Ahmad Al Youssef

Laurent Artola

Samuel Ducret

Guillaume Hubert

Raphael Buiron

Christian Poivey

Franck Perrier

S Parola

Single-Event Transients in Readout Circuitries at Low Temperature Down to 50 K

Keywords: Single event transient, heavy ions, infrared image sensors, low temperatures, ROIC

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

I. INTRODUCTION

NFRARED image sensors are used in many space applications [START_REF] Hopkinson | Radiation effects in CMOS active pixel sensor[END_REF]. The readout integrated circuitries (ROIC) of infrared sensors are based on CMOS technology. By the way, the digital CMOS circuitries of image sensors are known to be sensitive to single event effects (SEE) [START_REF] Hopkinson | Radiation effects in CMOS active pixel sensor[END_REF] [START_REF] Virmontois | Radiation-induced dose and single event effects in digital CMOS image sensors[END_REF]. Wherefore, Single-Event (SE) vulnerability in electronics parts has become a major constraint for space applications whatever the temperature conditions. Single-Event induced by the radiation environment in ICs at elevated temperatures (especially in Earth's orbits), from 200K up to 420K, are widely investigated [START_REF] Truyen | Temperature Effect on Heavy-Ion Induced Parasitic Current on SRAM by Device Simulation: Effect on SEU Sensitivity[END_REF]- [START_REF] Artola | Modeling of elevated temperatures impact on single event transient in advanced CMOS logics beyond the 65-nm technological node[END_REF]. However, infrared image sensors are used at very low temperatures (<200K) [START_REF] Artola | Single Event Upset Sensitivity of D-Flip Flop of Infrared Image Sensors for Low Temperature Applications Down to 77 K[END_REF], in order to reduce the dark current and to increase performances.

The goal of this paper is to study the SET sensitivity of two ROICs (ReadOut Integrated Circuit) for a temperature range from 50K up to 300K. The signature (duration, multiplicity and occurrence location) of measured SETs is investigated. This work is based on the analysis of irradiation data obtained under a heavy ions beam at the heavy ion facility based at Université Catholique de Louvain la Neuve, in Louvain la Neuve, Belgium.

The first section of this work presents the ROIC devices tested during the SEE campaign. Two ROICs were developed by Sofradir for near infrared (NIR) and infrared applications (IR) for this campaign. The experimental setup used during the heavy ion irradiations will be also presented in this section. The second section presents the experimental data under heavy ion beams. Finally, this work is completed by simulations with the aim to confirm the assumptions presented in the discussion of experimental results. The simulation work is based on the use of a Monte Carlo SEE prediction tool called MUSCA SEP3. This tool allows for providing SEE estimations and analysis by mean of a simulation flow based A. Al Youssef, L. Artola, G. Hubert, are with The French Aerospace Lab (ONERA), Toulouse, France (email: ahmad.al_youssef@onera.fr ) A. Al Youssef, S. Ducret, F. Perrier, S. Parola, R. Buiron are with infrared detectors company (Sofradir), Grenoble, France C. Poivey is with ESA, ESTEC, 2200 AG Noordwijk ZH the Netherlands on physical and electrical simulations, as presented in previous works [START_REF] Hubert | Operational SER calculations on the SAC-C orbit using the multi scales single event phenomena predictive platform (MUSCA SEP3)[END_REF]- [START_REF] Hubert | Single-event transient modeling in a 65-nm bulk CMOS technology based on multi-physical approach and electrical simulations[END_REF].

II. DESCRIPTION OF SEE IRRADIATION CAMPAIGN

A. Devices under Tests

The experimental SEE test vehicle was developed by Sofradir and includes two types of ROIC, as presented in Table I. The first ROIC will be called A in the paper. Two samples ("A1", "A3") of the ROIC A have been tested. ROIC A contains three pixel arrays corresponding to three spectral bands. The dimensions of the first and second arrays are 224 x 4 pixels (line x column). The third array is designed with 448 x 4 pixels table.

The second ROIC is called B. Two samples ("B1", "B2"), have been tested. This ROIC controls also three pixels arrays. The dimensions of the first pixels array is 224 x 8 (Line x column). The second and third arrays are design with a 112 x 4 pixel table.

As mentioned, the two readout circuits have been developed by Sofradir and work at 5V. During the whole SEE tests, the ROIC and its pixel tables are under the heavy ion beams. The results only characterize the silicon system (bare ROIC without MCT attached). I each irradiation run a GUARD (Graphical Universal Auto Range Delatcher) system has been used on the DUT's power in order to detect SEL and to prevent its destruction [START_REF] Artola | Single Event Upset Sensitivity of D-Flip Flop of Infrared Image Sensors for Low Temperature Applications Down to 77 K[END_REF]. The occurrences of SETs and SEFI have been detected and recorded during the test campaigns. However, no SEL has been measured during the campaign. The immunity of Sodrafir designs and technology against SEL has been analyzed in a previous work [START_REF] Al Youssef | Investigation of electrical latchup and SEL mechanisms at low temperature for applications down to 50K[END_REF]. In this paper, only SET cross sections will be presented. Experimental SET test vehicle contains two counters to record SETs. Short SET events are considered when the event duration corresponds to one video frame. Large SET events are considered when the event duration corresponds to two or more video frames, as presented in Table IV. Each short SET and large SET events are recorded in a registers of 30 bits. On the other hand, the measured SEFI events are presented and discussed in a dedicated paper [START_REF] Artola | Complex Single Event Effects in CMOS pixel selection table and readout integrated circuit dedicated for Infrared Image Sensors[END_REF]. After this description of the experimental setup and the DUT characteristics, the experimental SET data will be presented in the next section.

III. EXPERIMENTAL DATA

In this section, experimental cross sections are presented as a function of LET (Linear Energy Transfer), and for a temperature range from 50K up to 300K. As mentioned previously, SETs are separated into two categories described in Table IV: (a) single SETs detected correspond to an event which occurs only on one pixel (b) Multiple SETs correspond to several SETs detected (from two up to four SETs) which occur at least on two pixels. The total SET cross section has been also estimated. This total SET cross section corresponds to the sum of the two SET categories but also the SET events with the events number is higher than 4 but lower than the size of the column of the pixel table.

A. Impact of Cryogenic Temperatures on Large SETs

Sensitivity Under Heavy Ion Irradiations Fig. 1 and Fig. 2 present the large SET cross sections measured on one sample of the readout devices "A" and "B", respectively the samples A1 and B1. The total large SET cross section (black triangles), the large multiple SET (red squares) and the large single SET (blue diamonds) have been measured for a heavy ion with a LET of about 32MeV.cm 2 .mg -1 and for a range of temperatures from 50K up to 293K. The large multiple SETs cross sections are one decade lower than the large single SETs cross. Error bars were calculated and plotted for each cross section value. The statistical errors are very low because of the large events counts.

Fig. 3 and Fig. 4 present the short SET cross sections measured on one sample of the readout devices "A" and "B", respectively the samples A1 and B1. The total short SET cross section (black triangles), the short multiple SETs (red squares) and the short single SETs (blue diamonds) have been calculated for a heavy ion with a LET of about 32MeV.cm 2 .mg -1 and for a range of temperatures from 50K up to 293K. Note that short multiple SETs have been detected only for sample ''A1'' at 55K. This point is discussed in section III.B. Total SETs cross sections are very close to short single SETs cross sections. It means that, the occurrence probability of complex short SET events is very low. As previously, error bars were calculated and plotted for each value of cross section. The statistical errors are very low because of the large events counts.

The results highlight a limited temperature dependence of large and short SETs susceptibilities for the two ROICs. This trend is in good agreement with a previous work done on D-Flip Flop CMOS device, i.e., for temperatures down to 77 K [START_REF] Artola | Single Event Upset Sensitivity of D-Flip Flop of Infrared Image Sensors for Low Temperature Applications Down to 77 K[END_REF]. This limited impact temperature has been highlighted in CMOS gates due to two reasons [START_REF] Artola | Modeling of elevated temperatures impact on single event transient in advanced CMOS logics beyond the 65-nm technological node[END_REF]: (a) saturation of carrier mobility and (b) transistors threshold voltage [START_REF] Gadlage | Temperature dependence of digital singleevent transients in bulk and fully-depleted soi technologies[END_REF], [START_REF] Sze | Physics of Semiconductor Devices[END_REF]. The upset of the D-flip flop cell mainly depends on the temperature dependence of the threshold voltage of n-MOS and p-MOS transistor. However, because of the saturation of the carrier mobility variation, at low temperatures, the variation of the threshold voltage of n-MOS and p-MOS transistors is the same and constant [START_REF] Gadlage | Temperature dependence of digital singleevent transients in bulk and fully-depleted soi technologies[END_REF]. Fig. 1. Large SET experimental cross sections measured on the sample "A1" during the test campaign under heavy ion (32 MeV.cm 2 .mg -1 ), as a function of temperature from 50K to 293K. Fig. 2. Large SET experimental cross sections measured on the sample "B1" during the test campaign under heavy ion (32 MeV.cm 2 .mg -1 ), as a function of temperature from 50K to 293K. Fig. 3. Short SET experimental cross sections measured on the sample "A1" during the test campaign under heavy ion (32 MeV.cm 2 .mg -1 ), as a function of temperature from 50K to 293K. Fig. 4. Short SET experimental cross sections measured on the sample "B1" during the test campaign under heavy ion (32 MeV.cm 2 .mg -1 ), as a function of temperature from 50K to 293K.

B. Short SET Measurements under Heavy Ion Irradiations at 60K

As presented in Section II.B, the short SETs have been detected when a change of pixel level occurs during only one video frame. Fig. 5 and Fig. 6 present the short SET cross sections measured on two samples of ROIC A: the sample "A1" and sample "A3". The total short SET cross section (black triangles), the short multiple SET (red squares) and the short single SET (blue diamonds) have been calculated during the campaign at 60K for a range of LETs from 3.3MeV.cm 2 .mg -1 to 67MeV.cm 2 .mg -1 . Error bars were calculated and plotted for each value of cross section. As shown in Fig. 5, the short SET cross section measured on the sample "A1" increases as a function of LET and saturates above 32MeV.cm 2 .mg -1 .

The short multiple SET cross sections are two decades lower than the short single SETs cross sections. Same trends are validated in Fig. 6 with sample "A3" of the ROIC "A". Short multiple SET cross sections trends show a low occurrence of short multiple SET as presented in Fig. 3, Fig. 5 and Fig. 6. The reason for having few multiple short SET seems to be coherent because the probability of short SET on a pixel causes other short SETs on adjacent pixels is very small. This observation is more discussed in section IV. The results highlight limited impact of the part to part variability in the same lot on the occurrence of short SETs susceptibility at cryogenic temperature for the ROIC "A".

C.Large SET Measurements under Heavy Ion Irradiations at 60K

As presented in Section II.B, the large SETs have been detected when a change of pixel level occurs during two video frames or longer. Figs. 7, 8, 9, and 10 present the large SET cross sections calculated from experiments for the samples "A1", "A3", ''B1'' and ''B2" respectively. The total large SET (black triangles), the large multiple SET (red squares) and the large single SET (blue diamonds) cross sections have been calculated during the campaign at 60K for a range of LETs from 3.3MeV.cm 2 .mg -1 to 67MeV.cm 2 .mg -1 . As observed previously, the error bars were calculated and plotted for each cross section value. As shown in Fig. 7, the large SET cross sections increase as a function of LET and saturate above 32MeV.cm 2 .mg -1 . The large multiple SET (red squares) and single SET (blue diamonds) trends in Fig. 7 and Fig. 8 are very close and more significant compared with multiple short SET in Fig. 5 and Fig. 6. It means that, the large multiple SET susceptibility is higher than short multiple SET susceptibility. However, the large multiple SET susceptibility (red squares) is 80% lower than the large single SET susceptibility (blue diamonds) of the ROIC "B" as highlighted in Fig. 9. Sample "B1" is less sensitive to large SETs than sample "A1". Same trends are observed in Fig. 10 for the sample "B2" of the ROIC "B".

