MSE 428 Materials for Biomedical Applications

Transcription

1 Biomedical Applications of Biomaterials MSE 428 Materials for Biomedical Applications Important recall information from previous handouts: Biomaterials should: be biocompatible (be non-carcinogenic (not cancer-causing), non-pyrogenic (not cause fever responses), non-toxic, nonallergenic, blood compatible, non-inflammatory) have physical properties matching those of the tissue it replaces or is implanted in (e.g. density, form, roughness and surface topography) have suitable mechanical properties (compressive, tensile, shear, or impact) have suitable service lives (stable throuhout the life of the patient or degrade within the matter of days or weeks depending on the need) have chemical properties similar to that of tissue (e.g. hydrophilic or hydrophobic, have similar functional groups) be economical and widely available have suitable bioactivity (mostly inert but also must be able to carry drugs, bioactive agents,cells if need be) be easily processable and sterilizable Why Metals? high strength and resistance to fracture (reliable long-term implant performance in major load-bearing situations) biologically inactive and chemically inert so that they give no harmful effect to the human tissues ease of fabrication (well-established and widely available fabrication techniques (e.g., casting, forging, machining)) good electrical conductivity (favors their use for neuromuscular stimulation devices, the most common example being cardiac pacemakers) Failure of metals for biomedical devices o Corrosion: Metal implant is prone to corrosion during its services due to corrosive medium of implantation site. o Metal ions release: In most situations it is worst if metal ion release follow corrosion process which can be a toxic contaminant inside human body. o Fatigue and fracture: During its service most of metallic implants are subjected to cyclic loading inside the human body which leads to the possibility for fatigue fracture. o Wear (Together with corrosion process, wear is among the surface degradation that limits the use of metallic implant.) 1

2 Why Bioceramics? Biological compatibility and activity Inert in body (or bioactive in body); chemically inert in many environments High wear resistance (orthopedic & dental applications) Resistant to thermal and chemical changes (heat and corrosion resistant) High modulus (stiffness) & compressive strength Esthetic for dental applications Readily sterilized Their raw materials are both plentiful and inexpensive Failure of Bioceramics o High modulus (mistmatch with bone) o Brittle (low fracture resistance) o Low strength in tension (except carbon nanotubes) o Harder and stiffer than metals by more difficult to shape o very sensitive to notches or microcracks o If microcraks occur, they propagate slowly under load Why Polymers? Easily fabricated into many forms of final usage (oils, fabrics, films and solids) Non-corrosive in the body compered to the metals Bear a close resemblance to such natural tissues as collagen, which makes it possible to incorporate other substances by direct bonding Adhesive polymers can be used as a non-suturing method of closing wounds The density of polymers is closer to the density of the natural tissues. Failure of Polymers o Polymers deteriorate due to chemical, thermal, and physical factors. Chemical Effects: If a linear polymer is undergoing deterioration, the main chain will usually be randomly scissioned (cut). Sometimes depolymerization occurs, which differs from random chain scission. Crosslinking of a linear polymer may result in deterioration. Sterilization Effects: Some methods of sterilization may result in polymer deterioration. Mechanochemical Effects: cyclic or constant loading deteriorates polymers. In-Vivo Environmental Effects o Low modulus of elasticity and viscoelastic characteristics difficult to use for large load-bearing applications 2

3 o o The nature of the polymerization makes them biodegradable in the body (sometimes wanted but sometimes unwanted) Very hard to obtain pure medical grade polymers without such additives as antioxidant, plasticizers, agents etc. Why Natural Materials? very similar, often identical, to macromolecular substances which the biological environment The problems of toxicity and stimulation of a chronic inflammatory reaction, as well as lack of recognition by cells, which are frequently provoked by many synthetic polymers, may thereby be suppressed. the similarity to naturally occurring substances introduces the interesting capability of designing biomaterials that function biologically at the molecular, rather than the macroscopic, level. Disadvantages of Natural Materials o frequently quite immunogenic o because they are structurally much more complex than most synthetic polymers, their technological manipulation is quite a bit more elaborate 3

