Definition of Biocompatibility

A material is biocompatible when: 1) it is able to function in the applied environment 2) it is non-toxic/ non-injurious to biological systems 3) there is positive tissue response to material Biological environments are dynamic in nature, thus biocompatibility is an interactive property that takes into account all three interrelated factors (material properties, patient response and material function).

Introduction to Clinical Examples

There are a variety of dental materials and/or devices used in dental procedure, whether they be for restorative, prosthetic, therapeutic or examination purposes. These come in two major categories; intraoral and extraoral devices that are used to treat a patient. An intraoral dental material is fabricated inside the patients mouth. Conversely, extraoral devices are fabricated outside the oral cavity. The Amalgam Filling Amalgam is a mix of mercury (43-54%) and a powdered alloy made mostly of silver, tin, zinc and copper The amalgam filling is an intraoral device; as it is constructed inside the oral cavity. Amalgam is biocompatible; it is used widely in dental restorative procedures. It fulfils the criteria of biocompatibility in that it: o coexists with the biological equilibrium of the tooth and associated body systems o the material functions as it should in the oral environment o promotes a positive tissue response, in that the patient doesnt experience any adverse effects. the most probable NEGATIVE physiologic repercussion to dental amalgam in the oral cavity is marked by contact dermatitis or Coombs Type IV hypersensitivity and these reactions are experienced by less than 1% of patients that are treated. This has lead to some dental professionals falsely recognising other diseases as symptoms of amalgam toxicity. Custom Impression Tray Most commonly made using synthetic dental resins; methacrylates Not soluble in the saliva or any of the other fluids taken into the mouth and also impervious to oral fluids. Impression tray is tasteless, odourless, non-toxic, isnt irritating and doesnt do any harm to the oral tissues

Strong and hard, not brittle fulfils its role effectively as it is resilient to external forces The downside allergic reactions to methacrylates have been described before contact dermatitis, and delayed type IV hypersensitivity.

Evaluation of Biocompatibility of Materials (Tests)

Before the test
Must consider Location of a material In contact with hard or soft tissues? Internal or external to epithelium? Duration of the material Impression material: 5-10 mins Restorative material: many years Stresses placed on the material Physical, chemical or thermal

Types of Tests 1. In Vitro

- conducted outside of intact organism such as in test tube, flask etc - usually first test carried out to screen different materials e.g. check toxicity and acceptability as biomaterial - contact between biological system (cells, bacteria, enzymes etc) and materials Advantages - relatively cheap - relatively fast - relatively simple - conditions can be highly regulated: more accurate test results - can avoid ethical issues e.g. animal and usage testing Disadvantage - cant reproduce complex biological system - highly irrelevant testing conditions Evaluation of mutagenic potential of 4 metals using spot test Upper left, negative control with water; lower left, Ti-Co alloy; upper middle, Ni-Cr alloy; lower middle, Ti-Ag alloy; upper right, pure Ti; Lower right, positive control with mutagen.

2. Animal Test

- Common animals used mostly mammals e.g. mice, rats, hamsters, ferrets or guinea pigs -Might not be relevant to final use e.g. letting animals to eat the material to check its toxicity Advantages - allows to observe biological respond to a material - complex interactions Disadvantage - Expensive - time taken: may be long - Ethical/animal welfare issues - difficult to regulate conditions - may be irrelevant to human condition - Inadequate representative of human mouth

Polyethylene and nickel wire were inserted in mice for 7 days. C (control)- no inflammation PE- little inflammation Ni- severe inflammation

3. Usage Test
- clinical trial: in humans Advantages - test directly relevant to clinical usage - give most reliable test results of biocompatibility of a material Disadvantages - expensive - time consuming - difficult to control test conditions - ethical and legal issues

