Effect of immediate all-digital restoration of single posterior implants: The SafetyCrown concept on patient-reported outcome measures, accuracy, and treatment time-A randomized clinical trial.

OBJECTIVE: The SafetyCrown workflow facilitates the immediate restoration of posterior single sites with the one-abutment/one-time concept. This randomized clinical trial aimed to assess the direct effect of immediate restoration on dental patient-reported outcomes (dPROs), feasibility, implant accuracy, and time. MATERIALS AND METHODS: Participants with a single posterior edentulous site for late implant placement underwent optical impressions, shade selection, and cone beam computed tomography. After virtual treatment planning, they were randomized into the test group and the control group. For the test group, individual definitive hybrid abutments were prefabricated. The next step was a fully guided surgery with printed guides. After the implant was placed using guided surgery, the abutment was inserted. A chairside CAD/CAM workflow was used to provide the patient with a provisional restoration. Implants in the control group were left submerged to heal. Oral health-related quality of life (OHRQoL) was assessed using the OHIP-G14, and dPRO was measured using a 10-item visual analog scale (VAS) questionnaire. Additional measurements of implant accuracy and time were performed. Follow-up was performed 7 to 10 days after implant placement. RESULTS: Thirty-nine participants with 45 restorations were included (test group: 23, control: 22). Immediate restoration was successful in 21 out of 23 implants (91.3%) in the test group. Both groups exhibited decreased OHRQoL without significant intergroup differences, while patient satisfaction was high overall. Test group participants perceived higher benefits and satisfaction with immediate loading than participants in the control group. Implant accuracy averaged 0.60 mm at the shoulder and 0.95 mm at the apex. Operative time was longer in the immediate loading group (61.9 min) than in the control group (32.1 min) (p < 0.001). CONCLUSIONS: Considering the limitations, the immediate restoration of late placed posterior implants using the described workflow proved feasible in 21 out of 23 cases. Both groups achieved high patient satisfaction with no differences in OHRQoL during the first week. Patients who received immediate loading rated the benefits very highly and were satisfied with the provisional restoration during the healing period.

Maxillary and mandibular overdentures retained by two unsplinted narrow-diameter titanium-zirconium implants - A clinical pilot study.

OBJECTIVES: To evaluate the survival rates and marginal bone loss of narrow-diameter titanium-zirconium implants supporting complete maxillary and mandibular overdentures up to 3 years after loading. MATERIALS AND METHODS: Ten completely edentulous patients who were dissatisfied with their complete dentures were enrolled. Two narrow-diameter implants were placed in the canine region of the maxilla and mandible. After second-stage surgery, implant-supported overdentures (palatal-free) attached by parallel alignable stud-attachments were placed. Patients were followed periodically for up to 36 months. Standardized radiographs were taken at baseline, 12 and 36 months to analyze mean marginal bone level changes around the implants. RESULTS: The Kaplan-Meier survival rates were 100% for mandibular and 68.0% (SE ± 10.9%) for maxillary implants at 36 months (p = .008). Six maxillary implants failed after loading; no mandibular implants were lost. Five implants failed due to loss of osseointegration. One implant fractured. The mean marginal bone level changes around the analyzed implants (n = 28, 9 patients) were -0.71 ± 0.82 mm in the mandible and -2.08 ± 1.52 mm in the maxilla at the 36-month follow-up. The difference in marginal bone level changes between the maxilla and mandible was significant (p = .019) at the 12- and 36-month follow-ups. CONCLUSION: Two narrow-diameter titanium-zirconium implants with stud-attachments showed a highly satisfactory outcome in the mandible. The maxillary implants showed a high failure rate and significantly more bone loss over time than the mandibular implants. The minimal concept of two implants and an overdenture should be limited to the edentulous mandible.

SafetyCrown: a patient-centered, fully digital concept for immediate implant restoration following the one-abutment/one-time concept-a pilot case series of a new treatment concept.

