270 THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 12, No.6, 1999

Reviews-Technology and Medicine

Biomaterials: An Overview

M. s. VALIATHAN, v. KALLIYANA KRISHNAN

HISTORICALBiomaterials, an eclectic discipline, draws its strength from manysciences. From an uncertain start and tardy growth in the early partof the twentieth century, it matured rapidly within two or threedecades in the recent past. It has attracted much public attentionthrough spectacular devices such as pacemakers and joint pros-thesis but, at another level, caused occasional alarm throughcomplications such as those of the silicone breast implant whichbecame a cause celebre. One of the earliest applications took placein 1839 when vulcanized rubber was used as a denture basefollowing its invention by Goodyear. In subsequent years, almostevery polymeric material developed for industry drew the atten-tion of dental investigators who tried out phenol-formaldehydes,vinylchloride co-polymers, polystyrene, epoxy and other prod-ucts. In the early years of the present century, Carrel worked onblood-compatible materials by coating glass with paraffin andcollodion. While these efforts were prompted by the practicalneeds of specialties such as dentistry and vascular surgery, theexperiments of contemporary physiologists sought to study theblood compatibility of materials as a means for investigatingclotting. These unplanned and sporadic attempts had no more thanmodest success until acrylic resins appeared in 1937 and foundimmediate and widespread applications in dentistry and, to alesser extent, orthopaedics. The universal acceptance of acrylicresins and their offspring established an enduring aspect of bio-materials development. Instead of targeted development based onscientific criteria, biomaterials piggybacked on materials devel-oped for industrial applications and were met in turn by a surpris-ing degree of success. This trend gained momentum with theadvent of new materials during World War II; a further stimuluscame from the simultaneous advances in specialties such ascardiovascular surgery, orthopaedics, dentistry, plastic surgeryand nephrology. While the practice of appropriating materialsdeveloped for defence, space and other industrial applicationscontinued, the post-World War II phase posed new questions onbiocompatibility, biofunctionality, implant criteria and a host ofother issues and marked the beginning of the science of bio-materials.

BIOMATERIALS AND BIOCOMPA TIBILITYA biomaterial is defined as 'any substance (other than a drug) or

Manipal Academy of Higher Education, Manipal, Kamataka, IndiaM. S. VALIA THAN

Sree Chitra Tirunal Institute for Medical Sciences and Technology,Thiruvananthapuram 695011, Kerala, IndiaV. KALLIY ANA KRISHNAN Biomedical Technology Wing

Correspondence to M. S. VALlATHAN

© The National Medical Journal of India 1999

combination of substances, synthetic or natural in origin, whichcan be used for any period of time, as a whole or as a part of asystem which treats, augments or replaces any tissue, organ orfunction of the body'.' They may be metals and alloys, polymers,ceramics, carbon composites or biological tissues which havebeen chemically treated. It has been claimed that biomaterials arebeing used to produce 2700 different medical devices, 2000diagnostic products and 1500 disposables around the world. Theirapplications cover the entire field of medicine and every aspect ofpatient care. Indeed, the range of applications continues to growbeyond the traditional areas ofbioimplants and hospital disposablesand claim new turfs such as smart delivery systems for drugs,hybrid organs and tissue culture.

What distinguishes biomaterials from other classes of materi-als is their ability to remain in a biological environment withoutdamaging the surroundings and without getting damaged in thatprocess. These are the two sides of biocompatibility which acandidate biomaterial seeks to achieve in diverse environmentssuch as bone, blood vessel and the eye. The demands of biocom-patibility underlie the criteria for any material to qualify as abiomaterial.' In the fust place, they must be biochemically compa-tible, non-toxic, non-irritable, non-allergenic and non-carcino-genic; secondly, biomechanically compatible with surroundingtissues; thirdly, a bio-adhesive contact must be possible betweenthe materials and living tissues.

