Immediate versus Delayed Implant Placement in Patients with Tooth Agenesis: An In-Line Retrospective Pilot Study Comparing Clinical and Patient-Related Outcomes

This retrospective study compared clinical, radiological, and patientand clinician-reported outcomes between immediate and delayed implants placed in patients with tooth agenesis as part of one-stage implant therapy with a split-mouth design. A total of 12 sites of permanent tooth agenesis in five patients received 12 implants (2.4 implants per patient), six being immediate implants in deciduous teeth post-extraction sites, and six being late implants replacing already extracted or spontaneously lost deciduous teeth. Data reporting was performed descriptively without statistical comparative analysis between study groups. Radiographic crestal bone level changes between the time of surgery and 1-year post-surgery did not indicate any marked difference between treatment groups. Patient-reported outcomes related to post-surgical pain and patient preference indicated less pain in immediately treated sites, resulting in a corresponding patient preference related to this treatment modality. Clinician-rated satisfaction levels did not differ. The results of this pilot study support the use of immediate implant placement as a suitable procedure in cases of tooth agenesis.


Introduction
Dental agenesis (DA), i.e., the failure to develop permanent teeth, represents one of the most prevalent developmental anomalies in humans [1,2]. The absence of permanent teeth often requires complex and interdisciplinary treatment strategies, including the extraction of deciduous teeth or their management as part of restorative approaches [3].
The incidence and presentation of DA have been reported to vary geographically and depending on patient and anatomic factors. Excluding or including third molars, the incidence of DA has been reported to vary between 2.6 and 11.3% and 9 to 30%, respectively, with females displaying a 1.37 times higher incidence of DA compared to males [4][5][6]. The second mandibular premolars, followed by the maxillary lateral incisors, represent the most frequent anatomic sites for DA. Except for the latter location, the condition manifests mainly unilaterally [6].
While the aetiology of DA remains unclear, both congenital genetic and acquired factors may cause the failure to develop permanent teeth [2]. Inherited genetic factors may, e.g., be associated with systemically broader genetic syndromes, such as Down syndrome or ectodermal dysplasia. Acquired deficiencies leading to DA may, on the other hand, be related to the irradiation of tooth germs, endocrine and metabolic pathologies, trauma, osteomyelitis, and unintentional tooth bud removal during primary tooth extraction [2,6].
General guidelines define three main treatment options for DA: extraction and space closure, extraction and prosthetic replacement, and retention [3].

Study Setup
This study was conducted as a retrospective pilot study of routine patients undergoing implant therapy at the University Hospital of Geneva and presenting multiple agenesis sites with and without deciduous teeth in situ, allowing for an intra-patient comparison of implant survival and success as well as patient and clinician-reported outcomes between immediate, i.e., placed immediately after extraction and simultaneously bone augmented, and delayed implant placement procedures in fully healed extraction sockets of agenesis sites. The comparison of implant placement modalities was performed in terms of implant survival, 1-year follow-up general clinical assessment, radiological crestal bone levels, and patient and clinician-reported outcomes in terms of post-surgical pain, satisfaction, and preference.
Five patient records treated between 2020 and 2022 were identified that fulfilled the criteria of having undergone adequately documented implant therapeutic procedures in patients with multiple agenesis sites presenting at least on a deciduous tooth in situ. Sample size calculations were not performed as part of the retrospective approach. The comparison of placement modalities was based on six immediate and six delayed implants. Written informed consent was obtained from all patients to treat, document, and publish the treatment-related data. Treatment and reporting of treatment-related data adhered to the Helsinki Declaration of ethical principles by the World Medical Association. Based on the retrospective, non-interventional character of the study and the relatively low number of involved subjects (below five), this study was confirmed to be exempt from approval by the applicable Ethics Commission on Human Research of Geneva (CCER-Geneva).

Patient Characteristics
Patients described in this report were routine patients previously diagnosed with multiple tooth agenesis through panoramic radiographs. Patients reported herein were between 21 and 44 years old (3 women and 2 men) and demonstrated physical and psychological ability to undergo implant treatment (American Academy of Anesthesiologists class I or II). None of the patients displayed any systemic medical conditions contributing to implant treatment. All patients were non-smokers.
All patients were diagnosed with multiple tooth agenesis and displayed at least one deciduous non-conservable tooth eligible for immediate implant placement and another site of agenesis where the patient had already lost or needed to have the tooth extracted earlier for orthodontic reasons.

