Computer-Aided Design 37 (2005) 1151–1161 www.elsevier.com/locate/cad
Application of micro CT and computation modeling in bone tissue engineering Ho Saey Tuana, Dietmar W. Hutmachera,b,* b
a Division of Bioengineering, Faculty of Engineering, National University of Singapore, Singapore 119260 Department of orthopaedic Surgery, Faculty of Medicine, National University of Singapore, Singapore 119260
Accepted 2 February 2005
Abstract Computer aided technologies, medical imaging, and rapid prototyping has created new possibilities in biomedical engineering. The systematic variation of scaffold architecture as well as the mineralization inside a scaffold/bone construct can be studied using computer imaging technology and CAD/CAM and micro computed tomography (CT). In this paper, the potential of combining these technologies has been exploited in the study of scaffolds and osteochondral repair. Porosity, surface area per unit volume and the degree of interconnectivity were evaluated through imaging and computer aided manipulation of the scaffold scan data. For the osteochondral model, the spatial distribution and the degree of bone regeneration were evaluated. In this study the versatility of two softwares Mimics (Materialize), CTan and 3D realistic visualization (Skyscan) were assessed, too. q 2005 Elsevier Ltd. All rights reserved. Keywords: Computer aided design; Medical imaging; Scaffolds; Bone engineering; Micro CT
1. Introduction Tissue engineering is the application of that knowledge to the building or repairing of tissues. Generally, engineered tissue is a combination of living cells and a support structure called scaffolds. The scaffold, depending on the tissue or organ in production, can be anything from a matrix of collagen, a structural protein, to synthetic biodegradable plastic laced with chemicals that stimulate cell growth and multiplication. The ‘seeded’ cells that initiate regeneration come from laboratory cultures or from the patient’s own body. The utilization of computer aided technologies in tissue engineering has evolved over time and were termed by Sun et al. as ‘computer aided tissue engineering (CATE)’ [1]. Combining computer assisted design (CAD) with computer assisted manufacturing (CAM) is of particular
* Corresponding author. Tel.: C65 874 5105; fax: C65 777 3537. E-mail address:
[email protected] (D.W. Hutmacher).
0010-4485//$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.cad.2005.02.006
interest to tissue engineers to reproduce complex scaffold architectures without requiring the use of moulds. While the engineering potential of various scaffold architectures is considerable, the ability to design and optimise structures is still very much ad hoc since local structure and mechanical/transport properties have not been measurable during tissue growth in vitro or in vivo. Hence, computer aided design allows to design different scaffold architectures systemically. Previous studies have primarily used existing computer aided design (CAD) techniques to create a specific design. Hutmacher et al. [2] used Stratasys QuicksliceTM (QS) software to lay down alternating material patterns that produced triangular and polygonal pores in Polycaprolactone (PCL) scaffolds. Chu et al. [3] created hydroxyapatite (HA) scaffolds with interconnecting square pores using Unigraphics TM CAD software. Traditional methods for evaluating osseointegration of tissue engineered scaffold/cell constructs are based on 2D histological and radiographical techniques and in rare cases mechanical testing. To further the development of optimal scaffold architectures and to characterise accurately the growth of bone into scaffolds a fast and non-destructive
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technique to characterise and measure the 3D properties of scaffold/tissue composites during growth is required. Studies have been extensively done regarding issues like osteoporosis and the effects of aging on bone structure [4–11]. More recently, micro CT has been applied in bone engineering studies [12]. In Micro CT analyses, it is crucial that the scan data is to be processed by user friendly and comprehensive software. In our laboratory, we decided to apply Mimics, which is used by many CAD engineers; it also has a software package to manipulate and analyze micro CT data. The aim of this study was to assess the versatility of Mimics (Materialise) in assessing scaffold architecture and tissue engineered bone in an osteochondral defect model. We bench marked Mimics against the in built programs of the microtomographic scanner used (Skyscan) which were CTan and 3D realistic visualization.
