Twenty-five years of recombinant human growth factors rhPDGF-BB and rhBMP-2 in oral hard and soft tissue regeneration.

Contemporary oral tissue engineering strategies involve recombinant human growth factor approaches to stimulate diverse cellular processes including cell differentiation, migration, recruitment, and proliferation at grafted areas. Recombinant human growth factor applications in oral hard and soft tissue regeneration have been progressively researched over the last 25 years. Growth factor-mediated surgical approaches aim to accelerate healing, tissue reconstruction, and patient recovery. Thus, regenerative approaches involving growth factors such as recombinant human platelet-derived growth factor-BB (rhPDGF-BB) and recombinant human bone morphogenetic proteins (rhBMPs) have shown certain advantages over invasive traditional surgical approaches in severe hard and soft tissue defects. Several clinical studies assessed the outcomes of rhBMP-2 in diverse clinical applications for implant site development and bone augmentation. Current evidence regarding the clinical benefits of rhBMP-2 compared to conventional therapies is inconclusive. Nevertheless, it seems that rhBMP-2 can promote faster wound healing processes and enhance de novo bone formation, which may be particularly favorable in patients with compromised bone healing capacity or limited donor sites. rhPDGF-BB has been extensively applied for periodontal regenerative procedures and for the treatment of gingival recessions, showing consistent and positive outcomes. Nevertheless, current evidence regarding its benefits at implant and edentulous sites is limited. The present review explores and depicts the current applications, outcomes, and evidence-based clinical recommendations of rhPDGF-BB and rhBMPs for oral tissue regeneration.

Minimally invasive esthetic ridge preservation with growth-factor enhanced bone matrix.

OBJECTIVES: Extraction socket preservation procedures are critical to successful esthetic implant therapy. Conventional surgical approaches are technique sensitive and often result in alteration of the soft tissue architecture, which then requires additional corrective surgical procedures. This case series report presents the ability of flapless surgical techniques combined with a growth factor-enhanced bone matrix to provide esthetic ridge preservation at the time of extraction for compromised sockets. CLINICAL CONSIDERATIONS: When considering esthetic dental implant therapy, preservation, or further enhancement of the available tissue support at the time of tooth extraction may provide an improved esthetic outcome with reduced postoperative sequelae and decreased treatment duration. Advances in minimally invasive surgical techniques combined with recombinant growth factor technology offer an alternative for bone reconstruction while maintaining the gingival architecture for enhanced esthetic outcome. The combination of freeze-dried bone allograft (FDBA) and rhPDGF-BB (platelet-derived growth factor-BB) provides a growth-factor enhanced matrix to induce bone and soft tissue healing. CONCLUSIONS: The use of a growth-factor enhanced matrix is an option for minimally invasive ridge preservation procedures for sites with advanced bone loss. Further studies including randomized clinical trials are needed to better understand the extent and limits of these procedures. CLINICAL SIGNIFICANCE: The use of minimally invasive techniques with growth factors for esthetic ridge preservation reduces patient morbidity associated with more invasive approaches and increases the predictability for enhanced patient outcomes. By reducing the need for autogenous bone grafts the use of this technology is favorable for patient acceptance and ease of treatment process for esthetic dental implant therapy.

A randomized, controlled, multicentre clinical trial of post-extraction alveolar ridge preservation.

AIM: To compare the effectiveness of two-ridge preservation treatments. MATERIALS AND METHODS: Forty subjects with extraction sockets exhibiting substantial buccal dehiscences were enrolled and randomized across 10 standardized centres. Treatments were demineralized allograft plus reconstituted and cross-linked collagen membrane (DFDBA + RECXC) or deproteinized bovine bone mineral with collagen plus native, bilayer collagen membrane (DBBMC + NBCM). Socket dimensions were recorded at baseline and 6 months. Wound closure and soft tissue inflammation were followed post-operatively, and biopsies were retrieved for histomorphometric analysis at 6 months. RESULTS: Primary endpoint: at 6 months, extraction socket horizontal measures were significantly greater for DBBMC + NBCM (average 1.76 mm greater, p = 0.0256). Secondary and Exploratory endpoints: (1) lingual and buccal vertical bone changes were not significantly different between the two treatment modalities, (2) histomorphometric % new bone and % new bone + graft were not significantly different, but significantly more graft remnants remained for DBBMC; (3) at 1 month, incision line gaps were significantly greater and more incision lines remained open for DFDBA + RECXC; (4) higher inflammation at 1 week tended to correlate with lower ridge preservation results; and (5) deeper socket morphologies with thinner bony walls correlated with better ridge preservation. Thirty-seven of 40 sites had sufficient ridge dimension for implant placement at 6 months; the remainder were DFDBA + RECXC sites. CONCLUSION: DBBMC + NBCM provided better soft tissue healing and ridge preservation for implant placement. Deeper extraction sockets with higher and more intact bony walls responded more favourably to ridge preservation therapy.