On the other hand, the total large cross sections of samples "A1", "A3" of ROIC "A" and "B1", "B2" of ROIC "B" are dressed together in Fig. 11 as a function of LET in order to identify two points: (a) the impact of part to part variability in the same lot on the occurrence of large SET susceptibility at cryogenic temperatures for the ROICs "A" and ''B'' and (b) the SET sensitivity comparison between ROIC "A" and "B". the results highlight a limited impact of the part to part in the same lot variability in three points of ROIC "B", and a very limited impact of part to part variability between "A1", "A3".

For most points in Fig. 11, ROIC "B" is less sensitive to large SET than ROIC "A". This refers to the difference in design between ROIC "A" and "B". ROIC "B" has a pitch (distance between two pixels) twice as large as that of ROIC "A". All design elements are not available due to commercial sensitivities.

IV. DISCUSSION

In this section, the SET multiplicity is discussed. Three histograms that represent the occurrence of each SET category for both short and long SET types are presented in section IV.A. This multiplicity origin is investigated in section IV.B by the mean of SEE prediction tool, MUSCA SEP3.

A. Large and Short categories measurements

Fig. 12 presents a histogram of large SET events depending on their multiplicity. Each bar of the histogram represents the number of large SET events on the sample "A1" during test campaign at 60K. It has been irradiated at a fluence 1.10 6 .cm -2 with a heavy ion LET of about 32MeV.cm 2 .mg -1 . As mentioned, the ROIC A contains three pixel arrays. The dimensions of the first array are 224 x 4 pixels. Fig. 12. Number of Large SET events in each categories measured on the sample "A1" during the test campaign at 60K under heavy ion beam, fluence=10 6 .cm -2 , LET=32MeV.cm 2 .mg -1 .

(line x column). The second array is based on 224 x 4 pixels. The third array is based on 448 x 4 pixels. In this histogram, the single large SET events are the main events observed. The number of double large SET (120) is lower by a factor of three than the simple large SET numbers (369). Fig. 12 shows the low probability to observe more than two events on the neighborhood of a pixel. But the event with the seven multiple events during a single video frame seem to be not due to the strike of a heavy ion on the pixel arrays. In this histogram the category of events higher than 224 (the lower column size of pixel tables) is considered as complex SET events. The SEFI sensitivity of the two ROIC designs has been also presented in paper [START_REF] Artola | Complex Single Event Effects in CMOS pixel selection table and readout integrated circuit dedicated for Infrared Image Sensors[END_REF]. Two categories of SEFI have been shown: SEFI on the VIDEO frame and SEFI on a multiplexer which is used to control the phase of VIDEO signal. It seems that the design of the multiplexer and its configuration register is more sensitive to SEFIs for the ROIC "B" (NIR detector) than the ROIC "A" (IR detector). This difference in the SEFI sensitivity is highlighted by the LET threshold which is increased by a factor of 2. Finally, the limited temperature dependence of the SEFI video sensitivity of the two ROIC designs has been shown. The global SEFI sensitivities of the two ROIC are low and compliant with the Sofradir requirements [START_REF] Artola | Complex Single Event Effects in CMOS pixel selection table and readout integrated circuit dedicated for Infrared Image Sensors[END_REF]. Fig. 13 presents a histogram of short SET events depending on their multiplicity. Each bar of the histogram represents the number of short SET events on the sample "A3" during test campaign at 60K while it has been irradiated at a fluence 1.10 6 .cm -2 with a heavy ion with a LET of about 32MeV.cm 2 .mg -1 . As mentioned this sample contains three pixel arrays which have been described previously. In this histogram, the single short SET events are the main events observed. Two multiple short SET were observed, in two (category '2') and three (category '3') adjacent pixels as shown in Fig. 13. Fig. 13 shows the poor probability to observe more than one short SET on the neighborhood of a pixel. As previously, the events with the multiplicity higher than three during a single video frame does not seem to be due to the strike of a heavy ion on the pixel arrays and are considered as complex short SET. This same observation seems to strengthen the origin of the SETs. In this histogram the category of events higher than 224 (the lower column size of pixel tables) is considered as complex SET events.

A last observation of multiple short SETs is presented in Fig. 14. As previously, each bar of the histogram represents the number of short SET events on a sample of the ROIC B. During the test campaign at 60K, the device has been irradiated with a fluence of 1.10 6 .cm -2 with a heavy ion with a LET of 32.6MeV.cm 2 .mg -1 . As the difference of ROIC A, ROIC B contains three pixel arrays with the following dimensions: the first pixel array is 224 x 8 (Line x column). Fig. 13. Number of short SET events in each categories measured on the sample "A3" during the test campaign at 60K under heavy ion beam, fluence=10 6 .cm -2 , LET=32.6MeV.cm 2 .mg -1 .

The second and third arrays are 112 x 4 pixels. In this histogram, the single short SETs events are the only events observed and that confirm the first observation of single short SET in Fig. 13. But, no multiple short SETs were observed, only SEFI events were observed as shown in Fig. 14.

Finally, in order to confirm the hypothesis of the origin of the multiplicity of short and large SET an analysis has been performed by the mean of simulation based on the Monte Carlo SEE prediction tool, MUSCA SEP3. This analysis is presented in the next section. Fig. 14. Number of short SET events in each categories measured on the sample "B1" during the test campaign at 60K under heavy ion beam, fluence=10 6 .cm -2 , LET=32.6MeV.cm 2 .mg -1 .

B. Analysis Of SET Sensitivity trends by simulations

SEE prediction tools are used to analyze experimental data and confirm the hypotheses of the SEE experimental trends [START_REF] Artola | Modeling of elevated temperatures impact on single event transient in advanced CMOS logics beyond the 65-nm technological node[END_REF] [START_REF] Artola | Single Event Upset Sensitivity of D-Flip Flop of Infrared Image Sensors for Low Temperature Applications Down to 77 K[END_REF]. Based on the design parameters of the pixel table provided by Sofradir, the SET sensitivity of the ROIC has been calculated. 15 presents the SET cross sections calculated for sample "A1" under heavy ions. The multiplicity of the SET events is highlighted and it confirms that only two SET could be induced by a single particle in the pixel table for this technology. It means that the origin of events higher than four is due to events on the readout circuit, such as in a DFF of a line or column decoders of the pixel table.

V. CONCLUSIONS AND PERSPECTIVES

The SET sensitivity of two readout integrated circuits of infrared image sensor designed by Sofradir is investigated in this paper. Experimental data of short and large SETs obtained for a large range of temperature from 50K up to 300K under a heavy ions beam are presented and analyzed. The temperature impact on the SET cross sections is also presented. The results highlight a limited temperature dependence of the SET susceptibility of the two ROICs. The global SET sensitivities of the two ROIC are low and compliant with Sofradir requirements. The results also highlight a limited impact of the part to part variability in the same lot on the occurrence of SET susceptibility at cryogenic temperature for the ROIC "A" and ''B''. The multiplicity of short SET is lower than of large SET (by a factor of two decades). The multiplicity of the short and large SET events is investigated and analyzed by means of histograms of the short and large SET multiplicity. The two categories of multiplicity have been identified depending on the event location: occurrence one up to four SETs is due to an event in the pixel array, while a SEE occurrence with a higher SET multiplicity is due to an event on an adjacent control circuit. This analysis has been confirmed by simulations performed with the SEE simulation tool MUSCA SEP3.

Fig. 5 .

 5 Fig.5. Short SET experimental cross section measured on the sample "A1" during the test campaign, as a function of LET at 60K.

Fig. 6 .

 6 Fig.6. Short SET experimental cross section measured on the sample "A3" during the test campaign, as a function of LET at 60K.

Fig. 7 .Fig. 8 .

 78 Fig. 7. Large SET experimental cross sections measured on the sample "A1" during the test campaign, as a function of LET at 60K.

Fig. 9 .

 9 Fig. 9. Large SET experimental cross sections measured on the sample "B1" during the test campaign, as a function of LET at 60K.

Fig. 10 .

 10 Fig. 10. Large SET experimental cross sections measured on the sample "B2" during the test campaign, as a function of LET at 60K.

Fig. 15 .

 15 Fig. 15. Large SET experimental and simulated cross sections measured on the sample "A1", as a function of LET at 60K.

Fig.

  Fig.15presents the SET cross sections calculated for sample "A1" under heavy ions. The multiplicity of the SET events is highlighted and it confirms that only two SET could be induced by a single particle in the pixel table for this technology. It means that the origin of events higher

VI. ACKNOWLEDGMENT

The authors would like to thank TRAD for their support during heavy ions irradiations at UCL facility.


Wenjuan Gu

Diego Cattaruzza
email: diego.cattaruzza@inria.frmaxime.ogier

Maxime Ogier

Frédéric Semet
email: frederic.semet@centralelille.fr

Frédéric Semet Adaptive

Adaptive large neighborhood search for multicommodity VRP

Keywords: multicommodity VRP, adaptive large neighborhood search, local search

Introduction

In this work we study a vehicle routing problem where customers request multiple commodities. Different strategies to deliver a set of commodities to customers were presented in [START_REF] Archetti | Multicommodity vs. single-commodity routing[END_REF]. Among these strategies, a new one, the commodity-constrained split-delivery mixed routing problem (C-SDVRP) is presented and compared with classical ways to deliver multiple products (allowing to split a commodity or using vehicles dedicated to each commodity). In the C-SDVRP, the vehicles are flexible and can deliver any set of commodities, and a customer who requests multiple commodities can be delivered by different vehicles. When a commodity is delivered to a customer, the entire required amount is handed over. This problem arises for example in delivery of fresh fruits and vegetables to catering. In this case, products can easily be mixed into the same vehicle, and splitting the delivery of an individual commodity is not acceptable.

The C-SDVRP has first been studied in [START_REF] Archetti | Multicommodity vs. single-commodity routing[END_REF]. The authors proposed a branch-and-cut algorithm and a heuristic method. The heuristic consists in (1) making copies of each customer, one for each commodity required by the customer, and (2) using a heuristic for the capacitated VRP. In [START_REF] Archetti | A branch-price-and-cut algorithm for the commodity constrained split delivery vehicle routing problem[END_REF], the authors proposed an extended formulation for the C-SDVRP and developed a branch-price-and-cut algorithm.

This work proposes an adaptive large neighborhood search to solve the C-SDVRP, with the objective of obtaining very good solutions on small instances, and to be able to efficiently solve large instances.

Problem definition

The C-SDVRP can be defined based on a directed graph G = (V, A) in which V = {0} V C is the set of vertices, and A is the set of arcs. More precisely, V C = {1, ..., N C } represents the set of customer vertices, and 0 is the depot. A cost c ij is associated with each arc (i, j) ∈ A and represents the non-negative cost of travelling from i to j. Let M be the set of commodities that have to be delivered to the customers. Any customer i ∈ V C may request any set of commodities. The depot contains a fleet of identical vehicles with capacity Q, able to deliver any subset of commodities. The objective is to minimize the total travelling cost.