INTRODUCTION: The patient-centered SafetyCrown-workflow enables the immediate restoration of posterior missing teeth and short free-end situations following one-abutment/one-time within three visits and only one surgical approach. This prosthodontic rehabilitation aims to combine the advantages of cemented and screw-retained restorations. REPORT: The concept has been performed with 4 restorations in 3 patients and followed up for up to 1 year (mean: 11.2 months) without technical and/or biological complication. Visit 1: Intraoral optical impression, CBCT, and tooth shade selection. Virtual implant planning is performed, and a surgical guide is printed. After exporting the planned implant position, a tooth-colored abutment is fabricated from zirconia with a 1-mm supragingival cementation line, adhesively bonded to a titanium base. Visit 2: Fully navigated implant placement with insertion of the definitive abutment. Subsequently, optical impressions are prepared for A: immediate restoration using a PMMA crown without functional contacts; B: definitive crown fabricated from monolithic zirconia and individualized. The localization of the screw channel is marked using stain thus permitting precise screw channel access, if necessary. Visit 3: After osseointegration of the implant, the definitive crown is adhesively cemented supragingival. In a retrospective analysis of PROMs ('How stressful was the treatment process […]?' (0 = not stressful at all, 100 = very stressful), mean VAS score for SafetyCrown of 14 (SD 11.7) and 29.8 (SD 23.1) for standard procedure were present. CONCLUSION: The SafetyCrown offers a shortened, patient-oriented concept for implant-supported single-tooth reconstructions omitting second-stage surgery. Clinical performance and hypothesized prosthodontic benefits require confirmation via an RCT.

Effect of different dental implant drilling template designs on heat generation during osteotomy - an in vitro study.

OBJECTIVES: This in vitro study examined the effect of different implant drilling template designs on heat generation during osteotomy and on cooling fluid distribution. MATERIAL AND METHODS: Five different template designs were investigated in a standardized setup against a control group and a negative control group: Occlusal-splint-design (OSD), OSD-covering, OSD-lateral opening, Bar design, and Orientation template. Pilot and one consecutive drill were run at 800 rpm with external irrigation and 2-kg load. Thermocouples recorded temperature changes at depths of 3, 6, and 9 mm in a bovine rib model. In the second experimental setup, the drill channel of one rib sample was perforated, and the irrigation volume passing through the drill channel was collected separately over time. RESULTS: Following mean temperature rises occurred [in °C]: control, 4.9; negative control, 12; OSD, 5.6; OSD-covering, 4.7; OSD-lateral opening, 3.8; Bar design, 5.1; and Orientation template, 4.9. The highest temperature increases were found at a drilling depth of 6 mm (p < .006). The 2.2-mm drill resulted in a significantly higher temperature rise than the 2.8-mm drill (p < .001). The mean volume (ml/min) of irrigation through the drill channel was Control group-flow, 28.5; OSD, 4.1; OSD-covering, 2; OSD-lateral opening; 5.8; bar design, 4; and Orientation template, 24.1. CONCLUSION: Within the limitations, it was shown that fully guided drilling templates reduce the amount of cooling liquid at the point of osteotomy. The template design had an influence on the effective volume of the cooling liquid. However, this did not seem to increase the intraosseous temperature significantly.

Cemented versus screw-retained posterior implant-supported single crowns: A 24-month randomized controlled clinical trial.

OBJECTIVES: To compare the incidence of biological and technical complications of cemented and screw-retained monolithic lithium-disilicate implant-supported posterior single crowns. MATERIAL AND METHODS: Forty-one subjects with a total of 56 implants received randomly allocated 28 cemented and 28 screw-retained crowns. In the screw-retained group, monolithic lithium-disilicate restorations were luted to titanium bases extraorally. In the cemented group, monolithic lithium-disilicate crowns were cemented on individualized titanium abutments intraorally. All restorations were examined according to modified FDI criteria within 2 weeks of inserting the crowns (baseline) and after 12 (n = 46) and 24 (n = 43) months. Bone loss was evaluated by standardized radiographs at baseline and 12 months. RESULTS: After 12 months, the incidence of mucositis (positive bleeding on probing) was 14.2% (screw-retained) and 17.9% (cement-retained). The gingival and plaque index and a mean marginal bone loss between 0.03-0.15 mm showed no significant difference between the groups. In the cemented group, cement residues were detected at baseline at two restorations (6.9%) by radiographic examination. A complete digital workflow was realized in most cases (85.7%). At 24 months, no restoration had failed, and no chipping of the ceramic had occurred. In the screw-retained group, screw loosening occurred in one implant. In both groups, there was obvious deterioration in the quality of 32% of the occlusal and of 18% of the proximal contact points. CONCLUSIONS: The type of retention mode of monolithic implant-retained lithium-disilicate posterior crowns had no influence on the biological and technical complication rate.

