Surgical Research in Implant Dentistry

Foreword
Contents
1: The Method Sets the Tone
	1.1	 Introduction
	1.2	 The Heroes
	1.3	 The Endless Revolution
		1.3.1	 The Hypothesis
		1.3.2	 The Design
		1.3.3	 Evidence-Based Dentistry
	1.4	 Conclusion
	References
		Evidence-Based Dentistry Related References
2: Preclinical Studies Design and Place of Rodents
	2.1	 Experimental Animal Model
		2.1.1	 Animal Species: Naturally-Occurring, Purpose-Bread, and/or Genetically Modified
		2.1.2	 General Use in Medical Devices Research
		2.1.3	 Financial Considerations
	2.2	 Surgical Model
		2.2.1	 Surgical Anatomical Site and Surgical Procedures for Implant Dentistry
			2.2.1.1	 Surgical Locations
				Extraoral
					Anatomy and Histology
					Function and Physiology (Movement, Loading)
					Advantages/Inconveniences in Implant Dentistry
					Recommendations
				Intraoral
					Anatomy and Histology
					Function and Physiology (Movement, Loading, and Occlusion)
					Advantages/Inconveniences in Implant Dentistry Anatomy and Histology
					Recommendations
			2.2.1.2	 Surgical Procedures
				Extraoral: Description of the Procedures
					Animal Welfare, Preparation for Survival Surgery, and Anesthesia (General, Local)
					Surgical Step by Step: Anterior-Distal Surface of Femur Metaphysis
					Surgical Step-by-Step:Femoral Condyle
					Surgical Step by Step: Medial-Proximal Surface of Tibia Metaphysis
					Follow-up and Termination
					Recommendations
				Intraoral: Description of the Procedures
					Animal Welfare, Preparation for Survival Surgery and Anesthesia (General, Local)
					Surgical Step-by-Step: Rat
					Surgical Step-by-Step: Mouse
					Follow-Up and Termination
					Recommendations
	2.3	 Investigative Methods of Evaluation
		2.3.1	 X-Rays
		2.3.2	 Micro-CT
		2.3.3	 Histology (Remove Implant or Not)
		2.3.4	 Optics and Electronic Histology-Histomorphometry (Including Immunohistolabeling)
		2.3.5	 Biomechanics
			2.3.5.1	 Push-in Test
			2.3.5.2	 Pull-Out Test
		2.3.6	 Bacteriology
		2.3.7	 Genomics
	2.4	 Flag Ship Results from the Literature Using These Experimental-Surgical Models (Outlining Your Own Results): Critical Mini-Review
	2.5	 Expert Opinion: Balancing Models (Experimental and Surgical) Validation and Validity
	References
3: Preclinical Studies Design and Place of Rabbits
	3.1	 Experimental Animal Model
		3.1.1	 Animal Species: Naturally-Occurring, Purpose-Bred and/or Genetically Modified
			3.1.1.1	 Animal Welfare
			3.1.1.2	 Handling and Husbandry
			3.1.1.3	 Health Status
		3.1.2	 General Use in Medical Devices Research
		3.1.3	 Financial Considerations
	3.2	 Surgical Model: Surgical Anatomical Site and Surgical Procedures for Implant Dentistry
		3.2.1	 Surgical Locations, Anatomy, and Histology
			3.2.1.1	 General Anatomical Information
			3.2.1.2	 Extraoral
				Femur and Tibia
				Skull
			3.2.1.3	 Intra Oral
				Maxilla and Mandible
				Sinuses
			3.2.1.4	 Function and Physiology (Movement, Loading)
		3.2.2	 Surgical Procedures
			3.2.2.1	 Description of the Procedures; Preparation to Survival Surgery and Anesthesia (General, Local)
				Antibiotics
				Preoperative Care
				Intraoperative Care
				Postoperative Care
				Local Anesthesia
				Pain Management
				NSAIDs and Their Effect on Bone Healing
			3.2.2.2	 Description of the Procedures; Surgical Step by Step
			3.2.2.3	 Extraoral
				Tibia
				Femur
					Knee Joint
					Distal Femoral Lateral Condyle
					Distal Femoral Medial Condyle
					Diaphysis
				Skull
			3.2.2.4	 Intraoral
				Maxillary Sinus
				Maxilla
				Mandible
					Inferior Border Defect [104]
					Posterior Mandible Placement [105, 106]
					Placement in Mandible Body
					Alveolar Ridge Augmentation [110]