A prospective, randomized controlled preclinical trial to evaluate different formulations of biphasic calcium phosphate in combination with a hydroxyapatite collagen membrane to reconstruct deficient alveolar ridges.

Many patients and clinicians would prefer a synthetic particulate bone replacement graft, but most available alloplastic biomaterials have limited osteogenic potential. An alloplast with increased regenerative capacity would be advantageous for the treatment of localized alveolar ridge defects. This prospective, randomized controlled preclinical trial utilized 6 female foxhounds to analyze the osteogenic impact of different formulations of biphasic calcium phosphate (BCP) in combination with an hydroxyapatite-collagen membrane and their ability to reconstruct deficient alveolar ridges for future implant placement. The grafted sites were allowed to heal 3 months, and then trephine biopsies were obtained to perform light microscopic and histomorphometric analyses. All treated sites healed well with no early membrane exposure or adverse soft tissue responses during the healing period. The grafted sites exhibited greater radiopacity than the surrounding native bone with BCP particles seen as radiopaque granules. The graft particles appeared to be well-integrated and no areas of loose particles were observed. Histologic evaluation demonstrated BCP particles embedded in woven bone with dense connective tissue/marrow space. New bone growth was observed around the graft particles as well as within the structure of the graft particulate. There was intimate contact between the graft particles and newly formed bone, and graft particles were bridged by the newly formed bone in all biopsies from the tested groups. The present study results support the potential of these BCP graft particulates to stimulate new bone formation. Clinical studies are recommended to confirm these preclinical findings.

The clinical and histologic outcome of dental implant in large ridge defect regenerated with alloplast: a randomized controlled preclinical trial.

A basic tenet of successful osseointegration is that the implant resides in a sufficient quality and quantity of bone to ensure bone contact and thus stabilization. A prospective, randomized controlled preclinical trial was conducted to evaluate the bone-to-implant contact (BIC) when placing implants in bone regenerated by 3 different combinations of biphasic calcium phosphate (BCP). Dental implants were placed into the regenerated ridges of 6 female foxhounds; the ridges were reconstructed with different formulations of BCP in combination with an hydroxyapatite collagen membrane. They were retrieved after 3 months to perform light microscopic and histomorphometric analyses. Implants in each group appeared to be stable and osseointegrated. Light microscopic evaluation revealed tight contacts between the implant threads with the surrounding bone for all 4 groups. The mean BIC ranged from 64.7% to 73.7%. This preclinical trial provided clinical and histologic evidence to support the efficacy of all 3 formulations of BCP to treat large alveolar ridge defects to receive osseointegrated dental implants.

Tooth Retention and Clinical and Radiographic Long-Term Results Among Patients Treated with the Full-Mouth Laser-Assisted New Attachment Procedure (LANAP): A Case Series.