Treatment Procedure
All implant sites were clinically and periapically radiographically assessed regarding shape, volume, bone quality, and soft tissue status prior to treatment. The planning of the implant procedure, regarding position, type, and implant size, was performed based on clinical assessment and peri-apical radiographs. Teeth extractions and implant procedures were performed under local anaesthesia (4% articaine with 1:100,000 adrenaline (Ubistesin™ Forte, 3M ESPE, 3M Switzerland, Rueschlikon, Switzerland)). Co-amoxicillin (Co-amoximepha, Mepha, Mepha Switzerland, Basel, Switzerland) was administered one hour before surgery (2 g). Osteotomies were prepared «freehand» at the future implant positions after tooth extraction or exfoliation in sites with deciduous teeth in situ or after reflection of a full-thickness periosteal flap following midcrestal incisions intrasulculularly extended to adjacent sites for edentulous agenesis sites. Drilling was performed under constant sterile saline irrigation according to the manufacturer's instructions and using the corresponding drills and tools of the manufacturer (Straumann, Basel, Switzerland). The implant types and dimensions (BLT or BL implants, Straumann, Basel, Switzerland) are reported in Table 1. All implants were placed as part of the same dental appointment. If necessary, lateral and mesiodistal aspects of the implant were augmented using a mixture of autogenous bone chips retrieved during drilling and alloplastic bone (BoneCeramic ® , Straumann, Basel, Switzerland). Healing abutments were mounted, and primary wound closure was achieved (Supramid 4.0, B.Braun ® , Melsung, Germany) for transgingival healing. Nonsteroidal analgesics (Irfen 600 mg (Mepha, Mepha Switzerland, Basel, Switzerland) and Dafalgan 1000 mg (UPSA Switzerland, Zug, Switzerland)) were prescribed. Patients were instructed to follow post-surgical routines, including a soft-cold diet and antiseptic therapy with 0.2% Chlorhexidine rinses (Dentohexin, Streuli, Uznach, Switzerland) twice daily for 7 days. Patients were recalled after 10 days post-surgery for suture removal, and implants were restored with screw-retained full-ceramic (E-Max press, Ivoclar Vivadent, Schaan, Liechtenstein) 2 months after placement and recalled at 1 year post-loading.

Data Collection and Analysis
Data collection included demographic data such as age, gender, and patient history and considered any reported relevant systemic conditions, allergies, medical risks, and contraindications related to dental therapy. Data reporting as part of this pilot investigation was performed purely descriptively without performing statistical comparative analysis between study groups.

Radiographic Measurements
Marginal bone levels were measured following previously published procedures [29]. In brief, mesial and distal crestal bone margins were individually assessed at the time of implant placement and in consecutive intervals of 1-year post-surgery onwards using periapical radiographs (Romexis, Planmeca, Helsinki, and Finnland) by visually determining the distance between the most coronal level of crestal bone and any augmented areas proximal to the implant platform. Radiographs were dimensionally calibrated using the implant length or platform diameter. Digital intraoral periapical radiographs were taken (70 KVp, 7 mA) using a parallel cone technique with a digital sensor (Schick Technologies, Long Island City, NY, USA). A paralleling device and individualized bite blocks of polyvinyl siloxane impression material (Impregum, Espe Dental AG, Seefel, Germany) were used to standardize the X-ray geometry. Measurements were taken to the nearest millimetre using computer software (UTHSCSA Image Tool, Version 3.00, University of Texas Health Sciences, San Antonio, TX, USA).

Patient and Clinician-Reported Outcomes
Patient-reported postoperative pain was obtained from verbally interrogating patients at the 10 days and 2 months post-op reentries and asking them to rate their pain level on a scale ranging from 0 for no pain to 10 for maximum pain they experienced at the individual treatment sites at 3 days, 1 week, and 2 months post-surgery.
Patient and clinician-reported satisfaction was assessed immediately, i.e., 10 min, after completion of the implantation procedure, by verbal interrogation and prompting for assignment of one of the following attributes related to the overall experience of the procedure: completely satisfied, partly satisfied, not satisfied, unable to judge.
Patient preference between immediate and delayed procedures was assessed at the time of restoration by verbally interrogating the patient for any subjective preference between the individual procedures and any possible rationale behind their preference.
Verbal patient interrogation and assessment of pain levels or other sensations, as well as the assessment of patient satisfaction, represent an integral part of the routine treatment assessments at the University Hospital.