					Tooth Extraction Socket Model
				Osteoporosis Model
		3.2.3	 Follow-Up and Termination
		3.2.4	 Advantages and Inconveniences
			3.2.4.1	 General
			3.2.4.2	 Femur and Tibia
			3.2.4.3	 Maxilla and Mandible
			3.2.4.4	 Skull
		3.2.5	 Recommendations
	3.3	 Investigative Methods of Evaluation
		3.3.1	 Imaging
		3.3.2	 Optic and Electronic Histology-Histomorphometry (Including Immunohistolabelings)
		3.3.3	 Biomechanics
		3.3.4	 Biologic Fluids Analysis (Blood, Saliva, etc.)
		3.3.5	 Genomics
	3.4	 Discussion and Expert Opinion: Balancing Models (Experimental and Surgical) Validation and Validity
		3.4.1	 General Considerations
			3.4.1.1	 Choosing Animals
			3.4.1.2	 Implantation
		3.4.2	 Surgical Model
			3.4.2.1	 Femur and Tibia
			3.4.2.2	 Skull
			3.4.2.3	 Maxilla and Mandible
		3.4.3	 Ethical Considerations
	References
4: Preclinical Studies Design and Place of Swine
	4.1	 Experimental Animal Model
		4.1.1	 Animal Species
		4.1.2	 General Use in Medical Research
		4.1.3	 Financial and Ethical Considerations
	4.2	 Anatomical and Histological Characteristics of Porcine Bone
	4.3	 Intraoral Surgical Models
		4.3.1	 Anatomy of Mandible and Maxilla
		4.3.2	 Intraoral Osseous Defects for Bone Regeneration
			4.3.2.1	 Mandibular Bone Defects
			4.3.2.2	 Maxillary Bone Defects
			4.3.2.3	 Alveolar Ridge Augmentation
		4.3.3	 Intraoral Implant Osseointegration Models
		4.3.4	 Treatment of Peri-Implant Defects
		4.3.5	 Sinus Augmentation
	4.4	 Extraoral Surgical Models
		4.4.1	 Calvarial and Facial Bones
		4.4.2	 Long Bones
		4.4.3	 Other Locations
	4.5	 Description of Presurgical and Surgical Procedures
		4.5.1	 Presurgical
		4.5.2	 Induction, General, and Local Anesthesia
		4.5.3	 Postoperative Pain Control and Coverage
		4.5.4	 Description of the Extraoral Procedure
		4.5.5	 Conclusions
	4.6	 Investigative Methods of Evaluation
		4.6.1	 Radiographic Analyses
			4.6.1.1	 2D Radiographs
			4.6.1.2	 3D Radiographic Examinations
		4.6.2	 Histology-Histomorphometry
		4.6.3	 Biomechanics
		4.6.4	 Biologic Fluids Analysis
		4.6.5	 Bacteriology
		4.6.6	 Omics Analyses
	4.7	 Recommendations and Conclusion
	References
5: Preclinical Studies Design in the Canine Model
	5.1	 Introduction
	5.2	 Experimental Animal Model
		5.2.1	 The Canine
		5.2.2	 General Use in Medical Devices Research
		5.2.3	 Financial Considerations
	5.3	 Surgical Anatomy and Surgical Procedures for Implant Dentistry
		5.3.1	 Surgical Locations
			5.3.1.1	 Extraoral
				Intraoral
		5.3.2	 Surgical Procedures
			5.3.2.1	 Extraoral
			5.3.2.2	 Intraoral
				Examination/Recordkeeping/Sedation
				Anesthetic Protocol
				Analgesia
				Follow-Up and Termination
			5.3.2.3	 Surgical Step-by-Step
				General Principles
				Mandible
				Anterior Maxilla
				Recommendations
	5.4	 Investigative Methods of Evaluation
		5.4.1	 Intraoral Radiography
	5.5	 Flagship Results
		5.5.1	 Socket Healing
		5.5.2	 Implant Loading
		5.5.3	 Biologic Width at Implants
		5.5.4	 Guided Bone Regeneration (GBR)
		5.5.5	 Peri-implantitis
		5.5.6	 Immediate Implants
		5.5.7	 Bone Healing Around Implants
		5.5.8	 Alveolar Ridge Preservation
	5.6	 Conclusions
	References
6: Preclinical Studies Design and Place of Ovine and Caprine
	6.1	 Experimental Animal Model
		6.1.1	 Animal Species and Animal Model
		6.1.2	 General Use in Medical Device Research
		6.1.3	 Financial Consideration
	6.2	 Surgical Model
