Martial Grislin
email: grislin@univ-valenciennes.fr

Christophe Kolski

Jean-Claude Angue Lamih

HUMAN-COMPUTER INTERFACE EVALUATION IN INDUSTRIAL COMPLEX SYSTEMS: A REVIEW OF USABLE TECHNIQUES

Keywords: Human-Machine Interface, Evaluation, Industrial complex systems

In industrial complex systems, a human-computer interface can be composed with hundreds of graphic screens and thousand variables. Human tasks are complex; HCI evaluation in this application field is difficult. During many interface developments, evaluation is often neglected by lack of knowledge about the existing techniques. Several techniques exist and may be used. The paper is focused on expert-based and analytical evaluation techniques usable in this field.

INTRODUCTION

Contemporary literature mentions many techniques and tools for the evaluation phase -a crucial problem for the development team. Indeed many humancomputer interface evaluation techniques are available today, and it is difficult to choose those really suitable to a particular situation. Moreover, their use is a long and difficult task requiring expertise and patience. In this context, our objective consists in studying and organizing the techniques that can be used for supervisory control systems with several human, ecological, economical and/or technical constraints. We are interested in graphical human-machine interface used in a control room to resolve complex problems in a dynamic situation. In the first part, this paper describes briefly the evaluation principle and properties, and the usability target data to be collected. In the second part, on the basis of a review of evaluation techniques, a set of usable humanmachine interface evaluation techniques in industrial complex systems are identified and commented. This paper is focused on expert-based and analytical approaches.

EVALUATION PRINCIPLE

Usability evaluation aims at assessing the operator's ability to carry out his task. [START_REF] Senach | Évaluation ergonomique des interfaces homme-machine : une revue de la littérature[END_REF] explains that every evaluation consists in comparing an observed model of the system to be evaluated with a 'reference model' (fig. 1). In interactive software evaluation, the reference model can be based on usability standards or guidelines. During the development of HCI for the supervisory systems this evaluation based on a comparison is not easy. The two models (the observed one and the reference) provide a global model of the human-machine interaction. The observed model comes from design methods or from empirical evaluation. The reference model comes from task analysis methods, i.e., human oriented design. This evaluation principle helps the development team and enables to take into account the usability guidelines during the cycle. The realization and the validation of used models are the main difficulty in providing good evaluation. These descriptions are formal models of the dialogue between the human supervisor and the machine. Another important difficulty concerns the availability model: formalizing the man-machine interaction is not easy and there is often a gap between theory and reality. The problem is to know whether one can trust an evaluation based on a representation that may not reflect reality. The choice of a HMI model for evaluation is determined by the context. Thus the selection of adequate properties to evaluate quality depends not only on the evaluation objectives but also on the operators' characteristics and on the task requirements. The range of functions and the user-friendliness of an interface are significant properties, defined in the terms utility and usability. Utility determines whether the interface enables the user to achieve his goals, in terms of functional abilities, performance and aid quality. Usability describes the quality of the interaction between human and machine (ease of learning and use) and reflects the consistency of the design. An analysis of the interface and the interaction brings to light a set of target variables, i.e., basic data to be collected. There are two families of principal variables: a social and a practical acceptability (fig. 2). This second class includes current production, cost, reliability constraints, and usefulness of interface. Utility and more particularly usability is located in this criterion. Contemporary literature offers numerous usability and ergonomic recommendations: guidelines or standards. They can be used during evaluation as usability criteria to observe or measure. Relying on several works, [START_REF] Bastien | Ergonomic criteria for the evaluation of Human-computer Interfaces[END_REF] discussed a set of criteria and sub-criteria that take into account such recommendations (table 1). The whole criteria help the evaluation team to estimate the interface usability quality and to make the necessary decision concerning modification and/or improvement.

REVIEW OF USABLE EVALUATION TECHNIQUES

HCI evaluation depends on the characteristics of the situation to be evaluated. Workload concerns all interface elements that play a role in the reduction of the users' perceptual or cognitive load, and in the increase of the dialogue efficiency. This criterion includes two first areas. Concision (C6): individual items (data, commands, etc.) use the shortest possible items to be entered by the user (short items); and Minimal actions (C7): set of items (procedures) for which it is suggested to allow only the shortest, most necessary action. The third area is the Mental load (C8) or information density. It concerns the users' workload from a perceptual and cognitive point of view regarding the whole set of information presented. Explicit control C9 C10 Control in user entries favors focusing on the user's actions and therefore limits ambiguities and errors. Two sub criteria are defined. Explicit actions (C9): unambiguous user specification of an action or set of action; and User control (C10): allow processing of only what the user is asking for.

Adaptability C11 C12

The adaptability of the system refers to its capability to behave contextual and according to the users' needs and preferences: provide various ways for the user to interact. One general aim is Flexibility (C11): the capability of the interface to adapt to various user actions. One more specific aim is flexibility applied to users' experience, that is, Users' experience management (C12).

Error management C13 C14 C15

The aim is to avoid errors as much as possible. When errors occur, identify the error(s), its location, and means to correct the error(s). Error protection (C13): means available to detect and prevent data entry errors, command errors, or actions with destructive consequences. Quality of error messages (C14): phrasing and content of error message, their relevance, readability, and specificity about the nature of the errors (syntax, format) and the actions needed to correct them. Error correction (C15): means available to the users to correct their errors.

Consistency (C16)

Consistency refers to the way interface design choice (codes, naming, formats, procedures, etc.) are maintained in similar contexts, and are different when applied to different contexts. It concerns location (similar window location, message area location), format (similar screen formats), syntax, procedures (similar order in command language syntax, and procedures for menu selection), naming (similar naming of commands or menu option, abbreviations, and labels).

Signifiance of codes (C17)

It concerns the association between an individual term and/or sign (label, command, etc.) with its reference. Codes and names are significant to the users when there is a strong semantic relationship between such codes and the items or actions they refer to. Not the coding related to the distinction or grouping of several items belonging to the same class.

Compatibility (C18)

Compatibility refers to the match between users' characteristics (memory, perception, customs, skills, age, expectations, etc.) and task characteristic at the one hand, and the organization of the output, input, and dialogue for given application, on the other hand. It's also concerns the coherence between environments and between applications. [START_REF] Maguire | System Monitoring: Garbage Generator or Basic for comprehensive Evaluation system? The fifth conf[END_REF][START_REF] Senach | Évaluation ergonomique des interfaces homme-machine : une revue de la littérature[END_REF][START_REF] Whitefield | A framwork for human factors evaluation[END_REF][START_REF] Balbo | Un pas vers l'évaluation automatique des interfaces homme-machine[END_REF], with an update. We take into account only those usable for complex systems. We used those techniques currently in real and/or simulated industrial situation (chemical process, nuclear, automobile and rail transport, sub-marine…). This paper is focused on our last research in evaluation: an expert-based and an analytical approach. The next sub-section gives a short discussion about the techniques of other approaches (for more details, see [START_REF] Kolski | Ingénierie des interfaces hommemachine, conception et évaluation[END_REF].

Empirical and observing approaches

Empirical approaches consist in measuring representative users' performance with experimental methods and tools. The information from Use diagnosis technique facilitates design and improvement decision making. But, they do not take into account the temporal evolution of the system and the identification of the failure sequence is difficult for complex interactive systems. The Workload evaluation is based on the user's cognitive work observation. This qualitative or quantitative measuring of the user's activity contributes to the usability evaluation in line of the interactive system. Several methods and techniques are proposed [START_REF] Wierwille | Recommendation for mental workload measurement in a test and evaluation environment[END_REF]. The analysis of those methods leads to the conclusion that workload evaluation may be based on the use of several indicators: (i) a description of the user's work gives information about their different strategies, (ii) a subjective scale give a reference evaluation of the mental workload, and (iii) a physiological indicator informs of the user's capability and his vigilance level. Several recent works, in the LAMIH, devote an important development in a temporal model based method [START_REF] Berger | Real time assessment of human operator workload placed in a simulated multitask context of a monitoring and supervising process. ESA workshop[END_REF]Riera and Grislin 1995), and an eye scanning movement measure [START_REF] Simon | Is quantitative of eyse scanning movement relevant of eye scanning movements[END_REF]). The Design test methods realize an evaluation with an iterative cycle during the whole design process. At every development step, the interface is tested which generate modification, then tested in a new version, and so on until it is satisfactory. This evaluation engineering is very interesting for process control. It permits to take automatically into account the criteria and constraint related to the process control (production, economy…). But, those methods imply the use of a powerful and realist simulator, that is very expensive. Observing approaches group methods only based on the observation of specific aspects concerning the HCI. It consists in collecting representative data of the interaction, and to analyze those user activity traces. The collected data describe the event occurring during the user's activity: failures, orders modifications, stopping, takeoff, errors and correction actions, etc. In the supervisory of an industrial complex system with graphical aids tools, the operator uses mainly his visual sense. In this case, analysis of eye scanning movement is logically integrated in an evaluation process. This technique is usable in parallel of other analysis tools. Eye movement record is used in the LAMIH for the task analysis in the interface specification and/or improvement (Abed,90).

