What are biologic mediators? Which have been studied in reference to periodontal regeneration?
What type of material is enamel matrix derivative? Is it a graft? How is it made? What are the specific growth factors that it utilizes and what is the theory behind its use? What are the indications for its use? What are the contraindications?
Can Emdogain be used for intrabony defects? Is root surface treatment necessary to use this material? How are the roots treated now, and does that differ from previous applications of Emdogain? How does it compare to open flap debridement? How does it handle?
How does emdogain heal? Are there any controversies concerning its healing? Is there a difference in healing of animal or human studies, or between diseased root surface vs created defects? Have all of these results analyzed intrabony defects? Would that make a difference?
Emdogain is often used mixed with other materials. How does this compare to open flap debridement? How does this compare to emdogain alone? How does it compare to a more traditional GTR? Is it a justifiable expense to a patient?
What biologic modifiers have been studied in infrabony defects? Are these off-label uses or following manufacturer protocol? What are the advantages to biologic modifiers? What are the drawbacks?
What are biologic mediators? Which have been studied in reference to periodontal regeneration?
Kao, 2009 ARTICLE
P: Review the use of biologic mediators and tissue engineering in dentistry
D: In wound healing, the natural process usually results in tissue scarring or repair. Using tissue engineering, the wound healing process is manipulated so that tissue regeneration occurs. This manipulation usually involves one or more of the following three key elements: Signaling molecule, Scaffold or supporting matrices, and cells
1) Signaling molecules
- Research has focused on two main approaches: semipurified preparations (EMD, autologous PRP preparations) or recombinant growth factors (rhPDGF-BB, rhFGF, rhBMP)
1.1) PRP
- Source of growth factors in bone and periodontal regeneration
- 338% more in PRP
- Growth factors: PDGF, TGF-B, IGF, FGF-2, EGF, VEGF
- Stimulation the proliferation of fibroblasts and PDL cells. Extracellular matrix formation and neovascularization. Suppression of inflammatory cytokine release and limit inflammation.
- Contains high concentration of fibrinogen
1.2) EMD
- Harvested from porcine teeth
- Mechanism of action: EMD contains a mixture of low-molecular-weight proteins that stimulate cell growth and the differentiation of mesenchymal cells, including osteoblasts
- Contains TGF-B, BMP
- Stimulates endothelial cell proliferation and chemostaxis, and stimulates vascular endothelial cell growth factor production by PDL cells. When applied to root surfaces, the proteins are absorbed into the hydroxyapatite and collagen fibers of the root surface, where they induce cementum formation followed by periodontal regeneration
1.3) PDGF
- Potent mitogenic and chemotactic factor for mesenchymal cells in cell culture
1.4) FGF-2
- Ability to promote mesenchymal cell prolifereation and maintain the multipotent properties of these cells
- Promote proliferation of PDL cells and produce a regenerative environment that would support regeneration and angiogenesis
1.5) BMP
- A group of regulatory glycoproteins that are members of the TGF-B superfamily
- Stimulates differentiation of mesenchymal stem cells into chondroblasts and osteoblasts
- At least 7 BMPs have been isolated from bovine and human sources. In the field of periodontal regeneration, much of the research interest has focused on BMP-2, BMP-3, BMP-7
2) Scaffold or supporting matrices
- Bone allografts, synthetic and natural polymers, synthetic ceramics, bovine type I collagen, and calcium sulfate
- Provide physical support for the healing area so that there is no collapse of the surrounding tissue into the wound site
- To serve as a barrier to restrict cellular migration in a selective manner (principle of GTR)
- To serve as a scaffold for cellular migration and proliferation
- To potentially serve as a time-release mechanism for signaling molecule
3) Cell therapy
- Most common application involves a cell-expansion strategy in an ex vivo environment followed by transplantation back into the defect area
- Can combine with scaffold or supporting matrices
- Problem: Explanted material required a substantial volume of donor tissue and the advantage of this approach was not evident
Application of tissue-engineering principles: Periodontal regeneration
EMD
- Has been effective in the treatment of intrabony defects
- Histologic evidence for EMD-induced periodontal regeneration
rhPDGF
- Used in conjunction with allograft
- Histologic evidence of periodontal regeneration
- 0.3 mg/ml performed better than 1.0 mg/ml
rhFGF-2
- Histologic evidence of regeneration
What type of material is enamel matrix derivative? Is it a graft? How is it made? What are the specific growth factors that it utilizes and what is the theory behind its use? What are the indications for its use? What are the contraindications?
Lyngstadaas, 2009 ARTICLE
Background: Enamel matrix derivative (EMD) purified acid extract of proteins from pig enamel matrix (Emdogain; Straumann AG, Basel, Switzerland.)
Application: Amelogenins are dissolved in aqueous, acidic solution of PGA (propylene glycol alginate). Upon application, acidity of gel is neutralized and temp is increased which allows release of amelogenins. They can self assemble into insoluble nanospheres. Over the course of days and weeks, they are processed by matrix proteases, slowly releasing biologically active components into the local environment, promoting regeneration (possibly) by triggering a release of growth factors (TGF-B increased, as well as VEGF, PDGF, and IL-6). Can stimulate growth of mesenchymal cells, including fibroblasts, cementoblasts, osteoblasts and stem cells.
PDL: The role of enamel proteins in periodontal ligament formation is supported by their presence in initial cementum formation during normal development of tooth attachment. The amelogenins are known to self-assemble into supramolecular aggregates that form an insoluble extracellular matrix, with high affinity for HA and collagens. EMD has potential to trigger regenerative response in PDL cells.
Cementum: Amelogenin deposition precedes cementum formation, then EMD treatment probably mimics odontogenesis and works by restarting dormant developmental programs in cells for (re)generation of the tooth attachment apparatus. It has been assumed that the most important mechanism of action of EMD is to initiate periodontal regeneration through recruitment of cementoblasts to the root-surface and hence to stimulate these to form root-cementum.
Growth Factors: Amelogenins are rich in proline residues (30%) that are believed to inhibit the formation of classic secondary structures such as b-sheet, a-helix, and random coil, producing an intrinsically disordered protein .The activity of EMD has been compared with that of bone morphogenic proteins (BMP) and transforming growth factor (TGF)-b-like molecules (19). Full length amelogenin molecules have been shown to stimulate autocrine production of BMP while the smaller amelogenin fragments of leucine rich amelogenin peptide (LRAP)- and tyrosine-rich amelogenin peptide (TRAP)- related molecules stimulate autocrine production of TGF-b. It has also been shown that EMD increases autocrine synthesis of TGF-b in ligament fibroblasts while TGF-b itself is undetectable in the EMD formulation
Pulp: It has been shown that amelogenin participates in the maturation and growth of dental pulp cells during tooth formation. Experiments in pigs have compared the effect of EMD with calcium hydroxide when used for direct pulp capping. The histological evaluation demonstrated a significantly more pronounced formation of secondary dentine in teeth treated with amelogenin.
Bone: In a systematic review (SR) on the efficacy of EMD to promote regeneration of osseous tissue in intrabony defects, alone or in combination with membranes, a total of 20 in vivo studies with histomorphometric analysis were evaluated. The main results that were that EMD treatment significantly improved bone regeneration when compared with open-flap debridement. However, EMD was not more effective than traditional guided tissue regeneration (GTR)
Implants: Amelogenin is one such candidate that has a potential role in stimulating peri-implant bone growth. However, no studies so far have been able to demonstrate a significant effect from EMD or amelogenins on implant performance when analyzed by biomechanical testing. As far as a PDL tissue engineering on implant surface, this route might actually hinder cell attachment to the material surface.
Avulsion: Root surface conditioning with amelogenins could prevent root resorption and ankylosis, and stimulate periodontal ligament formation after repositioning of the avulsed tooth. Results have been mixed. Possible that when used with anti-inflammatory meds, EMD can support healing if teeth have been stored for time or in medium that does not support PDL reformation.