There are limited long-term treatment results for patients who receive full-mouth laser-assisted new attachment procedure (LANAP). The present study examined cases of full-mouth LANAP therapy for tooth retention, including clinical and radiographic changes. Sixty-six generalized stage III/IV periodontitis patients aged 30 to 76 years were identified via consecutive retrospective chart reviews in a private practice limited to periodontics. Following treatment with the LANAP protocol, differences between baseline and the patient's most recent periodontal maintenance visit (mean: 6.7 years) were determined regarding interproximal probing depths (iPD) and interproximal bone loss (iBL) percentages. Factors affecting tooth loss were analyzed using Cox proportional hazard regression survival analysis. The average tooth loss for the study population was 0.11 teeth/patient/year. Premolars were more likely to be retained compared to the reference group of incisors (hazard ratio = 0.38; 95% CI = 0.16 to 0.90; P = .03), adjusting for canines, molars, and other potential confounding factors. Age at the time of LANAP treatment, gender, history of diabetes, and baseline iBL and iPD were all significantly associated with tooth loss after full-mouth LANAP treatment. Clinical changes in iPD were more significant among premolars and molars when followed up for a period of less than 7 years. Tooth retention after full-mouth LANAP treatment was favorable in this cohort of private practice patients. Int J Periodontics Restorative Dent 2023;43:181-191. doi: 10.11607/prd.6418.

Human histologic evaluation of the use of the dental putty for bone formation in the maxillary sinus: case series.

A proof-of-principle study was conducted to assess the safety and efficacy of dental putty as an alternative sinus augmentation biomaterial. Six healthy patients requiring a total of 10 sinus augmentations received sinus augmentations. All patients volunteered and signed an informed consent based on the Helsinki declaration of 1975, as revised in 2000. The sinus augmentation was performed under local anesthesia with a mucoperiosteal flap elevated to expose the buccal wall of the maxillary sinus. The space was then filled with the dental putty in several increments, and the window was covered with an absorbable collagen membrane. Biopsies were harvested from all 10 treated sinuses using a 3-mm trephine bur at the time of implant placement at either 6 or at 9 months after sinus augmentation. All patients completed the study without complications, except for 1 patient who reported fistulas at 1 and 2 months after the surgery. Clinical reentry revealed that regenerated bone on the osteotomy site was soft and immature. The ground sections of the biopsied cores revealed minimum amounts of trabeculation surrounded by an abundant array of irregular-shaped residual alloplastic particles embedded in loose connective tissue. The present study's findings revealed inadequate bone formation, although the material appears to be bioinert as there is no elicitation of inflammatory response.

American Academy of Periodontology best evidence consensus statement on the use of biologics in clinical practice.

A biologic is a therapeutic agent with biological activity that is administered to achieve an enhanced regenerative or reparative effect. The use of biologics has progressively become a core component of contemporary periodontal practice. However, some questions remain about their safety, indications, and effectiveness in specific clinical scenarios. Given their availability for routine clinical use and the existing amount of related evidence, the goal of this American Academy of Periodontology (AAP) best evidence consensus (BEC) was to provide a state-of-the-art, evidence-based perspective on the therapeutic application of autologous blood-derived products (ABPs), enamel matrix derivative (EMD), recombinant human platelet-derived growth factor BB (rhPDGF-BB), and recombinant human bone morphogenetic protein 2 (rhBMP-2). A panel of experts with extensive knowledge on the science and clinical application of biologics was convened. Three systematic reviews covering the areas of periodontal plastic surgery, treatment of infrabony defects, and alveolar ridge preservation/reconstruction and implant site development were conducted a priori and provided the foundation for the deliberations. The expert panel debated the merits of published data and exchanged experiential information to formulate evidence-based consensus statements and recommendations for clinical practice and future research. Based on an analysis of the current evidence and expert opinion, the panel concluded that the appropriate use of biologics in periodontal practice is generally safe and provides added benefits to conventional treatment approaches. However, therapeutic benefits and risks range based on the specific biologics used as well as patient-related local and systemic factors. Given the limited evidence available for some indications (e.g., gingival augmentation therapy, alveolar ridge preservation/reconstruction, and implant site development), future clinical studies that can expand the knowledge base on the clinical use of biologics in periodontal practice are warranted.

Pilot clinical and histologic evaluations of a two-piece zirconia implant.