4 Applications of Biomaterials o CARDIOVASCULAR MEDICAL DEVICES o ORTHOPEDIC APPLICATIONS o DENTAL RESTORATIONS AND IMPLANTS o DRUG DELIVERY SYSTEMS o ADHESIVES AND SEALANTS o BURN DRESSINGS AND SKIN SUBSTITUTES o SUTURES o OPHTHALMOLOGIC APPLICATIONS o BIOELECTRODES o MEDICAL BIOSENSORS o COCHLEAR PROSTHESES o EXTRACORPOREAL ARTIFICIAL ORGANS o TISSUE ENGINEERING CARDIOVASCULAR MEDICAL DEVICES 1. SUBSTITUTE HEART VALVES 2. ENDOVASCULAR STENTS, VASCULAR GRAFTS, AND STENT GRAFTS 3. CARDIAC ASSIST AND REPLACEMENT DEVICES (FOR HEART FAILURE) 4. OTHER CARDIOVASCULAR DEVICES a. Cardiac Pacemakers b. Implantable Cardioverter-Defibrillators (ICDs) 5. MISCELLANEOUS CARDIOVASCULAR DEVICES 6. CARDIAC SUPPORT DEVICES SUBSTITUTE HEART VALVES Today s cardiac substitutes are of two generic types: mechanical valves biological tissue valves 4

5 Mechanical valves are composed of non-physiologic biomaterials that employ rigid, mobile occluders in a metallic cage (cobaltchrome or titanium alloy), or two carbon hemidisks in a carbon housing. Today, all mechanical valve occluders are fabricated from pyrolytic carbon. Pyrolytic carbon has high strength, fatigue and wear resistance, and exceptional biocompatibility, including thromboresistence (no blood clothing). The opening and closing of a prosthetic valve is purely passive, with the moving parts (occluder or disc(s)) responding to changes in pressure and blood flow within the chambers of the heart and great vessels. Patients receiving mechanical valves must be treated with lifelong anticoagulation to reduce the risk of thrombosis and thromboembolic events. Biologic tissue valves are similar to natural valves more than do mechanical valves. The term bioprostheses describes a special type of tissue valve composed of three cusps of tissue derived from animals most frequently either a porcine (pig) aortic valve or bovine (cow) pericardium each treated with glutaraldehyde to decrease its immunological reactivity, and kill the cells within the valve tissue. Bioprosthetic valve cusps are mounted on a metal or plastic stent with three posts (or struts) to simulate the geometry of a native valve. As with mechanical valves, the base ring is covered by a Dacron or Teflon covered sewing cuff to facilitate surgical implantation and healing. Four categories of valve-related problems are most important: 1. thrombosis (blood clothing) and thromboembolism (Exposure of blood to an artificial surface can induce thrombosis, and embolization) 2. infection 3. structural dysfunction (i.e., failure or degeneration of the biomaterials comprising a prosthesis)(if degradation occurs at valve materials, removal of valve is needed or cause valve-associated death of patient. Many valve models have been withdrawn from clinical use because of poor durability. Fractures of metallic or carbon components may be usually dangerous for patient. For bioprosthetic valves, example of structural dysfunction is calcification.) 4. non-structural dysfunction (related to healing of the valve in the site of implantation) 5

6 ENDOVASCULAR STENTS, VASCULAR GRAFTS, AND STENT GRAFTS endovascular (inside the blood vessel) manipulation stents blood vessel bypass or replacement grafts Stent technologies: bare metal stents Polymer coated drug-eluting stents completely resorbable/biodegradable stents Stents must be resistant to thrombosis (no blood clothing), flexible and they can be easily implanted. Vascular grafts are used to bypass a blocked vessel or to replace a part of vessel. Current synthetic vascular grafts are typically fabricated from polyethylene terephthalate (Dacron ) or expanded polytetrafluoroethylene (eptfe ), with the Dacron grafts being used for larger vessel applications and the eptfe used to bypass smaller vessels. Vascular grafts must be 1) resistant to thrombosis, 2) Resistant to smooth muscle cell caused intimal thickening 3) resistant to fatigue 4) resistant to aneurysm development (Aneurysm: an excessive localized enlargement of an artery (blood vessel) caused by a weakening of the artery wall) 5) have material compliance properties similar to the normal and diseased vessels 6) have a sufficient level of suturability. Stent grafts are composed of a synthetic fabric tube reinforced by a stent, whose struts facilitate rapid and stable expansion during insertion. This type of implant combines the features of stents and vascular grafts. OTHER CARDIOVASCULAR DEVICES Pacemakers are medical devices that provide impulses to the conduction system to initiate contraction. They can be either temporary or permanent. This system of interconnected components consisting of: A. A pulse generator which includes a power source and circuitry to initiate the electric stimulus and to sense cardiac electrical activity; B. one or more electrically insulated conductors leading from the pulse generator to the heart, with a bipolar electrode at the distal end of each; a tissue or blood and tissue interface between electrode and adjacent stimulatable cells. Implantable Cardioverter-Defibrillators (ICDs): The goal of ICDs is to prevent sudden death in patients with certain dangereous arrhythmias by resetting the heart s electrical activity and stimulating a normal cardiac rhythm.an ICD consists of similar components to a pacemaker. 6