Wound Healing: EMD is clinically reported to show exceptionally fast wound healing and minimal post op symptoms such as pain or swelling, possibly due to anti-inflammatory or anti-microbial effects. Amelogenins used in studies w/skin wound healing showed that the amount of granulation tissue in an EMD-treated wound was significantly increased, and that wound fill and re-epithelialization of full thickness wounds progressed almost twice as fast in the presence of EMD
BL: EMD appears to utilize a principle of biomimicry to stimulate growth factor expression, and acts as its own release device to ensure this stimulation occurs over time. Although its results are controversial in aspects of dentistry, it can be used in perio regeneration therapy, as well as several other aspects of dentistry.
Can Emdogain be used for intrabony defects? Is root surface treatment necessary to use this material? How are the roots treated now, and does that differ from previous applications of Emdogain? How does it compare to open flap debridement? How does it handle?
Heijl 1997 ARTICLE
Background: Prior to the formation of acellular cementum, enamel matrix proteins are secreted and temporally deposited onto the root surface providing an essential surface for the expression of cementum-forming cells. The discovery of the enamel matrix layer between the peripheral dentin and the developing cementum and its function provided the fundamental concept for enamel matrix derivatives (Emdogain-EMD)-supported tissue engineering in regenerative periodontal therapy.
P: To compare the long-term effect of EMD treatment as an adjunct to MWF with MWF w/ placebo.
M&M: A mulicenter RCT with split-mouth design involving 33 subjects with 34 paired test and control sites. The protocol required 2 interproximal sites, in the same jaw with PD ≥6 mm and an associated intrabony defect with a depth of ≥4 mm and a width of ≥2 mm measured radiographically. 1- and 2-wall defects were included. PPD, BOP, PI, CAL and radiographic bone levels were evaluated at baseline and then at 8, 16 and 36 months. The surgical areas were “etched” for 15 seconds with 37% phosphoric acid to remove the smear layer and allow enamel matrix proteins to precipitate onto a root surface. Doxycycline 200mg first day and then 100mg for 20 more days; in addition, patients were advised to rinse with CHX 0.2%/4-6 weeks post-op.
R: 1) BOP and PI were maintained throughout the study period. There were no differences between the test and control sites at any examination intervals.
2)
| CAL gain | 8 months | 16 months | 36 months |
| Test | 2.1mm | 2.3mm | 2.2mm |
| Control | 1.5mm | 1.7mm | 1.7mm |
3) The radiographic bone level continued to increase over the 36 months at the EMD-treated sites, while it remained close to the baseline level at the control sites. The SS radiographic bone gain at 36 months of 2.6 mm at EMD-treated sites.
BL: The favorable results obtained in the present clinical trial may indicate that EMD may be used conjunction with periodontal surgery in regenerative procedures.
Sculean 1999 ARTICLE
P: To evaluate the clinical outcome following the application of Emdogain in the treatment of intrabony periodontal defects.
M&M: 28 patients, 32-60 years old participated in the study. 32, 2- and 3-walled intrabony defects with a depth at least 6 mm were included. PD, REC and CAL were evaluated 1 week pre-sx and 8 months after treatment. CEJ was used as reference point. In case CEJ was not visible a restoration margin was used. Pre and post-op hard tissue changes were evaluated using standardized radiographs. Sx treatment: FTFs, defects degranulated, roots scaled and planed, root surfaces were etched with 37% phosphoric acid for 15s, rinsing with saline, application of Emdogain, flaps were coronally positioned to achieve primary closure. All patients received amoxicillin 500 mg tid for 1 week, 0.2% CHX mouthrinse twice a day for 6 weeks, SPT every 2 weeks by dental hygienist.
R: Post-op healing was uneventful in all cases. There were no complications such as allergic reactions, abscess formation, or infections throughout the entire study period. The mean PD was reduced from 8.7 mm at baseline to 4.3 mm after 8 months, the mean gingival recession increased from 1.8 mm to 3.3 mm, and the mean CAL changed from 10.6 mm to 7.6 mm. All investigated parameter changes were SS. New hard tissue formation was radiographically observed in 26 of the 32 defects.
AL #’s do not add up
BL: Treatment of intrabony periodontal defects with Emdogain may lead to significant improvements of all of the investigated clinical parameters. However, controlled histologic and clinical trials are needed to compare this treatment modality with other conventional and regenerative periodontal surgical methods
Froum, 2001 ARTICLE
P: To compare OFD with OFD and enamel matrix derivative (EMD) at 12 month re-entry.
M+M: 23 subjects with at least 2 intrabony defects were included. 53 defects received EMD with OFD (test) and 31 defects were treated with OFD alone (control). Customized acrylic stents were fabricated to serve as fixed reference points. Surgery consisted of: FTF, root debridement, and application of citric acid for 15 seconds with cotton pledgets for both EMD+OFD or OFD alone. EMD was prepared by mixing the 30mg powder with the propylene glycol alginate vehicle. Flaps sutured and a resin dressing applied. Prescribed tetracycline HCl 1g/day for 2 weeks. OHI and 0.12% CHX for 8 weeks. Pt returned every 2 weeks for 6 weeks and then 1x/month for 10 months. Re-entries were performed at least 1 year post-surgery. GI, PI, PD, FGM, CAL, crestal bone and depth of defect recorded at baseline and prior to re-entry. Statistical analysis was performed using generalized estimating equations??? to determine changes in GI, PI, PD, CAL, % of defect fill, and crestal resorption.
R: EMD + OFD was superior to OFD in all parameters measured. NSSD in PI and GI either initially or prior to re-entry. EMD+OFD had 2.7 mm greater PD reduction, 1.5mm greater CAL gain, and 2.4mm greater osseous fill as compared to OFD alone. Defect fill was more than 3x greater for test versus control group (74% defect fill with EMD versus 23% defect fill for control sites). Resolution after 12 months was 83% for EMD+OFD sites vs. 48% for OFD sites.
BL: In intraosseous defects, EMD + OFD is clinically superior to OFD alone in every parameter evaluated. Percentage fill of osseous defects treated with EMD+OFD compares favorably with results utilizing bone grafts or membrane barriers (stats from previously published literature).
Tonetti, 2002 ARTICLE
P: To compare the results with and without the application of emdogain (EMD) for the treatment of intrabony defects in a prospective, multicenter, RCT.
M&M: 172 pt with a deep intrabony pocket (≥3mm) in the IP area in the anterior and premolar area were selected for the study. Heavy smokers (>20 cigs/day) were excluded. Intitial therapy completed and the plaque score , bleeding score, PD, REC, CAL and mobility were measured at baseline with a pressure sensitive probe. Papilla preservation technique (simplified & modified) was used. The defects were debrided and root surfaces treated with EDTA for 2min (test and control group). EMD was placed in the test sides to overfill the defects. No EMD used for the controls. Flaps were placed back and sutured with Gore-tex sutures. Prophys were done 1-6 weeks, 3, 6, 9 months. After 1 year, 166 pts were in the study (83 test/control). The same measurements were done. NSSD between groups at baseline.
R: 166 pts were available for the 1-year follow-up. Initial mean PD was 8mm for test and 7.7 for control sites. Mean initial CAL was 9.4 for test and 9.1 for control group. 1 year after the therapy the CAL gain was 3.1±1.5mm for the test group and 2.5±1.5mm for the control (SSD), the PD decreased 3.9±1.7 mm for EMD treated defects and 3.3±1.7mm for the controls (SSD). NSSD in recession (0.8mm for test, 0.7mm control). Non-smokers had 0.4mm higher CALgain than smokers. Also, markedly corticalized and very cancellous bleeding intrabony defects had SS lower CALgains than defects with a regular cribiform bony lining. 3-wall defects had a 269% greater chance than 1-wall defects to gain 3mm CAL or more.
BL: Emd can have a greater increase CAL and decreasing PD when it is used with the papilla preservation technique for treating periodontal defects in comparison to the papilla preservation flap alone.
