NEXT PAGEThe recognition of biologic interactions between synthetic materials and body tissues has been translated into the twin operational concepts of biomaterials and compatibility. Biomaterials are manufactured substitutes for natural tissues. They are used in implants or to convey and process body fluids such as blood. Standard design considerations include:
Compatibility, on the hand, characterizes a set of material specifications and constraints which address the various aspects of material - tissue interactions. More specifically, hemocompatibility defines the ability of a biomaterial to stay in contact with blood for a clinically relevant period of time without causing alterations of the formed elements and plasma constituents of the blood or substantially altering the composition of the material itself.
Biocompatibility of the materials and their degraded products is required for resorb able implant development. Purified collagen materials have been extensively tested in clinical studies as implants and have proven to have no adverse effects. Despite the safety record of their implantation, during the preparation of collagen templates, small amounts of unwanted noncollegenous materials can be incorporated into the device such as salts and cross-linking agent, so a series of Biocompatibility testing must be conducted in order for the harmful agents of the materials do not cause any safety issues. Bench testing of a completed prototype has three major purposed :
1. To observe the mode of operation of the device and asses its performance under tightly controlled circumstances.
2. To define performance in quantitative terms over a wide range of environmental or input conditions.
3. To assess the device’s reliability and durability in a manner which can be further explained to the intended clinical use.
Outlook for Organ Replacement. A new generation of implantable material has begun to emerge through the collaboration of biomaterial science and cell biology.
This combination leads to a new class of biohybrid devices which includes:
Host Reactions to Biomaterials
Thrombosis - Coagulation of blood is an important consideration in the use of implants and in the tubing and other devises that will contain blood. The product of coagulation is a clot. If the clot is inside a blood vessel it is called a thrombus, and if it moves it’s called an embolus
Hemolysis - Disruption of erythrocytes (hemolysis) may occur in response to contact with foreign materials, or through mechanical stress. Hemolysis can also occur if the red blood cells are immersed in a hypotonic solution, (e.g., water).
Inflammation - Inflammation is a generalized response to tissue injury or destruction, such as occurs in surgical implantation. The classic signs of inflammation are: redness, swelling, heat, and pain.
Adaptation - The entire process of the blood-clotting is an adaptation, as a variety of coagulating agents are introduced to the wound site, in order to stop bleeding and aid in the response.
Infection and Sterilization - In addition to being clean and pyrogen free, an implant (or any material contacting a wound or blood) must be sterile
Methods of sterilization are as follows:
1. Cold solution
2. Dry heat
3. Moist heat (steam)
4. Gas
5. Radiation
Carcinogenesis - Cancer may be induced by exposure to chemical carcinogens or foreign bodies, or by mechanical irritation. Induction of cancer by implants is rare in humans, and its rate might be reduced even more by keeping the implant as small as possible.
Hypersensitivity - Foreign bodies can induce hypersensitivity or allergic response from the immune system. This is a cell-mediated, delayed hypersensitivity to antigens on the surface of the foreign body, but may be widely disseminated in the body if fine particles are released to the lymphatics or blood.
Systemic Effects - Most effects of implants are local, but dissolved metal ions and fine particles may be transported in the lymph and blood and thus have systemic effects, including potential carcinogens or hypersensitivity.
Two generalizations have been made of the progressive recognition of the tissue material interface:
1. All materials in contact with body fluids or living tissues undergo continued surface deposition of body components which alter their original properties.
2. All body tissues and fluids in contact with foreign material undergo a dynamic sequence of biologic reactions which evolve over weeks or months, and these reactions may remain active for as long as the contact persists and maybe even beyond.
Cardiovascular Implants
A variety of natural and synthetic materials have been used to replace blood vessels and valves that leak or do not perform the normal physiological functions. In cases such as aortic replacement, patient survival requires the use of synthetic materials since no other vessel of the size of the aorta can be used to replace large portions of the major elastic artery in the body. But, in other cases such as the replacement of small diameter vessels such as the coronary arteries, no synthetic material currently available meets the requirements for the design. Clinical use of both natural and synthetic materials has led to trial and error use of approaches that most commonly lead to patient survival.
The most commonly used valve replacements are mechanical devices involving a ball or disk in a housing, or bioprosthetic valves that are derivatives of natural valves. They are made of totally synthetic materials while bioprosthetic valves are pig or human valves that are chemically preserved and attached to a sewing string for stabilization during surgery. A disadvantage associated with mechanical valves is that patients receiving this prosthesis must be maintained on anticoagulant ti prevent systemic clotting while patients receiving bioprosthetic valves do not require anticoagulant therapy, but these valves fail by calcification and degeneration.
