University Politehnica of Bucharest, ROMANIA

Biomaterialele, si efectul nanodimensiunii

Conversia unor functii prin nanostructurare

1 Evolutia conceptului de biomaterial de la micro la nano

Este nanomaterialul asociat cu risc asupra sanatatii ?

Responsabilitatea sociala a nanotechnologiei
Continutul disciplinei 1C+2L

• Biomateriale scurt istoric al conceptului de la micro la nano

• Nanomateriale, nanotehnologie, bionanotehnologie

• Responsabilitatea sociala a nanotehnologiei, nanomaterialelor si a nanobiomaterialelor

• Nanoarhitecturi 1D de tip nanoparticule de elemente de diferite dimensiuni.

• nanoparticule Ag, si Au,Cu,Zn,Mg Efect antibacterian,biocompatibilitate, terapie

• Nanoarhitecturi de carbon.Nanotuburi ( MWCNT, SWCNT, simple si componente de

biomateriale hibride cu substante active inglobate ) Grafene.

• Nanoparticule de diferiti oxizi de metale valva. Agenti de contrast de diferite forme si marimi
• Nanotuburi , nanocanale si nanofire de metale valva (Ex Ti si Zr si aliajele lor ).

• Evaluarea disciplinei 50% activitate in timpul anului (30% laborator, 20% tema de casa )
• 50% examen
 Scurt istoric asupra drumului biomaterialelor de la
macro la micro si nano
• Inceputuri in epoca maiasa, (Au); Epoca precolumbiana
dinti din piatra prelucrata; in Egiptul sclavagist dinti de
la sclavi ,
• legaturi de sarma Au cu dinti sanatosi vecini (2500 iHr)
• Fenicienii 500 iHr aceleasegaturi de sarma, dinti fildes
fixati cu Au
• Evul mediu : transplante dentare de la un om la altul
(implantare mugure dentar in creasta de cocos)
• 1860: Lister dezvolta tehnica chirurgicala aseptica
• 1900: placi osoase utilizate pentru la fixa fracturi
• 1930: Introducerea otelului inox, aliajelor Co/Cr
• Magiolo 1908 inserarea unei radacini de Au in alveole ,
dupa extraxtie pe care se aplica ulterior o coroana cu
pivot
• Cauciuc, Au portelan, experimentate ca implante fildes
• 1938 : prima proteza totala de sold (P. Wiles)
 Biomateriale de implant
• 1940: Polimeri in medicina PMMA (polimetilmetacrilat)
pentru reparare oase; celuloza pentru dializa; nylon
pentru suturi
• 1952: valva cardiaca mecanica
• 1953: grefe vasculare Dacron (fibre polimeri)
• 1958: inlocuitor articulatie PMMA cimentat
• 1960 Implant BranemarK Ti
• 1960: primele valve cardiace comerciale
• 1970: film subtire rezistent de acoperire PEO (polietilen
oxid) proteina
• 1976: Amendament FDA pentru testarea si productia
biomaterialelor/ dispozitivelor
• 1976: Inima artificiala (W. Kolff)
• sfarsit de secol nanomateriale
 Biomaterial Definitii

• 1987, ESB [1], biomaterialul este un material neviu

utilizat intr-un dispozitiv medical in directa interactie cu
sistemul biologic.
• 5 ani mai tarziu dispare referirea la “nonviabilitate” [2],
• In1999 [3], definitia introduce termenul de a evalua a
trata a imbunatati sau a inlocui un organ sau o functie a
corpului viu;
• Alte dictionare introduc o alta abordare si semnificatie
privitoare la ‘bio’; de ex., Larousse Science defineste
biomaterialul ca pe un solid alcatuit din componente de
organism viu precum chitina, fibrinogen sau os [4].
• [1] Williams DF. Definitions in biomaterials. Amsterdam: Elsevier; 1987.
• [2] Doherty P, Williams RL, Williams DF, Lee AC. Biomaterials–tissue interfaces. Amsterdam: Elsevier; 1992.
• [3] Williams DF. The Williams dictionary of biomaterials. Liverpool: Liverpool University Press; 1999.
• [4] Walker PMB, editor. Larousse dictionary of science and technology. New York: Larousse Press; 2006.
 Asupra naturii biomaterialelor (D.F. Williams / Biomaterials 30 (2009) 5897–5909)

Materiale clasice, tehnologii clasice (a) grefa vascular; polyethylene terephthalate or

polytetrafluoroethylene ; (b) valva cardiaca mecanica ; alcatuita din aliaj titan ori cobalt-
crom, carbon pyrolytic carbon, si inel din polyethylene terephthalate, tehnologie standard
pentru elaborare metale, CVD pentru carbon ;(c) Valva cardiaca bioprostetica ; din aorta de
porcine cu polimer (e.g. acetyl copolymer) or metal; (d) STENT Intravascular; din TiNi,Co
ori 316 L cu acoperire polimeri
 Concepte viabile si non viabile asupra
biomaterialelor

• Williams afirma ca organele si tesuturile umane sau animale nu

sunt biomateriale daca nu sunt prelucrate.

• Acestea vor fi biomateriale dupa procesare.

• Procesarea prin monitorizarea temperaturii doar pentru a mentine

integritatea tesutului sau organului nu este suficienta.

• manipulare suficienta pentru ca acestea sa fie considerate

biomateriale se considera cea care schimba caracterul materialului
modificand raspunsul anticipat al recipientului in care se introduce.

• dispute asupra gradului de manipulare care separa un transplant

de ceea ce este mai corect de numit un organ obtinut inginereste.

• Separarea intre ingineria tisulara si dispozitivele implantabile.

 Ce este “bioperformanta” biomaterialului ?
• Performanta =indeplinirea unei activitati in raport cu standarde impuse
(precizie, viteze, cost etc) ; ex.performante inalte si performante slabe.
• Bioperformanta se refera la performanta in domeniul bioaplicatiilor si
poate avea mai multe valente cand vizeaza comportarea biomaterialelor;

• ex pentru materiale metalice implantabile:Ti, CoCr, Otel 316L

• Ti si alajele Ti sunt bioimplante preferate datorita proprietatilor: densitate
mica, biocompatibilitate, rezistenta la coroziune si uzura, proprietati
mecanice. La suprafata Ti apare spontan strat de oxid (3-7 nm)
nonstoichiometric, care da seama de proprietatile chimice si biologice
aleTi si are rol in adsorptia de proteine, cationi si anioni.