Cr: Stents were not used to take the measurements. No % defect fill, so tough to compare to other GTR studies. On average, pts had residual 4mm PDs (8mm initial – 3.9mm PD reduction). No reentry
Giannobile 2003 ARTICLE
Purpose: To evaluate the evidence to support the utilization of Enamel Matrix Derivative (EMD) and growth factors (GFs) for periodontal repair and regeneration associated with natural teeth.
Materials and methods: Review of literature until 2002, human and animal studies included but not in vitro studies. Meta-analyses were performed for studies that fulfilled the eligibility criteria for the following continuous variables: clinical attachment level (CAL), probing depth (PD), or bone level (radiographic, re-entry, or histologic)
Results: The animal trials revealed heterogeneous methodology and after statistical analysis it was concluded that animal data were insufficient for meta-analysis. 8 human studies were finally included (representing 511 subjects) because the majority of the rest studies had a low evidence rating. These data were about EMD, while data about GFs were insufficient to conduct a meta-analysis on their effect in periodontal repair or regeneration.
Conclusion: 1. There is evidence supporting the use of EMD for periodontal osseous defects to improve CAL and reduce PD, although long-term benefits have not been established.
2. EMD has demonstrated notable consistency among the studies investigated in terms of superiority to controls (in general compared to open flap debridement).
3. EMD appears to be safe for single and multiple administrations in terms of lack of elicitation of antibody responses or other local/systemic inflammatory events.
4. Preclinical and initial clinical data for growth factors appear promising but are insufficient to draw definitive conclusions at this time.
Parodi 2000 ARTICLE
Purpose: To verify whether differences exist in the results obtained at midterm(12months) and long term (36months) after the treatment of osseous defects with Emdogain
Materials and Methods
Results
Discussion
Francetti 2004 ARTICLE
P: To compare surgical treatment in combination with EMD to surgery alone in the treatment of intrabony periodontal defects.
M&M: 24 patients (11males/13 females), age 30-66 years, 1,2 or 3- wall defects with PPD >=6mm and IBD >=4mm. Preliminary clinical evaluation consisted of plaque index(PI), gingival index(GI), probing pocket depth(PPD) and periodontal attachment level(PAL) at the sites to be treated. IBD was evaluated radiographically. Also, full mouth plaque score (FMPs) and full mouth gingival bleeding (FMBs) were assessed. Non-surgical periodontal therapy consisted of full mouth SRP and detailed OHI. Patients of one group were treated with the simplified papilla preservation flap technique (SPP), while the patients of the second group were treated with SPP flap technique in combination with EMD after EDTA acid root conditioning ???. Radiographs were taken at baseline, at 12 and 24 months after surgery. At 12 and 24 months after surgery PPD, PAL, PI, GI, FMPs, FMBs and radiographic IBD were assessed.
R: In both groups a slight decrease in FMPs, FMBs, PI and GI was observed. No significant difference with respect to these parameters was observed between these two groups. In both groups a significant decrease of PPD, IBD and a significant improvement of PAL after 12 and 24 months were observed. The test group displayed better outcomes when compared with the control group for IBD, PPD and PAL gain of 12 months and only for PAL and IBD gain at 24 months.
BL: The adjunct of Emdogain in the treatment of intrabony periodontal defects possibly enhances periodontal tissue regeneration. Straumann® PrefGel is a pH neutral, 24% EDTA root surface conditioner intended for topical application onto exposed root surfaces during periodontal surgery.
How does emdogain heal? Are there any controversies concerning its healing? Is there a difference in healing of animal or human studies, or between diseased root surface vs created defects? Have all of these results analyzed intrabony defects? Would that make a difference?
Cochran DL 2003 ARTICLE
P: to evaluate the histologic regeneration of periodontal tissues in the baboon following the use of enamel matrix proteins.
M&M: Five baboons. Four one-walled defects; 2/3 down to the root surface and 1, 2, 4, and 6 mm wide were created bilaterally around 3 teeth in the mandibles. Plaque was allowed to accumulate around ligatures placed into the defects. After 2 months, the ligatures were removed, the teeth were scaled and root planed, and a notch was placed at the base of the defect. On one side of the mandible, EDTA and EMD were used to treat the defects. The other side served as a control, with EDTA treatment alone after SRP. Flaps were sutured and the animals were allowed to heal without OH procedures. After 5 months, the animals were sacrificed and the teeth were processed for histology.
R: Periodontal regeneration occurred in all sizes of the periodontal defects.
Qualitative findings:
- New cementum, periodontal ligament with Sharpey's fibers, and new bone tissue were observed. In many instances, dramatic tissue formation occurred far coronal to the base of the defects
- EMD treatment resulted in greater tissue formation than controls.
Quantitative findings:
- Horizontal bone fill occurred in defects that were initially 4 or 6 mm wide. The resultant width of the PDL was similar in all defects regardless of the original defect width.
- The cementum width was slightly greater in the wider (4 and 6 mm) defects compared to the more narrow (1 and 2 mm) defects
- When evaluating the combined 1 and 2 mm defects, the height of new cementum with EMD treatment was 45% greater than the control, with 31% greater new bone height versus the control.
- In the combined wider defects (4 and 6 mm), new tissue height was more similar between enamel matrix protein-treated defects and control defects. (The results from the wider defects must be interpreted cautiously, because the interproximal bone heights were resorbed more adjacent to the wider defects during the plaque accumulation period and likely limited the potential for regeneration).
BL: The treatment of various sized periodontal defects with EMD stimulated substantial periodontal regeneration.
Heijl, 1997 ARTICLE
Purpose: To histologically assess the effect of EMD on periodontal regeneration in one human experimental defect.
Methods: Experimental surgery was performed in a healthy male volunteer to create a buccal dehiscence defect in a mandibular incisor. Following bone removal and conditioning of the exposed root surface, EMD was applied onto the root surface. The flaps were then replaced and suture. Clinical healing was uneventful. After 4 months, the experimental tooth together with the surrounding soft and hard tissues was removed surgically for histological evaluation.
Results: The microscopic examination revealed formation of a new acellular extrinsic fiber cementum, which was firmly attached to the underlying dentin. A new PDL with inserting and functionally oriented collagen fibers and an associated alveolar bone was also present. The new cementum covered 73% of the original defect. Regain of bone was 65% of the pre-surgical bone height.
Conclusion: Adjunctive use of EMD could provide a regenerative technology with a potential for true periodontal regeneration.
Sculean, 2000 ARTICLE
P: To present the clinical and histological findings following treatment of human intrabony periodontal defects w/ Emdogain.
M&M: Case report of 2 pts (1M, 1F) 55 and 50 yrs old respectively, No Systemic dz. OHI, S/RP, 3 months prior Sx. FTF elevated, granulation tissue removed, S/RP, Notch at the most apical part of defect, and at the alveolar crest level. Root conditioning w/ 24% EDTA gel, tissues rinse w/ saline, Emdogain applied, flaps positioned coronally, and sutured. Amoxicillin 1g/day for 1week. Professional cleaning once a week for 6 weeks, and then once a month for 6 months. Tooth extracted w/ surrounding tissue, histo performed.
R/ Concl:
PDmm
|
CAL mm |
Recession mm |
New Bone |
cementum |
||||
Pre-op |
6 mon |
Pre-op |
6mon |
Pre-op |
6 mon |
|||
| Case1 (combined 1-2 wall defect) |
12 |
5 |
14 |
9 |
2 |
4 |
yes |
Yes
|
| Case2 (combined 1-2 wall defect) |
11 |
5 |
12 |
9 |
1 |
4 |
no |
Yes
|
BL: Emdogain possesses some potential for enhancing periodontal regeneration in human intrabony defects.
.
Parodi et al, 2000 ARTICLE
P: To evaluate clinically, radiographically and histologically the results obtained of the application of an enamel matrix derivative (Emdogain) in deep 1- and 2- wall interproximal defects.