Breast Implantation
There are several types of implants that have been used in breast augmentation:
Materials Used Modern day implants use only a limited number of materials for devise construction. Here are some of the materials and there uses :
Recently, the use of silicone implants have been limited by the FDA.
Complications Associated with Breast Implants
There are a number of complications which can occur as a result of breast implantation:
Implant Placement
Placement of the implant can be either beneath the glandular tissue where it can fill out the loss of breast tissue due to atrophy or it can be placed submuscularly. Subglandular placement requires the creation of a pocket within the breast tissue retaining the initial breast shape. A disadvantage of this placement is that conditions of the breasts including fibrocystic disease, may affect the softness of the implant.
Artificial Skin Replacement
Recent success in development of biodegradable materials that actively participate in dermal wound healing as well as advances in expansion and differentiation of dermal and epidermal cells in tissue culture has led to the growth of artificial skin. Growth of epidermal cells in culture and their use to cover wounds displayed that small pieces of rabbit skin could attach to support surfaces and proliferate to form layers of epithelial cells that propagate in tissue culture. Also, evidence was presented that human epidermal cells grown in vitro can be transplanted to the mouse and that growth and transplantation can continue in vivo in the mouse.
Reports were also made on the fabrication of a living skin equivalent consisting of dermal and epidermal components each made with cells taken from a potential graft recipient that were cultured on a contracted collagen matrix. The equivalent served as a substitute for skin in experimental animals after rapid vascularization. It inhibited wound contraction, and was immunologically tolerated. In later studies, it was proposes that allograft cells cultured on a collagen matrix were tolerated because cells without class II antigens were selected during in vitro cultivation and these cells were used to form a replacement.
Testing Biomaterials
How can biomaterials be evaluated to determine if they are biocompatible and assessed whether they function appropriately in the in vivo environment? The required testing procedures are as follows:
1) How do we test for life-time implantation?
Some biomaterials fulfill their intended function in seconds. Others are implanted for a lifetime(10 years? 70 years?)
2) Evaluation under in vitro (literally "in glass") conditions can provide rapid and inexpensive data on biological interaction. Whether the in vitro test is truly measuring what will occur in the much more complex environment in vivo, it minimizes the use of animals in research, a desirable goal. However, the results of in vitro tests may not be relevant to the implant situation.
3) Animals are used in testing biomaterials to model the environment that might be encountered in humans. However, there is great range in animal anatomy, physiology and biochemistry. Will the animal model provide data useful for predicting how a devise performs in humans ? Without validation through human clinical studies, it is often difficult to draw some strong conclusions from performance in animals. First, you need to choose the animal model that offers a reasonable parallel anatomically or biochemically to the situation in humans. Experiments designed to minimize the number of animals needed, insure the animals are treated humanely.
The pros and cons of testing material (a relatively low-cost procedure providing opportunities for carefully controlled experiments) versus evaluation in a devise configuration (an expensive and difficult-to-control, but completely relevant, situation) must also be weighed.
Testing always leads to experimental variability, particularly tests in living systems.
The more complex the system (e.g., a human versus cells in culture), the larger the variability. Statistics provides an assurance that within a defined probability, the results are meaningful. Statistics should be used at two stages in testing biomaterials. Before an experiment is performed, statistical experimental design will indicate the minimum number of samples that must be evaluated to yield meaningful results. After the experiment is completed, statistics will help to extract the maximum useful information.
The American Society for Testing and Materials (ASTM) and the International Standards Organization (ISO) can often provide detailed protocols for widely accepted, carefully thought out testing procedures.
In Vitro Assessment of Tissue Compatibility The term "cytotoxicity" means to cause toxic effects (death, alterations in cellular membrane permeability, enzymatic inhibition, etc.) At the cellular level. It is distinctly different from physical factors that affect cellular adhesion (surface charge of a material, hydrophobicity, hydrophilicity, etc.).
- Several methods have been validated for repeatability (comparable data among laboratories).
- Cell culture methods have been used to evaluate the biological compatibility of materials for more than two decades (Northup, 1986).
Toxicity A toxic material is defined as a material that releases a chemical in sufficient quantities to kill cells either directly of indirectly through inhibition of key metabolic pathways. Although a variety of factors affect the toxicity of a chemical (e.g., compound, temperature, test system), the most important is the dose or the amount of chemical delivered to the individual cell.
Delivered and Exposure Doses The concept of delivered dose refers to the dose that is actually absorbed by the cell. It differs form the concept of exposure dose, which is the amount applied to a test system.
