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Published in final edited form as: Dent Clin North Am. 2022 Sep 11;66(4):659–672. doi: 10.1016/j.cden.2022.05.011

Biomaterials for Periodontal Regeneration

Yuejia Deng 1, Yongxi Liang 1, Xiaohua Liu 1,*
PMCID: PMC10014143  NIHMSID: NIHMS1877387  PMID: 36216452

INTRODUCTION

Periodontitis, which causes the destruction of tooth supporting tissues, is one of the most prevalent chronic diseases in the United States.1 Patients with periodontitis suffer from the recession of gingival soft tissue, loss of periodontal ligament (PDL), and absorption of alveolar bone. According to the Centers for Disease Control and Prevention, more than 47% of adults aged 30 years and older have some degree of periodontal diseases.2 Currently, a common procedure for periodontitis treatment is scaling and root planning to remove plaque and calculus above and below the gumline. However, this procedure only delays the progression of local inflammation and cannot recover the lost tooth supporting tissues, including PDL, cementum, and alveolar bone. Therefore, there is an unmet need to reconstruct the damaged/lost periodontal tissues in a clinical setting.

Biomaterial-based approaches have been extensively explored to regenerate periodontal tissues.3 Guided tissue regeneration/guided bone regeneration (GTR/GBR) has been used for periodontal regeneration for many years.4 GTR/GBR works by adopting polymeric materials as a physical barrier. This barrier prevents the down-growth of connective and epithelial tissues into the defective site, therefore favoring the regeneration of periodontal tissues. The effectiveness of the GTR/GBR method has been confirmed for vertical alveolar bone loss (3 wall and class II furcation defects)5 but not for horizontal alveolar bone loss.6 Meanwhile, current GTR/GBR membranes lack tissue regenerative properties and have to be combined with grafts to enhance tissue regeneration.4,7,8

With the advancement of tissue engineering and nanotechnology, new biomimetic materials and scaffolding fabrication technologies that can recapitulate the microenvironment of natural extracellular matrix (ECM) have been developed for periodontal tissue regeneration. This article summarizes recent progress in periodontal regeneration from a biomaterial perspective. First, we provide an overview of GTR/GBR membranes and various natural and synthetic grafting biomaterials that are used for periodontal tissue regeneration. Next, we discuss the recent development of biomaterials and multifunctional scaffolds used for alveolar bone/PDL/cementum regeneration. Finally, we provide clinical care points and perspectives on the use of biomimetic scaffolding materials to reconstruct the hierarchical and functional periodontal tissues.

BIOMATERIALS FOR PERIODONTAL REGENERATION

Barrier Biomaterials

Barrier biomaterials act as a physical barrier to block fast-growing soft tissue cells (epithelial cells and gingival fibroblasts) from growing into defective sites during periodontal regeneration. Besides preventing undesired cell invasion, barrier materials also need to maintain mechanical stability to provide space for periodontal tissue regeneration. GTR/GBR membranes are barrier biomaterials and have been widely used for the treatment of periodontitis. According to the characteristics of degradation, GTR/GBR membranes can be divided into nonresorbable and resorbable barriers. Table 1 lists the commonly used commercial GTR/GBR membranes.

Table 1.

A list of the commonly used commercial guided tissue regeneration/guided bone regeneration membranes