An investigation was conducted to evaluate the clinical and histologic results of bone and soft tissue healing around a two-piece zirconia dental implant in a human model. A healthy female patient requiring tooth replacement with dental implants received a two-piece zirconia implant together with conventional titanium implants to be implemented in a prosthesis. Clinical and radiographic evaluations at 6 months revealed stable osseointegrated zirconia and titanium dental implants. Light microscopy and backscatter scanning electron microscopic analyses confirmed the biocompatibility and achievement of osseointegration, in addition to maintenance of the crestal bone level. The findings suggest that the bone-to-implant contact with a zirconia implant surface is sufficient to provide clinical and histologic evidence of osseointegration. The biopsied two-piece zirconia dental implant with platform switching demonstrated osseointegration occlusal to the implant-abutment junction, eliminating the significance of the microgap.

The feasibility of demineralized bone matrix and cancellous bone chips in conjunction with an extracellular matrix membrane for alveolar ridge preservation: a case series.

An investigation was conducted to test the feasibility of demineralized bone matrix and cancellous bone chips in a reverse-phase medium carrier (DynaBlast) in concert with an extracellular matrix membrane (DynaMatrix) to provide hard and soft tissue regeneration for the purpose of a ridge preservation procedure. Nine patients requiring extraction of 30 maxillary teeth were grafted with DynaBlast and DynaMatrix. Twenty sites attained primary flap closure over the grafted area (primary healing intention group), while 10 sites were assigned randomly to the secondary healing intention group, in which primary flap closure over the membrane was not achieved. Clinical and radiographic evaluations at 6 months revealed comparable bone formation for both groups. Histologic analyses of 21 harvested soft and hard tissue core biopsies revealed absence of the remnant membrane and consistent patterns of new bone formation. The efficacy and safety of DynaBlast and DynaMatrix have been validated clinically and histologically to preserve the dimensions of the alveolar process.

Tissue engineering with recombinant human platelet-derived growth factor BB for implant site development.

Currently, PDGF-BB is FDA-approved for periodontal regeneration as part of a dental bone-filling device only. Although this device uses beta-TCP as the scaffold carrier, there has been considerable clinical interest in combining this growth factor with other bone replacement grafts, particularly bone allografts. This article reports on clinical experiences using rhPDGF-BB with bone allografts for implant site development. After careful evaluation of clinical parameters and consideration of current and emerging evidence, the off-label use of rhPDGF-BB was determined in the following case reports to be consistent with good clinical practice and in the patient's best interest. Clinical, radiographic, and histologic observations from the following selected cases are presented to illustrate treatment outcomes achieved using this combination strategy: ridge preservation for extraction sockets with alveolar wall defects; ridge preservation for extraction sockets minimally invasive techniques; lateral ridge augmentation; and sinus augmentation. All of the cases presented and reviewed were surgically managed using 0.5 ml of 0.3 mg/ml of rhPDGF delivered using a particulate bone allograft (FDBA or DFDBA) as a scaffold. Controlled clinical trials are necessary to establish the relative effectiveness of rhPDGF-BB combined with different mammalian scaffolds for alveolar augmentation.

Tissue-engineered bilayered cell therapy for the treatment of oral mucosal defects: a case series.

In this case series, a tissue-engineered bilayered live cell therapy (LCT) is examined as an alternative to free gingival grafts in subjects with oral mucosal defects. Four patients with five sites requiring mucogingival surgery because of limited vestibular depth and limited keratinized oral mucosa were selected for treatment. All included patients had limited graft availability or preferred to avoid autogenous soft tissue grafting. The oral mucosal defects were treated with a tissue-engineered bilayered LCT, a circular disk of allogeneic live, human-derived, confluent, and bilayered keratinocyte and fibroblast cells. Sites were evaluated for wound healing, histologic appearance of the regenerated mucosa, and DNA persistence of the LCT. All sites healed uneventfully, with complete epithelialization by 14 days postoperative and no significant adverse events. The treated sites matched the surrounding tissues in both texture and color. Histologic samples revealed gingival tissue architecture characterized by a parakeratinized epithelium with a very sparse and diffuse chronic inflammatory response within the connective tissue. DNA persistence indicated that the pairs of samples (swab and biopsy) collected from each subject displayed the same identifier DNA, with no evidence of any other source. Further research is needed to evaluate the utility of LCT in clinical practice.

Computer-guided implant dentistry for precise implant placement: combining specialized stereolithographically generated drilling guides and surgical implant instrumentation.