EFFECT OF MATERIALS ON TISSUESIdeally, biomaterials should not induce any change or provoke anyreaction in the neighbouring or distant tissues: an alternate objec-tive for an implant would be the formation of a molecular bondbetween the material and host tissues. In practice, however, theformation of an ultra-thin capsule of fibrous tissue around theimplant is regarded as a mark of good biocompatibility. When thebiocompatibility is lacking, materials cause tissue reactions whichmay be systemic or local. Systemic responses are toxic or allergicand are triggered by the products of metallic corrosion and poly-mer degradation, release of microparticles from materials, and thepresence of contaminants. Adverse reactions at the local levelinclude tissue necrosis or proliferation which may progress to agranuloma.' Malignancy in the form of carcinoma and sarcomaalso occur in response to prosthetic implants and the mechanismof prosthetic carcinogenesis has been discussed for many years.'The carcinogens may be chemical leachables, biodegradationproducts or simple physical contact such as that of cobalt powder.Though carcinogenesis due to metallic or polymeric implants hasbeen observed in rodents, tumours have rarely occurred in humanswith the use of hundreds of thousands of metallic and polymericimplants. This must surely be an instance of species specificityworking to the advantage of human patients.

VALlATHAN , KALLlYANA KRISHNAN : BIOMATERIALS

A striking example of local response to foreign materials isclotting. Blood remains liquid in the vascular compartment eventhough the mechanisms-physical, chemical and rheological-underlying the non-clotting phenomenon or vascular homeostasisare not fully understood. In fact, few topics in biomaterials havereceived greater investigative attention than the role of plasmaprotein adsorption on foreign surfaces following exposure toblood. The adsorption of plasma proteins on foreign surfacesoccurs in a few seconds and triggers the coagulation sequence.The initial protein to be deposited is fibrinogen-designated asthe 'Vroman effect'-which is replaced within minutes by otherproteins.' This may be followed by thrombin generation andthrombus formation in the 'intrinsic pathway' of coagulation.Alternatively, platelets may deposit, aggregate and form platelet-fibrin thrombi in the 'extrinsic pathway'. The kinetics of proteinadsorption, effect of surfaces on adsorption and other phenomenahave been studied in detail and large amounts of data haveaccumulated since Vroman's observation." The agreement thatsurface modification holds the key to making a surface non-thrombogenic notwithstanding, the protein adsorption studieshave brought us no closer to the discovery of the key.

Effects of tissues on biomaterialsThe mills of tissues grind slowly but they seldom spare a foreignmaterial in their midst. The tissue environment is designed tomaintain its composition and constancy, and intrusions of anykind are poorly tolerated. Metals tend to corrode and plasticsdegrade in the body.' Metallic groups such as titanium, stainlesssteel and cobalt--chromium alloys are relatively successful asimplant materials because oxidation in the tissue environmentresults in the formation of an oxide layer of angstrom thickness onthe metallic surface-passivation in metallurgical jargon-andprotects the implant." On the other hand, biodegradation whichassails plastics is caused by enzymatic degradation, hydrolysis,free radicals and occasionally, microbial damage. Though anever-present possibility with implanted plastics, biodegradation,far from being a handicap, may be actively sought in certainapplications such as sutures and drug delivery systems.

CHOICE OF MATERIALS

The selection of a biomaterial for a given end-application must bebased on several criteria. These are: physico-chemical properties,function desired, nature of the physiological environment, ad-verse effects in case of failure, expected durability and consider-ations relating to cost and ease of production. Whatever the givenapplication may be, biocompatibility is a sine qua non for allbiomaterials.

It is a sobering thought that though the criteria outlined abovehave been prescribed for the choice of materials, many of thematerials introduced empirically four decades ago continue to bewidely and successfully used at present. A recently developedtilting disc cardiac valvular prosthesis, for example, employsHaynes 25 alloy, ultra-high-molecular weight polyethylene andpolyester cloth, all of which were clinically proven many yearsago.9•IO There are numerous other successful examples whichinclude polyvinylchloride, polymethyl methacrylate (PMMA),silicone, chromium--cobalt alloys, stainless steels and titaniumalloys. The historical success ofthese materials owes not so muchto meticulous selection based on biocompatibility criteria as toserendipity and continual refinements in fabrication technologiesincluding surface treatment. For example, the thrombo-resistanceof the Stellite 21 housing of Starr-Edward's valve has less to do

271

with the haemocompatibility ofthe Stellite 21 than with the metal-lographic polish used in the finishing operation of the device!