Fabrication, workflow and delivery of reconstruction: Summary and consensus statements of group 4. The 6th EAO Consensus Conference 2021.

OBJECTIVES: To report assessments of four systematic reviews (SRs) on (i) clinical outcomes of all-ceramic implant-supported crowns (iSCs), (ii) production time, effectiveness, and costs of computer-assisted manufacturing (CAM), (iii) computer-assisted implant planning and surgery (CAIPS) time and costs, and (iv) patient-reported outcome measures (PROMS). MATERIAL AND METHODS: An author group consisting of experienced clinicians and content experts discussed and evaluated the SRs and formulated consensus on the main findings, statements, clinical recommendations, and need for future research. RESULTS: All four SRs were conducted and reported according to PRISMA and detailed comprehensive search strategies in at least three bibliometric databases and hand searching. The search strategies were deemed reproducible. Variation was noted regarding language restrictions and inclusion of grey literature, but the search comprehensiveness appeared persuasive. The SRs included bias risk assessments of the primary studies, and their study methodology impacted the interpretations of the extracted data. CONCLUSIONS: (i) There is limited evidence (49 NRCT) showing that veneered and monolithic all-ceramic iSCs have excellent outcomes observed up to 3 years. (ii) There is no evidence evaluating production time and effectiveness comparing subtractive and additive CAM of implant models, abutments and crowns. (iii) There is limited evidence (4 RCT) that CAIPS involves more time and costs when considering the entire workflow and for diagnostics, manufacturing, and insertion of the restoration. Time seems to be the decisive factor for higher costs. (iv) Patients' comfort increases when optical compared to conventional impressions are used for fabricating iSCs and short-span FPDs (2 RCT, 5 NRCT).

5-year randomized multicenter clinical trial on single dental implants placed in the midline of the edentulous mandible.

OBJECTIVES: This multicenter randomized controlled clinical trial was conducted to investigate whether the loading protocol of single dental implants placed in the midline of edentulous mandibles will influence the implant survival or prosthetic maintenance. MATERIALS AND METHODS: In total, 158 patients were randomly assigned either to the immediate loading group (n = 81) or to the delayed loading group (n = 77). All implants were loaded with an overdenture retained by a ball attachment. RESULTS: After 5 years, 102 patients attended the follow-up investigation. Immediately loaded single implants in the midline of the edentulous mandible revealed a statistically significant lower survival rate than implants loaded conventionally over an observation period of 5 years. In the immediate loading group, 9 implants failed within the first three months of implant loading. No further implant loss was recorded for this group. Two implants failed in the delayed loading group, whereas one implant had to be removed during second-stage surgery and the second five years after implant loading. Non-inferiority of the survival rate of the midline implant of the immediate loading group, compared with the delayed loading group, could not be shown (p = .79, CI immediate loading: 74.9%; 100.0%, CI delayed loading: 73.0%; 100.0%). The observed difference in implant survival between the two treatment groups over time was statistically significant. CONCLUSIONS: The results of the present study indicate that immediate loading of a single mandibular implant in the edentulous mandible should be considered only in exceptional cases.

From a CAD/CAM-milled, allogeneic bone block to an implant-supported fixed partial denture with angulated screw channel: a case report.

Augmentation of alveolar ridge defects is a technique-sensitive procedure in dental implantology. Depending on the size of the defect, it may be necessary to use autogenous bone blocks. However, patients may be against these blocks as these procedures are surgically invasive.
Case report: This report describes the restoration of a partially edentulous mandible, which suffered a major bone defect from the right canine to the third molar site after multiple implant losses. The use of a CAD/CAM allogeneic cancellous bone block from a living donor bone was planned for the reconstruction of the alveolar ridge at the defected site. A CBCT scan was taken and the virtual planning of the bone augmentation and placement of four implants was performed. The milled bone block was fixed for augmentation and the implants were placed using a CBCT-generated surgical guide. After osseointegration, a CAD/CAM-fabricated screw-retained metal-ceramic implant fixed partial denture with angulated screw channels was delivered.
Results: The use of CAD/CAM-milled, allogeneic bone block resulted in a time-efficient and simplified reconstruction of the defect because no donor site was used, and the fit of the block on the native bone was uneventful and fast. At the 1-year follow-up, an average peri-implant vertical soft tissue decrease of 1 mm on buccal and 0.3 mm on lingual sites was observed and the peri-implant tissues were healthy.
Conclusions: The long-term success of this CAD/CAM cancellous bone block needs to be evaluated in well-designed clinical studies.