The problem involves two decisions : (1) finding a set of vehicle routes serving all customers ; (2) selecting commodities delivered to each customer. The constraints are : (1) each route starts and ends at the depot ; (2) the total quantity of commodities delivered by each vehicle does not exceed the vehicle capacity Q ; (3) each commodity requested by each customer must be delivered by a single vehicle ; (4) the demands of all customers need to be satisfied.

To solve the C-SDVRP, it is possible to duplicate the node associated with each customer by the number of commodities requested by the customer [START_REF] Archetti | Multicommodity vs. single-commodity routing[END_REF]. To each duplicated node, we then associate the demand of the customer for the corresponding commodity. For the sake of clarity, in the following we will call the duplicated nodes customer commodity.

In order to solve the C-SDVRP for large instances, we propose a heuristic method based on the ALNS framework of [START_REF] Ropke | An adaptive large neighborhood search heuristic for the pickup and delivery problem with time windows[END_REF]. Local search moves are also used in order to improve the solutions. A solution is represented as a set of routes. In order to take into account the specific features of C-SDVRP, a route can be represented : (1) as a sequence of customers, each customer having a set of commodities, or (2) as a sequence of customer commodities. In the first case, removing a customer from a route implies to remove the customer with the set of commodities delivered in this route, while in the second case it is possible to remove only one commodity.

ALNS relies on a set of removal and insertion heuristics which iteratively destroy and repair solutions. The probability to select a heuristic at a given iteration is influenced by its performance during past iterations. An initial solution is constructed as follows : (1) give a random sequence of customers commodities to construct a giant tour, (2) apply a split procedure [START_REF] Prins | A simple and effective evolutionary algorithm for the vehicle routing problem[END_REF] to get a solution, (3) apply local search to improve this solution. At each iteration, a simulated annealing criterion is used to accept a new solution.

Classical removal and insertion heuristics [START_REF] Ropke | An adaptive large neighborhood search heuristic for the pickup and delivery problem with time windows[END_REF] have been implemented. Removal heuristics are : random removal, worst removal and Shaw removal with a relatedness measure based on distance. Insertion heuristics are : greedy insertion and regret insertion. Worst removal and Shaw removal work with customers, while random removal can be applied either with customers or customer commodities. Insertion heuristics work with customer commodities.

In order to improve a solution, seven different local search moves are implemented. In the first three moves routes are considered as a set of customers. These moves are : (1) insert customer, (2) swap customers, (3) 2-opt of customers. Then, we propose two other classical moves adapted for customer commodities : (4) insert customer commodity, and (5) swap customer commodities. We also propose two other moves : (6) erase route : from a given route, remove the customer commodities until no other route has capacity to accept another customer commodity ; and (7) reassign commodities : for a given customer we propose a Mixed Integer Program to optimally assign all the commodities of this customer to the routes of the solution. Given a feasible solution, all 7 moves are iteratively applied one after the other, until no one improves the solution. Then, routes of the current solution are concatenated and split algorithm is applied. If this gives a better solution, the procedure is repeated.

Conclusions and perspectives

We test the efficiency of our ALNS on the instances proposed in [START_REF] Archetti | Multicommodity vs. single-commodity routing[END_REF]. Computational results show that our algorithm can solve to optimality 62 out of 64 small instances, and we provide some new best known values on mid-sized instances in reasonable computing time. The prospects are to implement other specific removal and insertion heuristics. Moreover, the proposed method can then be extended to other versions of the problems, like multi-depot version with a limited capacity of each commodity at each depot.


Christian Bruneau

Cédric Fischmeister

Alkene Metathesis for Transformations of Renewables

Introduction

With the depletion of fossil resources and the concerns about climate changing and environment protection, biomass is intensively considered as a sustainable source of raw material for the chemical industry and for the production of biofuels. [1][2][3][4] Beside the very abundant carbohydrate and lignocellulosic biomass, lipids and to a lesser extend terpenes are envisioned as promising candidates for the production of bio-sourced compounds with a broad range of applications. [5,6] Terpenes are of most importance in fragrance composition whereas fats and oils have already found application as bio-diesel fuel and they are also foreseen as a renewable source of polymers. The transformation of these renewable compounds into valuable molecules for the chemical industry using efficient and selective processes is therefore of prime importance. In this context, catalysis plays a pivotal role by offering efficient tools for converting biomass to more value added chemicals through economically and environmentally competitive processes. [7,8] In particular, olefin metathesis is one of the modern catalysed reaction which as impacted the world of homogeneous organometallic catalysis over the last 25 years. [9][START_REF]Handbook of Metathesis[END_REF][START_REF]Theory and Practice[END_REF] Continuous improvements of catalysts performances [12] and stability with better knowledge of activation and deactivation pathways [13][14][15] have rendered this process compatible with the transformation of bio-sourced compounds of variable purity. [16] In this chapter, we will review the main recent achievements and progress obtained in the valorisation of terpenes and lipids thanks to olefin metathesis.

Metathesis of unsaturated terpene derivatives

Terpenes are found in essential oils and constitutes a class of natural products that find direct applications and serve as feedstocks in flavor and fragrances industry and other potential applications due to their biological properties [17]. Terpenoids are chemically modified terpenes, essentially oxygenated derivatives such as alcohols, epoxides, ketones, aldehydes, carboxylic acids and esters. Chemical transformations of terpene derivatives have been investigated with the objective of producing new fine chemicals with high added value for diverse applications. Catalytic isomerization, rearrangements, cyclization, ring opening, hydrogenation, dehydrogenation, epoxidation, oxidation, hydration, hydroformylation, cyclopropanation are the most studied reactions [19][20][21]. Recent transformations of unsaturated terpenes and terpenoids based on olefin metathesis processes include ring closing metathesis of dienes, cross metathesis with ethylene and functional olefins to produce fine chemicals, ring opening metathesis and ring opening/cross metathesis for the production of reticulated polymers.

Ring closing metathesis

The ring closing metathesis of terpenes has been investigated with the monoterpenes citronellene 1, linalool 2, β-myrcene 3 and β-ocimene 4 (Scheme 1). Under RCM conditions, these terpenes containing a 1,6-diene structure eliminate isobutene and form cyclopentene derivatives from citronellene, linalool, and myrcene, and 2-methyl-1,3-cyclopentadiene in the case of βocimene.

Scheme 1. Terpenes used in ring closing metathesis

The first ring closing metathesis transformations of a monoterpene have been carried out with citronellene 1 in the presence of molybdenum and tungsten catalysts. With a catalyst loading as low as 0.1 mol%, the Schrock catalyst Mo(=CHC(Me)2Ph)((CF3)2MeCO)2(2,6-i Pr2(C6H3N) Mo1 catalyzed the ring closing metathesis of (-)-citronellene at room temperature into 3-methylcyclopentene 6 in 60% isolated yield without epimerization [22]. Each optically pure (R)-and (S)-citronellene enantiomer was converted into the corresponding (R)-6 and (S)-6 3-methylcyclopentene in 68-70% isolated yield and 97% enantiomeric excess with retention of configuration at 90 °C in 1,2,5-trichlorobenzene for 1 h in the presence of 2 mol% of WOCl2(2,6-Br2C6H3O)2 W1 as catalyst (Scheme 2) [23].

Scheme 2 Ring closing metathesis of citronellene 1 with Mo and W catalysts

Later on, this RCM reaction was achieved with full conversion of (R)-citronellene 1 with 0.5 mol% of the ruthenium catalyst Ru1 (Scheme 3) in toluene at 80 °C using microwave heating during 20 min [24].

Scheme 3. Structure of complex Ru1

A conversion of 93% of citronellene 1 was obtained during RCM at 60 °C for 6 h catalyzed by 84 ppm of second generation Hoveyda catalyst immobilized on silica [25,26]. In toluene at 80 °C, a TON of 16000 was obtained with very high conversion and selectivity, whereas the reaction carried out without solvent also gave full conversion of 1 but only 30% of 6 was formed together with high amounts of oligomers, and homometathesis and cycloisomerization by-products.

Ring closing metathesis of linalool 2 leading to isobutene 5 and 1-methylcyclopent-2-en-1-ol 7 as primary products, has been very often used as a model reaction to evaluate the catalytic properties of new ruthenium catalysts (Scheme 4).

Scheme 4 Ring closing metathesis of linalool 2

Several well-defined benzylidene ruthenium complexes and in situ generated ruthenium carbene moieties featuring a bidentate Schiff base ligand derived from salicylaldehyde [27][28][29], and a benzylidene ruthenium complex containing a tridentate phosphinesulfonate ligand [30] have revealed modest activities.

The most efficient ruthenium catalysts that have been used for this RCM reaction are presented in Scheme 5.

Scheme 5. Selected ruthenium catalysts used for linalool ring closing metathesis

In the presence of the first generation Grubbs catalyst Ru3 at room temperature in CDCl3 the reactivity of linalool 2 was one order of magnitude higher than that of citonellene 1, whereas the O-methoxy-protected linalool presented no reactivity even at 65 °C. These two results highlight the beneficial effect of the allylic alcohol functionality on the rate of the metathesis reaction as compared to isostructural terpene derivatives [31]. The second generation Grubbs catalyst Ru4 also gave full conversion whereas the Hoveyda-Grubbs catalysts Ru5 and Ru6 exhibited a slightly lower activity (Table 1 entries 1-4) [32,33]. Other second generation ruthenium complexes (Ru7, Ru8 and Ru9), equipped with a very bulky N-heterocyclic carbene ligand containing substituted naphthyl groups gave full conversion with excellent yields of isolated 1-methylcyclopent-2-en-1-ol 6 under mild conditions with 1 mol% of catalyst (Table 1 -entries 5-7) [34]. With Ru1 (Scheme 3) it was possible to reach full conversion within 10 min by increasing the catalyst loading to 0.5 mol% (Table 1-entries 8-10) [24]. The authors confirmed that the presence the allylic alcohol functionality increased the reaction rate since the full conversion of citronellene under similar conditions required a double time of 20 min.

The RCM of linalool has been investigated with Grubbs (Ru11, Ru12) and Hoveyda (Ru14, Ru15) second generation catalysts featuring frozen saturated N-heterocyclic imidazolinylidene ligands substituted on the backbone of the five-membered ring by two phenyl groups in syn-position and by ortho-tolyl groups at the nitrogen atoms with a syn or anti-conformation [35]. Full conversions of linalool were obtained with the Grubbs type catalysts Ru11, Ru12 and the less sterically hindered catalyst Ru10 when the reactions were performed with 1 mol% of catalyst in dichloromethane at 30 °C within 7 to 13 min (Table 1-entries [START_REF]Theory and Practice[END_REF][12][13]. With a lower catalyst loading of 0.1 mol%, the higher catalytic activity of the syn-isomer Ru11 was evidenced. The RCM reactions carried out at 60 °C in deuterated benzene in the presence of 1 mol% of the Hoveyda type catalysts Ru13, Ru14 and Ru15 led to full conversion within 6 min ( With catalysts Ru10, Ru11 and Ru12, complete dehydration of the alcohol took place after formation of 1-methylcyclopent-2-en-1-ol 7, to give first 2-methylcyclopentadiene (2-MCPD) 8 within 2 h, and then a mixture with its isomer 1-methylcyclopentadiene (1-MCPD) 9 (Scheme 7). With the phosphine-free Hoveyda type catalysts Ru13-Ru15, these subsequent reactions from 7 were much less pronounced. The second generation Hoveyda type complex Ru6 appeared as a good catalyst making the full conversion of 2 possible under neat conditions at room temperature with a catalyst loading of 0.1 mol% (Table 1 -entry 23) [36]. The Grubbs type catalysts Ru3 and Ru10 were less efficient and dehydration of 1-methylcyclopent-2-en-1-ol 7 to methylcyclopentadienes was observed with Ru3 and Ru6 when the temperature was increased to 60 °C.

