Patrick Rossignol
email: p.rossignol@chru-nancy.fr

PhD Luc Frimat

PhD Faiez Zannad

Pr Patrick Rossignol

The safety of mineralocorticoid antagonists in maintenance hemodialysis patients: Two steps forward

Keywords:

The Spin-D and MiREnDA trials taken together provide the reassuring demonstration that spironolactone up to 25 mg/d is reasonably safe, and that provided maintenance hemodialysis patients are properly monitored and investigators use a per-protocol therapeutic algorithm to manage hyperkalemia.

These results should encourage and reassure the investigators of the two currently ongoing large international, major outcome clinical trials, both of which are using spironolactone up to 25 mg/d: ACHIEVE (NCT03020303) and ALCHEMIST (NCT01848639).

In patients with end-stage renal disease (ESRD) on chronic dialysis, cardiovascular (CV) mortality is 10 to 20 times higher than in the general population and, among adults younger than 45 years, mortality rates are approximately 100 times higher than in the general population [START_REF] Rossignol | Roadmap for cardiovascular prevention trials in chronic kidney disease[END_REF] . Hence, treatments to improve survival, and more specifically cardiovascular outcomes, in this population are greatly needed. Disappointingly, few large outcome trials have been conducted specifically in the ESRD populations on dialysis: in a recent review, a less than two-page table was more than sufficient to summarize key randomized controlled trials and metaanalyses assessing mortality in ESRD as a primary endpoint! [START_REF] Ortiz | Epidemiology, contributors to, and clinical trials of mortality risk in chronic kidney failure[END_REF] . Few trials have reported beneficial treatment effects on cardiovascular outcomes, while many more were inconclusive due to study design limitations (e.g. open-label, small sample size, suboptimal target population) [START_REF] Rossignol | Cardiovascular outcome trials in patients with chronic kidney disease: challenges associated with selection of patients and endpoints[END_REF] .

Of note, a meta-analysis suggested that antihypertensive drugs as a whole may improve CV outcomes in normotensive and hypertensive patients with ESRD on chronic hemodialysis (HD) [START_REF] Agarwal | Blood pressure and mortality among hemodialysis patients[END_REF] . Mineralocorticoid receptor antagonists (MRAs) are one of the cornerstones of therapy in heart failure with reduced ejection fraction, except in patients with hyperkalemia and/or estimated glomerular filtration rate below 30 ml/min/1.73m 2 5 . However, practical implementation of high-grade trial evidence is hindered by physicians' apprehension regarding the hyperkalemia risk, inherently associated with renin-angiotensin aldosterone system (RAAS) blockade. Based on experimental and observational clinical data, it is clear that the RAAS plays a key role in the cardiovascular damage associated with chronic kidney disease.

Mineralocorticoid receptors are expressed not only in the epithelium but also in several nonepithelial sites (including the brain, heart, and vasculature), in addition to the fact that cardiovascular tissues can also synthesize aldosterone. Whether MRA may exhibit live-saving properties in chronic ESRD on HD is still unknown, despite the provocative results of an open-label randomized trial [START_REF] Pitt | Mineralocorticoid receptor antagonists in patients with end-stage renal disease on chronic hemodialysis[END_REF] . Upstream, relatively smallsized and short-term trials suggested an acceptable safety profile related to potassium and blood pressure, and even suggested a beneficial effect on cardiovascular structure and function [START_REF] Shavit | Aldosterone blockade and the mineralocorticoid receptor in the management of chronic kidney disease: current concepts and emerging treatment paradigms[END_REF] .

In this issue of the Journal, Charytan et al. [START_REF] Charytan | Safety and Cardiovascular Efficacy of Spironolactone in Dialysis-Dependent ESRD (SPin-D): A Randomized, Placebo-Controlled, Multiple Dosage Trial Kidney Int[END_REF] report results of the randomized placebocontrolled double-blind Safety and Cardiovascular Efficacy of Spironolactone in Dialysis-Dependent ESRD (Spin-D) trial. This was an early-phase dose-ranging safety and efficacy trial, with the MRA spironolactone (12.5, 25, 50 mg/d) in 129 chronic hemodialysis patients followed for up to 36 weeks. This is the first ever such trial reported in the hemodialysis setting and the authors should be complimented for the optimal design and conduct of the trial. In 125 (97%) of the 129 patients, it was possible to escalate the dose in accordance with the protocol, while 27 (21%) patients permanently discontinued the study drug, mainly for hyperkalemia (44%).

The authors rightly conclude that spironolactone was well tolerated compared with placebo. Indeed, for the two co-primary safety outcomes of potassium concentration >6.5 mEq/L and hypotension requiring hospitalization or emergency room visit, there was no overall difference between spironolactone and placebo groups. However, there was evidence of increasing hyperkalemia and hypotension rates with higher dosages (especially 50 mg/d). Serum potassium was measured at 3-5 days and 2 weeks after study drug initiation or dose increase, as well as monthly throughout the duration of treatment. A concomitant hyperkalemia management algorithm was also implemented, encompassing potential corrective actions (discontinuation or reduction of angiotensin converting enzyme inhibitor or angiotensin receptor blocker, dietary counseling, reduction of dialysate potassium concentrations to 2 mEq/L, reduction of study drug, etc.). Efficacy outcomes were considered exploratory. There were no convincing improvements in cardiac function (diastolic function, as assessed by the primary efficacy endpoint of changes in mitral annular E' velocity using tissue Doppler index echocardiography) and structure. Left ventricular mass index, left ventricular ejection fraction, and left ventricular global longitudinal strain did not improve.

Also in this issue of the Journal, Hammer et al. [START_REF] Hammer | Effect of spironolactone on left ventricular mass in hemodialysis patients: the MiREnDa study -a randomized controlled trial[END_REF] report the effect of spironolactone 50 mg once daily (n=50) or placebo (n=47) on left ventricular mass (LVM) of 97 chronic hemodialysis patients randomized 1:1 in a double-blind manner. The primary efficacy endpoint of this effect of spironolactone on left ventricular mass in hemodialysis patients (the MiREnDa) trial was the change in LVM index (LVMi) from baseline to 40 weeks of treatment as determined by cardiac magnetic resonance imaging (MRI).

This was an optimally-designed, conducted, and reported early-phase trial.

Treatment with 50 mg spironolactone had no significant effect on surrogate cardiovascular endpoints, using the gold standard MRI to assess left ventricular mass, left ventricular ejection fraction, and 24-h systolic or diastolic blood ambulatory pressure. However, 50 mg spironolactone resulted in a significantly higher incidence of moderate hyperkalemia, as defined by pre-dialysis potassium levels 6.0-6.5 mmol/L (155 vs. 80 events, P=0.034), whereas severe hyperkalemia episodes (predialysis potassium levels ≥6.5 mmol/L) were not significantly different between the two groups (spironolactone, 14 vs. placebo, 24 events, P=0.225). Of the 97 randomized patients, 77 took at least half a tablet of study medication for a minimum of 30 weeks, while the overall mean dose of spironolactone was 42 mg/day. A therapeutic algorithm to manage hyperkalemia was indeed implemented, encompassing temporarily withholding study medication, down-titration (25 mg /d) followed by a possible re-uptitration, enabled by potassium measurement prior to every dialysis session.

As rightly stated by both groups, the neutral effect of spironolactone on cardiovascular structure and function reported in this two relatively short-term (9month studies) does not preclude that MRAs have the potential to improve long-term cardiovascular outcomes in ESRD. There is indeed no evidence that changes in the investigated cardiovascular intermediate phenotypes may reliably predict morbidity and mortality benefits in outcome trials in chronic hemodialysis. Furthermore, patients with well-preserved diastolic function and LVM (Spin-D) and a relatively modest (40%) prevalence of left ventricular hypertrophy (MiREnDA) at baseline were enrolled, leaving little opportunity for improvement. Moreover, MRA may exhibit a beneficial effect independent and beyond decreasing LV mass, given their beneficial effects on cardiovascular remodeling, including fibrosis. Fibrosis, both in the heart and in the kidney, is the common consequence of inflammation-and oxidative stress-related endothelial dysfunction in aging, hypertension, diabetes mellitus and obesity, ultimately leading to cardiovascular disease, including atherosclerosis progression, heart failure, arrhythmias and chronic kidney disease [START_REF] Zannad | Cardiorenal Syndrome Revisited[END_REF] The investigators and their respective research staffs and networks involved in these two double-blind placebo-controlled cardiovascular outcome trials of spironolactone 25 mg/d must be encouraged to put their best effort to complete enrolment and follow-up in both trials. Their academic sponsors, the oversight, safety and adjudication committees, the supporting patient advocacy groups, and above all, the already-enrolled patients must readily be thanked and congratulated for all their effort, since they strongly contribute toward filling the compelling gap in knowledge in this very high-risk population which, regrettably, is almost systematically excluded from major pharma outcome clinical trials. Chronic ESRD patients and the medical community worldwide are eagerly awaiting the results, which may change medical practices and improve patient outcomes.

  (Figure).Therefore, the intermediate endpoints used in the Spin-D and MiREnDA trials are not informative with regard to outcome, and the ultimate risk-benefit ratio can only be established when the ongoing outcome trials will deliver. However, the most compelling result of the Spin-D and MiREnDA trials taken together is the reassuring demonstration that spironolactone up to 25 mg/d is reasonably safe, and that provided patients are properly monitored and investigators use a per-protocol therapeutic algorithm to manage hyperkalemia. These results should encourage and reassure the investigators of the two currently ongoing large international, major outcome clinical trials, both of which are using spironolactone up to 25 mg/d. The ALdosterone antagonist Chronic HEModialysis Interventional Survival Trial (ALCHEMIST, NCT01848639), is planning to recruit 825 high-risk chronic hemodialysis patients (i.e. presenting at least one of the following comorbidities, cardiovascular abnormalities or cardiovascular risk factors: left ventricular hypertrophy, left ventricular ejection fraction < 40%, large QRS > 0.14 sec or left bundle branch block; diabetes; history of cardiovascular disease, CRP > 5 mg/l for 3 months without documented infectious or neoplastic disease in progress). The primary composite endpoint is the time to onset of the first incident non-fatal myocardial infarction, acute coronary syndrome, hospitalization for heart failure, nonfatal stroke or cardiovascular-induced death. Over 620 patients have been enrolled in the ALCHEMIST trial to date. The Aldosterone bloCkade for Health Improvement EValuation in End-stage Renal Disease (ACHIEVE NCT03020303) is planning to recruit 2750 chronic hemodialysis or peritoneal dialysis patients (≥45 years, or ≥18 with a history of diabetes). The primary endpoint is death or hospitalization for heart failure.

Acknowledgements:

FZ and PR are supported by the French National Research Agency "Fighting Heart Failure" (ANR-15-RHU-0004), and the French PIA project «Lorraine Université d'Excellence » GEENAGE (ANR-15-IDEX-04-LUE) programs. The ALCHEMIST trial is sponsored by the CHRU de Brest, and is mainly funded by the French Programme Hospitalier de Recherche Clinique (PHRC-N). The authors thank Mr. Pierre Pothier for editing the manuscript.