Telescopic Crowns On Implants And Teeth: Evaluation Of A Clinical Study After 8 to 12 Years.

PURPOSE: To evaluate the outcome of a clinical study on telescopic-crown-retained removable dental prostheses (TCR-RDPs) on implants or implants and teeth after 8 to 12 years. MATERIALS AND METHODS: Between 1999 and 2002, 39 (41 jaws) patients received implant- or combined tooth-implant-supported TCR-RDPs in the maxilla and/or mandible. One-stage surgery was performed, and after a conventional healing period, TCR-RDPs were inserted. Thirty-one patients (33 prostheses) were available for annual follow-up investigations with a standardized protocol from 2010 until 2013. Cumulative survival and success of the abutments was estimated using the Kaplan-Meier method, and a Cox regression model was used to identify potential predictors for abutment complications. Patients' oral health-related quality of life (OHRQoL) was measured by means of the Oral Health Impact Profile (OHIP). RESULTS: After a mean observation period of 11.3 ± 1.1 years, all restorations were still functioning successfully. Two implants and 10 abutment teeth were lost, leading to significantly different implant and tooth survival rates of 97.6% (SE ± 1.7%) and 81.8% (SE 5.3%; P = .007). Implants placed in the mandible, and those in the group with a higher number of abutments (5 to 6 vs 2 to 4) showed higher success rates. The success rates of abutment teeth were not influenced by location (mandible vs maxilla) or number of abutments (5 to 6 vs 2 to 4). CONCLUSION: Implant- or combined tooth-implant-supported TCR-RDPs provided a satisfying treatment option for patients with severely reduced dentition in the long term. Due to the small sample size, the results presented should be interpreted with caution.

Single mandibular implant study (SMIS) - masticatory performance - results from a randomized clinical trial using two different loading protocols.

OBJECTIVES: This multi-centre randomized controlled trial was conducted to investigate, whether the masticatory performance of elderly edentulous patients is improved by placement of a single implant in the midline of the edentulous mandible, and whether improvements differ with respect to the loading protocol, i.e., implant is loaded either directly or three months later after second stage surgery. METHODS: Edentulous seniors aged 60-89 years were screened according to inclusion and exclusion criteria and 163 underwent implant placement. Of those, 158 were randomly assigned either to the direct loading group A (n=81) or the conventional loading group B (n=77). Chewing efficacy was obtained before treatment, one month after implant placement during the submerged healing phase (only group B) and 1 and 4 months after implant loading. RESULTS: The masticatory performance increased over time in both groups. Four months after loading, a significant increase was observed for both groups compared to the baseline data without implant (p≤0.05). However, between the two groups, chewing efficiency did not differ significantly at any point in time (p>0.05). CONCLUSIONS: A single midline implant in the edentulous mandible increases masticatory performance significantly, independently from the loading protocol. CLINICAL SIGNIFICANCE: A single midline implant in the edentulous mandible increases masticatory performance. The loading protocol has no influence.

Recent advances of ultrasound imaging in dentistry--a review of the literature.

Ultrasonography as an imaging modality in dentistry has been extensively explored in recent years due to several advantages that diagnostic ultrasound provides. It is a non-invasive, inexpensive, painless method and unlike X-ray, it does not cause harmful ionizing radiation. Ultrasound has a promising future as a diagnostic imaging tool in all specialties in dentistry, for both hard and soft tissue detection. The aim of this review is to provide the scientific community and clinicians with an overview of the most recent advances of ultrasound imaging in dentistry. The use of ultrasound is described and discussed in the fields of dental scanning, caries detection, dental fractures, soft tissue and periapical lesions, maxillofacial fractures, periodontal bony defects, gingival and muscle thickness, temporomandibular disorders, and implant dentistry.