2. Materials and methods 2.1. Micro-CT analysis The scanner used to examine the scaffolds and the regenerated bone was a Skyscan in vivo microtomograph, 1076. Both types of specimens were placed on a 68 mm wide sample holder. The rabbit condyles were placed with the axis of the femur perpendicular to the plane of scanning, while the scaffolds were placed with the height and width parallel to the scanning plane. The resolution for both groups of samples was set at 35 mm, an averaging of five was employed together with a filter of 1 mm aluminum, a rotation step of 0.88, the rotation angle was 1808. Approximately 500 scan slices were taken and files were reconstructed at a step size of four using a modified Feldkamp algorithm as provided by Skyscan. The output was a series of 120 serial 1968!1968 bitmap images. 2.2. Software Visualize the 3D representation of the scaffold, two software packages namely 3D realistic visualization and CTan (both by Skyscan) were used Mimics translates CT or MRI data into full 3D CAD, Finite Element meshes or Rapid Prototyping data within minutes. Based on the CT images, CAD objects can be created in Mimics. 3D realistic visualization provides 3D modeling while CTan calculates the parameters. In contrast, the software Mimics is able to fulfill the two roles at the same time. Hence, a direct comparison of computing power and user friendliness was done between the software packages. As for the rabbit condyles, Only Mimics was used as Ctan did not have the necessary function to do this type of analysis
2.3. Region of interest (ROI) A cubical region of interest (ROI) with 4 mm as the length and the width, and a height which covered the entire series of scan was chosen for the scaffolds. For the rabbit condyle bearing the defect, a cylindrical ROI with a diameter of 4 mm (diameter of defect) and a height of 5.46 mm (approximate depth of defect) was chosen. This represented the regenerated bone only. Since the boundaries of the original defect were visible from the scans, the ROI was set where the original defect was located. With the aim of studying the different degrees of bone regeneration with respect to location within the defect, the ROI was divided up radially and laterally. The ROI was sectioned into core, inner and outer shells. These radial sections were each divided into top, mid and bottom sections (Fig. 1). As the degree of bone regeneration was referenced back to the native rabbit condyle, a similar procedure with the ROI was performed on 12 pairs of medial condyles isolated from 12 rabbits which were approximately of the same age as those which received the scaffold cell constructs. 2.4. Thresholding As one of the aims of the experiment was to study the degree of bone regeneration within the defect, regenerated bone has to be isolated within the ROI. This isolation starts off with the establishment of the threshold ranges to be used. Thirty-six specimens of cancellous and cortical bone, muscle, skin tissue and articular cartilage were isolated from the 12 rabbits that yield the native condyles. Three specimens of each tissue were taken from each rabbit. The threshold of each tissue was arrived with the aid of the profiling function of Mimics (Fig. 6B). In analyzing the porosity of the scaffolds, the threshold to be used was readily obtained for each individual scaffold by employing the profiling function by Mimics (K872 toK185 Housefield units) or the threshold histogram (Fig. 6A) offered by CTan (grey values: 11–50).
Fig. 1. The sectioning of the cylindrical ROI.
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Fig. 2. The threshold ranges of TCP-PCL, PCL scaffold, cartilage, cortical, cancellous bone, skin and muscle are as shown. Region 1 is from K590 to K370 HU, while region 2 is from 17 to 1802 HU. Region 1 served to identify soft tissue and scaffold while region 2 served to identify bone.
2.5. Assessment of bone The volume of the bone isolated in a particular portion of the ROI, was divided by the total volume of the bone, soft tissue and scaffold of that portion, thus arriving at the bone volume fraction at that location. This value was expressed as a percentage of the bone volume fraction of the native rabbit condyle at that similar location. 2.6. Analyzing scaffold porosity and interconnectivity of the pore spaces After estimating the volume of the scaffold within the ROI, the empty space within was obtained by subtracting the scaffold volume within the ROI from the volume of the ROI. Dividing the volume of the empty space by the volume of the ROI gave porosity. In the calculation of the interconnectivity of the pore spaces, the threshold was firstly inverted and a 3D model of the pore spaces was created. Region growing operation was
performed so that the volume of the interconnected spaces could be calculated. This interconnected volume was divided by the total volume of the pore spaces, thus yielding the degree of interconnectivity. As this region growing function was absented in CTan and 3D realistic visualization, the analysis of interconnectivity could not be performed on these two programs.