Ruthenium complexes Ru17-Ru20 equipped with a benzylidene and a pyridine ligand with at least one chloride atom substituted by another halide or an alkoxide have been evaluated in ring closing metathesis of dienes [37,38]. In the presence of 0.05 mol% of catalyst in refluxing CDCl3, linalool was converted into 1-methylcyclopent-2-en-1-ol 7. Ru20 featuring two pentafluorophenoxy ligands exhibited an exceptional activity leading to full conversion in 1 hour, whereas the other catalyst precursors showed conversions located in the range 17-34% (Table 1 entries [27][28][29][30][31]. Nevertheless, all these ruthenium-pseudohalide catalysts led to 100% conversion in 15 min when the catalyst loading was as low as 0.5 mol%. The ring closing metathesis of β-myrcene 3 has been achieved with the second generation catalyst Ru4 at 40 °C in decalin as solvent (Scheme 7) [39]. From this triene 3, full conversion into 3-methylenecyclopentene 10 was obtained in the presence of 1 mol% of catalyst.

Scheme 7 Ring closing metathesis of β-myrcene 3 into 3-methylenecyclopentene 10

The diene 10 was then used for controlled cationic polymerization with a catalytic system based on i BuOCH(Cl)Me/ZnCl2/Et2O in toluene.

It has been shown that even in the presence of methyl acrylate 11 as cross metathesis partner, the ring closing metathesis of β-myrcene was favoured over the cross metathesis reaction [40]. The second generation benzylidene and indenylidene ruthenium catalysts Ru4 and Ru21 were led to excellent conversion of β-myrcene at 80 °C in the presence of 0.5 mol% of catalyst within 1 h with production of 10 in 62-67% GC yields and the cross metathesis product 12 in 13-14% (Scheme 8).

Scheme 8 Ring closing metathesis of β-myrcene in the presence of methyl acrylate

The RCM of cis-and trans-β-ocimene 13a and 13b, isomers of β-myrcene, (Scheme 9) has been studied in the presence of catalyst Ru21. The cis-derivative 13a was very reactive and led to 94% conversion after 1 h at 80 °C, whereas only 33% of the trans-isomer 13b was converted under the same conditions. However, the expected 2-methylcyclopentadiene 8 was formed in only 24% yield indicating that side or subsequent reactions took place.

Scheme 9. RCM of cis-and transβ-ocimene in the presence of Ru21 as catalyst

Cross Metathesis (CM)

Cross metathesis of terpenes with electron deficient olefins

The second generation Hoveyda catalysts have been found to be the most efficient catalysts for cross metathesis of terpenes and terpenoids with acrylic substrates. The cross metathesis of methyl acrylate 11a with the diterpenes citronellal 15, citronellol 16 and citral 17 was achieved in the presence of catalytic amounts of Ru6 in the green solvent dimethyl carbonate (DMC) at 60-80 °C leading to the cross metathesis products isolated in 42-70% yield (Scheme 10) [41]. With an acrylate as cross metathesis partner, not surprisingly the resulting double bond presented an E-configuration, exclusively. Dichloromethane [42] and glycerol [43] have also been used as solvent to perform these cross metathesis reactions with Ru4 and Ru6 as catalyst. In the case of linalool, the terminal and prenyl double bonds were involved in the cross metathesis process leading to the formation of the 1,9diester 20 with two (E)-double bonds in 40% yield obtained with only 0.5 mol% of catalyst Ru6 (Scheme 10) [43]. Dihydromyrcenol 21, a diterpenoid featuring one terminal double bond has been used in cross metathesis with n-butyl acrylate 11b in the presence of 1 mol% of Ru22 to give the (E)-isomer 22 in 75% yield after 18 h at 60 °C without solvent (Scheme 10) [44].

Cross metathesis of the more sterically hindered methyl methacrylate 23 required more demanding conditions. It was found that the best conditions for the transformation of 14, 16 and 18 were obtained under neat conditions at 80-90 °C with catalyst Ru6 (Scheme 11) [41]. Again, the reaction was stereoselective and only the (E)-isomers 24, 25, 26 were isolated in 75, 70 and 40% yield, respectively. These products formally correspond to new terpenoids with an oxidized prenyl group obtained without oxidation steps and generation of large amounts of wastes.

Scheme 11 Cross metathesis of terpenoids with methyl methacrylate

Cross metathesis of (S)-citronellal (S)-14 with methacrolein 27 was used to produce the optically pure dialdehyde 28 as the first step of the synthesis of the biologically active (-)-fusarisetin A [45]. The reaction was achieved in 75% yield with 5 mol% of the second generation Grubbs catalyst Ru4 in CH2Cl2 at 50 °C for 24 h (Scheme 12). With the catalyst Ru22, the cross metathesis of neat 21 performed at 60 °C with the ,β-unsaturated aldehydes 29 and 30 gave the same product, namely (E)-8-hydroxy-4,8,dimethylnon-2-enal 31, with high stereoselectivity (E/Z= 95:5 and 94:6, respectively), but acrolein 30 was more reactive than crotonaldehyde 29 leading to higher conversion with lower catalyst loading (Scheme 13) [44].

Scheme 12 Cross metathesis of (S)-citronellal with methacrolein Scheme 13 Cross metathesis of dihydromyrcenol with acrylic aldehyde

Cross metathesis of acyclic terpenes with terminal and internal olefins

A mixture of stereoisomers of the self-metathesis product 32 was produced in 82% yield when dihydromyrcenol 21 was treated at 80 °C for 3 h with 1 mol% of catalyst Ru22 under neat conditions (Scheme 14) [44]. When the terminal allylic alcohol 33 was used as cross metathesis partner,

Ethenolysis: double bond scission

Ethenolysis of terpene derivatives, which corresponds to cross metathesis with ethylene [48,49] and cleavage of internal double bonds to produce two different products has been used for degradation and analytical purposes rather than for target oriented synthesis. These applications involve terpenes with a high number of isoprene motifs and are not reported in details in this chapter. Among them, the triterpene squalene and the tetraterpene β-carotene have been selectively cleaved into shorter polyenes with ruthenium catalysts [50,51]. Ethenolysis has also been used to degrade polyisoprene and polyisoprene-containing copolymers in the presence of various catalysts based on molybdenum, tungsten or ruthenium [52][53][54][55][56][57][58][59]. Alkenolysis, which corresponds to cleavage with short internal alkenes has also been investigated [60,61] with limonene [62,63] and β-pinene [64], which have been used to produce terpene-terminated oligomers of isoprene.

Cross metathesis of cyclic terpenes

Cyclic terpenes are more sterically hindered than the acyclic ones, and the access to the reactive catalytic center might be difficult in some cases. However, with the non-functional terminal olefin 1-hexene 45, limonene 44 reacted in the presence of 2 mol% of Ru4 at 55 °C without solvent to give the cross metathesis product 46 in 40% yield (Scheme 17) [65].

Scheme 17 Cross metathesis of (D)-limonene with 1-hexene

This reactivity of limonene with a terminal olefin has been extended to the production of co-oligomers starting from 1,5-hexadiene in the presence of Ru4 (1 mol% with respect to the diene) in an excess of limonene as solvent (30 equiv.) at 45 °C. Polyhexadiene was formed together with hexadiene oligomers featuring one or two limonene ends [65].

It has been shown that β-pinene 47 and camphene 48 failed to give the cross metathesis reaction with N,O-protected allylglycine. On the other hand, the cross metathesis of these sterically hindered terpenes with the prenylglycine derivative 49 was possible with 5 mol% of Ru6 at 100 °C in the presence of a large excess of the cross metathesis partner and the modified terpenes 50 and 51 were obtained in 36 and 34% yield, respectively (Scheme 18) [66].

The cross metathesis with the aliphatic internal olefin (Z)-3-methylpent-2ene 52 with β-pinene has also been carried out with 5 mol% of catalyst Ru4 at 45 °C without solvent and the two possible cross metathesis products 53 and 54 have been observed (Scheme 18) [64].

Scheme 18 Cross metathesis involving β-pinene 47 and camphene 48

The general idea to make these cross metathesis reactions with bulky double bonds successful was to favour the productive with respect to the non-productive pathway by playing with the steric parameters of the cross metathesis partner [66,67]. Hence, the cross metathesis of β-pinene and camphene appeared to be more efficient with a trisubstituted olefin as cross metathesis partner than with a terminal olefin. This is in line with the computational studies, which indicated that non-productive metathesis of β-pinene in the presence of another olefin takes place in the presence of second generation ruthenium catalysts via formation of a carbene involving the pinene substrate, and that its self-metathesis does not occur because it is inhibited both by kinetic and thermodynamic factors [55].

Ring opening metathesis polymerization

Ring opening metathesis of terpenes is extremely scarce. Only recently, the ring opening metathesis of the sesquiterpenes caryophyllene 55 and humulene 56 has been reported [68]. The ruthenium catalysts Ru4 and Ru26 appeared to be the most active for this polymerization where only trisubstituted double bonds were involved (Scheme 19). Complete conversion of 55 was achieved even with 0.04 mol% of Ru26 at 25 °C and its exocyclic methylene group was not involved in the polymerization process.

Scheme 19 Ring opening metathesis of two sesquiiterpenes

Finally, functional hyperbranched polymers have been produced via ring opening metathesis polymerization of dicyclopentadiene in the presence of terpenes. D-Limonene, limonene oxide, β-pinene, carvone have been used as chain transfer agent to modify the physical properties and thermal stability of thermosets based on polydicyclopentadiene [69,70].

Metathesis of unsaturated fatty acid derivatives

Triglycerides are the main components of fats and oil leading to fatty acid and esters following hydrolysis or transesterification, respectively. They originate essentially from plant seeds or algaes and are composed of essentially mono-or poly-unsaturated linear carbon chain and a terminal carboxylic functional group. Oleochemistry is a well-developed domain in food industry as well as in biofuels and is based on the reactivity of the terminal carboxylic functional group or carbon-carbon double bond [71][72][73] and in some case on the presence of other functional groups present in the linear carbon chain, a typical example being castor oil. [74][75] Among the portfolio of carbon-carbon double bond transformations, olefin metathesis appears as a very efficient and versatile catalytic transformation offering a broad range of potential applications for the transformation and valorisation of fatty esters. The main transformations of fatty esters by olefin metathesis will be considered hereafter focusing on recent contributions.

