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University of Craiova Faculty of Mechanics Habilitation Thesis Mechanical Engineering Applications for Medical Systems Development Abstract Assoc. Prof. Dr. Eng. Lucian Gheorghe GRUIONU September, 25 th , 2017

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Page 1: Teza de Abilitare - GRUIONU LUCIAN - Rezumat EN · 3 A. INTRODUCTION This habilitation thesis presents my didactic and scientific work in detail, starting with the doctoral research

University of Craiova Faculty of Mechanics

Habilitation Thesis

Mechanical Engineering Applications for Medical Systems Development

Abstract

Assoc. Prof. Dr. Eng. Lucian Gheorghe GRUIONU

September, 25th, 2017

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TableofContents

A.INTRODUCTION................................................................................................................................................3B.APPLICATIONSOFENGINEERINGINDEVELOPMENTOFMEDICALSYSTEMS.................................................41. ModelingandFiniteElementAnalysiswithApplicationsinBiomechanics..........................4

1.1. Numericalapplicationsforsimulatingbiomechanicalkneejointbehavior......................41.2. Numericalstudiesonthemechanicalbehaviorofkneeandhipprosthesis.....................61.3. Numericalsimulationoftheboneremodeling.................................................................81.4. Evaluationofhemodynamicandoxygendelivery intissuesformicrovascularnetworks

builtbytissueengineering.................................................................................................................92. Hybridimagingsystemswithelectromagneticnavigationformedicalprocedures...........113. Navigation system for confocal laser endomicroscopy to improve peripheral lung lesion

biopsy 13C.FUTUREDEVELOPMENTDIRECTIONSONTEACHINGACTIVITYANDSCIENTIFICRESEARCH.......................174. Academicdevelopmentdirections.....................................................................................185. Directionsfordevelopmentinthefieldofscientificresearch............................................20

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A.INTRODUCTION

This habilitation thesis presents my didactic and scientific work in detail, starting with the doctoral research period and continuing the activities and results of the main research contracts I have conducted. Predominantly, didactic activity is oriented towards the relatively new areas of mechanical engineering such as computer-aided design and simulation, and my research is mainly directed towards applications of mechanical engineering in medicine.

The thesis is structured in three sections: an introductory section containing its summary, section B with a detailed presentation of my research activity, and a section C where I present the future directions of my personal academic development, specifically targeting future scientific research projects I plan to promote.

Section B presents my research studies in medical applications of mechanical engineering, that began during the doctoral period and continued during my US research internships and the competition winning contracts that I led to return to the country.

These studies address orthopedic subjects such as numerical modeling and numerical simulation of normal and prosthetic joints, normal and deficient human motion analysis, and applications of fluid mechanics in the study of blood flow through normal and tumor vessels. During the first one-year research period at Johns Hopkins University, Baltimore, USA, in the Urobotics Laboratory, I also actively participated in the design and development of robots and biopsy devices under radiological magnetic resonance guidance.

Next in this section I present the research studies I have carried out in recent years in a relatively new field in Romania and which I initiated following a research period at the Imaging Science and Information Systems Center of University of Georgetown, Washington, USA. They address the field of investigations and medical procedures with electromagnetic guidance and navigation, and have been funded through a series of grants that we have won and which led to the development of several prototypes, two patents and other five patent applications. Being passionate about the field of hybrid imaging and navigation systems in medicine, in 2010 I founded a spin-off based on the results of these studies, which led two nationally funded joint grants with both research and clinical activity. Also within this research area, I led as a director during 2014-2017, an international project with a consortium of prestigious partners from Norway and Romania.

During the intensive research work I have carried out over the past 20 years and which has also addressed other topics such as computer assisted design applications or numerical methods in robotics or medicine, I have occupied the following positions: director of an international research joint grant, director of 5 national funded research grant, and partner leader in 4 national funded research grants, with a total value over 2 million Euro, also I was researcher in 4 international research grants and 5 national research grants, all obtained by competition.

As a result of these funding, I created two new prototyping, mechanical engineering and biomedical laboratories at the University of Craiova, to which I contributed with equipment and software licenses with a total value of over 1.5 million Euro.

My research results are presented in 26 ISI indexed scientific papers as well as 77 papers presented at conferences or published in journals indexed in international databases such as PubMed, ScienceDirect, SCOPUS, etc. I also have an international patent, a national patent, and applied for 5 other patent applications.

My participation in the research teams of two of the world's top universities, Johns Hopkins University and Georgetown University, USA, as well as current collaborations in research contracts with number one University Harvard Medical School, USA, the prestigious SINTEF institute from Norway, St. Olav’s University Hospital and Norwegian University of Science and Technology from Trondheim, also demonstrate the quality of my research activity that I have tried to maintain at highest national and international level.

I am an active member of two international prestigious scientific societies, IEEE and the European Society of Biomechanics, an expert evaluator of the Romanian Agency for Quality Assurance

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in Higher Education (ARACIS) and a reviewer in the journals "International Journal of Computer Assisted Radiology and Surgery" and "International Journal of Advanced Robotic Systems ".

In the future, I plan to extend my academic activity by developing new Master of Science courses based on the methods, technologies and experience that I have acquired through the complex, interdisciplinary activities within the research contracts that I have led or participated in. In the field of scientific research, I want to maintain and develop the current field in which I am involved, that of engineering applications in the development of new medical systems and instruments, both through my direct participation as a researcher and as a future mentor of a doctoral team.

B. APPLICATIONS OF ENGINEERING IN DEVELOPMENT OFMEDICALSYSTEMS.

1. Modeling and Finite Element Analysis with Applications inBiomechanics. 1.1. Numerical applications for simulating biomechanical knee joint behavior.

In the first chapter of this habilitation thesis I presented succinctly the results of the research

obtained in the doctoral studies completed in 2004, followed by the activity from some of the grants that I have led and which I consider to be my contribution in the field of mechanical engineering applied in biomechanics. I have developed a number of proprietary numerical models for the main components of some joints, I have developed advanced studies for various clinical cases or sports activities as well as contributions to the design of simulators and prosthesis elements

The main objective of the doctoral research was to build a series of numerical models with finite elements capable of simulating the biomechanical phenomena that appear in the tibio-femoral joint during physical activities.

A first personal contribution presented in the PhD. thesis was the development of soft tissue constitutive relations. In the case of ligaments, the constitutive equation I have proposed has a phenomenological character by considering the general tissue behavior. I have modeled the non-linearities and relatively large deformations sustained by the tissue through a hyperplastic characteristic, derived from the deformation energy equation. I modeled the dependence of the deformation velocity by introducing a viscoelastic characteristic included in the constitutive equation as a Prony series. For cartilaginous tissue, I proposed a differentiated constitutive representation on two layers: the superficial one with a phenomenological formulation, of the hyperelastic type (Mooney-Rivlin) and the basic, with a microstructure of transverse isotropic type.