• Pe suprafata Ti, moleculele de TiO2 devin dipoli cu cap pozitiv Ti si

negativ de oxigen. In biofluide, OH- se leaga de Ti din TiO2 si formeaza
grupe TiOH.
• Oxidul impiedica eliberarea de ioni.
• Aliajele CoCr formeaza de asemenea oxizi pasivi care impiedica
coroziunea.
• Performanta in aceste cazuri este stabilitatea ( inclusiv eliberare minima
de ioni) si capacitatea de absorbtie proteine( pentru a ajuta fixarea ) sau
de desorbtie in cazul stenturilor
 Bioreactivitatea
•In abordarea macroscopica a materialelor,termenul de biocompatibilitate este
impartit in 2 categorii : bioactiv si bio-inert. De examplu, metalele precum Ti sunt
bioinerte (compatibile dar nonstimulative) si hidroxiapatita este bioactiva (capabila
sa induca functii intrinseci organismului biologic, cum ar fi osteo conductivitatea)
• Ti si Ta tratat la suprafata cu NaOH si tratament termic

Conceptul de metale bioactive.

•Kokubo T, Kim HM, Kawashita M Biomaterials. 2003 Jun;24(13):2161-75.

Bioactivitatea deobicei reprezinta un aspect pozitiv, un merit, dar exista si

situatii cand poate reprezenta un nemerit : pentru ambele situatii s-a introdus un
termen mai general bioreactivitatea (F. Watari Nanobiomedicine 1,2 pp 2-8,
2010) ex.
 Metale bioabsorbabile si biocorodabile
Performanta este legata de corodarea lor controlata

- Sticla metalica ( baza Mg ) in chirurgia ortopedica are dezavantaj

producerea de H2.; Se contracareaza dezavantajul cu suplimentarea
cantitatii de Zn (35% zinc, 5% calciu, 60% magneziu)

• Pentru stenturi s-au utilizat aliaje de fier ( stenturi traditionale) si

aliaje de Mg.
• Biocompatibilitatea lor depinde de solubilitatea lor si de eliberarea
produsilor de degradare. Toxicitatea locala este legata de
concentratia locala de elemente in timp. Toleranta tesutului pentru
mediul fiziologic din jurul metalului depinde de schimbarile din tesut
induse de coroziune.
• Peuster a raportat experimente cu stenturi de fier. Au implantat
stenturi din 41 mg (cantitatea de fier egala cu ingerarea pe luna ) in
aorta iepurilor albi si nu s-a observat tromboza sau alte evenimente
adverse timp de 18 luni.
• Cele mai folosite stenturi la ora actuala sunt de CoCr acoperit si
neacoperit.
 Stenturi din aliaje cu Mg
• Atractive pentru bioabsorbtie.
• Heublein si altii au condus teste preclinice in vitro si in vivo
• S-a demonstrat nivel ridicat de degradare de la 60 la 90 zile, in
timp ce integritatea totala a stentului ramanea doar 28 zile.

• In vitro s- a studiat integritatea stenturilor cu celule endotelilale

• Testele pe animale cu stenturi din aliaje Mg implantate in artera
coronara la porcine au demonstrat reducerea formarii de legaturi in
comparatie cu stenturile din 316 L,

• S-a observat remodelarea zonei din jurul stentului timp pana la 30

la zile cand a avut loc absorbtia completa.
• In plus nu apar evenimente tromboembolice (ocluzia unui vas
sanguin ca urmare a trecerii succesive de cheaguri sanguine
provenite de la o trombiza vasculara) iar cazurile de inflamare sunt
putine si de gravitate mult inferioara celor provocate de stenturi din
L316.
 “Best techniques” in evaluarea bioperformantei
• Eliberare de ioni (identificare si cuantificare);
technica ICP/MS ;
• Stabilitate electrochemica ( v. coroziune ) ;
• Structura filmului (FT-IR) ;
• Morfologia suprafetei si compozitia la
suprafata ( Scanning electronic microscopy
(ESEM) with an EDAX module (X ray energy
dispersive) ;
• Balanta hidrofil/hidrofob la interfata ;
• Analiza de suprafata (AFM) ;Microscopie TEM ;
• Biocompatibilitate (adeziune, proliferare
celulara, viabilitate MTT ) ;
• Efecte antimicrobiene ;
 Etape noi in evaluarea performantei materialelor
Nanotehnologia

Este nanotehnologia un domeniu nou si modern al stiintei ?

Desi conceptul este dezvoltat intre 1980s si 1990 Richard Feynman's in faimoasa
conferinta din 1959 "There's Plenty of Room at the Bottom“, fara sa introduca cuvantul
nanotehnologie a introdus semnificatia conceptului ,

Domeniul are insa radacini in lumea antica. Dupa standarde moderne materiale “bulk “ sunt
imbunatatite prin nanoarhitecturare. Dar a existat :
1. Lycurgus cup o cupa Romaan de sticla continand nanoparticule care aparea rosie privita
in lumina stralucitoare si verde in lumina reflectata.

1. Maya Blue, este un pigment stralucitor descoperit la in Chichen Itza, foarte rezistent la
uzura care contine un adaos poros in care colorantul indigo s-a combinat chimic
cformand un pigment stabil.

In 2006 in Germania s-au evidentiat nanofire si nanotuburi de carbon in sabiile din Damasc
ale sec 17.
 Nanoscience of an Ancient Pigment
Darrah Johnson-McDaniel , Christopher A. Barrett , Asma Sharafi , and Tina T. Salguero *
Department of Chemistry, University of Georgia, U.S.A J. Am. Chem. Soc., 2013, 135 (5), pp 1677–
1679

Egyptian blue, regarded as humanity’s first artificial pigment,

• The paper described monolayer nanosheets of calcium copper tetrasilicate,
CaCuSi4O10, which have strong near-IR luminescence and are amenable to solution
processing methods.
•The facile exfoliation of bulk CaCuSi4O10 into nanosheets is especially surprising in
view of the long history of this material as the colored component of Egyptian blue, a
well-known pigment from ancient times.
 Conversia unor functii prin nanostructurare.