Expert-based approaches

More often, the HCI evaluation requires an expert analysis. Expert-based approaches consist in comparing the interface with a human-computer interaction informal model (table 2). The Analyst's experience consists for the analyst in replacing the operator in his job. This technique let us see the difficulties met by the user. It is recommended for a simple task (office automation), but can rarely used when the task is complex. In a control room, this method raises a huge problem: it is not possible for the evaluator to use the supervisory system in line. The type of evaluation more currently used is the Human expertise. It is efficient and simple to organize for a rapid diagnosis of design errors. Every criterion is concerned as human-factor experts have to be able to use them. But this type of method is based on an individual reference model acquired with experience. Every specialist is focused on specific characteristic of the interface and bases his evaluation on his personal model. To get a more exhaustive approach of the HCI problems and to avoid a focusing error, it is necessary to take several different specialists, and therefore it implies an important cost. the Evaluation grid is very interesting for the measurement of the interface usability. This technique has to take into account every characteristic of the interface (an exhaustive list of criteria). It obtains an excellent result for a comparative evaluation of interfaces and prototypes. A, evaluation grid is usable by designers, human factor specialists, and sometimes by the final users. But they are difficult to understand for non-expert of human factors: recommendations are subjective and/or can be interpreted differently, and the notation is difficult to analyze. The grid is more adapted for a human-factor expert because they have already a mental model of the user's work. evaluation with a model of the interface or of the human-computer interaction. So, it is necessary to identify the pertinent variable, according to the evaluation objective and the task requirement (utility and usability). Then, the collected data analysis require measurement scale to be used during the comparison (a, exploitable and objective notation).

Analytical approaches

Analytical approaches consist in realizing the

Results may be integrated into a global appreciation of HCI. Those approaches use formal models and objective metrics. The models are used to predict some aspects of the interaction: task hierarchy, developing of the user action, time… The metrics allow to measure with objectivity some quality aspect of the interaction: consistency, compatibility with the mental scheme of the user, display quality… Those abstract representations allow to predict the performance of the system, which cannot be obtained with empirical approaches.

Predictive Task model. The task models consist in a hierarchical decomposition of task in order to formalize the cognitive activity of the user. In this type of model, the task is decomposed through a refining process starting from global task or from elementary task (descending and ascending analysis). The analysis provides a formal support for the predictive evaluation of the performance (a measurable description of the user's behavior). HTA is a hierarchical model of the user's task. Every task corresponding to a planning, a sequence (or a procedure), can be described for example with a petri net and execution conditions. GOMS predicts the length of the task realization, and describes the choice of methods. With its formal approach, GOMS has opened some interesting perspectives and has lead to defining of other models (e.g., KLM). The first version of that model was validated for very simple tasks (office automation). But this model is limited because it takes into account neither the user's errors, nor the resolution of the problem. This limitation does not allow its direct using for the prediction of the user's efficiency when he realizes a complex task. But we can note that a recent validation of highly interactive behaviors has been realized with an extended model tell CPM-GOMS based on a critical path method (Gray et al. 1993). The INRIA laboratory has developed the MAD method to facilitate the user's task description. The obtained task model shows the difference between functional logic and using logic. The user's characteristic is taken into account rather than the application functioning logic and than the computer constraint. This approach is very interesting, but there are some limitations. The interruption of the activity is not visible in the description The human errors and/or procedures are not taken into account in the description. Note that this formalism may be improved in the new version of MAD. Therefore some research in the LAMIH has developed a method based on SADT and Petri networks. In this method, SADT formalism realizes the functioning decomposition with a top down and a hierarchical point of view. Every module was structured according to the SADT diagram decomposition. In the end of these functioning decomposition phases, the decision behavior is described using synchronized petri network. The obtained model is next used during the usability evaluation for the user's activity analysis. This method has recently evolved with TOOD: Task Object Oriented Description [START_REF] Mahfoudhi | A new methodology for Man-Machine Systems analysis and design Design[END_REF].

Linguistic model: The linguistic model can describe the interactive task between the user and his interface, in order to evaluate the command language and its consistency. Those models explain the humanmachine interaction structure with a grammar. For instance, ALG proposes to describe the interface procedures used with production rules. But with the hierarchical description only, this grammar neither shows the relationship between the display, nor the dynamic of dialogue. CLG is a design oriented approach, usable also for the evaluation. The task description is transformed into a set of models realized on six levels: task and semantic for goals and sub-goals, syntax and interaction for the communication between the user and the system, presentation and input-output unit for physical component. This formalism allows to locate where the evaluation decision was critical for the user. For example: the interface efficiency is measured with an [START_REF] Payne | Task-action grammars: A model of the mental representation of task languages[END_REF][START_REF] Tauber | ETAG: Extended Task Action Grammar-A language for the description of the user's task language[END_REF] C1 C7 C8 C11 C12 estimation of the action speed or the apprenticeship duration. TAG model describes the mental representation of the interaction language. The task is broken up into simple routine sub-tasks (or action) which the user can execute without decision making. But TAG is limited to simple tasks, i.e., the description of specific system function. There is no relationship between the different simple tasks into the upper levels.

Conclusion. This hierarchical description of the task in elementary sub-tasks shows the abilities and the information necessary to the user. Tasks are structurally split up to describe the parallelism and the sequential ordering of the procedure. Today, this type of model is in evolution and can be used for design test in the place of empirical studies with prototype. But they limit the evaluation because they predict only the user's performance corresponding to the defined or analyzed model. For a simple task, the linguistic models give a good result. But after our first tests for interface evaluation in a complex industrial system control, those models don't give any more information than task model. The hierarchical aspect of the interaction is to be keep. The description of the human-machine dialogue as a software language (interesting for automation) help to detect some problem: consistency, interaction difficulty, compatibility of the apprenticeship. But some research might be developed to make them valid.

Quality formal model:

The quality formal models concern the measurement properties of the interface in a more practical view than the above model. They are currently based on a usability and ergonomic knowledge base. Table 4 lists some of them, nonexhaustively. The display evaluation of interactive system is based on the principle that some problems occurring during the use can be avoided a priori. The first type of automatic evaluation systems can analyze static information presentation. The Display analysis program measures the quality of alphanumeric language exclusively. The prototypes SYNOP and KRI/AG evaluate, respectively, the industrial mimic displays and the dialogue interfaces in a graphical environment. SYNOP modifies directly the screen, and KRI/AG provides a usability recommendation written like comments in textual reports. These two tools are limited: display assessment one to one without global view, non-fulfilment of the knowledge base. KRI/AG system, more recent, interprets the standard UIL format (User Interface Language). This characteristic is very interesting for an automatic evaluation, and can be integrated in a future evaluation tool. This first type of approach shows the possibility to automate the many design guidelines currently proposed in a daunting presentation (manual and guide on paper). Other automatic evaluation system based on knowledge base are able to generate the interface or specification. From a description of the system, that method aims at obtaining a display respecting basic recommendation. APT is too limited for industrial interface design because it can only represent and test static numeric data. The Perlman program can describe the display structure in different abstraction levels. The aspect link to the presentation are formalizes as a network, with relationship between the display structural properties and presentation rules. This type of approach is too limited as a design help of the aspect based on the presentation, without analyzing the use, nor the dynamic. Today, the automatic interface generator might concern the dynamic evaluation of the HCI. Ergo-conceptor, developed on the LAMIH, is based on the description of the application (i.e., an industrial system to be supervised). This tool assists the designer with some proposition of representation mode, supposedly adapted to the control task. The designer can choose directly that prescription and generates interactively the different mimic displays. This type of evaluation systems are interesting because they can automate several designs and realization steps. But there are also some problem: non-fulfilment of the knowledge base, difficulty to realize a good description of the application.

Conclusion:

Nowadays some researches are still carried out about some of the models which can not directly be used for an evaluation in an industrial situation. Their using demands an important and long formalism work and very little information was given about the method to realize the test during design. An other important point is that an evaluation tool of HCI can not be limited to an evaluation of exclusively every usability aspect. It might estimated the advantages and weaknesses. The analysis might concerns the input and output command language, and the screen organization. The different works presented in this section suggest that it is difficult to develop a tool able to evaluate every interface. A really satisfactory tool must be constituted on an evaluation environment.

CONCLUSION

Many HCI evaluation methods and techniques exist. Therefore some of them are usable for human-machine interface used in simple task (e.g., office automation). For several years, we have been testing some of those methods in industrial situations. The empirical, observing and expert-based approaches give relatively good results (of course some adjusting is still needed).

The realization of a controlled experiment and the recording, and then the data analyses take a very long time. It is currently non-compatible with the time requirement and delay of the system development.