Among the physico-chemical properties of candidate bio-materials, mechanical behaviour has supreme importance. Forimplants, flexibility, stiffness, creep, strength, wear and dimen-sional stability under various conditions are critical for trouble-free operation, and a choice must be made on the basis of the end-use of the device. A fracture plate, for example, must be rigidwhereas a vascular prosthesis would call for flexibility. Mechani-cal properties of materials under dynamic conditions such ascyclical loading are no less important than those in a static contextbecause many implants are subjected to severe and repeatedstresses in the body. Physical properties such as electrical conduc-tivity, light transparency and radio-opacity assume importance forspecific applications such as pacemaker electrodes, implantablelenses and certain dental and cardiac devices.

As biomaterials are clinically used as implants and disposables,their ability to withstand sterilization procedures is extremelyimportant. I I Moist heat by steam autoclave, ethylene oxide gasand dry heat are commonly used in hospitals for sterilizationwhich must be distinguished from disinfection by germicides.Steam sterilization is the safest, cheapest and most practicalmeans of sterilization which provides ideal conditions for thepenetration of porous materials such as fabrics and dressings andsterilizing metallic and ceramic devices. However, it is less thanideal for polymer-based devices which tolerate heat poorly andcall for ethylene oxide or gamma radiation treatment. Ethyleneoxide has the advantage of being not only a potent sterilant but isalso diffusive and can penetrate heat- or moisture-sensitive plas-tics and devices sealed in plastic films. However, polymers alsoabsorb and retain varying amounts of ethylene oxide which hastoxic properties. Therefore, it is necessary that articles sterilizedby ethylene oxide are 'degassed' in a well ventilated location atroom temperature for three to five days.

When a plastic biomaterial tolerates autoclaving poorly and isIikel y to react chemically wi th eth ylene oxide leading to ethox yla-tion, gamma radiation provides an effective alternative. Typi-cally, the source of gamma radiation is the C060 isotope which canbe effectively applied to even packaged polymeric products withthe assurance of killing all microorganisms. As radiation caninduce changes in the molecular structure of polymers and lead todegradation, a safe dosage level is critical, which is accepted to bein the 1 to 5 Mrad range.

BIOMATERIALS IN CURRENT USE

Biomaterials presently in common use are metals and alloys,polymers and ceramics.

Metals and alloysFor weight-bearing implants in particular, metals and alloys havebeen used widely for many years." Cast vitallium-a cobalt-chromium-molybdenum alloy-has been used for making surgi-cal appliances since 1936: stainless steel 316 and 316 L appearedin 1938: wrought vitallium, a cobalt--chromium-tungsten-nickelalloy was introduced in 1952. Pure titanium and titanium alloysentered later. These three groups dominate metallic implants, theshare of tantalum being quite small.

The main determinants in the selection of metals and alloys formedical use are corrosion resistance, biocompatibility, suitablemechanical properties, wear resistance, homogeneity and reason-able cost. As experience has shown that the cast and wrought.alloys of cobalt--chromium have excellent corrosion resistance, .

272

they are regularly employed in the production of bone and jointprostheses. Haynes 25-another cobalt-chromium alloy-formsthe material for the housing of the Chitra titling disc valveprosthesis. Stainless steel 316 and 316 L have also been employedextensively for surgical fixation and the manufacture of implants.Even though these austenitic type steels perform very well, thereis a statistical possibility of crevice corrosion and pitting in certainclinical situations, which would account for the edge whichcobalt-chromium alloys enjoy over stainless steels. The specialadvantages of titanium are its favourable strength-density ratio,corrosion resistance and biocompatibility. It has been used in thefabrication of many implants including joint prostheses andpacemaker encapsulation. The use of porous titanium, bioceramiccoating of metallic joint components and other technologies holdpromise for further improvements in the durability and fixation ofmetallic implants.

PolymersPolymers claim the major share of biomaterials and their medicalapplications already occupy the fourth-largest place among theindustrial use of polymers. Medical devices, consumables andtheir packaging claimed over 1000 million kg of plastics in 1992.