Individual Cases Description
Case 1: Case 1 describes a 24-year-old Caucasian referral male patient presenting with DA at sites #35 and #45, orthodontically treated for space maintenance. Tooth #75 was previously lost by spontaneous exfoliation (Figure 1). Tooth #85 was affected by severe rhizolysis, resulting in a poor prognosis for conservative treatment. The edentulous site was characterised by moderate atrophy in the horizontal and vertical directions with sufficient bone volume for implant placement. Tooth #85 was extracted under local anesthesia (LA), followed by the immediate placement of a BLT RC implant (4.1 × 10 mm) (Figures 2 and 3). Lateral and mesiodistal gaps around the implant were augmented. resulting in a poor prognosis for conservative treatment. The edentulous site was charac terised by moderate atrophy in the horizontal and vertical directions with sufficient bon volume for implant placement. Tooth #85 was extracted under local anesthesia (LA), fo lowed by the immediate placement of a BLT RC implant (4.1 × 10 mm) (Figures 2 and 3 Lateral and mesiodistal gaps around the implant were augmented.   resulting in a poor prognosis for conservative treatment. The edentulous site was ch terised by moderate atrophy in the horizontal and vertical directions with sufficient volume for implant placement. Tooth #85 was extracted under local anesthesia (LA lowed by the immediate placement of a BLT RC implant (4.1 × 10 mm) (Figures 2 an Lateral and mesiodistal gaps around the implant were augmented.   Edentulous site #35 received the same implant type after flap elevation, followe the placement of a healing abutment and primary wound closure ( Figure 4). Adeq primary stability was achieved at both sites. Figure 5 compares the postoperative intr control radiographs at both sites ( Figure 5).  At seven days postoperative, the patient described asymmetry and a stronger s tion of pain at site #35 compared to site #45. Clinically, the healing was adequate bilate at the 1-week check-up, and the sutures were removed on the left side.
Intraoral and radiographic assessments at the two-month reentry indicated adeq healing and osseointegration ( Figure 6), allowing for the delivery of screw-reta Edentulous site #35 received the same implant type after flap elevation, followed by the placement of a healing abutment and primary wound closure ( Figure 4). Adequate primary stability was achieved at both sites. Figure 5 compares the postoperative intraoral control radiographs at both sites ( Figure 5). Edentulous site #35 received the same implant type after flap elevation, followed by the placement of a healing abutment and primary wound closure ( Figure 4). Adequate primary stability was achieved at both sites. Figure 5 compares the postoperative intraoral control radiographs at both sites ( Figure 5).  At seven days postoperative, the patient described asymmetry and a stronger sensation of pain at site #35 compared to site #45. Clinically, the healing was adequate bilaterally at the 1-week check-up, and the sutures were removed on the left side.
Intraoral and radiographic assessments at the two-month reentry indicated adequate healing and osseointegration ( Figure 6), allowing for the delivery of screw-retained crowns. Figure 7 illustrates the clinical and radiological situations at the 1-year follow-up, indicating comparably stable bone levels for the two sites. An incomplete papilla was noted at the distal aspect of crown 35 (Figure 7). The patient expressed his satisfaction with the result on both sides without expressing an aesthetic preference. He also   Edentulous site #35 received the same implant type after flap elevation, followed by the placement of a healing abutment and primary wound closure ( Figure 4). Adequate primary stability was achieved at both sites. Figure 5 compares the postoperative intraoral control radiographs at both sites ( Figure 5).  At seven days postoperative, the patient described asymmetry and a stronger sensation of pain at site #35 compared to site #45. Clinically, the healing was adequate bilaterally at the 1-week check-up, and the sutures were removed on the left side.
Intraoral and radiographic assessments at the two-month reentry indicated adequate healing and osseointegration ( Figure 6), allowing for the delivery of screw-retained crowns. Figure 7 illustrates the clinical and radiological situations at the 1-year follow-up, indicating comparably stable bone levels for the two sites. An incomplete papilla was noted at the distal aspect of crown 35 (Figure 7). The patient expressed his satisfaction with the result on both sides without expressing an aesthetic preference. He also At seven days postoperative, the patient described asymmetry and a stronger sensation of pain at site #35 compared to site #45. Clinically, the healing was adequate bilaterally at the 1-week check-up, and the sutures were removed on the left side.
Intraoral and radiographic assessments at the two-month reentry indicated adequate healing and osseointegration ( Figure 6), allowing for the delivery of screw-retained crowns. Figure 7 illustrates the clinical and radiological situations at the 1-year follow-up, indicating comparably stable bone levels for the two sites. An incomplete papilla was noted at the distal aspect of crown 35 ( Figure 7). The patient expressed his satisfaction with the result on both sides without expressing an aesthetic preference. He also expressed superior postoperative comfort on the right side receiving immediate placement compared to the side treated with a delayed protocol. Appl expressed superior postoperative comfort on the right side receiving immediate placement compared to the side treated with a delayed protocol.

Case 2:
Case 2 describes the implant therapy of a 35-year-old African female patient at DA sites #35 and #45. An intraoral examination revealed site #45 to be edentulous following spontaneous exfoliation of tooth #85 several months prior to treatment. Tooth #75 displayed degree-three mobility in the context of periodontal disease, resulting in a poor prognosis for preservation. (Figure 8). expressed superior postoperative comfort on the right side receiving immediate placement compared to the side treated with a delayed protocol.