M&M: 21 patients presenting IP defects that could be treated with GTR were selected. Inclusion criteria: PDs 5mm and persistent BOP, radiographically identified osseous defect of at least 3mm depth and >2mm width. 7/21 patients smoked >10 cigarettes/day, 14/21 were non-smokers. The 1- and 2- wall intrabony defects were divided into deep (5-8 mm) and very deep (>9 mm) defects and were only located in max or mand anterior sextants. 1 week before sx clinical parameters were assessed: BOP, PI, PD, mobility index, gingival recession, CAL. Surgical bone level (CEJ-deepest osseous level) was measured during sx. Professional hygiene was performed monthly for 12 months. Surgery: FTFs, defects degranulated, roots scaled and planed, root surface was etched for smear layer removal (orthophosphoric acid 15s for first cases and EDTA for all other cases), rinsing with saline solution, application of Emdogain. All pts were put on bacampicillin (2,400 mg/day) and flurbiprofen (100 mg/day) for 2 weeks. At 12 months, cases were re-examined and clinical parameters were recorded. In 13/21 cases surgical re-entry was performed. Histological analysis was performed in 2 cases. Strange cut off #s for groups of PDs. May have change it to massage the results
R: 12 deep, 9 very deep defects grafted (EMDO only) following Emdogain protocol. The mean PD decreased from 8.1mm to 3.2 mm; CAL decreased from 10.4 mm to 7.0 mm; recession increased from 2.3 mm to 3.8 mm; and surgical bone level decreased from 9.6 mm to 7.1 mm.
NSD was noted between bone defects with 1 or 2 walls, smokers and nonsmokers, or most parameters for deep vs very deep. (SSD was found between deep and very deep defects when attachment gain was considered). Standardized and computerized radiographs at 12 months did not reveal significant improvement. Surgical reentry in only 13 cases; a rubber type hard tissue was found filling the defects. The histologic examination carried out on 2 block graft samples did not show evidence of new attachment.
BL: EMD showed good clinical results (reduction in PD) but no regeneration ability in human periodontal defects.
Yukna, 2000 ARTICLE
B: EMD (enamel matrix proteins) that are obtained from tooth germs of pigs, then processed and sterilized, and appear to stimulate the formation of periodontal attachment tissues.
P: To evaluate histology of wound healing following EMD therapy of periodontally affected roots to see if periodontal regeneration takes place.
M+M: Multicenter study (LSU and UT-San Antonio) with a total of 8 patients with 10 defects were enrolled. Isolated moderate-severe periodontitis, teeth treatment planned for extraction were included. Splinted teeth, SRP of adjacent teeth performed. Photos, recession, CAL, PD measurements were made prior to surgery, FTF elevated and notch placed. Measurements made from the base of defect to notch and from notch to crest. Root planed coronal to notch. Citric acid placed for 1 min. Intra-marrow penetration and EMD coated root surface with slight overfill of defect. Sutures and dressing placed for 2 weeks. NSAID, doxycycline, narcotics, and CHX given post-op. Patients were seen biweekly to monthly for prophylaxis and OHI. At 6 months, tooth removed en bloc and tooth bisected longitudinally. Ridge augmentation performed. Histology performed.
R: 10 defects resulted in 3 defects with regeneration, 3 with new attachment, and 4 with long junctional epithelium. The 3 regeneration cases showed parallel and perpendicular fibers. These also showed acellular and cellular cementum. No resorption, ankylosis, or inflammation noted.
PD reduction: 1-6 mm. CAL change: +6mm to –2mm. Recession: 0-5 mm.
BL: 60% (6/10) of defects showed either true regeneration or new attachment on a previously contaminated root surface. Deeper defects did not determine the type of healing.
Hammarstrom 1997 ARTICLE
P: To determine if application of enamel matrix on a denuded root surface could promote regeneration of all the periodontal tissue, and to try different vehicles for these proteins.
M&M: Homogenized enamel matrix was scraped from mandiblular, non-erupted, developing premolars and molars of approximately 6-month-old pigs. The homogenate was stored frozen and thawed before use. Enamel matrix derivative (EMD) was prepared by purification of acidic extract followed by lyophilization. It was applied either as a lyophilisate, and acidic aqueous solution, or in one of the following vehicles: propylene glycol alginate (PGA), hydroxyethyl cellulose (HEX), or dextran. In monkeys, flaps were raised form maxillary canine to first molar, and the buccal bone, PDL and cementum were removed with a bur to create a dehiscence. A notch was made to determine the extent of the defect. The distance of the CEJ-apical extent of the defect was roughly 6mm. Roots were conditioned with citric acid or 37% phosphoric acid and rinsed with saline prior to application of the preparations. All teeth in one quadrant received treatment and the contralateral quadrant usually served as the controls. After 8 weeks the monkeys were sacrificed and histological analysis performed.
R: In general, areas around control teeth and those only treated with EDTA showed more inflammation than the other sites. EMD in PGA gave about the same results as EMD with no vehicle. When EMD was in HEC or dextran, it had a less favorable appearance macroscopically and gave worse results than EMD alone, acidic extract, or EMD + PGA. The EMD, acidic extract, or EMD + PGA resulted in extensive regain of acellular cementum, PDL and alveolar bone (bone slightly more apical to cementum); the regeneration was between 60-80%. The other groups (HEX, dextran) displayed very little formation of new cementum and almost no bone, simply a long JE.
BL: One can expect 60-80% regeneration when EMD, acidic extract, or EMD + PGA is applied to sx-created buccal dehiscences in monkeys. Studying the best vehicle for Emdogain
Emdogain is often used mixed with other materials. How does this compare to open flap debridement? How does this compare to emdogain alone? How does it compare to a more traditional GTR? Is it a justifiable expense to a patient?
Camargo 2001 ARTICLE
Purpose: To evaluate the effectiveness of Enamel Matrix Proteins (EMPs) combined with Bovine Porous Bone Mineral (BPBM) in reducing PDs, improving CAL and promoting bone fill in intrabony defects in humans compared to results obtained by OFD alone.
Materials and Methods: 24 healthy patients, mean age 42 years old, 18 smokers and 6 non-smokers with matched pairs of interproximal defects were recruited for the study. Two similar interproximal defects of PDs 6mm or more after initial therapy should be in the same arch but not in the same interproximal area. Radiographic evidence of intrabony defects had to exist.
Exclusion criteria endodontically treated test and adjacent teeth, patients with systemic illnesses, immune – compromised or patients taking drugs known to cause gingival enlargement, patients allergic or sensitive to any medication to be used.
Initial therapy consisted of OHI, SRP, occlusal adjustment and teeth splinting if needed and re-eval was performed 6-8 weeks later. Split mouth study design: EMPs/BPBM (Emdogain + Bioss) on one defect and OFD as control on the other defect. Occlusal stents were fabricated to standardize the clinical measurements.
Full thickness flaps were elevated, complete debridement of the defect, scaling and root planing and standardized measurements of the osseous defects were made using the same stent. Control and test sites were treated with the same surgical procedure excluding the EDTA root treatment, EMPs and bone grafts. Flaps were sutured, periodontal dressing was placed, amoxicillin, CHX 0.12% and ibuprofen were prescribed.
Sutures were removed one week later, and teeth with class I mobility or more were splinted. Mechanical oral hygiene was initiated on the end of the second week.
6 months post-op clinical measurements were repeated and surgical reentries were performed.
Results: No cases of flap dehiscences or infection during healing period and all wounds were completely covered with soft tissue by day 14.
17 two-wall defects and 7 three-wall in the test group and 18 two-wall and 6 three-wall defect in the control group.
Differences in PD, AL, defect fill and alveolar crest levels:
|
Mean (initial-6 month) |
site | OFD | EMPs/BPBM | significance |
|
Bone fill
|
Buccal Lingual |
1.08 1.04 |
3.93 3.71 |
SSD |
|
Pocket reduction |
Buccal Lingual |
1.64 1.54 |
3.99 3.82 |
SSD |
|
Attachment gain |
Buccal Lingual |
1.44 1.42 |
3.48 3.41 |
SSD |
|
AL resorption |
Buccal Lingual |
0.41 0.46 |
0.38 0.40 |
NSSD |
Differences in recession, plaque and gingival sulcus index were not satistically significant.