. Poly-vinylchloride (PVC), polystyrene (PS), polyethylene (PE)and polypropylene (PP) lead the list and a significant proportionof biomedical polymers belong to the 'high performance' varietywhich call for outstanding mechanical properties, environmentalresistance, biocompatibility and sterilizability." The main appli-cations include long term and temporary therapeutic devices, drugdelivery systems, diagnostic aids and devices for bioengineering.Table I (reproduced from Tanazawa)" lists the current range ofapplications of polymers in medicine and illustrates the extra-ordinarily wide reach and importance of polymers.

A growing frontier ofbiomaterials is controlled drug deli very.The appeal of controlled delivery arises from the fact that manyengineered drugs are large, high molecular weight proteins whichcannot be administered orally. Moreover, in the absence of tar-

THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 12, No.6, 1999

geted release, large doses of the drug must be administered withthe possibility of side-effects and waste. In the most commonapproach, the drug is encased in a reservoir, from which it leachesout. Alternatively, it is compounded into a degradable polymer,from which it is gradually released as the polymer breaks down inthe body. An example of the latter is the Gliadel system for treat-ing brain tumours which was approved by the Food and DrugsAdministration, USA. To overcome the blood-brain barrier,Gliadel, a polymer disc compounded with an antimitotic drug(carmustine) is implanted in the site of the resected tumour. Therelease of the drug is, however, not strictly 'controlled' withGliadel systems, the sole control being the rate of breakdown ofthe polymer. As controlled delivery is the ideal, attempts are beingmade to engineer 'smart' release systems involving magnetic,ultrasonic and enzymatic switches. Other approaches under de-velopment include the implantation ofliving cells encapsulated ina matrix such as purified alginate or silica gel to permit the diffu-sion of proteins. Organ targeting through the blood stream bytagging drugs to well-defined biodegradable polymers as particu-late carriers at the micro- or nano-Ievel is also receiving investi-gative attention." Controlled drug release and targeted deliveryare two areas where polymers will play an increasingly importantrole in the coming years.

The same basic polymer used for controlled drug release mayhold potential as a scaffolding material for culturing cells such asthe endothelium. Given appropriate growth factors, protein engi-neering has provided the know-how for the precise attachment ofthe desired surface of cells to the polymer scaffold and theboosting of yields.

CeramicsIn recent years, various types of composites and bone cementscontaining ceramic and, usually, polymeric materials have beendeveloped for repairing bone defects. Bonfield's group havedeveloped a polyethylene-hydroxyapatite which has found clini-cal use for bone restoration, with the establishment of a 'seamless'

Field Application

TABLE1. Biomedical applications of polymers (reproduced from reference 13)

Polymers usedPurpose

Prosthesis of bone joints, tooth, etc.,artificial heart valves, blood vessels,shunt and skin, contact andintraocular lenses, patch grafting

Artificial heart, lung, blood, kidney,liver, pancreas, ventricular assistsystem, biological response modifier

Tubings, catheters, syringes, sutures, etc.

Devices for controlled delivery of drugs,targeting design of drugs, intelligent drugrelease systems

Reagents and tools with quick response,high accuracy and sensitivity

Synthetic substrate or carrier particlesfor cell culture, additives for cell fusion,hybrid organs

Plasma separation, cell separation,removal of virus and bacteria

Therapy Replacement or repair of injuredtissue

Assist or temporary substitution forphysiological functions of a failedorgan

Disposable articles in daily medicaltreatment

Drug formulation Novel drug delivery systems

Diagnosticexamination

New items in clinical laboratory tests

Bioengineering New technology in tissue culture invitro

Separation of blood components

UHMWHDPE, polyesters, silicones,PMMA, hydrogels, etc.

Polyurethanes, cellulose membranes, PTFE,PV A, alginate/polylysine microcapsules

HDPE, LDPE, PS, PVC, PGA, etc.

Hydrogels, polyglycolic and lactic acids, etc.

Polymer microspheres, polymer lattices, etc.

Polyethylene glycol, dextran, PM~, graftco-polymers.

