390  Advances in Production Engineering & Management ISSN 1854 ‐6250 Volu me 15 | Number 4 | Decem ber 2020 | pp 3 90–402 Journal ho me: a p em‐journal.or g https://doi.org /10.14743/apem2020.4.373 Original s cientif i c paper     A review of production technologies and materials for  manufacturing of cardiovascular stents  Polanec, B. a , Kramberger, J. a , Glodež, S. a,*    a University of Maribor, Faculty of Mechanical Engineering, Maribor, Slovenia      A B S T R A C T   A R T I C L E   I N F O The purpose of this article is t o give a g eneral o verview of t he p r oduction technol o gies o f stents w ith cons ideration of their d es ign and m aterials. Since the b eginning o f the u se o f stents i n medicine f or a therosclero sis treatment, t h e i r d e v e l o p m e n t h a s c h a n g e d r a p i d l y . V a r i o u s s t e n t s h a v e a l s o b een d evel‐ oped w ith the d evelopment o f materials science, t reatment t echn iques and new manufacturing processe s. I n this way the d evelopment h as s h ifted from the i nit i al b are‐metal stents ( BMS), to d rug‐eluting stents ( DES ) a n d b i o ‐ r e s o r b a b l e s t e n t s ( B R S ) , w h i c h a r e m a d e o f b i o d e g r a d a b l e p o l y m e rs o r met‐ a l s . Va r iou s s tu d ie s a g r ee tha t it w ill b e ne c e s sa r y to f u r the r r eview the e xper‐ imentally obtained m aterial pr ope r t i e s w i t h a n a l y t i c a l a n d n u m e ri cal studi e s. Here, the computational m odel ling (Finite element analysis – FE A and Co mp u‐ t a t i o n a l f l u i d d y n a m i c s – C F D ) w a s f o u n d a s a v a l u a b l e t o o l w h e n evaluatin g s t e n t m e c h a n i c s a n d o p t i m i z i n g s t e n t d e s i g n . T h e d e v e l o p m e n t o f t h e s t e n t manufacturing technologies h as a lso changed and been s upplement ed o ver the y ears. Nowadays, 3D p rinting could be a n exciting m anufactu ring m etho d t o p r o d u c e p o l y m e r i c b i o ‐ m a t e r i a l s , s u i t a b l e f o r t h e l a t e s t g e n eration of b io‐ degradable s tents applications. © 2020 CPE, Uni versity of M a r ib or. All rights re s erve d.   Keywords: Stent; Bare‐metal stent; Drug‐eluting st e nt; Bio‐resorbable s tent; Stent co atings; Drug delivery; Stent manufacturing; Stent material; Laser cutting; Additive manufacturing (3D pr i nt‐ ing) *Corresponding author: srecko.glodez@um.si (Glodež, S.) Article history: Received 22 Se ptember 2020 Revised 8 Dece m ber 2020 Accepted 12 De cember 2020     1. Introduction   A stent can be d efi n ed a s an e ndovascular prosthesis. They a re skelet al m eshes mad e o f met a l, p l a c e d i n s i d e a c l o g g e d c o r o n a r y a r t e r y . T h e s t e n t i s d e v e l o p e d f o r t h e p u r p o s e o f p r e v e n t i n g complications which occ u r in a therosclerosis. T he l atter is a c hronic disease caused b y the ac‐ cumulation o f fatty d eposits on the w a lls o f blood v essels, whi ch c auses the blood v essel s t o con‐ strict. In t his case, the supply of t issues is insufficient, wh ich may lead to a heart attack o r stroke. The most i mportant c har a cteristics o f a stent are c o rrosion res istance, l ow thrombosis r a te, bio‐ compatibility, r adiopacity, easy p ositioning, flexibi l ity, high r ad ial strength, low elastic displace‐ ment, uniformity, mi nim u m surfac e area, low p a ss profiles a nd l ow costs [1] . In 1977, the G erman physician Andreas Gruent zig perfor med t h e f irst co ron a ry b a llo on a ng i‐ oplasty on a conscious man. Problems which occu rred after such procedures w ere acut e vascu‐ lar closure, s h ort‐term e l a stic d isplac ement and prolonged r est enosis. Restenosis i s the artery’s response to s evere d a m a ge, caus ed b y ballo on an gioplasty. O ne o f its characteristics is the in‐ creased p roliferation o f smooth muscle c ells a nd d eposition out side the c ell matrix, leading to progressive luminal narrowing. Th is pheno men o n was obser v ed in 33 % of th e p a tients [1]. A review of production technologies and materials for manufacturing of cardiovascular stents   Advances in Production Engineering & Management 15(4) 2020  391 I n 1 9 8 6 , S i g u a r t a n d P u e l p e r f o r m e d a t e c h n i q u e w i t h a s e l f ‐ e x p anding s tainless‐steel stent on a human. T he techni q ue i nvolved the expansio n and p e rmanent i n stallation o f a m echanical support d evi c e. S ince t he n, m an y imp r ovem ents h ave be en m ade in t h e f i e l d s o f D e s i g n , M a t e r i ‐ a l s , I m p l e m e n t a t i o n t e c h n i q u e , e t c . A l l o f t h i s h a s h e l p e d t o i ncrease the use of s tents. F urther‐ more, with t he i nsertion o f th e stent, i t was proven that the r estenosis r ate decreased c ompar e d with t he b all oon angiopl a sty. H owever, a new problem can ari s e, w hich is called in‐stent r este‐ nosis (ISR). As a f i n al p r o duct, a neoi ntima for m ation app e ars, c onsisting o f smooth m uscle c ells and comp onents o f the extracellu lar matrix. Th e process of n eoi ntima for m ation stabilises in the human b o dy after about 3‐6 months. 2. Basic characteristics of stents  2.1 Stent shape  T h e s h a p e o f a s t e n t i s u s u a l l y c y l i n d r i c a l a n d h a s a t l e a s t o n e s t r u c t u r a l e l e m e n t ( F i g . 1 ) . T h e s e e le m e n ts a re a rra ng e d so tha t the stent ca n be stre tche d a n d co mpressed radially. The structural elem ents can be splints, rods, fibres, wires, or threads. The pl atform of the stent m u st p rovide [2]:  Mechanical c haracteristics w hich, in the p rocess, m eans that it m a t c h e s t h e c u r v a t u r e o f the v e ssel e a sily a ft er s tretchin g and maintains sufficient rad ial strength t o withstand the force of the l o ad on the arterial wall.  Radio imper m eability, to p revent the transmission of X ‐rays or other ionising r adiati on due to an y n ecessary i nterventio ns.  An e asily rep l aceabl e bas e , nam e ly, the stent shoul d h ave a n a r row profile in a compres sed s t a t e s o t h a t i t c a n b e p l a c e d e a s i l y a n d c a n p a s s t h r o u g h n a r r ow v eins, wi th s tenoses, ef‐ fortlessly.  Biocompati bility, which means th a t the m a t e ria l of the ste nt sh ould be compatibl e with the blood and the surrounding vascular w a ll.              Fig. 1 a) Designed model of a cardiova scular stent, b) Scanning elect ron micr ographs of a ste nt at 100  magnification with strut thickness of 150 µm [2] 2.2 Stent construction  The first stent implant e d into humans was the Wallstent. It h ad a s e l f ‐ e x p a n d i n g p l a t f o r m t h a t contain e d a stainless‐steel m etal s tr ucture. Th e Palmaz‐Schatz stent intr oduced a n alternativ e mechanism using an e xp andabl e b a lloon. T oday, all stents a r e m a de f rom this principle. Thes e stents h ave higher r adial strength a nd b etter clinical outcome t h a n t h e c o m p e t i n g m e s h a n d c o i l stent structures. Further platfo rm d evelopments have e stablishe d a balance betw een coil f lexi‐ bility a nd ra d ial strength of stent mod e ls with m e s h structures [3 ] . a ) b ) Polanec, Kramberger, Glodež    392  Advances in Production Engineering & Management 15(4) 2020 2.3 Stent geometry  T h e ma in a ttribute s of a ste nt a re its f lexibility a nd r adial s trength. T o achieve both, differ e nt geo m etric c onfi g uratio n s m ust be m ade. R ogers and Edelm a n [4] s howed that the g eometry of the stent is a n important factor i n rest enosis. If, at the s ame m a t erial and su rface ar ea, t h e nu m‐ b e r o f j u n c t i o n s o f t h e s u p p o r t s t r u t s i n c r e a s e s , t h e n t h e n e o i ntimal a r e a increases proportional‐ ly. Other researches h ave proved t hat this c ondition is a lso ne c e ssary to reduce v ascular damage [5, 6]. 