Initial stage in the analysis with finite elements, the determination of geometry, presents particular difficulties for biological models: the surfaces are of a high degree of complexity, the methods of obtaining dimensions present methodological, medical and ethical difficulties. The importance of a real geometry of the model with the lowest possible approximations is fundamental for the clinical validation of the results. We tried to avoid the idealized physical representations achieved so far in biomechanics by using a three-dimensional modeling procedure using the CT serial sections that led to an anatomically correct model.

The three-dimensional computational model of the knee joint that we have developed is characterized by high geometric accuracy and the possibility of reuse in various research fields. Joint movements are the boundary and initial conditions for finite element models. I determined the parameters of the movement both experimentally and by adapting some published cinematic data to the developed geometric model.

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The three-dimensional computational model complemented by the kinematic data set I consider is my second contribution, important in understanding the functionality of this joint. From the results of the finite elements method, I deduced that the developed constitutive equations give a near-reality behavior to the numerical model.

In the case of ligaments, the research I have carried out has led to a series of important conclusions, including:

- the distribution of deformations varies along the fibers, with a large gradient near the insertion area in the bone tissue;

- ligament ligation is uneven, with large variations in motion, with lateral ligaments maximum; - the visco-elastic component produce a gradual entry of the ligament under stress for high

velocity deformations due to the transfer of fluid from and to the tissue, resulting in an increase in the stresses recorded for the same type of stress with a material model without this component.

These results of the numerical analysis of ligaments I also consider to be a contribution in the biomedical field, important for surgical restoration, grafting or artificial implantation, of compromised ligament tissue.

Researches on contact and impact problems simulated at the joint surfaces (tibial plateau and femoral condyle) also provided a series of results from which I deduced important conclusions. Of these, I enumerate:

- due to the extremely low coefficient of friction, the percentage of shear in the resultant strain is relatively low ≅12%, for a general movement, for which sliding is an important component.

- the distribution of different collagen fibers for the two layers leads to lower shear strain as a value in the superficial layer of the deep, opposite the case of a homogeneous and isotropic layer, for which the shear strain decrease with depth. This results in a sliding phenomenon between the layers to the point where the collagen fibers in the lower layer change direction and oppose the sliding motion. The distribution of contact spots corresponds to the erosion zones observed on artificial implants, leading to their premature destruction.

These results of numerical analysis of cartilaginous tissue are an important contribution in the field of bioengineering, by explaining the complex mechanical phenomena occurring at the contact surface of the joints and whose knowledge is essential in the knee arthroplasty.

What I consider to be the most important to be highlighted at the end of this research program is the importance of using the finite element method in the mechanical behavioral simulations of biological systems with results whose applicability goes beyond the field of medicine. So I refer to the field of bio-engineering, which includes, among other things, the research and design of implants or specific materials, the industrial field through safety analysis of impact in the automotive or aviation sector and the design of sports equipment.

The whole methodology by which I have developed these numerical models and simulations, starting with the geometry, continuing with kinematics, cinetostatic, constitutive equations and finalizing with finite element analyzes, is an intrinsic contribution by establishing an orientation framework for future research of biomechanical systems. The numerical models I have developed can be complemented by following the same research methodology for the rest of the skeletal-muscle elements of the joints, the lower limb or even the entire human body to a level of complexity limited only by the computational technique needed to solve the analysis.

The research presented in this thesis continued for a two-year period as part of the grant for young researchers funded by CNCSIS, contract number 33547/2003, whose director I was and which had the title "Virtual biomechanical model for investigation, kinematic study and optimization of prostheses used to correct locomotor deficiencies. "

The following scientific papers resulted during doctoral studies:

1. Rinderu, P., C. Bratianu, L.G. Gruionu. A 3D finite element model of the cruciate ligaments in normal and special solicitations. in The 14-th Conference of the European Society of Biomechanics. 2004. Hertogenbosch, Netherlands.

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2. Bratianu, C., P. Rinderu, L.G. Gruionu. A 3D Finite Element Model of a Knee for Joint Contact Stress Analysis during Sport during Sport Activities. Key Engineering Materials, vol. 261-263, pag. 513-517, 2004, ISSN: 1013-9826, (ISI, IF 0.497).

3. Bratianu, C., L.G. Gruionu, P. Rinderu. Modeling and numerical simulation of tibio-femoral joint surface contact. in Proceedings of The 7-th International Conference on Mecatronics and Precision Engineering. 2004. Bucuresti, ISBN: 973-86886-1-2.

4. Bratianu, C., L.G. Gruionu. A Knee 3D computational model for stress analysis. in Performance Based Engineering for 21 Century. 2004. Iasi, ISBN: 973-667-063-5.

5. Rinderu E.T., Gruionu L.G., Rinderu P.L., Bratianu C., „A Finite Element Model of the Cruciate Ligaments”, European Congress of Sports Medicine, Hasselt, Belgium, 2003.

The following grants I have run as a director or partner director, have continued this research:

1. 2007-2009 – Director of a two years grant: “Improvements of the hip revision arthroplasty using computational, patient customized models for biomechanical evaluation”, supported by Ministry of Research and Education from Romania, Contract No. 27GR/11.05.2007.

2. 2006-2008 - Scientific director for a 3 years grant “Long term improvement of life quality for patients with arthroplasty through prosthesis functionality extension”, supported by Ministry of Research and Education from Romania, Contract No. 131/2006.

3. 2006-2008 - Scientific director for a 3 years grant “Patient customized recovering of the mobility for neurological and orthopedic pathology using interdisciplinary research methodology”, supported by Ministry of Research and Education from Romania, Contract No. 107/2006.

4. 2004-2006 – Director of a two years grant: „Computational method for evaluation of hemodynamics and oxygen transport in microvascular networks developed by tissue engineering”, supported by Romanian Academy of Science, Contract No. 125/2.09.2005.

5. 2004-2006 – Director of a two years grant: „Finite elements studies of shape and materials effect on knee implants behavior”, supported by National University Research Council from Romania, Contract No. 27661/14.03.2005.

6. 2003-2005 – Director of a two years grant: „Biomechanical virtual model for investigation, kinematics study and optimization of prosthetic implant for gait rehabilitation”, supported by National University Research Council from Romania, Contract No. 33547-2003.

Below are summarized the main research results of these grants.

1.2. Numerical studies on the mechanical behavior of knee and hip prosthesis

During the CEEX grant I led as a partner director for the University of Craiova, "Long-term

Improvement of the Quality of Life of Patients with Arthroplasties by Increasing the Durability of Functioning of Endoprostheses", financed by the Ministry of Education and Research, contract no. 131/2006) I have conducted a series of studies on the prosthesis of the knee and hip joint in order to determine the causes of malposition of the prosthesis elements and its effect in time.

The first objective of this study was to investigate the effect of malpositioning in the valgus and varus of the tibial component on the stress developed in polyethylene as well as in the subjacent bone. For this, a number of original numerical models of the anatomical elements (tibia, fibula, femur, cartilage, ligaments) of the knee have been developed (Figura 1, a, b) to simulate biomechanical phenomena occurring in the normal and prosthetic joint during physical activities for the purpose of evaluation factors that affect the duration of total knee prostheses.