Commercial Name Main Components Degradation Application Reference
Expanded polytetrafluoroethylene (ePTFE; GORE-TEX®: W.L. Gore & Associates; Flagstaff, AZ, USA) ePTFE Nondegradable GBR-implant
Bone regeneration		 Vaibhav et al,9 2021
Ti-250(Cytoplast®: Osteogenics Biomedical; Lubbock, USA) Titanium-reinforced high-density PTFE Nondegradable Vertical bone regeneration Windisch et al,10 2021
N-RES (Gore-Tex®) Titanium-reinforced ePTFE membrane Nondegradable GBR Naenni et al,11 2021
TR(OPENTEX® TR: Purgo; Seoul, Korea) Titanium-reinforced MP-ePTFE Nondegradable Vertical Ridge Augmentation Ji et al,12 20201
Bio-Gide®: Geistlich Pharma AG; Wolhusen, Switzerland Collagen derived from porcine skin 24 wk Two-wall intrabony defects, GBR Imber et al,13 2021
BioMend®: Zimmer Dental; Carlsbad, CA, USA Collagen type-I derived from bovine tendon 18 wk GTR Foo,14 2021
OssGuide®: SK Bioland; Cheonan, Korea Cross-linked-porcine pericardium-derived type I collagen 12–16 wk GTR Lee et al,15 2021
Genoss®: Genoss Company Limited; Suwon, Korea Cross-linked type-I collagen derived from bovine tendon N/A GBR-implant
Bone regeneration		 Cha et al, 16 2021
Tisseos®: Biomedical Tissues; La Chapelle-sur-Erdre, France Poly(lactic-co-glycolic acid) N/A GBR Naenn et al,17 2020
GUIDOR®: Guidor AB; Huddinge, Sweden Poly(lactic acid) 6 wk GBR Naenni et al,17 2020, Di Raimondo et al,18 2021
Straumann®: Straumann AG; Basel, Switzerland
MembraGel		 Polyethylene glycol membrane N/A GBR-implant
Bone regeneration		 Jung et al,19 2020
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Abbreviations: N-RES, Non-resorbable.

The first barrier membrane was made from ePTFE, a material that has excellent biocompatibility and mechanical stability.9 When high rigidity is required to maintain a large defect space, a titanium framework can be placed between 2 layers of e-PTFE.10 A recent clinical study adopted a titanium-reinforced microporous ePTFE (MP-ePTFE) for vertical ridge augmentation before dental implant placement.12 Micropores in the e-PTFE were used to reduce bacterial contamination and facilitate removal of the membrane material after tissue regeneration. The results in a 1-year follow-up indicated that the titanium-reinforced MP-ePTFE membrane is a promising barrier biomaterial for vertical ridge augmentation of severely resorbed ridges within posterior areas.12 Because PTFE is a non-resorbable membrane, patients need a second surgery to retrieve it, which increases the risk of site morbidity.20 In addition, ePTFE membranes have premature exposure rates of 30% to 40%, leading to significant increases in infection, contamination, and impaired bone augmentation.21 For these reasons, current clinical research is more focused on resorbable membranes.

The most popular resorbable membranes are fabricated from collagen that has high biocompatibility and is capable of promoting wound healing.11,13–15 Commercial collagen membranes such as Bio-Gide, BioMend, OssGuide, and Genoss have varied collagen types and structures (see Table 1). These membranes are resorbed via enzymatic degradation, such as collagenases, macrophage/polymorphonuclear leukocyte-derived enzymes, and bacterial proteases. Collagen membranes promote osteoblastic cell migration and new bone ingrowth.22 Because collagen is a natural biomaterial, its degradation rate depends on the sources of the material. Generally, collagen membranes have low mechanical strength and a rapid biodegradation rate. Several cross-linking methods have been developed to increase the mechanical properties and decrease the degradation rate.15,16 The cross-linked collagen membrane maintained the position of block bone substitutes in the early healing period of an lateral onlay graft.23 However, research showed that the cross-linked collagen membrane delayed the process of angiogenesis.24 A recent clinical trial showed that there was no significant difference in ridge preservation when comparing collagen membranes and PTFE.25

Other natural resorbable membrane biomaterials that have been tested include gelatin, chitosan, and silk fibroin.26–28 Gelatin is derived from collagen and has excellent biocompatibility to promote osteoblasts adhesive and growth, make it a promising biomaterial for GTR/GBR.29 Chitosan is derived from chitin via deacetylation and has high biocompatibility, antimicrobial activity, and wound healing potential.30 Silk fibroin is a protein extracted from Bombyx mori cocoons and possesses excellent biocompatibility as well as oxygen and water vapor permeability.31 Compared with collagen, these natural biomaterials used as barrier membranes are still at the preclinical stage, and there are no commercial products for GTR/GBR yet.