And moreover, the final users are rarely available or accessible, and the designers are not already convinced of the utility of those early-tests. In fact, the evaluation is considered more as a corrective function than as a generative information source for a design solution. Concerning the analytical approaches, someone of them raise a problem because of the dynamic of the situations to be evaluated. These are the aim of our present research in complex situations.

  Fig. 1. Evaluation principle

Fig. 4 .

 4 Fig. 4. Task description as a goal sub-goal hierarchic

Prompting (C1): provide guidance about what the user can do. Grouping of items by localization (C2): relationships

  When the interface to be evaluated exists, user behavior data analysis methods are recommended. Data are collected with observations or measures on real site or on laboratory.

	Table 1 Evaluation usability criteria, basic criteria in
	bold and numbered (Bastien and Scapin 1993)
	Criteria	Principle and objective
	Guidance	Guidance facilitates discovery and usage by helping the user to
	C1 C2 C3 C4 C5	identify further states and actions possible. between displayed
		information (organizing items into hierarchic lists, distinct areas,
		etc.),
		Those methods consist in realizing usability tests with
		real users or selected subjects for experiment. This
		evaluation type is realized a posteriori on an already
		used interface or a prototype. It provide opinion about
		their use. In this first case, several methods and
		techniques exist. They can be classified into three
		approaches (fig. 3): (1) empirical approaches, (2)
		observing approaches, (3) expert-based approaches.
		When the interface to be evaluated does not exist,
		analytical methods can be used. They allow an a
		priori analysis, i.e. provide an interface valuation
		before his real use. In this second case, the
		corresponding techniques can be classed into two
		approaches (fig. 3): (3) some expert-based approaches
		(already cited above), (4) analytical approaches.
		Analytical evaluation allows to describe an interface
		that responds to the operator requirement in terms of
		utility and usability. It takes into account the human
		oriented design recommendation and can be supported
		by an appropriate architecture of human-machine
		dialogue. Those methods can be used during interface
		specification and design, to check a priori the
		proposed interface usability quality. The usable

and Grouping of items by format (C3): distinguishing

  between functional areas, distinctive label of categories, color coding, etc.

Immediate feedback (C4): results of users' action. Clarity (C5): facilitate

	legibility
	User
	workload
	C6 C7 C8

Table 2

 2 Expert-based approaches

	Techniques	References	Usability criteria
	Analyst's	Sperandio, 1991
	experience
	Human	Molich et al. 90	every criteria
	expertise
	Evaluation	Smith and Mosier, 1986; Ravden	every criteria
	grid	and Johnson, 1989

  formal model: The human task modeling is particularly important if it facilitates the communication between the different agents of the development team: showing the user's assistance requirements, choosing the different aid's function… The modeling can be realized with different type of description. That model is based on a goal, sub-goal description (fig.4). Table3lists the most known ones among those which are usable for interactive applications.

		goal			Diffe re n t le ve ls
	subgoal	subgoal subgoal	subgoalt subgoal	subgoal	Syntaxic Conceptual Semantic
		subgoal	subgoal	subgoal	Lexical
		elementary goal

Table 3

 3 Example of predictive formal model: task and linguistic model

	Techniques	References	Usability criteria
	HTA	Annet et al., 1971; Stammer et	C1 C7 C8 C11 C12
		al. 1990
	GOMS	Card et al., 1983; Irving et al.,	C1 C7 C8 C11 C12
	KLM	1994
	MAD	Scapin and Pierret-Golbreich,	C1 C7 C8 C11 C12
		1989
	SADT-Petri	Abed, 1990; Mahfoudi et al.,	SADT: C1 C7 C8 C11 C12
	or TOOD	1995	Petri: C4 C9 C10 C13
	ALG	Reisner, 1984	C1 C7 C8 C11 C12
	CLG	Moran, 1981	C1 C4 C8 C9 C10 C12
			C13 C15 C16 C18
	TAG et
	ETAG

Table 4

 4 Example of quality formal model: display quality model and automatic generation

	Techniques	Reference	Usability criteria
	Display Analysis	Tullis, 1986	C2 C3 C5 C8
	Program
	SYNOP	Kolski, and Millot, 1991	C2 C3 C5 C8 C16
	KRI/AG	Lowgren and Nordqvist,	C2 C3 C5 C8 C16
		1990
	APT	Mackinlay, 1986	C2 C3 C5 C6 C8 C16 C18
	Data structure	Perlman, 1987	C2 C3 C5 C6 C8 C16 C18
	Ergo-conceptor	Kolski and Moussa, 1991 C2 C3 C5 C6 C8 C16 C18


Peter J Lenting
email: peter.lenting@inserm.fr

Claire Kizlik-Manson

Caterina Casari

Towards novel treatment options in von Willebrand disease

Keywords: von Willebrand disease, treatment, quality-of-life, bispecific antibody, aptamer

Deficiency or dysfunction of von Willebrand factor (VWF) is associated with a bleeding disorder known as von Willebrand disease (VWD). The clinical manifestations of VWD are heterogeneous, and are in part dictated by the structural or functional defects of VWF. The tools to control bleeding in VWD are dominated by VWF concentrates, desmopressin and anti-fibrinolytic therapy. In view of these treatments being considered as effective, it is surprising that quality-of-life studies consistently demonstrate a significant mental and physical burden in VWD patients, particularly in women.

Apparently, the current weaponry to support the management of VWD is insufficient to fully address the needs of the patients. It is important therefore to continue to search for innovative treatment options which could better serve the VWD patients. In this short review, two of such options are discussed in more detail: emicizumab to correct for the deficiency of factor VIII, and the pegylated aptamer BT200 to increase endogenous levels of the VWF/factor VIII complex.

Von Willebrand disease (VWD)

VWF is a multimeric plasma protein that plays an essential role in hemostasis, which is illustrated by the fact that its deficiency or dysfunction coincides with a severe bleeding disorder known as von Willebrand disease (VWD). [START_REF] Leebeek | Von Willebrand's Disease[END_REF] VWD distinguishes three different types: VWD-type 1 is characterized by reduced levels of a functionally normal VWF protein. VWD-type 2 refers to qualitative defects, with several subtypes according to the patients' functional defect. Finally, VWD-type 3 is manifested by severely reduced (<5%) circulating levels of VWF.

Hemostatic activities of VWF involve the recruitment of platelets to the growing thrombus at sites of vascular injury, as well as the protection of coagulation factor VIII (FVIII) against proteolytic degradation and premature clearance. [START_REF] Budde | Von Willebrand factor and von Willebrand disease[END_REF] Indeed, the absence of VWF antigen (as in VWD-type 3) is associated with markedly reduced levels of FVIII, resulting in a combined deficiency of VWF and FVIII. VWD-type 3 patients display a mixed bleeding phenotype, provoked by both defective platelet recruitment and impaired coagulation, and share some of the bleeding symptoms found in hemophilia patients. It is not surprising therefore, that upon the recognition of this complex bleeding disorder by Dr. von Willebrand, it was originally described as hereditary pseudo-hemophilia. 3,[START_REF] Willebrand | Hereditary pseudohaemophilia[END_REF]

Treatment options in VWD and hemophilia A

The interconnection between VWD and hemophilia A is also apparent from the overlap in treatment options, particularly in the period 1960-1980, when first cryoprecipitate and later on intermediatepurity concentrates containing both FVIII and VWF were used as replacement therapy for both hemophilia A and VWD. [START_REF] Berntorp | Humate-P: a systematic review[END_REF] However, a divergent path in treatment options developed since then. High purity FVIII concentrates (ie. poor in VWF content) were developed in the 1980s to serve hemophilia A patients and recombinant FVIII products became available in the 1990s. Additional developments allowed for the introduction of extended half-life variants of FVIII (pegylated-FVIII and FVIII-Fc fusion proteins) in the 2010s and more recently non-factor therapies have been approved (emicizumab) or are in advanced clinical development (fitusiran, concizumab, marstacimab). [START_REF] Mancuso | The changing treatment landscape in haemophilia: from standard half-life clotting factor concentrates to gene editing[END_REF] Finally, gene therapy for hemophilia A has undergone a rapid development over the last decade, and it seems conceivable that this approach may find regulatory approval within the next couple of years.

In contrast, fewer advances in the therapeutic management of VWD have been made over the last three decades: the introduction of a plasma-derived, FVIII-poor VWF concentrate in 2005 and of a recombinant VWF concentrate, approved in 2015 in the US and in 2017 in Europe. [START_REF] Goudemand | Pharmacokinetic studies on Wilfactin, a von Willebrand factor concentrate with a low factor VIII content treated with three virus-inactivation/removal methods[END_REF][START_REF] Franchini | Von Willebrand factor (Vonvendi(R)): the first recombinant product licensed for the treatment of von Willebrand disease[END_REF] This raises the question as to why there is such a disparity between the development of novel therapeutic options in VWD compared to hemophilia A?