Prosthetic alignment is one of the most important factors, both in terms of the correct functioning of the new joint and the survival duration of knee arthroplasty. Significant changes in the alignment of prosthetic components affect the distribution of stress in the knee joint. These changes may also affect the distribution of stresses on the contact surface, knee soft tissues, and the subjacent bone that is remodeling under these forces.

The research done by the team I conducted aimed to achieve concrete results, useful for the clinical medical activity, by studying the bone remodeling phenomena and polyethylene wear, which lead to the bone-implant assembly being destroyed over time. The numerical model of the joint, along

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with the motion kinematics, were used in the finite elements analysis of Scorpio Stryker's total knee-joint prosthesis behaviour, used for joint arthroplasty of the patients studied under this grant.

a b

c d Figura 1. Stress distribution (MPa) for a correct prosthesis (a, b), the CAD model (c) and the physical

simulator (d). To study the biomechanical changes that occur in various pathological cases and to determine

the effectiveness of various types of osteotomies, presenting various fixation and prosthesis systems, during this project was designed and developed by the team that I led a complex simulator, adaptable for simulation of knee and hip joint movements (Figura 1 c, d). The simulator allows a free flexion-extension movement between the femur and the tibia, having the hip and ankle joints attached to the support frame, respectively the base plates. An important feature of this simulator is that it does not directly control the kinematics of the knee. The forces acting on the joint are given by simulating the action of the quadriceps muscle and the external forces that are applied to the hip and ankle joints. Tests using the simulator can be performed on a normal or prosthetic joint, on an artificial or on a cadaver joint.

Simulator control: Due to the relatively large forces and rapid action required to simulate real-time activities with realistic body weight, servo-pneumatic drivers have been chosen. Each of the 5 movement axes features a feedback force sensor and can be operated with on-demand control. The operating system speed is 2Hz, programmable using the computer attached to the simulator. The simulator shows force / moment transducers after the three axes that will allow continuous or periodic monitoring. These parameters are essential for evaluating implant wear, changes in surface friction, etc. The simulator can work without supervision for 24 hours a day (important for implant testing and approval) allowing 172,000 cycles per day.

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The results obtained from the tests have shown that the simulator developed within this project can achieve a wide variety of load modes of the prosthetic joint, proving to be especially useful for the study of the mechanical behavior in a static and dynamic regime of total hip prostheses.

1.3. Numerical simulation of the bone remodeling. During the next grant that I led, "Finite Element Methods on Influence of Form and Material on

Performance in the Use of Knee Endoprostheses" funded by CNCSIS, Contract no. 27661 / March 14, 2005 I studied the complex phenomenon of bone remodeling that I was trying to simulate numerically.

The bone-implant interface deteriorates over time, resulting in loss of prosthetic components in total

knee arthroplasty due to bone resorption and resulting overload concentrations, and depends on the quality of the surrounding bone tissue, the mechanical and biological characteristics of the implant and the technique of implantation. Understanding the bone growth process is essential for a successful design of the knee prostheses. The objective of this study was to develop a computational model capable of simulating the process of bone formation at the interface with the implant under normal walking comparative stress conditions.

a b c

d e f Figura 2. Successive sections showing the density distribution through the tibial bone following simulation

before (a, b, c) and at (d, e, f) 10 months after arthroplasty and bone remodeling. For qualitative prediction, the internal mechanical stresses in the bone structure must be accurately

determined in terms of equivalent stresses and deformations, for which the finite element method has proved to be a particularly useful tool. By combining the mathematical description of the bone remodeling phenomenon with the finite element method, I made it possible to quantitatively predict the formation and resorption of bone tissue in real structures, and the results obtained I presented at the 5th World Biomechanical Congress in 2006 in Munich. These models are based on the principle that bone remodeling is induced by a local mechanical signal that activates regulatory cells (osteoblasts and osteoclasts). So, it is assumed that the bone has sensors that can cause mechanical stimuli and, depending on their value, may cause local bone adaptations.

To obtain a realistic simulation of the bone remodeling process, we followed two steps in this study: we developed a three-dimensional computational model of the knee joint before and after the

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prosthesis, and in the second stage we established a number of stress conditions of the joint as close as possible to reality, taking into account the biomechanical changes resulting from prosthesis ( Figura 2). This research algorithm was applied to a patient who underwent a complete knee

replacement operation following a knee arthritis, stage III according to the Alback classification. Simulated bone remodeling was based on the theory of adaptive bone remodeling as a result of

strain. The remodeling procedure assumed an iterative process due to non-linear conditions from the bone-implant interface. For the bone remodeling phenomenon only the internal trabecular bone was considered, the cortical was considered unaffected by the phenomenon to preserve the external shape of the bone. It was considered a threshold of 75% of the deformation energy for which no bone physiology transformation occurs. Bone modification as a result of the adaptation phenomenon consists of the time-dependent density variation for each finite element, and is triggered when an average value of the equivalent strain tensor is exceeded during the walking cycle.

In this study we considered that the adaptive phenomenon that alters the modulus of elasticity is in direct relationship with the von Mises tensor of strain. Therefore, the individual components of the tensor are considered stimuli, and a difference between the actual strain value and the reference value will lead to the adaptation of the elastic modulus at that location.

The prediction of the morphology of the tibial bone with arthroplasty, regarding the density distribution model, optimized according to the modeling rules presented, are similar to reality. The finite element model used is three-dimensional, and together with the stress cases it is identical to the tibial bone of the studied patient. Although the type of stimulus and the bone remodeling rule were purely theoretical, and the possibility that other phenomena stimuli and other rules would also be important, the results obtained during this study are very important.

A presentation of the algorithms and the obtained results I published in: 1. Gruionu, L. G., Rinderu, P. L., "Numerical simulation of bone ingrowth after total knee arthroplasty". 5th

World Congress of Biomechanics, Munich, Journal of Biomechanics, v39, s1, p412, 2006.(IF 2.364) ISSN: 0021-9290.

2. Georgeanu V., Atasiei T., Gruionu L., „Periprosthetic Bone Remodelling in Total Knee Arthroplasty”, MAEDICA – a Journal of Clinical Medicine 2014; 9(1): 56-61.

1.4. Evaluation of hemodynamic and oxygen delivery in tissues for microvascular networks built by tissue engineering.

The main objective of this 2-year grant that I led, "The computational method for the evaluation

of hemodynamic capacity and oxygen distribution in microvascular networks built for tissue engineering", funded by the Romanian Academy, Contract No. 125 / 2.09.2005, was to evaluate the hemodynamic performance and the distribution of oxygen in tissues by microvascular networks. The experimental models used in this grant were developed within the Interdisciplinary Program of Tissue Engineering of the University of Arizona, USA. The objective of the grant was achieved by developing a computational method for reconstruction and evaluation of microvascular networks. The overall hypothesis tested is that hemodynamics and oxygen diffusion in microvascular networks can be determined by detailed computational models based on experimental data.