Conclusion: Intrbony defects can successfully been treated with a combination of EMPs and BPBM, and result in significan reduction of PD, improvement of AL and promote bone fill.
Not a good study design. Should also have included bioss alone
Sculean 2000 ARTICLE
Purpose: To compare the clinical outcome following treatment of intrabony defects with a combination of Emdogain (EMD and Bovine derived xenografts BDX or Bovine derived xenografts alone
Materials and methods
Results
Discussion
Gurinsky 2004, ARTICLE
P: To compare the use of DFDBA+EMD to EMD alone in the treatment of human intrabony periodontal defects.
M&M: 40 patients, 67 sites, probing depth >=5mm, intrabony lesions with depth>=3mm. All baseline clinical parameters were obtained the day of the surgery and at 6-month post-surgery reentry. Soft tissue measurements: 1) CEJ-FGM, 2) FGM-base of the pocket 3) CEJ –base of the pocket. Hard tissue measurements: 1) CEJ- base of the pocket, 2) CEJ-alveolar crest 3) alveolar crest-base of the defect. All patients received SRP, OHI and occlusal adjustment. After 4-6 weeks re-eval. Each patient received either EMD alone or in combination with DFDBA. After 6 months of healing all measurements were repeated.
R: Soft tissue findings: Both groups demonstrated significant improvement from baseline. No statistical difference between the two groups. Hard tissue findings: The mean value for the bone fill in EMD+DFDBA group was 3.7mm (74.9%) while EMD alone demonstrated a bone fill of 2.6mm (55.3%). The combination of DFDBA+EMD yield statistically significant improvements in bone fill, crestal resorption and % of sites gaining greater than 50% and 90% bone fill when compared to EMD alone.
BL: The combination of DFDBA and EMD may enhance bone regeneration.
Silvestri 2003 ARTICLE
P: To compare the efficacy of GTR with non-resorbable membranes to Emdogain in infrabony defects.
M&M: 100 pt (50 EMD and 50 GTR) that had infrabony defect component of > 4mm were grafted at 6 centers (one university; five private practices). Pts were either nonsmokers or smoked less than 10 cigarettes/day (light smokers). Each pt received initial therapy and was randomly assigned to one group. In both groups, the roots were treated with EDTA 24% for 2 minutes. In the GTR group, the Gore membranes were removed 6 weeks after surgery, and tissues were coronally displaced to obtain complete coverage of newly formed tissues. Intrasurgically, the measurements recorded were CEJ-bottom alveolar crest and CEJ-bottom of bone defect. Pt received prophylaxis weekly for the first two months, and then every 3 months until one year after surgery. No probing or deep scaling was performed before the one-year follow-up. The treatments were then compared based on the percentage of their PAL gain and PD reduction.
R: Only 2 pts did not come to the one-year post-op visit. The percentage of smokers was 38% for GTR and 36% for EMD. Baseline parameters and outcomes were similar between groups (no significant difference). Membrane exposure occurred in 48% of the GTR group. The mean PAL expressed as a percent was 41% for EMD, while it was 48% for the GTR group (not statistically significant). When PAL > 8mm, GTR provided a statistically better outcome when compared to Emdogain by 0.3 mm. There was also a significant difference between the 3-wall group and the 1 and 2-wall groups. There was no significant difference between the 1 and 2-wall groups.
BL: There is no statistical difference between EMD and GTR with ePTFE membranes in defects with PAL < 8mm. If the PAL > 8mm, GTR provided better outcome. Results make sense. Gtr maintains the space better
Esposito 2009 ARTICLE review
Background: 2 past systematic reviews on the efficacy of bone graft materials for perio regeneration in intrabony defects was assessed (Trombelli 2002, Reynolds 2003). Trombelli concluded that there was variability with respect to different materials but that conclusions were difficult to reach b/c there was so much heterogenicity in the studies. Reynolds concluded that there were no differences in clinical outcome measures among various graft types.
Purpose: A Cochrane systematic review to test whether EMD is effective, and to compare EMD versus GTR, as well as various BG procedures for the treatment of intrabony defects.
M&M: A The Cochrane Oral Health Group Trials Register, CENTRAL, MEDLINE and EMBASE were searched. Selection criteria was randomized controlled trials on patients affected by periodontitis having intrabony defects of at least 3 mm treated with EMD compared with open flap debridement, GTR and various BG procedures with at least 1 year of follow-up. The outcome measures considered were: tooth loss, changes in CAL, PPD, and recession, bone levels from the bottom of the defects on intraoral radiographs, aesthetics and adverse events.
Results: A total of 13 trials were included out of 35 potentially eligible trials, all w/1-year follow up.
All applications of EMD included 36% ortho-phosphoric acid etch 15 seconds (to controls as well), 24% EDTA gel for 2 minutes (some only placed in EMD not controls, others used in both). 1 study used a 17% EDTA concentration. Most studies placed patient on a wide range of antibiotics afterwards; 2 apparently used CHX only.
Conclusion: One year after its application, EMD significantly improved PAL levels (1.1 mm) and reduced PPD (0.9 mm) when compared to a placebo or control, however, the clinical significance of this improvement is debatable. For a comparison of teeth needing extraction or additional surgical intervention, longer follow up and true blinding are necessary as generally this is at the subjective discretion of the treating dentist. In addition, a sensitivity analysis indicated that the overall treatment effect might be overestimated. The actual clinical advantages of using EMD are unknown. With the exception of significantly more postoperative complications and a slight increase in recession in the GTR group, there was no evidence of clinically important differences between GTR and EMD.
BL: At this time, there is statistical but possibly not clinical improvements with EMD compared to placebo or control, no evidence that more compromised teeth could be saved using EMD, and no patient preference for esthetic reasons. All results should be interpreted cautiously as differences in the trials reviewed make it difficult to draw conclusions.
Li 2012 ARTICLE
P: A meta-analysis comparing clinical outcomes of EMD used in combination with bone grafts and EMD alone
M&M: RCT’s were analyzed through 9/30/11, taken from Medlin, PubMed, Embase, and Cochrane. PD, CAL, Rec, and defect gain were the main clinical outcmes. Inclusion criterion: RCT, prospective, clinical outcomes measured at baseline and 6mo or more post-op, and data not published in another article.
R: Out of 446 articles screened for inclusion, 11 RCT’s met the inclusion criteria. At 6 to 8 mo f/u, there were 282 defects, 142 were treated with EMD plus one type of bone graft and 140 treated with EMD alone. Pooled estimates showed a 1.6mm more reduction in probing depth comparing the combination with EMD alone, which was shown to be NSSD. There was an improvement of 0.37mm in CAL when comparing the two groups, again shown to be NSSD. There was a 0.98mm more gain in bone fill with the comination graft which was shown to be SSD. 0.29mm less recession was seen in the combination cohort, which was a SSD.
In the 12mo group, data from 6 trials were available. 226 defects were treated, 113 with the combination and 113 w/ EMD alone. There was a 0.25mm more reduction in PD in the combination graft, which was NSSD. 0.34 more reduction in CAL was seen, which was NSSD. 0.75mm more bone gain was seen, which was SSD. Recession showed a 0.17 decrease in the combination, which was NSSD.
C: EMD used in combination with bone graft was statistically shown to be advantageous in bone fill and recession at 6-8mo, but no significant difference in recession was seen at 12mo. However, the clinical significance is questionable. NSSD wrt PDs and CALs
What biologic modifiers have been studied in infrabony defects? Are these off-label uses or following manufacturer protocol? What are the advantages to biologic modifiers? What are the drawbacks?