Safety Factors A highly sensitive test system is desirable for evaluating the hazard potentials of biomaterials because the inherent characteristics of the materials often do not allow the dose to be exaggerated.
Solubility Characteristics The principle components in medical devices are water-insoluble materials (polymers, metals, and ceramics), meaning that less than one part of the material is soluble in 10,000 parts of water. Till et al. (1982) have shown that the migration of chemicals from a solid plastic material into liquid solvents is controlled by diffusional resistance within the solid, chemical concentration, time, temperature, mass transfer resistance on the solvent side, fluid turbulence at the solid-solvent interface, and the partition coefficient of the chemical in the solvent.
Assay Methods
Three primary cell culture assays are used for evaluating biocompatibility:
- direct contact
- agar diffusion
- elution (also known as dilution)
Positive and negative controls are often included in the assays to ensure the operation and suitability of the test system. The negative control of choice is a high-density polyethylene
material.
Direct Contact Test - A near-confluent monolayer of L-929 mammalian fibroblast cells is prepared in a 35-mm-diameter cell culture plate. Live cells adhere to the culture plate and are stained by the cytochemical stain.
Agar Diffusion Test - A near-confluent monolayer of L-929 is prepared in a 60-mm diameter plate. The culture medium is removed and replaced with a culture medium containing 2% agar.
Elution Test - An extract of the material is prepared by using:
1) 0.9% sodium chloride or serum-free culture medium and a specified surface area of material per millimeter of extractant and,
2) extraction conditions that are appropriate for the application and physical characteristics of the material.
Table 1 lists advantages and disadvantages of the three assays. Thus, the major direction of new research will be in defining the benchmarks for application of quantitative methodology.
In Vivo Assessment of Tissue Compatibility
The in vivo assessment of the compatibility of biomaterials and medical devices with tissue is a critical element of the development and implementation of implants for human use. Animal models are necessary in order to account for the effects of the following biological interactions on the response to the biomaterial or medical devise.
The principles underlying the tissue response to implants are founded in the biomedical sciences (e.g., cell and molecular biology, biochemistry, and physiology).
- Surgical wounds in a vascular tissue (e.g., the cornea and the inner third of the meniscus) will not heal because of the limited potential for the proliferation of surrounding parenchymal cells into the wound site.
- Moreover, adjacent cells that have died as a result of the implant surgery will be replaced by fibroblasts and scar tissue.
- The presence of the implant can alter the stress distribution in the extracellular matrix, and thereby reduce or increase the strains experienced by the constituent cells.
- Hyperplasia and hypertrophy of tissue in which mechanical strains have increased due to the presence of an implant have also been seen.
Connective Tissue: Bone and Musculoskeletal Soft Tissue
- Implantation protocols developed to assess the compatibility of materials for orthopedic prostheses have understandably used bone as a site of implantation.
Evaluation of Blood-Materials Interactions
- Every day, thousands of devices made from synthetic materials or processed natural minerals are interfaced with blood. How can the biomaterials engineer know which materials might be best used in the fabricating of a blood-contacting devise ?
- "Blood compatibility" can be defined as the property of a material or devise that permits it to function in contact with blood without inducing adverse reactions.
- A material that will not trigger one response mechanism may be highly active in triggering another mechanism.
- A material that is not blood compatible, i.e., a thrombogenic material, would produce specific adverse reactions:
1) formation of clot or thrombus composed of various blood elements
2) shedding or nucleation of emboli (detached thrombus)
3) destruction of circulating blood components
4) activation of the complement system and other immunological pathways
Blood Interfacing Implants Blood comes in contact with foreign materials in extracorporeal devices such as catheters, kidney dialysis, blood oxygenator, and ventricular assist devices. This contact may also be more long term in vascular implants such as heart valve prostheses and vascular grafts.
Need to develop biomaterials for long term implants. The primary requirements for such biomaterials are:
ð! biocompatibility
ð! nontoxicity
ð! durability
ð! resistant to platelet deposition
ð! nondegradable in the physiological environment
Other design considerations include :
ð! suitable size and weight
Heart valve prostheses can be broadly classified into mechanical prostheses (made of non biological material) and bioprosthesis (made out of biological tissue).
Design if a Resorbable Collagen-Based Medical Implant Two types of implants are the permanent and resorbable implants. Permanent implants replace damaged tissues or organs and are fabricated from materials including metal and natural or synthetic polymers. Permanent implants made of synthetic or biological materials frequently suffer from the long term effects of material degradation. As a lack of the materials for permanent implants, resorbable implants, which are using resorbable templates to induce host tissue regeneration, have recently had widespread use. This area of research is categorized into synthetic and biological templates. Among the biological materials used for resorbable medical implant development, resorbable collagen has been one of the most popular materials.