•Ti este biocompatibil dar poate conduce la inflamatii , osteoliza , micro/nanoparticule (

artificial joint) eliberate prin abraziune.
• asbestul din compozit non-toxice minerale (silicati) poate provoca cancer (mesothelioma)
sub forma de nanoace..
•Mecanismul de conversie este bazat pe procese biologice de interactie particule–
celulel/tesut ca rezultat al efectului de nanodimensiune care induce reactii nonspecifice

• Apatita are biocompatibilitate excelenta si induce

formare de os nou la implantare dar nanoparticulele
formate la suprafata pot induce fagocitoza celulelor
si inflamarea tesutului

• Una din cauzele de insucces ale implantului dentar

sste praful fin de particule de apatita produs prin
Exfoliaere, delaminare.etc. Acesta induce inflamare
in partea periferica a implanului, care conduce la
resorptia noului os format. .
.

Materials Today martie 2011

 Clasificari de nanomateriale
-materialele la nanoscala pot fi clasificate tinand cont
de forma:

- tubular (nanotuburi),
-nanofire,
- sferice,
- forme neregulate,
- agregate in diferite formatiuni.

16
 Inginerie tisulara si nanomateriale

• Scopul ingineriei tisulare si a medicinei regenerativa:

dezvoltarea substituentilor biologici care insanatosesc,
mentin sau imbunatatesc tesutul deteriorat si
functionalitatea unui organ.
• Nanotehnologia si bionanomaterialele pot imita
proprietatiile de suprafata (incluzand topografia, energia,
etc. ) tesutului natural.
• Nanomaterialele dispun de proprietati mai bune
citocompatibile, mecanice, electrice, optice, catalitice si
magnetice fata de materialele conventionale.

• Nano-esafoade biomimetice pentru

imbunatatirea ingineriei tisulare.
• vasculare, nanomaterialele de viitor pentru aplicatii
ortopedice.
 Inginerie tisulara
Bionanotehnologie si bionanomateriale: promisiuni pentru
regenerare celulara imbunatatita

Avantajele biomimetice ale nanomaterialelor (A) nanostructura ierarhica auto-

ansamblata a osului, (B) Nanofaza de titan (sus, imaginea AFM) si esafodul HA
nanocristalin/HRN hidrogel (jos, imagine SEM)
 Inginerie tisulara
Nanotehnologie si nanomateriale: promisiuni pentru regenerare celulara
imbunatatita

Avantajele biomimetice ale nanomaterialelor (C)Ilustrare schematica a mecanismului prin care

nanomaterialele pot fi superioare materialelor conventionale pentru regenerare osoasa.
Suprafetele bioactive ale nanomaterialelor imita pe cele ale oaselor naturale pentru a
promova adsorptia marita a proteinelor si stimuleaza mai eficient formarea de os nou fata
de materiale conventionale.
 Nanobiomaterial : un biomaterial compus din componente la scala
nano

• Studii In vitro pentru nanobiomateriale Biocompatibilitate

• Celulele in corp sunt predispuse sa a interactioneze cu

suprafete nanostructurate dezvoltand biomimetism.

• Proliferarea migrarea si matricea extracelulara produsa de

celule in timpul repararii tesutului sunt procese dependente
de adsorbtia de proteine.
• Caracteristicile adsorbtiei de proteine sunt in schimb
dependente de caracteristicile de suprafata ale materialelor
implantabile

• Integrinele sunt receptori transmembranari care

interactiioneaza cu stratul de proteine adsorbit pe scafold .
Aceste interactii sunt guvernate de evenimentele moleculare la
scala nano.
 Coexistenta biomaterial –tesut gazda
• Modul in care biomaterialul si un tesut gazda isi accepta mutual
coexistenta a fundamentat notiunea de biocompatibilitate.

• aceasta coexistenta poate fi un compromis cu performanta

biomaterialului ;conduce la intelegerea fenomenului de biocompatibiliate.
• D.F. Williams a formulat aprecieri diferite pentru biocompatibilitate in
functie de durata de viata a implantului si a conchis ca pe termen lung
singura cerinta pentru biocompatibilitate este ca materialul sa nu
agreseze tesutul.
• Rareori introducerea activitatii biologice intr-un biomaterial este
sinonima cu succesul clinic.
• Aceasta activitate devine importanta pentru utilizarea biomaterialelor in
inginerie tisulara, medicamente cu eliberare controlata sisteme si aplicatii
in biotehnologie unde interactiile intre biomateriale si componentele
tesutului sunt necesare.

• Cu aceasta abordare s-a dezvoltat o noua paradigma pentru conceptul

de biocompatibilitate.
 Materialele biocompatible prezinta comportari
diferite functie de dimensiune
•Materialele biocompatible prezinta comportari diferite functie de
dimensiune. The transition of bioreaction occurs at the critical sizes of
approximately 100 mm,10 mm and 200 nm.

• This physical size effect is nonspecific,which is independent of material

type, and especially pronounced for a cell size of less than approximately
10 mm.
•It causes stimulus through the biological process of phagocytosis in cell
and inflammation in tissue.
•When the particle size is 200 nm or less, they become less stimulative and
the recognition by body defence systems becomes weaker. They may
invade directly into the internal body through the respiratory or digestive
system and diffuse inside the whole body.

•Thus, the physical micro/nanosizing of materials makes them

biointeractive with cells and tissue.
Watari, F.: Bioreactive nature of nanobiomaterials, Nanobiomedicine, 1, 2-8 (2010).
 Scafold
Concept central in ingineria tisulara.