Case 2:
Case 2 describes the implant therapy of a 35-year-old African female patient at DA sites #35 and #45. An intraoral examination revealed site #45 to be edentulous following spontaneous exfoliation of tooth #85 several months prior to treatment. Tooth #75 displayed degree-three mobility in the context of periodontal disease, resulting in a poor prognosis for preservation. (Figure 8).

Case 2:
Case 2 describes the implant therapy of a 35-year-old African female patient at DA sites #35 and #45. An intraoral examination revealed site #45 to be edentulous following spontaneous exfoliation of tooth #85 several months prior to treatment. Tooth #75 displayed degree-three mobility in the context of periodontal disease, resulting in a poor prognosis for preservation. (Figure 8). Tooth 75 was extracted under AL, followed by the immediate placement of a BLT RC 4.1 × 10 mm implant at site #35. Delayed implant placement of the same implant type, in analogy to the above-presented procedures, was performed at site 45.
At seven days post-op, the wound healing was adequate. The patient reported to have experienced pain on the right side for the first 3 days, relieved by paracetamol 1 g, and no symptoms on the left side. Clinically, there was no evidence of infection or swelling on either side. The screw-retained crowns were delivered two months post-surgery (Figure 9), and the clinical and radiological situations were stable at the 1-year follow-up appointment ( Figure 10).  Tooth 75 was extracted under AL, followed by the immediate placement of a BLT RC 4.1 × 10 mm implant at site #35. Delayed implant placement of the same implant type, in analogy to the above-presented procedures, was performed at site 45.
At seven days post-op, the wound healing was adequate. The patient reported to have experienced pain on the right side for the first 3 days, relieved by paracetamol 1 g, and no symptoms on the left side. Clinically, there was no evidence of infection or swelling on either side. The screw-retained crowns were delivered two months post-surgery (Figure 9), and the clinical and radiological situations were stable at the 1-year follow-up appointment ( Figure 10). Tooth 75 was extracted under AL, followed by the immediate placement of a BLT RC 4.1 × 10 mm implant at site #35. Delayed implant placement of the same implant type, in analogy to the above-presented procedures, was performed at site 45.
At seven days post-op, the wound healing was adequate. The patient reported to have experienced pain on the right side for the first 3 days, relieved by paracetamol 1 g, and no symptoms on the left side. Clinically, there was no evidence of infection or swelling on either side. The screw-retained crowns were delivered two months post-surgery (Figure 9), and the clinical and radiological situations were stable at the 1-year follow-up appointment ( Figure 10).  Case 3 describes a 44-year-old female Caucasian patient with controlled type I diabetes presenting at the University Hospital with a chief complaint of pain at tooth #85. Radiographic and intraoral examination revealed DA at sites #35 and #45, with tooth #75  Case 3 describes a 44-year-old female Caucasian patient with controlled type I diabetes presenting at the University Hospital with a chief complaint of pain at tooth #85. Radiographic and intraoral examination revealed DA at sites #35 and #45, with tooth #75 missing. Tooth #85 presented pulp necrosis due to perforating caries ( Figure 11). As the prognosis of tooth #85 was poor, the tooth was extracted under local anaesthesia, followed by the immediate placement of a BLT RC 4.1 × 10 mm implant (Figures 12 and 13). Site #35 received the same implant type following the delayed procedure described above. Screw-retained crowns were delivered 2 months post-surgery ( Figure 14). 1-and 2-year follow-up examinations revealed stable clinical and radiological situations.