The major limitations of natural biomaterials are batch-to-batch differences and inferior mechanical properties.32 To overcome those drawbacks, several synthetic biodegradable polymers have been synthesized for resorbable GTR/GBR membranes. These polymers include poly(lactic acid), poly(glycolic acid), polyethylene glycol membrane, poly(ε-caprolactone) (PCL), poly(lactic-co-glycolic acid) (PLGA), and their copolymers. However, these synthetic biomaterials lack cell recognition cues and often need surface modification to enhance cell–material interactions. Currently, there are a few commercially available synthetic resorbable membranes on market and many more synthetic polymer membranes are under the animal study phase or in preclinical trials.

Membrane-related infection is the main reason for clinical failure of GTR/GBR due to the complicated biofilm environment in the oral cavity. Recent studies have incorporated different bioactive components to the GTR/GBR membranes to acquire sufficient antibacterial properties. A study added magnesium oxide nanoparticles (NPs) into PCL/gelatin membranes using a coaxial electrospinning technique to enhance antibacterial activity.33 Similarly, ZnO NPs were introduced into chitin as an antibacterial component to form a functional barrier membrane.34 The ZnO NPs in the barrier membrane displayed a good antibacterial activity by slowly releasing Zn2+ and improved osteogenic capability in a rat periodontal defect model.34 However, the periodontal bone defect was only partially repaired after the ZnO-containing barrier membrane was completely degraded, indicating the necessity of tailoring the degradation rate of the barrier membrane. Surface coating is another approach to incorporate antimicrobial silver NPs into GTR/GBR membranes.35 The in vitro experiment demonstrated the antimicrobial ability of surface-modified GTR/GBR membrane against Staphylococcus aureus and Escherichia coli.35 However, further studies are needed to identify the long-term antibacterial activity in vivo.

Grafting Biomaterials

Graft materials are commonly used with barrier membranes to achieve periodontal regeneration and alveolar ridge reconstruction. The graft materials can be divided into autografts, allografts, xenografts, and alloplastic materials. A comprehensive search shows that there have been 144 bone graft materials for periodontal use in the United States.36 Among those products, the number of allografts is the highest, followed by alloplastic materials and xenografts. Because autografts are harvested from the own body of the patient, it possesses all the properties required for new tissue regrowth and structural reconstruction and is considered the gold standard. However, second site morbidity and limited quantities of available tissue limits its application. Allografts are harvested from one individual for transplantation to another. Two of the widely used bone allografts are the freeze-dried bone allograft (FDBA) and the demineralized freeze-dried bone allograft (DFDBA). A recent randomized clinical trial shows that corticocancellous FDBA along with a collagen membrane was effective for horizontal augmentation of the edentulous ridge.37 Furthermore, adding autogenous bone to the FDBA did not significantly increase the quality and quantity of regenerated bone.37 When used in ridge preservation of nonmolar tooth sites, there was no significant difference in vital bone formation or dimensional changes among cortical FDBA, 50/50 cortical FDBA/cancellous FDBA, and cancellous FDBA.38 A study that examined the effect of block allografts on the treatment of intrabony defects in periodontitis showed that both the FDBA and DFDBA significantly improved the periodontal prognosis of teeth with intrabony defects at 12 months postsurgery.39 Another randomized controlled clinical trial compared the healing of nonmolar extraction sites grafted with either FDBA or a 70/30 FDBA/DFDBA in alveolar ridge preservation.40 The results showed that the 70/30 FDBA/DFDBA had better vital bone formation while providing similar dimensional stability of the alveolar ridge. A long-term evaluation further indicated that the 70/30 FDBA/DFDBA had approximately twice as much vital bone and half as much residual graft material after 18 to 20 weeks of healing compared with only 8 to 10 weeks of healing.41