• Furnizeaza structura suport pentru aderarea si cresterea celulelor

• Pot avea forme si compozitii diferite (spuma, fibre, retele, geluri)
• Pot fi obtinute dintr-o gama larga de materiale
• Sunt uzual biodegradabile

• Reprezinta o aplicatie majora a polimerilor in ingineria tisulara

Polimeri sintetici biodegradabili: poli acid L-lactic (PLLA), poli acid
D,L- lactic (PDLLA), poli acid glicolic (PGA), poli acid lactic-co-glicolic
(PLGA), poli hidroxi butirati, poli ε-caprolactona, polidioxanona,
polianhidride, polifosfazene, polipeptide, etc
• Polimeri naturali biodegradabili: celuloza, chitina, chitosan, dextran,
colagen, gelatina, fibrina, fibrinogen, cazeina, etc
Criterii pentru utilizarea structurilor scaffold in ingineria tisulara

• Promoveaza adeziunea
celulara
• Creste proliferarea celulara
• Retentia functiei celulei
diferentiate
• Biodegradabilitatea
• Biocompatibilitatea
• Inalta porozitate
• Raport mare suprafata/volum
• Rezistenta mecanica
• Distributie uniforma si pori
interconectati
 O noua paradigma asupra biomaterialului

• In acceptia ingineriei tisulare se schimba controlul si intelegerea

notiunii de biomaterial.

• Conceptul de material tangibil solid fabricat top-down nu mai este

suficient; luam in considerare nanoparticulele active , hydrogeluri,
agenti de contrast solubili, sisteme biologice autoasamblate, celule
si virusuri.

• materialul ’ poate fi deci o entitate singulara bine definita

precum titanul si aliajele sau hydroxyapatita, ori poate fi un
virus acoperit cu film de polymer cationic , ori un organ
ingineresc.

• Importanta este functia biomaterialului care directioneaza cursul unui

treatament medical , sau intervine in tratament si diagnoza si trebuie
sa realizeze aceasta controland interactiile biologice a caror
mecanism nu il cunoastem in intregime.
 Celula, citoschelet, biomaterial (2007-2009)
• Celula poate fi un biomaterial dupa Kasza et al. si poate avea
proprietati analoge cu materialele clasice. Viscoelasticitatea, de ex
permite ca celula sa fie considerata un sistem polimeric ce raspunde la
stimuli.
• Rolul cytoskeletului : Smith il defineste ca pe un polimer pe baza unui
scaffold .
• Trepat afirma ca cytoskeletul unei celule vii aderente este cea mai
complexa forma de “soft” material care exista in natura.

• Stamenovic descrie proprietatile reologice ale celulelor mamare, in

termeni de model sticlos moale.
• biomaterial = o substanta care a fost procesata pentru a primi o forma
care singura sau ca o parte a unui complex este folosita pentru a
controla interactiile dintre componentii unui sistem viu, drumul unui
proces terapeutic sau al diagnosticului, in medicina umana sau
veterinara .
• [1].Kasza KE, Rowat AC, Liu J, Angelini CP, Brangwynne CP, Koenderink GH, et al.The cell as a material. Curr Opin Cell Biol 2007;19:101–7
• [2]Smith D, Gentry B, Stuhrmann B, Huber F, Strehle D, Brunner C, et al. The cytoskeleton: an active polymer-based scaffold. Biophys Rev Lett 2009;4
• (1–2):179–208.
• [3] Trepat X, Lenormand G, Fredberg JJ. Universality in cell mechanics. Soft Mater 2008;4(9):1750–9.
• [4] Stamenovic D. Rheological behavior of mammalian cells. Cell Mol Life Sci2008;65(22):3592–605.
Evolutia stiintei biomaterialelor spre suporturi populate de celule
utilizate in reconstructia de organe

Principiul realizarii unui construct pentru ingineria tisularaTEC“tissue-

engineered construct”care contine un scaffold sau o matrice,celule vii
si/sau molecule biologic active-pentru repararea si regenerarea tesuturilor.
 Evolutia descoperirii biomaterialelor in functie de proprietatile matricei
extracelulare (ECM)
(Partea extracelulara a unui tesut animal, suport pentru celule, functii importante de comunicare
celula-celula, celula mediu. Contine proteoglicani, polizaharide non-proteoglicani, fibre (colagen,
elastina), alte proteine (fibronectina, )

• Prima generatie – materiale bulk, ca Ti,

Dacron si poli-etilena – durabile si bune
proprietati mecanice
– bioinerte si nedegradabile
A doua generatie – modificate biochimic sau
chimic pentru a dobandi proprietati
biologice adecvate ; – permite adsorbtia
proteinelor ECM pe suprafata materialului
– reactii de schimb ionic a sticlei bioactive,
dizolvarea si reorganizarea fosfatului de
calciu amorf si degradarea hidrolitica a poli-
uretanilor si poli-esterilor.
Generatia 3 activa fizico chimic
A patra generatie – activa biochimic Generatia 5 incorporare de
incorporarea de secvente biomimetice tesut si celulecelule
(peptide) pentru interactia cu proteine tinta suprafata biologica
(receptori de adeziune);imobilizarea colagen
peptide, etc
 Biomaterialele si nanotehnologia
- Un nanomaterial este orice forma de material care
este compus din parti functionale distincte cu
dimensiuni ( macar una dintre dimensiuni)de
ordinul 100 nm sau mai putin “(D.F.Williams The
relationship between biomaterials and
nanotechnology Biomaterials 2008, 29,1737-1738
• Dezvoltarea nanotehnologiei are o mare influenta
asupra vietii, dar efectul micro/nanodimensiunilor
asupra organismelor biologice nu este total
cunoscut.
• Efectul nanodimensiunii materialelor asupra
organismelor vii este : ne-specific, biointeractiv,si
imbraca si aspecte fizice.
Nanosizing effect (cresterea suprafetei
specifice )
 Critical size

become less stimulative

Natura bilaterala a nanomaterialelor
•Depinzand de dimensiunea lor nanoparticulele si
nanomaterialele in general isi sustin natura bilaterala
cu efecte pozitive si negative
•Micro/nanoparticulele se considera biointeractive
cand insusi dimensiunea induce raspunsul biologic;
sub 10µm, mai pot cauza si stimula inflamari ale
tesutului .
•Acest efect este o problema in expunerea pe termen
lung ori in cazul unei cantitati mari de (ex. Osteoliza
cauzata de abraziune in incheieturi artificiale ).
 Relatia biomaterialor cu nanotehnologia
• In multe aplicatii biomateriale in mod specific sunt prezentate
ca o entitate cu dimensiuni la nanoscala.
• o structura interna nano (de ex molecule sau cristale) nu
poate fi considerate apriori nanostructura.