Figure title: putative pathophysiological mechanisms and conditions targeted by mineralocorticoid receptor antagonism in chronic hemodialysis cardiovascular outcome trials

Disclosures:

Patrick Rossignol: Personal fees (consulting) from Novartis, NovoNordisk, Relypsa, AstraZeneca, Grünenthal, Idorsia, Stealth Peptides, Fresenius, Vifor Fresenius Medical Care Renal Pharma, Vifor; lecture fees from Bayer and CVRx; cofounder of CardioRenal Luc Frimat: Travel grants from Astellas, Fresenius, Novartis, Roche. Faiez Zannad: Personal fees for Steering Committee membership from Janssen, Bayer, Pfizer, Novartis, Boston Scientific, Resmed, Takeda, General Electric, and Boehringer Ingelheim; consultancy for Amgen, CVRx, Quantum Genomics, Relypsa, ZS Pharma, AstraZeneca, GSK; founder of Cardiovascular Clinical Trialists (CVCT) and of CardioRenal.


Melania Reggente

Mohamed Harhash

Sébastien Kriegel

Wenjia He

Patrick Masson

Jacques Faerber

Geneviève Pourroy

Heinz He

Adèle Carrado

Sebastien Kriegel

Heinz Palkowski

Adele Carradò

Resin-free three-layered Ti/PMMA/Ti sandwich materials: Adhesion and formability study

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Skull injur ies caused by trauma and pat hologies, such as t umor , infect ious diseases or congenital defor mit ies, may r esult int o ser ious funct ional , aest het ical and psychological sequel s, requir ing t he r econstruct ion of compl ex craniofacial pr ostheses. In t his f iel d, t he choice of suitabl e biomat er ial s is t he ma in challenge. Currently, differ ent classes of mono-mat er ial s, such as pol ymer s, ceramics and l ight metal s ar e empl oyed t o fabr icat e skull and mandibl e pr ostheses [START_REF] Aydin | Cranio plasty: r eview of mat er ial s and t echniques[END_REF] .

In part icular , pol y(methyl met hacrylate) (PMMA) [START_REF] Or Igitano | Reconstruct ing compl ex cranial defect s wit h a pr efor med cranial pr ost hesis[END_REF] , pol yether et her ket one (PEEK) [START_REF] Let Haus | Cranioplasty wit h cust omized t itanium and PEEK impl ant s in a mechanical stress model[END_REF][START_REF] Th Ien | Co mpar ison of pol yether etherketone and t itanium cranioplasty aft er decompr essive craniectomy[END_REF] , hydroxya pat i t e (HA) [START_REF] Eppl Ey | Hydroxya pat it e cranioplasty: 2. cl inical exper ience wit h a new quick-sett ing mat er ial[END_REF][START_REF] Ducic | Titanium mesh and hydroxya pat it e cement cranioplasty: a report of 20 cases[END_REF][START_REF] Costant Ino | Ex per imental hydroxya pat i t e cement cranioplasty[END_REF] and t itanium (Ti) [START_REF] Th Ien | Co mpar ison of pol yether etherketone and t itanium cranioplasty aft er decompr essive craniectomy[END_REF][START_REF] Ducic | Titanium mesh and hydroxya pat it e cement cranioplasty: a report of 20 cases[END_REF][START_REF] Ca Braja | Long-t er m r esult s following t itanium cranioplasty of large skull defect s[END_REF] are t he most widel y used mat er ial s in t he cranioplasty r econstruct ion. Ti r ema ins t he most widel y used metal in biomedical a ppl icat ions due t o it s biocompat ibil i ty [START_REF] Queir Oz | In vivo evaluat ion of cp Ti impl ant s wit h modified surfaces by laser bea m wit h and wit hout hydroxya pat it e chemical deposit ion and wit hout and wit h t her mal treat ment : t opogra phic charact er izat ion and hist omor phometr ic analysis in rabbit s[END_REF][START_REF] Debr | Du pr et -Bor ies, Impl antat ion of an Art ificial Larynx aft er Total Laryngectomy[END_REF][START_REF] Carradò | Nanoporous hydroxya pat i t e/sodium t itanat e bilayer on t itanium implant s for impr oved ost eoint egrat ion[END_REF] . In part icular , Ti-based plat es ar e generally used t o built -up craniofacial pr osthesis and r eplace t he bone. As an exa mpl e, l ight Ti skull and mandibl e pr ost heses ar e fabr icat ed by using Sel ect ive Laser Melt ing or 3D r econstruct ion t echniques from medical images, which al so r educes t he possibil i ty of errors dur ing surgery [START_REF] Dobr Za Ski | Por ous sel ect ive laser melt ed Ti and Ti 6 Al 4 V mat er ial s for medical a ppl icat ions[END_REF][START_REF] Muell Er | The funct ional and aest het ic r econstruct ion of midfacial and or bital defect s by combining fr ee fla p transfer and craniofacial pr osthesis[END_REF][START_REF] Jardini | Cranial r econstruct ion: 3D biomodel and custom-built implant cr eat ed using addit ive manufactur ing[END_REF][START_REF] Rotaru | Sel ect ive laser melted t itanium implant s: a new t echnique for t he reconstruct ion of ext ensive zygomat ic compl ex defect s[END_REF] . Mor eover , PMMA is al so ext ensively used in cranioplasty, due t o it s biocompat ibil ity, str ength, l ow cost and t he possibil it y of preoperat ive use [START_REF] Huang | Craniofacial r econstruct ion wit h pol y (met hyl met hacrylat e) cust omized cranial implant s[END_REF][START_REF] Ridwan-Pra Mana | Structural and mechanical impl icat ions of PMMA impl ant sha pe and int erface geometry in cranioplasty-A f init e el ement st udy[END_REF] . On t he ot her hand, t hese mat er ial s ar e used as mat er ial s in food pr ocessing wher e biol ogical aspect s have t o be taken int o account .

However , t he mono-mater ial s pr esent many drawbacks, such as ina ppropr iat e mechanical pr opert ies or t heir high weight in t he case of metals. For medical use, t he discr epancy exist ing bet ween t he mechanical pr opert ies and t he densit y of t he impl ant and t he bone t o be r eplaced results in stress shiel ding which r epr esent s t he most l imit ing factor for a successful subst it ut e [START_REF] Ridzwan | Pr obl em of stress shiel ding and impr ovement t o t he hip impl ant designs: a r eview[END_REF][START_REF] Ruys | Bio mimet ic biomat er ial s: structure and a ppl icat ions[END_REF] .

Since t he mono-mat er ial s alone cannot sol ve t his discr epancy in an opt imal way, t he devel opment of hybr id structures -made of pol ymer s and metal s exhibit ing new funct ional i t iescan be a suitabl e a ppr oach in many fiel ds of a ppl icat ion [START_REF] Harr | A per spect ive view of composit e mat er ial s devel opment[END_REF] . Indeed, t hey take t he advantage of expl oit ing bot h t he l ow densit y and t he l ight weight , specific of pol ymer s [START_REF] Landel | Mechanical pr opert ies of pol ymer s and composit es[END_REF] , and t he high bending resistance and l oad ca pacit y pr oper of t he metal s [START_REF] Harr | A per spect ive view of composit e mat er ial s devel opment[END_REF] . Ther efor e, by combining t hese t wo mat er ial s, structur es possessing new pr opert ies, such as h igh-energy absor pt ion, high corrosion and mechanical r esistance coupl ed wit h a l ight weight , can be fabr icat ed [START_REF] Thomsen | Sandwich Structur es 7: Advancing wit h Sandwich Structures and Mat er ial s: Pr oceedings of t he 7t h Int ional Confer ence on Sandwich Structures, Aal borg Univer sit[END_REF] . In part icular , layered structur es, such as sandwich mat er ial s, composed of t wo metall ic skin sheets and a pol ymer cor e can be an int er est ing alt ernat ive t o design innovative part s [START_REF] Harhash | Light weight t itanium/pol ymer / t itanium sandwich sheet for technical and biomedical a ppl icat ion[END_REF] . Such sandwich structur es are used in t he a ircraft , automot ive and naval industry because of t heir high acoust ic and da mping ca pacit y [START_REF] Chen | Vibrat ion da mping charact er ist ics of la minat ed st eel sheet[END_REF][START_REF] Ber Nd | Metal For ming of Vibrat ion-Da mping Composit e Sheet s[END_REF] , h igh st iffness and strength, good for mabil it y and l ight weight [START_REF] Harr | A per spect ive view of composit e mat er ial s devel opment[END_REF][START_REF] Parfitt | Adsorpt ion from sol ut ion at t he sol id/l iquid int erface[END_REF][START_REF] Libr | Recent development s in t he model ing and behavior of advanced sandwich construct ions: a survey[END_REF][START_REF] Sokolova | Metal -pol ymer -metal sandwiches wit h local metal r einforcements: A st udy on for mabil ity by deep drawing and bending[END_REF] . In t hese syst ems, an epoxy r esin is commonl y used as an adhesive agent t o st ick t he pol ymer cor e onto the metal skin sheet s ensur ing good bonding between t he t wo component s even under shear load [START_REF] Harhash | Light weight t itanium/pol ymer / t itanium sandwich sheet for technical and biomedical a ppl icat ion[END_REF] . The t oxicit y of t his adhesive layer [START_REF] Kost Oryz | In vitro cytotoxicit y of sol id epoxy-based dental resins and t heir component s[END_REF] evidently pr event s t heir a ppl icat ion in t he biomedical fiel d and food pr oduct ion. In our pr evious work [START_REF] Harhash | Light weight t itanium/pol ymer / t itanium sandwich sheet for technical and biomedical a ppl icat ion[END_REF] , it was shown t hat , following t he rul e of mixt ur es, t he mechanical pr opert ies of t he whol e sandwich can be ta il or ed according t o t he skin and cor e t hicknesses (or rather t heir volume fract ions) achieving sandwich configurat ions wit h desir ed pr opert ies. In t his way, structures wit h t he necessary and designed st iffness and strength can be pr oduced. Mor eover , t heir for mabil it y int o compl ex sha pes -as r equir ed in t he fabr icat ion of pr ostheses or special part s in industry -can be assur ed by sel ect ing t he pr oper sandwich component s, adjust ing t he skin /cor e t hickness configurat ion and impr oving t he metal /polymer bonding strength.

Although sandwich structures seem t o be well adapt ed t o t he mechanical propert ies r equir ed in biomat er ial s, t he use of an epoxy r esin is a ser ious drawback for in vivo a ppl icat ions and if being used in t he food industry [START_REF] Kost Oryz | In vitro cytotoxicit y of sol id epoxy-based dental resins and t heir component s[END_REF] . Thus, in order t o ext end t heir a ppl icat ions, t he challenge is t o establ ish a strong, biocompat ibl e bonding bet ween metal and pol ymer to include a polymer component bet ween t wo metal sheet s wit hout using an epoxy r esin able t o att enuat e str essshiel ding effect s.