Adverse effects
Being biocompatible is all well and good, but what happens when things aren't well and good? When a dental material causes unwanted effects upon the body, it is termed an 'adverse effect'. There are four main divisions of adverse effects, however, the boundaries between each is not clear cut, and as more is gleaned concerning materials and its cellular impact, the boundaires between each group dissapear. However, the distinctions are still used and are described as toxicity, inflammation, allergic, and mutagenic. Toxicity Toxicity was the first biological response that was activiely tested for. Toxicity refers to a materials toxic and/or poisonous characteristcs and is determined by a materials ability to realease harmful particles into the body. AN example of this would be lead in early dentistry. Most toxic materials are no longer used. Inflammation Inflammation is a complex biological reaction, ehich can results from toxicity or alergic reations. It is typically characterised by edema of the tissue. Immune response consists of many different cells, - Neutrophils in short term inflammation - Monocytes and other lymphocytes in long term inflammation Current dental material testing in this field is mainly concerned. even if no toxicity is present. Dental amterials play a vital role in inflammation responses becuase pulpal and periodontal disease is usally chronic inflammatiort responses and longterm infections. Thus, solving inlfmmation would solve many cases of pulpal and periodontal disease. Allergic Reesponses Commonly known biological response, but is not well defined. it is basically a material that is normally accepted that is detected as foreign by a particular individual. The immune system then responds disaporportionally. This response involves the whole immune system, so can by a systemic effect by nature. There are several types of allergic reactions taken from Gell and Coombs classification of immune response: I immediate atopic anaphylactic antigen reacts with most cells + basal cells II cytotxicty hypersensitivity reaction III immense complex hypersensitivity IV delayed or cell-mediated hypersensitivty V stimulating antibody reaction VI antibody dependent, cell mediated cytotoxicity

Histologically, can be hard to differentiate bewtween loe grade toxicity and inflammation. The main difference is that allergies affect some people and is disproportionate to the amount of substnace, while a non allergic reaction is common thoughout the population and is proportinal to the amount of substnace. Mutagenic These occur when a material alters the base pairing of DNA, resulting in a mutation. This can be due to the material either directly changing the DNA or inderectly by affecting the processes which maint DNA integrity. Normal mutations occur quite commonly, and the body uses energy and implements different processes to repair DNA. Many factors influence the occurence of mutations such as radiation, cheicals and errors in DNA replication process. Dental materials also influence mutagenicity, some metals (nickel, copper, beryllium) and other materials - some root canal sealers - are know to do this. Form and route of exposure critical to mutagenity. However, Mutagenicity does now imply carcinogenic, as most mutations have no effect or are repaired by the DNA repair porcesses. In fact, no dental materials have show to be carcinogenic in a patients' mouth. Systemic and Local These four divisions can also be described as having a local or systemic effect on the body. Any material can have alocal or systemic effect, depending on a variety of factors, including substance, response of body, which determine nature, severity and location. Local examples include pulp, periodontium and root apex. local and systemic are determined by distribution. systemic effects occur when a substance is allowed to traverse the body, this can occur in several ways, such as ingestion and then absorbtion in the gut, inhaled vapour, release at tooth apex, and absorption throuth the oral mucosa. This is then distributed through diffusion or through the lyphatic and/or bascular system. Pathologically, both are affected by duration/concentration of exposure, excretion site, and site of exposure. For example, Mercury has long life in body, so can acuumulate to critical levels more readily than others that are excreted. Also to be noted is that tissues may not react the same to different materials, while some organs actiavely alter substnaces for digestion or absorption, such as the liver. Key Principles of Adverse Effects There are two main principles when determining biocompatibility, corrosion and surface characteristics. Corrosion results in substnaces from the material being release into the body. This is a broad definition and can apply to any material. For example gold crown can release metal ions due to electrochemical process or mechanical wear. Some materials have cyclical stresses create realease substance into the mouth while others are designed to break down in the oral cavity. This degredation process is always occurring, even if not visible to the naked eye. the biological response from degradation epends on composition, form and location. The oral cavity also plays a role in the degradation process. Different environment effect dental materials in ways that are hard to determine. FOr exmaple, a person who drinks a lot of coke will have a low pH value in the mouth, whieh will effect the degradation of

ceramics and metals. These types of variables can by specific or common (such as occlusal forces). Therefore, it is a dynamic relationship between the material and mouth. Where the material affects the mouth and the mouth affects the material. Surface characteristics can grewatly affect the effects a material has on the body. ZThe surface of a material can be significantly different from the inside. A gold crown may be 70% gold by weight on average, but it has been recorded that the gold on the surafce can be 95% by weight. An example of surface characteristics and a biological response is that titanium alloys can induce osseointegration due to an oxide layer on the surface (it should be noted that titanium is one of the best metals to be used in the body as there have been few, if any, cases of individuals being allergic to titanium, while its toxicity, inflammation and mutagenic effects are non-existent). However, surface characteristics can have negative impacts as well. Rough srufaces can be areas where bacteria readily adhere to, accerleating disease.

Immuntoxicity As before, as more knowledge becomes available concerning the itneraction between a material and cells, the divions of inflammatory, allergic, and mutagenic reactions become grayed. For example, monocytes control the immune response so if a material affects the monocytes, immune response can be amplified, showing both inflammatory and toxicity characteristic. Another example, mercury and palladium effect cellular processes, that can cause effects upon cell function due to changes in glutathione, imporntant in maintining oxidative stress in cells.