• Ex. in ce masura fulerenele sunt nanomateriale ori numai

molecule. O clasă de compusi înruditi, practic fulerene mult
alungite, sunt nanotuburile de carbon.

• Este important ca un nanomaterial sa aiba proprietati

distincte de materialul “bulk” ca o consecinta a alcaturii
sale din parti functionale distincte.
• Aceste proprietati conduc la eficienta crescuta la
functionalizare si la targetare.
• de ex interactiile intre DNA si materialele nanostructurate,
sau aspecte biotechnologice ale biomaterialelor, incluzand
agentii de imbunatatire a imaginilor.
 Interactia dintre un biomaterial si
mediul biologic
• Interactia dintre un biomaterial si mediul biologic in care este implantat (celule,
tesuturi,lichide biologice) este dinamica si complexa. Celulele prin intermediul
proteinelor, anticorpilor sau fagocitelor pot actiona asupra materialului putand
conduce la degradarea lui si eliberarea din el a unor produse solubile,toxice, ce
pot afecta tesutul gazda.Caracteristicile fizico-chimice, mecanice si morfologice
ale dispozitivului pot avea un impact asupra tesutului gazda
caracteristicile chimice ale suprafetei,

produsii de degradare/uzura eliberati

biomaterial
→
← anticorpi, enzime si
alte proteine,fagocite
 Antagonismul dintre nanotehnologie si
nanotoxicologie
• Recunoasterea efectului dimensiunii si formei nanostructurilor
esentiala pentru intelegerea si dezvoltarea aplicatiilor biomedicale ale
nanotehnologiei.

• Functii inalte insotite de producerea riscului induc antagonism intre

nanotehnologie si
nanotoxicologie.
• Din punct de vedere al bioreactivitatii sunt diferite capete ale
sistemului de evaluare pentru fiintele umane respectiv merite si
nemerite, desi ele deriva din acelasi mecanism.

• Este necesara deci o analiza de risc care sa se bazeze pe un set de

teste de biocompatibilitate
 Analiza riscului
• Riscul potential al nanobiomaterialelor este legat de
expunerea tesuturilor umane la miscarea nanoparticulelor in
perioada :
• elaborarii lor ( pe ruta pulmonara, dermica, oral sau ocular);
• – dupa implantare nano-particulele (eliberarea medicament ,
dendrimeri) ori biomateriale constand din nanoparticule , prin
produsi de degradare solubili sau insolubili,
• Caracterizarea fizico chimica a nanobiomaterialelor
• – Dimensiunea si distributia dimensiunii
• – Structura cristalina
• Compozitia chimica
• Energia de suprafata
• Biodegradare in vitro
• (ISO 10993)
• – In vitro adsorbtie de proteine
• Teste generale de biocompatibilitate
 Este nanotehnologia asociata cu risc asupra
sanatatii ?
• Nanotehnologia are potential urias de influentare pozitiva a calitatii
vietii prin multe rezultate legate de medicina si biotehnologie;
• prima etapa nanomaterialul este un panaceu universal
• nanotehnologia este asociata cu risc asupra sanatatii

• Commisia Europeana [1,2] ingrijorata privitor la efectele

adverse ale nanoparticulelor.

• Nanoparticulele apar in numeroase procese naturale in ecosfera ca

produse secundare de ex. in combustie.

• Nanotechnologiile genereaza nanoparticule, a caror distributie si

destin in mediu si in organismul uman nu este clarificat.
• subiectul este important in special in legatura cu aspectul inhalarii, a
toxicologiei si a patologiei.
• [1]European Commission, Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR). Opinion on ‘the scientific
aspects of the existing and proposed definitions relating to products of nanoscience and nanotechnologies. Adopted. Brussels: European
Commission; 29 November 2007.
• [2] European Commission, Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR). Opinion on ‘the
appropriateness of existing methodologies to assess the potential risks associated with engineered and adventitious products of
nanotechology
IDENTIFICATION OF DANGERS

Health Effects of Nanoparticles

NPs soluble in biological fluids dissolve and their toxic effects are related to chemical
components, independent of the particle’s initial size. These effects are not specific to
nanometric dimensions.

The situation is different for NPs that are insoluble or very weakly soluble in the
organism. This is because a product mass of the same chemical composition is
normally more toxic if it is nanoscaled than if it is larger in size.

Absorption of synthesized nanoparticles

The greatest absorption of dusts in the work environment normally occurs through the
pulmonary route. The leading particularity of NPs is based on pulmonary deposition
In fact, the deposit site is highly dependent on their size.

Whereas NPs of one or a few nm will be deposited mainly in the nose and throat,
more than 50% of NPs of 15-20 nm will be deposited at the alveolar level
l
Nature 444, 267-269 | doi:10.1038/444267a; Published online 15 November 2006
O cotitura in perceptia meritelor si nemeritelor
Safe handling of nanotechnology
Andrew D. Maynard1, Robert J. Aitken, Tilman Butz, Vicki Colvin, Ken Donaldson, Günter Oberdörster, Martin A. Philbert,
John Ryan, Anthony Seaton, Vicki Stone, Sally S. Tinkle, Lang Tran, Nigel J. Walker & David B. Warheit

Fears over the possible dangers of some nanotechnologies

proposing five grand challenges to stimulate research ; all relevant to the safety of nanotechnology.
Testing strategies to establish the nanomaterials safety :
ECETOC Conclusion
The European Centre for Ecotoxicology and Toxicology of Chemicals in 2005
develop testing strategies. The primary questions to be addressed were :
What can we do today, and what do we need tomorrow?