In general , t he durabil ity of a pol ymer -metal int erface strongly depends on t he adhesion strength bet ween t he t wo component s. Since chemical bonds bet ween metal and pol ymer are not spontaneously establ ished, t hese layer ed hybr id polymer -metal mat er ial s oft en exhibit undesir ed delaminat ion phenomena due t o a weak int erfacial adhesion bet ween metal and polymer result ing in t he pr emature fa il ur e of t he ent ir e syst em [START_REF] Fujimot | Dela minat ion of abluminal pol ymer of biol imus-el ut ing st ent[END_REF][START_REF] Sun | Tr ibological pr opert ies of chemically bonded pol yimide fil ms on sil icon wit h pol yglycidyl met hacrylat e brush as adhesive layer[END_REF] . Thus, r ecently graft ed pol ymer s (i.e. pol ymer cha ins wit h an extremit y coval ently bound t o a substrate) wer e pr oposed as adhesives t o be insert ed bet ween a metal substrat e and a pol ymer coat ing [START_REF] Sun | Tr ibological pr opert ies of chemically bonded pol yimide fil ms on sil icon wit h pol yglycidyl met hacrylat e brush as adhesive layer[END_REF][START_REF] Shaulov | Pol y (met hyl met hacrylate) graft ing onto stainl ess st eel surfaces: a ppl icat ion t o drug-el ut ing st ent s[END_REF][START_REF] Sh Imizu | Impr oved adhesion between PMMA and stainless st eel modified wit h PMMA br ushes[END_REF][START_REF] Sh Imizu | Durabil it y of peek adhesive t o stainl ess st eel modified wit h aryldiazonium salts[END_REF][START_REF] Al Ageel | Bonding metal s t o poly (met hyl met hacrylate) using aryldiazonium salts[END_REF] . In part icular , it has been shown that by expl oit ing t he miscibil it y bet ween t he surface-confined pol ymer cha ins and t hose of a bul k [START_REF] Aubouy | End-t et her ed cha ins in pol ymer ic matr ixes[END_REF][START_REF] Gut Owski | Int erface/ int er phase engineer ing of pol ymer s for adhesion enhancement : Part ii. t heor et ical and t echnological aspect s of surface-engineer ed inter phaseint erface syst ems for adhesion enhancement[END_REF][START_REF] Sides | Effect of end-t ether ed pol ymer s on surface adhesion of glassy pol ymer s[END_REF][START_REF] Ra | Rubber -r ubber adhesion wit h connector mol ecul es[END_REF][START_REF] Kunz | In it ial stages of int erdiffusion of PMMA across an int erface[END_REF] , melt [START_REF] Sh Imizu | Impr oved adhesion between PMMA and stainless st eel modified wit h PMMA br ushes[END_REF] or sol ut ion pol ymer [START_REF] Al Ageel | Bonding metal s t o poly (met hyl met hacrylate) using aryldiazonium salts[END_REF] , t he metal /pol ymer adhesion strength is enhanced and t heir durabil it y impr oved [START_REF] Sun | Tr ibological pr opert ies of chemically bonded pol yimide fil ms on sil icon wit h pol yglycidyl met hacrylat e brush as adhesive layer[END_REF][START_REF] Sh Imizu | Impr oved adhesion between PMMA and stainless st eel modified wit h PMMA br ushes[END_REF][START_REF] Al Ageel | Bonding metal s t o poly (met hyl met hacrylate) using aryldiazonium salts[END_REF] . Indeed, when t wo compat ibl e pol ymer s (i.e. pol ymer of t he sa me natur e) ent er in int imat e contact , a part ial int er penetrat ion bet ween t he chains of t wo mat er ial s is establ ished, according t o t he diffusion t heory descr ibed by t he r eptat ion model [START_REF] Ra | Rubber -r ubber adhesion wit h connector mol ecul es[END_REF][START_REF] Kunz | In it ial stages of int erdiffusion of PMMA across an int erface[END_REF][START_REF] Schnell | Direct correlat ion bet ween int erfacial widt h and adhesion in glassy pol ymer s[END_REF] , and, as a result , entangl ement s point s ar e cr eat ed [START_REF] Gut Owski | Int erface/ int er phase engineer ing of pol ymer s for adhesion enhancement : Part ii. t heor et ical and t echnological aspect s of surface-engineer ed inter phaseint erface syst ems for adhesion enhancement[END_REF][START_REF] Sides | Effect of end-t ether ed pol ymer s on surface adhesion of glassy pol ymer s[END_REF] . The degr ee of int er penetrat ion depends on t hree ma in factors: (i) t he br ushes surface densit y (i.e. t he number of graft ed cha in per nm 2 ); (ii) t he brushes cha ins l ength; and (iii) t he mol ecular weight distr ibut ion (MWD) [START_REF] Gut Owski | Int erface/ int er phase engineer ing of pol ymer s for adhesion enhancement : Part ii. t heor et ical and t echnological aspect s of surface-engineer ed inter phaseint erface syst ems for adhesion enhancement[END_REF][START_REF] Sides | Effect of end-t ether ed pol ymer s on surface adhesion of glassy pol ymer s[END_REF][START_REF] Gay | Wett ing of a pol ymer brush by a chemically ident ical pol ymer melt[END_REF][START_REF] Laub | Effect of brush pol ydisper sit y on t he int er phase bet ween end-graft ed br ushes and pol ymer ic matr ixes[END_REF] . Long cha ins in t he l ow-densit y r egime (al so call ed as mushroom r egime) ar e r equir ed t o obtain a good penetrat ion. Since in t his r egime t he overlap between adjacent cha ins are avoided, t hey have enough fr ee-vol ume t o move, r e-arrange and inter penetrate in t he adher ing mat er ial [START_REF] Gut Owski | Int erface/ int er phase engineer ing of pol ymer s for adhesion enhancement : Part ii. t heor et ical and t echnological aspect s of surface-engineer ed inter phaseint erface syst ems for adhesion enhancement[END_REF][START_REF] Sides | Effect of end-t ether ed pol ymer s on surface adhesion of glassy pol ymer s[END_REF] . It has al so been demonstrated that higher cha in l engths result in an impr ovement of t he adhesiveness bet ween t he pol ymer bulk and t he br ushes [START_REF] Gut Owski | Int erface/ int er phase engineer ing of pol ymer s for adhesion enhancement : Part ii. t heor et ical and t echnological aspect s of surface-engineer ed inter phaseint erface syst ems for adhesion enhancement[END_REF] . In part icular , an incr ease of the t ensil e str ength of a junct ion for med by graft ed PMMA cha ins int er penetrat ed in a melt ed PMMA matr ix wer e report ed when l onger brushes cha ins wer e considered, due t o a deeper penetrat ion of t he PMMA brushes int o t he bul k PMMA [START_REF] Sh Imizu | Impr oved adhesion between PMMA and stainless st eel modified wit h PMMA br ushes[END_REF] . Since, it has been demonstrat ed t hat brushes wit h a degr ee of pol ymer izat ion (i.e. t he rat io bet ween t he molecular weight of t he graft ed cha ins and t he mol ecular mass of t he monomer ) gr eat er t han or equal t o 200 is necessary t o establ ish physical entangl ement s wit h t he adjacent pol ymer bul k 37 , t he o pt imizat ion of coating met hods enabl ing the pr oduct ion of fil ms wit h large t hicknesses (few micr ometres) ar e desir ed [START_REF] Fr Iis | Hydrophil ic pol ymer br ush layer s on stainl ess st eel using mult i layer ed ATRP in it iator layer[END_REF] .

In t his cont ext , t he idea of t his work was t o empl oy surface-confined polymer s t o fabr icate biocompat ibl e r esin -fr ee sandwich mat er ial s by sticking t he pol ymer cor e on t he metall ic skins pr eviousl y coat ed wit h graft ed pol ymer cha ins. As pr oof of concept for biomedical a ppl icat ions, Ti and PMMA wer e empl oyed and Ti/PMMA/Ti sandwiches pr oduced. Indeed, despit e t he significant discr epancy bet ween t he mechanical pr opert ies of Ti and t hose of t he surrounding t issues, which oft en r esults in a stress shiel ding [START_REF] Queir Oz | In vivo evaluat ion of cp Ti impl ant s wit h modified surfaces by laser bea m wit h and wit hout hydroxya pat it e chemical deposit ion and wit hout and wit h t her mal treat ment : t opogra phic charact er izat ion and hist omor phometr ic analysis in rabbit s[END_REF][START_REF] Debr | Du pr et -Bor ies, Impl antat ion of an Art ificial Larynx aft er Total Laryngectomy[END_REF] . In order t o r educe t his t issue-implant mechanical impa ir ment , a t echnique t o incor porat e a pol ymer component t o Ti impl ant s was devel oped and sandwich mat er ial s, made of t wo Ti skins and a PMMA cor e, wer e pr oduced using graft ed pol ymer cha ins as an adhesive. Ther efor e, surface-confined PMMA cha ins replaced t he epoxy r esin l ayer and t he adhesion bet ween t hese t ether ed cha ins and t hose of an adher ing PMMA sheet (used as cor e mat er ial ) was establ ished by expl oit ing t heir miscibil ity through t he for mat ion of entangl ement s. In part icular , t he PMMA cha ins wer e grown on alkal iact ivat ed Ti surfaces [START_REF] Reggent E | A novel alkal i-act ivat ion of t itanium substrates t o grow t hick and coval ently bound PMMA l ayer s[END_REF] through surface-init iat ed at om transfer radical pol ymer izat ion (SI-ATRP) [START_REF] Wang | Controlled/"l iv ing" radical pol ymer izat ion. At om transfer radical pol ymer izat ion in t he pr esence of transit ion-metal compl exes[END_REF] using phosphonic acid der ivat ives as coupl ing agent s and mal ononitr i l e as pol ymer izat ion act ivator [START_REF] Guerrero | Anchor ing of Phosphonate and Phosphinat e Coupl ing Mol ecul es on Tit ania Part icl es[END_REF][START_REF] Ver Gnat | Enhancement of st yrene conver sion in organic/inorganic hybr id mat er ial s by using malononitr il e in controlled radical pol ymer izat ion[END_REF] . Being t he establ ished graduat e structur e charact er ized by a high Ti/PMMA adhesion strength [START_REF] Reggent E | A novel alkal i-act ivat ion of t itanium substrates t o grow t hick and coval ently bound PMMA l ayer s[END_REF] , h igh t hickness (i.e. l ong PMMA cha ins) [START_REF] Reggent E | A novel alkal i-act ivat ion of t itanium substrates t o grow t hick and coval ently bound PMMA l ayer s[END_REF] and a porous structure (i.e. h igh fr ee vol ume) [START_REF] Reggent E | A novel alkal i-act ivat ion of t itanium substrates t o grow t hick and coval ently bound PMMA l ayer s[END_REF][START_REF] Reggent E | Mult iscal e mechanical charact er izat ion of hybr id Ti/PMMA l ayer ed mater ial s[END_REF] t he possibil it y t o use t hese PMMA-coat ed Ti surfaces for t he pr oduct ion of sandwich is shown her e. Indeed, Ti/PMMA/Ti sandwiches wer e obtained by hotpr essing, expl oit ing t he int er penetrat ion bet ween t he graft ed PMMA chains and t hose of an adher ing PMMA foil used as cor e mat er ial [START_REF] Sun | Tr ibological pr opert ies of chemically bonded pol yimide fil ms on sil icon wit h pol yglycidyl met hacrylat e brush as adhesive layer[END_REF][START_REF] Shaulov | Pol y (met hyl met hacrylate) graft ing onto stainl ess st eel surfaces: a ppl icat ion t o drug-el ut ing st ent s[END_REF][START_REF] Sh Imizu | Impr oved adhesion between PMMA and stainless st eel modified wit h PMMA br ushes[END_REF][START_REF] Sh Imizu | Durabil it y of peek adhesive t o stainl ess st eel modified wit h aryldiazonium salts[END_REF][START_REF] Al Ageel | Bonding metal s t o poly (met hyl met hacrylate) using aryldiazonium salts[END_REF][START_REF] Aubouy | End-t et her ed cha ins in pol ymer ic matr ixes[END_REF][START_REF] Gut Owski | Int erface/ int er phase engineer ing of pol ymer s for adhesion enhancement : Part ii. t heor et ical and t echnological aspect s of surface-engineer ed inter phaseint erface syst ems for adhesion enhancement[END_REF] . Mor eover , t he Ti/PMMA/Ti bonding strength, mechanical pr opert ies and for ming behaviour were evaluat ed perfor ming pull -off t est s, standard tensil e, bending, Er ichsen and deep-drawing t est s, r espect ivel y. ). The sa mpl es wer e cut wit h a metallogra phical saw and an edge from t he backside was pol ished wit h a 25° bevel (SiC P1000 pa per ) to r educe t he t hickness of Ti t o pol ish by t he ion bea m. The cross pol ishing was t hen perfor med fr om t he back side (6 keV, Ar ). By t his way, t he organic mat er iel was pr ot ect ed by t he Ti it self and very few exposed to t he ion bea m. Then it s featur es st udied using SEM analysis conduct ed on a Zeiss Gemini SEM 500 SEM.