Case 3:
Case 3 describes a 44-year-old female Caucasian patient with controlled type I diabetes presenting at the University Hospital with a chief complaint of pain at tooth #85. Radiographic and intraoral examination revealed DA at sites #35 and #45, with tooth #75 missing. Tooth #85 presented pulp necrosis due to perforating caries ( Figure 11). As the prognosis of tooth #85 was poor, the tooth was extracted under local anaesthesia, followed by the immediate placement of a BLT RC 4.1 × 10 mm implant (Figures 12 and 13). Site #35 received the same implant type following the delayed procedure described above. Screwretained crowns were delivered 2 months post-surgery ( Figure 14). 1-and 2-year followup examinations revealed stable clinical and radiological situations.      This case illustrates the treatment of a 27-year-old female Caucasian DA patient wh consulted the University Hospital for a second opinion on treatment options for sites #3 and #45. Tooth #75 was absent and lost four months prior. Tooth #85 was affected by pul necrosis due to perforating caries, as evidenced by recent radiographs obtained at a    This case illustrates the treatment of a 27-year-old female Caucasian DA patient wh consulted the University Hospital for a second opinion on treatment options for sites #3 and #45. Tooth #75 was absent and lost four months prior. Tooth #85 was affected by pul necrosis due to perforating caries, as evidenced by recent radiographs obtained at a This case illustrates the treatment of a 27-year-old female Caucasian DA patient who consulted the University Hospital for a second opinion on treatment options for sites #35 and #45. Tooth #75 was absent and lost four months prior. Tooth #85 was affected by pulp necrosis due to perforating caries, as evidenced by recent radiographs obtained at an external dental office (Figure 15), and was repeatedly reported as painful by the patient. Based on the poor prognosis and after patient consent, tooth #85 was extracted, followed by the immediate placement of a BLT RC 4.1 × 10 mm implant. Site #35 was treated using the same implant type and following the described delayed protocol (Figure 16), followed by restoration of both sites at 2 months post-surgery. The clinical and radiological situations were stable at the 1-year follow-up appointment ( Figure 17).
Appl. Sci. 2023, 13, x FOR PEER REVIEW 11 external dental office (Figure 15), and was repeatedly reported as painful by the pa Based on the poor prognosis and after patient consent, tooth #85 was extracted, foll by the immediate placement of a BLT RC 4.1 × 10 mm implant. Site #35 was treated the same implant type and following the described delayed protocol (Figure 16), foll by restoration of both sites at 2 months post-surgery. The clinical and radiological tions were stable at the 1-year follow-up appointment ( Figure 17).          The orthodontic treatment plan included the extraction of teeth #73 and #83 and the orthodontic movement of teeth #34 and #44 to the canine position. Teeth #75 and #85 were mesioverted by hemi-sectioning, removal of the distal segments, and endodontic treatment of the mesial roots. The resulting tooth segments were used in a transitory fashion as a dental anchorage during the orthodontic procedure ( Figure 19). After completion of the prosthetic phase, sites #35 and #45 were treated by delayed implant placement of two BL RC 4.1 × 10 mm implants. Implant-supported bridges in positions #34, #35, #44, and #45 using cantilever extensions to positions #34 and #44, respectively, were used due to the high position of the foramen at these sites ( Figure 20). The orthodontic treatment plan included the extraction of teeth #73 and #83 and the orthodontic movement of teeth #34 and #44 to the canine position. Teeth #75 and #85 were mesioverted by hemi-sectioning, removal of the distal segments, and endodontic treatment of the mesial roots. The resulting tooth segments were used in a transitory fashion as a dental anchorage during the orthodontic procedure ( Figure 19). After completion of the prosthetic phase, sites #35 and #45 were treated by delayed implant placement of two BL RC 4.1 × 10 mm implants. Implant-supported bridges in positions #34, #35, #44, and #45 using cantilever extensions to positions #34 and #44, respectively, were used due to the high position of the foramen at these sites ( Figure 20). ment of the mesial roots. The resulting tooth segments were used in a transitory fashio as a dental anchorage during the orthodontic procedure ( Figure 19). After completion o the prosthetic phase, sites #35 and #45 were treated by delayed implant placement of tw BL RC 4.1 × 10 mm implants. Implant-supported bridges in positions #34, #35, #44, an #45 using cantilever extensions to positions #34 and #44, respectively, were used due t the high position of the foramen at these sites ( Figure 20).   as a dental anchorage during the orthodontic procedure ( Figure 19). After completion o the prosthetic phase, sites #35 and #45 were treated by delayed implant placement of tw BL RC 4.1 × 10 mm implants. Implant-supported bridges in positions #34, #35, #44, an #45 using cantilever extensions to positions #34 and #44, respectively, were used due t the high position of the foramen at these sites ( Figure 20).   For the upper arch, the treatment plan included tooth alignment by preserving teeth #13 and #23 in the first premolar position. Mild odontoplasty, comprising grinding of the canine tips, was applied. Due to complete rhizolysis of the roots of teeth #53 and #63 and the resulting poor prognosis (Figures 21 and 22), the treatment plan for these sites consisted of immediate implant placement and provisionalization and subsequent replacement of the provisional with final crowns. For the upper arch, the treatment plan included tooth alignment by preserving teeth #13 and #23 in the first premolar position. Mild odontoplasty, comprising grinding of the canine tips, was applied. Due to complete rhizolysis of the roots of teeth #53 and #63 and the resulting poor prognosis (Figures 21 and 22), the treatment plan for these sites con sisted of immediate implant placement and provisionalization and subsequent replace ment of the provisional with final crowns.     Figures 23 and 24 illustrate the extraction of teeth #53 and #63, followed by the im mediate placement of two BLT NC 4.1 × 12 mm implants at sites #13 and #23. Lateral an mesiodistal defects were gap augmented ( Figure 24). An impression was taken intraoper atively, and healing screws were placed before placing the provisional crowns a few hour later. Postoperative intraoral control radiographs were taken. Postoperative instruction were given (Figures 25 and 26).   Figures 23 and 24 illustrate the extraction of teeth #53 and #63, followed by the immediate placement of two BLT NC 4.1 × 12 mm implants at sites #13 and #23. Lateral and mesiodistal defects were gap augmented ( Figure 24). An impression was taken intraoperatively, and healing screws were placed before placing the provisional crowns a few hours later. Postoperative intraoral control radiographs were taken. Postoperative instructions were given (Figures 25 and 26).   Figures 23 and 24 illustrate the extraction of teeth #53 and #63, followed by the im mediate placement of two BLT NC 4.1 × 12 mm implants at sites #13 and #23. Lateral an mesiodistal defects were gap augmented ( Figure 24). An impression was taken intraoper atively, and healing screws were placed before placing the provisional crowns a few hour later. Postoperative intraoral control radiographs were taken. Postoperative instruction were given (Figures 25 and 26).      At the seven-day reentry, the healing of the four operated sites was assessed as ade quate, and the sutures were removed at sites #35 and #45. The patient was very satisfied with the aesthetic result of the implant-supported crowns in positions #13 and #23 (Figur 26), while emphasising that the treatment in the maxilla was not very painful compared to the treatment in the mandible. The clinical and radiological situations were stable at th 1-and 2-year follow-up appointments ( Figure 27).     At the seven-day reentry, the healing of the four operated sites was assessed as adequate, and the sutures were removed at sites #35 and #45. The patient was very satisfied with the aesthetic result of the implant-supported crowns in positions #13 and #23 ( Figure  26), while emphasising that the treatment in the maxilla was not very painful compared to the treatment in the mandible. The clinical and radiological situations were stable at the 1-and 2-year follow-up appointments ( Figure 27).  At the seven-day reentry, the healing of the four operated sites was assessed as adequate, and the sutures were removed at sites #35 and #45. The patient was very satisfied with the aesthetic result of the implant-supported crowns in positions #13 and #23 (Figure 26), while emphasising that the treatment in the maxilla was not very painful compared to the treatment in the mandible. The clinical and radiological situations were stable at the 1-and 2-year follow-up appointments ( Figure 27). Figure 24. Illustration of the treatment sequence of site #23, including situations after extractio after implant and osteotomy preparation in lateral and occlusal views, implant placement, im sion coping installation, and provisionalization after gap augmentation with a healing abutm  At the seven-day reentry, the healing of the four operated sites was assessed as quate, and the sutures were removed at sites #35 and #45. The patient was very sati with the aesthetic result of the implant-supported crowns in positions #13 and #23 (F 26), while emphasising that the treatment in the maxilla was not very painful comp to the treatment in the mandible. The clinical and radiological situations were stable a 1-and 2-year follow-up appointments ( Figure 27).