Xenografts are obtained from different species and prepared by various procedures. Two of the most used xenografts in dentistry are deproteinated bovine bone matrix (DBBM) and demineralized porcine bone matrix (DPBM).42,43 DBBM has been used in GBR and ridge preservation. The combination of DBBM with recombinant human bone morphogenetic protein-2 resulted in similar bone quantity and quality of lateral ridge augmentation when compared with an autogenous bone block.44 A recent finding suggested that DPBM and DBBM had comparable histomorphometric outcomes and dimensional stability of ridge preservation.45 A meta-analysis and systematic review concluded that the use of DBBM for site preservation provided no additional benefits in terms of postextraction new bone formation when compared with natural healing.46 Similar to allografts, the major concerns associated with xenografts are antigenicity and the risk of disease transmission from donor to recipient.

Alloplastic grafts are synthetic materials and can avoid the above disadvantages of allografts and xenografts. In addition, alloplastic grafts are osteoconductive and cost effective. Although there are many graft products that have been approved in the United States,47 β-tricalcium phosphate (β-TCP), biphasic calcium sulfate (BCS), biphasic calcium phosphate, and hydroxyapatite (HA) are popular alloplastic grafts used in regenerative dentistry. β-TCP is a widely used synthetic bone graft substitute and possesses excellent biocompatibility.48 β-TCP facilitates the in-growth of cellular and vascular components and has degradation rates similar to the rate of new bone formation.49,50 A systematic review and meta-analysis found that β-TCP had the potential for additional clinical improvement in probing pocket depth and clinical attachment level compared with open flap debridement in infrabony defects.51 A multicenter randomized controlled trial compared the efficacy of PLGA-coated β-TCP (PLGA-β-TCP) on alveolar ridge preservation, and the result showed that PLGA-β-TCP had similar outcomes in terms of maintenance of alveolar bone dimensions, feasibility of implant placement, peri-implant bone level stability, and implant survival up to 12 months postloading.52 A prospective clinical trial on ridge preservation showed that a combination of β-TCP with BCS was superior to natural healing processes in terms of horizontal dimensional changes after 4 months.53 In addition, a histologic analysis indicated that the percentage of residual graft was relatively small and without evidence of an inflammatory response or graft encapsulation. HA has a chemical formula of Ca10(OH)2(PO4)6 that is almost identical to the inorganic portion of the bone matrix.54 A clinical and histologic evaluation of the healing of human intrabony defects from a small number of samples indicated that nano-HA had limited potential to promote periodontal regeneration in human intrabony defects.55 Meanwhile, long-term studies for the efficacy of the calcium phosphate ceramics on periodontal regeneration are currently lacking.

New Biomaterials and Scaffolds for Periodontal Regeneration

As shown above, clinical research of periodontal biomaterials predominantly focuses on applications for alveolar bone regeneration. Currently, most of the studies on the regeneration of cementum/PDL or the whole periodontium is at the preclinical stage.56 Although conventional biomaterials are still the main sources for periodontal regeneration,57 there are some new biomaterials that have been developed for cementum/PDL/alveolar bone regeneration in recent years. Table 2 lists the biomaterials that were recently tested for periodontal tissue regeneration (all are within the last 5 years).

Table 2.

Summary of biomaterials used for periodontal tissue regeneration in recent years

Materials Functions
Au nanoparticles58 Regulate inflammatory response and the cross talk between macrophages and PDL cells to inhibit ligature-induced periodontitis
TiO259 Induce osteogenic differentiation and implant integration
CaF260 Enhance osteogenic and cementogenic differentiation of PDLSCs
Mg-doped hydroxyapatite61 Enhance osteogenesis of PDLSCs
P11–4 peptide62,63 Induce PDLSC osteogenic differentiation and periodontal regeneration
Exopolysaccharide64 Enhance cell migration and wound healing
Gelatin methacrylate + HA65 Induce PDLSCs to differentiate into osteoblasts and promoted new bone formation in nude mice
Chitin + PLGA + nBGC66 Regulate degradation and mechanical stability. Enhance osteogenic capacity in bone and cementum layers
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Abbreviation: nBGC, nanobioactive glass ceramic; PDLSC, peridontal ligament stem cell.