Experimental

Ti/PMMA/Ti sandwich production

Resin -fr ee Ti/PMMA/Ti sandwiches of differ ent sizes wer e pr oduced by hot -pr essing. A PMMA foil 0.5 mm t hick, used a s cor e mat er ial , was insert ed bet ween t wo PMMA-coat ed Ti sheet s.

Since t he manufactur ing pr ocess, r egarding t he bonding pr opert ies bet ween metal and pol ymer , is independent from t he t hicknesses of t he partner s, and wit h t he a im of fir stly pr oving t he feasibil it y of pr oducing suitabl e r esin -fr ee sandwich mat er ial s, t he combinat ions t est ed wer e chosen depending on t he mat er ial s ava ilabl e.

A l ayup of t he t hr ee component s was t hen hot -pr essed t oget her above t he PMMA glass transit ion temperature and melt ing temperature (111°C and 160°C, r espect ivel y). Bonding was achieved by expl oit ing t he int er penetrat ion of t he graft ed PMMA cha ins int o t he cha ins of t he adher ing PMMA foil , which l ed t o t he for mat ion of entanglement s [START_REF] Sun | Tr ibological pr opert ies of chemically bonded pol yimide fil ms on sil icon wit h pol yglycidyl met hacrylat e brush as adhesive layer[END_REF][START_REF] Sh Imizu | Impr oved adhesion between PMMA and stainless st eel modified wit h PMMA br ushes[END_REF] .

The ma in paramet er s involved in t he hot -pr essing pr ocess ar e t ime, t emperature and pr essur e.

The o pt imized combinat ions of t hese t hr ee paramet er s for t he Ti/PMMA/Ti sandwiches pr oduct ion wer e assessed perfor ming a parametr ic st udy. For each paramet er , t hr ee values wer e consider ed as follows: T = 170, 180 and 200°C, t = 30, 60 and 90 min and p = 0.1, 0.2 and 0.4

MPa . Thus, t he maximum number of paramet er combinat ions (i.e. possible exper iment s) was 3 [START_REF] Let Haus | Cranioplasty wit h cust omized t itanium and PEEK impl ant s in a mechanical stress model[END_REF] , which wer e r educed t o an opt imized number of 19 ex per iment s, by using a design of exper iment s (Do E) t ool , na mel y Minitab (Minitab Inc.). Successivel y, t he best condit ions for t he sandwich pr oduct ion wer e chosen as t he ones guarantying t he highest value of bonding strength, evaluated per for ming pull -off t est s. The o pt imum was ident ified wit h t = 90 min , T = 180°C and p = 0.2 MPa , so , Ti/PMMA/Ti of differ ent sizes were pr oduced under t hese condit ion t o perfor m mechanical and for ming test s.

Investigation of the Ti/PMMA/Ti cross-section microstructure

The microstructure of the Ti/PMMA/Ti cr oss-sect ions wer e analysed by Opt ical microscopy.

The sa mpl es wer e pr epared by cutt ing, wit h a shear cutt ing bank, a small piece (20 × 10 mm 2 ) of a Ti/PMMA/Ti sandwich from an A6-sized one. Then, t he cross-sect ion of t he sa mpl es was mount ed using cold mount ing r esin and successivel y pr epar ed for t he observat ion by wetgr inding using SiC pa pers and pol ishing it wit h synt het ic pol ishing fibre cl oth wit h dia mond past e (in a sequence of 6, 3 and finally 1 µm). Finally, t he pol ished Ti/PMMA/Ti cr oss-sect ions wer e observed by o pt ical micr oscopy (Ol ympus IX70 and Zeiss Ax io Imager ).

Evaluation of the Ti/PMMA/Ti sandwich adhesion: Pull-off tests

The Ti/PMMA/Ti adhesion strength was evaluated perfor ming pull -off test s. For t hese t est s, sandwiches made of t wo (20 × 20) mm 2 Ti skin sheet s and a PMMA core 0.5 mm t hick wer e pr oduced using t he condit ions l ist ed in Tabl e 2, at l east t hr ee sa mpl es each in most of t he condit ions. A t wo-component s adhesive (3M scotch-wel d DP 490 Structural adhesive epoxy) was used t o st ick t heir ext ernal surfaces onto an (20 × 20 × 100) mm 3 stainl ess st eel bar . Befor e test ing, t he gl ue was cur ed by heat ing it at 60°C for 24 h , and t hen it was kept at room temperature for 48 h . The sa mpl es wer e t hen mount ed on t he univer sal t est ing machine and t he test s perfor med using a speed of 0.1 mm/min .

Evaluation of the Ti/PMMA/Ti sandwich adhesion: Shear-tests

The shear r esistance of t he Ti/PMMA/TI sandwiches was evaluat ed perfor ming singl e shear test s using a univer sal t est ing machine wit h an appl ied speed of 1 mm/min . Sandwiches of t wo PMMA-coat ed Ti sheet s (25 × 100 × 0.4 mm 3 ) and a PMMA cor e foil, 0. The strain fiel d was det er mined using phot ogrammetry (GOM Ar gus) for t he differ ent successive st eps. For t his analysis and for a pr ecise evaluat ion, f ine dot patt ern (0.5 mm point dia met er wit h 1 mm d istance of t he adjacent dot centres) was et ched on t he Ti sheet s by means of an el ectrolyt ic marking syst em (EU-Cl assic, Östl ing Marking Syst ems GmbH). Successivel y, a GOM Ar gus syst em was used t o det er mine t he strains. The r esults were obtained in t er ms of the distr ibut ion of t he ma jor strain in a sect ion along t he sa mpl e l ength; in addit ion, 3D phot ogrammetr ic images show t he cr it ical r egions of t he sha ped sa mpl es.

Wher eas, t he spr ing-back rat ios (K) ar e det er mined based on t he angl e ratio bet ween t he angl e aft er unloading ( 2 ) wit h respect of t he one in t he l oading condit ion ( 1 ):

= (1)
A small spr ing-back is achieved if t he K value is close t o 1.

The spr ing-back degr ee (K) is correlat ed t o elastic modulus in t he plane strain condit ion (E ' ) according t o t he geometrical and mechanical pr opert ies of t he t est ed sheet s 50 :

= × × - × × + (2)
wher e R i is t he init ial bend radius befor e spr ing-back, t is t he sheet t hickness, YS is it s yiel d strength.

In (2) E ' is expr essed as a funct ion of t he Poisson rat ion (??) [START_REF] Marciniak | Mechanics of sheet metal for ming[END_REF] :

= (3)
According t o (2), l ower spr ingback (i.e., bett er angl e stabil it y) is expect ed wit h l ower YS/E rat io as well as l ower R/t rat io.

Deep-drawing tests

The possibil it y of sha ping for ms t hat ar e mor e compl ex was invest igat ed by t est ing t he for ming pr opert ies of Ti/PMMA/Ti sandwiches wit h different t hicknesses (0.2/0.5/0.

Erichsen test

Er ichsen t est s -g iving infor mat ion on t he str etching behaviour of sheet mater ial -wer e carr ied out on 0.2/0.5/0.2 Ti/PMMA/Ti sandwiches. A st andard 25 mm d ia met er semi-spher ical punch was used. Dur ing t he t est , t he punch displacement rat e was kept constant at 0.5 mm/s. The for ming l imit s wer e deter mined in t er ms of t he corresponding punch displacement when cracking occur s (na mel y the Er ichsen Index (IE)) and for ming force could be det er mined.

Results

Grafted PMMA layer bounded on Ti surfaces

The cross-sect ion of PMMA cha ins graft ed on a Ti substrate obtained following a t hr ee-st ep strat egy [START_REF] Reggent E | A novel alkal i-act ivat ion of t itanium substrates t o grow t hick and coval ently bound PMMA l ayer s[END_REF] 1a) [START_REF] Reggent E | A novel alkal i-act ivat ion of t itanium substrates t o grow t hick and coval ently bound PMMA l ayer s[END_REF][START_REF] Reggent E | Mult iscal e mechanical charact er izat ion of hybr id Ti/PMMA l ayer ed mater ial s[END_REF] .

Addit ionally, t he effect of using a short er ATRP init iator (i.e., a commer cial bromoisobutyratepr opyl -1-phosphonic acid, C 7 H 14 O 5 PBr ) on t he polymer t hickness and structur e was invest igat ed.

Wher eas, a compar ison bet ween t he surface morphol ogies befor e and after t he graft ing of t he two (differ ent in size) init iator mol ecul es t ogether wit h t he corresponding EDX spectra, is pr esent ed in Figure 2. The SEM micr ogra phs highl ight t hat t he surface features change aft er t he graft ing r eact ion. In particular , t he surface, modified wit h t he short er init iator (Figure 2b), was charact er ized by t he organic mol ecul es bounded around t he pillars l eft by alkal i-act ivat ed Ti surfaces. Thus, it l ed t o a mor phology similar t o t hat of t he micr oporous l ayer (Figure 2a) but less branched. Inst ead, t he graft ing of t he l onger init iator r esult s in a mor e compact structure composed of shar per pillars (Figure 2c). Thus, as expect ed, t he l onger init iator fill ed up better the por es l eft by t he alkal i tr eat ment . 2d and Figure 2e).

Then, taking int o account t he differ ence in t he number of mol s pr oduced by using shorter mol ecul es, t he r eagent s quant it y r equir ed for t he pol ymer izat ion was r ecalculat ed in funct ion of the init iator 's number of mol s and t he ATRP consequently carr ied-out . As pr eviousl y underl ined, the graft ing r eact ion wit h t he short er init iator l eads t o a mor e open surface structure, which results in t he growth of less densel y packed PMMA l ayer s (Figure 3). Indeed, it a ppear s highl y por ous and composed of globul es of organic mat er ial s pr efer ent ially grown around t he pillars of the microporous layer . Thus, for t he pur pose of this work, in order t o get longer graft ed PMMA cha ins, -guarantying a bett er int er penetrat ion int o t he ones of t he adher ing PMMA foil , and t hus a stronger bond [START_REF] Sokolova | Metal -pol ymer -metal sandwiches wit h local metal r einforcements: A st udy on for mabil ity by deep drawing and bending[END_REF] -t he l ong br omoisobutyrate-undecyl -1-phosphonic acid ATRP in it iator was empl oyed. 4b). In t his work, we sel ect ed t he following pr ocess condit ions:

Production of

temperature T = 180 °C, t ime t = 90 min and pr essur e p = 0.2 MPa , which ensur e t he highest possibl e pull -off str ength (24 MPa ) avoiding a squeezing-out and degradat ion of t he pol ymer .