3. Results 3.1. Osteochondral model The threshold values used for the osteochondral model are shown on Fig. 2. Bone was identified in the threshold range of K17 to 1802 Hounsfield units (HU), while soft tissue and scaffold (PCL and TCP-PCL) were identified in the range of K590 to K370 HU. It should be noted that even though the thresholding of soft tissue (skin) falls to
Fig. 3. A shows the ROI being isolated from the rabbit medial condyle. Red representing soft tissue and scaffold, while white represents bone. B shows the ROI in more detail. The ROI is sectioned out radially and laterally as shown in C. The outer, inner shells and the core are as shown on D, E and F respectively. Each of these radial sections are further divided into top, mid and bottom sections as shown by the different colors in each of D, E and F.
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Fig. 4. The overall degree of bone regeneration of 3, 6 and 9 months occurring in the defect created on the medial rabbit condyles is as shown on (A). (C, E and G) The degree of regeneration occurring on the top, mid and bottom sections, respectively. (B, D and F) The localization of the bone regenerated at the outer, inner shells and core of the top, mid and bottom sections, respectively.
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K812 HU, it was observed that below K590 HU, artifacts started appearing. The 3D model of the regenerated bone was created and sectioned as shown on Fig. 3. The degree of bone regeneration for 3, 6, and 9 month samples of the rabbit medial condyle was analyzed. The total bone regeneration within the defect showed an initial increase from 0 to 6 months (Fig. 4A), and a later decrease from 6 to 9 months. This trend was observed in the top and bottom sections (Fig. 4C and G). However for the mid sections (Fig. 4E), the degree of bone regeneration increased from 0 to 73.39G22.17% at the third month and it remained approximately the same for the next 6 months. Further division of the top, mid and bottom sections into core, inner and out shells allows further insight into the localized bone regeneration. For the top section, there was an initial increase and later decrease in the degree of bone regenerated in the inner shells and core (Fig. 4B). A similar trend was observed for the core of the mid section (Fig. 4D) and applied generally for all the radial parts of the bottom section (Fig. 4F). However, for the outer and inner shells of the mid section, an initial increase followed by a constant degree of bone regeneration was noted between 3 and 9 months. For the outer shell of the top section, an increase in bone regeneration was noted for the first 6 months. Bone regeneration later remained constant.
per design were fabricated and passed over for MicroCT scanning. Table 1 shows the porosity values as calculated from the two 3D modeling programs. Fig. 5 shows the 3D models of the scanned specimens. The porosity values, surface area per unit volume and the degree of interconnectivity were in the same range for both software programs, thus demonstrating the reliability of micro CT analysis. The two programs offer comparative quality of 3D models, however, Mimics showed a greater manipulability and was more user friendly. It is noted that for the scaffold analysis, the thresholding reaches up to K872 while it was not possible for the osteochondral model due to the formation of artifacts below K590 HU. When the threshold was below K590 HU for the osteochondral model, Mimics recognizes the surrounding air as part of the model. This occurrence could be attributed to the possibility that artifacts arose more readily for samples containing a mixture of materials as in a rabbit condyle. The condyle would contain fluids, cancellous and cortical bone, a range of soft tissues, cell and scaffold constructs. But for samples that were made up of a single material (scaffold analysis), artifacts would arise at lower thresholds. As for the analysis of the scaffold using 3D realistic visualization and CTan, artifacts occurred when the threshold falls below the grey value of 11.
3.2. Scaffold analysis
4. Discussion
Four different scaffold architectures were designed using AutoCAD and then exported as STLfiles. An inhouse built RP machine was used to fabricate the scaffolds by using two different biodegradable polymers. Four scaffolds
4.1. Osteochondral model The technique of Micro CT has been used in the study in calvarial bone defect models [12,13]. One of the main
Table 1 Porosity values as obtained via pycnometer method and micro CT scanning No.
