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BEFORE THE LATE 1950S, BIOMECHANI-cal sciences and engineering were in aslump. Prostheses were rudimentaryand unimaginative, and biomaterials sci-ence simply did not exist. Until thispoint, according to The Cultural Body,wooden peg-legs and gold teeth werethe only clinically and socially acceptedprosthetic devices; the only acceptedtransplantation procedure was bloodtransfusion. Three major events helpedpropel biomechanics out of the darkages and create the field of biomaterialscience as a requisite for the productionof functional medical devices.

The first major event was the race tothe moon. Starting in the late 1950s,massive government spending providedthe motivation and resources needed toanswer a rather daunting question: howwould the human body react to thestress induced during space travel andextended periods of time spent inmicrogravity?

The second major event was theimproved technological capability ofthe digital computer, which was firstdeveloped around 1945, that allowed

researchers new computational freedomand computational power in the highlycomplex and nonlinear world of biomechanics.

The final event was the birth ofmodern biology, which provided asound scientific basis for biomechanicsat the microscopic level. In 1951, LinusPauling began to uncover the basicstructure of protein, and in 1953,Watson and Crick revealed the doublehelical structure of DNA.

These three events provided themotivation and technology that led to aproliferation of advancements in bio-medical instrumentation. Within adecade, an explosion of new clinicalapplications had been realized. Mostnotably, the artificial hip joint, the artifi-cial kidney and heart, the lungmachine, the cardiac pacemaker, andthe prosthetic cardiac valve were allproduced during that time period. Thisarticle will provide a glimpse into a fun-damental part of the process that wasdeveloped over the past six decades tocreate those devices: the materials outof which they are made.

A widely accepted and useful defini-tion of a biomaterial offered by Williamsis “a nonviable material used in a med-ical device that is intended to interactwith biological systems for the purposeof improving health.” A more recentconsensus definition of a biomaterialexcludes the word “nonviable” due tothe development of tissue-engineeredscaffolds and hybrid prosthetics in whichliving cells are combined with nonorgan-ic material. Today, there are a relativelylimited number of different biomaterialsbeing used in the clinical setting.Standard polymers, metals, and ceramicsencompass the bulk of functional bioma-terials. One may wonder why so fewbiomaterials are accepted clinically. Theanswer to this lies in the fact that thepositive effect a material has on themechanical soundness of a device oftenis negated by its incompatibility with thetissue with which it will be in contact.This problem, referred to as biocompati-bility, is the first issue, in addition to abasic material utility analysis, that anengineer must consider for a candidatebiomaterial when improving an existingdevice or creating a new one.

BIOCOMPATIBILITYBiocompatibility is defined by

Williams as the ability of a material toperform with an appropriate hostresponse in a specific application. Thismeans that the material must elicit thecorrect reaction, or lack of reaction,from any tissue with which it is in director indirect contact for a particular treat-ment. Identification of a material withgood biocompatibility requires a host ofdifferent tests. These tests fall into twogeneral categories: in vitro and in vivo.In vitro testing is used to determine theoverall tradeoff between performanceand biocompatibility that can bereached with a certain material. In vivotesting tackles questions relating to theperformance of a biomaterial in a clinicalsituation.

The distinction between in vitro test-ing versus in vivo testing is that in vitrotesting occurs in an artificial environ-ment, whereas in vivo testing takesplace within a living system. Generally,in vitro tests identify cytotoxicity, cellactivation, cell adhesion, or necrosisdue to a particular biomaterial usingcell cultures. In vitro testing employsthree main types of assays to determinebasic information about the material inquestion: direct contact, agar diffusion,and extract dilution.

© MASTERSERIES

Fundamental considerations for biomaterial selection

JONATHAN P. NEWMAN

12 IEEE POTENTIALS

A direct contact assay is the most gen-eral and simple test for biocompatibilityand usually is used to identify possiblecandidate biomaterials for a new applica-tion. The material under investigation isplaced in direct physical contact withcells that it will encounter while in useand can identify any adverse reactionthat the cells may have to the foreignmaterial. This type of test has a distinctadvantage in that it can be used to seethe effects of a potential biomaterial on asingle type of cell in isolation withoutsecondary interactions that would occurin a living organism. Cells needed forthese tests can usually be acquired fromdifferent cell lines that are widely avail-able though various cell repositories.

An agar-diffusion assay is used toquantify the susceptibility or resistance ofa bacterial strain to a potential biomateri-al (see Fig. 1). First, a bacterial suspen-sion is spread on the surface of an agargel assay. Then, the material in questionis placed in different wells cut into thegel. A zone of inhibition will formaround the material where no bacteriagrow because of the material’s inhibitiveeffect. The area of this zone can be usedto determine a material’s potential sus-ceptibility to bacterial infection whenplaced in a living system. If there appearsto be no zone of inhibition around thematerial, then the bacteria on the agarassay is deemed resistant to that material.