Why needing better treatment options for VWD?

The lack of developments with regard to VWD could potentially be ascribed to the absence of a need for such new therapeutics. Indeed, Dr. Mannucci recently expressed that "the weapons currently available for the clinician to manage patients with VWD are satisfactory". [START_REF] Mannucci | New therapies for von Willebrand disease[END_REF] It seems conceivable that when one assumes such a perspective, there would indeed be little incentive to look for new or improved therapeutic strategies.

But is it actually true that the current arsenal of treatment options is satisfactory? One possibility to address this question is to analyze studies that have assessed the quality-of-life situation of VWD patients. These studies consistently teach us that severe and moderate VWD patients have clinically and statistically significant reductions in nearly all health related quality-of-life domains, both physically and mentally (reviewed in Denis et al.). [START_REF] Denis | von Willebrand disease: what does the future hold?[END_REF] These results have not changed over the last 25 years. [START_REF] Kadir | Quality of life during menstruation in patients with inherited bleeding disorders[END_REF][START_REF] Govorov | Heavy menstrual bleeding and health-associated quality of life in women with von Willebrand's disease[END_REF][START_REF] Xu | Relative contributions of bleeding scores and iron status on health-related quality of life in von Willebrand disease: a cross-sectional study[END_REF] In particular, women express considerable morbidity in emotion and pain. Dr. Kouides stated that "VWD on clinical grounds is primarily a diseases of women". [START_REF] Kouides | Females with von Willebrand disease: 72 years as the silent majority[END_REF] Indeed, VWD in women is frequently manifested in associated with heavy menstrual bleeding and its associated pain (observed in 32-100% of patients), postpartum hemorrhage (15-60% of patients) and hysterectomy (10-26% of patients). 15- 5 So yes, existing treatment options can be effective, but they do not seem to fulfil the need of the patients. We should therefore try to improve therapeutic approaches with the aim to achieve superior efficacy and ameliorate the quality-of-life situation of these patients.

Challenges in developing novel treatment options for VWD

What options do we have to improve the clinical management of VWD? First, prophylactic treatment in VWD is less frequent compared to hemophilia A. This may originate from the perception that bleeding symptoms are commonly believed to be less serious than hemophilia-related symptoms. [START_REF] Berntorp | Differential response to bypassing agents complicates treatment in patients with haemophilia and inhibitors[END_REF] Nevertheless, the initiation of prophylaxis for VWD patients was found to significantly reduce the rate of bleeding episodes and the need for hospitalization. [START_REF] Holm | Bleeding-related hospitalization in patients with von Willebrand disease and the impact of prophylaxis: Results from national registers in Sweden compared with normal controls and participants in the von Willebrand Disease Prophylaxis Network[END_REF][START_REF] Peyvandi | A phase III study comparing secondary long-term prophylaxis versus on-demand treatment with vWF/FVIII concentrates in severe inherited von Willebrand disease[END_REF] Thus, more frequent application of prophylaxis would already be a step forward. In this respect, the development of extended half-life variants would be welcome. This would be feasible from a technical point of view, given two preliminary studies describing such molecules that were published in 2006 and 2013, respectively. [START_REF] Turecek | Biochemical and Functional Characterization of PEGylated rVWF[END_REF][START_REF] Schulte | Innovative coagulation factors: albumin fusion technology and recombinant singlechain factor VIII[END_REF] It is unclear why no clinical evaluation of these molecules has been initiated. Another approach would be to focus more on the specific defect of the molecule (such as reduced synthesis, reduced multimerization, increased degradation, impaired platelet binding, defective FVIII binding, etcetera) and try to address these specific defects. Indeed, VWD is a heterogeneous disease, and the bleeding tendency is variable between the different VWD types. By focusing on the specific defect of the VWF protein, it would be possible to serve the specific needs of patients having similar functional or structural defects, rather than using a one-size-fits-all approach using full-length VWF.

In this review, we will focus on two potential options to expand the weaponry available to the clinician to manage VWD, with particular reference to a defect-specific approach: the bispecific antibody emicizumab and the aptamer BT200.

Correcting FVIII-deficiency in VWD

VWF functions as a chaperone-protein for FVIII in the circulation by forming a tight non-covalent complex, and when VWF is unable to perform this chaperone-function, FVIII is eliminated rapidly from the circulation. [START_REF] Lenting | The life cycle of coagulation factor VIII in view of its structure and function[END_REF][START_REF] Pipe | Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A[END_REF] FVIII binding can be impaired in the presence of specific mutations within the FVIIIinteractive site (referred to as VWD-type 2N), and patients with these mutations manifest a bleeding phenotype resembling those of hemophilia A patients. [START_REF] Seidizadeh | Von Willebrand disease type 2N: An update[END_REF] A secondary deficiency of FVIII is also observed in patients with VWD-type 3, who have a virtual absence of VWF antigen. The bleeding phenotype in VWD-type 3 patients is therefore more complex as a result of a combined deficiency of VWF and FVIII. It is difficult to estimate which portion of the bleeding phenotype is due to the absence of VWF and which portion is due to the absence of FVIII.

Nevertheless, some insight into the contribution of FVIII-deficiency to the bleeding phenotype in VWDtype 3 patients has been obtained from treating these patients with recombinant VWF-free FVIII concentrates during surgical interventions. In four different cases (abdominal surgery [START_REF] Bergamaschini | Posttransfusion anaphylactic reactions in a patient with severe von Willebrand disease: role of complement and alloantibodies to von Willebrand factor[END_REF] , cesarean section [START_REF] Boyer-Neumann | Multi-therapeutic approach to manage delivery in an alloimmunized patient with type 3 von Willebrand disease[END_REF] , teeth extraction [START_REF] Sakurai | Successful use of recombinant factor VIII devoid of von Willebrand factor during multiple teeth extractions in a patient with type 3 von Willebrand disease[END_REF] and orthopedic surgery [START_REF] Pergantou | The challenging management of a child with type 3 von Willebrand disease and antibodies to von Willebrand factor[END_REF] ), the use of recombinant FVIII resulted in sufficient hemostatic activity, suggesting that by increasing FVIII levels an important part of the bleeding phenotype can be corrected.

For long-term treatment of VWD-type 3 patients, the use of recombinant FVIII concentrates is not very practical, given its short half-life and the need for frequent intravenous infusions. However, the arrival of the bispecific antibody emicizumab opens another perspective in this regard. Emicizumab mimics some of the cofactor activities of FVIII, and its use in hemophilia A patients is associated with marked reductions in annualized bleeding rates. [START_REF] Callaghan | Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies[END_REF] Importantly, emicizumab has a half-life of about 4 weeks, allowing it to be applied subcutaneously in a weekly or biweekly fashion. As such, emicizumab could be an alternative to FVIII in the treatment of VWD-type 3 or type 2N to compensate for the absence of FVIII. An early example of how emicizumab could be beneficial to reduce the bleeding tendency in VWD-type 3 patients was reported by Weyand and colleagues in 2021. [START_REF] Weyand | Efficacy of emicizumab in a pediatric patient with type 3 von Willebrand disease and alloantibodies[END_REF] They described the case of a young boy with VWD-type 3, who had developed antibodies against both VWF and FVIII upon treatment with VWF/FVIII concentrates (Fig. 1). Subsequent change to off-label treatment with recombinant factor VIIa (270µg/kg; 3 times/week) did little to resolve the bleeding complications. The patient was then transitioned to daily infusions using activated prothrombin complex concentrates (100 U/kg) initially, which was reduced to three times/week later on. Unfortunately, this treatment still required co-treatment with recombinant factor VIIa upon breakthrough bleeds, and the treatment burden was experienced as being too heavy. At this point, the treating physicians decided to initiate off-label treatment with emicizumab (4 weeks of loading dose (3 mg/kg), followed by 1.5 mg/kg once weekly) given subcutaneously. Surprisingly, the patient remained free of spontaneous bleeding complications during the following 9 months of follow up, and required a single additional treatment with recombinant factor VIIa upon a trauma-induced soft tissue hematoma. Apparently, correcting FVIII deficiency using emicizumab proved to be of benefit in this particular case.

At this moment, several additional cases of off-label use of emicizumab in VWD patients have been reported, some in abstract form and some as case reports (for review see Thomas and colleagues). [START_REF] Thomas | Off-label use of emicizumab in persons with acquired haemophilia A and von Willebrand disease: A scoping review of the literature[END_REF] In general, emicizumab use has been associated with a markedly improved hemostatic profile, manifested by reduced or lack of hospitalisations, transfusions, joint bleeds and major spontaneous bleeds. It thus seems that correcting the FVIII deficiency in VWD-type 3 ameliorates the bleeding phenotype in these patients. Given the long half-life of emicizumab, its possibility to be applied subcutaneously and the promising data reported regarding VWD-type 3, it would be of interest to evaluate its efficacy in an appropriately designed clinical study. It should be noted that also efanesoctocog/BIVV001, a FVIII-variant having a half-life of 38-43 h 35 , could be of relevance in this regard.