According to the project proposal, a first specific objective, completed in the first year of research, was the development of a software module with the aim of automatically developement the bi-dimensional and three-dimensional geometric model of the microvascular network obtained experimentally.

In the first phase experimental data was obtained by the University of Arizona laboratory. The entire experimental activity involved collaboration with members of the Biomedical Engineering Laboratory at the University of Arizona. The entire US experimental activity (materials, reagents, equipment, laboratory animals) was funded by US collaborators.

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In the first stage, the objective was achieved, namely to develop a software module for geometric and computational, bi- and three-dimensional automated modeling of experimentally obtained micro-vascular networks (Figura 3). All the experimental data required for this phase of the project were obtained from the Biomedical Engineering Laboratories of the University of Arizona, USA, and based on them the expected software module was developed. This first stage of the research project solved the problem of geometric modeling of micro-vascular networks, difficult to obtain by the usual methods used for biological models of normal size.

a b

c d Figura 3. The selection screen of points (a) with another type of network, of great complexity, also developed artificially in the laboratory. The three-dimensional network model with the color map (b) on the depth of the

preparation ranging from 0 to surface and up to 100 microns total thickness. An STL representation of the model (c, d) suitable for subsequent modeling by the finite element method for hemodynamic calculation.

În continuare s-a trecut în etapa a doua de cercetare la obiectivul 2 - dezvoltarea unui modul

software cu scopul de a evalua performanţa reţelei microvasculare. Ipoteza demonstrată de acest obiectiv cu ajutorul modulelor software dezvoltate este că folosind condiţiile la limită obţinute experimental (curenţii de sânge şi presiunea la intrare şi ieşire din reţea) şi un model geometric realist se pot estima variabilele hemodinamice în fiecare vas din reţeaua microvasculară. Calculând performanţa hemodinamică a reţelei adică valorile curenţilor de sânge şi gradienţii de presiune pentru fiecare vas din reţea s-a putut simula adaptarea unei reţele vasculare în cazul întreruperii alimentării unui vas, ca urmare a unor afecțiuni cardiovasculare.

Next, we went to the second stage of research at Objective 2 - developing a software module to evaluate the performance of the microvascular network. The hypothesis demonstrated by this objective with the help of the developed software modules is that using the experimentally obtained boundary conditions (blood currents and inlet and outlet pressure) and a realistic geometric model, the haemodynamic variables can be estimated in each vessel in the microvascular network. By calculating the hemodynamic performance of the network, ie the blood flow and pressure gradient values for each vessel in the network, it was possible to simulate the adaptation of a vascular network in the event of a vessel disruption due to cardiovascular disease.

The full completion of the two objectives has made it possible to better define the performance of

the microvascular networks necessary for the vascularization of certain types of biological tissues created in the laboratory.

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The dissemination of the results of these research, which continued through collaboration in the years that followed with the US laboratories, was made in the following scientific papers:

1. Gruionu, G., J.B. Hoying, M.H. Laughlin, G.M. Constantinescu, L.G. Gruionu, T.W. Secomb, Simulation

of blood flow and structural adaptation in arteriolar arcade network of miniature swine triceps muscle: Maintenance of perfusion following partial removal of blood supply. FASEB Journal, 2003. 17(4): p. A551 ISSN: 0892-6638, (indexat ISI).

2. Gruionu, G., J.B. Hoying, L.G. Gruionu, M.H. Laughlin, T.W. Secomb, Structural adaptation increases predicted perfusion capacity following vessel obstruction in the arteriolar arcade network of pig skeletal muscle. American Journal of Physiology: Heart and Circulatory Physiology, vol 288 (6): H2778-H2784, 2005 ISSN:0363-6135. (indexat în ISI şi PubMed/Medline, factor impact 3.560)

2. Hybridimagingsystemswithelectromagneticnavigationformedicalprocedures

In the following I continue to present my research activity as director in a project funded by the

European Structural Funds, which led to the establishment of spin-off for research and development in the medical field and the development of a hybrid navigation and imaging system called TRIGER, with applications in gastroenterology: "Innovative system for early diagnosis, exact staging and monitoring of treatment of patients with digestive tumors (TRIGER)", co-financed by the European Social Fund for Regional Development under the Sectoral Operational Program "Increasing Economic Competitiveness" 285 / 16-12-2010, ID No. 983 Code SMIS-CSNR 19782. Part of the team of this complex interdisciplinary project that I led were mechanics and biomedical engineers specialists, doctors, IT engineers and specialists in electronics and automation.

Precise diagnosis and staging in abdominal and thoracic pathologies are specific for ultrasound endoscopy (EUS) procedures that generate high resolution images of the organs in various gastroenterological disorders. At the same time, linear EUS systems allow EUS-guided fine-biopsied procedures as well as cytological and micro-histological diagnostics, especially for lymph nodes and pancreas. Although these systems have provided an improved image and have been commercially available since the early 1980s, their adoption by gastroenterologists in clinical practice has been hesitant due to the large learning curve, the small viewing field, the difficult interpretation of EUS images as well as difficulties in navigation.

To solve this limitation, we built the TRIGER system and tested it for feasibility during EUS procedures during routine EUS examinations where the live image provided by the EUS probe was superimposed over virtual section reconstructed from the computerized tomography stack acquired before the procedure.

The results of these tests we published in the article: L. Gruionu, et al., “A novel fusion imaging system for endoscopic ultrasound”, Endoscopic Ultrasound, 5(1):35-

42, 2016. doi: 10.4103/2303-9027.175882. Sistemul de imagistica hibrida si navigatie TRIGER® (patent 127716/29.08.2014) utilizeaza un

sistem de tracking electromagnetic Aurora (Northern Digital Inc., Ontario, Canada) cu un generator planar de camp magnetic (cu volumul de 500x500x500mm) pentru pozitionare spatiala, conectat la un calculator care ruleaza un software proprietar de navigatie, impreuna cu un cateter customizat, plasat in canalul de lucru al endoscopului, si un marker activ cu 6 grade de libertate (Northern Digital Inc., Ontario, Canada) plasat pe pieptul pacientului (Figura 4). Cateterul pentru navigatie a fost realizat dintr-un ac fin pentru biopsie aspirativa (FNA) in care de acul de biopsie a fost atasat un senzor electromagnetic cu 6 grade de libertate (Northern Digital Inc., Ontario, Canada) astfel incat preluarea de probe sa fie in continuare posibila. Senzorul electromagnetic este montat aproape de capatul tubului cateterului, si este sigilat pentru a nu intra in contact cu tesutul pacientului.

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Figura 4. Components of the TRIGER imaging fusion system. During the registration procedure 4 coordinate

systems (CS1-4) are used which provide the necessary framework for the orientation of the preoperative imaging from the tomograph, with the intraoperative ones from the ecoendoscope and the space position of the caterer;

as well as catheter alignment with the 3D virtual model obtained from the CT imaging series.