Moldagem em implantodontia / Impression in implantodontics

Neste artigo é realizada uma revisão da literatura sobre moldagem em Implantodontia. São descritos os diferentes tipos de materiais de moldagem utilizados e principais propriedades, tipos de moldeiras, diferentes técnicas de moldagem e métodos e dos modelos obtidos. Suas composições, propriedades, vantagens e desvantagens são apresentadas e comparadas, além de como as técnicas e materiais podem influenciar as decisões clínicas

Facial self-perception, well-being, and aesthetic surgery.

BACKGROUND: It is controversial whether impaired well-being is associated with (a) an increased likelihood of having a negative body/facial image; or (b) dissatisfaction with the postoperative result following aesthetic surgery. We set out to improve current knowledge in this matter. METHODS: A total of 324 subjects (n = 162 females, n = 162 males, 18-30 years) were photographed, asked to complete the adjective mood scale and to rate 46 statements regarding their own appearance, and its impact on social functioning as well as their willingness to undergo aesthetic surgery on a visual analog scale. The photographs of these subjects were also assessed by 50 independent judges. RESULTS: Average self-awarded ratings of appearance were significantly more positive in subjects with normal as compared to those with impaired well-being (P = 0.014). Items regarding the impact of appearance on social functioning were answered significantly more negatively by subjects with impaired well-being as compared with those with the normal well-being (P = 0.001). Subjects with impaired well-being did not declare an increased willingness to undergo aesthetic surgery (P > 0.197). Assessment by the independent judges did not reveal differences in the average level of attractiveness of subjects with impaired well-being and those with normal well-being (P = 0.666). CONCLUSIONS: Impaired well-being is associated with impaired facial selfperception, independent of attractiveness. Willingness to undergo aesthetic surgery seems not to be affected by one's sense of well-being. In the subjects with impaired well-being who undergo aesthetic surgery, facial self-perception seems unlikely to be improved.

Performance of ultrasonic devices for bone surgery and associated intraosseous temperature development.

PURPOSE: The purpose of this study was to evaluate and to compare the bone-cutting performance and intraosseous temperature development of three modern ultrasonic devices for bone surgery (UDBS). MATERIALS AND METHODS: The following UDBS and associated cutting tips (straight bone saws) were used in this study: (1) Piezosurgery II professional, tip OT 7 (Mectron); (2) Piezotome, tip BS 1 (Acteon); and (3) SurgySonic, tip ES007 (American Dental Systems/Gunther Jerney). In the experimental setup UDBS, handpieces were immobilized, and bone specimens from the middiaphysis of a bovine femur were moved in a longitudinal direction under the cutting tip to a standardized depth of 3.0 mm. Intraosseous temperature development was measured using a glass-fiber isolated thermocouple. The cutting performance was defined by the time required to reach the cutting depth of 3.0 mm. Statistical analysis was performed using the Wilcoxon rank sum test. RESULTS: The median increase (25th through 75th percentiles) of the local intraosseous temperature was 3.0 degrees C (2.2 degrees C to 4.2 degrees C) for the SurgySonic, 2.2 degrees C (1.8 degrees C to 3.2 degrees C) for the Piezosurgery II, and 1.1 degrees C (0.7 degrees C to 1.6 degrees C) for the Piezotome. The median cutting performance was 0.31 mm/s (0.11 to 0.46 mm/s) for the Piezotome, 0.25 mm/s (0.23 to 0.27 mm/s) for the Piezosurgery II, and 0.04 mm/s (0.03 to 0.05 mm/s) for the SurgySonic. CONCLUSIONS: Among the three tested UDBS, the Piezotome and the Piezosurgery II showed a significantly higher cutting performance than the SurgySonic. The Piezotome produced the smallest increase in intraosseous temperature.

Nasal shape and gender of the observer: implications for rhinoplasty.

BACKGROUND: In a previous study we focused on gender specific nasal shapes. The aim of this study was to evaluate if preferences in nasal shape are also dependent on the gender of the observer. METHODS: Stratified on the basis of each photographed subject's (n=311) own evaluation, female and male composite pictures of "average" (n=128, each), "optimal" (n=16, each) and "most unpleasant" (n=8, each) noses were created in a previous study. These composites were assessed by 308 independent female and male judges using a visual analogue scale. RESULTS: On average, female judges were found to accord significantly higher ratings of attractiveness as compared to male judges for the composite images independent of the gender of the person shown (p=0.020). The difference was greatest when assessing most unpleasant male composites (p<0.003) but was not apparent when assessing "optimal" female and "optimal" male noses. Despite this, women displayed the same preferences for "optimal" and "average" noses as compared to the "most unpleasant" noses. In assessing their own noses, women were significantly less satisfied with their appearance in general (p=0.001) as compared to men. CONCLUSIONS: In comparison to men, women are more critical in assessing the appearance of their own nose as opposed to the noses of other people. The implications of this for rhinoplasty, so far as considering the degree of influence of the gender of a person assessing a prospective patient's nose remains a matter of conjecture.