The regeneration of alveolar bone, cementum, and PDL requires biomaterials with different characteristics.57 Some new biomaterials have been developed for multifunctional purposes. For example, several minerals or metallic compounds were reported to play multifunctional roles in periodontal regeneration, including osteogenesis/cementogenesis enhancement, mineralization regulation, and inflammation regulation.58–60 Overall, examination of those biomaterials for periodontal application are still at the early stage and some studies even did not have in vivo results.59–61,64

Biomaterials need to be fabricated into suitable scaffolds to perform their functions. A scaffold provides a biomimetic microenvironment to guide periodontal tissue repair and regeneration. Obviously, the periodontium has a hierarchical structure that contains both soft and hard tissues, making it complicated to design the scaffold. For example, a scaffold for alveolar bone and PDL regeneration should have one side to promote osteoblast differentiation and mineralization, whereas the other side to promote antimineralization and enhance PDL formation. Considerable progress has been made in scaffolding design for periodontal regeneration during the last decade. These scaffolds were generally fabricated into multilayered structures.66 For example, a trilayered scaffold was designed to regenerate both hard (cementum and alveolar bone) and soft (PDL) periodontal tissues (Fig. 1). In that study, the chitin-(PLGA)/nano-bioactive glass ceramic (nBGC)/cementum protein 1 was for the cementum layer, the chitin–PLGA/fibroblast growth factor 2 (FGF2) was for the PDL layer, and the chitin–PLGA/nBGC/Platelet-rich plasma (PRP) was for the alveolar bone layer. The trilayered composite scaffold with growth factors showed complete defect closure and the formation of new cementum, fibrous PDL, and alveolar bone after implantation of 3 months in a rabbit periodontal defect model.66

Fig. 1.

Fig. 1.

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Design of trilayered membranes to regenerate cementum, PDL, and alveolar bone. (Adapted from Sowmya S, Mony U, Jayachandran P, et al. Tri-Layered Nanocomposite Hydrogel Scaffold for the Concurrent Regeneration of Cementum, Periodontal Ligament, and Alveolar Bone. Adv Healthc Mater. 2017;6(7).)

Electrospinning is a widely used method in fabricating scaffolds with nanofibrous architecture that mimics the structure of the natural ECM, which has been proved to be beneficial for many biological functions.67 Its surface-to-volume ratio of the nanofibrous membrane allows more protein absorption and provides more binding sites to cell receptors.68 One limitation of electrospinning is its difficulty in generating macropores inside the scaffold for alveolar bone regeneration. Therefore, electrospinning needs to be combined with other technologies (eg, 3-dimensional [3D] printing) to fabricate multilayered periodontal scaffolds.