The three major themes of the workshop were:

(1) the need for enhanced efforts in nanomaterial characterization;
(2) methodologies for assessments of airborne and internal exposures to
nanomaterials;
(3) evaluation of the hazard potential--primarily focusing on pulmonary or dermal
routes of exposures.

Conclusions :
For the development of nanoparticle characterization, the working definition of
nanoparticles was defined as
< 100 nm in one dimension or < 1000 nm to include aggregates and agglomerates.
Many physical factors can influence toxicity, including
nanoparticle composition, it is dissolution,
surface area and characteristics,
size, size distribution,
and shape that largely determine the functional, toxicological and environmental
impact of nanomaterials.
 ECETOC Conclusion
Is a need to develop instruments which are smaller, more portable, With regard to
a general testing approach for human health hazard evaluation of
nanoparticles, a first step to determine potency may include a prioritization-
related in vitro screening strategy to assess the possible reactivity,
biomarkers of inflammation and cellular uptake of nanoparticles;
however this process should be validated using in vivo techniques.

1 in vivo testing strategy could include a short-term inhalation or intratracheal

instillation of nanoparticles as the route of exposure in the lungs of rats or
mice. The endpoints that should be assessed include indices of lung
inflammation, cytotoxicity, and cell proliferation, as well as histopathology of
the respiratory tract and the major extra pulmonary organs. For Tier 2 in vivo
testing for hazard identification, a longer term inhalation study is
recommended, and this would include more substantive mechanistic
endpoints such as determination of particle deposition, translocation, and
disposition within the body.
Additional studies could be done
 The social responsibility of Nanoscience and Nanotechnology: an
integral approach
Journal of Nanoparticle Research March 2013, 15:1534

• The concept of social responsibility provides the ideal framework for

reflection on the social and environmental impact of NPs (1–100 nm
generated from research in nanoscience and nanotechnology.
• The model proposed relates the essential aspects of these concepts
by connecting the classical sequence Research–Development–
Innovation (R&D&I) to nanoscience and nanotechnology (N&N) and
social responsibility (SR).
• This paper identifies the stakeholders of the process

• provides an extensive definition of SR and related concepts.

• describes the internal and external connotations of the implementation

of SR at research centers and nanotechnological industries,
• discusses the social implications of nanoscience and nanotechnology
with provision for subjects such as nanoethics, nanotoxicity,
• and nanomedicine, which have emerged from the
widespread use of nanomaterials by today’s society.
Responsabilitate sociala

Definitie si aspecte generale

• Cadru etic care sugereaza obligatia unui individ

• sau organizatie sa actioneze in beneficiu societatii
in general.

• datoria oricarui individ de a actiona pentru

mentinerea unui echilibru intre economie si ecosistem

• Poate fi pasiva cand impiedica actiuni negative,

• sau
activa cind actioneaza pentru reusita scopurilor pozitive

• De exemplu introducerea unor reguli proprii ( la nivel de companniae sau

individual )pentru respectarea mediului si a sanatatii este un aspect activ

• Multe reguli sunt introduse la presiunea publica (ex )

Oameii de stiinta, si inginerii au responsabilitate colectiva pentru alegerea muncii lor mai
mare decat a oamenilor obisnuiti privitor la utilizarea cunoasterii stiintifice..

Dar nu pot fi blamati total pentru nemeritele acestei cunoasteri

Gradul inalt de specializare , fragmentarea cunoasterii conduce la imprastierea

responsabilitatii morale astfel ca „ toti cei implicati sunt raspunzatori,dar nimeni nu este
responsabil

Alta problema este ignoranta care este o scuza acceptabila pentru cei implicati in cercetarea
fundamenntala dar mai subtire pentru cei din cercetarea aplicativa. As
In Moral Responsibility and the Ignorant Scientist: scire "Ignorance is not an excuse
precisely because scientists can be blamed for being ignorant

Alt punct este responsabilitatea finantatorilor ( compaiile sau guvernul )

Cum platitorii de taxe furnizeaza indirect sume pentrucercetare care sunt mari, cercetatorii
sunt dependenti de platitori..
Nanotechnology possesses two contradictory connotations, :
1)the production of new materials with outstanding mechanical,optical,
electric, and magnetic properties which is highly positive;
2uncertain effects on human health and the environment, which is highly
negative.

Number of papers on nanoparticles toxicity published in

recent five-year periods and since 2010 (Source SciFinder)
 Big problems with little particles ( Aprilie 2015 )
• There is a risk that poor toxicology studies could start undermining the
success of nanomaterials and NP

• the research is still in its infancy, the long-term effects of NP on human health
and the environment remain poorly understood. Concerns have also been
raised about the way nanomaterial toxicity data is reported.
• In 2009, the University of Ulster releasead an investigation into a link between
man made NP and Alzheimer’s and Parkinson’s disease. V. Howard, a
toxicologist, and C.Holscher, an expert in Alzheimer’s disease, were
investigating whether human engineered titanium dioxide – the active
ingredient in sunscreen – can induce neurodegenerative disease. They
observed that NP can have an impact on the protein misfolding associated
with the diseases. The response was that there was nothing wrong with the
work, but that the risk was probably low as previous research had shown that
the NP can’t penetrate the skin and that there were even indications that the
nanoparticles form a strong protective barrier on the skin.
 Handbook of standard procedures for nanoparticles testing

• One reason that errors like this are being made is that a large number of
groups carry out their toxicology studies without any knowledge about
toxicology rules, (Krug).

• This is a situation that he has tried to rectify. In 2011, as part of a European

Commission funded project called Nanommune, Krug edited a handbook of
standard procedures for nanoparticles testing that described ways to prepare
nanomaterials for assays, how to prepare suspensions, how to do the toxicity
assays and how to validate the toxicity assays.

• ‘It’s freely available on the web but nobody respects it,’ laments Krug. ‘New
projects funded by the European Commission do not state that researchers
have to use these handbooks. So the same mistakes that were made 10
years ago are being repeated again and again
 The concept of social responsibility
• combination of several key words including “responsibility,
stakeholders, quality of life (social welfare), sustainability.