Could emicizumab or efanesoctocog also be efficient in other types of VWD? Naturally, one would think of VWD-type 2N, where VWF functions normally in the process of platelet recruitment, but lacks its protective action towards FVIII. As for emicizumab, a recent study evaluated its effect on ex vivo thrombus formation in a microfluidic perfusion chamber using blood from 5 different VWD-type 2A patients. [START_REF] Yaoi | Emicizumab improves thrombus formation of type 2A von willebrand disease under high shear condition[END_REF] VWF:RCo/VWF:Ag ratios were ≤0.35, while FVIII activity levels were 20-40%. As expected, the addition of VWF (1.6 U/ml) to the patients' blood increased surface coverage and thrombus height 5-6-fold upon perfusion over a collagen-surface. In contrast, the addition of FVIII (1 U/ml) had little or any effect. It was surprising therefore that the addition of emicizumab (100 µg/ml) increased both surface coverage and thrombus height 3-4-fold. While it is yet unclear by which mechanism emicizumab improves thrombus formation under these conditions, these in vitro data are encouraging and favor further research in this direction.

Increasing endogenous VWF levels

Desmopressin has been a powerful tool in the treatment of patients with VWD-type 1, as it induces a rise in VWF levels to achieve improved hemostatic activity. 9,37 However, post-treatment increases of VWF are transient and limited by the short half-life of VWF, and repetitive use results in diminished responsiveness (tachyphylaxis). [START_REF] Federici | The use of desmopressin in von Willebrand disease: the experience of the first 30 years (1977-2007)[END_REF] Also, desmopressin has variable efficacy in VWD-type 2A and 2M, is contra-indicated for VWD-type 2B, and cannot be used in the vast majority of VWD-type 3 patients. [START_REF] Federici | The use of desmopressin in von Willebrand disease: the experience of the first 30 years (1977-2007)[END_REF] An alternative approach to increase VWF levels in the patient could be by delaying its clearance rather than to enhance its production or secretion. Clearance of VWF can be delayed by bridging it for example to endogenous albumin or IgG, driving VWF into the FcRn-mediated recycling pathway, or by directly preventing its interaction with clearance receptors.

Several clearance receptors for VWF have been described, including LRP1, CD204/SR-AI, Stabilin-2, CLEC4M and Macrophage galactose-type lectin. [START_REF] Rastegarlari | Macrophage LRP1 contributes to the clearance of von Willebrand factor[END_REF][START_REF] Wohner | Macrophage scavenger receptor SR-AI contributes to the clearance of von Willebrand factor[END_REF][START_REF] Swystun | Genetic regulation of plasma von Willebrand factor levels in health and disease[END_REF][START_REF] Rydz | The C-type lectin receptor CLEC4M binds, internalizes and clears von Willebrand factor and contributes to the variation in plasma von Willebrand factor levels[END_REF][START_REF] Ward | A novel role for the macrophage galactose-type lectin receptor in mediating von Willebrand factor clearance[END_REF] In vitro and in vivo studies have shown that blocking the binding of VWF to these receptors interferes with its cellular uptake and prolongs its circulatory half-life. [START_REF] Rastegarlari | Macrophage LRP1 contributes to the clearance of von Willebrand factor[END_REF][START_REF] Wohner | Macrophage scavenger receptor SR-AI contributes to the clearance of von Willebrand factor[END_REF][START_REF] Swystun | Genetic regulation of plasma von Willebrand factor levels in health and disease[END_REF][START_REF] Rydz | The C-type lectin receptor CLEC4M binds, internalizes and clears von Willebrand factor and contributes to the variation in plasma von Willebrand factor levels[END_REF][START_REF] Ward | A novel role for the macrophage galactose-type lectin receptor in mediating von Willebrand factor clearance[END_REF] It would be of interest to develop agents that interfere with the binding of VWF to one or more of these receptors, while maintaining the functional integrity of VWF.

A first step in this direction has already been made by Kovacevic and colleagues, who recently described an aptamer (designated BT200) that seems to interfere with the clearance of VWF. 43 BT200 is a short hairpin-structured oligonucleotide, and is an optimized derivative of the previously described aptamer ARC1779. [START_REF] Gilbert | First-in-human evaluation of anti von Willebrand factor therapeutic aptamer ARC1779 in healthy volunteers[END_REF] Both aptamers bind to the VWF A1 domain and block its interaction with the platelet-receptor Glycoprotein Iba. [START_REF] Zhu | The development and characterization of a long acting antithrombotic von Willebrand factor (VWF) aptamer[END_REF] Indeed, BT200 was originally developed as an inhibitor of VWF-platelet interactions, aiming the treatment of thrombotic complications. [START_REF] Gilbert | First-in-human evaluation of anti von Willebrand factor therapeutic aptamer ARC1779 in healthy volunteers[END_REF] In preliminary studies using ARC1779, it was observed that the infusion of this agent in VWD-type 2B patients was not only associated with increased platelet counts by preventing the formation of VWF/platelet complexes, but also with increased VWF levels. [START_REF] Jilma-Stohlawetz | The anti-von Willebrand factor aptamer ARC1779 increases von Willebrand factor levels and platelet counts in patients with type 2B von Willebrand disease[END_REF] This latter aspect has now been evaluated in a more detailed manner using the improved derivative BT200 in a dose-escalation study in human volunteers. [START_REF] Kovacevic | The von Willebrand factor A-1 domain binding aptamer BT200 elevates plasma levels of VWF and FVIII: a first-in-human trial[END_REF] A dosedependent increase in VWF and FVIII levels were observed upon repetitive, subcutaneous treatment using BT200 (0.18-36 mg). Maximal increase was 3-4 fold for VWF and 2.5-fold for FVIII (Figure 2). Interestingly, the same aptamer has also been tested in hemophilia A patients, finding that BT200 increases endogenous FVIII levels about 2-fold, and prolongs the half-life of exogenously administered FVIII concentrates 2-7 fold. [START_REF] Ay | The VWF-A1 domain binding aptamer BT200 prolongs the halflives of different factor VIII (FVIII) products in patients with severe haemophilia A and increases FVIII levels in non-severe haemophilia A[END_REF] These preliminary data are more than promising, but of course additional clinical evaluation is still necessary. For example, it is worth noting that low plasma levels of BT200 (≥0.7 µg/ml) are associated with prolonged collagen/ADP closure times (≥140 s) in the platelet function analyzer. [START_REF] Kovacevic | The von Willebrand factor A-1 domain binding aptamer BT200 elevates plasma levels of VWF and FVIII: a first-in-human trial[END_REF] It is essential therefore to find the optimal dosing that allows increased FVIII and VWF levels without compromising the patient's hemostatic activity. Furthermore, it would be necessary to identify which types of VWD would benefit from this molecule. Akin to desmopressin, BT200 would probably not be very useful in VWD-type 3, as VWF levels are virtually absent. Also, it remains to be investigated how effective it will be to increase levels of functionally inactive VWF variants in VWDtype 2A, VWD-type 2M or VWD-type 2N.

In summary, there is accumulating evidence from preclinical and clinical studies that other strategies than desmopressin can result in prolonged increase of endogenous VWF and FVIII levels. It seems conceivable that such approaches may find their place in the arsenal of treatment options that the clinician has available in the management of VWD.

Conclusion

The development of alternative treatment options for hemophilia A has left some VWD patients with the question whether such innovative paths are also on the horizon for them. Fortunately, we can now is associated with VWF levels being increased 3-4 fold, while its use in mild/moderate hemophilia A patients increase FVIII levels 2-3 fold. [START_REF] Kovacevic | The von Willebrand factor A-1 domain binding aptamer BT200 elevates plasma levels of VWF and FVIII: a first-in-human trial[END_REF][START_REF] Ay | The VWF-A1 domain binding aptamer BT200 prolongs the halflives of different factor VIII (FVIII) products in patients with severe haemophilia A and increases FVIII levels in non-severe haemophilia A[END_REF]

Figure 1 :Figure 2 :

 12 Figure 1: Emicizumab for VWD-type 3. Early case report by Weyand and colleagues on the off-label

answer this question positively. In this review, we described two options, which at the relative short term could become available for these patients. A more extensive description of the different opportunities for innovation was published in 2021. [START_REF] Denis | von Willebrand disease: what does the future hold?[END_REF] These innovative paths are not only limited to protein-based strategies but also genetic approaches are in early stage preclinical development. With genetic approaches, one should think of siRNA-based techniques to silence mutant alleles or even gene therapy. [START_REF] Campioni | In vivo modulation of a dominant-negative variant in mouse models of von Willebrand disease type 2A[END_REF][START_REF] De Jong | Ex vivo Improvement of a von Willebrand Disease Type 2A Phenotype Using an Allele-Specific Small-Interfering RNA[END_REF][START_REF] Barbon | Development of a dual hybrid AAV vector for endothelialtargeted expression of von Willebrand factor[END_REF] However, many hurdles are there to take in order to make these approaches clinically viable.