2.4 Stent strut thickness   Various clinical studies and resea r c h e s h a v e s h o w n t h a t t h e d e g ree of r estenosis d epen ds on th e t h i c k n e s s o f t h e s p l i n t . T h e t h i n n e r t h e s p l i n t , t h e l o w e r t h e rate o f rest enosis. Two stent brac e thicknesses were c ompared in [ 7] . A 50 µm s plint thickness cause d 1 5 % re ste nosis, a n d a 14 0 µ m c a u s e d 2 6 % r e s t e n o s i s . T h e t h i c k n e s s o f t h e s p l i n t h a s m o r e e ffect on rest enosi s t han its geo m etr y . Because of t h a t, t hey started using metal splints wit h a mini m u m thickn ess (60‐1 0 0 µm). T he d esign and fab r ication of t he s tent p lat f orm are tw o c rucial f actors in clinical success. Also, great attention is pai d to the opti m isation of materials and the design of th e stent p l atform. 3. Materials for the stent's platform  The choice o f materials for stent s i s v e r y i m p o r t a n t ( s e e T a b l e 1 ) . T h e y m u s t h a v e s e v e r a l i m ‐ portant char acteristics, s uch as s uffic i ent mech an ical s trength a n d d u c t i l i t y , t h e y m u s t b e b i o ‐ compatibl e a nd a ntib act e rial. The m a terial m ust also b e fle x ible , a n d m u s t h a v e t h e a b i l i t y t o s p r e a d . N o n ‐ b i o c o m p a t i b l e m a t e r i a l c a n t r i g g e r a n i m m u n e r e s p o n s e a n d l e a d t o r a p i d c e l l p r o ‐ liferatio n vi a a ste nt, le ading t o a cytot oxic e ffect an d chron ic inflammation [8]. 3.1 Bare‐metal stents (BMS)  The first generation of stents we re bare‐metal stents (BMS), w h ere 31 6L s t a inless steel was used as a b as e m a terial. Th e main b en efit c haracterist i cs o f such s t ents w ere h i gh d urabilit y, c orro‐ sion resistan ce a nd b ioco mpatibility. H owever, th ese stents a r e p o o r l y d e g r a d a b l e , w h i c h m a y cause in flam matio n a fter s ome p e riod o f i m plem en tation. Improv em en ts i n stent design h ave b een m ade possible due to t he d evelo p ment i n th e sci‐ e n c e o f m a t e r i a l s . S i g n i f i c a n t p r o g r e s s i n t h i s a r e a i s s e e n i n t h e u s e o f m e t a l a l l o y s t h a t h a v e higher mechanical strength (comp ared to 316L stainless steel). Greater strength is crucial for the possibility o f using thinner splints. T hose a re m or e effective and reduce f urther h ealth problems, which can oc cur later [9]. I n recent years, the e m pha sis ha s be en placed on r e search on the types o f m a t e r i a l s f o r s t e n t s , w h e r e t h e e m p h a s i s h a s p r i m a r i l y b e e n on observing th e mechanic al properties a nd b iocomp atibility of m aterials [ 10, 11]. T h e grea test p rogress has been m ade in the use o f a l l oys and rep r esentati ve m at erials f o r b are m e tal s , s uch as n i c kel‐titanium, cobalt‐ chromium, magnesiu m, p latinum‐iri d ium, e tc. The best m ec hanical s trength was shown by the c o b a l t ‐ c h r o m i u m a l l o y ; t h u s , i t i s u s e d m o s t l y f o r t h e s t e n t p l atform. Th e use o f m etal a lloys r e‐ d u c e d t h e t h i c k n e s s o f t h e s t r u t s , i m p r o v e d p e r f o r m a n c e , a n d m a intained r adial strength. The disadvantage o f these stents i s the o ccurrence o f l ate rest eno si s w h i c h m a y b e a v o i d e d w i t h t h e use o f drug‐ eluting stents. 3.2 Drug‐eluting stents (DES)  A d r u g ‐ e l u t i n g S t e n t ( D E S ) c a n l oad and deliver medicine that i s inserted i nto polymer coatings on the sur f ace of b are‐ metal stents. Drug‐eluti ng s tents began to d ev elop b ecaus e o f restenosis problems a ft er i mplant at ion o f t he p r e vious stent s . They h ave b ee n shown to r educe th e rate o f restenosis d evelop ment [ 12]. DES pr esents a r evolution in s tent d evelop ment. Th e fi rst genera‐ tion was Cyp her D ES ( Co rdis Corp., Johnson & Joh n son). Problems w ith th ese stents m anifested as t hromb o s i s (cloggin g o f the veins) . There f ore, t he r ese a rche rs f ocused t heir d evelop ment on improving DES. A review of production technologies and materials for manufacturing of cardiovascular stents   Advances in Production Engineering & Management 15(4) 2020  393 In g en eral, t h ree k e y c o mpon ents c o n tribute to o verall ste n t saf e t y a n d e f f i c a c y , n a m e l y t h e stent platfor m , the remedy, and the medicine c oating tech n ology . Hence, i t can be a rgued that t h e d e s i g n o f a D E S s t e n t i s a m u l t i d i s c i p l i n a r y p r o c e s s . F o r t h e d e v e l o p m e n t o f D E S i t i s n e c e s ‐ s a r y t o i n t e r v e n e i n t h e sc i e n c e o f m a t e r i a l s , i n t h e f i e l d o f engineering, a dvanced technology, for the use of m edicine ar eas such a s ph ysiology, ph armac o logy a nd che m istry. Deliver y engi neer‐ ing, p har m ac eutical scien c e, a nd, agai n, c hemistry, are once mo re i mport a nt f or d eli v erin g a me‐ dicament t o the req u ired l ocation. T h e p erforman ce o f t he stent d epends on the optimisation o f each o f t h es e aspects [1 3, 1 4 ] . Diffe r ent gen e rat i ons o f stent s h a v e a l w a y s u s e d t h e m o s t a d ‐ vanced s t e nt p latfor m d u ring t h e ir d evelopmen t . The first gener ation, w hich includes Cypher (Cordis Corp.) in Fi g. 2 A and Taxus ( Boston Scien c e) in Fig. 2 B , used a s tainless‐steel p latform w i t h a s p l i n t t h i c k n e s s o f 1 3 0 ‐ 1 4 0 µ m . L a t e r g e n e r a t i o n s s u c h a s Driver ( Medtronic), Multi‐Link vision (Abb o t V ascular) s hown i n Fig. 2 C and Omega (Bosto n Scie ntific) have thinner splints (80‐ 9 0 µ m ) . N e w e r p l a t f o r m s a r e b i o d e g r a d a b l e . T o e n s u r e s u f f i c i e n t r adial strength, these splints h a d t o b e m a d e t h i c k e r [ 1 5 ] . T h e s h a p e o f t h e s p l i n t h a s c h a n g e d, w ith development from r ec‐ tangular t o r o und shap es a nd with t h e latest D ES wi t h rounded e dges. The DES design i ncluded optimising d rug releas e based on the pr oposed d rug actio n m echa‐ nisms. T he f i r st g ener atio n contain e d drug c oatin g s to e nsure l ong‐t erm rel e ase within 90 days [16]. Co mpu ter m odels s how that th ere are opp o rtunities to o pti mise d rug release further for e x i s t i n g a n d n e w d r u g s . T o a c h i e v e t h e d e s i r e d r e l e a s e p r o f i l e , i t i s n e c e s s a r y t o a t t a c h a b i o l o g i ‐ cal agent to t he s urfac e o f the stent. T he p ossibili ties o f pol ymer‐b ased a nd non‐polymer‐b a sed systems are being in vesti g at ed [16].   