7 Problems for Pacemakers and ICDs Some mechanical failures include electrode dislodgment, lead fractures, electrode corrosion, and insulation failure. Failures of the hardware, including the battery/capacitor and charge circuit, connectors and leads are the most common device malfunctions, with software problems being less prevalent. Many complications relate to the interaction of the device biomaterials with the host tissue. These include infection, thrombosis, and thromboembolism, etc. ORTHOPEDIC APPLICATIONS 1. Fracture fixation devices: a. Spinal fixation devices b. Fracture plates c. Wires, pins, and screws d. Intramedullary devices e. Artificial ligaments 2. Joint replacement: a. Hip b. Knee c. Spine d. Ankle e. Shoulder f. Elbow g. Wrist h. Finger 3. Dynamic stabilization devices (new): Spine stabilization devices Orthopedic biomaterials are generally limited to those materials that withstand cyclic loadbearing applications. While metals, polymers, and ceramics are used in orthopedics. New biomaterials for orthopedic purposes face the same concerns present in current implants: (1) the material must not adversely affect its biological environment; (2) in return the material must not be adversely affected by the surrounding host tissues and fluids; and (3) new materials must exceed the performance of present materials. 7

8 CURRENT BIOMATERIALS IN TOTAL HIP REPLACEMENT: Total Hip replacement is typically constructed of a titanium or cobalt chromium alloy femoral stem (cemented with PMMA, or press fit into place), connected to a modular cobalt chrome alloy or ceramic femoral head that articulates on a ultra-high molecular weight polyethylene (UHMWPE) or ceramic acetabular cup (insert) fitted into a titanium or cobalt chromium cup liner (acetabular shell) which is cemented, screwed or press fitted into place. Metals appropriate material properties such as high strength, fracture toughness, hardness, and biocompatibility necessary for most loadbearing roles required in fracture fixation and total joint replacement. Since the principal function of the long bones of the lower body is to act as loadbearing members, it was reasonable that the initial materials introduced to replace joints, such as artificial hips, were metals. Both stainless steel, such as 316L, and cobalt chromium alloys became the early materials of choice, because of their relatively good corrosion resistance and reasonable fatigue life within the human body. Of course, their stiffness, rigidity, and strength exceeded those of bone considerably. However, in certain applications, owing to size restrictions and design limitations, fatigue failures did occur. Metals for orthopedic applications should provide appropriate properties, such as high strength, ductility, fracture toughness, hardness, corrosion resistance, formability, and biocompatibility necessary for use in loadbearing roles required in fracture fixation and total joint replacement. Implant alloys mechanical properties such as high strength and corrosion resistance are paramount. Polymers are most commonly used in orthopedics as articulating bearing surfaces of joint replacements and as an interpositional cementing material between the implant surface and bone. Polymers used as articulating surfaces must have a low coefficient of friction, and low wear rates when in articulating contact with the opposing surface, which is usually made of metal. ultrahigh molecular weight polyethylene (UHMWPE) Polymers used for fixation as a structural interface between the implant component and bone tissue require the appropriate mechanical properties of a polymer, which can be molded into shape and cured in vivo. polymethylmethacrylate (PMMA) Ceramics (ceramic-on-ceramic bearing hip implant) The primary reason for the introduction of this alternative bearing surface is the superior wear resistance of ceramics when compared to metal metal or metal polymer bearing surfaces. This, and other improved properties such as resistance to further oxidation (implying inertness within the body), high stiffness, and low friction require the use of full-density, controlled, small, uniform grain size ceramic materials. Ceramics, because of their ionic bonds and chemical stability, are also relatively biocompatible. Problems about fracture toughness and wear have been solved by reducing grain size, increasing purity, lowering porosity, and improving manufacturing techniques. 8