The TRIGER Hybrid and Navigation Imaging System (patent 127716 / 29.08.2014) uses an Aurora electromagnetic tracking system (Northern Digital Inc., Ontario, Canada) with a planar magnetic field generator (500x500x500mm) for spatial positioning connected to a computer running a navigation software, along with a customized catheter placed in the endoscope working channel, and a 6-degree active marker (Northern Digital Inc., Ontario, Canada) placed on the patient's chest (Figura 4). The navigation catheter was developed from a fine needle biopsy needle (FNA) where an electromagnetic sensor with 6 degrees of freedom (Northern Digital Inc., Ontario, Canada) was attached to the biopsy needle without affecting the main function of the instrument. The electromagnetic sensor is mounted close to the end of the catheter tube and sealed to avoid contact with the patient's tissue.

The navigation software allows the operator to load the CT sections, create a 3D model of the patient's anatomy, perform the co-registration operation between the patient's EUS space and the CT space, identify and allow navigation to the target, and allow for fine tunning of the registration (Figura 5).

a b Figura 5. A representative screen capture for the EUS-CT fusion imaging system interface, for a clinical

procedure on a patient: (a) - lower aorta recording, image acquired from the esophagus; (b) - recording of a small tumor (lipoma), image aquired from the esophagus. In addition to the vascular structures and the target (tumor),

there is no correspondence between the visible anatomical structures on the EUS and the CT, since the lung tissue (containing air) and the bone structure of the column are visible only on the CT and the EUS has a viewing

field limited.

The navigation interface includes several windows like recording, fine calibration of orientation and positioning, dual-view EUS image - CT section. During the EUS procedure, navigation is facilitated by overlapping the real-time position of the endoscope tip with the virtual volume of the patient's anatomy. A correction of the registration is automatically made by the system if the patient moves, by using the sensor placed on the patient's chest, which offers real-time position and orientation relative to the magnetic field generator.

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The imaging fusion software's registration and navigation functions were developed by the team I conducted using open-source ITK, VTK and IGSTK libraries to synchronize imaging information from both imaging modalities.

Feasibility tests for the imaging fusion system were initially performed on an abdominal / mediastinal artificial model. A series of case studies for 20 patients with multiple pancreatic and mediastinal pathologies were performed by routine CT / EUS procedures. The CT-EUS fusion imaging sessions were conducted simultaneously with the classic EUS scanning procedure with electromagnetic guidance navigation and real-time co-registration of EUS images with CT sections previously acquired.

Based on the tests, it has been established that the hybrid imaging system increases the accuracy of tumor reach by combining a detailed CT scan with real-time images from eco-endoscopy without modifying the standard clinical procedure. Based on the assessment by experienced gastroenterologists, the EUS-CT hybrid imaging procedure does not significantly increase the time of the procedure even if multiple realignments and registrations are required. A major advantage of using the system is the ability to achieve target lesions by concomitant use of EUS and CT images that allow the physician to navigate and take biopsies between large blood vessels or other anatomical points and to visualize the presence of targets on both EUS images and CT after using contrast agents.

In conclusion, the hybrid imaging based on EUS-CT registration is feasible and accurate. Hybrid imaging with electromagnetic navigation will improve lesion detection and characterization by simultaneous CT/MR visualization of EUS targets. It can also be used as a training tool that can reduce the learning curve of EUS procedures and increase user confidence by improving navigation to determine targets previously identified in CT or MRI images. Further studies are needed to identify the multiple clinical benefits and training of healthcare professionals by combining the hybrid imaging system with the advanced ultrasonic endoscopy procedures with aspirational fine puncture.

3. Navigation system for confocal laser endomicroscopy to improveperipherallunglesionbiopsy

In the following, I present the results of the international research project that I led as a director

during the period from 1.07.2014 to 30.04.2017, entitled "Navigation system for laser confocal endomicroscopy for improving the peripheral leisure of plamani (NAVICAD)", financed through the Financial Mechanism - European Economic Area and Norwegian Financial Mechanism 2009-2014, the Program "Research in Priority Areas" under contract no. 3SEE / 30.06.2014, Code: EEA-J RP-RO-NO-2013-1-0123, DoRIS code RO14 - 0016 with the Ministry of National Education and Scientific Research.

The members of the consortium were the University of Craiova, Romania (coordinator), Politehnica University Bucharest, Romania (partner), SINTEF Technology and Society, Norway (partner), St. Olavs Hospital, Norway (partner).

The total value of the project was 1.1 million euro, the project duration was 34 months, and was completed on April 30, 2017.

The overall objectives of the NAVICAD project were: 1) development of an innovative bronchoscopy instrument composed of a steerable biopsy

forceps with electromagnetic tracking, including Cellvizio's fiber optics for CLE optical biopsy. 2) Design and implementation of a CAD system based on ANNs (Artificial Neural Networks) for

the interpretation of FDs (Fractal Dimensions) and lacunarity of pCLE images in quasi-real time. 3) NAVICAD software development for hybrid imaging, navigation and virtual bronchioscopy. Following the tests of the Mechanical and Biomedical Engineering Laboratory that I have set

up and run at the University of Craiova, we have chosen the final solution for this complex instrument (Figura 6): a 3-lumens PTFE catheter with outer diameter 2.5 mm and 1200 mm long.

The catheter has a 1.2 mm channel, a 0.7 mm channel, and a 0.5 channel. The catheter is mounted in a specially designed handle that allows axial translation and tip bending of a maneuverable

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guide wire that is installed in the 0.7 mm channel. This guide wire serves to solve the catheter steering function to allow for the orientation and choice of a particular path through the lung pathways. The wire allows bending of 180 degrees, for navigating through complex intersections. An electromagnetic tracking sensor with 5 degrees of freedom, manufactured by Northern Digital Inc., is installed inside the 0.5 channel. and is used by the Navicad system to determine the space position of the catheter tip using the Aurora electromagnetic tracking system. The 1.2 mm diameter channel is used for two operations: the optical biopsy, using the Cellvizio Confocal Miniprobe AQ-Flex 19 Optical Fiber from Mauna Kea or the classic biopsy when a 25G biopsy needle, specially customized within the project, is inserted through this channel. All the parts included in the handle were made by 3D prototyping on the Stratasys Fortus 400mc professional printer from ULTEM material, that is well-known by its good dimensional stability and outstanding resistance to breaking and corrosive agents.

a b Figura 6. The ultimate instrument prototype, made by 3D printing from ULTEM, on a FDM, STRATASYS

Fortus 400mc printer.

In order to evaluate the instrument precision, it was found necessary to carry out a series of numerical studies to assess the amplitude and frequency of movement of the peripheral nodules due to respiration and cardiac movements. The results of this research are extensively exposed in the grant reports, and the following published papers:

1. Horia-Alexandru Petrescu, Daniel Vlasceanu, Stefan Dan Pastrama and Lucian Gruionu, “Numerical

analysis for determining the displacements of a lung tumor”, Key Engineering Materials Vol. 638 (2015) pp. 177-182, Trans Tech Publications, Switzerland, doi:10.4028/www.scientific.net/KEM.638.177.