Fig. 2 a) Cypher by Johnson & J o hnson, b) Tax u s by Bos ton Sc ientific, c) Xienc eV by Abbott [4 4] Release of drugs with permanent polymers A w i d e r a n g e o f p o l y m e r s h a s b e e n i n v e s t i g a t e d a s a p o s s i b l e s o lution for stent coating [17]. The first two generations u sed durabl e polymer co atings c ontai ni ng t h e d r u g ( p a c l i t a x e l ) a n d a c o ‐ polymer of p oly (styrene‐B‐isobut y l e n e B ‐ s t y r e n e ) . R e s e a r c h h a s l e d t o i m p r o v e m e n t s i n d r u g effic a cy and the develop ment of impr oved approaches for sten t d rug administration [18]. The first‐generation o f DES reported hypersensitive responses t o polymers. There f ore, r e‐ search e fforts h ave evolved towa rds greater bioc ompatibility. T he b iomimetic polymer Phos‐ phorylcholin e (ChoP) w as u sed in the E ndeavor stent (Medtr onic) [ 1 9 ] . B e c a u s e t h i s s t e n t r e ‐ l e a s e d d r u g s t o o q u i c k l y , t h e y b e g a n d e v e l o p i n g t h e E n d e a v o r R e solute D ES, which released the drug s lowly o ver the time. The di ffer ence w as i n t h e new Bio L i n x polymer blend, w hich c ontains Polyvinyl Pirolipon as a c arrier l ayer f or the d rug, w hich is m ostly rel e ased o ver t w o mo nths [20]. To i mp rove b iocompatibility, p oly (vinylidene fluoride ‐ co ‐ h exafluor opropylene) (PVDF‐ H F P ) w a s u s e d a s t h e o u t e r c a r r i e r l a y e r f o r t h e d r u g ( E v e r o l i m us). T his combination is u sed in DES at A bb o t V ascular an d Promus E l e ment B osto n Scientific. Res earch [ 21] has show n that p ro‐ longed e xpo s ure to d ur able p olymer c oatin g s pr olongs the h e alin g tim e o f blood v es sels. As a solution, f urther r esearc h has gone i nto the use of d egrad a bl e polymer coatings a nd p olymer‐ free coatin g s . Release of drugs with degradable polymers The lat e st g eneratio n of D ES i n cludes several bioc ompatible pol ymers to a lleviate the i n flamm a ‐ t i o n a n d t h r o m b o s i s r i s k . D e g r a d a b l e p o l y m e r s a r e l a c t i d e a n d g lycolide. Degrad ation produces lactic a nd g l y colic acid, which is m etabolised to non‐to xic pr od u c t s i n t h e b o d y . S t e n t s c o a t e d b ) a) c) Polanec, Kramberger, Glodež    394  Advances in Production Engineering & Management 15(4) 2020 with p oly (lactide‐co‐glycolide) ( PLGA ) were c onsi d ered i n the study [22]. They produced differ‐ ent release p r ofiles, and focused on chan ging t h e r ate, d uratio n of d rug release by c hanging the number o f layers, and the ratio of l actide a nd g lyc o lide. In v ivo, they d iscovered that t he c ombi‐ nation of p aclitaxel and PLGA d ecelerates t he f or matio n o f n e ointima in p igs. S imilar r esults we re obta ine d in vitro with the use of poly (d, 1 , 1 ‐ la ctide ‐ c o ‐ glycolide) when paclitaxel or siro‐ l i m u s w a s r e l e a s e d [ 2 3 ] . P o l y ( d , 1 ) l a c t i d e ( P D L L A ) i s a p o l y m e r c o a t i n g u s e d i n m a n y s t e n t s , such a s BioMatrix (Bios ensors, In ternational) a nd N obori (Terum o) Biolimus A9. These stents were a mong t he f irst t o apply a polymer‐drug c oati ng only to t h e non‐lumi n ous s ide of t he s tent, w h i c h w a s a n i n n o v a t i o n . T h i s r e s u l t e d i n b e t t e r d r u g d e l i v e r y to the a rtery tissue and faster e n d o t h e l i a l i s a t i o n . T h e s e s t e n t s h a v e a r e l a t i v e l y t h i c k s p l i n t (120 μm). S tent S ynergy (Boston Scientific), w hich u ses a very t hin layer of P LGA for the contr olled release of E verolimus, h as a platinum‐ch r omium plat form w ith a splint thickness of 7 4‐81 μm. T h e s e s p l i n t s h a v e s h o w n clinical bene fits o f use. N everth eless, t he s econd g eneration o f DESs w ere fabricated o n conve n ‐ tional b a re‐ m et al s tent p latforms a nd traditional coating appli cation tech niques. Some s tents, h o w e v e r , h a v e u s e d a l t e r n a t i v e c o a t i n g t e c h n i q u e s ( C o r d i s C o r p . ) . S u c h p l a t f o r m d e s i g n s a l l o w precise loading of d rug l a yers a nd p olymer l ayer s in s pecially design ed t anks i nside t h e splint [24]. Such a c ombin e d approach i s u s ed i n the Yukon stent ( T rans l u m i n a G m b H ) . T h e s t e n t i s b a s e d o n t h e a p p l i c a t i o n o f a p o l y m e r l a y e r o f p o l y l a c t i d e P L A (with drug a pplication), on a mi‐ croporous s tainless‐steel s tent platform with S hellac resin coa t i ng. Th e an al ysis [25] f ou nd t hat the biod egr a dable D E S p o lymer‐co at ed s tent i mp roved safet y a nd efficac y c ompared to t he o rig ‐ inal g ener ations o f durable polymers in DES. L ess well known is h o w m u c h t h e b i o d e g r a d a b l e polymer in D ES has impr oved th e sec ond gener ati on o f p erma nent DES. Release of polymer ‐free drugs DES polymer ‐ free stents m ust includ e o t h e r m e c h a n i s m s t o c o nt r o l the release of d rugs f rom the stent surface. T he i ntrod u ction of s ur face p orosit y on macro‐ a nd m icro‐ or n ano‐struct ures h as proven t o be a p opular a pproach t o controlling d rug releas e. I t w as p roven clinicall y that t he most u seful structures w ere macro a nd m icroporous. The Jonus Ta crolimus‐eluting carbostent (Sorin G roup ) have s uch stents, with p ores o r h o les or g rooves, w i t h s l o t s a t t h e m a c r o l e v e l , a n d a stent system filled with Medtronic [26]. T h e f i r s t s t e n t i n u s e w i t h a m i c r o p o r o u s s u r f a c e w a s t h e Y u k o n s t e n t ( T r a n s l u m i n a G m b H ) [27]. The usual stent plate was made o f stainless steel, sandbl asted, i n order to create a rough s u r f a c e t r e a t m e n t h a v i n g m i c r o p o r o u s h o l e s 1 ‐ 2 μ m i n s i z e , w h i c h were f illed with s pr ay‐coated drugs to e ns ure the controlled rel e a s e o f t h e d r u g . T h e a d v a n t a g e o f t h i s s t e n t w a s t h a t i t r e ‐ duced the rate of restenosis and accel e rated endothelialisation [ 28]. Newer microporous s tents, D ES BioFreedom (Biosensors I nternatio nal), create a rough sur‐ f a c e u s i n g t h e i r m i c r o ‐ a b r a s i o n p r o c e d u r e . T h i s g i v e s a t r e a t e d s u r f a c e ( l i k e Y u k o n ' s ) . T h i s s t e n t allows f or m ore targeted d rug delivery t o a lesion. The devel o p me nt of al ternativ e ap proaches w i t h t h e c o a t i n g o f p o l y m e r ‐ f r e e d r u g s c o n t i n u e s , w h i c h i s a l s o r eflected i n the em er genc e of patents for various techn o logies [ 29]. An i mportant r ole in f u r ther d evelo p ment w ill b e p layed b y t h e b i o c o m p a t i b l e s u r f a c e a n d , t h u s , a l s o b y s u c h s t e n t s , w h i c h inhibit neointima and acceler‐ ate t h e r e gen e ration o f a healthy endothelium. 3.3 Bio‐resorbable stents (BRS)  The d e sire f or e ver better result s and the reduction of probl em s, a nd, thus, the compl e te r ec ov‐ ery of b lo od v essels, led to t he c oncep t of c omplet e decomposi ti o n o f t h e d e v i c e , a n d t h u s d e v e l ‐ oped b io‐res orbabl e sten ts. BRS can b e m ade o f b io‐resorbable po l y m e r s o r m e t a l s . B R S m a d e o f p o l y m e r s h a v e e m e r g e d f r o m m a t e r i a l s s u c h a s P L L A ( P o l y ‐ L ‐ L a c t i c A c i d ) . P L L A i s a t h e r m o ‐ p l a s t i c p o l y m e r , n a m e l y , a l i p h a t i c p o l y e s t e r . I t c o n s i s t s o f t h e L‐enantiomer o f lactic a cid (2‐ h y d r o x y p r o p i o n i c a c i d ) . P L L A h a s a h i g h s o l i d i t y . A t 5 5 ° C , i t h a s a r e v e r s i b l e t r a n s i t i o n f r o m a relatively hard state to a s tate l ike th at o f rubber. At 1 75 ° C, i t h a s a m e l t i n g p o i n t , a n d t h e t e m ‐ perature r equired for pr ocessing i s 18 5‐19 0 °C. Ho wever, a p ro b lem arises, becaus e, a t 1 85 °C, it begi ns t o lose m olecul ar w eight, d ue t o chain reac tions a nd t h er m a l d e c o m p o s i t i o n . P L L A i s d e ‐ graded b y h y drolysis o f the est e r bo nd a nd m et abolised to w a ter a nd c ar bon dio x ide. D ecomp o ‐ A review of production technologies and materials for manufacturing of cardiovascular stents   Advances in Production Engineering & Management 15(4) 2020  395 sition takes place in f ive steps. I t begi ns w ith th e absorption o f w a t e r f r o m t h e s u r r o u n d i n g t i s ‐ sue and cont inues with d epolymerisation, r esulting i n loss of mo l e c u l a r w e i g h t . T h e t h i r d s t e p i s t h e c r u s h i n g o f t h e p o l y m e r , w h i c h c a u s e s a l o s s o f m a s s r e s u l t ing in l oss of r adial soli dity. This is w here the c hain b reakage occurs, and the shorter chains a re e x c i s e d f r o m t h e p o l y m e r s t e n t . Cells p rocess small pol y mer chains b y ph agocyt osis ( a proc ess i n which a cell devours and di‐ gests solid particles), then m et abolises t hem t o L ‐lactate a nd converts t hem to p yruvate. Py‐ ruvate is eventually brok e n down int o carbo n dio xide and wat er. T he f irst ste nt ma de from PLLA t h a t c o u l d b e a b s o r b e d i n h u m a n s w a s t h e I g a k i ‐ T a m a i s t e n t ( I g a k i M e d i c a l P l a n n i n g C o . , L t d . ) . I t had a helical structure of a z igzag spiral c oil. T he l ength of the stent w a s 12 m m and t h e thick‐ n e s s o f t h e s p l i n t w a s 0 . 