Dohan 2009, NO ARTICLE PRP, PRF and PDGF
Disc: A classification of the different platelet concentrates and an overview of the available systems are presented. The use of platelet concentrates to improve healing has been explored considerably during the last decade. Platelets contain high quantities of key growth factors, such as PDGF-AB (platelet derived growth factor- AB), TGF-1 (transforming growth factor -1) and VEGF (vascular endothelial growth factor), which are able to stimulate cell proliferation, matrix remodeling and angiogenesis. All available PRP (platelet rich plasma) techniques have some points in common: blood is collected with anticoagulant just before or during the surgery and is immediately processed with centrifugation. The time for platelet concentrate preparation is variable but it is always completed within an hour. Step 1 :Softspin short centrifugation. This step is designed to separate the blood into 3 layers, red blood cells (RBCs) are found at the bottom, acellular plasma (PPP-platelet poor plasma) is the supernatant and a “buffy coat” (BC) layer appears in between, in which platelets are concentrated. The “buffy coat” layer is typically of whitish colour and contains the major proportion of the platelets and leukocytes. Step 2a: For production of pure PRP, PPP and superficial BC are transferred to another tube. After hardspin centrifugation, most of the PPP layer is discarded. The final P-PRP concentrate consists of an undetermined fraction of BC (containing a large number of platelets) suspended in some fibrin-rich plasma. Most leukocytes are not collected. Step 2b: For production of leukocyte-rich PRP (L-PRP), PPP the entire BC layer and some residual RBCs are transferred to another tube. After hardspin centrifugation, the PPP is discarded. The final L-PRP consists of the entire BC, which contains most of the platelets and leukocytes, and residual RBCs suspended in some fibrin-rich plasma. Because the manual PRP process is not clearly defined, this protocol might randomly lead to P-PRP or L-PRP.
Different protocols exist for step 2.
3 main sets of parameters are necessary for a clear classification of platelet concentrates. The first set of parameters (A) relates to the preparation kits and centrifuges used. The second type of parameters (B) relates to the content of the concentrate (platelets/leukocytes). The third set (C) relates to the fibrin network that supports the platelet and leukocyte concentration during its application.
Actual available methods can be classified into 4 main categories depending on the characteristics of the obtained product: 1) pure PRP (P-PRP), 2) leukocyte rich PRP (L-PRP) 3) pure PRF (P-PRF) and 4) leukocyte-rich PRF (L-PRF). In each category, the concentrate can be produced by different processes, either in fully automatized set-up or by manual protocols.
Anitua’s PRGF: Venus blood is collected and centrifuged in several small tubes to obtain the three typical layers: RBCs, “buffy coat” and acellular plasma. The upper part of acellular plasma is called plasma poor in growth factors (PPGF)(1ml) and is discarded from each tube by careful pipetting. The remaining plasma is called PRGF (plasma rich in growth factors) and is collected with a pipette. The PRGF fraction (1ml) is collected and fibrin polymerization is induced by a 10% calcium chloride solution. After 15 to 20 min, an unstable PRGF gel is formed that will need to be used immediately.
The first published in vitro studies demonstrated a general tendency to stimulate the proliferation of several cell types, including osteoblasts, fibroblasts, tendon cells, chondrocytes, periodontal ligament cells and bone mesenchymal stem cells. However, contrasting results have also been reported. Clinical studies have indicated that platelet gels can shorten recovery time, reduce surgery-related swelling and pain, accelerate the repair of soft tissues and increase bone regeneration in the short term. Used in Membranes for lat window and to mix with graft materials during sinus aug.
Tobita, 2013 NO ARTICLE mesenchymal stromal cells
B: The implantation of mesenchymal stromal cells (MSCs) that can differentiate into osteoblasts, cementoblasts or PDL cells has been viewed as a promising approach for periodontal tissue regeneration. Although bone marrow is most abundant source for MSCs, other tissues like periosteum, muscle and adipose tissue also contain MSCs. Adipose tissue is attractive because of its abundance and accessibility. Adipose derived stem cells (ASCs) are isolated from fat tissue and can differentiate into cartilage, bone, and skeletal muscle.
P: To examine the combined implantation of autologous adipose tissue-derived stem cells (ASCs) and autologous platelet-rich plasma (PRP) in periodontal tissue engineering in a canine periodontal tissue defect model.
M+M: 8 beagle dogs (9-10 months old) anesthetized. Inguinal fat pads harvested, washed, minced and enzymatically digested, cells centrifuged for 5 min to obtain high density ASC, cells were resuspended and plated. Perio defects penetrating to furcation were generated in all dogs. Bilateral second, third, and fourth mandibular premolars were selected as experimental teeth. The height from top of bifurcation to reduced alveolar crest of the defect was 5mm; the apical extent of defect was marked with a notch. Root surfaces had all PDL and cementum removed. Prior to implantation of ASCs, blood was drawn and centrifuged for 10 mins from all dogsharvest plasma supernatant and buffy coat (consisting of platelets and leukocytes) into neutral tubeneutral tubes centrifuged for 15 mins to concentrate plateletsfinal PRP. ASCs were mixed with 1 mL PRP. The ASC/PRP mixture and PRP alone were activated with 2%CaCl2 and then 500microL of ASC/PRP gel or PRP gel alone were implanted into perio defect in each dog bilaterally. Non-implant sites also prepared. Animals sacrificed at 1 or 2 months post-implantation. Radiographs were taken. Histo and immunohisto analysis performed.
R:
At 1 month: Newly formed bone was detected at lower extent of perio defect in all 3 groups after implantation, in control group ingrowth of epithelium into upper part of defect was observed. ASC/PRP group cell arrangements observed on surface of dentin and newly formed cementum-like structures evident. PDL-like structures vertically integrated with newly formed cementum-like structures.
At 2 months : ASC/PRP group showed newly formed bone, but granular tissue was seen in upper and middle regions of defect in PRP only and control groups. ASC/PRP clearly exhibited newly formed cementum-like structures. PRP only and control groups had some newly formed cementum-like structures but no PDL-like structures were observed.
Percent areas of newly formed bone:
1 month: ASC/PRP- 35.1%; PRP only- 33.6%; control-37%
2 months: ASC/PRP- 63.9%; PRP only- 53.7%; control-40.3%
Percent areas of newly formed cementum:
1 month: ASC/PRP- 36.4%; PRP only- 37.7%; control-38.7%
2 months: ASC/PRP- 84.7%; PRP only- 62.5%; control-61.7%
ASC/PRP group showed newly formed bone and cementum-like structures significantly increased in defect region between 1 month and 2 months post implantation. NSSD between ASC/PRP group and PRP only a
nd control groups.
BL: The combined implantation of ASCs and PRP has potential to induce periodontal tissue regeneration in a canine model.
Pradeep 2012 ARTICLE
P: To investigate the additional efficacy of autologous PRF or PRP with OFD in the tx of 3-wall intrabony defects (IBD) compared with OFD alone.
M&M: This is a randomized, double-masked, controlled clinical trial with a 9-month follow-up. 54 healthy pts were included with at least a 3mm IBD as well as a 5mm PD after phase I therapy. Pts with aggressive perio and smokers were excluded. Pts received either OFD alone or OFD + PRP or OFD + PRF. Clinical measurements were taken with customized stents at baseline and 9 months. Standardized PAs were taken as well. Pts were seen weekly for 1-month POT, and again at 3 and 9 months.
R: 38 sites were from single rooted teeth, and 52 sites were from multi-rooted teeth. Both PRF (3.77 +/- 1.19mm) and PRP (3.77 +/- 1.07mm) sites presented with significantly greater PD reduction at 9 months. CALgain was also greater in the PRF (3.17 +/- 1.3mm) and PRP (2.93 +/- 1.1mm) groups, but this was not SS compared with the control. Also, SS greater rx bone fill was found in PRF (55% +/- 11.4%) and PRP (57% +/- 14%) compared with the control (2% +/- 15%).
BL: PRF or PRP are beneficial in the treatment of intrabony defects when compared to OFD alone.
Lekovic 2012 ARTICLE
Purpose: To evaluate the effectiveness of platelet-rich fibrin (PRF) in promoting clinical signs of periodontal regeneration in human intrabony defects and further assess the ability of bovine bone porous mineral (BPBM) to augment the regenerative effects of PRF in similar defects.