Evaluation of the Ti/PMMA/Ti adhesion strength

The pull -off t est s performed (as sketched in Figure 5a The br ittleness of t he PMMA is ex pect ed t o influence t he str ess-strain behaviour of t he ent i r e sandwich sheet s under t ensil e l oading as well as t he for ming behaviour under bending and deepdrawing l oading condit ions. In t his r egard, it was observed t hat t he PMMA cor e cracks earl ier than t he pur e Ti skin sheet s in t he sandwich (in strain range bet ween 22% and 28%, r ed curves) wit h a strain differ ence of about 2% at t he end of the t ensil e t est ing (see black arrows in Figure 8). Neverthel ess, t he t otal el ongat ion of t he Ti/PMMA/Ti sandwiches fail ur es comes cl ose t o that ones of t he Ti sheets. It is not eworthy t o ment ion t hat even if t here was a sl ight strain differ ence bet ween t he Ti and PMMA inside t he sandwich sheet , no delaminat ion fa il ur e could be stat ed.

Further mor e, using t he Ro M 23 (Eq . ( 1)) t he Young's modulus of t he sandwich (E SMs ) can be pr edict ed using t he PMMA (EPMMA) and Ti sheet s (E Ti ) Young's modul i combined wit h t heir volume fract ion (f PMMA and f Ti , r espect ivel y), as follows:

= +
As stat ed befor e [START_REF] Harhash | Light weight t itanium/pol ymer / t itanium sandwich sheet for technical and biomedical a ppl icat ion[END_REF] , depending on t he t hickness rat io of t he mono-mat er ial s, it is possibl e t o design t he mechanical propert ies of t he ent ir e sandwich syst em, according t o t he Ro M. Thus, as an exa mpl e, wit h a high rat io of pol ymer t he yield and ult imat e t ensil e stresses (YS and UTS) as well as t he Young's modulus (E) can be r educed, in order t o r each pr opert ies comparabl e t o t hat of t he cort ical bone [START_REF] Tekiner | An exper imental st udy on t he examinat ion of spr ingback of sheet metal s wit h several t hicknesses and propert ies in bending dies[END_REF][START_REF] Marciniak | Mechanics of sheet metal for ming[END_REF] . Indeed, consider ing t hat the chosen Ti sheet and PMMA foil have a

Young's modulus equal to (108 ± 7) GPa and (2.0 ± 0.1) GPa , t wo combinat ions of t he Ti and PMMA t hicknesses r equir ed t o get a Ti/PMMA/Ti sandwich possessing a st iffness of about 32

GPa and an UTS of 162 MPa wer e suggest ed. Firstly, a symmetr ic structur e (Ti/PMMA/Ti *1 in Table 2), composed of t wo Ti sheet s 0.2 mm t hick and a PMMA foil 1.0 mm t hick (corresponding t o a PMMA vol ume fract ion equal t o 0.71). Secondly, by ma intaining t he sa me PMMA vol ume fract ion, an asymmetr ic Ti/PMMA/Ti combinat ion could be obtained using t wo Ti sheet s 0.2 and 0.4 mm t hick and a PMMA core of 1.5 (Ti/PMMA/Ti *2 in Table 2). Th is may result in a decr ease of t he bio -mechanical impa ir ment exist ing bet ween t he bone and t he impl ant .

Forming properties of Ti/PMMA/Ti sandwiches

The ca pabil it y of sha ping Ti/PMMA/Ti sandwiches was invest igat ed perfor ming bending, Er ichsen and deep-drawing t est s. For t his pur pose, bot h, symmetr ic and asymmetr ic Ti/PMMA/Ti structures wer e analysed.

Three-point bending test

The bending pr opert ies of t he TI/PMMA/Ti sandwiches wer e invest igated perfor ming t hr eepo int bending t est s using punch sizes of 3 mm and 6 mm in dia met er . As report ed in Figure 9a, wit h a 6 mm punch all the t est ed sa mpl es (dashed l ines) exhibit ed neit her cracking nor delaminat ion or int erlaminar shear ing at t he sampl e edges u p t o a bending angl e of 180°.

Besides, t he observed Ti/PMMA good adhesion, the duct il it y of t he PMMA cor e was enough t o accompl ish cracking-fr ee bending o perat ion in all t he sandwich structures (Figure 9b). The bending force-displacement curve for t he asymmetr ic sandwich (0.4/0.5/0.2, black, dashed l ine in Figure 9a) is l ocat ed bet ween t he t wo symmetr ic ones, i.e. 0.4/0.5/0.4 and 0.2/0.5/0.2. The punch was set in contact wit h t he t hinner Ti sheet , so t he t hicker (out er ) l ayer could wit hstand a higher bending l oad. As expect ed, t he bending t ests carr ied-out wit h t he small er punch (dia met er of 3 mm) on t he symmetr ic sandwich combinat ions (i.e. 0.2/0.5/0.2 and 0.4/0.5/0.4) r esult in an incr ease of t he bending forces for both combinat ions t est ed (l ight bl ue and r ed sol id l ines in Figure 9a, r espect ivel y).

Mor eover , t he sandwich combinat ion built -up using t he t hinner Ti sheet s (i.e. t he 0.2/0.5/0.2 sandwich), bent wit h 3t he 3 mm punch showed a significant decr ease of t he for ming l imit (sol id red l ine in Figure 9a). As depict ed in Figure 9a, cracking (highl ight ed in Figure 9c) t ook place at a punch displacement of a ppr ox.16 mm, corresponding t o a bending angle of a ppr ox. 80°.

The pr evious bending result s can be further expl a ined by analysing t he strain fiel d on t he surface of t he bent Ti sampl es. Figure 10 shows the average value of t he maximum ma jor strain det er mined from t he middl e part of t he bent sa mples shown in Figure 11. As ex pect ed, wit h t he small er punch size (3 mm, t he sol id l ines) higher strain values r esult ed l eading t o earl ier fa ilure by cracking at about 80° in case of t he t hinner Ti sheet (0.2 mm).

Addit ionally, t he strain l evel s, using t he 6 mm punch, ar e l ess, even at higher bending angl es, because of t he r educed l oad on t he out side of t he sheet . 13a and Figure 13b).

Wher eas, all t he Ti/PMMA/Ti sandwich combinat ions (0.4/0.5/0.4 (black), 0.4/0.5/0.2 (r ed), 0.4/0.5/0.2 (gr een) in Figure 13a) wer e compl et ely drawn wit hout visual cracking of t he Ti skin sheet s (see Figure 13c and Figure 13d in t he part icular case of a 0.2/0.5/0.2 Ti/PMMA/Ti structur e), due t o t he good for ming behaviour of the latter one (bl ue l ine in Figure 13a).

Neverthel ess, in correspondence of a 6 mm punch displacement , a small decay of t he force was observed, possibl y indicat ing cracking of t he polymer cor e. As no delaminat ion occurred, t he cracking of t he pol ymer cor e was ignor ed wit h respect t o t he overall drawing behaviour of t he whol e sandwich. The drawing pr opert ies of the invest igat ed sandwich combinat ion ar e summar ized in Table 3.

Erichsen tests

The cracking l imit of t he sandwich sheet (0.2/0.5/0.2, l ight bl ue curves in Figure 14a) is t he sa me as for t he Ti sheet (r ed curves in Figure 14a); however -as expected -t he force of t he sandwich is t wice t hat of t he pur e Ti sheet . Although t he PMMA foil s (black curves) show a higher Er ichsen index IE of 10 mm compar ed t o the sandwich sheet and the Ti one, t he fa i lure mechanism is t otally differ ent exhibit ing cl early a br ittle cracking mechanism (Figure 14b-d).

Thus, we can stat e t hat the defor mat ion behaviour of t he invest igat ed sandwiches is good and sufficient for a compl ex sha ping. The fa il ur e of t he PMMA foil is delayed by t he support ing effect of t he Ti sheet s. Mor eover , t he cracking of t he pol ymer can be avoided or delayed by pr ocessing under el evat ed t emperatur es or using a mor e duct il e PMMA derivat e.

Conclusions

Surface

FiguresFigure 1 :

 1 Figures

Figure 2 :

 2 Figure 2: SEM mic r o g r a ph s o f a : a ) a l k a l i-a c t iv a t e d s u r f a c e ; b ) C 7 H 14 O 5 PBr in it ia t o r mo d if ie d s u r f a c e a n d c ) C 15 H 30 O 5 PBr in it ia t o r mo d if ie d s u r f a c e . EDX s pe c t r a o f : d ) a l k a l i-a c t iv a t e d s u r f a c e ; e ) C 7 H 14 O 5 PBr in it ia t o r mo d if ie d s u r f a c e a n d f ) C 15 H 30 O 5 PBr in it ia t o r mo d if ie d s u r f a c e .

Figure 3 :

 3 Figure 3: SEM mic r o g r a ph o f t h e PMMA l a y e r g r o w n s t a r t in g f r o m a s h o r t -in it ia t o r (C 7 H 14 O 5 PBr ) mo d if ie d Ti s u r f a c e .

Figure 4 :

 4 Figure 4: Co n t o u r c h a r t s s h o w in g t h e mu t u a l e f f e c t o f t h e h o t -pr e s s in g t ime a n d t e mpe r a t u r e a t c o n s t a n t pr e s s u r e s o f 0.1 MPa (a ), 0.2 MPa (b ) a n d 0.4 MPa (c ) o n t h e Ti/PMMA/Ti pu l l -o f f s t r e n g t h .

Figure 5 :

 5 Figure 5: a ) s c h e ma t iz a t io n o f t h e pu l l -o f f t e s t s e t -u p. Th e e x t e r n a l pa r t o f t h e s a n d w ic h w a s f ix e d o n a s t e e l s u ppo r t r e q u ir e d t o in s e r t t h e s a mpl e in t h e u n iv e r s a l t e s t in g ma c h in e . b ) St r e s s -s t r a in c u r v e s o b t a in e d pe r f o r min g t h e pu l l -o f f t e s t s o f t h r e e Ti/PMMA/Ti s a n d w ic h e s pr o d u c e d w it h t h e id e n t if ie d o pt imu m c o n d it io n s . c ) Fr a c t u r e s u r f a c e s o f a r e pr e s e n t a t iv e Ti/PMMA/Ti s a n d w ic h a f t e r pu l l -o f f t e s t t o g e t h e r w it h t w o SEM mic r o g r a ph s r e c o r d e d o n b o t h t h e s id e s o f t h e f r a c t u r e s u r f a c e s . d ) EDX s pe c t r a a Ti/PMMMA/Ti s a n d w ic h s u r f a c e f r a c t u r e (b l a c k l in e c o r r e s po n d s t o po in t SF1 a n d t h e r e d

Figure 6 :Figure 7 :

 67 Figure 6: a ) Sc h e ma t iz a t io n o f t h e s a mpl e g e o me t r y u s e d t o pe r f o r m s h e a r t e s t s . b ) Sh e a r s t r e s s -d is pl a c e me n t f o r t h r e e s a n d w ic h s a mpl e s (Ti/PMMA/Ti: 0.4/0.5/0.4) pr o d u c e d u s in g t h e

Figure 8 :

 8 Figure 8: St r e s s -s t r a in c u r v e s o f Ti (b l a c k c u r v e s , u ppe r t h r e e o n e s ), PMMA (b l u e c u r v e, l o w e r o n e ) a s w e l l a s Ti/PMMA/Ti (r e d c u r v e s , me d iu m t h r e e o n e s ) s a mpl e s o b t a in e d pe r f o r min g t e n s il e t e s t s .