		6.2.1	 Surgical Locations
			6.2.1.1	 Extraoral
			6.2.1.2	 Intraoral
		6.2.2	 Surgical Procedures
			6.2.2.1	 Extraoral Description of the Procedures
				Pelvic Bone
				Tibia and Femur
			6.2.2.2	 Intraoral Description of the Procedures
				Maxillary Sinus
				Mandible
	6.3	 Investigative Methods of Evaluation
		6.3.1	 Clinical Macroscopic Evaluation
		6.3.2	 Radiographs
		6.3.3	 Microradiography
		6.3.4	 Computer Tomography (CT)
		6.3.5	 Micro-CT
		6.3.6	 Histology
		6.3.7	 Biomechanics
		6.3.8	 Biologic Analysis of Fluids (Blood, Saliva, etc.)
		6.3.9	 Bacteriology
		6.3.10	 Genomics
	6.4	 Flagship Results
	6.5	 Expert Opinion
	References
7: Clinical Investigations in Implant Dentistry: Experimentation Versus Observation and the Future of Merging Data
	7.1	 Introduction
	7.2	 Systematic Reviews and Meta-Analyses
	7.3	 Types of Clinical Investigations in Implant Dentistry
		7.3.1	 Experimental Studies
		7.3.2	 Observational Studies
			7.3.2.1	 Case Reports
			7.3.2.2	 Case Series
			7.3.2.3	 Case–Control Studies
			7.3.2.4	 Cross-Sectional Studies
			7.3.2.5	 Cohort Studies
				Advantages
				Limitations
				Sample Size
				Prospective or Retrospective Cohort Studies
			7.3.2.6	 Data Collection, Standardization, and Evaluation for Observational Studies
			7.3.2.7	 Analysis and Interpretation
				Data Quality, Missing, or Incomplete Data
		7.3.3	 Going Forward: A Proposal for Data Collection Standardization and Protocols
	7.4	 Conclusion: A New Paradigm for Clinical Investigations in Implant Dentistry—Real-World Evidence
	References
8: Translational Aspects in Living Mammalian Organisms
	8.1	 General Definition of Translation
	8.2	 Importance of Parallel and Complementary Study Designs
		8.2.1	 Observational Human Clinical Studies vs. Observational Animal Studies
		8.2.2	 Experimental Human Clinical Studies vs. Experimental Animal Studies
	8.3	 Choice of the Experimental Model in Implant Dentistry
		8.3.1	 Introduction
		8.3.2	 Animal Selection
		8.3.3	 Remarks and Recommendations
		8.3.4	 Animal Species and Bones Used in Experimental Dental Implantology
			8.3.4.1	 Rodents
			8.3.4.2	 Rabbits
			8.3.4.3	 Canine
			8.3.4.4	 Pigs
			8.3.4.5	 Sheep/Goats
			8.3.4.6	 Nonhuman Primates
		8.3.5	 Ethical
		8.3.6	 Regulatory Affairs
		8.3.7	 Main Experimental Models
			8.3.7.1	 Implant Osseointegration Process
			8.3.7.2	 Immediate Implant Placement
			8.3.7.3	 Peri-Implantitis Therapy
			8.3.7.4	 Bone Regeneration Around Implants
		8.3.8	 Quality Control (GLP, GCP, GCLP)
		8.3.9	 Economic Aspects
		8.3.10	 Publications
	8.4	 Management of the Translational Chain
		8.4.1	 Successive and/or Complimentary Investigations (In Vitro, In Vivo, Human)
		8.4.2	 Speed and Efficiency (from the Bench to the Dental Chair)
	References
9: Biomechanics of the Radicular Component of Endosteal Implants
	9.1	 Introduction
	9.2	 In Vitro Mechanical Testing Methods
		9.2.1	 Single Load to Failure (SLF)
		9.2.2	 Initial Concepts on Fatigue
			9.2.2.1	 Fatigue Life (Constant Stress)
			9.2.2.2	 Fatigue Limit/Resistance
			9.2.2.3	 Step-Stress Accelerated Life Testing (SSALT)
	9.3	 Fractographic Analysis of Failed Implants and Prostheses
	9.4	 In Vivo Testing
	9.5	 Digital Simulation: In Silico Analysis
		9.5.1	 Model Construction
		9.5.2	 The Analysis
		9.5.3	 Materials Properties
		9.5.4	 Boundaries and Bone-Implant Interface
		9.5.5	 Loading Conditions