9 ORTHOPEDIC BIOMATERIALS: CLINICAL PROBLEMS Implant biocompatibility/performance is dependent on the type and amount of degradation produced by wear and electrochemical corrosion. Host response to orthopedic implant debris is central to clinical performance. Implant loosening is the predominant factor limiting the longevity of current total joint replacements; other reasons include infection, recurrent dislocation, fracture, and surgical error. DENTAL APPLICATIONS Tooth Filling Materials is stiff and strong; the filling must have adequate mechanical properties. As with other biomaterials, dental materials must be adequately stable in the hydrated environment in which they are placed, and they must not injure tissues. Thermal expansion is relevant in the dental setting, since temperatures in the mouth can vary considerably due to consumption of hot or cold foods. Metallic filling materials, including silver amalgam and gold. Composite filling materials contain a polymer matrix and ceramic inclusions. A dental implant is actually a replacement for the root or roots of a tooth. All commercially available dental implants are made of either titanium or titanium alloys. For crown, ceramics can be used. Alterations of implant design have included changes in the pitch of screws, tapering of screw threads as well as tapering of the implants to mimic the root of a tooth. The post will be covered with an appropriate crown after the implant has been fixed firmly for about 14 months. DRUG DELIVERY SYSTEMS A wide variety of polymeric biomaterials are components of the various formulations and devices that are routinely used for delivering drugs to the body. The major advantage of developing drug delivery systems release drugs in a controlled manner. It can be seen that the blood plasma level following a single dose application of a drug rapidly rises, and then gradually decreases as the drug is consumed by biological system and eliminated from the body. need repeated drug application at defined time Drug delivery system longer time effective drug, no need frequently drug application 9

10 Controlled drug delivery drug level in blood plasma is maintained within the therapeutic index for a long period of time. Why controlled drug delivery? To achieve prolong therapeutic effect; Implies predictability in drug release kinetics; Deliver the drug at predetermined rate, locally or systematically. Advantages of Controlled Drug Delivery Reduction in frequency of drug administration Improved patient compliance Reduction in drug level fluctuation in blood Reduction in total drug usage when compared with conventional therapy Reduction in drug accumulation with chronic therapy Reduction in drug toxicity (local/systemic) Stabilization of medical condition (because of more uniform drug levels) Improvement in bioavailability of some drugs because of spatial control (Bioavailability: the rate and extent to which an active agent is absorbed and becomes available at the site of action and therefore gives a therapeutic response.) Economical to the health care providers and the patient Controlled drug delivery can be broadly classified under the following five categories: 1. Diffusion controlled systems a. Membrane controlled reservoir systems (capsules) The drug is contained in the core of the reservoir and is covered by a thin polymer membrane. The drug is delivered from the device through diffusion across the polymer membrane. The rate of drug release is controlled by the thickness, physiochemical characteristics, and porosity of the polymer membrane. b. Monolithic matrix systems The drug is either dissolved or dispersed in the polymer matrix and is released through diffusion. The driving force for the drug release is the drug concentration gradient between the matrix and the surrounding environment. 10

11 2. Water penetration controlled systems a. Osmotic pressure controlled drug delivery systems osmotic pressure the pressure that is generated when the water flows from a higher concentration to a lower concentration across the semi-permeable membrane. Example: capsules b. Swelling controlled drug delivery systems The drug is dispersed or dissolved in a hydrophilic polymer when it is in a glassy state. Since the glassy state of the polymer is hard and rigid, the diffusion of the drug is very slow. However, when such a polymer is placed in an aqueous environment, it swells due to the penetration of water molecules into the matrix. As the water infusion causes the glass transition temperature of the polymer to be lowered below the ambient temperature, the drug diffuses out of the swollen rubbery polymer matrix. 3. Chemically controlled systems a. Polymer drug dispersion systems the drug is uniformly dispersed or dissolved in a biodegradable polymer, and the drug release mainly occurs due to the degradation of the polymer under physiological conditions. In polymer drug dispersion systems, the drug is delivered from the polymer either by surface erosion or bulk degradation. b. Polymer drug conjugate systems the drug is covalently attached to the backbone of the polymer, and the drug release mainly occurs through the cleavage of polymer drug bonds under physiological conditions. 11