PTFE poly tetra f1uoroethylene PV A polyvinylaJcoholPv'C polyvinyJchloride PGA polyglycolic acid

UHMWHOPE ultra high molecular weight polyethylene PMMA polymethyl methacrylateHOPE high density polyethylene LOPE low density polyethylene PS polystyrene

VALIATHAN, KALLIYANA KRISHNAN : BIOMATERIALS

bond between the composite and bone." However, as the polymerdoes not degrade well enough, purely calcium phosphate-basedsynthetic ceramics have also been made for hard tissue replace-ment. The resorbable bioceramics are alumino-calcium-phos-phorus oxide, tricalcium phosphate, and hydroxyapatite. All thesematerials have been used in powder or porous block form forcorrecting maxillofacial and other bone defects in dental andorthopaedic surgery." An equally important application of bio-ceramic has been as coatings on orthopaedic and dental implantsto improve their fixation in tissues. As PMMA cement fixation isknown to loosen over time, porous ceramic-coated orthopaedicprostheses have offered an attractive alternative method forimplant fixation. The hydroxyapatite type of calcium phosphatecoatings on metal implants develop five to eight times the inter-face shear strength of identical uncoated metal surfaces and offergreat promise for improving implant fixation.'?

INDIAN SCENARIOMedical devices such as implants and disposables are almostwholly imported and, in this respect, share the fate of medicalinstruments in India. Biomaterials remained on the fringes for thematerial scientists whose community is strong in India; physi-cians hardly took note ofbiomaterials and remained content to usenewer generations of devices as long as they kept coming fromabroad; industry, averse to indigenous research and development,saw no merit in supporting research on biomaterials and medicaldevices. This situation is happily changing and, in the last ten tofifteen years, more than ninety indigenous industries and a fewjoint ventures with foreign collaboration have become opera-tional. However, research and development in medical devicesremains woefully inadequate and confined to the Sree ChitraTirunal Institute, Thiruvananthapuram; Defence Research andDevelopment Organization (DRDO) laboratories and other insti-tutions here and there in India. On the other hand, academicinterest has grown with the advent of professional societies forbiomaterials and biomedical engineering and the publication ofjournals. The Materials Research Society of India has a section onbiomaterials.

According to the estimates of the Commerce Department ofthe USA, the global market for medical devices amounted to US$130 billion in 1996 and the figure was expected to double by AD

2000. Trade literature estimated the Indian market at US$ 680million (Rs 2720 crores) in 1995 with a projected growth rate of15%-20% annually." What should interest technologists andindustry is not only the huge size of the market but also theimmense social benefit of medical devices, a partial list of whichincludes many millions of common items such as disposablesyringes, intravenous solution bottles, intravenous sets and bloodbags, all registering brisk annual growth rates according to theIndian Plastics Institute. In this context, it is surprising that thegovernment has not enacted a devices legislation and put an endto the appearance of substandard and unsafe devices which clutterthe Indian market!

Obviously India cannot depend, as she does at present, onforeign industry to supply her massive needs for medical devices.A major effort is overdue for developing a self-generating base forresearch and development in the medical devices industry whichcould confidently face the challenge of global trade. In meetingthis challenge, Indian medical scientists have an opportunity, ifnot an obligation, to join with industry, technologists and materialscientists in a cooperative and productive endeavour.

273

PROSPECTSAdvances in modem biology and biotechnology have cast theirmantle on biomaterials and ushered in tissue engineering whichholds considerable promise for organ replacement. As organsfrom cadaveric and living donors are scarce and the waiting list ofrecipients constantly growing, the possibility of creating reliableand cost-effective organ substitutes by tissue engineering isexciting. The techniques which have enjoyed varying degrees ofsuccess include cell and organ culture, endothelial pavementingon biomaterials to enhance haemocompatibility, bonding of phos-phoryl choline and heparin molecules to prosthetic surfaces tomimic cell surface and constructing biodegradable polymer scaf-folds as extracellular matrix for implanted cells. 19-21 These devel-opments in the laboratory anticipate clinical applications such asextracorporeal liver assist device, perfluorocarbons for oxygentransport, small artery replacement, temporary intracaval mem-brane lung, better artificial skin and collagen conduits to promoteneural regeneration. Tissue engineering has taken a major step ingreening medical technology and 'clothing non-living materialsin natural garments' .22