Figure 9 :

 9 Figure 9: a ) Be n d in g f o r c e -d is pl a c e me n t c u r v e s f o r d if f e r e n t t h ic k n e s s c o mb in a t io n s a n d pu n c h d ia me t e r s o f 3 mm a n d 6 mm. b ) Ti/PMMA/Ti s a n d w ic h e s b e n t u p t o 180° w it h a 6 mm pu n c h . c ) Ti/PMMA/Ti s a n d w ic h e s b e n t u p t o a b o u t 80° w it h a 3 mm pu n c h .

Figure 10 :

 10 Figure 10: Av e r a g e ma x imu m ma jo r s t r a in s o f t h e b e n t s a mpl e s in c o r r e l a t io n w it h t h e pu n c h s iz e , b e n d in g a n g l e a n d s k in /c o r e t h ic k n e s s c o n f ig u r a t io n s .

Figure 11 :

 11 Figure 11: Ph o t o g r a mme t r ic ima g e s o f t h e b e n t s a mpl e s a t 90°. *: in d ic a t in g t h e Ti s k in s h e et in c o n t a c t w it h t h e pu n c h d u r in g t h e b e n d in g t e s t .

Figure 12 :

 12 Figure 12: Spr in g b a c k r a t io o f t h e Ti/PMMA/Ti s a n d w ic h e s in c o r r e l a t io n w it h t h e s k in /c o r e t h ic k n e s s a n d t h e b e n d in g a n g l e s (45°, 90° a n d 135°). Pu n c h d ia me t e r s : 3 mm (s o l id l in e s ), 6 mm (d o t t e d l in e s ).

Figure 13 :

 13 Figure 13: a ) Dr a w in g f o r c e -pu n c h d is pl a c e me n t c u r v e s f o r t h e t e s t e d c o mb in a t io n s (ß 0 = 1,8), b ) Cr a c k in g o f t h e PMMA f o il 0.5 mm t h ic k , d r a w n u p t o a d is pl a c e me n t o f 6 mm. c ) 0.2/0.5/0.2 Ti/PMMA/Ti, d r a w n u p t o a d is pl a c e me n t o f 6 mm. d ) 0.2/0.5/0.2 Ti/PMMA/Ti c o mpl e t e l y d r a w n .

Figure 14 :

 14 Figure 14: a ) Dr a w in g f o r c e -pu n c h d is pl a c e me n t c u r v e s f o r t h e t e s t e d ma t e r ia l s a c c o r d in g t o Er ic h s e n t e s t a n d b ) t h e c r a c k e d s a mpl e s s h o w in g t h e c e n t r a l f a il u r e l o c a t io n (t w o s a mpl e s /e a c h c o n d it io n w e r e t e s t e d ).

2.1 Sample preparation

	PMMA foil s (0.5 mm t hick) containing Ba SO 4 f iller s and Grade 2 Ti sheet s of differ ent sizes (20
	× 20 × 0.4 mm 3 , 20 × 60 × 0.4 mm 3 , 20 × 80 × 0.4 mm 3 , 20 × 80 × 0.2 mm 3 , 25 × 100 × 0.4
	mm 3 , 70 × 70 × 0.4 mm 3 , 105 × 148 × 0.2 mm 3 ) wer e used. These sizes were chosen wit h r espect
	of t he minimal sized r equest ed by each mechanical t est perfor med (e.g., pull -off, bending,
	drawing). Befor e operat ion, PMMA foil s wer e r insed several t imes wit h et hanol and Ti sheet s
	cl eaned by ultrasonicat ion in acetone, et hanol , and deionized wat er , 10 min each. The solvent s
	wer e purchased from Carlo Er ba .

2.2 Grafting of PMMA chains on Ti substrates

	undecyl -1-phosphonic acid (C 15 H 30 O 5 PBr ) was immobil ized on t he Ti surfaces using a "graft ing
	from" met hod perfor med in a 0.05 M in it iator concentrated aqueous sol ution at 100°C for 3 h ;
	Th ir dly, a SI-ATRP was carr ied out t o grow the PMMA cha ins according t o a pr eviously
	descr ibed pr ocedur e 45 . The init iator -modified sa mpl es wer e suspended in a flask equipped wit h a
	magnet ic bar , which was t hen degassed t hr ee t imes (by alt ernat ing vacuum and argon) and
	finally fill ed wit h argon. Reagent s wer e t hen added t o t he flask according t o t he following order
	and concentrat ions: [Cu (I)Br ]: 14 mM; [PMDETA]: 12 mM; [anisol e]: 4.1 M; [mal ononitr i l e]:
	14 mM; [MMA]: 5.3 M. Wher eas, because of t he r equir ed gr eat er sol ut ion vol ume, A6-sized Ti
	sheet s wer e tr eat ed using t he following conditions: Cu (I)Br ]: 3 mM; [PMDETA]: 3 mM;
	[anisol e]: 3.7 M; [mal ononitr i l e]: 3 mM; [MMA]: 5.3 M. At t he end of t he pol ymer izat ion
	react ion, t he sa mpl es (her eaft er called PMMA-coat ed Ti) wer e cl eaned for 10 min in an
	ultrasonic bath containing met hanol t o r emove t he unt ether ed pol ymer as well as t he r esidues of
	Cu (I)Br and PMDETA.
	PMMA cha ins wer e graft ed onto Ti substrat es using a t hr ee st eps strategy pr eviously
	devel oped 45 . Wit h r espect t o t his met hodology, only t he graft ing condit ions wer e opt imized by
	considerably r educing t he tr eat ment t ime and t he init iator concentrat ion. Fir stly, Ti surfaces
	wer e act ivat ed by immer sing t he Ti sheet s for 1h in a 2M sodium hydroxide (Na OH)
	concentrat ed aqueous solut ion heat ed up t o 80°C 45 . Secondly, a synthesized br omoisobutyrate-

2.3 Chemical characterization of the grafted PMMA layers

	Wor kstat ion AURIGA-Zeiss 405 Micr oscope. The analysis of t he Ti/PMMA/Ti sandwich
	fractur e surfaces aft er pull -off t est s wer e st udied on a Zeiss GeminiSEM 500 SEM f itt ed wit h an
	EDX syst em from EDAX (Octane El it e SDD detect or + TEAM soft ware).
	2.
	Aft er each st ep of t he PMMA-coat ed Ti synt hesis pr ocedur e (na mel y, t he alkal i tr eat ment , t he
	graft ing of t he init iator and t he pol ymer izat ion) t he chemical pr opert ies of sa mpl es' surfaces
	wer e invest igat ed. In part icular , att enuat ed total r efl ect ion Four ier transfor med infrared
	spectroscopy (ATR-FTIR) analysis -perfor med wit h a Per kinEl mer spectromet er wit h a
	resolut ion of 4 c m -1 -was used t o scan t he surface-exposed chemical groups, wher eas, energy
	disper sive x -ray spectroscopy (EDX) allowed individuat ing surfaces' elemental composit ion.
	Th is latter analysis was carr ied out using a Quantax EDX syst em embedded in a crossBea m®

4 Morphological characterization of the grafted PMMA layers

	Scanning el ectron microscopy (SEM) was employed t o follow t he evolut ion of t he surface
	mor phology aft er each steps of t he synthesis pr ocedur e and t o invest igat e the r esult ing PMMA-
	coat ed Ti cr oss-sect ion. In part icular , t he mor phology aft er t he alkal i activat ion, t he graft ing of
	the init iator and t he SI-ATRP r eact ion was imaged wit h a crossBea m® Wor kstat ion AURIGA-
	Zeiss 405 Micr oscope. Inst ead, t he sa mpl e's cross-sect ion was fir stly pr epared using a ion bea m
	cross-pol isher (Hit achi IM4000+

10 Forming behaviour of Ti/PMMA/Ti sandwiches The

  The bending pr opert ies of t he Ti/PMMA/Ti sandwiches wer e invest igat ed per for ming t hr ee-point

	× 60 mm2 and 20 × 80 mm2) and t hicknesses (0.2 mm, 0.4 mm) wer e pr oduced under t he
	obtained o pt imum condit ions. The following symmetr ic and asymmetr ic Ti/PMMA/Ti
	configurat ions wer e pr oduced: (i) 0.2/0.5/0.2; (ii) 0.2/0.5/0.4; (iii) 0.4/0.5/0.4.
	2.10.1 Three-point bending tests

5 mm t hick, wer e pr oduced according t o t he o pt imum pr ocessing condit ions. A defined overla pping ar ea of about 275 mm 2 (25 × 11 mm 2 ) based on t he t hickness and t he yiel d strength of t he Ti sheet s was chosen following ASTM D3165.

2.9 Tensile properties of the Ti/PMMA/Ti sandwiches

The mechanical pr operties of t he Ti sheet s, PMMA foil s as well as t he ones of Ti/PMMA/Ti sandwiches made of t wo PMMA-coat ed Ti sheet s 0.2 mm t hick and a PMMA cor e 0.5 mm t hick (her e aft er not ed as 0.2/0.5/0.2 sandwiches) wer e det er mined by uniaxial t ensil e t est ing.

According t o ASTM E8, t ensil e sa mpl es of Ti and Ti/PMMA/Ti sandwich wer e pr epar ed. In part icular , Ti/PMMA/Ti sandwich sa mpl es were cut from an A6-sized sandwich pr eviously pr oduced using t he paramet er descr ibed in sect ion 2.4.1. Wher eas, PMMA foil s wer e pr epar ed and t est ed according t o EN ISO 527-3-1B-50.

2.

for ming behaviour of Ti/PMMA/Ti sandwiches wer e analysed per for ming t hr ee-point bending as well as deep drawing and Er ichsen t ests. These t est s allow ident ifying and correlat ing the possibl e fa il ur e modes ar ising from for ming such t hr ee-layer ed sandwich mat er ials under differ ent l oading condit ions. In pr incipl e, fa il ur e can be expect ed in t he for m of: 1) cracking of the out er Ti skin sheet , which is mor e pr obabl e for t hin ones; 2) cracking of t he cor e layer , especially if t he cor e has br ittle nature; or 3) int erlaminar delaminat ion in case of weak skin/cor e adhesion charact er ist ics. To t his pur pose, combinat ions of sandwiches wit h differ ent Ti size (20 bending t est s using punch sizes of 3 mm and 6 mm in dia met er . In part icular , t he 3 mm punch was used t o invest igat e the pr opert ies of t he 0.2/0.5/0.2 and 0.4/0.5/0.4 sandwiches, whil e t he 6 mm punch was taken for the asymmetr ic 0.2/0.5/0.4 ones. The t est speed was kept constant at 0.3 mm/s. The per for med t est strategy was t he following: Fir stly, t he maximum achievabl e bending angl e, defined as t he ones at which a visibl e fa il ure of t he syst ems (l ist ed above) occurred, was det er mined. Secondly, t o follow t he devel opment of t he bent sandwiches' strains as well as t he degr ee of t heir spr ingback, st epwise t est s wer e perfor med using a 45° st ep sequence. For t his, t he test was st opped at t he specified angl e under l oad, the strain distr ibut ion and t he spr ingback wer e evaluat ed and document ed, pr ior t o carrying on t he next st ep. It is not eworthy t o ment ion t hat the bending angl e was controll ed by t he pr eviousl y det er mined bending displacement according t o the controll ing equat ion of

DIN EN ISO 7438-2005.