Extract dilution assays are used todetermine if extracts of a biomaterial (asubmaterial within a biomaterial) may becytotoxic in any way. Both hydrophilicand hydrophobic solvents are used to

extract low-molecular-weight materialsfrom a candidate biomaterial at varyingconcentrations. Each of these extracts istested for cytotoxicity or any other harm-ful reaction in a cell culture.

When considering in vivo testing,there are two important purposes fortesting on living biological systems. Thefirst is to screen for a new biomaterialby incorporating it into a living systemand observing any obvious complica-tions or abnormalities. The complexnature of a living system is impossibleto create in a cell culture. Before aresearcher burdens him or herself withextensive in vitro testing, it is a goodidea to see whether this endeavor isworth pursuing rather than being sur-prised by an interaction in the livingsystem that causes the biomaterial to beincompatible. The second purpose forin vivo testing is verification of the bio-compatibility of the final, or “as used”product. A final product must pass amultitude of different in vivo testsbefore it will be accepted clinically.Recently, there have been extensiveefforts put forth by the U.S. Food andDrug Administration (FDA) and its regu-latory agencies to standardize and regu-late in vivo testing requirements for bio-materials to reach the clinical level.

Medical devices are categorized bythe tissue that the instrument will con-tact and the duration of that contact.Table 1 displays a standard categoriza-tion scheme for medical devices basedon principles and guidelines that havebeen used in the past to create safe andfunctional medical equipment. To

decide what in vivo testing protocolsare appropriate, the instrument underinvestigation must be characterizedusing this scheme.

Ultimately, “end use” in vivo testingwill determine an instrument’s biocom-patibility. For a new biomaterial, extraprecautions must be made to ensurebiocompatibility. If an instrument beingtested does not fit easily into the cate-gories presented in Table 1, then invivo tests associated with more thanone category may be necessary. On theother hand, when designing a newdevice with biomaterials that have beentested exhaustively in vivo, some invivo tests are not necessary to gain reg-ulatory authorization. Some common invivo tests are listed in Table 2.

BIOLOGICAL FUNCTIONThe degree of a biomaterial’s bio-

compatibility is clearly not a designer’sonly concern. Steps must be taken toensure that the biomaterial will be fullycompatible with its environment as wellas biologically functional. The function-ality of a material is determined by itsperformance in a specific application.For example, the material used to cre-ate an artificial hip joint must have highsheer strength, be durable enough tolast many years without any majordegradation, and have good ductilitymaking it difficult to fracture. The leadsof a pacemaker must be highly resistantto degradation and must be imperviousto the build up of organic insulatingsubstances around electrical contacts. Abone-void filler must degrade at a rate

a b

Table 1. Classification of devices by tissue contact and duration of contact.

Tissue Contact1) Surface Instruments

• Epidermal• Mucosal membranes• Compromised surfaces

2) External Communicating Devices• Blood path, indirect• Tissue, bone, or dentin linking• Circulating blood

3) Implant Devices• Soft tissue or bone• Blood

Duration of Contact1) Limited: less than 24 hours2) Extended: more than 24 hours, less than 30 days3) Permanent: more than 30 days

Adapted from: Anderson, James M., “Fundamental biological requirements of a biomaterial,” inAn Introduction to Biomaterials, Scott A. Guelcher and Jeffery O. Hollinger, Eds. Boca Raton, FL:CRC Press, 2006, pg. 7.

Fig. 1 Agar diffusion occurs from the wellat position (a) outward, creating a concen-tration gradient of the substance beingtested. Because the zone of inhibition hasa radius that ends at position (b), it can bestated that the concentration at that dis-tance from the well is the lowest at whichthe bacteria is inhibited successfully.

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constant to that of new bone growth sonone of the material is present by thetime the bone has fully healed. In thisaspect of a biomaterial, there exists adelicate trade-off between functionalityand compatibility to produce a high-quality device. The scale of this trade-off can be adjusted depending on theapplication. For instance, in a devicethat will only come into contact withthe body for a short period of time,slightly toxic, inflammatory, or immune-system responses can be excepted if theperformance of the material far exceedsits more biocompatible counterparts.

Some of the design and testing todetermine the biological functionalityof a biomaterial is carried out by mate-rials scientists, chemists, and biome-chanical engineers long before it isever subjected to any in vitro or in vivotesting. However, testing for biologicalfunction and biocompatibility is gener-ally carried out in parallel. This way,general problems can be identifiedearly, and tests become more specificand rigorous as candidate biomaterialsprove their capability. As a generalrule, the design of a clinical instrumentmust be based strictly in terms of func-tion and not true biological structure.The end product may look nothing likethe body part it is designed to replace,and this is most often the case. This isexemplified in the modern devices fortranstibial (below the knee) prosthesesas in Fig. 2 and the artificial cardiacvalve as seen in Fig. 3.