The application of computed tomography (CT) and the use of computer software for dental implant therapy have significantly increased during the last several years. Dental implant positioning can be either "partially guided," where only osteotomy sites are prepared using sequential, removable surgical drilling guides (generated using computer software and through the process of stereolithography), or "totally guided," whereby one guide is used for osteotomy site preparation as well as implant delivery. Recently, the guided delivery of manufacturer-specific internal-connection implants has become available. Individualized protocols and specific instrumentation are employed under this approach to CT-based implant surgery. The purpose of this article is to expand on previous publications related to the use of prosthetically directed implant placement using computer software to ensure precise placement and predictable prosthetic outcomes. Three case reports are presented where precision-guided CT-based surgery was employed and the immediate delivery of a dental prosthesis was facilitated.

The clinical efficacy of DynaMatrix extracellular membrane in augmenting keratinized tissue.

This study was conducted to compare the efficacy and feasibility of an extracellular matrix membrane (DynaMatrix) with that of an autogenous gingival graft in increasing the width of attached keratinized tissue. Six patients with an inadequate amount of attached keratinized gingiva on the bilateral facial aspect of the mandibular posterior teeth were recruited for this study. The defect sites were randomly subjected to receive either test (DynaMatrix membrane) or control (autogenous gingival graft) treatment. Both test and control sites achieved a clinically significant increase in the amount of keratinized gingiva, and the DynaMatrix membrane-treated sites blended well with the surrounding tissue, with a better appearance when compared to the autogenous gingival grafted sites. The biopsy specimens of both test and control sites appeared to be similar histologically, with mature connective tissue covered by keratinized epithelium. The results of both clinical and histologic evaluations have suggested a potential application of an extracellular matrix membrane in achieving gingival augmentation.

Histologic evidence of a connective tissue attachment to laser microgrooved abutments: a canine study.

Previous research has demonstrated the effectiveness of laser-ablated microgrooves placed on implant collars to support direct connective tissue attachments to altered implant surfaces. Such a direct connective tissue attachment serves as a physiologic barrier to the apical migration of the junctional epithelium and prevents crestal bone resorption. The current prospective preclinical trial sought to evaluate bone and soft tissue healing patterns when laser-ablated microgrooves were placed on the abutment. A canine model was selected for comparison to previous investigations that examined the negative bone and soft tissue sequelae of the implant-abutment microgap. The results demonstrate significant improvement in peri-implant hard and soft tissue healing compared to traditional machined abutment surfaces.

Human Clinical and Histologic Evaluations of Laser-Assisted Periodontal Therapy with a 9.3-µm CO² Laser System.

This investigation was designed to evaluate the healing response of 9.3-µm CO2 laser-assisted periodontal therapy. Five patients presenting with moderate to severe periodontitis, with an initial pocket depth (PD) ≥ 5 mm and with teeth predetermined to be surgically extracted, were enrolled and consented to treatment with full-mouth CO2 laser-assisted therapy. The laser treatment was carried out in the Ultraguide Mode at a setting of 0.25-mm spot size, with an average power of 0.65 to 1.15 watts and 20% mist. The laser tip was passed from the gingival margin and down apically to the base of the pocket with a sweeping L motion. The teeth were intensely scaled with piezoultrasonic instrumentation afterwards. A second pass of the laser tip was performed for the study teeth. At 9 months, all patients were clinically reevaluated. For sites with an initial pocket depth of ≥ 7 mm, a mean PD reduction of 3.97 ± 1.36 mm and a mean clinical attachment level gain of 3.54 ± 1.54 mm were achieved, resulting in a mean PD of 3.91 ± 0.77 mm. En bloc biopsy samples of four teeth were obtained and analyzed; two demonstrated histologic evidence of new bone formation while the other two healed with a long junctional epithelium with minimal inflammatory infiltrate. Further long-term clinical studies are needed to investigate the treatment stability obtained with a 9.3-µm CO2 laser compared to conventional surgical therapy. Nevertheless, the encouraging clinical results indicated that adjunctive use of the 9.3-µm CO2 laser-assisted periodontal therapy can be beneficial for treatment of periodontally compromised patients.