Material
Angle (8)
Nozzle diameter (mm)
Fill gap (mm)
Porosity— pinometer (%)
Porosity— Mimics (%)
Porosity— CTan (%)
Surface area/ volume— Mimics (mm2/mm3)
Surface area/ volume— Ctan (mm2/mm3)
1
Copolymer of PEG, PCL and PLA Copolymer of PEG, PCL and PLA Copolymer of PEG, PCL and PLA Copolymer of PEG, PCL and PLA Copolymer of PEG, PCL and PLA Copolymer of PEG, PCL and PLA Copolymer of PEG, PCL and PLA PCL
0/90/180
0.3
1
70.7G0.8
80.4
77.1
14.2
21.1
99.9
0/60/120
0.3
1
67.6G1.2
58.9
63.1
8.5
12.2
99.7
0/45/90/135
0.3
1
65.7G0.7
54.0
58.7
8.7
13.1
99.9
0/30/60/90/ 120/150 0/90/180
0.3
1
61.1G1.8
64.4
66.6
9.3
12.4
100
0.5
1.5
72.1G0.4
75.0
74.8
8.7
11.6
100
0/60/120
0.5
1.5
70.6G0.7
75.5
70.1
9.1
12.9
100
0/45/90/135
0.5
1.5
68.3G2.2
70.4
67.8
8.2
10.6
100
0/90/180
0.5
1.5
64.0G0.7
61.8
66.3
7.2
9.8
100
3 2 3 4 5 6 8
The CT data was either process via Mimics or Ctan. The degree of pore space interconnectivity as obtained via Mimics.
Interconnectivity (%)
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advantages of using micro CT to observe bone regeneration would be the absence of extensive sample preparation as would be required during histological analysis. Moreover it is non-destructive; thus making it a valuable assay tool when scarcity of samples is a factor. Furthermore, simulated mechanical analysis can be carried out on micro CT data through the usage of finite element models [14]. Micro CT forms the main analytical tool in this experiment, its usage was furthered by the approach to
track down spatial bone regeneration patterns within the defect. The aim was to reveal the radial and lateral development of osteochondral repair. It should be noted that in the assessment of cartilage repair (Fig. 3B) micro CT analysis has to be coupled with histology to confirm the presence of cartilage regeneration. The reason was due to the threshold range (K590 to K370 HU) that was used. This range encompasses not just cartilage but also scaffold and other soft tissues. Thus without histological confirmation, the scaffold on the surface
Fig. 5. (A–F) Images of scaffold sample 5 (08/908/1808). (A–C) were obtained via Mimics while (D–F) were obtained via 3D realistic visualizations. Measuring of the dimensions of the 3D model is only available for Mimics as shown by the measuring line and measurements in (A–C). 3D realistic visualization does not have this measuring function. (G–L) Images of scaffold sample 6 (08/608/1208). (G–I) were obtained via Mimics while (J–L) were obtained via 3D realistic visualizations. (A, D, G, J) are side views. (B, E, H, K) are top views. (C, F, I, L) are isometric views.
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Fig. 5 (continued)
might be mistaken as regenerated cartilage and vice versa. The osteochondral model has been experimented by various groups and one of the main approaches involved would be that of histological observation of the regenerated bone and cartilage [16–20]. Such histological assays would often include plastic embedding, decalcification and sectioning [19]. Some groups quantify their observations by means of a histological scoring system [16–18]. Radiography SEM and measurement of calcium content through calorimetric assay (are also qualitative or
semi-quantitative tools in assessing the degree of bone repair [20–23]). 4.2. Scaffold analysis In the study of the structural properties of the scaffold, various methods have been used by other research groups. SEM has been commonly used in the examination of the scaffolds. [24–28]. The porosity of the scaffold can be theoretically calculated from the CAD design. Actual porosity measurement are usually done by
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quantifying deposition geometries [29] or from pcynometer measurements [28]. Due to lack of accuracy of the above mentioned methods, Micro CT has been proposed to analyse the scaffold architecture. Scaffold visualization coupled with the calculation of actual porosity [30] and the degree of interconnectivity [30,31] were possible depending on the software that processes the scan data. The analysis of the physical properties of the scaffold by combining micro CT scanning with biomedical imaging/CAD has several advantages. First, it is non-destructive and minimal sample preparation is required by using powerful 3D software the concept enables the visualization and analysis of the 3D morphology of the scaffold. Furthermore it allows the user to examine and analysis in detail any part of the scaffold with respect to internal architecture and interconnectivity, as digital manipulation can be easily achieved with the 3D models. 