		9.5.6	 Mesh Generation and Output
	9.6	 Expert Opinion
	References
10: Radiographic Imaging in Implant Dentistry
	10.1	 Introduction
	10.2	 Periapical Radiographs
		10.2.1	 Distortion
		10.2.2	 Projection Geometry
		10.2.3	 Reliability of Measurements
	10.3	 Panoramic Radiographs
		10.3.1	 Distortion
	10.4	 3-D Radiography
		10.4.1	 CBCT
		10.4.2	 MRI
	10.5	 Subtraction Radiography
	10.6	 Micro CT
	10.7	 Conclusion
	References
11: Biological Events at the Interface Between the Radicular Part of a Dental Implant and Bone
	11.1	 Definition of the Interface
	11.2	 Material and Surface Designs
	11.3	 Protein-Surface Interactions
	11.4	 Immune Response at the Interface
		11.4.1	 Neutrophils
		11.4.2	 Macrophages
		11.4.3	 Foreign Body Giant Cells
		11.4.4	 Dendritic Cells
		11.4.5	 B Cells, T Cells
	11.5	 Assessment of Osteogenesis
	11.6	 Bone Remodeling and the Importance of Osteoclasts
	11.7	 Expert Opinion
	References
12: Mechanics of the Implant-Abutment-Connection
	12.1	 Design of the Implant-Abutment Connection
		12.1.1	 Types and Classification of the Implant-Abutment Complex
		12.1.2	 Position Stability of IAC
		12.1.3	 Metrologic Methods in Research Evaluating the IAC
		12.1.4	 Implant Material
	12.2	 Mechanical Properties of the IAC
		12.2.1	 Mechanical Joint Stability
		12.2.2	 Finite Element Analysis
		12.2.3	 Mechanical Testing
	12.3	 Visualization of the Micromechanics of the IAC
		12.3.1	 Micro-Mechanics of Two-Piece Dental Implants and Synchrotron Radiation
		12.3.2	 Metal and Ceramic Ions and Particles in Peri-Implant Tissue
		12.3.3	 Techniques for Chemical Element Detection in Human Tissue Around Dental Implants
	References
13: Mechanics of the Prosthetic Rehabilitation
	13.1	 Part I: Relevant Factors of Mechanics of the Prosthetic Rehabilitation
		13.1.1	 Passive Fit and Misfit
		13.1.2	 Fabrication Techniques and Fit
		13.1.3	 Material of the Prosthesis
		13.1.4	 Prosthetic Plan
		13.1.5	 Retention: Screw-Retained and Cement-Retained Prostheses
			13.1.5.1	 Screw-Retained Implant Prostheses
			13.1.5.2	 Cement-Retained Implant Prostheses
			13.1.5.3	 Retention Control
		13.1.6	 Occlusal Loading of Implant Prosthesis
			13.1.6.1	 Occlusal Overloading Factors
			13.1.6.2	 Control and Maintenance of Implant Occlusion
		13.1.7	 Patient-Related Variables
	13.2	 Part II: Mechanical Complications
		13.2.1	 Implant Fractures
			13.2.1.1	 Prevention
			13.2.1.2	 Treatment
		13.2.2	 Screw Loosening and Fractures
			13.2.2.1	 Prevention
			13.2.2.2	 Treatment
		13.2.3	 Prosthesis or Framework Fractures
			13.2.3.1	 Prevention
			13.2.3.2	 Treatment
		13.2.4	 Fracture of the Veneering Material
			13.2.4.1	 Prevention
			13.2.4.2	 Treatment
		13.2.5	 Incidence of Mechanical Complications: Related Clinical Studies
	References
14: Imaging of Non-resorbable Bone Substitutes
	14.1	 Introduction
		14.1.1	 Guided Bone Regeneration
		14.1.2	 Principles of Bone Grafting
		14.1.3	 Graft Materials
			14.1.3.1	 Heterologous Grafts (Xenografts)
			14.1.3.2	 Alloplastic Grafts
				Hydroxyapatite Allografts
				Tricalcic Phosphate Grafts
				Bioglass Grafts
				Coralline Hydroxyapatite Grafts
				Polylactic Acid and Polyglycolic Acid
	14.2	 Imaging Characteristics of Non-resorbable Bone Substitutes
		14.2.1	 Non-resorbable Bone Substitutes
		14.2.2	 Composite Grafts
	14.3	 Imaging Modalities for the Visualization of Non-resorbable Bone Substitutes and Peri-Implant Bony Interface
