Regenerative Medicine: Individualizing and Optimizing Patient Care

Periodontitis can cause significant destruction of the periodontium, a complex organ consisting of alveolar bone, periodontal ligament (PDL), cementum, and gingiva. Loss of the periodontium may ultimately lead to complete loss of natural dentition or its form, function, and/or esthetics. Periodontal regeneration is defined in the American Academy of Periodontology's (AAP) Glossary of Periodontal Terms as "the restoration of lost periodontium, including the formation of new bone, new cementum, and a functionally oriented periodontal ligament."¹ True periodontal regeneration can only be appreciated through histologic evaluation. Numerous advancements have been introduced in the fields of cell and molecular biology, and current techniques that include both mechanical and biologic approaches for periodontal regeneration are being validated and researched.

Guided tissue regeneration (GTR) is a surgical approach with the goal of achieving new bone, cementum, and PDL attachment to a periodontally diseased tooth using barrier devices or membranes to provide space maintenance, epithelial cell exclusion, and wound stabilization.¹ Space maintenance and epithelial cell exclusion enable the formation and maturation of mesenchymal cell-derived periodontal tissues, while wound stability facilitates undisturbed blood clot adhesion and maturation of the cells therein on an instrumented root surface.

Guided bone regeneration (GBR) procedures are intended to regain and increase the alveolar bone height and width in edentulous areas to facilitate dental implant placement and/or support ailing implants. The goals of GBR are the maintenance of the post-extractive alveolar ridge volume, reconstruction of the alveolar bone lost by tooth extraction in preparation for future implant placement, improved esthetics of edentulous areas or correction of peri-implant dehiscences and fenestrations, and/or, finally, reconstruction of peri-implant bone lost following peri-implant disease.² GBR procedures aim to achieve exclusion of epithelium and connective tissue; space maintenance; stability of the blood and fibrin clot; and tension-free, primary wound closure.³

Bone regeneration with bone replacement graft materials may be facilitated through either osteogenesis, osteoinduction, or osteoconduction. Osteogenesis is the formation and development of bone by differentiated osteoblasts within the graft material. Osteoinduction allows the transformation of host mesenchymal stem cells into osteoblasts or chondroblasts through growth factors that naturally exist in living bone. Osteoconduction provides a bio-inert scaffold, or physical matrix, for the deposition of new bone from surrounding osteogenic cells or encourages differentiated mesenchymal cells to grow along the graft surface.^4-6

According to Miron and Zhang, the ideal bone grafting material should have three key characteristics. First, it should consist of osteogenic progenitor cells within the bone grafting scaffold capable of depositing new bone matrix. Second, it should exhibit osteoinductive potential by recruiting and inducing mesenchymal stem cells to differentiate into mature bone-forming osteoblasts. Lastly, the material should provide a scaffold that enables 3-dimesional (3D) stability and ingrowth of desired tissues.⁷ Ideally, a bone graft should be biocompatible, non-allergenic, non-toxic, and safe; it should demonstrate proper geometry and handling, have good mechanical stability, and pose no risk of disease transmission.^7,8

Numerous bone grafting materials have been introduced, validated, and used in periodontal regeneration and alveolar ridge augmentation procedures, including autografts, allografts, xenografts, and alloplasts. In total, more than 100 bone grafting materials are currently on the market.Many clinicians consider autogenous bone harvested as either a bone block or particulate bone to be the gold standard because its biologic properties comprise osteoconduction, osteoinduction, and osteogenesis.⁷

Bone allografts from a human cadaver typically are categorized as fresh-frozen bone or freeze-dried bone, with the latter including freeze-dried bone allograft (FDBA) and demineralized FDBA (DFDBA). Allograft material has been used in periodontal therapy for more than 40 years and has seen a widespread increase in recent years. ^9,10 Fresh-frozen allografts are generally avoided in dentate patients due to surgical morbidity, increased incidence of external root resorption, and the existence of suitable alternatives.^11-13

FDBA and DFDBA work by employing different mechanisms. FDBA is mineralized and provides a slower resorption rate, resulting in better space maintenance properties. FDBA is osteoconductive and more radiopaque than DFDBA. DFDBA is demineralized, releases more bone morphogenic proteins (BMPs) than FDBA, has a faster resorption rate, is potentially osteoinductive, and is more radiolucent due to its loss of mineralized components. The primary indications for FDBA include GBR, extraction socket grafting, sinus augmentation, and treatment of peri-implant defects.⁷ The primary indication for DFDBA is periodontal regeneration.⁷