Gender and nasal shape: measures for rhinoplasty.

BACKGROUND: Gender-specific nasal shapes are recommended for rhinoplasty. This study was conducted to clarify whether there truly are gender-related differences and to determine optimal nasal shapes in a Caucasian population. METHODS: The authors created female and male composite photographs of "average" (n = 128 each), "optimal" (n = 16 each), and "most unpleasant" (n = 8 each) noses stratified on the basis of each photographed subject's (n = 311) own evaluation of the attractiveness of her or his nose, using a visual analogue scale. These composites were also assessed by 308 independent judges. RESULTS: Optimal female noses showed a horizontally and vertically lower nasion and were concave to straight in profile as compared with optimal male noses, which had a vertically and horizontally higher nasion and a straight profile. A supratip break was not found in any of the composites. At least half of the judges rated average and optimal male composite noses as female. A significant majority mistook the composite of the most unpleasant female noses as male (frontal view, 62.0 percent; lateral view, 72.4 percent; p < 0.001). Optimal and average female and male noses were found to be independently significantly more attractive than the most unpleasant ones (p < 0.001, n = 308 judges). Women and men with a straight or concave profile were significantly (p = 0.017 and p = 0.006, respectively) more satisfied with the appearance of their nose than those with nasal humps. CONCLUSIONS: Gender-related differences in nasal shape appear to be subtle, with nasion position being one of the main factors. A nasal hump and a supratip break are not desirable.

Facial attractiveness: visual impact of symmetry increases significantly towards the midline.

Symmetry is thought to be a major prerequisite for an attractive face. Many faces are not symmetric, yet are still regarded as beautiful. What role, then, does asymmetry play in the perception of beauty? We studied the assessment of computer-manipulated images by independent judges (n = 200-250): part A: nevi located at different positions; part B: standardized changes of the orbital region. The results showed that slight lateral orbital and facial asymmetry does not impair attractiveness at all and that asymmetries close to the midline are significantly less attractive than those affecting the lateral aspect of the face (P < 0.001). A single nevus which is located laterally on the face is significantly more attractive than a nevus close to the midline (P < 0.001). Faces with a completely symmetric bilateral pair of nevi in the same lateral positions (perceived as attractive when alone), received the worst ratings (P < 0.001). Symmetry is a characteristic of the attractive face, but there are exceptions to the rule. Under certain conditions symmetry can be completely unattractive. The visual impact of symmetry on the perception of beauty increases significantly when approaching the midline.

[Facial aesthetics part I - the significance of the triangle of yarbus]. / Gesichtsästhetik Teil 1: Die Bedeutung der Symmetrieebene des Gesichts.

When humans observe a face, the eyes, mouth and nose regions are the preferred targets of the centre of gaze, with the outlines of eye position recordings approximating a triangle with vertices located in the centre of the eyes and mouth [31]. We studied the significance of cutaneous asymmetries inside and outside the Yarbus triangle on the basis of the assessment of digitally-manipulated images by 201 independent judges. We show that certain facial variations (such as naevi) are more attractive when asymmetrical than symmetrical (p<0,001). They appear more attractive when located laterally rather than medially, particularly so when located outside the Yarbus triangle as compared to inside it (p<0,001). The significance of facial symmetry increases significantly when approaching the Yarbus triangle or the midline, respectively.

Man as living bioreactor: fate of an exogenously prepared customized tissue-engineered mandible.

In 2004, we reported a novel method of repairing a human mandible by in vivo tissue engineering. The patient served as his own bioreactor as the exogenously prepared customized mandible replacement was grown inside his latissimus dorsi muscle prior to transplantation to repair the existing defect. Our technique was developed through extensive experience with an animal model. We describe our and the patient's experiences with this procedure. We give details to the benefits and limitations of this technique as it stands and outline issues that should be addressed in future human clinical trials.