  Deep-drawing t est s wer e per for med at room t emperatur e (RT) unt il fa il ure or compl et e cup drawing using a drawing rat io ß 0 = 1.8, i.e., t he ratio bet ween t he dia met er s of t he blank (60 mm) and punch (33 mm). During t he t est s, t he drawing speed was kept constant at 0.5 mm/s. As t he bending t est s, deep drawing t est s wer e performed st epwise based on the fa il ur e l imit of t he drawn sandwich sa mpl es. At 6.8 mm, no visual cracking of t he Ti skin sheet s occurred. In t his regard, t he deep drawing was carr ied out fir st unt i l a displacement of 5 mm, pr ogr essively followed up t o 10 mm displacement s. Finally, t he compl et e drawing of t he t est sa mpl es was accompl ished. Mor eover , for compar ison, t he drawing pr opert ies of Ti sheet s of 0.2 mm thickness and t hose of t he PMMA foil s wit h a t hickness of 0.5 mm wer e invest igat ed perfor ming the t est s according t o t he sa me pr ocedur e.

	2, 0.4/0.5/0.4 and t he
	asymmetr ic 0.2/0.5/0.4).

  was performed t o incr ease t he hydroxyl groups' cont ent enabl ing t he phosphonic acid t o anchor . Th is tr eat ment r epr esent s t he key el ement of t he pr ocedur e and l ed t o the for mat ion of a nanostructured por ous layer (see t he bottom t op-view microgra ph in Figure1b) the int erconnect ed porosity of which was used as scaffold t o dr ive t he following pol ymer izat ion and t o cr eat e a further mechanical int erlocking bet ween t he substrat e and t he growing PMMA layer . In t he second st ep, t he ATRP in it iator (2-bromo-2-met hyl -pr opionic acid 11-phosphonoundecyl est er , C 7 H 14 O 5 PBr ) was graft ed on t he alkal i-act ivat ed Ti surfaces (see Figure1bin t he middl e); t he anchor ing was establ ished by cr eating coval ent Ti-O-P bonds bet ween t he surface hydroxyl groups and t he phosphonic acid der ivat ive[START_REF] Reggent E | A novel alkal i-act ivat ion of t itanium substrates t o grow t hick and coval ently bound PMMA l ayer s[END_REF][START_REF] Guerrero | Anchor ing of Phosphonate and Phosphinat e Coupl ing Mol ecul es on Tit ania Part icl es[END_REF][START_REF] Ver Gnat | Enhancement of st yrene conver sion in organic/inorganic hybr id mat er ial s by using malononitr il e in controlled radical pol ymer izat ion[END_REF] . Co mpar ed t o our pr evious work[START_REF] Reggent E | A novel alkal i-act ivat ion of t itanium substrates t o grow t hick and coval ently bound PMMA l ayer s[END_REF] , we could r educe t he t ime of t he graft ing treat ment from 24h t o 3h . Indeed, by measur ing t he pH dur ing t he r eact ion, a plateau was r eached aft er 3h and no mor e var iat ions wer e det ect ed.

is shown in Figure 1a. In t he fir st st ep, a chemical act ivat ion of t he Ti surfaces in a basic media Mor eover , t he ATRP init iator concentrat ion was decr eased t o 0.05 M wit hout not icing significant differ ence in t he r esult ing surfaces pr eviousl y treat ed wit h a ~0.8 M init iator concentrat ion (for a mor phological and chemical compar ison bet ween a 3h and a 24h C 7 H 14 O 5 PBr -modified Ti surfaces see Figure S1 in t he suppl ementary infor mat ion (SI)).

Finally, in t he t hir d st ep, t he hybr id PMMA-coated Ti surfaces wer e obtained by growing t he PMMA cha ins from t he init iator -modified Ti surfaces. As highl ight ed by t he SEM micr ogra ph in Figure

1b

(t op) t he pol ymer izat ion r eact ion r esults in a r ounded PMMA l ayer cover ing t he ent ir e surface, charact er ized by an underneath porosity l ocal ized at t he Ti/PMMA int erface (Figure

Ti/PMMA/Ti resin-free sandwiches

  higher temperatur es (200°C), which is not r ecommended t o be used. Indeed, it should be consider ed t hat the pr ocessing t emperatur e should not over st ep or even come close t o

	the degradat ion t emperatur e of t he PMMA foil (~205 °C see Figure SI.2), especially in case of
	long hot -pr essing t imes. On t he ot her side, by incr easing t he pr essur e to 0.4 MPa , t he t ime
	requir ed t o r each t he maximum pull -off str ength is r educed, however , t he temperature should be
	Successivel y, a pr ocedure t o st ick a 0.5 mm t hick PMMA foil bet ween t wo synthesized
	st ill above 195 °C t o del iver high str engths (see Figure 4c). Mor eover , t he h igh pr essur e l ed t o a
	PMMA-coat ed Ti sheet s was devel oped by r eplacing t he epoxy-r esin, usually empl oyed in t he
	squeeze-out of t he PMMA cor e and/or t he possible onset of t he PMMA degradat ion, which can
	fabr icat ion of sandwich mat er ial s, wit h t he pr eviousl y grown t ether ed pol ymer cha ins. Thus,
	correlat ion bet ween hot -pr essing t ime and t emperature at a constant pr essure of 0.1 MPa (Figure
	4a), 0.2 MPa (Figure 4b) and 0.4 MPa (Figure 4c), r espect ivel y. In general , it can be stat ed t hat

resin -fr ee Ti/PMMA/Ti sandwiches wer e pr oduced by hot -pr essing. The best possibl e exper imental condit ions for t he Ti/PMMA/Ti sandwiches pr oduct ion wer e a ssessed perfor ming a parametr ic st udy using a design of exper iment s (Do E) met hod, adopt ing Min itab Inc. as t ool for the data analysis. In part icular , in or der t o r educe t he number of t he exper iment s t o be perfor med, an opt imal factor ial Do E pl an was a ppl ied by hypothesizing t hat t he simultaneous int eract ion of the t hr ee paramet er s involved in t he pr oduction (i.e. t emperatur e, t ime and pr essur e) is negl igibl e. In t his way, 19 ex per imental combinat ions (l ist ed in Table

1

) wer e sel ect ed and Ti/PMMA/Ti sandwiches wer e accordingly pr oduced.

Then, t he corresponding Ti/PMMA adhesion strength was evaluat ed perfor ming pull -off t est s using (20 × 20) mm 2 sandwich sa mpl es. The o pt imum condit ions for t he sandwich pr oduct ion wer e chosen as t he ones guarantying t he highest value of t he bonding strength according t o t he data r eport ed in Tabl e 1 and t he gra phical r epresentat ion in Figure

4

. Th is latter shows t he by incr easing t he hot -pr essing t ime and/or t he t emperatur e, t he pull -off str ength impr oves. When a pr essur e of 0.1 MPa is a ppl ied (see Figure

4a

), the maximum possibl e pull -off str ength can be reached only at lead t o undesir ed t hickness inhomogeneit ies. Wher eas, by a ppl ying a pr essur e of 0.2 MPa , t he maximum pull -off strength can be r eached at an average t emperatur e of 180 °C and a t ime mor e than 80 min (see Figure

  In part icular , t wo sa mpl es (Ti/PMMA/Ti 1 and Ti/PMMA/Ti 3 ) br oke wit hin t he gl ue used t o mount t he sa mpl e t o the st eel support (see Figure5a) indicat ing t hat the Ti/PMMA adhesion strength is higher t han that of t he Ti/st eel gl ue. Wher eas, in t he last sa mpl e (Ti/PMMA/Ti-2 ) fa ilur e occurred wit hin t he PMMA sheet (at 24 MPa ). The EDX el emental analysis and t he SEM micr ogra phs of t he PMMA foil (Figure5e) -used as cor e mat er ial -showed t hat it contains Ba SO 4 f ill er s (whit e spot s in Figure5e). Since traces of Ba SO 4 part icl es wer e found al so in t he Ti/PMMA/Ti surface fracture (SF) (see Figure5cand EDX spectra in Figure5d), we concluded t hat t he fracture occurred wit hin the PMMA cor e and consequently t he fa il ur e mechanism is of cohesive natur e. Addit ionally, t he shear r esistances of the sandwiches wer e evaluat ed perfor ming singl e shear t est s on Ti/PMMA/Ti sa mpl es as schemat ized in Figure6a. Two metal sheet s (schemat ized in black in Figure6a) wer e insert ed bet ween t he sa mpl e and the jaws of t he t ensil e machine in order t o ensur e t he axial it y and avoid bending phenomena dur ing t he t est s.In order t o invest igat e bot h t he mechanical pr opert ies and t he forming behaviour ofTi/PMMA/Ti sandwiches, A6-sized Ti sheet s (105 × 148) mm 2 × 0.2 mm t hick, wer e coat ed wit h graft ed PMMA cha ins by empl oying a larger vol ume of sol ut ion (~ 1000 ml ) contained in a bigger r eactor . Despit e a t hicker PMMA l ayer was obtained in t he part of t he Ti sheet closer to the magnet ic st irrer (due t o an unst eady mixing of t he r eagent s), t he ent ir e surface was compl et ely cover ed (see FigureS3in SI). Then, A6-sized Ti/PMMA/Ti sandwiches wer e pr oduced by hot -pr essing (see Figure7a), as pr eviousl y expla ined, using a 0.5 mm t hick PMMA foil as cor e mat er ial . The r esult ing sandwich cross-sect ion, obtained by cutt ing a A6-sized sandwich, was analysed by o pt ical microscopy and t he corresponding image is displayed in e t ensil e strength (UTS) of 441 MPa as well as a strain at fa il ur e of 27% (see Table2), whil e t he PMMA foil shows a br ittle behaviour (bl ue curves). St iffness and UTSs values of t he sa mpl es ar e l ist ed in Table2.