2. E. Nutu, H. Petrescu, D. Vlasceanu, L. Gruionu, S. D. Pastrama, “Development of a finite element model for lung tumor displacements during breathing”, Materials Today: Proceedings 3 (2016) 1091 – 1096, DOI: 10.1016/j.matpr.2016.03.054, Volume 3, Issue 4, 2016, Pages 1091–1096.

The design and development of the NAVICAD navigation module was the next stage of the

project in which the software was developed which allows for a preoperative plan of the procedure, a segmentation of the airways, the selection of targets (lung nodules) and anatomical markers, the reconstruction 3D volume, manual adjustment of direction and orientation above all axes, and a complex patient-virtual model imaging registration operation. NAVICAD virtual navigation methods are based on the rotation and translation of the OpenGL "camera" through which the virtual 3D scene is seen. There are two ways to use the camera: "free camera" ("local" rotation around the camera's co-ordinates) and "look at the camera" ("global" rotations around the coordinate axes of the virtual scene).

The design and implementation of the NAVICAD diagnostic module involved the development of a three-component algorithm: one for fractal dimension and lacunarity calculus for each intra-operator CLE image, and the second part of the NAVICAD CAD module includes an algorithm for calculating the presence matrix of gray levels in the image. This is considered a statistical method for examining a texture that reflects the spatial relationship between pixels

For component three of the algorithm, a parameter was added to identify the number of elements of a certain shape and size determined by another computation: the contour of anatomical entities such as pulmonary cell nuclei were identified and counted using the Marching Square algorithm followed by a linear interpolation through which the area / perimeter ratio is calculated for these entities as a measure of their circularity.

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The data obtained with this algorithm is interpreted using a feed forward back propagation neural network. The algorithm was tested with very good results on post-operative samples from four human lung tumors and adjacent lung tissue obtained with the primitive formation, the diagnostic error found for the module computation was 16.23%.

a b

Figura 7. NAVICAD system set-up for model tests (a) and 3D navigation screen during procedure (b).

For the purpose of laboratory testing of the NAVICAD system, a realistic anatomical lung airways phantom (Figura 7) has been developed that includes thoracic and abdominal breathing. Five plastic spheres were fixed on peripheral areas of the artificial model that are visible on tomography scanning and which were the targets to be touched with the biopsy needle during the tests. The whole artificial model was scanned using a Siemens SOMATOM Emotion medical tomograph with a 1.5 mm section depth (Figura 7). NAVICAD system evaluation studies have been carried out with the participation of the specialists in pneumology of the University of Medicine and Pharmacy of Craiova. These tests have proven the utility of the biopsy system and biopsy instrument, especially for un-experienced users, for bronchoscope invisible targets. There is an increase in average accuracy in achieving the targets together with a decrease in the time of the procedure. The NAVICAD System trials continued with small-scale animal clinical trials in the Norwegian partner facilities (Figura 8), namely at the St. Olavs University Hospital, Trondheim.

a b Figura 8. Images from NAVICAD System Animal Testing at St. Olavs, Trondheim, Norway.

The project research was presented in 9 articles in ISI journals and 14 presentations at international

conferences: 1. Lucian Gheorghe Gruionu, Teodor Popa, Catalin Ciobîrca, Adrian Saftoiu, Costin Streba, Ana-Maria Ioncica,

Thomas Langø, Gabriel Gruionu, "A novel fusion imaging guiding system for bronchoscopy", Design of Medical Devices - Europe Edition Oct. 22-24, 2014, Delft. Prezentare orala + Articol publicat in volumul de lucrari al congresului.

2. Horia-Alexandru Petrescu, Daniel Vlasceanu, Stefan Dan Pastrama and Lucian Gruionu, “Numerical analysis for determining the displacements of a lung tumor”, Key Engineering Materials Vol. 638 (2015) pp. 177-182, Trans Tech Publications, Switzerland, doi:10.4028/www.scientific.net/KEM.638.177.

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3. Langø T et al. „Navigation and intraoperative imaging in minimally invasive interventions”, Keynote lecture at the Design of Medical Devices (DMD) 2014 congress, Delft, Netherlands, 22-24 October 2014.

4. Catalin Ciobirca, Teodoru Popa, Gabriel Gruionu, Thomas Lango, Hakon OlavLeira, Stefan Dan Pastrama, Lucian Gheorghe Gruionu, “Virtual bronchoscopy method based on marching cubes algorithm” ICSAAM 2015, The 6th International Conference on Structural Analysis of Advanced Materials 08 - 11 September 2015, Porto, Portugal.

5. Horia Petrescu, Emil Nutu, Daniel Vlasceanu, Lucian Gruionu, Stefan Dan Pastrama, “Development of a finite element model for lung tumor displacements during breathing”, 32nd Danubia-Adria Symposium on Advances in Experimental Mechanics, Starý Smokovec, Slovakia, 2015.

6. Catalin Ciobirca, Gabriel Gruionu, Teodoru Popa, Stefan Dan Pastrama, Thomas Lango, Hakon Olav Leira, Lucian Gheorghe Gruionu, “Collision detection algorithm forimproved electromagnetic tracking navigation in bronchoscopy”, Design of Medical Devices - Europe Edition Sept. 8-9, 2015, Vienne.

7. Sorger H, Hofstad EF, Amundsen T, Langø T, Leira HO. „A novel platform for electromagnetic navigated ultrasound bronchoscopy (EBUS)”. International Journal of Computer Assisted Radiology and Surgery, DOI 10.1007/s11548-015-1326-7.

8. Smistad E, Falch TL, Bozorgi M, Elster AC, Lindseth F. „Medical Image Segmentation on GPUs - A Comprehensive Review. Medical Image Analysis”, 2015 Feb;20(1):1-18. doi: 10.1016/j.media.2014.10.012. PMID: 25534282.

9. Bakeng JBL, Hofstad EF, Solberg OV, Tangen GA, Amundsen T, Langø T, Askeland C, Reinertsen I, Selbekk T, Leira HO. Using the CustusX toolkit to create an image guided bronchoscopy application: Fraxinus. Submitted as full paper to IPCAI/CARS, if accepted it will be published in IJCARS, November 2015.

10. Sorger H, Amundsen T, Hofstad EF, Langø T, Leira HO. A novel multimodal image guiding system for navigated endobronchial ultrasound (EBUS): human pilot study. Presentation at the 3rd European Congress for Bronchology and Interventional Pulmonology (ECBIP). 23-25 April, 2015, Barcelona, Spain.

11. Reynisson PJ, Langø T, Scali M, Leira HO, Hernes TAN, Hofstad EF, Lindseth F, Sorger H, Smistad E, Amundsen T. Centrelines and airways extraction from lung CT for navigated bronchoscopy: a comparison of three methods. Presentation at the 3rd European Congress for Bronchology and Interventional Pulmonology (ECBIP). 23-25 April, 2015, Barcelona, Spain.