1 7 m m [ 3 0 ] . T h e m e n t i o n e d s t e n t w a s a self‐exp anding, mo u n ted on a standard b alloon for angi oplasty. T h e s tudy s howed that, after the expansio n, the s tent d id not cause any signific ant i n fl am mator y r esponse i n p atients. S el f‐e xpansion occurred within 2 0 to 30 minutes after installation. T he s tent p rovided radial s upport f o r 6 m o n t h s a n d w a s a b s o r b e d completely i n 2‐3 years. T his stent required heat for the self‐ expanding process; therefore, it h as not b een used i n the coro nary a rt eries since. A m o r e advanced fo r m o f a s t e n t i s t h e B R S , l i k e a small mesh t ube whos e base i s ma de o f Poly‐L‐l actide (PLLA) cov ered w i t h a surfac e layer o f Poly‐D‐lactide ( PDLLA) t h at r eleases an a ntiprol i ferati ve d rug. T hey are compara b le t o DES. H o w e v e r , l o w e r e f f i c i e n c y a n d a h i g h e r r i s k o f t h r o m b o s i s a p p e a r e d . I t p r o v i d e d m e c h a n i c a l support to the coronary artery, a nd its degrad a tion time was tw o ye ars [ 31‐ 33] (Fig. 3 ). The crucial a dvanta ge o f a bi odeg ra dab l e p o l ym e r s t e n t i s i n t h e slower a nd l onger r el ease o f d r u g s . T h e i r d i s a d v a n t a g e i s l o w e r m e c h a n i c a l s t r e n g t h , a n d , c o nsequ e ntly, the splint m ust be thicker. Biological problems, su ch a s inflammatory r eactions a n d increased n eointi ma, ar e c a u s e d m a i n l y b y t h e i r d e c o m p o s i n g p r o d u c t s . D u e t o t h e s e p r o b l e m s , b i o d e g r a d a b l e m e t a l s t e n t s w i t h a l l o y s b a s e d o n i r o n ( F e ) a n d m a g n e s i u m ( M g ) , a n d l a t e r b a s e d o n z i n c ( Z n ) , h a v e started to develop in th e l a st t en y ears [ 34]. I n s tud i es [ 35, 36], t h ey w er e est a blishing c h a racter‐ istics a nd b iocompati b ility, a nd t h e y d e t e r m i n e d t h a t a b i o d e g r adabl e F e‐based stent is b iocom ‐ patible and has proper m echanical properties. Their degradation is slow a nd c auses poor r egen‐ eration with i ron o x ide re sidues [37, 3 8]. Another gro u p of b iode gradable s t e n t s are ma gne s ium‐based stent s (M g). Mg‐allo ys a r e w ell biocomp a tib l e and have g ood m echa nical proper ties; on th e other h a n d , t h e i r d e c o m p o s i t i o n t i m e i s s l i g h t l y t o o f a s t . T h e r e f o r e , s t e n t s w e r e m a d e f r o m a M g‐alloy with a n optimised extru‐ sion process and, they w e re tre ated w ith heat. This w ay a m ore e v e n d e g r a d a t i o n a n d m i n i m a l infla m m a tio n in vivo was achie ved. This is how th e WE 4 3 allo y w as f or me d [39]. T h e n e w e r g e n e r a t i o n o f t h e b i o ‐ r e s o r b a b l e s t e n t s w a s b a s e d o n z i n c ( Z n ) . I t h a s a b e t t e r i n vivo d egrad a tion rat e t h a n its predecessor. Z inc‐based BVS is a n e w g e n e r a t i o n t h a t h a s m a n y advantages o ver other materials: A n ideal rate o f in v ivo degra dation, overall biocompatibility and less proliferatio n of s mooth mus cle c ells, and a go od a nt ib acterial e f f e ct. The r e sponse to infla m m a tio n is like t hat of B VS in F e i n viv o [ 40‐ 4 4 ]. A review o f the current s tate o f BRS s h ows that th e m ost co mmon ly u sed biodegradable ma‐ terial i s poly‐1‐lactic ac id, fo llowed by m agnesium. Other inve stigated m aterials a re t yrosine polycarbonate, p olymer s alicylic a cid and iron. F ig. 4 shows BR Ss a lso demonstrat ed b y optical coherenc e tomogr aphy ( OCT) [ 15]. Fig. 3 a) PLLA bio‐resorbable stent, b) Magnified image of the stent [ 31] b ) a) Polanec, Kramberger, Glodež    396  Advances in Production Engineering & Management 15(4) 2020 Fig. 4 Design and OCT appe ar ance of BRSs [1 5]   Table 1 An ove r view of stent materials B M S D E SB R S Adv a ntages  Good mechanic a l properties, durability, g ood processing, biocomp a tibil i t y , corros i o n resi stance  Reduction of ne oint ima due to drug release  Slow and prolonged drug relea s e  Reduction of adverse clinical events due to complete stent degrada t ion  Po ssi bi li ty o f resto r i n g v a scular function and performing MRI exam‐ inatio n after s te nt degradation Disadvantages  Thick splints  Poor degradability  Occurrence of late throm‐ bo si s  Lower mechanical strength Limi tatio n s  Occurrence of late restenosis  Design of DES i s a multi‐ disciplinary process  The material m ust be a biodegr ada‐ ble polymer or metal  Thicker s plints Prospects  Development stents from metal alloys, sm art memory alloys and poly m ers  Development drug‐eluting stents  Development of several generations of DES  It leads to the develop‐ ment of BRS stents  Development of BRS metal stent with Fe, Mg, an d Zn based alloys  Good mechanic a l properties  Good degradation and biocom p ati‐ bility 4. Production technologies for manufacturing of stents  A r e v i e w t h r o u g h v a r i o u s l i t e r a t u r e s h o w s t h a t , i n t h e m a n u f a c t ure of a s ten t , a distinction must be m ade bet w een t he m anufacture o f a stent and a stent‐graft (s ee T a ble 2). T h is c an b e divided into n itinol s tent a nd p olymer f ilm fabrication. N itinol s tents a r e m a d e b y l a s e r c u t t i n g , w e a v i n g , or s uturing processes, h ence, th e same a s bare‐metal s tents. T h e stent‐ gr aft also c ont ains a p ol‐ ymer f il m fo r which mou l dings are used a s for text iles. Looms ar e u s e d , t h e m a t e r i a l i s e x t r u d e d , a n e l e c t r o s t a t i c b a s e i s u s e d , a n d i t h a s a m i c r o t o n a n o c om p o sition [46]. F o r the manufacture of stents, the fo llowing p rod u ction processes are men tioned in the l iterature: T he f ilament winding phase, m icro ‐EDM u sing e lectro‐erosi on, s tent i njection, l aser cutting a nd a dditive m anufactur‐ ing technology, which also inclu des Selective las e r melting. A review of production technologies and materials for manufacturing of cardiovascular stents   Advances in Production Engineering & Management 15(4) 2020  397 4.1 The manufacture of a stent‐graft  T h e e x i s t i n g m e t h o d s f o r i n t e g r a t i n g m e t a l a n d f i l m m o u l d s i n c l ude sewing a nd a pplicat ion. T h e sewing m eth o d perfor ms e asy pen e tr ation of t he f ilm, w hich o fte n results in tearing. Another bad attribut e is t hat this m ethod t a kes a lot of t i m e to m ake. In the a pplicati on method, the out e r f i l m i s a p p l i e d t o t h e s u r f a c e o f t h e i n n e r f i l m o f t h e s t e n t ‐ g raft. When the s olution evaporates, the inner an d outer film w rap tightly around t he m et al s tent. T his method a voids possible tear‐ ing caused b y hand s ewi n g and has great e r e ffici ency [ 45]. Ther efore, t h e m etal s ten t i s com‐ bine d with the f ilm by the de position m e thod. Howe ve r, it is difficult to us e 3D printing for direct integr ation and to d esign composite mat e rials containin g a c o v er f i l m a n d m e t a l s t e n t . T o s o l v e this p roblem, the Rapid Prototyping Sacrificial C or e‐Coating Te chnique (RPSC CF) c a n be u sed, first proposed b y H u an g et al. [ 4 7 ] . A v a s c u l a r s t e n t w a s d e s i g n e d u s i n g a p a t i e n t ' s C o m p u t e d Tomogr aphy (CT) sc an. A water‐soluble sacrificial c ore was fabri c a t e d u s i n g F D M ( F u s e d D e p o ‐ sition Model l ing). With the a pplication process, b iopolymer mat erial was applied layer by l ayer. In t he n ext s tep, a Nitinol alloy w a s w o v e n i n t o t h e s t e n t a n d c o a t e d a g a i n w i t h t h e b i o p o l y m e r . This integrates the alloy and po lymer film into the stent. T he wall structure of t he m ultilayer t u b e c a n a l s o b e f o r m e d l a y e r b y l a y e r u s i n g c o a t i n g , i n j e c t i o n m oulding or o ther m ateri a l appli‐ cation proc edures, and fi nally, th e inner core is dis s olved to obt a in a stent. 