12 4. Responsive systems The drug delivery systems which respond to external stimuli such as temperature, ph, solvents, ultrasound, electric field, and magnetic field are called responsive delivery systems or smart delivery systems. Depending on the type of stimuli and the nature of the polymer, the responses include hydration or dehydration, dissolution or precipitation, swelling or collapse, hydrophilicity or hydrophobicity, phase separation, and degradation. 5. Particle based systems Microparticles typically have a particle size of 1 μm to 1000 μm in diameter. Polymer-based microparticles used for drug delivery can be broadly classified into microcapsules and microspheres. Since microcapsules contain drugs in the core that is surrounded by a rate-controlling polymer membrane, they can be grouped under membranecontrolled reservoir systems. No outer membrane is present in microspheres, and the drug is uniformly distributed in the polymer matrix (they can be grouped under monolithic matrix systems). The drug is released from the microspheres by diffusion. Nanoparticles Nanoscale drug delivery systems (can be broadly classified into nanocapsules and nanospheres) Targeted drug delivery systems Despite great potential, many promising drugs remain limited by low stability, toxicity, inefficient administration, and the need for multiple doses. Targeted drug delivery systems offer great promise for improving the specificity of new therapeutics and revitalizing conventional therapies limited by adverse side-effects. For example, while chemotherapy is effective for the treatment of cancers, it is widely known for harmful side-effects on healthy tissues. Moreover, such factors contribute not only to poor efficacy, but also reduce patient compliance. Development a targeted drug delivery system for chemotherapy drugs will reduce side-effects, increase drug efficacy at the diseased region and increase patient compliance. There are two general classes of targeting, passive and active. Passive targeting is dependent on the physicochemical properties of the drug/carrier system. Targeting is achieved by tailoring the properties of the delivery system to exploit physiological properties of target tissues, while simultaneously minimizing uptake into undesired tissues. This is often achieved by altering surface charge, hydrophobicity, and size and shape of the carrier system. Active targeting is based on molecular recognition of specific receptors on cellular or extracellular targets where the effect of the drug is desired. Injected Drug Delivery systems: Micro/nano capsules, Micro/nano spheres, Polymer-drug conjugates,micelle,liposomes, Hydrogels,Denrimers. 12

13 Hydrogels have received significant attention because of their high water contents and related potential for many biomedical applications. Many natural polymers such as collagen, gelatin, fibrin and others can be used to form hydrogels, and synthetic polymers can also be used as hydrogels. These types of gels show large and significant changes in their swelling ratio due to small changes in environmental conditions, such as ph, temperature, ionic strength, nature and composition of the swelling agent (including affinity solutes), light (visible versus UV), electrical, and magnetic stimuli smart or intelligent hydrogels. The ability of ph- or temperature-responsive gels to exhibit rapid changes in their swelling behavior and pore structure in response to changes in environmental conditions lends these materials favorable characteristics as carriers for delivery of drugs, including peptides and proteins. This type of behavior may also allow these materials to serve as self-regulated, pulsatile or oscillating drug delivery systems.. ADHESIVES AND SEALANTS Adhesive = cement, glue, paste, fixative, and bonding agent. Functions: 1. Bonding function creation of a durable interfacial bond between a biomaterial and its host tissue 2. Space filling an adhesive biomaterial may be required to fulfil a space filling role replacing some or all of any lost natural tissue. 3. Sealing the prevention of ingress of moisture, air, biological fluids, bacteria or other species through the adhesively bonded zone. 4. Further functions Some adhesives may be designed to exhibit antibacterial action, delivery of drugs or beneficial ions. Types: A. HARD TISSUE ADHESIVES: BONE AND TOOTH CEMENTS: Implant fixation has been achieved with acrylic bone cement for many years.alternative Bone-Cements: Calcium Phosphate including HA [Ca10(PO4)6OH2] and TCP [Ca3(PO4)2]. Poly-Electrolyte Cements: Zinc Polycarboxylates and Glass Ionomers. B. Soft Tissue Adhesives and Sealants: Most soft tissue adhesives are intended to be temporary. That is, they are removed or degrade when wound healing is sufficiently advanced for the tissue to maintain its integrity. 13