12. Reynisson PJ, Langø T, Leira HO, Hernes TAN, Hofstad EF, Askeland C, Lindseth F, Sorger H, Amundsen T. New Vizualisation Technique for Navigational Bronchoscopy: Technical Development on Anchored to Centerline Curved Surface and Implementation on Lung Patient. Presentation at the 3rd European Congress for Bronchology and Interventional Pulmonology (ECBIP). 23-25 April, 2015, Barcelona, Spain.

13. Hofstad EF, Langø T, Sorger H, Leira HO, Amundsen T. Automatic registration of CT images to patient during bronchoscopy - A clinical pilot study. Presentation at the 3rd European Congress for Bronchology and Interventional Pulmonology (ECBIP). 23-25 April, 2015, Barcelona, Spain.

14. Catalin Ciobirca, Teodoru Popa, Gabriel Gruionu, Thomas Lango, Hakon Olav Leira, Stefan Dan Pastrama, Lucian Gheorghe Gruionu, Virtual bronchoscopy method based on marching cubes and an efficient collision detection and resolution algorithm, Ciência & Tecnologia dos Materiais, 28(2), 2016.

15. E. Nutu, H. Petrescu, D. Vlasceanu, L. Gruionu, S. D. Pastrama, “Development of a finite element model for lung tumor displacements during breathing”, Materials Today: Proceedings 3 (2016) 1091 – 1096, DOI: 10.1016/j.matpr.2016.03.054, Volume 3, Issue 4, 2016, Pages 1091–1096.

16. Daniela Ştefănescu, Costin Streba, Elena Tatiana Cârţână, Adrian Săftoiu, Gabriel Gruionu, Lucian Gheorghe Gruionu, “Computer aided diagnosis for confocal laser endomicroscopy”, PLoS One. 2016, 11(5):e0154863. doi: 10.1371/journal.pone.0154863.

17. L. Gruionu, D. Stefanescu, C. Streba, T. Cartana, A. Saftoiu, G. Gruionu, „Automatic diagnosis module for in-vivo optical biopsy”, CARS 2016 Computer Assisted Radiology and Surgery, June 21 - 25, 2016, Convention Center Heidelberg, Germany, Joint Congress of IFCARS / ISCAS / CAR / CMI / CAD / IPCAI, www.cars-int.org, Int J CARS (2016) 11 (Suppl 1):S1–S286 DOI 10.1007/s11548-016-1412-5.

18. C. Ciobirca, G. Gruionu, T. Lango, H. Olav Leira, S. D. Pastrama, T. Popa, L. G. Gruionu, „Three dimensional data generation and graphical representation of theoretical tracheobronchial trees and lung model”, CARS 2016 Computer Assisted Radiology and Surgery, June 21 - 25, 2016, Convention Center Heidelberg, Germany, Joint Congress of IFCARS / ISCAS / CAR / CMI / CAD / IPCAI, www.cars-int.org, Int J CARS (2016) 11 (Suppl 1):S1–S286 DOI 10.1007/s11548-016-1412-5.

19. Gabriel Gruionu, Despina Bazoo, Nir Maimon, Mara Onita-Lenco, Lucian G. Gruionu, Peigen Huang, Lance L. Munn, „Implantable Tissue Isolation Chambers for Analyzing Tumor Dynamics In Vivo”, Lab Chip. 2016;16(10):1840-51. doi: 10.1039/c6lc00237d.

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20. Costin Teodor Streba, Ana Maria Gîltan, Ioana Andreea Gheonea, Alin Demetrian, Adrian Săftoiu, Andreea-Valentina Soimu, Gabriel Gruionu, Lucian Gheorghe Gruionu, „Utility of confocal laser endomicroscopy in pulmonology and lung cancer”, Rom J Morphol Embryol 2016, 57(4):1–7.

21. Gruionu L.G., Streba C., Săftoiu A., Lango T., Gruionu G., „Evaluation of a novel navigation system for bronchoscopy using a deformable lung phantom”, Computer Assisted Radiology and Surgery, Barcelona, 2017 (Accepted for oral presentation).

22. Ciobirca C., Udristoiu A., Lango T., Pastrama S., Gruionu G., Gruionu L., „Virtual bronchoscopy and path planning without tracheobronchial tree segmentation”, Computer Assisted Radiology and Surgery, Barcelona, 2017 (Accepted for poster presentation).

23. Erlend, Fagertun Hofstad, Hanne Sorger, Janne Beate Lervik Bakeng, Lucian Gruionu, Håkon Olav Leira, Tore Amundsen, Thomas Langø, “Intraoperative localized constrained registration in navigated bronchoscopy”, Medical Physics, DOI:10.1002/mp.12361

Also, following the project: - a patent application was filed: "Multifunctional Instrument for Bronchoscopy",

A/00251/26.04.2017. - a national workshop was organized at the end of the project, on 27.04.2017, at the INCESA

Institute of the University of Craiova. - the results were presented at two other 2 national workshops. The results of the project were presented to doctors from two major hospitals in Romania and

a hospital in Norway: "Marius Nasta" Pneumophysiology Institute Bucharest, Emergency Hospital No. 1 in Craiova, University Hospital St. Olavs, Trondheim, Norway.

The activity also consisted in the dissemination of the project results and the planning of some actions for the commercial exploitation of these results. Given the complexity of the developed NAVICAD system, which for clinical use requires the extension of the research activity started in this project through extensive clinical trials that require considerable financial effort, it was decided to contact international companies that have similar systems in their portfolio: Olympus Inc., Pentax Medical, Boston Scientific Inc, Fujitsu Medical, Siemens Medical Inc., Philips Medical Inc., etc.

The NAVICAD system and the results obtained from the tests were presented at the following international conferences:

- Design of Medical Devices - Europe - Sessions of 2015 and 2016 - Delft, The Netherlands. - CARS 2016 Computer Assisted Radiology and Surgery, Convention Center Heidelberg,

Germany, Joint Congress of IFCARS / ISCAS / CAR / CMI / CAD / IPCAI. - 3rd European Congress for Bronchology and Interventional Pulmonology (ECBIP), 2016. - The Biomedical Engineering Society Conference, USA, sessions of 2015 and 2016. - CARS 2017 Computer Assisted Radiology and Surgery, Barcelona, Spain, Joint Congress of

IFCARS / ISCAS / CAR / CMI / CAD / IPCAI.

C. FUTURE DEVELOPMENT DIRECTIONS ON TEACHINGACTIVITYANDSCIENTIFICRESEARCH My future activities, both research and didactic, aim to be a continuation of the projects I have led, and to benefit from the national and international experience gained during the last 16 years of university activity and 20 years of research, the main objective being to contribute to the advancement of the mechanical field, especially for medical applications. The specific objectives of future activities will be to: - knowledge transfer of medical engineering applications to students in all training cycles, from undergraduate to master and PhD by proposing new courses and endowing new laboratories, - research / development of new innovative medical systems or equipment from the prototype stage to the final stage of the technology transfer to industry and market.