Physical Dimension The physical dimension of a template defines the boundary of regeneration, thus the size of the collagen template should match the tissue defect to be repaired.
Apparent Density The apparent density is defined as the weight of the dry matrix in a unit volume of matrix, thus it is a direct measure of the empty space which is not occupied by the matrix material per se in the dry state.
Biodegradable Polymeric Biomaterials This class of biomaterials has two advantages that nonbiodegradable materials do not have. First, they don’t elicit permanent chronic foreign - body reaction due to the fact that they would be gradually absorbed by the human body, and they do not permanently retain trace of residual in the implantation sites. Second, some of them have recently found to be able to regenerate tissues, tissue regeneration, through the interaction with biodegradation with immunological cells like macrophages. Therefore, surgical implants made from biodegradable materials could be used as temporary scaffold for tissue regeneration.
The recent introduction of several new synthetic and natural biodegradable polymeric biomaterials. All of them can be categorized into 8 groups :
1. Biodegradable linear aliphatic polyesters and their copolymers within the aliphatic polyester family
2. Biodegradable copolymers between linear aliphatic polyesters and monomers other than linear aliphatic polyesters
3. Polyanhydrides
4. Poly(orthoesters)
5. Poly(ester - ethers) such as poly-p-dioxanone
6. Biodegradable polysaccarides such as hyaluronic acid, chitin, and chitsone
7. Polyamino acids such as poly-L-glutamic acid and poly-L-lysine
8. Inorganic biodegradable polymers which have nitrogen-phosphorus backbone instead of ester linkage
Biology and Composition of Bone
Bone - a structural as well as metabolic tissue
Structural functions - include providing support for the body against gravity acting as a rigid lever system for muscular action. Serving as a protective covering for vital internal organs such as the heart, brain, and blood forming bone marrow.
Metabolic functions - lies in the ability to serve as a repository for Ca+2 which is necessary for nerve conduction, muscle contraction, clot formation and cell secretion.
Bone Development - Embryologically, bone may be detected by 8 weeks in the developing human.
1. Osteoblast - bone forming cells
2. Osteoclast - bone destroying cells
Types of Bone - Bone cells produce 2 types of tissue
1. Lamellar bone - highly organized and regularly oriented tissue
- more slowly forming
- contains thin layers of bone with collagen fiber orientation
2. Woven Bone - poorly organized, randomly oriented
- associated with periods of rapid formation such as active growth or infracture repair
- has a lower mineral content
Bone as a Living Organ
Bone is living - most evident by the blood circulation
Blood transports materials to and from bone, and bone can change, grow, or be removed by resorption, and these processes are stress dependent.
The mechanical stresses modulate the change, growth and resorption of bone
An understressed bone can become weaker
An overstressed bone can also become weaker
A proper range of stresses exist which is optimal for the bone
200 distinct bones in the human adult (not including teeth)
Bones are grouped in 4 classes :
1. Long bone : In limbs, arms, legs - Consist of a shaft with 2 ends
Ex. Tibia, ulna, radius
2. Short bone : Small bones tightened together by ligaments found in wrist and ankle
3. Flat bone : Broad bones, serve as protective role. Found in scalp, pelvis
4. Irregular bone : None of the other characteristics and sacrum
Mechanical Properties of the Bone
1. Stress-strain curve
Tensile compression, and shear stresses invariably occur in combination
2. Load-deformation curve
E : measure of the intrinsic stiffness of the material
Ex. Compare bone properties from a sumo wrestler and those of a female gymnast. Wrestler’s bone has a greater rigidity but the E is the same.
Materials, Prosthetic and Treatment Devices
Models and Physiology The biomedical engineer uses physical and mathematical models to predict or control the behavior of an organ, or system of organs, and to design devices for diagnosis, therapy or rehabilitation. To construct models, it is necessary to have a base of emperical data. Collecting of data and testing of models are most oftern performed on animals.
Biomaterials Biomaterials are manufactured substitutes for natural tissues. Standard design considerations such as strength and deformation, fatigue and creep, friction and wear resistance, flow resistance and pressure drop, thermal stability and expansion, electrical conductivity, optical transparency and refractive index. A material is biocompatible if it evokes a minimal adverse biological response.