Harvesting of organs such as kidney, heart, aortic valve, lungand liver from humans and aortic valve and skin from pigssustains much of transplant surgery which has not only savedmany thousands of lives and opened new vistas in immunologybut also laid an altruistic milestone in the progress of medicine.Nevertheless, organ harvest is a reflection on biomaterials scienceand devices engineering which are yet to go beyond mechanicalmimicry and reproduce the functions of organs reliably anddurably. This alone would do away with the present commodi-fication of human and animal organs. Time was when aortichomograft was successfully introduced to reconstruct the ab-dominal aorta, and homograft preservation and tissue banking setvascular surgery ablaze with enthusiasm in the 1950s. When thesynthetic vascular grafts of polyester yarn appeared a few yearslater, aortic homografts died quietly and gave out the lesson thatorgan grafts, howsoever successful, will give way to the productsof technological innovation when they mature and pass the testsof safety, efficacy and durability. Biomaterials and medical de-vices are a long way from making organ grafts obsolete but thequest goes on.

REFERENCESDefinitions. In: Boretos IW, Eden M (eds). Contemporary biomaterials. NewJersey:Noyes Publications, 1984:651-2.

2 Peppas NA, Langer R. New challenges in biomaterials.Science 1994;263: 1715-20.3 Dumitriu S, Dumitriu D. Biocompatibilityofpolymers.In: Dumitriu S (ed).Polymeric

biomaterials. New York:Marcel Dekker, 1994:107-8.4 Brand KG. Do implanted medical devices cause cancer? J Biomat Appl 1994;8:

325-43.5 Vroman L, Adams AL. Identification of rapid changes at plasma-solid interfaces. J

Biomed Mater Res 1969;3:43-67.6 Brash JL. Role of plasma protein adsorption in the response of blood to foreign

surfaces.!n: Sharma CP, Szycher M (eds). Blood compatible materials and devices.Lancaster:Technomic Publishing, 1991 :3-24.

7 Williams OF, RoafR.lmplants in surgery. London:WB Saunders, 1973:9-10.8 Silva R, Bartosa MA, Rondot B, Cunha Belo M. Impedance and photoelectrochemical

measurements on passive films formed on metallic biomaterials. Br Corros J1990;25:136-40.

9 Valiathan MS. A heart valve substitute. CurrSci 1991;61:77-81.10 Muraleedharan CV, Bhuvaneshwar GS, Valiathan MS. Materials for Chitra heart

valve prosthesis. Metal Mater Processes 1995;7:147-58.II Szycher M. Sterilisation of medical devices. In: Sharma CP, Szycher M (eds).Blood

compatible materials and devices. Lancaster:Technomic Publishing, 1991 :87 ...• 2.12 WeismanS. Metals for implantation in the human body.AnnNY AcadSci 1968;146:80-

95.13 Tanazawa H. Biomedical polymers: Current status and overview. In: Tsuruta T,

Hayashi T, Kataoka K, Ishihara K, Kimura Y. (eds). Biomedical applications of •polymeric materials. CRC Press, USA, 1993:2-15.

274

14 Jayakrishnan A, Latha MS. Biodegradable polymeric microspheres as drug carriers.In: Jain NK (ed). Controlled and novel drug delivery. New Delhi:CBS Publishers,1997:236-55.

15 Bonfield W, Behiri JC, Doyle C, Bowman J, Abram J. Hydroxyapatite reinforcedpolyethylene composites for bone replacement. In: Ducheyne P, Van der Perre G,Aubert AE (eds). Biomaterials and biomechanics. Amsterdam:Elsevier Science,1984:421-6.

16 Bajpai PK. Ceramic-polyfunctional carboxylic acid composites for re-constructivesurgery of hard tissues. In: Sharma CP, Szycher M (eds).Bloodcompatible materialsand devices. Lancaster:Technomic Publishing, 1991 :289-303.

17 Cook SO, Thomas KA, Brinker MR. Bioactive ceramic coatings for orthopaedic and

THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 12, NO. 6,1999

dental implant applications. In: Sharma CP, Szycher M (eds). Blood compatiblematerials and devices. Lancaster:Technomic Publishing, 1991 :279-87.

18 Kader V, Priestly DA. India's medical device market is becoming too big to ignore.Med Device Diagnos Industry 1997;April:85-6.

19 Weizman SK, Rose DG, Jarrel BE. Microvascular endothelial cell seeding ofPTFEvascular grafts. J Biomed Mater Res 1994;28:203-12.