Another factor used to define amaterial’s functionality is ease of use ina professional setting. Complex storage,sterilization, or handling procedures fora biomaterial are a great hindrance in aclinical situation. An engineer designing

a biomaterial, or the device in which itwill be used, must take into considera-tion the inherent difficulty that will arisewhile trying to incorporate the deviceinto the human body. For example,during surgery to replace a cardiacvalve, time is precious, and the artificialvalve must be simple and easy toinstall. Sterilization is a key issue in thisregard that needs to be dealt with care-fully. It is possible that autoclaving,radiation sterilization, or ethylene oxidesterilization may lead to unwanted alter-ations of the biomaterial that could elic-it problems with biocompatibility orbiological function.

REGULATORY ISSUESBefore a medical device can be used

clinically, it must prove both its func-tionality and biocompatibility accordingto a series of standards provided by theCenter for Devices and RadiologicalHealth, a regulatory body of the FDA.Regulatory control of biomaterials focus-es on their end use rather than thematerials themselves. Therefore, theguidelines set forth, specifically theInternational Organization forStandardization (ISO) 10,993 standard:

“Biological Evaluation of MedicalDevices, in Presenting a SystematicApproach to In Vivo Assessment ofTissue Compatibility of MedicalDevices,” concentrate heavily on in vivotesting. However, this should not under-state the importance of in vitro testing.In vitro testing allows verification ofnew biomaterials that is needed beforethey can be incorporated into medicalinstruments and tested in vivo. Table 3displays a list of the 18 ISO 10993 stan-dards issued to date by the ISO’sTechnical Committee 194.

ISO 10993 Biological Evaluation ofMedical Devices provides an excellentoverview of the testing needed to provea biomaterial’s safety and biocompatibili-ty for use in a clinical instrument. Itplaces emphasis on the importance ofsound experimental methods and coverssafety issues such as leachables, extracta-bles, and temporal degradation, whichmay not be obvious to a designer butare essential when considering the safetyof a biomaterial. However, as can berecognized from the list of tests in Table3, the ISO 10993 standards are solelyconcerned with biocompatibility andsafety. The functionality of the deviceand the appropriateness of the materialin question for a certain purpose is leftup to the designer to determine.

BIOMATERIALS IN THE CLINICA clinically applicable biomaterial is

the product of an extensive and diverseset of experimental analyses. Biomaterialshave been implemented clinically inalmost every type of medicine, from den-tal work, to organ replacement, to pros-thetics, to drug delivery systems. Some ofthe most commonly used biomaterialsbeing employed clinically appear inTable 4. It is surprising how many ofthese materials are now commonplace inmodern medicine, considering that lessthan 40 years ago, almost none of thesebiomaterials were used.

Fig. 3 An artificial cardiac valve<http://ninsight.at/bioSamplesHeartValve.shtml.> Used with permission.

Fig. 2 The Flex Foot Cheetah, atranstibial prosthetic device. Used withpermission of Ossur Americas.

Table 2. In vivo testing classes for biocompatibility.

14 IEEE POTENTIALS

SensitizationIrritationIntradermal ReactivityAcute Toxicity (less than 24 hours of exposure)Subacute Toxicity (14–28 days of exposure)Chronic Toxicity (24 hrs-10% of lifespan of animal of exposure)GenotoxicityImplantation (pathological effects on living tissue)HemocompatibiltiyCarcinogenicityReproductive and Developmental ToxicityBiodegradationImmune system response

Adapted from: Anderson, James M., “Fundamental biological requirements of a biomaterial,” inAn Introduction to Biomaterials, Scott A. Guelcher and Jeffery O. Hollinger, Eds. Boca Raton,FL: CRC Press, 2006, pg. 8.

CONCLUSIONSThe human body is the result of

millions of years of evolution duringwhich countless variations and trialsdriven by a commanding environmentoccurred. The result is a magnificentdisplay of efficiency, robustness, andcomplexity. Trying to introduceincredibly simple instruments intosuch a complex structure is challeng-ing. Because of the complex nature ofthe human body, specific problemswith biomaterial biocompatibility andfunction are almost impossible to pre-dict without extensive testing in cellcultures as well as in living systems.Because of the extensive nature ofthese tests, strict regulatory protocolsare required to ensure that reliableproducts are produced. The consider-ations for the selection of biomaterialspresented in this article are funda-mental. Before proceeding to theadvanced stages of instrument designand implementation, it is imperativethat a biomaterial prove i tself inregard to these primary issues. As thefield of biomechanical engineeringprogresses and new biomaterials areneeded for excit ing new designs,these fundamental considerations forbiomaterials selection may change.However, the basic principals guidingthem will remain paramount to anyperson wishing to design a functionalinstrument.