	Figure 7b.
	Ti/PMMA adhesion str ength is t otally due t o (t he onl y) mechanical int erlocking of t he PMMA
	int o t he irr egular i t ies of the Ti surfaces since no chemical treat ment was perfor med on t he metal
	sheet s and al so due t o t he inertness behaviour of t he PMMA, which possesses a l ow
	adhesiveness nature.
	Mor eover , t he Ti/PMMA/Ti fa il ur e mechanism was ident ified by analysing t he mor phology

) on t hr ee Ti/PMMA/Ti sandwiches pr oduced using t he o pt imized condit ions l ed t o t he r esults shown in Figure

5b

. and t he chemical composit ion of t he sandwich fracture surfaces aft er t he pull -off t est s (a repr esentat ive image of which is shown in Figure

5c

), by using SEM-EDX measur ement s. The r esult s of t hr ee r epr esentat ive Ti/PMMA/Ti sandwiches ar e shown in Figure

6b

. It can be po int ed out t hat fa il ur e occurred wit hin t he PMMA foil (see t he surface fractur e in Figure

6c

) for ult imat e shear str ength of (10 ± 2) MPa . For compar ison, t he shear r esistance of t hr ee sandwiches composed of t wo br ushed Ti sheet skins (0.4 mm t hick) and a PMMA foil wit h a thickness of 0.5 mm were al so invest igat ed. The average Ti surface r oughness aft er t he br ushing treat ment was found equal t o (2.7 ± 0.3) µm, al most five t imes higher t han t hose of t he untreat ed ones (0.5 ± 0.1) µm. The r esult s allowed evaluat ing a Ti/PMMA bonding strength of (0.9 ± 0.1) MPa , which is much l ower t han t hose obtained using t he PMMA-coat ed Ti sa mpl es. The weak 3.4 A6-sized Ti/PMMA/Ti sandwiches: scale-up of the fabrication process

3.5 Mechanical properties of Ti/PMMA/Ti sandwiches

In or der t o st udy t he mechanical pr opert ies of t his syst em as well as t he ones of Ti sheet s and PMMA foil s mono-mater ial s, mini-t ensil e sa mples of Ti and Ti/PMMA/Ti sandwiches wer e pr epar ed, according t o ASTM E8. PMMA sa mpl es wer e pr epar ed and test ed according t o EN ISO 527-3-1B-50. The results of t he t ensil e t ests ar e given in Figure

8

. As ex pect ed, t he Ti sheet s (black curves) exhibit t he highest str ength values wit h a Young's modulus of 108 GPa and an ult imat

  The spr ingback rat ios (K) of t he Ti/PMMA/Ti sandwiches in correlat ion wit h t he skin/cor e t hickness and t he bending angl es (45°, 90° and 135°) using t he 3 mm and 6 mm punch diamet er s ar e shown in Figure12.Mor eover , for analysing t he possibil it ies of sha ping mor e compl ex component s, deep drawing and Er ichsen t est s wer e perfor med. Due t o t he br ittle behaviour of t he PMMA (see Figure8), t he pur e PMMA foil fa il ed earl ier at a punch displacement of only ~6 mm (see viol et l ine in Figure

	3.6.2 Deep drawing
	Due t o t he high elast ic / l ow plast ic strain fract ion exist ing at t his angl e for t he fir st bending
	st ep (45°) l ower K-values -h igher spr ingback angl es -for all t he sandwich r esult s wer e
	observed. For t he sa me sandwich sheet s wit h t he larger bending punch diamet er , l ower K-values
	result ed, t oo, which is in accordance wit h t he fundamentals of spr ingback propert ies (as shown in
	(1)) Further mor e, t he asymmetr ic sandwich (0.4/0.5/0.2*) shows an int er mediat e K-value
	pr ogr ess wit h t he bending angl e, l ocat ed bet ween the t wo symmetr ic ones, i.e. t he 0.2/0.5/0.2 and
	0.4/0.5/0.4. It can be stated, t hat bending of t he sandwich sheet s is in good agr eement t o t he
	guidel ines r ecommended for monol it hic sheet metals, wher e t he radius of the bending punch (r )
	is suggest ed t o be t wice t he sheet t hickness (t ), i.e. ! ≥ 2$. Safe bending pr ocess can be achieved
	wit h a rat io of t he punch radius R t o t he mat er ial s t hickness of 3 (R/t >3). For high strength
	mat er ial s, R > 5t may be requir ed 51 .

  -confined PMMA cha ins wer e successfully gr own on large Ti substrat es (u p t o DIN A6 size) t hrough SI-ATRP coupl ed wit h a "graft ing from" met hod using phosphonic acids as coupl ing agent s t o ensure t he metal -pol ymer coval ent bonding. They wer e used as adhesive layer s for t he fabr icat ion of biocompat ibl e r esin-fr ee sandwich mat er ials pr oduced by hotpr essing. In part icular , t et her ed PMMA cha ins wer e used t o r eplace t he epoxy r esin -usually empl oyed in sandwich mat er ial s t o st ick t he pol ymer cor e onto t he metal skin sheet s -and ensure the bonding t hrough t he for mat ion of entangl ement s caused by t he inter penetrat ion of t he 180°, 90 min and 0.2 MPa ), a high bonding strength (pull -off strength higher t han 20 MPa and a shear r esistance of 10 MPa ) and good for ming pr opert ies could be achieved. The mechanical pr opert ies det er mined by t ensil e t esting showed t hat t he fa ilur e of t he sandwiches ma inl y depends on t he fail ur e strain of t he Ti skin sheet s; wher eas, t he br ittle fa il ur e nature of t he PMMA d id not r emarkabl y influence t he fa il ur e strain of t he sandwich. Addit ionally, t he r ul e of mixt ur e was ver ified wit h t he obtained st iffness-and str ength-r elat ed pr opert ies (E, YS, UTS and ER10). Appl ying t his r ule, t wo sandwich combinat ions (symmetr ic and asymmetr ic) possessing mechanical pr opert ies -especially Young's modulus -cl ose t o t hat of the cort ical bone wer e pr oposed. Thr ee-point bending and deep-drawing t est s wer e perfor med to analyse t he for ming behaviour . In part icular , despit e t he l ow duct il it y of t he PMMA cor e, delaminat ion-fr ee bending operat ion up t o 180° were achieved wit hout cracking of t he Ti/PMMA/Ti sandwiches made of thicker Ti skin sheet s (0.4 mm) for bot h bending punches (3 mm and 6 mm in dia met er ).However , for t he small er bending punch t he bending angl e was l imit ed t o 80° if t hinner Ti skin sheet s (0.2 mm) wer e used. Further mor e, Ti/PMMA/Ti could be compl etel y deep-drawn wit hout visual cracking of t he Ti skin sheet s, t hanks t o the good for ming behaviour of t he metal . The sa me behaviour could be stat ed for t he Er ichsen t est , wher e t he br ittle natur e of PMMA has no

tether ed PMMA cha ins into t hose of t he PMMA cor e. Ti/PMMA/Ti sandwiches wer e pr ocessed demonstrat ing t hat , for the sandwich pr oduct ion, t et her ed pol ymer cha ins can r eplace epoxyresin. In t his way, t he o pt imum Ti/PMMA/Ti sandwiches hot -pr essing paramet er s (t emperatur e, t ime and pr essur e), del iver ing t he highest Ti/PMMA adhesion, wer e developed using an opt imal factor ial exper imental pl an defined by t he design of exper iment s met hod. Wit h t he o pt imum condit ions (negat ive influence on t he for ming l imit s or even on t he Ti/PMMA int erface qual it y, indeed no delaminat ion t ook place.

Table 2 :

 2 Te n s il e pr o pe r t ie s o f t h e mo n o -ma t e r ia l s (Ti, PMMA) a n d t h e s a n d w ic h e s (Ti/PMMA/Ti) a s w e l l a s t h e o r e t ic a l v a l u e s (Ti/PMMA/Ti* 1 , Ti/PMMA/Ti* 2 ) pr o po s e d u s in g t h e Ro M pr o v id in g me c h a n ic a l pr o pe r t ie s c l o s e t o t h e c o r t ic a l b o n e ( = 15 -30*+,)[START_REF] Rho | Young's modulus of trabecular and cort ical bone mat er ial : ultrasonic and microt ensil e measurement s[END_REF][START_REF] Zysset | El ast ic modulus and hardness of cort ical and trabecular bone lamellae measur ed by nanoindentat ion in t he human femur[END_REF] .Wh e r e , f PMMA : v o l u me f r a c t io n , YS a n d UTS: y ie l d s t r e n g t h a n d u l t ima t e t e n s il e s t r e n g t h , E: Yo u n g 's mo d u l u s a n d ER: e l o n g a t io n t o r u pt u r e .

	Sample	Thickness [mm]	[-]	E [GPa] Experim. RoM Experim. RoM Experim. RoM UTS [MPa] YS [MPa]	ER[%]
	Ti	0.2	0	108 ± 7		441 ± 14	-	289 ± 15	-	27 ± 1
	PMMA	0.5	1.0 2.0 ± 0.1		51 ± 1	-	-	-	6 ± 1
	Ti/PMMA/Ti	0.9 (0.2/0.5/0.2)	0.55	51 ± 3	55 245 ± 10 246 179 ± 14 170 27 ± 3
	Ti/PMMA/Ti* 1	1.4 (0.2/1.0/0.2)	0.71	-	32	-	162	-	119	27**
	Ti/PMMA/Ti* 2	2.1 (0.4/1.5/0.2)	0.71	-	32	-	162	-	119	27**

*: calculated sandwich combination; **: expected, based on the strain at failure of the Ti sheet

Table 3 :

 3 De e p-d r a w in g pa r a me t e r s u s e d f o r t h e mo n o ma t e r ia l s (Ti a n d PMMA) a s w e l l a s t h e Ti/PMMA/Ti s a n d w ic h in a d d it io n t o t h e o b t a in e d r e s u l t s . Dr a w in g r a t io , ß 0 = 1.8. Refers to the outer skin sheet (not in contact with the punch under deep drawing)

	Sample	Thickness	Blank holding	Max. drawing	Drawing depth
	notation	[mm]	force [kN]	force [kN]	[mm]
	Ti	0.2	10	17±2	Drawn cup
	PMMA	0.5	8	5±1	~6 mm cracking
	Ti/PMMA/Ti 0.4/0.5/0.4 Ti/PMMA/Ti 0.4*/0.5/0.2 Ti/PMMA/Ti 0.2/0.5/0.2	8 8 7	45±1 35±1 30±1	Drawn cup: • No cracking of the skin sheets • Cracking of the
					PMMA core
	*

o pt imu m c o n d it io n s (T = 180°C, t = 90 min , p = 0.2 MPa ). c ) Re pr e s e n t a t iv e f r a c t u r e s u r f a c e s a f t e r s h e a r t e s t s .

Acknowledgements

We grat efully acknowl edge t he financial support pr ovided by t he Ger man Research Foundat ion: DFG, grant no. PA 837/44-1, by IDEX Un iver sit é of Strasbourg as well as Fr iedr ich Gustav Theis Kaltwal zwerke GmbH for suppl ying us with t he Ti sheet s.

Supplementary Information

The following addit ional analyses ar e incl uded: (i) charact er izat ion of t he graft ed-Ti surfaces aft er 3h and 24h ; (ii) Charact er izat ion of t he PMMA melt ing and glass transit ion t emperatures;

(iii) Mor phological charact er izat ion of A6-sized PMMA-coat ed Ti sa mpl es.

AUTHOR INFORMATION

Corresponding Author * melania . r eggent e@epfl.ch * heinz.pal kowski@t u-clausthal .de Tables Table 1: Ex pe r ime n t a l pa r a me t e r s u s e d f o r t h e Ti/PMMA/Ti s a n d w ic h pr o d u c t io n -a c c o r d in g t o t h e Do E pl a n -a n d t h e ir c o r r e s po n d in g a d h e s io n s t r e n g t h e v a l u a t e d in pu l l -o f f t e s t s .