Results
The clinical and radiological observations of the five documented cases are illustrated above. Individual and average marginal bone levels and patient-and clinician-reported outcomes are reported in Tables 2 and 3 3.1. Clinical Results Table 1 reports patient demographics and treatment sites. The five treated patients presented with 18 DA sites, excluding third molars (Table 1). All patients had agenesis of both second mandibular premolars. Four patients were treated in a split-mouth arrangement, receiving contralateral immediate or delayed implant placement. One patient (case 5) presented ten DA sites and received two immediately placed and restored maxillary implants and two delayed implants in the mandible.
The pre-treatment radiographic evaluation indicated adequate alveolar dimensions, allowing implant placement in the ideal prosthetic positions in all patients. Primary stability in terms of insertion torque was adequate in all patients and ranged between 30 and 45 Ncm. Healing after implant placement was uneventful in all cases.
In all cases, lateral or mesiodistal defects of immediate placement groups were augmented using a mixture of autogenous bone chips collected during drilling and alloplastic bone (Bone Ceramic ® Straumann, Basel, Switzerland) for each site. Delayed implant sites usually displayed some level of horizontal atrophy, which did not influence implant placement at the ideal prosthetic positions. None of the grafts at the immediate sites showed signs of infection, necrosis, wound dehiscence, or other types of complications. All implants could be successfully restored and loaded, and they were followed up for clinical and radiographic examination for at least 1 year. All implants presented without any pathological signs at 1-year follow-up.
The aesthetic results in terms of soft tissues, including papillae, gingival zenith contour, and soft tissue quality, were ideal for all cases (score PES: 10), except for case 1, which displayed a loss of the distal papilla at the site of late implant placement after 1 year.