READ MORE ABOUT IT• “The Cultural Body: The History of

Prostheses,” University of Iowa MedicalMuseum Online, (2006). University ofIowa, [Online]. Available: http://www.uihealthcare.com/depts/med-museum.

• J.M. Anderson, “Fundamental bio-logical requirements of a biomaterial,”in An Introduction to Biomaterials, S.A.Guelcher and J.O. Hollinger, Eds. BocaRaton, FL: CRC Press, 2006, pp. 3–15.

• P.M. Galletti, “Prostheses and artifi-cial organs,” in The BiomedicalEngineering Handbook, J.D. Bronzino,Ed. Boca Raton, FL: CRC Press, 1995, pp.1827–2038.

• J.D. Humphery and S.L. Delange,An Introduction to Biomechanics: Solidsand Fluids, Analysis and Design. NewYork: Spring-Verlag, 2004.

• R.F. Wallin and P.J. Upman, “Apractical Guide to ISO 10993,” MedicalDevice and Diagnostic Industry Mag.,Jan. 1998. [Online]. Available:http://www.devicelink.com/ mddi/

archive/98/01/023.html• D.F. Williams, “Definitions in biomate-rials,” in Proc. Consensus Conf. EuropeanSociety for Biomaterials, Chester,England, Mar. 3–5, 1986, vol. 4, 1987.

ABOUT THE AUTHORJonathan P. Newman (jonathan.p.new-

man@gmail.com) is a B.S. candidate in theDepartment of Bioengineering at the StateUniversity of New York, Binghamton, NY.

Table 4. Common biomaterials and their uses.

Metals and Alloys316L stainless steel Fracture repair, stents, surgical instrumentsCP-Ti, Ti-Al-V, Ti-Al-Nb Bone replacement, joint replacement, facture repair, dental

implants, pacemaker capsulesCo-Cr-Mo, Cr-Ni-Cr-Mo Bone replacement, joint replacement, dental restoration,

heart valvesNi-Ti Bone plates, stents, orthodontic wiresGold Alloys Dental restorationSilver Antibacterial AgentsPlatinum, Pt-Ir Electric leadsHg-Ag-Sn amalgam Dental restoration

Ceramics and GlassesAlumina Joint replacement, dental implantsZirconica Joint replacementCalcium phosphates Bone repair, metal surface coatingsBioactive glasses Bone replacementPorcelain Dental restorationCarbons Heart valves, percutaneous devices, dental implants

PolymersPolyethylene Joint replacementPolypropylene SuturesPET Vascular prostheses, suturesPTFE Soft tissue augmentation, vascular prosthesesPolyesters Vascular prostheses, drug-deliveryPolyurethanes Blood contact devicesSilicones Soft tissue replacement, ophthalmologyHydrogels Ophthalmology, drug-delivery

CompositesPMMA-glass fillers Dental cementsBIS-GMA-quartz/silica filler Dental restoration

Adapted from: “Overview of biomaterials and their use in medical devices,” Handbook forMaterials for Medical Devices, J.R. Davis, Ed. ASM International, 2003.

Table 3. ISO 10993 standards.

10993-1: “Guidance on Selection of Tests”10993-2: “Animal Welfare Requirements”10993-3: “Tests for Genotoxicity, Carcinogenicity, and Reproductive Toxicity”10993-4: “Selection of Tests for Interactions with Blood”10993-5: “Tests for Cytotoxicity-In Vitro Methods”10993-6: “Tests for Local Effects After Implantation”10993-7: “Ethylene Oxide Sterilization Residuals”10993-8: “Selection and Qualification of Reference Materials for Biological Tests”10993-9: “Framework for Identification and Quantification of Potential Degradation Products”10993-10: “Tests for Irritation and Delayed-Type Hypersensitivity”10993-11: “Tests for Systemic Toxicity”10993-12: “Sample Preparation and Reference Materials”10993-13: “Identification and Qualification of Degradation Products from Polymeric Medical

Devices”10993-14: “Identification and Qualification of Degradation Products from Ceramics” 10993-15: “Identification and Qualification of Degradation Products from Metals and Alloys”10993-16: “Toxicokinetic Study Design for Degradation Products and Leachables”10993-17: “Establishment of Allowable Limits for Leachable Substances”10993-18: “Chemical Characterization of Materials”

Adapted from: http://www.devicelink.com/mddi/archive/98/01/023.html

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