon Shield intrauterine device, which caused thousands of reported injuries  These incidents helped underscore the need for regulation  In 1976 the Medical Device Amendments were passed  Purpose was to ensure safety and effectiveness of medical devices, including diagnostic products  Required manufacturers to register with FDA and follow quality control procedures  Introduced the concept of premarket approval by FDA for certain products

11 Takeaway Points  Simply choosing materials based on their physical properties is a recipe for disaster  To design medical devices that are both safe and effective, we must also consider how materials interact with biological systems  This is why the biomaterials field exists  The word “biomaterials” implies an intersection of biology and materials  Put simply, we must perform biologically relevant testing and ensure biocompatibility  Discussion: How do we define biocompatibility?

12 13 The Intersection of Materials and Biology  When a synthetic material is placed in a biological milieu (e.g., implantation in a living organism), a series of reactions is initiated almost instantaneously  Water molecules and ions reach the surface of the material nearly instantaneously  Subsequently, proteins reach the surface and may coat it  Cells then interact with this coated surface  Additionally, materials must contend with the body’s protective and reparative responses  Blood coagulation (hemostasis) Implantation is an Injury  Inflammation  Wound healing AND  Innate immune system Biomaterials are Foreign  Adaptive immunity Objects 14 Cell and Molecular Biology (prerequisite knowledge)  The basic functional attributes of cells include  Protection  Signaling  Nutrient absorption and assimilation  Energy generation  Macromolecule synthesis  Growth https://bio.libretexts.org/Bookshelves/Cell_and_Molecular_Biology/Book%3A_Basic_Cell_and_Molecu  Reproduction lar_Biology_(Bergtrom)/16%3A_Membrane_Structure/16.02%3A_Plasma_Membrane_Structure

 However, most cells in the body are differentiated and exhibit specialization  Differentiation allows for a division of labor in the performance and coordination of complex functions carried out in architecturally distinct and organized tissues and organs  Examples: conductivity (nervous system), contraction (muscle), protection (immune system), absorption/secretion (gastrointestinal tract), transport (cardiovascular system)  Receptors on the surfaces of cells enable them to sense and respond to stimuli  Differentiated cells (e.g., macrophages) can exhibit different phenotypes www.socrative.com 15 BMEN344 Discussion Questions  What cells types do you know?

 What is meant by cell phenotype?

 How are the actions of cells (e.g., secretory activity, proliferation, migration) regulated?

16 17 https://libretexts.org/ 18 https://bio.libretexts.org/Bookshelves/Cell_and_Molecular_Biology/Book%3A_Basic_Cell_and_Molecular_Biology_(Bergtrom) Overview of Cell-Matrix Interactions, Signaling, and Regulation of Cell Behavior  Stromal cells, parenchymal cells, capillaries, and nerves are embedded with an extracellular matrix (ECM) and physically and functionally integrated in tissues and organs  The ECM comprises the biological material produced by and residing in between cells  The ECM provides physical support to cells (they can adhere to it) but also regulates cell behavior  The ECM is dynamic and is remodeled by cells

19 Fig. 2.4.1.4 Overview of Cell-Matrix Interactions, Signaling, and Regulation of Cell Behavior  Receptors called integrins bind to extracellular matrix proteins (e.g., collagen, fibronectin, laminin) and mediate cell-matrix interactions  Other receptors called cadherins and Cell Adhesion Molecules mediate cell- cell interactions  Other receptors bind soluble molecules that are secreted by cells  Growth factors  Cytokines  Chemokines  Key point: Engagement of specific receptors triggers signal transduction pathways that affect gene expression and cell activity 20 Fig. 2.4.1.5 Overview of Cell-Matrix Interactions, Signaling, and Regulation of Cell Behavior  Receptors called integrins bind to extracellular matrix proteins (e.g., collagen, fibronectin, laminin) and mediate cell-matrix interactions  Other receptors called cadherins and Cell Adhesion Molecules mediate cell- cell interactions  Other receptors bind soluble molecules that are secreted by cells  Growth factors  Cytokines  Chemokines  Key point: Engagement of specific receptors triggers signal transduction pathways that affect gene expression and cell activity 21 Fig. 2.4.1.6 Overview of Cell-Matrix Interactions, Signaling, and Regulation of Cell Behavior

 Growth factor – broad class of cell signaling molecules (generally proteins) that can act on a variety of cell types or may have a specific target population  Promote cell proliferation and differentiation  Also influence cell movement, contractility, protein synthesis (i.e., almost any cellular activity)  Key regulators of tissue repair and wound healing  Some examples: vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet derived growth factor (PDGF), epidermal growth factor (EGF) 22 https://www.rndsystems.com/pathways/vegf-vegf-r2-signaling-pathways Overview of Cell-Matrix Interactions, Signaling, and Regulation of Cell Behavior

 Cytokine – a more narrow (but still broad) class of cell signaling molecules  Historically refers to signaling molecules that regulate immune cells, but the term is often used interchangeably with growth factor  Examples: interferons (IFNs), interleukins (ILs), and tumor necrosis factors (TNFs)  Chemokine – class of cell signaling molecules that guide cell migration  Chemotaxis is directional cell movement in response to a chemical gradient

23 Cell and Tissue Injury  Cells and tissues attempt to maintain their milieu and function within a relatively narrow range of physiologic parameters  Adaptative mechanisms exist to preserve tissue function and homeostasis when physiologic stresses or pathologic stimuli are encountered…but they have a limit  Exceeding this limit results in cell injury and death  Necrosis (cell death due to irreversible injury) results in an inflammatory response  Apoptosis (programmed cell death) results in little to no inflammatory response  Two important causes of injury are toxic injury and trauma  Chemical agents (components of food, naturally occurring toxins, hormones, synthetic drugs, environmental pollutants, poisons, ethanol) can cause cell injury  Chemicals are used to synthesize materials  Direct mechanical force (trauma, pressure), temperature extremes, electric shock, and ionizing radiation can also cause cell injury  Surgery is traumatic and causes irreversible injury  Excessive inflammation can also cause injury Fig. 2.4.1.12 24 Response to Tissue Injury and Biomaterials Macrophages play a key role in the response  A key protective response of an organism is its to injury ability to eliminate damaged tissues and foreign invaders (e.g., microbes, exogenous nonbiological materials like splinters)  Immune protection  To restore homeostasis, damaged tissues must be repaired  In limited cases, tissue regeneration is possible and normal structure and function can be restored  More commonly, the damaged tissue is replaced with fibrotic scar tissue  When foreign bodies are present and cannot be eliminated, they are encapsulated in fibrous tissue to isolate them from the rest of the body Fig. 2.4.1.16  Foreign body reaction (FBR) 25 Introduction to the Foreign Body Reaction

 Discussion:  What drives this biological response?  Does fibrous encapsulation indicate that a material is not biocompatible?

26 Ratner. Regen Biomater. 2016;3(2): 107-10. The Intersection of Materials and Biology  When a synthetic material is placed in a biological milieu (e.g., implantation in a living organism), a series of reactions is initiated almost instantaneously  Water molecules and ions reach the surface of the material nearly instantaneously  Subsequently, proteins reach the surface and may coat it  Cells then interact with this coated surface  Additionally, materials must contend with the body’s protective and reparative responses  Blood coagulation (hemostasis) Implantation is an Injury  Inflammation  Wound healing AND  Innate immune system Biomaterials are Foreign  Adaptive immunity Objects 27