(PRF is believed to release polypeptide GFs such as TGF-β1, PDGF, vascular endothelial growth factor and matrix glycoproteins into the surgical wound for at least 7 days).
Materials and methods: 17 systemically healthy patients, 11 women and six men 44 years mean age, with matched pairs of interproximal intrabony defects. Inclusion criteria: two similar interproximal defects of PD 6mm or more 6 weeks after initial therapy., 2- or 3-wall defects (not craters), vital teeth, PI and GI less 1 or less and radiographic evidence of intrabony defects. Exclusion criteria: systemic illnesses, immune-compromised patients, pregnant women, pts taking drugs known to cause gingival enlargement.
Initial therapy included SRP, OHI, occlusal adjustment if needed and re-eval in 6-8 weeks. Split-mouth design, and two interproximal sites were assigned to the PRF or PRF-BPBM group. Stents were fabricated to measure PD, AL, and recession. GI and PI were also calculated.
In the surgery buccal and lingual FTF were elevated, debridement of the defects and SRP were performed and measurements of the bony defects were performed with the use of the stent. Defects were filled with Bio-Oss and PRF or with PRF alone and covered with a membrane of compressed PRF. Flaps were sutured with 4-0 silk and dressing was placed. Amoxicillin 500mg every 8h for 7 days and 0.12%Chx every 12 hours for 14 days were prescribed. Sutures were removed in one week, patients were examined weekly up to one month and then at 2,3 and 6 months post-op. During the first four visits sites were evaluated using the healing index (HI: 1 for poor healing up to 5 for excellent healing).
In six months clinical measurements were performed, radiographs were taken and surgical re-entry was done.
Results: The differences in PD, AL and defect fill were statistically significant in 6 months in favor of the PRF-BPBM group.
PRF |
PRF-BPBM |
|||
| Mean |
Buccal |
Lingual |
Buccal |
Lingual |
| PD reduction |
3.35±0.68mm |
3.24±0.73mm |
4.47±0.78mm |
4.29±0.82mm |
| AL gain |
2.24±0.73mm |
2.12±0.78mm |
3.82±0.78mm |
3.71±0.75mm |
| Defect fill |
2.21±0.68mm |
2.06±0.64mm |
4.06±0.87mm |
3.94±0.73mm |
Plaque measurements, healing index and bleeding index were not significantly different between the two groups at baseline or at 6 months.
Conclusion: 1) PRF results in significant improvements of PD, CAL and defect fill compared with baseline and
2) BPBM significantly increases the regenerative effects observed with PRF in the treatment of human intrabony defects.
Cochran 2000 ARTICLE Bone Morphogenic protein (BMP)
Purpose: to monitor the long-term safety of patients treated with rhBMP-2 loaded in an absorbable collagen sponge ACS and to evaluate the dental implants placed in sites treated with this bone differentiation factor.
Materials and Methods
Results
Conclusions
Choi 2002 ARTICLE
P: To evaluate regeneration of alveolar bone and cementum, and associated root resorption and ankylosis following surgical implantation of rhBMP-2/ACS (recombinant human bone morphogenetic protein-2 with an absorabable collagen plug).
M&M: 8 Mongrel dogs, bilateral 3-wall intrabony defects were surgically induced in the premolar region in the maxilla and mandible, root planning performed, reference notch made at base of defect. Defects received rhBMP-2/ACS, buffer/ACS (surgical control) or nothing (control). Primary closure obtained, post op Abx, CHX. Evaluated daily gingival health, maintenance of suture line closure, edema, evidence of tissue necrosis or infx prior to suture removal and then 2x/week after suture removal. Photos and radiographs taken at time of surgery, post surgery, and 8,16,24 wks after. Animals sacrificed at 24 weeks and histo analysis performed.
R: Surgical implantation of rhBMP-2/ACS resulted in accelerated enhanced bone formation in the 3-wall intrabony periodontal defects but no apparent enhancement of cementum regeneration. rhBMP-2/ACS did not appear to be associated with aberrant healing events such as root resorption and ankylosis.
BL: Surgical implantation of rhBMP-2/ACS may be used safely to support regeneration of alveolar bone in intrabony periodontal defects in dogs without adverse events such as root resorption or ankylosis complicating the regenerative procedure.
Chiu, 2013 ARTICLE
BG: BMP-6 acts as an osteoinductive factor during endochondral bone formation in vivo and osteoblastic mesenchymal cell differentiation in vitro. Thus, BMP-6 has been suspected of fulfilling an important and unique role during the early stage of osteoprogenitor cell differentiation. Moreover, BMP-6 induces formation of more and larger bone nodules as well as increased osteocalcin secretion and is a 2-fold greater potent inducer of osteoblast differentiation than BMP-2 in vitro.
P: To evaluate periodontal wound healing/regeneration following application of a synthetic BMP-6 polypeptide to surgically created supra-alveolar periodontal defects in dogs
M&M: Eleven female Beagle dogs, 18-24 months old. Oral prophylaxis was performed 2 weeks prior to experimental surgeries. Bilateral supra-alveolar periodontal defects were created at the mandibular 2nd and 3rd premolars. Defect was approximated 4-5 mm from the CEJ to surgically reduced alveolar crest. Synthetic BMP-6 at 0.25, 1.0, 2.0 mg/ml on absorbable collagen sponge (ACS) was used. ACS was soak-loaded in BMP-6 solution to get dose/defect of 0.1, 0.4, 0.8 mg of BMP-6 for experiment sites and in sterile water for control site. Each treatment was randomly applied to each defect in 4 quadrants. The mucogingival flaps were advanced and adapted to submerge the crowns of the teeth and sutured. Animals were sacrificed at 8 weeks. Histology performed.
R: Healing was generally uneventful. Found cementum formation (mainly acellular), new bone, PDL. Ankylosis was not observed. The higher the concentration of BMP-6, the higher the frequency of membrane exposure (did you mean the ACS was exposed?) and the less new tissue formation. All concentrations performed better than control.
BL: Application of BMP-6/ACS onto surgically created supra-alveolar defects enhanced periodontal wound healing/regeneration. The low BMP-6 0.25 mg/ml concentration provided the most effective dose.
Nevins et al; 2003 ARTICLE
Background: Purified recombinant human platelet-derived growth factor BB (rhPDGF-BB) is a potent wound healing growth factor and stimulator of the proliferation and recruitment of both periodontal ligament (PDL) and bone cells. This is the first report of periodontal regeneration demonstrated histologically in human Class II furcation defects.
Purpose: Hypothesis Application of rhPDGF-BB mixed in bone allograft would induce regeneration of a complete new attachment apparatus, including bone, PDL and cementum in human interproximal intrabony defects and molar Class II furcation lesions.
Methods: 9 non-smokers patients (15 sites) with advanced periodontitis, at least one tooth requiring extraction due to an extensive interproximal intrabony (7mm vertical defect) and/or molar Class II furcation defect (5x7mm) were entered into the study. 11 defects were randomly selected to receive rhPDGF-BB. Following FTF reflection and initial debridement, the tooth roots were notched at the apical extent of the calculus, the osseous defects were thoroughly debrided, and the tooth root(s) were planed/prepared. The osseous defects were then filled with demineralized freeze-dried bone allograft (DFDBA) saturated with one of three concentrations of rhPDGF-BB (0.5 mg/ml, 1.0 mg/ml, or 5.0 mg/ml). 4 IP defects were treated anorganic bovine bone in collagen (ABB-C) and a bilayer Bio-gide membrane. Radiographs, clinical probing depths, and attachment levels were obtained preoperatively (at baseline) and 9 months later. At 9 months postoperatively, the study tooth and surrounding tissues were removed en bloc. Clinical and radiographic data were analyzed for change from baseline by defect type and PDGF concentration. The histology was performed
Results: The post-surgical wound rapidly healed and was characterized by firm, pink gingivae within 7 to 10 days of surgery. There were no unfavorable tissue reactions or other safety concerns associated with the treatments throughout the course of the study.