4.3. Comparison of Mimics and CTan/3D realistic visualization It is observed that Mimics allowed a greater degree of image manipulation compared to CTan and 3D realistic visualization (Table 2). Complex ROI of specific dimensions could be created in Mimics based on the following reasons. ROI is created on the Mimics segmentation mask, and a total of 16 colored segmentation masks are available. Hence multiple ROIs are possible. Versatile editing functions are available which aid in the isolation of structures. Furthermore, boolean operations allow the combinations of two different ROIs. Visualization is all encompassing in Mimcs with three simultaneous 2D views (Fig. 6B). They are the original axial view of the image, coronal and sagittal views. ROI can be manipulated on all three views unlike in CTan which has only the original axial view (Fig. 6A). Contrast enhancement, panning and zooming is available for the 2D and 3D images; all these features will aid the user to isolate the ROI efficiently according to the various requirements. Unlike CTan, Mimics offer 2D as well as 3D manipulation all on the same program. CTan is not able to create the 3D model by itself as the processed files have to be exported
to CTvol or 3D realistic visualization (both are from Skyscan). Measurement is one of the key features of Mimics. Distance measurements can be easily carried on 2D and 3D images, not so for CTan and 3D realistic visualization as the function is omitted for 3D models. The measurement of threshold is easily achieved with the use of the profile line which can draw across any desired part of the 2D image, thus displaying a threshold profile (Fig. 6B). CTan employs a threshold histogram (Fig. 6A) that serves a similar function as that of the thresholding profile. It is to be kept in mind that Mimics is not just applicable to micro CT images but also to MRI data, thus providing wide range of applications ranging from diagnostics and surgery planning to interfacing with rapid prototyping systems. One significant advantage of CTan over Mimics would be the ability to compute various structural bone parameters like the degree of anisotropy, Trabecular Bone Pattern Factor (TBPF), Structural Model Index (SMI), Euler number and trabecular thickness. These parameters are used to assess the trabecular structure. Mimics was originally developed to support CAD engineers in their routine work. Only at later stage software modules were added for the medical imaging society, however, a software package to do specialized bone calculation is not available, yet. In the analysis of the scaffold, Mimics was relatively easy to use in isolating a ROI of specific dimensions at a particular location in the scaffold. Measurements of the 3D model could be easily carried out, while this was not possible with 3D realistic visualization. Regional growing which was crucial in deriving the degree of pore interconnectivity was only possible with Mimics. For the osteochondral model, the creation of the ROI of specific dimensions allowed the regenerated bone to be isolated out from the surrounding tissue in the rabbit condyle. 3D realistic visualization and CTan did not offer such an option and thus could not be employed in the osteochondral study. Furthermore the division of the top, mid and bottom sections individually into core, inner and outer shells, was only possible with Mimics due to the superior editing functions.
Table 2 A comparison of Mimics against CTan and 3D realistic visualization Features
Mimics
3D realistic visualizations and CTan
1. ROI 2. Visualization 3. Versatility
Of specific dimensions Three simultaneous 2D views 2D and 3D manipulation possible on a single program MRI, CT and interface with rapid prototyping Possible Possible for 2D and 3D Not available
Not of specific dimensions Only one 2D view Two programs have to coupled together to achieve the same results Only micro CT and CT Not possible Only available for 2D on CTan Available
4. 5. 6. 7.
Usage Region growing Measurement function Specific bone parameter calculation
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Fig. 6. (A) A window from CTan. As shown the ROI could only be modified on a single view. The threshold histogram is circled red and the values are in grey values. (B) A window from Mimics. The three views allow a greater freedom in the modifying of the ROI. The only the profile line (pointed by the red arrow) is drawn across the area of focus, a threshold profile appears (circled red).