20 Ahrendt G, Chickering DE, Ranieri JP. Angiogenic growth factors: A preview fortissue engineering. Tissue Engineering 1998;4: 117-30.

21 Shivakumar K, Renuka Nair R, Jayakrishnan A, Kartha CC, Valiathan MS. Celladhesion and growth on synthetic hydrogel beads. Bull Mater Sci 1989;12:27-32.

22 Valiathan MS, Heparin bonding-then and now.Bull Mater Sci 1994;17: 1199-213.

The impact of new technologies on vaccines

G. P. TALWAR, MANISH DIWAN, FAREHA RAZVI, RITU MALHOTRA

ABSTRACTVast changes are taking place in vaccinology consequent to theintroduction of new technologies. Amongst the vaccines includedin the Expanded Programme of Immunization (EPI), the pertussisvaccine has been replaced by acellular purified fractions devoidof side-effects. Non-pathogenic but immunogenic mutants oftetanus and diptheria toxins are likely to replace the toxoids. Aneffective vaccine against hepatitis B prepared by recombinanttechnology is in large-scale use. Conjugated vaccines againstHaemophilus influenzae b, S. pneumococcus and meningococcusare now available, as also vaccines against mumps, rubella andmeasles. Combination vaccines have been devised to limit thenumber of injections. Vaccine delivery systems have beendeveloped to deliver multiple doses of the vaccine at a singlecontact point. A genetically-engineered oral vaccine for typhoidimparts better and longer duration of immunity. Oral vaccines forcholera and other enteric infections are under clinical trials. Thenose as a route for immunization is showing promise for mucosalimmunity and for anti-inflammatory experimental vaccines againstmultiple sclerosis and insulin-dependent diabetes mellitus. Therange of vaccines has expanded to include pathogens resident inthe body such as Helicobacter pylori (duodenal ulcer), S. mutans(dental caries), and human papilloma virus (carcinoma of thecervix). An important progress isthe recognition that DNA alonecan constitute the vaccines, inducing both humoral and cell-mediated immune responses. A large number of DNA vaccineshave been made and shown interesting results in experimentalanimals. Live recombinant vaccines against rabies and rinderpesthave proven to be highly effective for controlling these infections

Talwar Research Foundation, New Delhi, IndiaG.P.TALWAR, MANISHDIWAN, FAREHARAZVI,RITU MALHOTRA

Correspondence to G. P. TALWAR

© The National Medical Journal of India 1999

in the field, and those for AIDS are under clinical trial. Potentadjuvants have added to the efficacy of the vaccines.

New technologies have emerged to 'humanize' mousemonoclonals by genetic engineering and express these efficientlyin plants. These recombinant antibodies are opening out an eraof highly specific and safe therapeutic interventions. Humanrecombinant antibodies would be invaluable for treating patientswith terminal tetanus and rabies. Antibodies are already in use fortreatment of cancer, rheumatoid arthritis and allergies. Anadvantage of preformed antibodies directed at a defined targetand given in adequate amounts is the certainty of efficacy in everyrecipient, in contrast to vaccines, where the quality and quantumof immune response varies from individual to individual.Natl Med J India 1999;12:274-80

INTRODUCTIONVaccines have had a profound effect on health care. The mereintroduction of a handful of vaccines in the Expanded ProgrammeofImmunization (EPI) drastically reduced infant mortality, espe- .cially in economically-emerging countries. Thanks to a vaccine,albeit of Jennerian descent, smallpox has been eradicated from thesurface of the earth. It is expected that with aggressive andsystematic use of two vaccines (the Salk killed vaccine and theSabin oral vaccine), poliomyelitis will be eradicated globally inthe future. Similar achievements can be expected for other infec-tions such as leprosy, where the infecting microorganism breedsprimarily in humans and for which vaccines have now beendeveloped. Vaccines not only prevent disease but also by virtue oftheir property of enhancing immunity in humans (and animals),render them as inhospitable territory for propagation of patho-gens, thereby curtailing the focus of infection and its transmissionto others. _

With the input of new technologies, old vaccines are undergo-ing improvement. New vaccines are being made to replace thoseconferring insufficient or regionally variable immunity, as is 'thecase with tuberculosis. The range of vaccines has expanded.