Self metathesis

The early days of olefin metathesis of fatty esters concerned essentially the self-metathesis reaction promoted by heterogeneous catalysts. [76] This reaction later developed with homogeneous catalysts offers an easy access to fatty dieters of interest for the production of polyesters. As depicted in Scheme 20, methyl oleate 59 can be converted into dimethyl 9-octadecene-1,18-dioate 60 and 9-octadecene 61 in general in an equilibrium mixture unless polyunsaturated fatty esters are used. [77] A number of reviews cover this topic that will not be further developed in this chapter. [78][79][80] Scheme 20: Self-metathesis of methyl oleate 59

Cross Metathesis

Cross metathesis is another important transformation that allows the introduction of a variety of functional groups. [81] In contrast to self-metathesis, cross-metathesis can easily be brought to high conversion and selectivity using an excess of one of the reagent in general the less prone to self-metathesis and/or the less expensive. Two different reactions can be applied to fatty esters derivatives. The first one, cross-metathesis with ethylene ("ethenolysis") has been used in order to cleave fatty esters into 2 terminal olefins whereas cross-metathesis with functional olefins aims at preparing bi-functional molecules as polymer precursors.

Ethenolysis

The ethenolysis of fatty esters has been used to shorten the chain length of fatty esters thereby producing valuable medium chain compounds for polymer industry. For instance, the ethenolysis of methyl oleate 59 produces methyl 9-decenoate 62 and n-1-decene 63, two compounds with many applications in fragrance, polymers and surfactants (Scheme 21). [48,49] Scheme 21 Ethenolysis of methyl oleate An early report by Mol in 1981 paved the way to future developments in ethenolysis of fatty esters. This work identified what will be one of the major challenge of ethenolysis. Indeed, selectivity to the desired products 62 and 63 is hampered by self-metathesis reactions leading to undesired compounds 60 and 61. However, the ethylene pressure is an efficient manifold to access high selectivity. For instance a Re/Al/Sn catalyst delivered up to 29% of self-metathesis products when the reaction was conducted under 2 bar of ethylene pressure but self-metathesis was almost totally suppressed when the reaction was conducted with 50 bar of ethylene pressure. [84] Since this first report, many improvements have been achieved owing to the development of well-defined catalysts. In a thorough experimental and computational study, researchers at Dow Chemical reported a TON of 15000 obtained with Grubbs catalyst Ru3 in the ethenolysis of methyl oleate hence raising the issue of the economic viability of this process for which a TON of 50000 would be required. [85] A major improvement came in 2008 when the group of Schrodi reported a TON of 35000 and selectivity of 83% obtained with the Ru-CAAC Ru27 (CAAC: CycloAlkylAminoCarbene) catalyst Ru27 (Scheme 22). [86] More recently, Grubbs and Bertrand studied the structure/activity relationship of a series of Ru-CAAC complexes where they reported the highest TON ever reported in ethenolysis with a slightly different catalyst Ru28 (Scheme 22). [87] Of note, they highlighted the dramatic influence of the feed purity. If the necessity to use low hydroperoxidecontaining methyl oleate is a known issue necessitating pre-treatment of the oil feed, [88][89][90][91][92] the influence of the ethylene gas purity was studied and found to be also a major parameter to consider for achieving high TONs.

The highest TON still reported to date (340 000) was thus obtained at 40 °C with a catalyst loading of 1 ppm and an ethylene purity and pressure of 99.995% and 10 bar, respectively. If the vast majority of ethenolysis transformation of fatty esters has been performed with ruthenium based catalysts, this reaction was also reported with molybdenum catalyst but with moderate TONs.

[93]

Scheme 22. Ru-CAAC catalyst in ethenolysis of methyl oleate

Alkenolysis

Beside the cleavage by ethenolysis of fatty esters, researchers sought a more efficient cleavage process by considering the formation of ruthenium methylidene species as the Achilles' heel of this reaction. Another type of fatty ester cleavage denoted as alkenolysis was thus investigated. In 2006, Jackson and Robinson reported the cross-metathesis of natural oils with 2-butene. At that time, the purity of both methyl oleate and 2-butene were identified as key issues for achieving high TONs. A productivity as high as 470 000 was achieved at -5 °C and Hoveyda catalyst Ru6 with triply distilled methyl oleate and 2-butene free of 1,3-butadiene, which acted as a catalyst poison. [94] In 2012, Meier used the cross-metathesis of oil-derived biodiesel with 1-hexene in order to shorten the chain length of the fatty ester chains. Best results (TONs > 2000) were obtained with Umicore M51 Ru23. [95] It must be noted that alkenolysis was also used for the simple determination of double bond positions in long chain olefins including fatty esters. [96] Alkenolysis of fatty esters was transferred into an industrial process by Elevance in a joint venture with Wilmar. This metathesis process is used to produce chemical intermediates by cross-metathesis of natural oils with 1-butene. [97,98] Very recently, Mecking extended alkenolysis to algaes' based poly-unsaturated fatty derivatives in particular the penta-unsaturated eicosapentaenoic ester. Several ruthenium catalysts were evaluated in the butenolysis reaction of this compound with 2-butene searching for high conversion and selectivity. Most second generation ruthenium catalysts were found competent for this reaction but the selectivity for the desired methyl 5-heptenoate was not exceeding 48%. However, increasing the catalyst loading to 0.2 mol% per double bond led to a selectivity of 95% for the desired product. [99] Interestingly, the self-metathesis of eicosapentaenoic acid opens the way toward the synthesis of biosourced benzene.

[100]

Cross Metathesis with functional olefins

Olefin metathesis has been used for the polymerization of long chain fatty esters under various manners.

[101] The cross metathesis of fatty esters with functional olefins is a one stone two birds process as it shortens the carbon chain length while introducing a second functional group. The prepared homo-or hetero-bifunctional compounds are of great interest for the preparation of short chain polymer precursors. Cross-metathesis with acrylic derivatives have been extensively studied for the preparation for diesters [102-105] and nitrile-esters [106-111] derivatives for the production of polyesters and polyamides, respectively (Scheme 23). Other cross metathesis partners such as allyl chloride, [112] acrolein [113,92] and alkynes [114,115] have also been used. The direct synthesis of bifunctional compounds incorporating a carboxylic acid function was reported by Schrekker. [119] In this comparative study, the benefit of using acrylic acid or maleic acid instead of methyl acrylate or maleate was established. Better conversion and selectivity were obtained using ultra-pure methyl oleate 59 and Hoveyda catalyst Ru6 in THF at 60 °C. It is postulated that these results are likely due to the higher steric hindrance of esters vs acid. An important contribution came in 2015 from the group of Gauvin. It was demonstrated that the use of methyl crotonate 76 as cross metathesis partner led to significant improvements in terms of activity and selectivity for the cross metathesis products (Scheme 26).

[120] As an example, a productive TON of 35450 was obtained with 26 ppm of catalyst Ru23. This protocol was scaled up to 50 g using an industrial grade feed under bulk conditions at 60 °C. A high conversion and selectivity for cross products of 96% and 97% were obtained, respectively. As exemplified here above the transformation of fatty esters by olefin metathesis aims almost exclusively at the synthesis of polymer precursors. In 2012, the use of methyl ricinoleate 86 as a platform chemical for the synthesis of high-added value chemicals was reported (Scheme 28). The synthetic strategy involved the functionalisation of methyl ricinoleate using the hydroxyl group present in the carbon chain and further ring closing metathesis. This methodology enabled the synthesis of a variety of compounds of interest for flavour or fragrance composition.

[124] The esters by-products of these reactions can be directly valorised by cross-metathesis transformations as described in 3.2.3.

Scheme 6

 6 Scheme 6Dehydration of 1-methylcyclopent-2-en-1-ol 6 catalyzed by Grubbs type catalyst

Table 1

 1

	-entries 17-19). With

Table 1 .

 1 Efficient ring closing metathesis of linalool 2

	Entry	Catalyst	Catalyst	Solvent	T (°C)	t (min)	Conversion a	Ref
			(mol%)				or yield* b (%)
		Ru3	5	CDCl3	rt	60	100	17
		Ru4	5	CDCl3	rt	60	100	17
		Ru5	5	CDCl3	rt	60	65	17
		Ru6	5	CDCl3	rt	60	95	17
		Ru7	1	CH2Cl2	rt	30	92*	18
		Ru8	1	CH2Cl2	rt	6	88*	18
		Ru9	1	CH2Cl2	rt	6	94*	18
		Ru1	0.1	toluene	80	60	43	8
		Ru1	0.1	DMC	80	60	40	8
		Ru1	0.5	toluene	80	10	100	8
		Ru10	1	CD2Cl2	30	13	100	19
		Ru11	1	CD2Cl2	30	7	100	19
		Ru12	1	CD2Cl2	30	10	100	19
		Ru10	0.1	CD2Cl2	30	60	30	19
		Ru11	0.1	CD2Cl2	30	60	59	19
		Ru12	0.1	CD2Cl2	30	60	33	19
		Ru13	1	C6D6	60	6	100	19
		Ru14	1	C6D6	60	6	100	19
		Ru15	1	C6D6	60	6	100	19
		Ru13	0.1	C6D6	60	6	>98	19
		Ru14	0.1	C6D6	60	6	>98	19
		Ru15	0.1	C6D6	60	6	90	19

a Conversion determined by

1

H NMR or GC. b Isolated yield

-b, 23, 27, 29, 30.

  34 was obtained in 43% yield after 24 h at 50 °C. Cross metathesis with methyl oleate 35 featuring a cis internal double bond led to 36 and 37 in 61% and 71%yield, respectively. These two products correspond to the reaction of 21 with each side of the double bond of 35 (Scheme 14). In this case, the (E)stereoisomers are the major ones (E/Z= 86:14 and 87:13) but as expected in a much less pronounced ratio than with the previous electron deficient olefins 11a

Scheme 14 Cross metathesis of dihydromyrcenol 21with non-activated olefins

The conjugated diene 40 was prepared in two steps in two steps from citronellal 14. The cross metathesis of 14 with allyl chloride 38 was first carried out in the presence of 2 mol% of catalyst Ru23 in refluxing dichloromethane for 5 h with an excess of 38 leading to the isolation of 39 in 65% yield with a E/Z ratio of 8.5:1. The ruthenium-catalysed dehydrochlorination reaction was then performed at room temperature with 5 mol% of [Cp*Ru(MeCN)3][PF6] as catalyst and provided 40 in 65% yield with a E/Z ratio of 8:1. (Scheme 15)

[46]

.

Scheme 15 Cross metathesis of citronellal with allyl chloride followed by diene formation

The ruthenium complexes Ru24-Ru25 featuring a 4-NMe2-substituted and 4,5-(NMe2)2-disubstituted imidazolylidene carbene ligand were evaluated in the cross metathesis of citronellol benzyl ether 41 with cis-1,4-diacetoxybut-2-ene 42 containing an internal double bond (Scheme 16)

[47]

. Under the conditions reported in Scheme 16, these ruthenium benzylidene complexes led to the formation of 43 in 77 and 85% yield, respectively. It is noteworthy that under similar conditions Hoveyda type catalysts equipped with the same N-heterocyclic ligands were less efficient as they delivered 43 with only 25% yield. Scheme 16 Cross metathesis of citronellol benzyl ether 41 with cis-1,4-diacetoxybut-2-ene 42

  Again, the best results were obtained with a high catalyst loading (4 mol%) of the indenylidene catalyst Ru21 and the formation of the self-metathesis product of 72 could not be reduced below 25%. Similarly, the investigation of the cross metathesis of 72 with dimethyl maleate and methyl acrylate 11 was realized. It was demonstrated that at 80 °C in toluene, the cross metathesis with methyl acrylate was faster and required lower catalyst loading (0.5 mol%) than the cross metathesis involving dimethyl maleate.[118] Scheme 25 CM of methyl 10-undecenoate 72 with diethyl maleate 73

	groups. As presented earlier for alkenolysis of methyl oleate, this process
	would be an ethylene free process when fatty esters such as methyl oleate
	59 are used. In 2011, Behr reported the cross metathesis of methyl oleate 59
	with cis-2-butene-1,4-diyl diacetate 69 (Scheme 24). The Schiff-base ruthe-
	nium catalyst was found the most efficient for this reaction leading to high
	conversion of methyl oleate. However, high selectivity could not be ob-
	tained even with a catalyst loading of 2 mol% [116]
	Scheme 23 Cross-metathesis of methyl oleate with methyl acrylate and acrylonitrile
	Following these pioneering researches on the preparation of bifunctional
	monomers using terminal functional olefins, several groups investigated
	cross metathesis reactions with internal olefins bearing one or two functional

Scheme 24 CM of methyl oleate with cis-2-butene-1,4-diyl diacetate At the same period, this group also investigated the cross metathesis of methyl 10-undecenoate 72 (arising from the pyrolysis of castor oil) with diethyl maleate 73 leading to the diester 74 (Scheme 25).[117] Experimental parameters as well as various ruthenium-based catalysts were investigated.