Apart from the technical aspects, also other issues are of relevance for innovative agents becoming available for patients. There should be the support from clinicians themselves to welcome such new products, and of industry to believe that such products are viable from a commercial point of view.

Only together (researchers, clinicians and other health care professionals, industry and patient groups) it is possible to enter a brighter future in which the quality-of-life standards for VWD patients are finally being improved.

Author contributions

All authors contributed to the writing of the manuscript.

Conflict of interest

PJL declares to receive research funding from the Agence National de la Recherche, Pfizer, Roche, Sanofi and Sobi, and speakers fees from CSL Behring, LFB Biomédicaments, Sanofi, Sobi. CKM and CC declare no conflict of interest


M Sahli

M Abid

T Barrière

B Mamen

Investigation on machining of a Ti-6Al-4V alloy using FEM Simulation and experimental analysis

Keywords: Titanium turning, cutting tools, FE simulation, chip

Titanium alloys have been attracting from the more industries, especially, industry aerospace due to their very important high strength to weight ratio. Furthermore, they were classified as difficult to machine materials due to low tool life in machining processes. In this study, a FE model has been developed to simulate the turning stage of Ti-6Al-4V alloy. A 3D model with thermo-mechanical coupling has been proposed to study the influence of cutting parameters and also lubrication on the performance of cutting tools. The constants of the Johnson-Cook constitutive model of Ti-6Al-4V alloy were identified using inverse analysis based on the process parameters of the orthogonal cutting. The predictive FE model has been validated based on an orthogonal cutting test. The investigations indicated that this approach estimates the resultant cutting forces with low prediction errors. Indeed, the predicted forces showed good agreement with the experimental data, with minimum and maximum error magnitudes of 2.8 and 8.7% for cutting force, and 1.3 and 6.8% for feed force, respectively.

Introduction

Metal chip removal machining was frequently used in the mechanical fabrication industry [START_REF] Palaniappan | Influence of workpiece texture and strain hardening on chip formation during machining of Ti-6Al-4V alloy[END_REF][START_REF] Calamaz | A new material model for 2D numerical simulation of serrated chip formation when machining titanium alloy Ti-6Al-4V[END_REF][START_REF] Zhang | Experiment and simulation of milling temperature field on hardened steel die with sinusoidal surface[END_REF][START_REF] Lotfi | Characterization of various coatings on wear suppression in turning of Inconel 625: A three-dimensional numerical simulation[END_REF]. It makes it possible to obtain parts of complex shape characterized by a low roughness of the surface states at a fairly low cost, etc. Some alloys such as super alloys-based Cr, Ni and Ti were machined in a conventional manner and lead to rapid wear of the edges of cutting inserts for their high strength and abrasiveness, even at fairly high cutting speeds. Their low thermal conductivity therefore prevents the dissipation of the heat generated by the cutting, which causes a rapid increase in the heat increase of the workpiece [START_REF] Yang | Hybrid modeling with finite element and statistical methods for residual stress prediction in peripheral milling of titanium alloy Ti-6Al-4V[END_REF][START_REF] Bäker | A finite element model of high speed metal cutting with adiabatic shearing[END_REF][START_REF] Yang | Investigation on the temperature field under the action of the blunt tool edge for precision cutting of titanium alloys[END_REF]. This leads to early damage of the cutting insert and directly affects the final quality of the workpiece and its machined surface [START_REF] Wang | Simulation study on defect formation mechanism of the machined surface in milling of high volume fraction SiCp/Al composite[END_REF][START_REF] Liu | Simulation study of the influence of cutting speed and tool-particle interaction location on surface formation mechanism in micromachining SiCp/Al composites[END_REF]. Chip formation will affect machining temperature, cutting force, tool life and other cutting process parameters [START_REF] Li | Effect of cutting parameters and tool rake angle on the chip formation and adiabatic shear characteristics in machining Ti-6Al-4V titanium alloy[END_REF][START_REF] Li | Effect of cutting speed on chip formation and wear mechanisms of coated carbide tools when ultra-highspeed face milling titanium alloy Ti-6Al-4V[END_REF]. The selection of appropriate cutting parameters therefore essentially improves the surface integrity induced by machining [START_REF] Hou | Effect of cutting parameters on surface quality in multi-step turning of Ti-6Al-4V titanium alloy[END_REF]. Vyas and Shaw and Hua and Shivpuri indicate that the titanium alloy chip segmentation was due to a crack initiation companioned by propagation inside the primary shear zone [START_REF] Vyas | Mechanics of saw-tooth chip formation in metal cutting[END_REF][START_REF] Hua | Prediction of chip morphology and segmentation during the machining of titanium alloys[END_REF].

In this context, it was interesting to propose a reliable 3D FE model which allows us a better understanding of the cutting insert-part interaction during the machining of this type of alloys. Numerical simulation of machining process and the residual stresses induced by the cutting operation have been investigated by many researchers [START_REF] Umer | Modeling machining of particle-reinforced aluminum-based metal matrix composites using cohesive zone elements[END_REF][START_REF] Zhang | A modified Johnson-Cook model of dynamic tensile behaviors for 7075-T6 aluminum alloy[END_REF][START_REF] Chen | Numerical modeling of Ti-6Al-4V alloy orthogonal cutting considering microstructure dependent work hardening and energy density-based failure behaviors[END_REF][START_REF] Burhanuddin | FEM simulation of machining AISI 1045 steel using driven rotary tool[END_REF][START_REF] Li | FEM-simulation of machining induced surface plastic deformation and microstructural texture evolution of Ti-6Al-4V alloy[END_REF][START_REF] Zhou | Multiscale research of microstructure evolution during turning Ti-6Al-4V alloy based on FE and CA[END_REF]. Li et al. have set up an experimental plan to study the effect of machining parameters and the inclination angle of the cutting tool on the chips formation during the machining of the titanium alloy Ti-6Al -4V [START_REF] Li | Effect of cutting parameters and tool rake angle on the chip formation and adiabatic shear characteristics in machining Ti-6Al-4V titanium alloy[END_REF]. Chen et al. performed a numerical study to analyse the high-speed machining of titanium alloy Ti-6Al-4V using the Johnson-Cook material model coupled with a ductile failure criterion to analyse the process parameters effect on machining on the final morphology of the chips [START_REF] Chen | Finite element simulation of highspeed machining of titanium alloy (Ti-6Al-4V) based on ductile failure model[END_REF]. Takahashi et al. studied numerically analysed the effects of the rotational speed of the workpiece on the sense of chip flow and the cutting force of tools during turning process [START_REF] Zhang | Experiment and simulation of milling temperature field on hardened steel die with sinusoidal surface[END_REF]. It was concluded that the machining force significantly reduced by increasing the rotational speed of the tool when the sense of chip flow was tilted towards the direction of the tool rotation. Chen et al. proposed an FE model for machining strain prediction using the finite element method that takes into account the strain during the previous cut and the nominal depth of cut of the current cut [START_REF] Chen | Deformation prediction and error compensation in multilayer milling processes for thin-walled parts[END_REF]. Zhao et al. proposed a 2D model to study the orthogonal cutting of SiCp/2024Al [START_REF] Zhou | Finite element and experimental studies of the cutting process of SiCp/Al composites with PCD tools[END_REF]. It was observed that the interaction tool with the elements of the reinforcement was the main reason for the defects observed on the machining surface and the wear of the cutting inserts. The modeling of metal cutting has therefore proved to be particularly complex due to the diversity of the physical phenomena involved, in particular thermomechanical coupling, contact / friction and material rupture. This was because during filming, plastic deformation and friction work were the main sources of heat in the processing area and can significantly increase the temperature in the cutting area. This increase in temperature can significantly affect various mechanical and thermal properties of the material of the part.

In summary, several analytical, FE simulation and experimental methods have been implemented to study the machining of mechanical parts. Researchers mainly focused on developing models of the workpiece-tool machining system and correlating them with machining stability using analytical and finite element methods. Rare were those who have proposed models with thermomechanical coupling for the machining of mechanical parts in Ti-6Al-4V alloy. Therefore, the objective of this work was to develop a 3D FE model with a generalized Johnson-Cook (JC) constitutive law and very realistic initial and boundary conditions to obtain the response adapted to the applied cutting conditions. Such a model would facilitate a closer approximation to the machining knowledge of Ti-6Al-4V alloy parts without performing the machining experiments.