Marginal Bone Level Outcomes
As indicated by the comparison of radiographically determined post-loading and 1-year follow-up marginal bone levels in Tables 2 and 3 and the corresponding plot in Figure 28, radiographic bone levels were adequate and remained overall stable over the follow-up period (Tables 2 and 3). The qualitative comparison of temporal changes between the post-OP and 1-year follow-up outcomes did not indicate any pronounced difference between immediately placed and augmented implants and implants placed as part of a delayed protocol. Specifically, the resulting mesiodistal average marginal bone level changes between the time of implant placement and the 1-year post-placement follow-up timepoint were −0.50 ± 0.58 mm for immediate implant placement sites and −0.18 ± 0.175 mm for late implant placement sites. None of the implant sites showed crestal bone loss below the implant platform. post-OP and 1-year follow-up outcomes did not indicate any pronounced difference between immediately placed and augmented implants and implants placed as part of a delayed protocol. Specifically, the resulting mesiodistal average marginal bone level changes between the time of implant placement and the 1-year post-placement follow-up timepoint were −0.50 ± 0.58 mm for immediate implant placement sites and −0.18 ± 0.175 mm for late implant placement sites. None of the implant sites showed crestal bone loss below the implant platform.  Table 4 summarises pain levels ranging from 0 for no pain to 10 for maximum pain 3 days, 1 week, and 2 months post-surgery as reported by the patients per site receiving immediate and delayed implant placement, respectively. Overall, moderate pain levels (1 to 3) were reported specifically after 3 days and at sites that received delayed placement compared to the low pain levels (0 to 1) after immediate placement. 1 week post-placement, none of the patients reported any pain at the immediate placement sites, while 3 patients reported some pain at the delayed sites. None of the patients reported pain after 2 months post-placement. Table 4. Patient-reported post-operative pain per treatment site and type, i.e., immediate vs. delayed implant treatments, at 3 days, 1 week, and 2 months post-surgery, as rated on a scale from 0 to 10, with 0 for no pain and 10 for maximum pain. L and R indicate the left and right treatment sites, respectively.  Tables 5 and 6 report the patient-and clinician-reported satisfaction levels with the surgical procedure 10 min and 2 months after surgery, respectively. Four patients reported complete satisfaction with the procedure, while one patient (case 5 patient) reported being partly satisfied and exhausted after receiving four implants, i.e., one per quadrant comprising LA. All patients reported complete satisfaction with the treatment after prosthetic delivery. None of the patients expressed any pronounced levels of dissatisfaction with the procedures. The operating clinician (A.P.) reported satisfaction with all procedures without noticing a pronounced difference between immediate or delayed procedures from an operation time or technical complexity point of view.

Patient Post-Surgical Pain, Preference, and Patient and Clinician Satisfaction
80% of the patients reported preferring the immediate procedure due to having experienced less pain and perceiving the immediate procedure as faster overall (Table 7). One patient (Case 5) attributed the reason for preferring the immediate procedure to the fact that this patient received an immediate restoration. All other patients received restorations at the 2-month follow-up, irrespective of placement modality. One patient did not report any preference between the immediate or delayed placement protocols.