4.2 Stent fabrication technologies  Wire winding with the help of laser local welding This p rocedure w as u sed mostly i n the initial stages o f stent f abricatio n w hen stents w ere made of s tainl e ss steel. Each u nit related to the l aser l oc al w eldin g. D ifficulties in s uch stent manufac‐ t u r e a r i s e i n l o c a t i n g t h e w e l d , d u e t o t h e s m a l l s i z e a n d c o m p l e x i t y o f t h e v a s c u l a r s t e n t s t r u c ‐ ture [ 46]. Micro ‐EDM A micro‐elec trical discharge mach ini n g (micro‐ E DM) is a p r o cess w h e r e t h e m a t e r i a l r e m o v a l occurs b y electro‐erosion due to e lec tric discharge generated b etwe en clo sely s paced electrodes i n t h e p r e s e n c e o f a d i e l e c t r i c m e d i u m . T h e s h a p e o f a s t e n t ’ s cells i s the mirror image of the electrode [ 4 8]. Injection moulding We d istingui sh b etween l ow‐pressure r eaction inj e ction moul ding ( R I M ) a n d h i g h ‐ s p e e d i n j e c ‐ tion (HSI). H SI i s the inj e ction into a m ould w ith a signi f icant l y h i g h e r s p e e d ( m o r e t h a n 5 0 0 mm/s) a t lower temper atures, which reduces polymer degradation. H S I w a s u s e d f o r s t e n t s o f arbitrary ge ometries w it h high r adial length, smal l offset, and s h a p e s t a b i l i t y . T h i s a v o i d e d t h e n e g a t i v e e f f e c t s o f l a s e r c u t t i n g . R I M i s a t e c h n i c a l p r o c e s s f or m aking polymer products. T he m o l t e n p o l y m e r i s i n j e c t e d a t h i g h p r e s s u r e i n t o a m o u l d , w h i c h c a n b e m a d e o f m e t a l ( s t e e l o r a lum inium ) . Products a re f orm e d directly in the mould. T he prod ucts ca n be solid or ha v e a foam s t r u c t u r e . S t e n t s m a d e i n t h i s w a y h a v e l o w t o l e r a n c e , t h e p o s s ibility of c oating d ifferent m ateri‐ als, no visu al d efects, ar e durable, a nd o ffer f lexi bility. The a d d i t i o n a l a d v a n t a g e i s t h a t t h i s k i n d of p roductio n offers l ow tool c osts. However, the d isadvantages o f this p rocess to p roduce s tents are mainl y i n the un eve n d esign, s low fabrication and high r equi r e m e n t s f o r i n j e c t i o n m o u l d s , and th e asso ciated hig he r costs [45, 4 6]. Laser cutting It i s a commonly widely u sed manufacturing technique for indust rial a pplications, mainly p ro‐ ducing b are‐ metal and polymer st ents. Las e r cutting is a technol o g y w h e r e a h i g h e n e r g y d e n s i t y laser beam f ocuses on a raw tube s urface. The stent is m ade of a nano or m icrotube b y l a ser cut‐ ting t o prod uce the desir e d structural e lements. D i ffer e nt t ype s of l asers h a ve b een used i n stent m a n u f a c t u r e , i n c l u d i n g C O 2 l a s e r s, N d:YAG lasers , fiber lasers, e x c i m e r l a s e r s , a n d u l t r a ‐ s h o r t pulse lasers. The disadvantage o f laser cutting i s that t his pr ocess can c a use th ermal damage such a s heat‐affected zone (HAZ) , striation, r ec ast layer, m icr oc racks, tensile r esidual stress, a nd Polanec, Kramberger, Glodež    398  Advances in Production Engineering & Management 15(4) 2020 d r o s s . T h e s p l i n t s m a y h a v e s h a r p e d g e s d u e t o s u c h c o n s t r u c t i o n, d amagi n g th e vessel or c aus e un‐stable bl ood f low aft e r implantat i on. H owever, the supportin g compo n ent is r ectangular, causing local eddy b lood f lows, follow e d by l eukoc y te a ggregati on leading t o r esten o sis. Some post‐processing t echniq u e s are used, like a nne alin g and electro polishing to o vercome t he t her‐ mal da‐mages. Due to introducing these p ost‐processing techn iqu es, the m a nu facturin g cost a re raised. Over the l ast decade, ultra‐short pulse lasers (picosec ond a nd f emt o second) have b een avail a ble for high p recision processin g , which are an a lter nativ e t o t h e l o n g e r p u l s e l a s e r s f o r m a c h i n i n g t h i n m a t e r i a l s f o r s t e n t a p p l i c a t i o n s . A l t h o u g h t h e t h e r m a l e f f e c t i s r e d u c e d , d e b r i s and recast fo r mation still have to be re m ov ed by ot her m e thods [4 7, 4 8]. Additive manufacturing technology I n t h e c a s e o f m e t a l s t e n t s , t h i s t e c h n o l o g y d o e s n o t w o r k d u e t o o x i d a t i o n p r o b l e m s . A d d i t i v e production i s s uitable for biodegr a dable poly mer stents. In 2 0 13 , F l e g e a t a l . [ 4 9 ] u s e d P L L A a n d P C L m a t e r i a l f o r t h e f i r s t t i m e f o r p r o c e s s i n g s e l e c t i v e l a s e r m e l t i n g ( S L M ) . S L M i s a n a d d i t i v e t e c h n i q u e i n w h i c h a l a s e r b e a m m e l t s a n d j o i n s t h e m a t e r i a l l a yer b y l ay e r s electively [50]. The disadvantages of this process ar e reflected in p oor s urface a cc uracy and a long m a n u f acturin g p r o c e s s . D u e t o t h e p o o r p r o p e r t i e s o f S L M , P a r k et al . [51] u s e d bio cuttin g t echnolo g y in 201 5. The disadvantages o f thi s technolo g y have b een d e mo nstrated in th e difficulty o f stent personal‐ isation and the length y stent fabrication process. T he p rocedur e takes more t han 10 hours. Tum b leston e et al . [ 52] d eveloped t h e c ontin uous l iquid interface producti on (CL IP) t e chnology. This i s a pro c ess where UV p rojectio n hardens a photosensiti ve resin. T he l iquid resin maintains a stable a rea of the l iquid, a nd e nsures c ontinuous s olidificat ion due to c on tact w ith oxygen. The good f eatur e s of t his process are the h i gher s peed o f 3D p rinting , n a me l y b y 2 5 t o 1 0 0 t i m e s , a n d i n t h e h i g h p r e c i s i o n o f t h e p r o d u c t s u r f a c e . I n 2 0 1 6 , d e g r a d a b l e c i t r a t e ‐ b a s e d p o l y m e r m a t e r i a l was synthesised using the micro CLIP process [53]. This process g av e th e s t ent very g o o d prop‐ erties, such a s good e las ticity, g ood s trength, o xi dation resis tance and bi odegrad a bili ty. The man u f a cturing time i s short, a nd, afte r 180 days, the stent deg rades by 2 5 % . The procedure als o has negative properties which we re s hown d uring clinical tes ts. T he m echanical prop erties o f t h e s t e n t d o n o t m a t c h t h e B R S , t h e m a t e r i a l s a r e n o t F D A a p p r o ved and th e biocompati bility i s question able . In 201 7, W are et al . [54] used photopolymerisable m aterials that can be embedded using the mi cro C LIP method t o print flexible B RS , meeting th e requirements f or p recision bio‐ medical