In this study, machining tests of Ti-6Al-4V alloy under starved or full lubrication were performed at different cutting speeds using conventional tools. We also focused on the investigation of the cutting effects on the cutting performance in terms of cutting forces and friction coefficient. Then, 3D model with thermo-mechanical coupling has been proposed to study the influence of cutting parameters on the performance of cutting tools. This model was allowed us on the one hand to study the chip formation and on the other hand, to predict the stresses distributions, cutting forces and temperatures evolutions in the workpiece and the cutting insert.

Materials and experimental methods 2.1. Materials

Machining experiments were carried-out on a cylindrical part made of wrought titanium alloy (Ti-6Al-4V) with a diameter of 50 mm and a length of 200 mm. In these tests, cemented carbide cutting inserts supplied by Sandvik Company were used. These GC6050 type inserts with a titanium-aluminum nitride (TiAlN) coating have been tested under different cutting conditions. The physical characteristics of the material to be machined and those of the cutting inserts were shown in Tables 1 and2.

Proprieties

Experimental methods

The cutting effects on machining performance were carried-out on a GILDEMEISTER CTX 320 linear cnc lathe V6 under different cutting conditions and with starved or full lubrication. The cutting experiments were stopped after a cutting length of 100 mm and the chips were collected. Kistler quartz multicomponent dynamometer (type 9257B) features a measuring range of up to 10 kN was used to measure the cutting force values in the machining experiments. All the tests were carried-out using the following parameters: feed rate f = 0.2 mm/revolution; cutting depth ap = 0.5 mm; cutting speed of 40-200 m/min.

Experimental results and discussion

Figure 1 illustrates the cutting force evolution for textured tools, during the machining phase under conditions lubricated by starved or complete fluid system. It can be observed that the experimental values of the recorded machining force were very stable during the machining phase under complete lubricated conditions.

The same values of the three cutting force components remained constant using starved lubrication in the interval between the first 30 to 40 s; then an increase was observed around 20% to 24% (see Fig. 1). Figure 2 shows the friction coefficient evolution as a function of the cutting speed under two lubricated conditions. The results obtained showed that the values of the friction coefficient decreased from 5% to 7% when the cutting speed increased for the machining phase either under complete lubrication or even under insufficient lubrication. It was clear that full lubrication of the cutting tool improves tribological performance a little better.

FE simulation of the turning process 4.1. Material constitutive model

The constitutive model of Johnson-Cook (JC) was utilised to modelling the mechanical behaviour of the material to be machined [START_REF] Johnson | A constitutive model and data for metals subjected to large strains, high strain rates and high temperatures[END_REF]. It allows thermomechanical coupling to be taken into account in this process in order to correctly allowing reproducing the thermo-mechanical phenomena interconnection in the cutting area. In this FE model, the influence of strain, strain rate and temperature on yield stress were defined by three multiplicative terms.

where σ was the flow stress, ε was the true strain, ε˙0 was the reference true strain rate, ε˙ was the true strain rate, T0 was the ambient temperature, Tm was the workpiece material melting temperature, T was the workpiece temperature. n was the strain hardening rate index, A was the initial yield stress, B was the hardening coefficient, C was the strain rate sensitivity coefficient, m was the temperature softening index, T0 was the lowest experimental temperature, and Tm was the material melting temperature.

The first term of the law J-C illustrates the work hardening behaviour of the material. It consists of the parameters B and n, namely the coefficient of resistance and work hardening. The second term corresponds to the effect of the strain rate. Finally, the third term relates the temperature factor defined differently for different materials. The specific values of the parameters were shown in Table 3.

FE Turning process simulation

Finite element analysis software LSDYNA/Explicit was used, and threedimensional model was applied. Coupled thermomechanical analysis was used to include thermal effects.

The 3D model developed in this work simulates the orthogonal cutting of an ordinary carbon steel cylindrical part made using a coated tungsten carbide cutting insert (K10). The geometric dimensions of the cylindrical bars considered in our 3D model were 200 mm in length by 50 mm in diameter. The cutting insert geometry was taken in accordance with a CNMA 120408 type cutting insert. The relative movement between the cylindrical bar and the cutting insert was simulated by a horizontal translational movement at constant speed. It was affected on all the nodes of the cutting tool, which was assumed to be rigid and undeformable. The nodes along the left and bottom sides of the cylindrical bars were fixed. In this study, different cutting speeds varying between 40 m/min and 200 m/min were tested. The cutting-edge engagement length was 0.4 mm.

The mechanical behaviour of the cutting inserts was considered to be thermoelastic while the titanium alloy has been taken into account thanks to the constitutive model J-C. The cylindrical bars and the cutting tool have been described with an adaptive mesh by 28,000 and 36,000 tetrahedron-mesh elements, respectively. Coulomb friction was used to model the friction with a coefficient value defined at the cylindrical bar-cutting insert interface in agreement with Bäker et al. [START_REF] Bäker | A finite element model of high speed metal cutting with adiabatic shearing[END_REF] and Calamaz et al. [START_REF] Calamaz | A new material model for 2D numerical simulation of serrated chip formation when machining titanium alloy Ti-6Al-4V[END_REF]. Figure 4 illustrates a descriptive diagram of the CAD of the initial geometry and the initial conditions and limits imposed.

An FE model has been used to predict the cutting force when machining Ti-6Al-4V alloy parts under different conditions. The cutting temperature, the friction coefficient at the tool-chip interface and the constitutive model of the material have been taken into account in the proposed FE model. A flowchart of the cutting force prediction was depicted in Fig. 5.

Numerical simulations and discussion

Stress distribution

Von Mises stress isovalues at a time step of 3 s were illustrated in Figure 6. The stresses were more and more distributed in the cut zone. It was clearly seen that the stress concentration zone was located near the cutting edge. The results also indicate that chips along the shear plane experience greater stresses. It was also important to numerically study the chip formation clockwork to see if the developed EF model was able to reproduce them according to the literature. Figure 7 shows the division of the shear band during the turning process, phenomenon related in the literature by Bäker et al. [START_REF] Bäker | A finite element model of high speed metal cutting with adiabatic shearing[END_REF]. It has been observed that the shear was very localized in the form of a very narrow shear band which forms in two joining parts. This was because this shear band starts near the cutting edge radius of the tool and gradually spreads to the free surface of the workpiece. Then, it progresses from the free surface to the radius of the tool.

Moreover, Hou and Komanduri indicated that the cutting speed has been the important parameter for the appearance of shear bands and propose a critical cutting speed around 9 m/min above which a thermoplastic instability takes place [START_REF] Chen | Deformation prediction and error compensation in multilayer milling processes for thin-walled parts[END_REF]. Also, Baker et al. proposed a critical strain value close to 0.25 below which the strain hardening phenomenon may occur and above this value the Ti-6Al-4V alloy may exhibit softening [START_REF] Baker | A finite element model of high speed metal cutting with adiabatic shearing[END_REF]. This phenomenon would normally primarily promote chip segmentation during machining process by introducing an easy-slip band in the primary shear zone.

Effects of Vc over output responses

Three cutting speed of 120 m/min, 160 m/min and 180 m/min were tested to study its influence on the final chip morphology (see Fig. 8). The chip was found to be divided into two parts, one continuous and the other segmented. However, the more the cutting speed increases, the more the chip segmentation phenomenon becomes more and more pronounced. This was due, among other things, to the effect of thermal conduction located in the shear bands. This high heating greatly influences the stiffness of the material and therefore produces a more segmented chip.

Cutting temperature

During the machining, the temperature of the interaction area of the cutting tool and workpiece becomes high. Figure 9 shows the temperature field at the interface, the shear zone and the cutting face of the tool when turning a Ti-6Al-4V cylindrical bar for different cutting speeds from 120 m/min to 200 m/min. It was clearly observed that the zone at maximum temperature was mainly detected at the level of the chipcutter wafer contact zone and near the primary shear zone. The minimum cutting temperature obtained by the EF model was approximately 680 °C at 120 m/min and it increases significantly to a maximum of 533 °C at 200 m/min, recorded at the tool interface-chip (see Fig. 9). The effect of increased cutting temperature caused by higher feed rate was relatively moderate compared to that caused by higher cutting speed [START_REF] Li | Effect of cutting speed on chip formation and wear mechanisms of coated carbide tools when ultra-highspeed face milling titanium alloy Ti-6Al-4V[END_REF].

In addition, several studies have indicated that often high temperatures can occur during the machining operation of this type of alloy classified as difficult to machine metal [START_REF] Jianxin | JiePerformance of carbide tools with textured rake-face filled with solid lubricants in dry cutting processes[END_REF]. The low thermal conductivity of this alloy may explain this phenomenon caused by the trapping of heat produced locally in the cutting zone, resulting in a higher turning temperature [START_REF] Calamaz | A new material model for 2D numerical simulation of serrated chip formation when machining titanium alloy Ti-6Al-4V[END_REF][START_REF] Yang | Hybrid modeling with finite element and statistical methods for residual stress prediction in peripheral milling of titanium alloy Ti-6Al-4V[END_REF]. Many researchers have worked on temperature measurement and prediction. A review of some experimental measurement can be found in Komanduri and Hou [START_REF] Calamaz | A finite element model of high speed machining of TA6V titanium alloy[END_REF].