		14.3.1	 Intraoral Film Radiography/Extraoral Panoramic Image
		14.3.2	 Micro-Computed Tomography (In-Vitro Assessment)
		14.3.3	 Magnetic Resonance Imaging (MRI)
		14.3.4	 Multispiral-Computed Tomography (MSCT)
		14.3.5	 Cone-Beam CT (CBCT)
			14.3.5.1	 Accuracy of CBCT Measurements in Bone Regeneration Procedure Using NRBS
	References
15: Biology of Low-Substitution Bone Substitutes
	15.1	 Introduction
	15.2	 Use of Low-Substitution Materials in Contour Augmentation
	15.3	 Typical Resin and Paraffin Embedding
	15.4	 Understanding Monocyte/Macrophage Lineage Differentiation to Osteoclasts and Multi-Nucleated Giant Cells
	15.5	 Monocyte to Macrophage Polarization Around Bone Biomaterials
	15.6	 Multi-Nucleated Giant Cells as Previously Described: The Foreign Body Giant Cell
	15.7	 Osteoclasts
	15.8	 Recent Understanding of Multi-Nucleated Giant Cells
	15.9	 Atherosclerotic ‘Foam’ Cells
		15.9.1 Study Designs: Materials Related to Specific Procedures and Expected Outcomes—In Vitro Analysis
	15.10	 Conclusion from In Vitro Experiments
		15.10.1 Study Designs: Materials-Related Specific Procedures and Expected Outcomes—In Vivo Analysis and Clinical Findings
	15.11	 Expert Opinion
	References
16: Imaging of Resorbable Bone Substitute Materials
	16.1	 Introduction
	16.2	 Radiography
		16.2.1	 Rotational Panoramic Radiography (OPG/OPT/PAN/ DPR)
		16.2.2	 Computer Tomography (CT)
			16.2.2.1	 High-Resolution Peripheral Quantitative CT (HR-pQCT)
			16.2.2.2	 Micro-CT and Nano-CT
			16.2.2.3	 Synchrotron Radiation Micro-computed Tomography (SR μCT)
			16.2.2.4	 Cone-Beam Computed Tomography (CBCT)
		16.2.3	 Scanning Electron Microscopy (SEM)
	16.3	 Ultrasonography
	16.4	 Comparison of Bone Graft Materials Using Different Imaging Techniques in Dentistry
		16.4.1	 Autogenous Grafts
		16.4.2	 Allogeneic Grafts
		16.4.3	 Xenogeneic Grafts
		16.4.4	 Alloplastic Grafts
	16.5	 Conclusion
	References
17: Biology of Resorbable Bone Substitutes: CaP-Based and Polymers
	17.1	 Introduction
	17.2	 Methods
		17.2.1	 Ex Situ Methodologies
			17.2.1.1	 Analyses of Physical and Chemical Properties of Bone Substitutes
			17.2.1.2	 Methods for Analysis of Ex Situ Degradation of Bone Substitutes
		17.2.2	 In Vitro Methodologies
			17.2.2.1	 Methods for Analyzing Regenerative Effects of Bone Substitutes
			17.2.2.2	 Methods for Analysis of Resorbability of Bone Substitutes
			17.2.2.3	 Methods for the Analysis of Inflammatory Cell Responses to Bone Substitutes
		17.2.3	 Preclinical In Vivo Studies
			17.2.3.1	 Experimental Animals and Implantation Models
			17.2.3.2	 (Pre-)Treatment of Tissue Explants and Biopsies
			17.2.3.3	 (Immuno-)Histochemical Staining Methods
		17.2.4	 Analysis Methods for Preclinical Tissue Explants and Clinical Biopsies
			17.2.4.1	 Methods for Analysis of Bone Healing Mediated by Bone Substitutes
			17.2.4.2	 Methods for Analysis of Resorbability of Bone Substitutes
			17.2.4.3	 Methods for the Analysis of Inflammatory Tissue Responses to Bone Substitutes
	References
18: Membranes and Soft Tissues Enhancers
	18.1	 Introduction
	18.2	 Use of Membranes
		18.2.1	 Studies on Membrane Materials
		18.2.2	 Studies on Biologics
	18.3	 Use of Autogenous Soft Tissue Grafts and Soft Tissue Substitutes
		18.3.1	 Currently Available Concepts for Peri-implant Soft Tissue Enhancement