devices. A ccordi n g to r esear c h [56], the Micro CLIP pro cess has quite a few ad vant ages over S LM. The stent fabr ication time is reduced (it is possible t o f a bricat e a stent o f l e n gth 2 cm, with 4 ,000 l a yers i n 2 6 .5 m inut es), t he s urface t reatm e nt i s of b e t t e r q u a l i t y , t h e m e c h a n i c a l p r o p e r t i e s a r e u n i f i e d a n d m a t c h N i s t e n t s . I n 2 0 1 7 , C a b r e r a et al. [ 5 5 ] p r i n t e d a s t e n t w i t h Fused Depos i tion Modelling ( FD M) a s shown in F ig. 5. T he p rintin g d e v i c e u s e d w a s t h e B a k e r Bot by R eplicator, t he m aterial was Ther mo‐Plas t ic Copolyes t er (TPC). T he s tent m ade in t his way fused with the v essel wa ll in 8 ‐1 6 we e k s. Gue rra et al . [ 56, 57] u sed the same t echn o l ogy th e f o l l o w i n g y e a r a n d u s e d P C L f o r t h e m a t e r i a l . T h e d i s a d v a n t a g e o f t h i s s t e n t w a s i n t h e p o o r r e s ‐ olution, a nd m an y experi ments per f o r med. W ith this p rocedure, t he p rocess of 3 D stent printing was researc h ed thoroughly. L ei et al . [44] m entio n ed a c o m bi nation of b io 3 D printin g a nd e lec‐ tro‐bondin g technolo g y t o f orm a pol y ( p‐dioxano n e) s liding s ten t ( P P D O ) f o r t h e i n n e r l a y e r with 3 D prin ting a nd p repared a mixt ure of c hit o san and poly‐ ( vinyl alcohol) ( PVA) f or t he o ut‐ e r l a y e r w i t h e l e c t r o s p i n n i n g a n d i n t h i s w a y p l a n t e d t h e c e l l s on the stent. D ue t o t h e natural biologic al m aterial o n th e o ut er l ay er, cell adhesion and proli feration wer e g ood. In [ 44] the au‐ t h o r s a l s o d e s c r i b e d t h e d e v e l o p m e n t o f a 4 ‐ a x i s 3 D p r i n t i n g p l atform with FDM technology. An a d d i t i o n a l a x l e i s a d d e d t o t h e p l a t f o r m , n a m e l y a r o t a t i n g s p i ndle s tructure, so that it i s possible to a void t he s upporting structure and develop a set of m ini scr ew e xtrusio n nozzles. This nozzle u s e s g r a n u l a r b i o l o g i c a l m a t e r i a l , a n d t h e d i a m e t e r o f t h e e x t r u d e d w i r e i s 1 0 0 µ m . P C L a n d P L L A m a t e r i a l w e r e u s e d t o s t u d y t h e e f f e c t s o f r a p i d r a t e q u e n ching and centrifugation on the mecha n ical p roperties o f the st e nt a n d to opti mise the m. The l ume n d i amet er o f an o rgan a nd s tent l en gth are two paramet ers defined, a mong m an y others. Th e design o pti m izati on of a s tent a nd u sing t h e 3 D pri nting tec h nique allow s a p atient‐ specific pers onaliz a tion o f the devic e . A review of production technologies and materials for manufacturing of cardiovascular stents   Advances in Production Engineering & Management 15(4) 2020  399 Fig. 5 3D printed FDM‐stent [53] Table 2 An ove rview of fabrica ti on techniques for stent W ire winding Injectio n and co mpres s i on moulding proce ss Laser cutting Additive manufacturing Advantages W idespre a d use of stents made in this way  No visual defects, dura‐ ble, offer flexibility  Fast production  F a st pro cessi ng  High accuracy  Dev e lo pment o f many differ‐ ent additive pro duction tech‐ niques  High efficiency Disadvantages Diffi culties in lo c at‐ ing the weld  Design restriction  Slow fabrication  Thermal damage  Sharp edg es  Incomp atible f o r all material  Poor surface ac c uracy  Long manufacturing process Limi tatio n s Only for stainle ss steel  High requireme n ts for moulds  Heat load of the material  Unsuitable for metal stent because of the oxidati on pro blems  Nozzle diameter limitat ion Pro s pects F o r stai n less steel  Po ssi bi li ty o f coati n g different material  For all types of materials  Po ssi bi li ty o f individualiza‐ tion  Rapid pro t o t y p ing Economic aspect  Low cost for tools  High investment and operating co sts  Low cos t 5. Conclusion  T h i s r e s e a r c h p a p e r c o n t a i n s a n o v e r v i e w o f t h e d e v e l o p m e n t o f th e sten ts a nd the t echnology for their production. D ifferent s tent s ystems, new materi als, m etallic and polymeric, a nd b io‐ resorbabl e s tents can be traced in v arious s tudies. It w ill be challenging to d iscover an ideal stent suitable f or a ll pati ents an d t h e i r h e a l t h p r o b l e m s . T h e l e sion char ac teristics of i ndividual patients, thei r age, their p roneness to r estenosis a nd thrombosi s d i f f e r s o m u c h t h a t i t i s d i f f i c u l t t o p r o d u c e a s i n g l e d e v i c e t h a t w o u l d e l i m i n a t e s u c h a d i v e r s e spectrum o f problems. The desire for the most qualified and usefu l stent, however, offers broad ar eas for further research. Finding the stents’ best m anufacturing p rocess has to b e consid ered b esides t he s tents’ m e‐ cha n ica l and me d ica l prope rtie s. T he ste nt industry ne e d s to ma ke conti n uo us advanc e s towards improving mechanical p roperties and reducing this medical devic e's costs by d eveloping new production technolo g ies. I n this c ontext, A dditive M an ufacturin g techniques c ould b e more e co‐ nomical t han traditional laser mi cro‐cutting u s e d for manufactu ring s tents bas e d on m etallic m a t e r i a l s . N o w a d a y s , 3 D p r i n t i n g c o u l d b e a n e x c i t i n g m a n u f a c t u ring m ethod to p roduce p oly‐ meric biomaterials, suitable f or t h e l a t e s t g e n e r a t i o n o f b i o d e gradabl e s te nts applicati ons. Fur‐ ther u nderst anding a nd a ctualisatio n of those m anufacturing m eth o d s a r e r e q u i r e d i n t h e f i e l d of St e nt Tech nology. Comput ation a l modelling i s a valuabl e t ool w hen evalu a tin g s ten t mech ani c s and optimizin g stent design. Finite e l e ment a nalysis (FEA) and computational f luid d ynamics (CFD) are effici ent methods to i nvestigate a nd o ptimize a stent's mechanical b eh avi our virtually. FEA can help u n‐ d e r s t a n d t h e r o l e o f t h e d i f f e r e n t g e o m e t r i c a l a n d m e c h a n i c a l b ehaviour o f the stents. Besides analysi n g st ents’ m e cha n ical b eh avi o ur d uring t h e develop m ent pr o c e s s , t h e s e m e t h o d s c a n b e combin ed wi t h special p a tient i m ages to plan a surgery proced u re. Polanec, Kramberger, Glodež The challenges associated with stents are numerous, like material, geometry, manufacturing process, biocompatibility, etc. Among the traditional design and manufacture, the most challeng- ing is the development of a new generation of biodegradable materials, where medical devices function only during a specific period and then degrade. Acknowledgements The authors acknowledge the financial support of the Research Core Funding (No. P2-0063) from the Slovenian Re- search Agency and of the Research Program OP20-04332 which is co-financed by the Republic of Slovenia and the European Union under the European Structural and Investment Funds. References [1] Fogarotto, F. (2010). Finite element analysis of coronary artery stenting, Università degli Studi di Pavia Facoltà di Ingegneria, Pavia, Italy, from http://www-2.unipv.it/compmech/dissertations/fogarotto.pdf, accessed July 2020. [2] McCormic, C. (2018). 