Human histologic evaluation of mineralized collagen bone substitute and recombinant platelet-derived growth factor-BB to create bone for implant placement in extraction socket defects at 4 and 6 months: a case series.

The objective of this pilot study was to assess whether mineralized collagen bone substitute (MCBS) combined with recombinant human platelet-derived growth factor-BB (0.3 mg/mL) would generate adequate viable bone in buccal wall extraction defects to accommodate implant placement. The primary outcome variable was bone quality, as measured by microcomputed tomography and histologic evaluation. This was successfully accomplished in all eight specimens obtained from seven patients. The secondary outcome variables were bone quality and quantity as observed clinically, radiographically, and by the primary stability of implants at the time of placement. Soft tissue healing was excellent, and there were no unanticipated adverse events. Robust bone formation accompanied by MCBS resorption was evident in all 4- and 6-month specimens. This was accomplished without barrier membranes.

Minimally invasive alveolar ridge augmentation procedure (tunneling technique) using rhPDGF-BB in combination with three matrices: a case series.

This study investigated a minimally invasive surgical procedure for alveolar ridge augmentation that combined recombinant human platelet-derived growth factor BB (rhPDGF-BB) and three different matrices. The minimally invasive tunneling ridge augmentation procedure was applied to 12 patients randomized into three groups: rhPDGF-BB (0.3 mg/mL) was combined with freeze-dried bone allograft (FDBA; group A), anorganic bovine bone graft (ABBG; group B), or anorganic bovine bone graft/mineralized collagen bone substitute (ABBG/MCBS; group C). Computed tomography (CT) scans were obtained presurgically and prior to 14-week re-entry surgery. Clinical reentry revealed adequate bone volume to place implants in all patients in groups A and B and two of four patients in group C. Trephine core biopsies were obtained and evaluated by microCT, backscatter scanning electron microscopy (BE-SEM), and light microscopy. New bone formation was consistently observed with BE-SEM and histologic analysis for group A and B specimens. Newly formed woven and lamellar bone were in close contact with graft particles. The ABBG/MCBS specimens (group C) had more variable results, with fibrous encapsulation of graft particles and limited histologic evidence of new bone formation. Within the limits of this study, the FDBA and ABBG carriers appear to be appropriate scaffolds to deliver rhPDGF-BB for ridge augmentation via minimally invasive surgical techniques.

Human histologic evaluation of anorganic bovine bone mineral combined with recombinant human platelet-derived growth factor BB in maxillary sinus augmentation: case series study.

The objective of this proof-of-principle study was to examine the potential for improved bone regenerative outcomes in maxillary sinus augmentation procedures when recombinant human platelet-derived growth factor BB (0.3 mg/mL) is combined with particulate anorganic bovine bone mineral. The surgical outcomes in all treated sites were uneventful at 6 to 8 months, with sufficient regenerated bone present to allow successful placement of maxillary posterior implants. Large areas of dense, well-formed lamellar bone were seen throughout the intact core specimens in more than half of the grafted sites. Abundant numbers of osteoblasts were noted in concert with significant osteoid in all sites, indicating ongoing osteogenesis. A number of cores demonstrated efficient replacement of the normally slowly resorbing anorganic bovine bone mineral matrix particles with newly formed bone when the matrix was saturated with recombinant human platelet-derived growth factor BB.

The efficacy of demineralized bone matrix and cancellous bone chips for maxillary sinus augmentation.

Demineralized bone matrix and cancellous bone chips in a reverse-phase medium carrier (DynaBlast, Keystone Dental) were used to augment the maxillary sinuses in 8 patients requiring 10 sinus augmentations. Clinical reentry after 6 to 7 months (mean, 6.2 months) and computed tomographic scan evaluation at 5 months demonstrated new bone formation as well as sufficient radiopaque volume to place implants in all sites. Microcomputed tomographic evaluation and histomorphometric analysis of sinus core biopsies confirmed the formation of new bone and demonstrated three distinctive mineralization patterns that have been previously described. DynaBlast can be considered a viable alternative to the use of autogenous bone or other types of grafting materials.