• ISO 26000:2010 defines SR as ‘‘The responsibility of an’’ organization for

the impacts of its decisions and activities on society and the environment
through transparent and ethical behavior that contributes to sustainable
development, including health and the welfare of society; takes into
account the expectations of stakeholders; is in compliance with
applicable law and consistent with international norms of behavior; and is
integrated throughout the organization and practiced in its relationships.’’

• The stakeholders of nanotechnological industries are of mixed type since

they possess the typical external connotations of corporations in relation
to society and the environment—both of which are ultimately affected by
nanomaterials—, and also internal connotations as recipients of the
‘‘products’’
stakeholders’’ designated the individuals or groups that can not only be favorably or adversely

affected by the activities of an organization or area, but also influence on their decisions, having
dual (active and passive) nature

Social responsibility in nanoscience and nanotechnology in the twofold domain of R&D&I

and corporate social performance (CSP) in nanoscience research centers and
nanotechnological enterprises
Principiile responsabilitatii sociale ( SR) conform ISO 26000:2010 si
semnificatia atingerii asteptarilor
actionariatului
 Differences between social responsibility (SR) domains:
corporate social responsibility (CSR) and corporate social
performance (CSP)
Clarkson scale of commitment to the implementation of social responsibility and
position of RS in emerging technologies such as nanotechnology
 Differences between the reactive and proactive
approaches to social responsibility (den Hond et al. 2007 )
• Reactive approach Proactive approach

• Comply with the minimum legislation Expand the legislation to comply with

• Maintain current reputation Improve existing reputation

• Maintain current staff Recruit the best available employees
• Maintain current morale and spirits Improve current morale

• Maintain current efficiency and benefits Increase both

• Maintain brand or style Gradually improve them with added

values

• Adopt the ‘‘good business’’notion Adopt the ‘‘good business’’

 Internal and external connotations of social
responsibility in N&N ( performanta sociala a companiilor si
responsabilitate sociala a companiilor )
Tipuri de actionariat in nanotechnologii & nanomateriale si
2 tipuri de relatii intre.
 The EU's new legislation on medical devices was debated in
Parliament 19 March 2014
• , The term 'medical device' covers products used internally and externally
by patients and doctors., including sticking plasters, contact lenses,
pregnancy tests, dentalfilling materials, X-ray machines, pacemakers,
breast implants, hipreplacements and HIV blood tests.

• These are intended for use in the diagnosis of disease or other

conditions,or in the cure, mitigation, treatment and prevention of disease.
• They are a ranked from Class I, a low-risk category that would include
spectacles, to high-risk Class III items such as hip replacements and
pacemakers.

• German proposed a centralised approval system to make medical devices

safer for patients. Following the 2012 scandal involving breast implants
manufactured by French Poly Implant Prothèse, the E U has proposed a
system where countries mutually recognise decisions taken by national
bodies but stopped short of proposing a centralised approval system.

• Under the Commission proposal, national bodies would be responsible for

approvals but would be able to review, making the system safer for
patients.
•
. "Let's not make the rules more strict where there isn't a
need."
In USA, the Food and Drug Administration has a pre-market approval
(PMA) process for so-called 'Class III' devices that represent the highest
risk to public health, or "novel technologies".
Conclusion of debat . All the crises could not have been avoided by a
pre-market authorisation system.
"From a purely practical European single market point of view... A
producer is interested in a centralised system but not having to go
through a mutual recognition procedure where you never have any idea
what you end up with,
" the industry would prefer a system with fewer but more certified notified
bodies.
At the same time, the Commission should increase the number of audits.
"We believe that if we do this we can maintain a decentralised system
which will provide safe and effective devices for patients in atimely
manner,".
Actual view of risk Nano Dimension ( Israel Company ) Nano Dimension's
unique products combine three advanced technologies: 3D inkjet, 3D software and
nanomaterials. The company's primary products include the first 3D printer in development,
dedicated to printing multi-layer PCBs (printed circuit boards) and advanced
nanotechnology-based conductive and dielectric inks Files U.S. Patent Application for
Conversion of MRI and CT Scans for 3D Printing of Tissues and Organs 2016

The patent covers a number of aspects relating to 3D printing of human

tissues and organs by using stem cells and inkjet technology. The patent
application concerns converting MRI and CT scans and resulting images
in order to create a 3D structure of organs ( initial step in bioprinting ), In
October 2016, Harvard relised first heart-on-a-chip with integrated
sensors. The device, which is a micro-physiological system, mimics the
behavior of human tissue .

"Risk Factors" in Nano Dimension's annual report on Form 20-F filed with
the Securities and Exchange Commission ("SEC") on March 7, 2017,
and in any subsequent filings with the SEC. Except as otherwise required
by law, Nano Dimension undertakes no obligation to publicly release any
revisions to these forward-looking statements to reflect events or
circumstances after the date hereof or to reflect the occurrence of
unanticipated events
 january 2015
Publication of titles and references of harmonised standards under Union harmonisation
legislation EN ISO 18113-1:2011
EN 556-2:2003
Sterilization of medical devices — Requirements for medical devices to be designated
‘STERILE’ — Part 2: Requirements for aseptically processed medical devices

In vitro diagnostic medical devices — Information supplied by the manufacturer (labelling) —

Part 1: Terms, definitions and general requirements (ISO 18113-1:2009)
First publication 27.04 2012.Date of cessation of presumption of conformity of superseded
standard 30.04 2012

same Part 2: In vitro diagnostic reagents for professional use (ISO 18113-2:2009)
Same Part 3: In vitro diagnostic instruments for professional use (ISO 18113-3:2009)
Same part 4 labelling

The new (or amended) standard has the same scope as the superseded standard. On the date
stated, the superseded standard ceases to give presumption of conformity with the essential or
other requirements of the relevant Union legislation
 • Proposed strategies to teaching ethics of
nanotechnology.