1 – Overview of cardiovascular stent designs, In: Wall, J.G., Podbielska, H., Wawrzyńska, M. (eds.), Finite element analysis of coronary artery stenting, Elsevier, Duxford, UK, 3-26, doi: 10.1016/B978-0-08- 100496-8.00001-9. [3] Sigwart, U., Puel, J., Mirkovitch, V., Joffre, F., Kappenberger, L. (1987). Intravascular stents to prevent occlusion and re-stenosis after transluminal angioplasty, The New England Journal of Medicine, Vol. 316, No. 12, 701-706, doi: 10.1056/NEJM198703193161201. [4] Rogers, C., Edelman, E.R. (1995). Endovascular stent design dictates experimental restenosis and thrombosis, Circulation, Vol. 91, No. 12, 2995-3001, doi:10.1161/01.CIR.91.12.2995. [5] Schwartz, R.S., Chronos, N.A., Virmani, R. (2004). Preclinical restenosis models and drug-eluting stents: still important, still much to learn, Journal of the American College of Cardiology, Vol. 44, No. 7, 1373-1385, doi: 10.1016/j.jacc.2004.04.060. [6] Morton, A.C., Crossman, D., Gunn, J. (2004). The influence of physical stent parameters upon restenosis, Patholo- gie Biologie, Vol. 52, No. 4, 196-205, doi: 10.1016/j.patbio.2004.03.013. [7] Pache, J., Kastrati, A., Mehilli, J., Schühlen, H., Dotzer, F., Hausleiter, J., Fleckenstein, M., Neumann F.-J., Sattelber- ger, U., Schmitt, C., Müller, M., Dirschinger, J., Schömig, A. (2003). Intracoronary stenting and angiographic re- sults. Strut thickness effect on restenosis outcome (ISAR-STEREO-2) trial, Journal of the American College of Car- diology, Vol. 41, No. 8, 1283-1288, doi: 10.1016/S0735-1097(03)00119-0. [8] Jayendiran, R., Nour, B., Ruimi, A. (2018). Fluid-structure interaction (FSI) analysis of stent-graft for aortic endo- vascular aneurysm repair (EVAR): Material and structural considerations, Material and structural considerations, Vol. 87, 95-110, doi: 10.1016/j.jmbbm. 2018.07.020. [9] O’Brien, B., Carroll, W. (2009). The evolution of cardiovascular stent materials and surfaces in response to clini- cal drivers: A review, Acta Biomaterialia, Vol. 5, No. 4, 945-958, doi: 10.1016/j.actbio.2008.11.012. [10] Bertrand, O.F., Sipehia, R., Mongrain, R., Rodés, J., Tardif, J.-C., Bilodeau, L., Côté, G., Bourassa, M.G. (1998). Bio- compatibility aspects of new stent technology, Journal of the American College of Cardiology, Vol. 32, No. 3, 562- 571, doi: 10.1016/S0735-1097(98)00289-7. [11] Mani, G., Feldman, M.D., Patel, D., Agrawal, C.M. (2007). Coronary stents: A materials perspective, Biomaterials, Vol. 28, No. 9, 1689-1710, doi: 10.1016/j.biomaterials.2006.11.042. [12] Pache, J., Dibra, A., Mehilli, J., Dirschinger, J., Schö mig, A., Kastrati, A. (2005). Drug-eluting stents compared with thin-strut bare stents for the reduction of restenosis: A prospective, randomized trial, European Heart Journal, Vol. 26, No. 13, 1262-1268, doi: 10.1093/eurheartj/ehi098. [13] Htay, T., Liu, M.W. (2005). Drug-eluting stent: A review and update, Vascular Health and Risk Management, Vol. 1, No. 4, 263-276, doi: 10.2147/vhrm.2005.1.4.263. [14] Yang, C., Burt, H.M. (2006). Drug-eluting stents: factors governing local pharmacokinetics, Advanced Drug Deliv- ery Reviews, Vol. 58, No. 3, 402-411, doi: 10.1016/j.addr.2006.01.017. [15] Sotomi, Y., Onuma, Y., Collet, C., Tenekecioglu, E., Virmani, R., Kleiman, N.S., Serruys, P.W. (2017). Bioresorbable scaffold: the emerging reality and future directions, Circulation Research, Vol. 120, No. 8, 1341-1352, doi: 10.1161/CIRCRESAHA.117.310275. [16] Venkatraman, S., Boey, F. (2007). Release profiles in drug-eluting stents: Issues and uncertainties, Journal of Controlled Release, Vol. 120, No. 3, 149-160, doi: 10.1016/j.jconrel.2007.04.022. [17] Commandeur, S., van Beusekom, H.M.M., van der Giessen, W.J. (2006). Polymers, drug release, and drug-eluting stents, Journal of Interventional Cardiology, Vol.19, No. 6, 500-506, doi: 10.1111/j.1540-8183.2006.00198.x. [18] Joner, M., Finn, A.V., Farb, A., Mont, E.K., Kolodgie, F.D., Ladich, E., Kutys, R., Skorija, K., Gold, H.K., Virmani, R. (2006). Pathology of drug-eluting stents in humans: Delayed healing and late thrombotic risk, Journal of the American College of Cardiology, Vol. 48, No. 1, 193-202, doi: 10.1016/j.jacc.2006.03.042. [19] Garcia-Touchard, A., Burke, S.E., Toner, J.L., Cromack, K., Schwartz, R.S. (2006). Zotarolimus-eluting stents reduce experimental coronary artery neointimal hyperplasia after 4 weeks, European Heart Journal, Vol. 27, No. 8, 988- 993, doi: 10.1093/eurheartj/ehi752. 400 Advances in Production Engineering & Management 15(4) 2020 A review of production technologies and materials for manufacturing of cardiovascular stents [20] Brugaletta, S., Burzotta, F., Sabaté, M. (2009). Zotarolimus for the treatment of coronary artery disease: Patho- physiology, DES design, clinical evaluation and future perspective, Expert Opinion on Pharmacotherapy, Vol. 10, No. 6, 1047-1058, doi: 10.1517/14656560902837998. [21] Byrne, R.A., Joner, M., Kastrati, A. (2009). Polymer coatings and delayed arterial healing following drug-eluting stent implantation, Minerva Cardioangiologica, Vol. 57, No. 5, 567-584. [22] Finkelstein, A., McClean, D., Kar, S., Takizawa, K., Varghese, K., Baek, N., Park, K., Fishbein, M.C., Makkar, R., Lit- vack, F., Eigler, N.L. (2003). Local drug delivery via a coronary stent with programmable release pharmacokinet- ics, Circulation, Vol. 107 No. 5, 777-784, doi: 10.1161/01.CIR.0000050367.65079.71. [23] Alexis, F., Venkatraman, S.S., Rath, S.K., Boey, F. (2004). In vitro study of release mechanisms of paclitaxel and rapamycin from drug-incorporated biodegradable stent matrices, Journal of Controlled Release, Vol. 98, No. 1, 67- 74, doi: 10.1016/j.jconrel.2004.04.011. [24] Falotico, R., Parker, T., Grishaber, R., Price, S., Cohen, S.A., Rogers, C. (2009). NEVO TM : A new generation of siroli- mus-eluting coronary stent, EuroIntervention, Vol. 5 (Supplement F), F88-F93. [25] Stefanini, G.G., Byrne, R.A., Serruys, P.W., de Waha, A., Meier, B., Massberg, S., Jüni, P., Schömig, A., Windecker, S., Kastrati, A. (2012). Biodegradable polymer drug-eluting stents reduce the risk of stent thrombosis at 4 years in patients undergoing percutaneous coronary intervention: A pooled analysis of individual patient data from the ISAR-TEST 3, ISAR-TEST 4, and LEADERS randomized trials, European Heart Journal, Vol. 33, No. 10, 1214-1222, doi: 10.1093/eurheartj/ehs086. [26] O'Brien, B., Zafar, H., Ibrahim, A., Zafar, J., Sharif, F. (2016). Coronary stent materials and coatings: A technology and performance update, Annals of Biomedical Engineering, Vol. 44, No. 2, 523-535, doi: 10.1007/s10439-015- 1380-x. [27] Wessely, R., Hausleiter, J., Michaelis, C., Jaschke, B., Vogeser, M., Milz, S., Behnisch, B., Schratzenstaller, T., Renke- Gluszko, M., Stöver, E., Wintermantel, E., Kastrati, A., Schömig, A. (2005). Inhibition of neointima formation by a novel drug-eluting stent system that allows for dose-adjustable, multiple, and on-site stent coating, Arterioscle- rosis, Thrombosis, and Vascular Biology, Vol. 25, No. 4, 748-753, doi: 10.1161/01.ATV.0000157579.52566.ee. [28] Dibra, A., Kastrati, A., Mehilli, J., Pache, J., von Oepen, R., Dirschinger, J., Schömig, A. (2005). Influence of stent surface topography on the outcomes of patients undergoing coronary stenting: A randomized double-blind con- trolled trial, Catheterization & Cardiovascular Interventions, Vol. 65, No. 3, 374-380, doi: 10.1002/ccd.20400. [29] Demidov, V., Currie, D., Wen, J. (2017). Patent watch: Patent insight into polymer-free drug-eluting stents, Nature Reviews Drug Discovery, Vol. 16, No. 4, 230-231, doi: 10.1038/nrd.2017.32. [30] Schwartz, R.S., Chronos, N.A., Virmani, R. (2004). Preclinical restenosis models and drug-eluting stents: Still important, still much to learn, Journal of the American College of Cardiology, Vol. 44, No. 7, 1373-1385, doi: 10.1016/j.jacc.2004.04.060. [31] Ormiston, J.A., Serruys, P.W., Regar E., Dudek, D., Thuesen, L., Webster, M.W.I., Onuma, Y., Garcia-Garcia, H.M., McGreevy, R. (2008). A bioabsorbable everolimus-eluting coronary stent system for patients with single de-novo coronary artery lesions (ABSORB): A prospective open-label trial, The Lancet, Vol. 371, No. 9616, 899-907, doi: 10.1016/S0140-6736(08)60415-8. [32] Onuma, Y., Serruys, P.W., Perkins, L.E.L., Okamura, T., Gonzalo, N., García-García, H.M., Regar, E., Kamberi, M., Powers, J.C., Rapoza, R., van