Lubrication effects

To study the lubrication effect on the stress state of the Ti-6Al-4V part and the shape of the chips, friction values were taken into account, equal to 0.2 for a lubrication complete and 0.6 for severe machining at the insert cylindrical bar cutter interfaces. Figure 10 shows that there was a remarkable difference between the chips shape obtained when machining with full or severe lubrication. In machining condition with complete lubrication i.e. contact with very low friction, the final chip shape characterized by a radius of curvature at the interface of the cylindrical bar cutter insert was approximately 2, 5 lower than machining with severe lubrication. In addition, the chips thickness obtained by simulation in full lubrication was greater than that of machining with severe lubrication.

Moreover, it was interesting to indicate the weak influence of the friction coefficient on the cutting force, as it was quite clear in Fig. 11. This observation was predictable because the general shape of the chip remains almost the same whatever it was. lubrication conditions, that was, the value of the friction coefficient. Calamaz et al. studied the influence of different friction models on the numerical results of Ti-6Al-4V machining simulations. They concluded that most mechanical results for the studied workpiece/tool couple were not influenced by the friction model except the temperature at the tool-chip interface [START_REF] Calamaz | A finite element model of high speed machining of TA6V titanium alloy[END_REF].

Indeed, during machining, energy will be transformed in the form of heat, which causes softening at the chip/tool interface, that was to say of the contact surfaces during turning [START_REF] Hou | On a thermo-mechanical model of shear instability in machining[END_REF][START_REF] Komanduri | A review of the experimental techniques for the measurement of heat and temperatures generated in some manufacturing processes and tribology[END_REF]. Similar trends were also indicated by Filice et al. [START_REF] Filice | On the FE codes capability for tool temperature calculation in machining processes[END_REF] and Calamaz et al. [START_REF] Calamaz | A new material model for 2D numerical simulation of serrated chip formation when machining titanium alloy Ti-6Al-4V[END_REF].

FE model validation

Figure 12 illustrates a comparative analysis of our numerical simulations and those resulting from the experimental results during the operation of turning the titanium alloy in conditions of full or starved lubricant. The same tendency was observed for the feed forces and the thrust forces generated during cutting. They were less noticeably affected by cutting speed. This variation was estimated between 175 ± 5N whatever the lubrication conditions. Also, the friction coefficients also follow the same trend as those of the cutting forces whether for the experimental conditions as for those obtained in simulations (see Fig. 13). In addition, we can see that our numerical data was slightly lower than the experimental data probably due to the complexity of the cutting conditions, the turning environment, and also due to the measurement error and vibrations not taken into account in our model. It can be concluded that the results provided by the 3D model were in good agreement under the two conditions of complete or starved lubrication with the experimental data with an error difference of only 5 to 10%. To complete our comparative analysis of the chip obtained and its morphology, measurements of the geometric characteristics of the chip shape were carried-out. Three morphological data were used, namely the spacing of peaks, valleys and segments. It was noted that a well agreement was observed with mean relative errors close to 10% between our numerical data and the experimental results (see Table 4). Based on comparison and analysis of the chip morphology and cutting force on the simulation and experiment, the two-dimensional orthogonal cutting simulation model for Ti-6Al-4V alloy was reasonable and reliable. Thus, this model can be used to simulate and predict the actual machining process of Ti-6Al-4V alloy.

Conclusion

The simulations and FE experiments have clearly shown that the lubrication conditions as well as the cutting parameters lead to a marked improvement in the cutting performance of the tools and also to an increased tool life in the machining of the alloy of titanium Ti-6Al-4V. The FE simulation with the model parameters reported in this work has been well validated experimentally in the estimation of tool cutting forces in the Ti-6Al-4V titanium alloy. Other interesting findings were listed below:  The level of equivalent plastic deformations was 5 to 7% higher for high cutting speeds leading to more wavy chips;  Turning was accompanied by considerable heat generation in the cutting zone, affecting material properties of the treated workpiece.  The temperature in the cutting region was about 119° under starved lubrication lower due to the elimination of friction heating;  The drop in process temperature was recorded for numerical simulations of cutting with reduced feed; this result was in good agreement with our experimental measurements and was explained by a reduced rate of material removal.

The results revealed that the model could correctly predict the cylindrical turning step with acceptable errors. The numerical results show good agreement in the experimentally measured values of the machining experiments.

Future work will mainly focus on the final morphology of the chips formed and also on the cutting mechanism. Particular attention will be paid to the shape of the cutting tools (cutting angles....) as well as to the cutting parameters such as the feed rate, the cutting speed and the radial depth of cut. This will facilitate establishing the robustness of the proposed model and potential dependencies on various

Fig. 1 .

 1 Fig.1. Cutting forces evolution vs. time in textured cutting surface under (a) full lubrication and (b) starved lubrication (cutting velocity: 160 m/min).

Fig. 2 .

 2 Fig.2. Friction coefficient vs. cutting speed of workpiece during machining process.

Figure 3

 3 Figure 3 shows the evolution of the three components values of the cutting tools measured at different cutting speeds varying from 40 to 200 m/min. They were obtained during the turning operation carried-out under both different lubrication conditions. The cutting speed significantly affected the cutting force of the cutting inserts. The cutting behaviour of the tools decreased in both lubrication cases of the order of 7% to 10%.

Fig. 3 .

 3 Fig.3. Evolution of cutting forces vs. cutting speeds obtained using textured cutting inserts under (a) complete fluid lubrication and (b) starved fluid lubrication.

Fig. 5 .

 5 Fig. 5. Flow chart of a FE predictive cutting force model of the machining process for Ti-6Al-4V alloy.

Fig. 6 .

 6 Fig.6. Von Mises stress distribution during chips formation

Fig. 7 .

 7 Fig.7. Shear band during chips formation.

Fig. 8 .

 8 Fig.8. Effective stress distribution in chip according to cutting speed variation for starved lubrication (µ = 0.6) and f = 0.2 mm/rev: (a) Vc = 120 m/min, (b) Vc = 160 m/min and (c) Vc = 180 m/min.

Fig. 9 .

 9 Fig.9. Temperature distribution over the cutting zones for (a) full lubrication conditions (µ=0.2), and (b) starved lubrication (µ=0.6).

Fig. 10 .

 10 Fig.10. Numerical machining results in the cutting regions under starved lubrication conditions: (a) Temperature distributions, (b) Von-Mises stress, (c) Effective strain and (d) Resultant displacement (μ = 0.6, t =1.515 s, Vc = 200 m/min).

Fig. 11 .

 11 Fig.11. Evolution of the average cutting and feed forces versus coefficient of friction for f = 0.2 mm/rev, and Vc = 180 m/min.

Fig. 12 .

 12 Fig.12. Comparison of experimental and simulated cutting forces under starved lubrication.

Fig. 13 .

 13 Fig.13. Comparison of experimental and simulated cutting forces under full lubrication conditions.

heat capacity [J/(kg°C)]

		Workpiece (Ti6Al4V)	Tool (Wc-Co)
	Density	4430	15700
	Young's modulus [MPa]	1.13xe5	6.50xe5
	Poisson ratio	0.34	0.25
	Thermal conductivity [w/(m°C)]	K(T)	91
	Specific Cp(T)	206

Table 1 .

 1 Material characteristics for the cylindrical bar and the cutting insert used in FE simulations.

	Proprieties/Temperature [°C]	0	250	500	750	1000	1250	1500
	K(T) [w/(m°C)]	6.651 6.996 8.591 8.591 15.031 19.106 22.286
	Cp(T) [J/(kg°C)]	483.3 535.8 588.3 640.8 600.19	645.2	690.2

Table 2 .

 2 Temperature dependent properties of titanium alloy[START_REF] Chen | WuA simulation study on the effect of microtextured tools during orthogonal cutting of titanium alloy Ti-6Al-4V[END_REF].

Table 3

 3 summarizes the Johnson-Cook parameters of Ti6Al4V alloy based on α phase using in our numerical analysis.

	Yield	Hardening	Hardening	Strain rate	Thermal	Tmelt [°C]	Troom [°C]
	strength	modulus	coefficient	sensitivity	softening
	A [MPa]	B [MPa]	n	C	coefficient
					m
	889.37	683.71	0.451	0.035	1	1647	21

Table 3 .

 3 Johnson-Cook material constants of titanium alloy used for FE simulations.

Table 4 .

 4 Comparative results concerning chip morphology characteristics.

Fig.4. (a) CAD model of cutting insert and workpiece and (b) thermo-mechanical initial conditions of the cutting insert and workpiece for orthogonal cutting process.

parameters. Finally, a special attention should be paid to appropriate selection of the Johnson-Cook (J-C) constitutive parameters.