14 BURN DRESSINGS AND SKIN SUBSTITUTES Deeper skin injuries due to deep cuts, burns or degloving injuries can cause significant physiological derangement, expose the body to a risk of systemic infection, and become a life-threatening problem. Large skin deficits have motivated the development of improved technologies to replace and restore skin. wound dressings and skin substitutes Types: naturally occurring or biological dressing substitute synthetic polymer sheets, polymer foam or spray SUTURES A suture, by definition, is any strand of material that is used to ligate (tie) blood vessels or approximate tissue. Suture is manufactured in many sizes, and is selected by the surgeon based on a number of factors, including: surgical site; patient age and weight; immune history and response; presence of disease or infection; and personal history with suture materials. The suture device is comprised of: (1) the suture strand; (2) the surgical needle; and (3) the packaging material used to protect the suture and needle during storage. Types of sutures: o Silk Sutures o Cotton Sutures o Polyester Sutures o Nylon Sutures o Polypropylene Sutures o Ultra-High Molecular Weight Polyethylene o (UHMWPE) Sutures o Stainless Steel Sutures o Synthetic Absorbable Sutures OPHTHALMOLOGIC APPLICATIONS Many considerations for ophthalmic biomaterials are biocompatibility, mechanical properties and stability, material degradation, manufacturability, and implant design optimization. Unique to ophthalmology, the functionality of ocular biomaterials is often based on the optical properties of the material. The optical properties are critical for contact lenses, artificial corneas, corneal inlays or onlays, as well as intraocular lenses. The materials for these devices must be transparent and have a refractive index equal to or greater than that of the tissue it is replacing. Additionally, the stability of the material in the eye, lack of toxicity, 14

15 and long term functionality of the product or device over time is critical. Optical devices need to be mechanically stable, because any tilt or decentration of these optical medical devices will lead to unfavorable visual performance. Any material used for a corneal application, such as contact lenses or corneal inlays, must have acceptable oxygen and nutrient permeability. For contact lenses, the surface wettability is important for a tear film for patient comfort. As contact lenses are implants exposed to proteins and lipid deposits in the tear film, the material must allow removal and/or be resistant to protein and lipid deposits. BIOELECTRODES Bioelectrodes are sensors used to transmit information into or out of the body. ELECTRODE MATERIALS: o Noble Metals: Platinum, Iridium o Non-Noble Metals: electrodes that require high mechanical and fatigue strength may be made from non-noblemetals/alloys. 316LVM stainless steel, nickel cobalt-based alloys, Titanium,Tantalum APPLICATIONS of Bioelectrodes: Cardiology Neurology Electrical bone-growth stimulating devices for treating nonunion fractures, and for enhancing spinal fusion Brain Computer Interface (BCI). The ability to interface a computer directly to the brain via electrodes has the potential to restore functionality to those paralyzed or with vision or speech deficits. MEDICAL BIOSENSORS uses biological molecules, tissues, organisms or principles to measure chemical or biochemical concentrations. Biomedical sensors are sensors that detect medically relevant parameters; these could range from simple physical parameters like blood pressure or temperature, to analytes for which biosensors are appropriate (e.g., blood glucose). Biomedical sensors fall into two general categories: physical and chemical. Physical parameters of biomedical importance include pressure, volume, flow, electrical potential, and temperature, of which pressure, temperature, and flow are generally the most clinically significant, and lend themselves to the use of small in vivo sensors. Chemical sensing generally involves the determination of the concentration of a chemical species in a volume of gas, liquid or tissue. Chemical indicators of health: ph, ions, blood gases, drugs, hormones, proteins, viruses, bacteria, parasites and tumors Types of sensors: Noncontacting Sensors. Non-contacting sensors produce only a minimal perturbation of the sample to be monitored. In general, such measurements are limited to the use of electromagnetic radiation such as light or sampling the gas or liquid phase near a sample. 15