Discussion
This pilot study retrospectively, for the first time, directly compared immediate and delayed implant placement modalities in patients presenting multiple, mainly bilateral, symmetric dental agenesis second premolar sites with and without deciduous teeth in situ. The observations of this study indicate comparable outcomes in terms of clinical outcomes, namely esthetic and radiographic outcomes after 1-year post-surgery, and clinical complexity. Further, the results indicated a trend towards less pain and increased patient preference in sites treated with immediate placement compared to delayed procedures.
While Branemark, in his seminal work [30], suggested a conservative healing period between tooth extraction and implant placement, immediate insertion of implants into fresh extraction sockets has become a routine protocol supported by literature and recent consensus statements [31,32]. On the other hand, immediate implant placement-type 1, according to Hammerle et al., 2004 [32,33], as defined by the placement of an implant into a tooth socket concurrently with extraction, has also been associated with a significantly elevated risk for complications, such as, e.g., midfacial mucosal recession and papillary height loss following resorption of the facial and interproximal bone [34,35]. Elevated complication risks were reported for immediate implants in conditions showing, e.g., a deficient buccal and interproximal bone or soft tissue, a thin periodontal biotype, and the absence of implant primary stability [35]. As a result, selection criteria to avoid these clinical scenarios need to be adopted, which may, on the other hand, limit the applicability of immediate placement [35]. Although simultaneous biomaterial grafting may support augmenting buccal bone defects, intrasurgical complications, such as fracturing the cortical buccal bone wall by ankylosed teeth, may further restrict the ability to deliver an immediate placement [36,37]. Interestingly, the current notion that patients would prefer immediate implant placement (and loading) compared to delayed implant placement could not be substantiated by the present literature or recent consensus reviews, which was recently attributed to the fact that study designs were not necessarily adequate to test patientreported outcomes [38].
Compared to the immediate placement in the extraction socket of succedaneous teeth, the anatomy of the extraction sites of deciduous teeth, specifically in the presence of DA, may significantly change the operative complexity and risk profiles in favour of immediate placement. Specifically, the apical bone in the treated DA patients was widely intact, reducing and largely eliminating the difficulty related to the restricted visibility of the bone socket in flapless surgery and facilitating drilling and insertion of the implant to obtain primary stability. Furthermore, no late aesthetic complications related to post-extraction bone resorption/remodelling documented for extraction sockets were observed herein. This favourable healing pattern around immediately placed implants in deciduous teeth post-extraction sockets might be related to the phenotype of the buccal wall in DA patients that presented a vestibular cortical plate in continuity with the alveolar bone, in contrast to the situation with succedaneous teeth with roots that potentially occupy the volume of the alveolar ridge entirely. Consequently, the gap between the implant and the socket wall in DA deciduous tooth extraction sites may affect the outcome of immediate implant placement to a lesser extent, promoting the volumetric stability of the alveolar bone crest.
Another interesting observation was related to the fact that patients experienced less pain in sites treated with the immediate procedure compared to the delayed placement procedure, resulting in an overall preference among patients for the immediate procedure. The observed difference in comfort between placement modalities was probably related to the fact that immediate placement was performed flapless, while delayed procedures involved completely exposing the osseous edentulous site by raising a full-thickness flap.
Patient-reported outcomes between immediate and delayed procedures in non-DA patients were previously investigated by, e.g., Tonetti et al. (2016) [39]. The authors did not identify any differences between treatment modalities related to post-op pain or discomfort. Interestingly, the authors also mentioned, in contrast to the herein-reported observations, a tendency toward a greater incidence of post-op complaints during the early healing phases in immediate placement patients. Differences in surgical procedures, patient profiles, and clinical routines, comprising surgical procedures and study setups, may limit the comparability of this aspect between studies.
Several other studies and reviews confirm and support the overall high clinical success and survival rates of dental implants in DA patients [12]. King et al., e.g., reported high implant survival rates of 96.8% over a follow-up period of 36 months following delayed placement of small-diameter implants in edentulous maxillary lateral and mandibular incisor regions caused by DA [14]. In a similar investigation, Roccuzzo et al. very recently reported high 99% survival rates, low levels of crestal bone loss, and good to excellent esthetic scores 1 year after delayed placement of small-diameter implants for the rehabilitation of patients with congenitally missing maxillary incisors [40]. To our knowledge, this is the first report that directly compares clinical and patient-reported aspects between implant placement modalities as part of an intra-individual comparative split-mouth design. With regards to the treatment indication, i.e., DA patients, the setups of other studies indicate a relatively broad homogeneity of patient populations with regards to anatomic, genetic, and age-related factors, often requiring a range of diverse therapeutic measures as part of multidisciplinary approaches preceding or concomitant orthodontic treatment [41]. While potentially rendering comparison of treatment outcomes more difficult compared to the herein-used inter-patient comparative approach, inter-patient comparative study designs have shown overall high rates of patient satisfaction and clinical and aesthetic success of implant treatment in DA patients, confirming the herein observed results [41]. Additionally, some recently introduced compounds have been demonstrated to significantly influence the oral environment, e.g., probiotics, which have been shown to modify clinical and microbiological parameters in periodontal patients [42][43][44]. Future clinical trials may also consider these products as adjuvants in patients with mini-implant-supported prostheses.
The outcomes and observations reported herein may be limited by the low number of subjects and the descriptive nature of this study, which deliberately refrains from any detailed statistical comparison between groups. Further limitations might be related to the retrospective nature of the investigation, limiting its general ability to compare specific study aspects in a more focused manner by adapting methodological approaches and the study design to one or several specific research questions. Nevertheless, the authors believe that the approach and study model, i.e., patients displaying multiple agenesis sites with and without present teeth for an intra-patient comparison, might be specifically suitable and valuable in analyzing specific outcomes in the relatively inhomogeneous study population of DA patients. At the same time, this pilot investigation indicates that the herein-used study design may be well suited for dedicated future comparative follow-up studies with high statistical power and relatively low subject numbers.

Conclusions
Within the limitations of this pilot investigation, the herein-presented intra-patient comparison between immediate and delayed implant placement modalities in dental agenesis sites suggests comparable outcomes of both placement modalities in terms of clinical and radiological outcomes at similar surgical complexity levels. Patient-reported outcomes in favour of immediate placement were observed. Further follow-up studies are required to substantiate these provisional observations. Author Contributions: Draft of the manuscript, preparation of images, patient treatment, P.A.; draft of the manuscript, radiological interpretation, preparation of images, S.H.; conception, drafting, and critical review of the manuscript, T.L. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.

Institutional Review Board Statement:
The presented study adhered to the Helsinki Declaration of ethical principles by the World Medical Association. Based on the retrospective, non-interventional character of the study and the relatively low number of involved subjects (below 5), this study was confirmed to be exempt from approval by the applicable Ethics Commission on Human Research of Geneva (CCER-Geneva).
Informed Consent Statement: Written informed consent was obtained from the patient to publish this paper.