  Scheme 26 CM of methyl oleate 59 with methyl crotonate 76Similarly, the same group investigated the influence of nitrile-functionalized olefins on the outcome of cross metathesis with methyl oleate. Cross metathesis of methyl oleate was conducted with either acrylonitrile or crotonitrile (Scheme 27).[121] Under similar conditions i.e. Ru23 1 mol% , toluene, 60 °C, 4 h, a higher conversion was obtained with crotonitrile (75% vs 22%) but the highest selectivity was obtained with acrylonitrile (86% vs 82%). However, higher selectivity could be obtained at 110 °C but the process suffered from a rather high catalyst loading limiting the TON to values below 250.

Scheme 27 CM of methyl oleate 59 with crotonitrile 81

Scheme 10 Cross metathesis of terpenoids with acrylates

Scheme 28 High added-value compounds from methyl ricinoleate (castor oil)

Conclusion


Manish Chauhan

Nikhil Deshpande
email: nikhil.deshpande@iit.it.

Claudio Pacchierotti

Leonardo Meli

Domenico Prattichizzo

Darwin G Caldwell

Leonardo S Mattos

A Robotic Microsurgical Forceps for Transoral Laser Microsurgery

Keywords: Robot-assisted microsurgical forceps, robotic teleoperation, tissue gripping haptic feedback, robotic medical instruments, minimally invasive surgery, transoral laser microsurgery

Purpose:

In Transoral Laser Microsurgery (TLM), the close curved cylindrical structure of the laryngeal region offers functional challenges to surgeons who operate on its malignancies with rigid, single degree-of-freedom (DOF) forceps. These challenges include surgeon hand tremors, poor reachability, poor tissue surface perception, and reduced ergonomy in design. The integrated robotic microsurgical forceps presented here, is capable of addressing the above challenges through tele-operated tissue manipulation in TLM.

Methods:

The proposed device is designed in compliance with the spatial constraints in TLM. It incorporates a novel 2-DOF motorized microsurgical forceps end-effector, which is integrated with a commercial 6-DOF serial robotic manipulator. The integrated device is tele-operated through the haptic master interface, Omega.7. The device is augmented with a force sensor to measure tissue gripping force. The device is called RMF-2F, i.e., robotic microsurgical forceps with 2-DOF end-effector and force sensing. RMF-2F is evaluated through validation trials and pick-n-place experiments with subjects. Furthermore, the device is trialled with expert surgeons through preliminary tasks in a simulated surgical scenario.

Results: RMF-2F shows a motion tracking error of less than 400μm. User trials demonstrate the device's accuracy in task completion and ease of manoeuvrability using the Omega.7 through improved trajectory following and execution times. The tissue gripping force shows better regulation with haptic feedback (1.624 N) than without haptic feedback (2.116 N).

Surgeons positively evaluated the device with appreciation for improved access in the larynx and gripping force feedback.

Conclusions: RMF-2F offers an ergonomic and intuitive interface for intraoperative tissue manipulation in TLM.

The device performance, usability, and haptic feedback capability were positively evaluated by users as well as expert surgeons. RMF-2F introduces the benefits of robotic teleoperation including, (i) overcoming hand tremors and wrist excursions, (ii) improved reachability and accuracy, and (iii) tissue gripping feedback for safe tissue manipulation.

INTRODUCTION

Transoral Laser Microsurgery (TLM) is a non-invasive surgery for the treatment of laryngeal malignancies, e.g., cysts, polyps, nodules, or cancerous tumours. Introduced by Jako et al. [START_REF] Jako | Laser surgery of the vocal cords: an experimental study with carbon-dioxide lasers on dogs[END_REF], the traditional technique, as seen in Fig. 1(a), involves inserting a laryngoscope (length = 180mm, cross-section 16 X 23mm 2 ) into the patient's mouth to expose the surgical site. This allows a direct line-of-sight for the surgical microscope.

A laser micro-manipulator, consisting of a beam-splitter mirror and a small mechanical joystick, is coupled to the surgical microscope. The free-beam CO2 surgical laser is aimed manually at the site by moving the mirror.

Additionally, manually handled microsurgical instruments allow intraoperative tissue manipulation and extraction.

Problem Formulation

The manual microsurgical instruments in traditional TLM have scissor-like handles for open-close operation. The most common instrument, the microsurgical forceps (micro-forceps), is used for: (i) tissue manipulation (grasping, orienting, removing); (ii) stretching tissue for precise laser cutting and ensuring minimal thermal damage to healthy tissue; and (iii) orienting tissue to view pathologies. Figure 1(b) shows the dimensions of the various components within the TLM setup. As is seen, within the standard 400mm laser focal distance between the base of the microscope and the surgical site, a narrow 50~100mm range is available for inserting and manoeuvring the micro-forceps. Furthermore, these tools being rigid shaft cause: (i) constrained accessibility in the laryngeal region; (ii) unstable handling due to hand tremors and wrist excursions; and (iii) poor tissue gripping perception. This makes their usage cumbersome and non-ergonomic [START_REF] Liverneaux | Telemicrosurgery: robot assisted microsurgery[END_REF][START_REF] Hirano | Morphological structure of the vocal cord as a vibrator and its variations[END_REF].

To overcome the above-mentioned limitations, robotic assistance has been introduced in laryngeal surgery [START_REF]Da Vinci Surgical System[END_REF]. Towards this end, Simaan et al. [START_REF] Simaan | A dexterous system for laryngeal surgery[END_REF] presented snake-like manipulators having tip dexterity for tissue manipulation and suturing. Wang et al. [START_REF] Wang | Kinematic design for robot-assisted laryngeal surgery systems[END_REF] presented a robot-assisted master-slave system consisting of two symmetrical 9 degrees-of-freedom (DOFs) cable-driven manipulators, with quick-change interfaces for surgical tools. Solares and Strome [START_REF] Solares | Transoral robot-assisted co2 laser supraglottic laryngectomy: Experimental and clinical data[END_REF] and Desai et al. [START_REF] Desai | Transoral robotic surgery using a carbon dioxide flexible laser for tumors of the upper aerodigestive tract[END_REF] explored the utility of the da Vinci Surgical System [START_REF]Da Vinci Surgical System[END_REF] but found the size of the da Vinci tool shafts as a major limitation. These endeavours seek to replace the microscope with dedicated instrument arms entering through the laryngoscope. Importantly, although targeted at laryngeal surgery, the above systems cannot be used in TLM, since there would be no available access for the free-beam laser. He et al. [START_REF] He | A new ENT microsurgery robot: error analysis and implementation[END_REF] overcame this drawback through their cooperatively controlled teleoperation robot. In this approach, the instruments can be directly attached / detached from the 3-DOF wrist of the robot itself. Their design serves as an important guidepost for the research in this paper.

On a related note, tissue haptic perception is widely considered to be valuable for robot-assisted surgical procedures, showing enhanced perception accuracy, decreased completion times, and decreased peak and mean applied forces [START_REF] Van Der Meijden | The value of haptic feedback in conventional and robot-assisted minimal invasive surgery and virtual reality training: a current review[END_REF]. In TLM, given that the thickness of the laryngeal tissue is about 3~5mm [START_REF] Jako | Laser surgery of the vocal cords: an experimental study with carbon-dioxide lasers on dogs[END_REF], especially in the vocal cords, the regulation of tissue gripping forces is critical in avoiding tissue trauma or rupture. The lack of gripping force feedback is also a limitation with He et al. [START_REF] He | A new ENT microsurgery robot: error analysis and implementation[END_REF].

With the above background, the goal of this article is the introduction of robotic micro-forceps in TLM with a suitable haptic handling interface.

Contributions

Previously, in [START_REF] Deshpande | Robot-assisted microsurgical forceps with haptic feedback for transoral laser microsurgery[END_REF], the authors presented a first robotic micro-forceps prototype, which was bulky and unusable under the TLM microscope. In [START_REF] Chauhan | Design and control of a novel robotic microsurgical forceps for Transoral Laser Microsurgery[END_REF], a second version was designed, having a motorized 1-DOF endeffector, which complied with the constraints of TLM and was integrated with a force sensor. Its haptic master interface provided teleoperation control through gesture scaling and elimination of hand tremors and wrist excursions [START_REF] Chauhan | Design and control of a novel robotic microsurgical forceps for Transoral Laser Microsurgery[END_REF]. The haptic feedback facilitated better regulation of gripping force application [START_REF] Chauhan | Design and control of a novel robotic microsurgical forceps for Transoral Laser Microsurgery[END_REF]. Taking this previous research forward, this article presents the design of an improved version of the robotic micro-forceps device, having:

(i) a motorized 2-DOF micro-forceps end-effector, with gripper jaw open/close and tool-shaft rotation for enhanced reachability. The previous version in [START_REF] Chauhan | Design and control of a novel robotic microsurgical forceps for Transoral Laser Microsurgery[END_REF] was only 1-DOF;

(ii) teleoperation control similar to [START_REF] Deshpande | Robot-assisted microsurgical forceps with haptic feedback for transoral laser microsurgery[END_REF];

(iii) tissue gripping force (TGF) capability with impedance-based feedback (as opposed to proportional feedback [START_REF] Chauhan | Design and control of a novel robotic microsurgical forceps for Transoral Laser Microsurgery[END_REF]) for improved tissue surface perception; and

(iv) updated experimental evaluation including phantom tissue-based test-bed along with preliminary validation with expert surgeons, which was not done in [START_REF] Chauhan | Design and control of a novel robotic microsurgical forceps for Transoral Laser Microsurgery[END_REF].

The 2-DOF end-effector, integrated with a commercial 6-DOF serial manipulator arm (UR5 [13]) and the force sensor (ATI Nano17 [14]), forms the RMF-2F, i.e., robotic microsurgical forceps with 2-DOF endeffector and force feedback, as seen in Fig. 2(a). The device is configured to be a 5-DOF setup: 3-DOF Cartesian positioning at the surgical site combined with the 2-DOF end-effector. The RMF-2F is controlled by a haptic master device under unilateral teleoperation through the Omega.7 haptic master interface [15]. The following sections discuss the design, analysis, and evaluation of the proposed device.