Effect on Material The effect should be resistant to corrosion. 316L stainless steel, cobalt alloys, titanium and alloys. Ceramics are resistant to corrosion in the tissue environment. They have good strength in compression and are hard, and thus wear resistant, but brittle. However, a ceramic coated metal should respond like a ceramic. High-density polyethylene is resistant to deterioration, and rigid polyvinyl chloride may become brittle as platicizers leach out. Polymethylmethacrylate (PMMA) may be deteriorated by heat sterilization. Polytetrafluoroethylene (PTFE) (Teflon) is inert and not affected in solid form, but small particles may cause tissue irritation. Composites of fibers strong in tension, with a matrix strong in compression, combine strength, toughness, and stiffness and may permit parts to be made lighter or stronger.
Effect on Tissues Effects include thrombosis and hemolysis, inflammation and adaptation, infection, carcinogenesis, or hypersensitivity.
Thrombosis This is the coagulation of blood. The product of coagulation is a clot. If the clot is inside a blood vessel it is called a thrombus, and if the clot is moving it is called an embolus. In some cases, heparin may have to be added to the blood.
Hemolysis Disruption of erythrocytes through mechanical stress. Shear stresses above 1500 to 3000 dyne/cm2 can cause hemolysis. It can also occur if the red blood cells are immersed in a hypotonic solution such as distilled water.
Inflammation Inflammation is a generalized response to tissue injury or destruction. Signs of inflammation are redness (rubor), swelling (tumor), heat (calor), and pain (dolor). The inflammation results in the release of kinins. Edema, and thus swelling results.
Adaptation Neutrophils migrate to the wound site within minutes to hours, and persist for days. The inflammatory response ends with encapsulation of the wound by mature scar tissue, which is relatively acellular.
Infection and Sterilization There is a race between regenerating tissue and bacteria for sites on or near an implant. In addition to being clean and pyrogen free, an implant must be sterile. Cold (room temperature). Dry heat consists of heating at 320 degrees F to 350 degrees F for 0.5 to 2 hours.
Carcinogenesis Cancer may be induced by exposure to chemical carcinogens or foreign bodies (FB), or by mechanical irritation. Other metalic carcinogens are cadmium, lead, and beryllium. The latent period may be 20 years, amd polymers are usually inert, but leaching of fillers should be considered for carcinogenic potential.
Systemic Effects Fine particles may be transported in the lymph and blood and thus have systemic effects.
Artificial Hip Joints The mechanical properties of soft tissues are characterized by a nonlinear stress-strain relationship. The stress-strain loop is repeatable. That is there is hysteresis. Soft tissues exhibit viscoelasticity : after sudden stretching, the stress gradually decreases with time (stress relaxation).
Bone is an inhomogeneous, anisotropic, viscoelastic material. For most purposes, however, it is sufficient to assume that bone is linearly elastic so that :
An example of the use of biomaterials is replacement of a joint by metal and polymer.
Heart Valve Prosthesis
Replacement of diseased or defective heart valves by mechanical prostheses has been accomplished. Some types of artificial mitral valves include the tilting disk, leaflet, and caged ball designs. The caged ball design is durable, minimizes hemolysis, and has the longest history ofclinical use. Materials of of construction include include titanium, stellite 21 alloy, pyrolytic carbon, silicon rubber, and Dacron polyester cloth for attachment of the valve body to the heart tissue. Pyrolytic carbon and silicone rubber resist thrombus formation because the material becomes covered with protein, approximating tissue. Porcine valves are also used ; they are treated with preservatives such as glutaraldehyde to reduce antigenicity and improve stability of the collagen.
Design considerations include reducing resistance to blood flow when the valve is open and minimizing back flow when it is closed, preventing mechanical hemolysis resulting from turbulance or excessive shear, using nonthrombogenic materials and preventing stasis, minimizing wear and fatigue and designing for a lifetime of 10 to 30 years, providing a simple and secure attachment method, and alloying for sterilization, noiseless operation, and operation in any position. Despite the thromboresistant design, at present it is necessary for the patient to receive anticoagulant agents indefinitely to minimze thromboembolism.
Artificial Kidney
Renal Physiology The functional unit of the kidney is the nephron, composed of (1) the glomerulus, a membrane or filter, (2) the proximal tubule, (3) the loop of Henle, and (4) the distal tubule. The collective glomerular filtration rate is about 120 ml/min. The kidneys also help maintain the acis-base balance. It is involved in the synthesis of vitamin D. If there is severe damage, options are either a kidney transplant, an "artificial kidney" or dialysis machine. For example, it may remove substances that the natural kidney recylces, and fails to remove some substances.
NEXT PAGE