4.4. Errors of micro CT scan Micro CT scanning is a versatile tool for both measuring the degree of bone regeneration and the porosity of scaffolds. However, there are drawbacks in this approach. One of which was that for the osteochondral model, not all tissue and scaffold within the ROI were captured by the scanning process. Approximately 20% of the ROI of the condyle defects could not captured by the scanning process. This was compared to that of approximately 13% for the native condyle. These
values were arrived by comparing the combined volume of the regenerated bone, soft tissue and scaffold found in the ROI to the volume of a solid cylinder with the same dimensions as the ROI (4 mm diameter, 5.46 mm height). As the top of the ROI is curved as it is the surface of the condyle, the top of the solid cylinder was modified so as to have the same contour as that of naı¨ve condyle, thus achieving a better comparison in terms of volume. The inability of the scanning process to capture the entire volume of the ROI was due to the ranges of threshold used (Fig. 2). There is a gap of K370 to K17 HU that
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was not employed in thresholding the ROI. The reason for so was that scaffold, soft tissue and bone all fall into this threshold gap, thus the material captured by this threshold range could not be distinguished into soft tissue, scaffold or bone. A higher percentage of the ROI was not captured for the condyle defect compare to the naı¨ve condyles, this was probably because of the presence of the scaffold within the defect. It was suspected that a high percentage of PCL-TCP scaffold was not captured in the imaging process. Moreover as the threshold of soft tissue and scaffold severely overlaps, it was not possible to separate them out in the image processing step. Another issue encountered during micro CT scanning would be that of beam hardening [12]. This effect arose because the X-ray source used a polychromatic beam. The lower energy X-rays were relatively more absorbed as they entered the sample hence leaving the center of the sample exposed to high energy X-rays. This implied that the threshold distribution depended on both the density of sample and the overall sample dimensions resulting in a difference between the observed threshold value and the local material density. However, in the osteochondral model, absolute threshold values were not needed as comparative analyses between the defect and naı¨ve samples were conducted. Furthermore the condyles of both groups were approximately of the same size. In conclusion, we have demonstrated successfully that systematic variation of scaffold architecture as well as the mineralization inside a scaffold/bone construct can be studied by combining computer imaging technology and CAD/CAM and micro computed tomography (CT).
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Mr Ho Saey Tuan is currently doing his PhD with the Graduate Program of Bioengineering at the National University of Singapore. The project is entitled Tissue engineering of an osteochondral transplant by using a cell/ scaffold construct. He has been working on this project for the last 1 year and his expertise would include micro CT and histology analysis.
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Dr Dietmar W. Hutmacher recieved his first degree in Biomedical Engineering in 1988. Thereafter, he pursued a career in the medical device and biotechnology industry as Head of R&D and Managing Director. DWH received his M.B.A. in 1999 from the Henley Management College. In 2001 he was awarded his PhD in the Department of Orthopedic Surgery, National University of Singapore for his work on bone tissue engineering. Currently, he is holding a joint position as Assistant Professor at the Faculty of Engineering and Faculty of Medicine. Within five years he was able to establish an interdisciplinary research group in Southeast Asia which is already making an impact on the biomedical and tissue engineering society via numerous journal and book publications. His article Polymeric Scaffolds in Tissue Engineering Bone and Cartilage. Biomaterials 2000, 21:2529–2543 is cited more than 200 times by today. As the first faculty member in both of my departments he received the NUS Young Investigator Award (2002). Over the last 3 years my students received several prizes. In 2004 year we were awarded the Best Article published in the International Journal of Oral Maxillofacial Implants in 2002 Schantz JT, Hutmacher DW, Ng KW, Teoh SH, Khor HL, and Lim TC. Evaluation of a Tissue Engineered Membrane-Cell Construct for Guided Bone Regeneration. He serves on the Editorial Board of a number of Journals e.g. Biomaterials and Journal of Biomaterials Science and routinely review manuscripts for leading journals such as Nature, Tissue Engineering, etc. Furthermore, do I serve on the advisory board of a Singapore headquartered biotech company. DWH is a co-founder and shareholder of 2 Singapore-based companies. All his projects are multidisciplinary and are executed in collaboration with clinical partners mainly from orthopaedic, plastic and reconstructive surgery as well as dentistry. For the time being my staff count on the projects DWH directs and/or co-direct are: 4 PostDoc’s, 3 Research engineers, two lab officers. Currently, DWH is supervising and co-supervising 10 PhD 3 Master and 6 undergraduate students.