DESIGN OF THE MOTORIZED 2-DOF MICRO-FORCEPS END-EFFECTOR

Figure 1(b) points to the key dimensions in TLM while Table 1 lists the key features, which are considered in the design of the motorized 2-DOF end-effector. The values for these features are arrived at empirically through measurements of the traditional setup and discussions with expert surgeons. Any mechanism to be used under the microscope, in-line with the surgical line-of-sight, and parallel to the laser beam, would need to have a small thickness to avoid vision occlusion and interference with the laser. Consequently, any actuators for the motorized DOFs would have to be placed away from the line-of-sight. Features 1 and 2 in the Table are therefore, derived from the dimensional constraints of TLM.

The main components of the 2-DOF micro-forceps are the: (i) tool shaft, (ii) tool shaft holder, and (iii) tool actuation mechanism.

The Tool Shaft

The traditional tool shaft has an outer diameter of ϕ = 2mm with an inner translating wire (itw, ϕ = 1mm).

The translation of this wire by 3mm (determined experimentally) provides the open-close DOF for the tool jaws.

To adapt it, the proximal end of the shaft is modified by attaching a hollow extension tube with external M3 threading to it. This modification is termed as the docking interface (DI) (Refer Fig. 3). The itw passes through the hollow DI to attach to the tool actuation mechanism for the open/close DOF, while the outer shaft attaches to the tool shaft holder.

The Tool Shaft Holder

Figure 4 shows the design of the tool shaft holder, which supports the tool shaft as well as the tool actuation mechanism. It comprises of three sub-frames: F1, F2, and F3. A housing, HS, mounted on F1 at P1, supports the tool shaft. HS houses two small ball bearings Bf and Br. The DI is held within the bearings to incorporate the rotational DOF. HS is designed to have a cross-sectional thickness of 8mm.

The sub-frames F1 and F2 are rigidly connected at P2. The sub-frame F3 supports the linear actuator driving the open/close DOF while F2 supports the rotary motor providing the rotational DOF. The mechanisms are explained in the following subsections.

The Tool Actuation Mechanism

The tool actuation mechanism has two main components: the Open/Close DOF and the Rotational DOF.

Open/Close DOF

This mechanism is adopted directly from the design in [START_REF] Chauhan | Design and control of a novel robotic microsurgical forceps for Transoral Laser Microsurgery[END_REF]. Figure 5 shows the mechanism consisting of five linkages (L1, L2, L3, L4, L5), designed to provide linear translation of the itw. The hinge link L1 is considered as ground. L2 forms the input link along the actuator axis and it transfers direct motion to L3, which in-turn transfers inverse motion to L4 about L1. L4 is directly coupled to the driven link L5, which is attached to the itw. The Nanotec L2018 linear actuator, with 30N feed force, drives the open/close DOF.

The detailed mechanism design using the graphical synthesis method is presented in [START_REF] Chauhan | Design and control of a novel robotic microsurgical forceps for Transoral Laser Microsurgery[END_REF]. There are two key insights in the design:

(i) The force sensor is located at L2 with its measurement axis coincident with the actuator axis. The reaction force of the closing of the forceps on tissue is transmitted through the itw and the linkages on to the sensor surface, which in-turn outputs a signal in direct proportion to the gripping action.

(ii) As stated in Table 1, the optimal displacement between the tool-base and the microscope line-of-sight is 200mm. Here, through the choices of 50mm and 150mm for the lengths of L3 and L4, the total distance between the tool shaft axis and the actuator axis becomes 200mm. Additionally, the link-length ratio for L4:L3 becomes 3:1. Thus, a 1mm displacement of L2 results in a 3mm displacement of L5 and the itw, resulting in the open/close of the micro-forceps jaws.

Rotational DOF

The mechanism for the rotational DOF is implemented as the coordinated motion of three components:

(i) Miter Gear assembly (MG); (ii) Spur gear assembly (SG); and (iii) Modified link L5 mechanism (ML5) (Refer Fig. 6).

(i) Miter Gear assembly, (MG):

The tool shaft rotation is made possible through a miter-gear assembly with an outer diameter1 of 8mm (Refer Fig. 6(a)). The gear GO is mounted onto a shaft SO such that it is orthogonal to the tool shaft axis. The axial gear GA is mounted co-axially with the tool shaft axis and attaches rigidly to the DI of the tool shaft. The miter-gear assembly GO-to-GA transfers rotation to the tool shaft through DI.

(ii) Spur Gear assembly, (SG):

The shaft SO rotates through a low-backlash 1:1 spur-gear assembly (SG1 and SG2) (Refer Fig. 6(b)). This assembly transfers the rotary motion of the actuator (RM, Nanotec SC2018 with 1.8 N-cm torque) to SO, and thereby to MG. An additional ball bearing (Bb) supports the rotation of SO and reduces the vibrations in the rotation.

(iii) Modified link L5 in the open/close DOF, (ML5):

To allow simultaneous rotation and translation of the itw (through the DI), a suitable adaptation is necessary in link L5. Three components are introduced for this purpose: (i) a specially designed holder (HI) with set-screws to attach the itw. The holder includes a small shaft extension; (ii) this extension is inserted into a small ball-bearing (BS), thereby allowing HI to rotate freely; (iii) BS is held within a housing HB which is integrated with link L4 (Refer Fig. 6(c)).

With these adaptations, the motorized micro-forceps has 2-DOFs in compliance with the TLM constraints.

INTEGRATION OF THE ROBOTIC MICRO-FORCEPS -RMF-2F

As seen in Fig. 2, the 2-DOF motorized micro-forceps tool is attached as an end-effector to the UR5 robotic manipulator at a 90 o angle, resulting in the RMF-2F device. The UR5, seen in Fig. 2 2.

TELEOPERATION CONTROL AND VALIDATION

A master haptic interface, the Force Dimension Omega.7, as seen in Fig. 2(d the RMF-2F device, ensuring minimal time delay between the two. A two-layer, time-domain controller [START_REF] Franken | Bilateral telemanipulation with time delays: A two-layer approach combining passivity and transparency[END_REF] preserves the stability and transparency of the system.

(i) Since the kinematics of the master interface and the RMF-2F are non-homothetic, a unilateral velocitybased teleoperation controller is implemented. This was suitable for the requirements of the narrow workspace inside the laryngoscope. The 3-DOF master end-effector velocity (𝑞̇ℎ ∈ ℝ 3 ) is filtered and scaled with a gesture scaling factor ζ and mapped to the velocity (𝑞̇𝑟 ∈ ℝ 3 ) of the RMF-2F, as shown in Eq. 2. The constants have values: ζ = 0.2 and β = 0.025, adapted from [START_REF] Deshpande | Robot-assisted microsurgical forceps with haptic feedback for transoral laser microsurgery[END_REF].

𝑞̇ℎ 𝑘 = (1 -𝛽) • 𝑞̇ℎ 𝑘-1 + 𝛽 • 𝑞̇ℎ 𝑞̇𝑟 𝑘 = 𝐽 -1 • 𝑞̇ℎ 𝑘 • 𝜁 (2)
𝐽 -1 is the inverse of the manipulator Jacobian matrix, 𝐽 ∈ ℝ 3𝑥3 . The integrated system was characterized in [START_REF] Deshpande | Robot-assisted microsurgical forceps with haptic feedback for transoral laser microsurgery[END_REF] giving a low position mapping error of 0.3901mm ± 0.3829mm, signifying transparency and accuracy. Figure 7(a) shows a sample plot for the tracking error in one axis.

(ii) For the end-effector, the jaw open/close and tool-tip rotation are controlled unilaterally. The relationship is shown by Eq. 3, where η1 = 3 and η2 = 2 are empirically chosen to compensate for the friction and hysteresis in the system. The position command loop runs at 100Hz.

[ 𝑞 𝑟𝑜𝑡 𝑞 𝑗𝑎𝑤 ] = [ 𝜂 1 0 0 𝜂 2 ] [ 𝑞 ℎ 𝑦𝑎𝑤 𝑞 ℎ 𝑔𝑟𝑖𝑝 ] (3)
(iii) For force sensing, the ATI Nano17 Force/Torque sensor (Fig. 2(c), 𝜙 = 17mm, L = 14.5mm), offers a fine resolution of 3.125 mN with sensing up to 70 N, and registering data at 7 kHz. The characterization of the TGF at the sensor was done in [START_REF] Deshpande | Robot-assisted microsurgical forceps with haptic feedback for transoral laser microsurgery[END_REF].

EXPERIMENTAL EVALUATION

The performance of the RMF-2F device was validated through evaluation experiments simulating real surgical actions like grasping, pulling, and manipulating the laryngeal tissue. These trials were performed with 10 non-medical subjects (mean age = 28.2 years; 8 males, 2 females) with no prior experience in such tasks. The trials consisted of pick-rotate-n-place tasks, as seen in Fig. 8. A test-bed with cavities for different 3D-printed shapes (triangle, rectangle, semi-circle, and circular ring) was prepared. The shapes were fixed with artificial tissue-like material to provide tissue-gripping sensation. This phantom tissue is a bi-component polyurethane elastomer (F-105 A/B 5 shore, BJB Enterprise) added with a softening agent (SC-22, BJB Enterprise) [START_REF] Ciullo | Development of a surgical stereo endoscopic image dataset for validating 3D stereo reconstruction algorithms[END_REF]. For uniformity of results, each trial began with the RMF-2F in home position (15mm above the test-bed center). The experiments were conducted in two conditions, C1 (haptic feedback activated) vs. C2 (haptic feedback deactivated).

In condition C1, the measured TGF is rendered to the gripper DOF of Omega.7. To do this, the force sensor value is first filtered using a low-pass filter (β = 0.001, Eq. 4), to suppress noisy signals. It is then scaled based on the internal angle of the micro-forceps jaws using Eq. 5. The value rendered to the gripper DOF is calculated using Eq. 6. Here, Ω 𝑔 is the maximum internal angle of the jaws in open position, i.e., 90⁰, and 𝜔 𝑔 𝑘 is the internal angle at instant k. After extensive offline testing, the values of the constants were obtained as c = 1.5

and γ = 1/20, giving 1.5 < k k < 5.5. The rendered force therefore varies in proportion to the sensed force as well as the internal angle of the gripping jaws, giving an impedance-based haptic feedback.

𝑓 𝑔 𝑘 = (1 -𝛽). 𝑓 𝑔 𝑘-1 + 𝛽. 𝑓 𝑔 𝑠𝑒𝑛𝑠𝑜𝑟 (4)
𝑘 𝑘 = 𝛾. (𝛺 𝑔 -𝜔 𝑔 𝑘 ) + 𝑐 (5)

𝑓 𝑔 𝑜𝑚𝑒𝑔𝑎 = { 0, 𝑓 𝑔 𝑘 ≤ 0 𝑘 𝑘 • 𝑓 𝑔 𝑘 , 𝑓 𝑔 𝑘 > 0 (6)
𝑓 𝑔 𝑠𝑒𝑛𝑠𝑜𝑟 is calibrated to avoid the values from the free-space open/close of the RMF-2F. The haptic feedback loop runs at 500Hz to ensure transparency. Figure 9 shows the behaviour of Eq. 6 for 𝜔 𝑔 𝑘 , 𝑓 𝑔 𝑘 , and 𝑓 𝑔 𝑜𝑚𝑒𝑔𝑎 with a sample trial with the Triangle shape. As is seen, 𝑓 𝑔 𝑘 varies between -1 and 2 N, while 𝑓 𝑔 𝑜𝑚𝑒𝑔𝑎 varies between 0-10 N, through the various phases of: closed jaws (0⁰ angle), micro-forceps opening ('A'), shape gripped ('B'), shape release initiated ('C'), and shape released ('D').