Beusekom, H., van der Giessen, W., Virmani, R. (2010). Intracoronary optical coher- ence tomography and histology at 1 month and 2, 3, and 4 years after implantation of everolimus-eluting biore- sorbable vascular scaffolds in a porcine coronary artery model: An attempt to decipher the human optical coher- ence tomography images in the ABSORB trial, Circulation, Vol. 122, No. 22, 2288-2300, doi: 10.1161/ CIRCULA- TIONAHA.109.921528. [33] Alexy, R.D., Levi, D.S. (2013). Materials and manufacturing technologies available for production of a pediatric bioabsorbable stent, BioMed Research International, Vol. 2013, Article ID 137985, doi: 10.1155/2013/137985. [34] Beshchasna, N., Saqib, M., Kraskiewicz, H., Wasyluk, Ł., Kuzmin, O., Duta, O.C., Ficai, D., Ghizdavet, Z., Marin, A., Ficai, A., Sun, Z., Pichugin, V.F., Opitz, J., Andronescu, E. (2020). Recent advances in manufacturing innovative stents, Pharmaceutics, Vol. 12, No. 4, 349, doi: /10.3390/pharmaceutics12040349. [35] Peuster, M., Wohlsein, P., Brügmann, M., Ehlerding, M., Seidler, K., Fink, C., Brauer, H., Fischer, A., Hausdorf, G. (2001). A novel approach to temporary stenting: Degradable cardiovascular stents produced from corrodible metal – results 6-18 months after implantation into New Zealand white rabbits, Heart, Vol. 86, No. 5, 563-569, doi: 10.1136/heart.86.5.563. [36] Huang, T., Cheng, J., Zheng, Y.F. (2014). In vitro degradation and biocompatibility of Fe-Pd and Fe-Pt composites fabricated by spark plasma sintering, Material Science and Engineering: C, Vol. 35, 43-53, doi: 10.1016/j.msec. 2013.10.023. [37] Bowen, P.K., Drelich, J., Goldman, J. (2013). Zinc exhibits ideal physiological corrosion behavior for bioabsorba- ble stents, Advanced Materials, Vol. 25. No. 18, 2577-2582, doi: 10.1002/adma.201300226. [38] Pierson, D., Edick, J., Tauscher, A., Pokorney, E., Bowen, P., Gelbaugh, J., Stinson, J., Getty, H., Lee, C.H., Drelich, J., Goldman, J. (2012). A simplified in vivo approach for evaluating the bioabsorbable behavior of candidate stent materials, Journal Biomedicine Materials and Research, Vol. 100B, No. 1, 58-67, doi: 10.1002/jbm.b.31922. [39] Erbel, R., Di Mario, C., Bartunek, J., Bonnier, J., de Bruyne, B., Eberli, F., Erne, P., Haude, M., Heublein, B., Horring- an, M., Ilsley, C., Böse D., Koolen, J., Lüscher, T.F., Weissman, N., Waksman, R. (2007). Temporary scaffolding of coronary arteries with bioabsorbable magnesium stents: a prospective, non-randomised multicentre trial, The Lancet, Vol. 369, No. 9576, 1869-1875, doi: 10.1016/S0140-6736(07)60853-8. [40] Su, Y., Cockerill, I., Wang, Y., Qin, Y.-X., Chang, L., Zheng, Y., Zhu, D. (2019). Zinc-based biomaterials for regenera- tion and therapy, Trends in Biotechnology, Vol. 37, No. 4, 428-441, doi: 10.1016/j.tibtech.2018.10.009. Advances in Production Engineering & Management 15(4) 2020 401 Polanec, Kramberger, Glodež [41] Yang, H., Wang, C., Liu, C., Chen, H., Wu, Y., Han, J., Jia, Z., Lin, W., Zhang, D., Li, W., Yuan, W., Guo, H., Li, H., Yang, G., Kong, D., Zhu, D., Takashima, K., Ruan, L., Nie, J., Li, X., Zheng, Y. (2017). Evolution of the degradation mechanism of pure zinc stent in the one-year study of rabbit abdominal aorta model, Biomaterials, Vol. 145, 92-105, doi: 10.1016/j.biomaterials.2017.08.022. [42] Bowen, P.K., Shearier, E.R., Zhao, S., Guillory 2nd, R.J., Zhao, F., Goldman, J., Drelich, J.W. (2016). Biodegradable metals for cardiovascular stents: From clinical concerns to recent Zn-alloys, Advanced Healthare Materials, Vol. 5, No. 10, 1121-1140, doi: 10.1002/adhm.201501019. [43] Zhu, D., Su, Y., Zheng, Y., Fu, B., Tang, L., Qin, Y.-X. (2018). Zinc regulates vascular endothelial cell activity through zinc-sensing receptor ZnR/GPR39, American Journal of Physiology – Cell Physiology, Vol. 314, No. 4, C404-C414, doi: 10.1152/ajpcell.00279.2017. [44] Lei, Y., Chen, X., Li, Z., Zhang, L., Sun, W., Li, L., Tang, F. (2020). A new process for customized patient-specific aortic stent graft using 3D printing technique, Medical Engineering and Physics, Vol. 77, 80-87, doi: 10.1016/ j.medengphy.2019.12.002. [45] Yang, L., Chen, X., Zhang, L., Li, L., Kang, S., Wang, C., Sun, W. (2019). Additive manufacturing in vascular stent fabrication, MATEC Web of Conf., 2018 International Conference on Materials Science and Manufacturing Engi- neering, Vol. 253, Article number 03003, doi: 10.1051/matecconf/201925303003. [46] Zhang, L., Chen, X., Liu, M. (2017). Research of customized aortic stent graft manufacture, IOP Conference Series: Materials Science and Engineering, Vol. 187, 012027, doi: 10.1088/1757-899x/187/1/012027. [47] Huang, B., Gale, D.C., Gale, Hossainy, S.F.A. (2011). Fabricating polymer stents with injection molding, Patent Application Publication, No. US 2011/0169197 A1. [48] Guerra, A.J., Ciurana, J. (2018). Stent's manufacturing field: Past, present, and future prospects, In: Angiography, Amukçu, B. (ed.), IntechOpen, 41-60, doi: 10.5772/intechopen.81668. [49] Flege, C., Vogt, F., Höges, S., Jauer, L., Borinski, M., Schulte, V.A., Hoffmann, R., Poprawe, R., Meiners, W., Jobmann, M., Wissenbach, K., Blindt, R. (2013). Development and characterization of a coronary polylactic acid stent proto- type generated by selective laser melting, Journal of Materials Science: Materials in Medicine, Vol. 24, No. 1, 241- 255, doi: 10.1007/s10856-012-4779-z. [50] Finazzi, V., Demir, A.G., Biffi, C.A., Chiastra, C., Migliavacca, F., Petrini, L., Previtali, B. (2019). Design rules for producing cardiovascular stents by selective laser melting: Geometrical constraints and opportunities, Procedia Structural Integrity. Vol. 15, 16-23, doi: 10.1016/j.prostr.2019.07.004. [51] Park, S.A., Lee, S.J., Lim, K.S., Bae, I.H., Lee, J.H., Kim, W.D., Jeon, M.H., Park, J.-K. (2015). In vivo evaluation and characterization of a bio-absorbable drug-coated stent fabricated using a 3D-printing system, Materials Letters, Vol. 141, 355-358, doi: 10.1016/j.matlet.2014.11.119. [52] Tumbleston, J.R., Shirvanyants, D., Ermoshkin, N., Janusziewicz, R., Johnson, A.R., Kelly, D., Chen, K., Pinschmidt, R., Rolland, J.P., Ermoshkin, A., Samulski, E.T., DeSimone, J.M. (2015). Additive manufacturing. Continuous liquid interface production of 3D objects, Science, Vol. 347, No. 6228, 1349-1352, doi: 10.1126/science.aaa2397. [53] van Lith, R., Baker, E., Ware, H., Yang, J., Farsheed, A.C., Sun, C., Ameer, G. (2017). 3D-printing strong high- resolution antioxidant bioresorbable vascular stents, Advanced Materials Technologies, Vol. 1, No. 9, doi: 10.1002/admt.201600138. [54] Ware, H.O.T., Farsheed, A.C., van Lith, R., Baker, E., Ameer, G., Sun. C. (2017). Process development for high- resolution 3D-printing of bioresorbable vascular stents, In: Proceedings Volume 10115, Advanced Fabrication Technologies for Micro/Nano Optics and Photonics X, SPIE OPTO, 2017, San Francisco, California, USA, doi: 10.1117/12.2252856. [55] Cabrera, M.S., Sanders, B., Goor, O.J.G.M., Driessen-Mol, A., Oomens, C.W.J., Baaijens, F.P.T. (2017). Computational- ly designed 3D printed self-expandable polymer stents with biodegradation capacity for minimally invasive heart valve implantation: A proof-of-concept study, 3D Printing and Additive Manufacturing, Vol. 4, No. 1, 19-29, doi: 10.1089/3dp.2016.0052. [56] Guerra, A.J., Ciurana, J. (2017). 3D-printed bioabsordable polycaprolactone stent: The effect of process parame- ters on its physical features, Materials & Design, Vol. 137, 430-437, doi: 10.1016/j.matdes.2017.10.045. [57] Guerra, A., Roca, A., de Ciurana, J. (2017). A novel 3D additive manufacturing machine to biodegradable stents, Procedia Manufacturing, Vol. 13, 718-723, doi: 10.1016/j.promfg.2017.09.118. 402 Advances in Production Engineering & Management 15(4) 2020