Sarment, 2006 ARTICLE PDGF
Background: cell-surface receptors on periodontal and alveolar bone cells are stimulated by PDGF causing a positive effect on the DNA replication and chemotaxis of these cells. Pyridinoline cross-linked carboxyterminal telopeptide of Type I collagen (ICTP) has been shown as a biomarker for bone turnover.
P: To examine the quantity of ICTP released into periodontal wound fluid during tissue repair after periodontal reconstruction with PDGF-BB.
MM: 5 centers, 47 patients, PD >7 mm with at least 4 mm bony defect, were divided into 3 groups: b-TCP, b-TCP + 0.3 mg rhPDGF, and b-TCP w/ 1 mg rhPDGF. GCF (wound fluid) collected by strips at baseline, weeks 3, 6, 12, 18 and 24 after surgery. Radioimmunoassay was utilized to examine ICTP volume.
R: The b-TCP carrier alone group shows a decrease in the amount of ICTP released in the wound fluid up to week 24. The 0.3 and 1.0 mg/ml PDGF-BB groups had an increase in the amount of ICTP released up to 6 weeks. There were statistically significant differences at the week 6 time point between b-TCP carrier alone group versus 0.3 mg/ml PDGF-BB group (p<0.05) and between b-TCP alone versus the 1.0 mg/ml PDGF-BB-treated lesions (p<0.03). No difference was seen b/t the two PDGF-BB groups at either time frame.
C: rhPDGF increase ICTP in gingival wound fluid after surgery
`and at 6 months group 1 CAL gain continued to be greater than group 3. % bone fill was SS increased at 6 months for group 1 compared with both groups 2 and 3.
BL: Combining rhPDGF with bone graft or synthetic bone substitute for perio defects has potential to result in regeneration of bone and soft tissue. rhPDGF-BB has the promise to accelerate healing an formation of more abundant and higher quality of bone without needing to harvest autogenous bone. “rhPDGF-BB in combo with osteoconductive matrices has potential to become standard of care.”
CR: Samuel Lynch is president of BioMimetic and GEM 21S is a registered trademark of BioMimetic Therapeutics, Inc.
Mishra 2013 ARTICLE
P: To evaluate modified minimally invasive surgical technique (M-MIST) with PDGF vs without PDGF in the treatment of intrabony defects.
M&M: 24 systemically healthy pts without a history of perio tx in the past 3 months were selected for the study. Smokers were excluded. A tooth with at least 5mm CAL and a 5mm PD with an intrabony defect depth of 3mm was selected. Defects with a buccal or lingual extension were excluded. OHI and initial therapy was performed on all pts and perio sx was performed wherever necessary prior to regenerative therapy. Pts wre randomly assigned to test (PDGF)or control group (no PDGF). The study was double-blind. All clinical parameters wre recorded at enrollment, baseline, 3 months and 6 moths-POT. Pas were taken (not standardized).
R: 22 pts completed the 6-month follow-up. Baseline clinical and rx defect characteristics between the groups were NSSD. CALgain and linear bone growth was 3.0 and 1.9 in test group and 2.6 and 1.9 in the control group. These differences were NSSD. All subjects had a CALgain of 2mm and above, with most pts showing a gain of 2-3mm.
BL: PDGF did not have a significant impact on the outcome of sx when the M-MIST technique is utilized for intrabony defects.
Oates 1993 ARTICLE
Background: PDGF is a potent mitogen for cells of mesenchymal origin. Active PDGF protein dimers can be produced by the combination of PDGF A-chian and B-chain polypeptides into 3 identified isoforms, AA, BB, AB, each of which has unique binding affinities for the PDGF receptors α or β on the cell membrane. IL-1 is synthesized by a wide variety of cells including periosteal fibroblasts, macrophages and gingival fibroblasts. TGF-β is released at wound sites by platelets and macrophages. Osseous tissue provides one of the largest storage sites for TGF-β.
Purpose: To characterize the individual and interactive effects of PDGF-AA and PDGF-BB, IL-1β and TGF-β1 on the mitogenesis of fibroblast – like cells derived from human periodontal ligament.
Materials and methods: Cells were obtained from PDL explants from 4 premolars which were extracted for non-periodontal reasons. Cells cultured had a fibroblast-like morphology and a comparable rate of proliferation. Cells were cultured in different plates, GFs were added and cells were labeled and then tested for functional activity.
Results: PDGF-AA and –BB were found to be potent mitogens for human PDL cells enhancing the mitogenic activity 10- and 12- fold respectively. This response was dose dependent and fro PDGF –AA time dependent too, with the 24-hour response greater than the 48-hour.
Addition of IL-1β produced no mitogenic enhancement. High concentrations of IL-1β produced significant inhibition of the mitogenic response, no time dependence was shown.
TGF-β produced increase in mitogenic response. Greatest response was after 48 hours. Concentration rate examined was 0.01 ng/ml to 2.0 ng/ml with 1.0 ng/ml producing the greatest response. This response was weak comparing to the one induced by PDGF isoforms.
Pre-incubation with TGF-β ffro 8-24 hours prior to IL-1β showed increased mitogenic activity comparing to no or 1-hour of TGF-β pre-incubation.
Conclusion: All three PDGF isoforms may play critical role in modulating oral fibroblast cell proliferation.
TGF-β1 was found to be a weak mitogen for the human PDL cells, but modulates the cellular response to both PDGF isoforms.
IL-1β is not mitogenic, it inhibits PDL cell mitogenesis at higher concentration.
Effect of GFs and their interaction in human PFL cell mitogenesis are complex and may involve regulation t both the protein and receptor level.
Giannobile 2001 ARTICLE
Purpose: to determine the ability of a recombinant adenovirus encoding PDGF-A to transduce and modulate the activity of cementoblasts.
Materials and method
Results
Discussion
Conclusion
Inukai 2013 - No ARTICLE
BG- Mesenchymal stem cells (MSC) are well known to secrete a variety of growth factors and cytokines. Recent in vitro studies have indicated that the paracrine effects of growth factors and cytokines secreted from implanted MSC’s may promote tissue regeneration. Previous reports have shown that bone marrow derived MSC-CM (conditioned medium from cultured mesenchymal stem cells) have a very high potential for bone regeneration that is mediated by the cooperative effects of cytokines such as insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and transforming growth factor- β1 (TGF-β1), which regulate several events of osteogenesis, including angiogenesis, cell migration, proliferation, and osteoblast differentiation.
P: To evaluate the effect of MSC-CM on periodontal regeneration.
M&M: 5 hybrid dogs, that had prior mand 1st, 3rd, or 4th PMs extracted and allowed to heal for 8 weeks. dMSC-CM and dPDLC (PDL cells) were obtained from the dogs prior to surgery. FTF elevated, box-type 1-wall infrabony defects (4mm x 5mm) were created at the distal aspect of the 2nd and mesial aspect of the 4th PM’s in the R and L quads. Root planning performed, reference notch made at apical extent (5mm from CEJ). Defects were randomly divided into 3 groups: MSC-CM plus scaffold (TERUPLUG), PBS (phosphate buffered saline) plus scaffold, or no implant. Standardized radiographs obtained initially and at 4 weeks. Post op abx, CHX rinse, 4 weeks dogs sacrificed and histo eval. Parameters analyzed included: cementum regeneration height, bone regeneration height, bone regeneration area. Migration assays performed and ELISA used for cytokine evaluation.
R: MSC-CM stimulated migration and proliferation of dMSC’s and dPDLC’s. Cytokines such as insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), transforming growth factor- β1 (TGF-β1), and hepatocyte growth factor were detected in MSC-CM. MSC-CM group showed cementum regeneration height of 3.01m, bone regeneration height of 3.19mm, and bone regeneration area of 4.89mm. A large amount of new lamellar and woven bone formation was observed. Thick layered and cellular cementum was also frequently observed in the MSC-SM group.
BL: These findings suggest that MSC-CM enhanced regeneration due to multiple cytokines contained in the MSC-CM.
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