Influence of Oral Anatomy to Biological Response

Enamel-dentine-pulp environment Enamel Enamel is highly crystalline. It is generally impermeable to material compounds, bacteria and their products although permeable by some substances like peroxides in bleach. Acid etching is where minerals in the enamel are dissolved for better bonding of restorations. Dentine The composite nature of dentine allows bonding of materials because acids selectively dissolve the mineralized matrix but not the collagen. Therefore dentine restorations attempt to penetrate the undissolved collagen matrix. If enamel is violated then dentinal tubules may serve as conduits by which infection may reach the pulp of the tooth. When dentine is cut a smear layer of debris covers the dentine and inhibits diffusion. The smear layer may be contaminated and is not well bounded to the uncut adjacent dentine. Many restorative procedures involved removal of the smear layer to promote stronger bonding.

Central to the success of a restoration is the quality of the restoration-dentin seal. The sealant must cover the dentine tubules and any compromise of the seal can lead to 2 decay.

Pulp

The odontoblasts are welded together by tight junctions that limit diffusion. Cutting devices may destroy odontoblasts, unless conservative measures such as water cooling are used. The pulp supplies the cells, which replace any odontoblast destroyed during cavity preparation or material placement and allows the tooth to repair dentine. Some materials, such as calcium hydroxide seem to promote the formation of reparative dentine. Dentine tubules are surrounded by extracellular fluid that is continuous with the extracellular fluid of the pulp. The perception of pain in the pulp is believed to be related to the movement of this fluid and its influence on odontoblastic processes.

Periodontal attachment Because many dental restorations are near or in the periodontal attachment area, the biocompatibility of these materials may influence the normal periodontal function. The periodontal pocket is a unique microenvironment that may allow concentrations of material components to reach high levels. Some alloys release sufficient amounts of copper and mercery that cause inflammation in the periodontal and gingival tissue. When the pulp of the tooth is destroyed, endodontic materials are placed in the pulpal space. Incorrect procedure may cause the filling materials to extrude from the apex into the periapical area and cause additional damage.

Bone Bone is also considered as part of the oral cavity. It was then discovered that metal titanium could become permanently incorporated with bone. That is, the living bone could become so fused with the titanium oxide layer of the implant that the two could not be separated without fracture. Osseointegration Consequently, Osseointegration was originally defined as a direct structural and functional connection between ordered living bone and the surface of a loadcarrying implant. It is now said that an implant is regarded as osseointegrated when there is no progressive relative movement between the implant and the bone with which it has direct contact. In practice, this means that in osseointegration there is an anchorage mechanism whereby nonvital components can be reliably and predictably incorporated into living bone and that this anchorage can persist under all normal conditions of loading. Biointegration

The main difference is that the implant is coated with bioactive materials such as hydroxyapatite. These bioactive materials stimulate bone formation leading to a physico-chemical bond. The implant is ankylosed with the bone.

Consequences involved with non-biocompatible materials.

Microleakage A passage of fluid and bacteria in micro gaps (10^-6m) between restoration and tooth Considered the most significant hazard and greatest risk to the pulp Causes? During placement, it can occur when the dental polymer shrinks and causes a gap. Air bubbles during the mixing of the material Poor adhesion and wetting Over time, mechanical loading Thermal stresses Effects: Bacteria, food debris and saliva can be drawn into the gap through to the pulp leading to infection Furthermore, breakdown of the material is encouraged and consequently the structure will change over time, leading to larger gaps and then more leakage.

Microleakage can then lead to corrosion in amalgam. The saliva in the space can act as an electrolyte, enhancing more corrosion in the amalgam Electrolyte: Medium for ions to pass through Then copper and mercury can be released from the amalgam filling which will then cause numerous adverse affects which can be both local or systemic. Furthermore, it can affect the edges of teeth which will lead to plaque formation and secondary caries.

References:

Effect of base/liner use on restoration leakage, K.R. MARSHALL, B.R. HOLMAN, and J.A. VON FRAUNHOFER, University of Maryland Dental School, Baltimore, USA Oxford Handbook of Clinical Dentistry - 4th Ed. (2005), David A. Mitchell and Laura Mitchell with contributions from Paul Brunton. R. Van Noort, Introduction to Dental Materials Mosby 1994 (2nd ed. June 2002) R.G. Craig, J.M. Powers, Restorative Dental Materials 11th ed. Mosby 2002 Anusavice K.J. Phillips Science of dental materials. 11th Ed. Missouri: Saunders; 2003 Von Recum A.F, editor. Handbook of biomaterials evaluation. 2nd Ed. New York: Macmillan Publishing Company; 1986