16 Contacting Sensors may be either Noninvasive or Invasive. Direct physical contact with a sample allows a rich exchange of chemical information. Sample Removal Sensors. Once removed, a fluid can be pretreated to make it less likely to adversely affect the functioning of a sensor. COCHLEAR PROSTHESES Cochlear prostheses help the deaf to contact the auditory environment. Electrode arrays change electrical currents into the ionic currents that can stimulate neurons. Materials issues are salient in the design and construction of electrode arrays. The polymers that are used to insulate the arrays must be compatible with the tissues. Noble metals, that is, gold, platinum, iridium, and some of their alloys have been used extensively. EXTRACORPOREAL ARTIFICIAL ORGANS Extracorporeal circulation is, by definition, any procedure in which blood is taken from a patient, treated, and then returned. This includes devices used for dialysis in kidney replacement therapy, plasma separation, and extracorporeal oxygenation. All these procedures involve the contact of blood with biomaterials, mechanical pumping of the blood, and mass transfer to and from the blood. Exposure of the blood to the biomaterials of the extracorporeal circuit will result in platelet activation, activation of the intrinsic pathway of coagulation, and complement activation. Complement and platelet activation will result in a systemic inflammatory response. Dialysis is the process of solute transfer across a semi-permeable membrane, and is similar in principle to diffusion. Metabolic wastes are transferred from the blood into the dialysate, due to the concentration gradient. Plasma separation can be achieved by centrifugal or membrane methods. In a batch method, anticoagulated blood is removed from the patient, and then centrifuged to separate the plasma, red blood cells, and buffy coat (lymphocytes and platelets). Blood Oxygenation: Within the oxygenator, the blood and gas are separated by a membrane which is permeable only to gas. 16

17 TISSUE ENGINEERING Every year thousands of human lives are lost due to a lack of organs available for transplantation. Successful tissue engineering can solve this problem by re-growing the patients own organs. Successful tissue engineering can also potentially provide skin for burn victims and repair nerves and restore function to those paralyzed. Tissue engineering an interdisciplinary field that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function or a whole organ. The basic principle of tissue engineering involves: A. Cells: the use of living cells to repair or re-grow a tissue or organ damaged by disease or trauma. B. Scaffolds: For most applications, these cells need a carrier as well as a structural or mechanical support to be able to function normally, and to proliferate and form tissue. These supports are called scaffolds and are fabricated from biomaterials. The basic tissue engineering methodology involves: i. harvesting appropriate cells from the body and ii. seeding them on a three-dimensional porous scaffold structure or construct. iii. These cell biomaterial constructs are then placed in the correct environment (in vitro or in vivo) to encourage the formation of tissue. The cells can be differentiated cells such as osteoblasts for bone growth, chondrocytes for cartilage, or endothelial and smooth muscle cells for vasculature. The use of precursor or stem cells is also a possibility and is the subject of many scientific studies. Polymers, ceramics, metals, and natural materials have all been considered as candidate scaffold materials for various tissue engineering applications. The first step in tissue engineering is the identification of the type of tissue that needs to be repaired or regenerated and the extent of damage. (different tissue types can require very different strategies and techniques.) Depending on the clinical need, one of three tissue engineering approaches can be used: A. scaffold-based a scaffold without any cells may be used to fill the tissue defect. Native cells can then infiltrate this scaffold from the surrounding tissue. Biochemical molecules can be attached to or released from the scaffold to encourage cell attachment, and to enhance cell function. Depending on its location, a variety of cells types can migrate into the scaffold. This approach can be an advantage if the migrating cells are the kind required for the regeneration of that specific tissue. B. cell-based cells may be introduced into the defect without a scaffold or matrix. The cells can be at different levels of development stem cells or differentiated cells. This approach can be successful when the cells are introduced into an area where there is existing matrix to support them. C. cell-loaded scaffolds use a scaffold preloaded with cells. 17