3D printing is a rapid process that allows precise control over the shape and porosity of a scaffold. A biomimetic 3D printing scaffold was developed to regenerate alveolar bone-PDL-cementum complex structure (Fig. 2). When the scaffold was combined with human gingival fibroblasts transduced with AdCMV (AdCMV)-Bone morphogenetic protein 7 (BMP7), it formed tooth cementum-like tissue, ligament, and bone structures, indicating the promising of the use of customized periodontal scaffolds for regenerating multitissue interfaces.69 However, in vivo results showed that the aligned collagen fibers were deposited parallel to the dentin surface. A technology named melt electrowritten (MEW) was recently developed to bridge the gap between solution electrospinning and 3D printing.70 Because a high voltage is added at the tip of jet, the MEW filaments display a smaller diameter than that of the fibers directly printed from fused-deposition modeling. The MEW enables the deposition of straight polymeric fibers in a layer-by-layer manner and the introduction of well-defined macropores in 3D matrices. However, the MEW is a melt-based additive manufacture process that forms the fibers with diameters at a micrometer level that cannot truly mimic the nanofibrous architecture of ECM. Meanwhile, the compressive yield strength of the polycaprolactone scaffolds fabricated from the MEW was only 1 to 3 kPa,71 which needs to be significantly increased before the practical application. Overall, the 3D printing and the utilization of a biphasic or triphasic scaffold for periodontal regeneration is still in the early phases of development. More advanced technologies and in vivo studies (especially with the use of a disease model) are necessary to move this research forward in the future.

Fig. 2.

Fig. 2.

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Three-dimensional printing hybrid scaffolds for periodontal tissue regeneration. (A) Schematic illustration of printing hybrid scaffolds. (B) Assembly of the hybrid scaffold with a human tooth dentin slice for periodontal tissue regeneration. (Adapted from Park CH, Rios HF, Jin Q, et al. Biomimetic hybrid scaffolds for engineering human tooth-ligament interfaces. Biomaterials. 2010;31(23):5945-5952.)

SUMMARY

Periodontal tissue regeneration requires functional regeneration of tooth supporting periodontium, which contains cementum, connective PDL, and alveolar bone as well as surrounding soft tissues.72 Biomaterials play a pivotal role in preventing undesired epithelial and gingival fibroblast cell migration as well as guiding other periodontal tissue regeneration. Currently, biomaterials used in clinical settings are mainly focused on physical barrier functions using the GBR/GTR approach. Although nonresorbable membranes are still widely used in clinical practice, resorbable natural and synthetic membranes have become increasingly attractive because they avoid secondary surgery and meet minimally invasive surgery requirements. However, the outcomes of using resorbable barrier membranes varied in different cases according to the defect severity and heterogeneity of patients.73

Choosing an ideal grafting material is challenging because each grafting material has advantages and limitations. A suitable bone grafting material should be biocompatible, osteoconductive, osteoinductive, and resorbable.

Multifunctional and multiphasic scaffolds have been designed to regenerate the whole periodontium, including alveolar bone, cementum, and PDL. Mimicking the nanofibrous architecture of natural ECM during scaffolding design provides a better microenvironment for cell proliferation, differentiation, and new tissue formation. Constructing scaffolds with microgrooves and microchannels is a strategy in guiding PDL fiber formation. Temporally and spatially controlled drug/growth factor delivery from multiphasic scaffolds is essential in guiding the growth and differentiation of each cell type in the periodontal defective area. Bioactive NPs are incorporated into the scaffold to enhance the antioxidation, anti-inflammation, antibacterial activities, and angiogenic potential.74 However, most of the studies related to new biomaterials and scaffolds are in their early phases and more in vivo experiments are needed before clinical trials.

KEY POINTS.

  • Resorbable natural and synthetic barrier membranes have received increasing attractions for use in periodontal regeneration.

  • The regeneration of alveolar bone, cementum, and periodontal ligament requires different characteristics of biomaterials.

  • More multicentered long clinical studies are needed to provide a better evidence-based clinical guide for biomaterials use.

CLINICS CARE POINTS.

  • Both non-resorbable and resorbable GTR membranes are used in daily practice depending on the need of the case.

  • GTR membranes combined with bone grafts enhance tissue regeneration.

  • Further in vivo and clinical studies are needed to provide a better evidence-based clinical guide for biomaterial selection.

ACKNOWLEDGMENTS

This study was supported by National Institute of Dental and Craniofacial Research (NIDCR) grant numbers DE024979 and DE029860 (X. Liu). The authors thank Meghann Holt for her assistance with the editing of this article.

Footnotes

DISCLOSURE

No competing financial interests exist.

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