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4. Academicdevelopmentdirections At the academic level, I plan to introduce courses of medical applications that address both biomechanics of tissues and organs, as well as the design of medical instruments with complex, classical or compliant mechanisms, or automated equipments that integrate complex software applications, all starting from a solid engineering base. To support these courses, I plan to further develop / equip the labs that I have set up throughout my careers and that currently have international standards equipment with a total value of over € 1.5 million, coming mainly from the projects I have led or in which I have been a member. The most important laboratories I have developed in recent years are the Mechanical and Biomedical Engineering Laboratory of the Faculty of Mechanics, and the Microtechnology Laboratory at the INCESA Institute of the University of Craiova, both of which have exceptional facilities: - ANSYS (Ansys Inc., USA) and ABAQUS (HKS Inc., USA) licenses for structural, fluid and multiphysics finite elements analysis. - Pro / Engineer CREO (PTC Inc, USA) and SolidWorks (Dassault Systemes, France) for computer aided design, - 3DXpert (3DSystems) license for data processing, STL editor for modeling on 3D printers, model analysis / conversion / repairs, etc. - Mimics suite license (Materialise, Belgium), for operations on anatomical models obtained from medical images, custom implant design and other medical devices, analysis and planning of surgical procedures, etc. - AnyBody license (AnyBody Technology, A / G, Holland) software for analysis and simulation of movements of the human skeletal-muscule system, computation of forces and reactions in the joints, ergonometry analysis, etc.

a b c

d e f Figura 9. The 3DSystem ProX DMP 320 printer (a) for metal powders and some parts made to date (b), and

the Stratasys Fortus 400mc (c) printer and plastics parts: biopsy instrument from biocompatible polycarbonate PC-ISO (d), the components of a biopsy instrument from ULTEM, (e) a 3D human jaw for surgical reconstruction

planning developed in collaboration with Tufts University, Boston, USA.

As equipment, the laboratories contain a complete suite for prototyping for the most varied fields, of which:

- ProX DMP 320 metal powder, high precision 3D printer, from 3DSystems, Inc., USA (Figura 9, a) using titanium, high alloyed steel or CoCr powder for additive manufacturing process, and which can be used to produce the most complex and topological optimized parts for automotive or aerospace, medical implants, etc.

- high precision professional equipment, 3D printer FORTUS 400mc from STRATASYS Ltd., USA (Figura 9, c) for rapid prototyping through additive manufacturing using 14 types of plastics,

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including biocompatible PC-ISO, nylon for automotive applications or special material, ULTEM with high mechanical, thermal and chemical resistance, for applications in the aerospace industry.

a b c

d e f Figura 10. a) Vertical machining center, 5 axis, CNC HAAS Automation, Inc., with Renishaw

positioning system and ESPRIT CAM software. (b) 4-axis CNC machining center ISEL ICV4030 (c) Laser Nd: YAG system KLS 246 ROFIN-LASAG AG for precision cutting/welding for metal or ceramic; (d) Quantum MX840 HBM acquisition and analysis system sensors and software CATMAN software.

(e) AURORA electromagnetic tracking system with flat or tabletop magnetic field generator, and POLARIS-Vicra optical tracking system (f) POLARIS-Vicra both of Northern Digital Inc. for medical

imaging and navigation applications in endoscopic procedures or surgery.

For mechanical machining by conventional technologies, laboratories also have exceptional equipment:

- 5-axis HAAS MiniMill machining center with milling and drilling precision up to 5 microns (Figura 10 a),

- 4-axis mini-machining center ISEL ICV4030 (Figura 10 b) - Lasag KLS 246 Nd:YAG laser 4-axis, for welding and cutting precision parts (Figura 10 c), - Quantum MX840 HBM Acquisition System with sensors for force, pressure, displacement and

temperature (Figura 10 d), - pulmonary simulator for the testing of navigation systems in bronchoscopy, self-concept,

developed by our team within the projects, - knee joint simulation for prosthesis typing, self-concept, developed within projects, - Optical tracking system, Polaris Vicra, Ndigital Inc. (Figura 10 f) - Electro magnetic tracking system AURORA Tabletop, Ndigital Inc. (Figura 10 e) - 4 multiprocessor graphics cards with professional graphics cards Nvidia Quadro 6000 and Tesla. At present, within these laboratories, within the research projects I lead is working a multidisciplinary

team of 10 researchers from scientific fields such as IT, medicine, automation, mechanics, biomedical engineering, electrotechnics.

For the future, I want continue the development of these laboratories by: - the purchase of equipment to enable the manufacturing of complex catheters and guidewires for

endoscopic medical procedures with built-in sensors and handling characteristics - metallic fabrics, equipment for soldering and deforming plastic tubes, ultraviolet lamp, development of equipment for tube and guiding wire testing.

- the purchase of equipment for making mechanical parts for the development of robotic instruments and equipment for medicine - the laboratories are mostly equipped with these devices. It will be acquired

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a lathe for small parts and high precision as well as equipment for mechanical tests (stretching, compression, bending, fatigue)

- aquisition of a specialized laser for metallic stent cutting.

5. Directionsfordevelopmentinthefieldofscientificresearch My research / development activities have been funded so far through an international and 5 national research contracts in which I was director, 4 national contracts for which I was partner director, and 4 other international contracts and 5 national contracts where I participated as a team member, with a total value of over 4 million. This activity will continue with the recently started European Structural Funded project "Strengthening research and development capacity in imaging and advanced technology for minimally invasive medical procedures - iMTECH" Contract no. 65 / 08-09-2016, ID P_37_357, SMIS Code: 103633 for which I am a co-director. This 2 million-euro funding project contains a four-year research plan detailing the research direction that I want to pursue in the coming years, especially in the field of engineering applications in medicine. The specific objective of the project is to develop the functional prototype of a complex medical platform for diagnostics and treatment in oncology, with two components, software and hardware, used in a variety of medical procedures in oncology for which it was found that it is necessary to improve the visualization and guidance of the doctor to reach difficult targets for diagnostic and treatment purposes. The platform that will address diagnostic and treatment procedures in oncology will be modular for future expansion to other medical specialties such as orthopedics (correct positioning of prostheses), cardiology (stent placement), or cranial surgery (instrument guiding). A project whose funding has also recently begun and I lead as a director is "Innovative Portable Insufflation Device to Stop Uncontrolled Abdominal Hemorrhage in Civil and Military Trauma (PAID)", Contract No. 244PED / 2017, Project Code: PN-III-P2-2.1-PED-2016-1587 The purpose of the project is to develop a portable device (PAID) that will provide rapid and controlled insufflation in the abdominal cavity to significantly stop bleeding. As a result of these projects that I will lead as a director or co-director in the next 3 years, there will be a series of innovative technologies and prototypes that will be developed and involve the protection of intellectual property by patenting. For the future, I am thinking of advancing the system prototype from the project to the marketable level, and addressing potential customers: medical system manufacturers and instruments (Philips Medical, Olympus, Pentax, Hitachi, Medtronic, Cook, Storz, etc.). The medical platform to be developed in my future research activity, I appreciate it will be ready for licensing, clinical trial approval, FDA and CE Mark approval, production and marketing.