Xenografts, derived from animal or plant species, do not possess any form of osteogenic or osteoinductive potential due to the complete deproteinization process to which they are subject, which is necessary to guard against rejection and prevent allergenicity. Recent research has focused on xenografts' non- or low-resorbable properties, which make them desirable bone grafts in a variety of clinical settings.⁷ Deproteinized bovine bone mineral (DBBM) is the most widely used xenograft in the world. Its use has mainly been either alone or in combination with an allograft for contour augmentation in implant dentistry, filling narrow gaps in immediate implant placement, sinus augmentation procedures, vertical augmentation procedures, and major reconstructive surgery following ccancer.⁷

Studies have shown that more than half of all grafting procedures are augmented with allografts, which have been utilized in periodontology, oral surgery, and implant surgical procedures for the replacement of lost bone.⁷ The use of bone grafts continues to grow, as the current estimated global market value now surpasses $2.5 billion annually, with more than 2.2 million intraoral bone grafting procedures performed.⁷

To augment the efficacy of bone replacement materials, adjunctive techniques and materials are frequently used, such as ancillary growth factors and biologically active regenerative materials. These include enamel matrix derivative (EMD), recombinant human platelet-derived growth factor-beta beta (rhPDGF-ßß), P-15, platelet-rich plasma (PRP), platelet-rich fibrin (PRF), and recombinant human fibroblast growth factor-2 (rhFGF-2), as well as recombinant human BMP-2 for GBR specifically.^14,15

Next-generation biomaterials also have been identified as emerging mechanisms for enhanced bone and soft-tissue growth. Osteoinductive synthetic bone grafts, 3D-printed bone grafts, and novel bone adhesives currently are being investigated as means to facilitate bone-to-bone and bone-to-implant adhesion. Additionally, ground dentin as an autologous source for bone regeneration has been used similarly to FDBA at lower costs to both patient and practitioner. Other emerging biomaterials include atelocollagen-derived xenografts, osteoinductive synthetic bone grafts (eg, Osopia, Nextgen Biomaterials, nextgenbiomaterials.com), bioresorbable bone adhesive (eg, Tetranite^®, LaunchPad Medical, launchpadmedical.com), Osteogain^™ liquid formulation of EMD (Straumann, straumann.com), and hyaluronic acid.⁷

Additional emerging adjunctive materials to augment bone regenerative outcomes include rhFGF-2, teriparatide bone anabolic, and mesenchymal stem cell allografts.^16,17 Furthermore, the autotransplantation of adipose, connective tissue, or oral tissue-derived mesenchymal stem cells has been explored as a source of osteogenic cells that may allow for decreased surgical morbidity and mortality. More research is needed regarding clinical indications of these next-generation biomaterials.⁷

Other innovative regenerative approaches include therapies directed at resolving inflammation, treatments that take into account the influence of the microbiome, therapies that involve the local regulation of phosphate and pyrophosphate metabolism, laser therapy/photodynamic therapy for hard tissue and implant disinfection, and treatment directed at harnessing the potential of existing therapies that are used for other purposes.^16,18,19 According to the AAP Best Evidence Review on laser therapy for treatment of peri-implant mucositis and peri-implantitis, results of a meta-analysis indicate that when treating peri-implantitis with resective surgical treatment no statistically significant differences were noted in probing depth reduction, clinical attachment level gain, residual recession, and plaque index reduction between groups with and without adjunctive laser treatment after 6 months postoperatively.²⁰ Some data does suggest that laser therapy may be beneficial when used as an adjunct with regenerative therapies, but current studies include various laser types and protocols and further investigations should be performed to identify ideal protocols and quantify the overall potential benefit of this approach.^21,22

Barrier membranes, both resorbable and nonresorbable, are integral to providing isolation of a defect to guard against gingival soft-tissue invasion and allow space maintenance for both GBR and GTR. Resorbable membranes, including cross-linked collagen barrier membranes, have been used adjunctly in numerous procedures such as ridge preservation, sinus augmentation, periodontal regeneration, and treatment of gingival recession. They do not require a secondary surgery for removal and are highly biocompatible. Nonresorbable membranes, such as polytetrafluoroethylene (PTFE) membranes, with or without titanium reinforcement and titanium mesh, have been utilized for ridge preservation techniques and large and/or vertical GBR procedures requiring increased mechanical stability.

Further research is paramount to identify the potential benefits of next-generation biologic agents for periodontal and hard- and soft-tissue regeneration. Long-term effects, proper carriers, and ideal concentration/dosage of growth factors and other adjuncts, among other confounding considerations,^14,15 need to be studied.

Jennifer Hirsch Doobrow, DMD,
Private Practice, specializing in Periodontics and Implant Dentistry, Cullman, Alabama; Diplomate, American Board of Periodontology; Fellow, American College of Dentists and International College of Dentists