• Nanotechnology and nanosciences have engineering codes of ethics. In the last

10 years the a discussion of the ethical dimensions of nanotech-funding for
nanotechnology research has increased.

• the educational impact of nanotechnology and the possible consequent- process

and practice of engineering and what is critical of its products and processes on
human life. Multiple thinkers and philosophers wrote regard.

The contents of the strategies and about both negative and positive effects of
nanotech- ideas focus on the practical aspects of ethical issues on humans and
societies. nanotechnology and its societal impact.

It also considerable amount of views about nanotechnology builds a relation between

these issues and engineering that range from calling for the abandonment and codes
of ethics. The components of the blockage of all efforts in that direction to complete
strategies are based on best-practices to produce support and encouragement in
hopes that nanotech- independent life-long self-learners and critical thinkers will be
the next big jump in ameliorating human life.
The new standard has a broader scope than the superseded standard. On the
date stated the superseded standard ceases to give presumption of conformity
with the essential or other requirements of the relevant Union legislation

The new standard has a narrower scope than the superseded standard. On
the date stated the (partially) superseded standard ceases to give presumption
of conformity with the essential or other requirements of the relevant Union
legislation for those products or services that fall within the scope of the new
standard.

Presumption of conformity with the essential or other requirements or

products or services that still fall within the scope of the (partially) superseded
standard, but that do not fall within the scope of the new standard, is
unaffected

Publication of the references in the Official Journal of the European

Union does not imply that the standards are available in all the official
languages of the European Union
This new list replaces all the previous lists published in the Official
Journal of the European Union. The European Commission ensures the
updating of this list.
 Teaching ethics of nanotechnology in engineering in relation to
engineering codes of ethics.

it is not a new philosophical view about ethics of nanotechnology or a discussion of the

ethical dimensions of nanotechnology; is an attempt of how to incorporate ethics of
nanotechnology in the practice of engineering and what is critical to know in that regard.

The presented strategies focus on the practical aspects of ethical issues

related to nanotechnology and its societal impact.

The pedagogical components of the strategies are based on best-practices to produce

independent life-long self-learners and critical thinkers.

These strategies and ideas can be incorporated as a whole or in part, in the engineering
curriculum, to raise awareness of the ethical issues related to nanotechnology, improve the
level of professionalism among
engineering graduates, and apply ABET criteria (Accreditation Board for Engineering and
Technology, Inc., is a non-governmental organization that accredits post-secondary
education programs in "applied science, computing, engineering, and engineering
technology“).
 Ex. Prioritati nationale privitor la dezvoltarea responsabila a
nanotechnologiei

Australia:
the government’s approach is for health, safety and Environmental .The high level
objectives set out in the approach are : protect the health and safety of humans and
the environment; foster informed community debate; achieve economic and social
benefits from the responsible development of nanotechnology.

Germany:
the “Nano-Initiative – Action Plan 2015” is the common platform for the safe,
sustainable and successful handling of nanotechnology . The action framework
pools different approaches from SME-support, new lead innovations over enhanced
risk research up to a comprehensive dialogue with the public regarding the chances
and impacts of nanotechnology. Another focus was and still is the regulation of
nanomaterials-containing products. It is currently examined to which extent the
European and national legal frameworks need to be adapted to the use of
nanomaterials in products in order to ensure consumer safety.
Ex. Prioritati nationale privitor la dezvoltarea responsabila a
nanotechnologiei
Korea:
the National Comprehensive Development Plan for Nanotechnology has five
major goals, among which are strengthening the social and ethical
responsibilities of nanotechnology R&D. The development plan specifies the
objectives for addressing EHS concerns:
•by establishing a legal and regulatory framework for nanotechnology EHS;
•by developing fundamentals of nanotechnology EHS measurements and
• by enhancing networks and collaborations for EHS research.
Norway:
the Government’s R&D Strategy for Nanotech. promotes responsible
technological development by:
•facilitating an increase in the proportion of publicly funded R&D efforts in this
field accounted for by EHS and ELSA research to a level which is among the
highest internationally;
•facilitating the integration of EHS and ELSA into technology development
projects involving Nanotech., by making the EU “Code of Conduct for
Responsible Nanosciences and Nanotech. Research” the norm for national R&D
efforts;
•and co-operating with the Norwegian Board of Technology to increase the social
dialogue.
 Ex. of national priorities for the responsible development of
nanotechnology
The Netherlands:

main research theme of the national research programme on Nanotech.

NanoNextNL, is specifically dedicated to risk research and technology assessment
(RATA theme). Also are −Awareness raising with PhD-students, and researchers of
industry via a training on technology aspects and risks of Nanotech.;

−The obligation for Nanotech. PhDs to pay attention, e.g. by writing a chapter in their
thesis, adding an annex or separate document etc., on the possible risks that may be
related to their research;

−Creating interaction between the RATA-theme and other themes within

NanoNextNL that are more focused on applications of Nanotech. and generic
technology development;
−Research in other themes may not be directly related to risk research, but it will in
some cases result in new research equipment that can also be used in risk research.
New EU regulations –

nanomaterials in food introduced by the European Food Safety Authority

(EFSA).
agreed in November 2015, and come into effect by the end of 2017 – state
that, “Engineered nanomaterials require a Novel Food authorisation before
being used in foodstuffs.”

A nanomaterial is being defined by the EU as an “intentionally manufactured

material where one or more external dimensions is in the size range 1 nm to
100 nm

The biggest concern with the legislation as it currently stands is a “risk of over-
application of the precautionary principle when regulating nanomaterials.”
Raportul risk beneficiu in nanotehnologii
Nanoview – Influencing factors on the perception of nanotechnology
and target group-specific risk communication strategies
Federal Institut e for Risk Assessment Raport final 2016
1.Aprobarea aplicatiilor nano la mediu si sanatate.
Atitudine fata de nanotehnologie
Sanatate si riscuri ecologice
Riscuri pentru societate
Potentialul nanotehnologiei
Raport risk/beneficiu in aplicatii pentru alimente si cosmetice
Raport risk/beneficiu in aplicatii medicale si de mediu