18 Cells for tissue engineering can be obtained from a variety of sources: autologous (cells are obtained from the donor for re-implantation in the donor), allogenic (cells are obtained from another individual of the same species), syngenic (cell donor is genetically identical, such as a twin or a clone), and xenogenic (cells are obtained from a different species). (Example: from pig to human) Instead of using tissue specific cells, the use of stem cells is also a possibility for tissue engineering applications. Stem cells are cells that have not yet differentiated terminally and have the potential to give rise to different types of cells. The three important characteristics that distinguish stem cells from other cell types are that (1) they have the ability to self-renew through cell division for a long period of time, (2) they are non-specific cells, and (3) they can be induced to transform into tissue or organ-specific cells under the right physiologic or laboratory conditions. Scaffold properties (Scaffolds can be porous structures or gels.) 1. The biomaterial(s) used should be biocompatible for the specific application. 2. The material should have the ability to be remodeled in vivo or be biodegradable so that it does not retain its original form over the long term and is gradually dissolved or incorporated in the tissue. 3. The biodegradation or remodeling should be synchronized with tissue regeneration so that the scaffold initially does provide adequate support to the cells but does not interfere with the regenerative process or tissue function over the long term. 4. The scaffold should have high permeability to enable adequate diffusion of nutrients for the cells and the removal of waste products. 5. The scaffold porosity should be sufficiently high to allow for the ingress of cells and provide the cells space to proliferate and form the extracellular matrix (ECM). 6. The pore size of the scaffold should be optimum for the cells in use. 7. Cells respond biochemically to applied stresses and thus the scaffold or cell carrier should possess mechanical properties that closely mimic those of the surrounding native tissue so that the cells are subjected to the correct stress microenvironment. 8. The scaffold or carrier should ideally encourage and promote the formation of ECM. 9. The surface of the scaffold should be conducive to cell attachment and should facilitate normal cell functions. This may occur naturally due to the inherent properties of the biomaterial or may require appropriate surface modification. 10. The scaffold should have the ability to act as a carrier for biomolecules such as growth factors to stimulate the repair process. 18

19 Scaffold Preparation Methods: Solvent casting and particulate leaching the polymer is first dissolved in an organic solvent. Particles of a water soluble material, generically called the porogen, are then mixed into the solution. Examples of the porogen include common salt and sugar. The solvent is then removed via evaporation and the resulting polymer particle composite is immersed in water to dissolve and extract the porogen particles. The particles leave behind empty spaces thereby creating porosity. The size, shape, and quantity of the particles determine the pore size, porosity, and interconnectivity of the resulting foam or sponge-like scaffolds. Electrospinning electrospinning involves the dissolution of the polymer in an organic solvent and the ejection of the solution through a fine needle. A metal receptor, which can be a foil, plate, or rotating mandrel, is placed so that there is an air gap between it and the needle. When a high voltage is applied between the needle and the receptor, the applied voltage exerts forces on the surface of the polymer solution which exceed the surface tension. As a result, a charged polymer jet is ejected from the needle and is deposited on the receptor in the form of micrometer- or nanometer-scale (diameter) fibers. Solid free form fabrication (SFFF) The solid free form fabrication (SFFF) process involves the formation of 3D-structured layers using rapid prototyping (RP) manufacturing. The object is first modeled using computer-aided design which is rendered into a series of thin, stacked virtual cross-sections by the software. Starting from the bottom, the RP machine lays down a layer of material corresponding to a cross-section. Based on the additive principle of laying materials in layers, the scaffold is created by laying subsequent layers over the preceding layers. Each layer is attached to the preceding layer by using either a solvent or heat-induced adhesion. The advantage of the SFFF process is that closely controlled and repeatable, reproducible architectures can be produced for scaffolds. In general, there are several different techniques that can be categorized under the umbrella of SFFF, including: i. fused deposition modeling involves the use of a heated nozzle to extrude a polymeric fiber. ii. selective laser sintering: an infrared laser is used to melt a thin layer of polymer powder at selected points so that it adheres to the layer below. After a layer is sintered, a new layer of powder is added, and the process is repeated to create a 3D structure. 19

20 iii. stereolithography involves a highly focused ultraviolet (UV) beam used to photopolymerize a liquid, photocurable monomer at precise spots. After each layer is cured, a new layer of liquid monomer is added, and the process is repeated to create a 3D structure. iv. 3D printing: the process first involves the spreading of a layer of a powder material. This powder could be a polymer or a ceramic or a composite. An inkjet print head is then used to precisely deposit a binder on the powder material. The scaffold is created by repeating this process of laying down layers of the powder followed by the deposition of binder from the inkjet print head. 20