			18.3.1.1	 In Vitro Concepts
			18.3.1.2	 Pre-clinical Concepts
		18.3.2	 Limitation of the Current Pre-clinical Models
		18.3.3	 Factors That Influence the Outcome
		18.3.4	 Clinically Relevant Emerging Endpoints
		18.3.5	 Future Perspectives
	References
19: Biomarkers for Implant Dentistry Studies
	19.1	 Importance of Monitoring the Peri-implant Health
	19.2	 Looking Behind: Clinical Diagnostic Tools
		19.2.1	 Saliva
			19.2.1.1	 Saliva Collection Methods, Preparation for Analysis
				Guidelines for Collection of Saliva
				Methods for Collection of the Whole Saliva
				Processing and Storage for Downstream Analysis
		19.2.2	 Peri-implant Crevicular Fluid
			19.2.2.1	 Collection Methods, Preparation for Analysis
				Guideline for the Collection of PICF
				Collection Methods
				Sample Process and Storage
	19.3	 Proteins Biomarkers of Peri-implantitis
	19.4	 Microbial Markers of Peri-implantitis
	19.5	 Biomarkers Beyond Proteins and Microbial Profiles
	19.6	 Expert Opinion: Choice and Use of Biomarkers for Pre-clinical and Clinical Investigations
	References
20: Computer-Assisted Implant Dentistry
	20.1	 Precision Digital Technologies
	20.2	 Methodological Designs in Computer-Assisted Implant Dentistry: Diagnostic Studies of Accuracy—In Vitro, In Vivo, and Clinical Studies
		20.2.1	 Role of the Different Study Research Designs in Current Computer-Assisted Implant Dentistry
		20.2.2	 Assessment Tools for Improving the Quality of Research Reporting
	20.3	 Guided Surgery
		20.3.1	 Diagnostics
			20.3.1.1	 Three-Dimensional Computed Tomography Imaging
				CBCT for Diagnosis Outcome Assessment
				CBCT Treatment Outcome Assessment
			20.3.1.2	 Intra, Extra-Oral, and Facial Scanners
				Accuracy Evaluation
				Photogrammetry: A New Tool for Full-Arch Implant Impressions?
				Intraoral and Facial Scanners: Powerful Tools for Diagnostic Studies
		20.3.2	 Planning
			20.3.2.1	 CT-Based Implant-Planning Software
				In Vitro and Ex Vivo Experiments
				In Vivo Studies
			20.3.2.2	 Computer-Aided Design/Computer-Aided Manufacturing (CAD/CAM) Technology
				In Vitro Studies
		20.3.3	 Guided Implant Surgery
			20.3.3.1	 Static Guidance
			20.3.3.2	 Dynamic Implant Guidance
			20.3.3.3	 Study Design to Evaluate Accuracy in Guided Implant Placement
				In Vitro
				In Vivo
	20.4	 Computer-Assisted Rehabilitation
		20.4.1	 CAD-CAM Restorations, Abutments, and Superstructures
			20.4.1.1	 Data Acquisition in Computer-Assisted Restorations
			20.4.1.2	 Computer-Assisted Milling
			20.4.1.3	 In Vitro Study Design
			20.4.1.4	 In Vivo Study Design
		20.4.2	 Monitoring Occlusion, Parafunction, and Orthofunction
			20.4.2.1	 Digital Articulators, Facebows, and Jaw-Tracking Devices
				In Vitro Study Design
				In Vivo Study Design
		20.4.3	 Virtual Dental Patients: Digital Superimposition Techniques
	20.5	 Critical Appraisal of Flagship Results from the Literature Related to Specific Methodologies and Outcomes
		20.5.1	 Computer-Guided Implant Placement
		20.5.2	 Digital Implant Impression Procedures
		20.5.3	 CAD/CAM Implant Dental Restorations
			20.5.3.1	 Milling
	20.6	 Expert Opinion: Main Outcomes to Assess/Achieve in the Next Years—Expected Breakthroughs
	References
21: Insight into the Statistical Procedure
	21.1	 Statistical Analysis
	21.2	 Sample Size Determination
	21.3	 Probability Distributions
	21.4	 The Role of a Statistician
	References