Subjects conducted 8 trials each (twice on each shape) in the following order: (i) Semi-circle, (ii) Ring, (iii) Triangle, and (iv) Rectangle. The conditions C1 and C2 were randomized across the trials to obtain un-biased evaluation. The device performance was analysed by measuring the: (i) Trajectory followed by the RMF-2F for the tasks; (ii) Execution time required to conduct the tasks; (iii) Number of failed attempts during task execution; and (iv) TGF feedback performance in C1 and C2 conditions.

Trajectory Analysis

Figure 10(a) shows a sample trajectory for the RMF-2F with the Triangle shape, starting from the home position, picking-up the object from its cavity, and then placing it in the other cavity. The re-orientation of the objects during the trial is quantified (180⁰ in case of the Triangle) in Fig. 10(b), where the radial direction represents the time in seconds. For analysing the usability of the device, the trajectory ratio was used as a metric.

With 8 consecutive trials, the trajectory length for the first trial was used as the basis against which the ratios for the 7 succeeding trials were calculated. Figure 11(a) shows the overall trend of the ratios over time indicating that the subjects find the device easy and quick to learn. The ratio of the 8 th -to-1 st trial is 0.6988, while the average ratio over the 7 trials is 0.9111. The positive performance for the device is attributed to the ease-of-learning offered by the Omega.7 interface and its transparent integration with the RMF-2F.

Execution Time and Controllability

A similar downward trend in the time taken for the task completion demonstrates the RMF-2F's easeof-learn-ability. Figure 11(b) shows such trends for the two metrics: (i) time to lift the shape from the cavity (Tlift); and (ii) time to transfer the shape (Ttotal). As observed, Tlift goes from 43.2s to 28.8s, an improvement of 33.3%.

The same trend is seen for Ttotal, going from 84.2s to 49.9s, giving an improvement of almost 40%.

In terms of controllability, over all the trials (a total of 80), only 18 failed attempts (failure to lift the shape or transfer it to the other cavity) were recorded in task execution.

Tissue Gripping Force analysis

TGF feedback analysis was conducted using the 𝑓 𝑔 𝑘 value from Eq. 6. Figure 12(a) shows a sample trial for the Triangle shape in the C1 and C2 conditions, where the difference in levels of force is evident. The highlighted locations indicate phases of the task. The analysis shows that the average TGF applied on the phantom tissue is less in condition C1 (1.624 N) in comparison to C2 (2.116 N), as seen in Fig. 12(b). This difference is statistically significant according to the Student's t-test (p = 0.0486). Similarly, the value for the maximum TGF is less in C1 (5.532 N) than in C2 (6.768 N), although not statistically significant (p > 0.05). For soft tissue, the closing of the RMF-2F jaws displaces the tissue around the jaws, thereby causing a non-linear variance (and reduction) in the gripping force over time. By incorporating the internal jaw angle in the force feedback, this effect of squeezing soft tissue can be compensated for, providing a more natural tissue gripping sensation. This demonstrates better regulation of gripping forces in the C1 condition, where the subjects applied less force on the phantom tissue, as against the C2 condition. It allows better tissue surface perception and improved safety against potential tissue trauma.

Furthermore, in terms of controllability, out of the 18 failed trials recorded, 8 were in the C1 condition and 10 in the C2 condition. Although positive for C1, this data is not conclusive enough.

Preliminary Surgeon Trials

To introduce RMF-2F in the TLM operating room (OR), it is important to understand the suitability of its functionality and features for the surgeons. In this regard, three surgeons from the Ospedale San Martino in Genova (Italy) were invited to perform preliminary experiments using the RMF-2F device. To simulate real surgery, ex-vivo pig larynxes, held in a specially designed holder, were used. Pig larynxes, available at the supermarket, resemble the human larynx closely and surgeons use them frequently for training purposes [START_REF] Jiang | Comparison of the phonation related structures among pig, dog, whitetailed deer, and human larynges[END_REF]. The surgical setup, with surgical microscope, laryngoscope, laser micro-manipulator, larynx-holder, and the RMF-2F, is seen in Fig. 13. When positioned properly, the pig larynx provides similar constraints as in the real TLM surgery, and thus is an optimal test-bed to evaluate the overall RMF-2F design. The surgeons were asked to perform grasping, pulling, turning, and manipulation of the larynx tissue. The surgeons provided useful informal feedback:

(i) Tool-tip rotation: This functionality was appreciated by the surgeons since it helped them reach different areas of the vocal region. They were able to grip-n-turn the tissue for better exposition.

(ii) Appreciation of TGF feedback: While using the device under two different feedback conditions (C1 and C2), surgeons could distinguish between gripping action on tissues and regulate the applied forces.

(iii) Vision occlusion under microscope:

The surgeons complained about partial vision occlusion during usage. This implies the need to further reduce the device dimensions.

DISCUSSIONS

The RMF-2F device is a first-of-its-kind device introducing robotic assistance and haptic feedback in TLM, while also complying with the associated spatial constraints. The positive evaluations from the non-medical subjects and surgeons demonstrate that the RMF-2F would be beneficial in the TLM OR. The ergonomics and comfort while controlling the device, tissue perception through haptic feedback, and reachability with the device are key improvements introduced by RMF-2F.

The evaluations pointed to the required improvements as well. The cantilever tool shaft introduced small vibrations at the tip and caused the vision occlusion mentioned by the surgeons. Based on comments by the surgeons, an additional DOF for tip articulation may would allow overcoming these issues through better tip control, while also enhancing accessibility. This re-design is currently under investigation.

The surgeon trials also highlighted the need for training in using a device like the RMF-2F, especially through haptic teleoperation. Years of prior training allows surgeons to use traditional manual tools under the microscope effortlessly. With similar experience, surgeons may be able to easily manoeuvre robotic devices through teleoperation as well. In future research, along with improvements in device form-factor, the gripping force shall be further investigated for isolating different components like stretching, twisting, etc. The limits of stability and transparency shall also be established for intuitiveness in robotic teleoperation. To minimize vision occlusion and avoid tool interference with laser path, sufficient distance between the laryngoscope entry point and the designed tool base is necessary.

2.

Tool cross-section under the microscope of <10mm.

To maintain minimum vision occlusion, when viewed through the microscope.

3.

Introduce tissue surface perception through haptic feedback.

To receive tissue gripping force feedback.

4.

Introduce tool rotation DOF. Enhance tool capability for enhanced workspace and reachability. Table 2

  (b), has a payload capacity of 5 kg, repeatability of 0.1mm, a reach radius of 850mm, and can be controlled at 125 Hz. These values make it suitable for precise teleoperation control. Since the motorized micro-forceps already has a rotational DOF, the final orientation DOF of the UR5 is not used. The D-H parameters of the integrated RMF-2F device are suitably updated as a 5-DOF global device (3-DOF positioning + 1 DOF rotation + 1 DOF open/close), as given in Table

  ), teleoperates the RMF-2F. The Omega.7 has 7-DOFs (6-DOF motion + 1-DOF gripper), of which the three translational DOFs and the gripper DOF are active. The three translational DOFs control the 3-DOF positioning of the RMF-2F. The yaw DOF of the Omega.7 commands the rotational DOF of the RMF-2F, while the gripper DOF commands its open/close. Omega.7 provides active gravity compensation to improve the teleoperation transparency and reduce the operator's fatigue. The integrated system uses a dedicated gigabit Ethernet connection between the master and

Figure 7 (

 7 b) shows the TGF value varying non-linearly from the fully open position of the micro-forceps (0N, tissue not touching the jaws) to the fully-closed position (16N). The inset in Fig. 7(b) shows the customized characterization setup.

  This paper presented a novel design of the 5-DOF RMF-2F device for intraoperative use in TLM, integrated with the Omega.7 teleoperation haptic master and the ATI Nano17 force sensor. The RMF-2F device offers: (i) motorized tool-tip open/close and rotation; (ii) precise motion, stable positioning, no hand tremors, reduced wrist excursions, and gesture scaling through teleoperation; and (iii) improved safety through tissue gripping haptic feedback.

Fig. 1 Fig. 2

 12 Fig.1 Traditional TLM surgical setup: (a) overall dimensions; (b) dimensions around the laryngoscope Fig.2 The 5-DOF "RMF-2F" device. (a) 2-DOF micro-forceps end-effector integrated with the 6-DOF UR5 robot and the ATI Nano17 force sensor; (b) UR5; (c) ATI Nano17; (d) Omega.7.

Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 11 Fig. 12

 34567891112 Fig.[START_REF] Hirano | Morphological structure of the vocal cord as a vibrator and its variations[END_REF] The tool shaft Fig.[START_REF]Da Vinci Surgical System[END_REF] The tool shaft holder Fig.[START_REF] Simaan | A dexterous system for laryngeal surgery[END_REF] The tool actuation mechanism Fig.6 Detailed view of the rotational DOF of the tool actuation mechanism. (a) Miter Gear Assembly, (MG); (b) Spur Gear Assembly, (SG); (c) Link L5 modification, (ML5) Fig.7 Characterization of the RMF-2F: (a) Motion control evaluation; (b) TGF sensing (Inset: Characterization setup) Fig.8 Experimental evaluation setup. (a) Subject performing trial; (b) Test bed dimensions; (c) Test bed with phantom tissue shapes Fig.9 Sample trial depicting behaviour of Eq. 6. The highlighted locations indicate the phases of the trial: 'A' = Micro-forceps opening; 'B' = Shape gripped; 'C' = Shape release initiated; 'D' = Shape release completed Fig.10 RMF-2F trajectory during a sample trial. (a) 3-DOF position during task; (b) Angular orientation during task Fig.11 Results of experimental evaluation. (a) Overall trajectory ratio; (d) Execution time Fig.12 Results of TGF analysis. (a) Difference in TGF values for C1 and C2 condition for a sample trial; (b) Comparison of mean and maximum TGF Fig.13 Setup for preliminary trials of RMF-2F with expert surgeons

TABLE 1 : 1 .

 11 Design specifications of the microsurgical forceps Design Needs / Features Remarks Displacement from microscope line-of-sight of 200mm.

Table 1

 1

TABLE 2 :

 2 D-H Parameters for the RMF-2F integrated device Rotary; F = Fixed. 𝑙 6 = 210mm, 𝑙 7 = 200mm are dimensions of micro-forceps. 𝑞 𝑟𝑜𝑡 = rotary DOF.

	Joint	Type	a (m)	α (radians)	d (m)	q (radians)
	1	R	0.00000	𝜋/2	𝑑 1 = 0.089159	𝑞 1
	2	R	-0.42500	0.0	0.0000	𝑞 2
	3	R	-0.39225	0.0	0.0000	𝑞 3
	4	F	0.00000	𝜋/2	𝑑 4 = 0.10915	0
	5	F	0.00000	-𝜋/2	𝑑 5 = 0.09465	0
	6	F	0.00000	0.0	𝑑 6 = 0.0823 + 𝑙 6	0
	7	R	0.00000	𝜋/2	𝑑 7 = 0.108 + 𝑙 7	𝑞 𝑟𝑜𝑡
	R =

This is within the HS thickness of 8mm.

The research was carried out at the The study did not receive any external funding.