Received: 15 June 2019 Revised: 3 August 2019 Accepted: 10 August 2019 DOI: 10.1002/JPER.19-0351 REVIEW Extracellular matrix-based scaffolding technologies for periodontal and peri-implant soft tissue regeneration Lorenzo Tavelli1 Michael K. McGuire1,2,3 Giovanni Zucchelli1,4 Giulio Rasperini1,5 Stephen E. Feinberg6 Hom-Lay Wang1 William V. Giannobile1,7 1Department of Periodontics & Oral Medicine, University of Michigan, School of Dentistry, Ann Arbor, MI, USA 2Private practice, Houston, TX, USA 3Department of Periodontics, University of Texas, Dental Branch Houston and Health Science Center, San Antonio, TX, USA 4Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy 5Department of Biomedical, Surgical and Dental Sciences, University of Milan, Foundation IRCCS Ca’ Granda Policlinic, Milan, Italy 6Department of Oral and Maxillofacial Surgery, University of Michigan, Ann Arbor, MI, USA 7Department of Biomedical Engineering & Biointerfaces Institute, College of Engineering, University of Michigan, Ann Arbor, MI, USA Correspondence Abstract William V.Giannobile, DDS, MS, DMSc, The present article focuses on the properties and indications of scaffold-based extra- Najjar Professor of Dentistry and Chair, cellular matrix (ECM) technologies as alternatives to autogenous soft tissue grafts Department of Periodontics and Oral Medicine, University of Michigan, School for periodontal and peri-implant plastic surgical reconstruction. The different pro- of Dentistry, 1011 North University Avenue, cessing methods for the creation of cell-free constructs resulting in preservation of Ann Arbor, MI 48109-1078, USA. Email: [email protected] the extracellular matrices influence the characteristics and behavior of scaffolding biomaterials. The aim of this review is to discuss the properties, clinical applica- tion, and limitations of ECM-based scaffold technologies in periodontal and peri- implant soft tissue augmentation when used as alternatives to autogenous soft tissue grafts. KEYWORDS acellular dermal graft, collagen matrix, dental implant, gingival recession, soft tissue augmentation, soft tissue volume 1 SCAFFOLD CONSTRUCTS FOR Ideally, biomaterials should be characterized by certain prop- SOFT TISSUE AUGMENTATION erties, including biocompatibility, ease in surgical site adap- tation and positioning, space maintenance, clot stabilization, Biomaterials have progressively gained popularity in peri- tissue integration, cell invasion/guidance, and promotion of odontics due to their advantages compared with autogenous cellular proliferation.3 Based on their origin, scaffolds can grafts, such as unrestricted availability, avoidance of a sec- be classified as allogenic, xenogeneic, alloplastic, and liv- ondary surgical site, reduction of the surgical time, and ing constructs (when they include cells). This review aims patient’s preference.1 Indeed, the risk of developing moder- to present the characteristics, clinical application, and limi- ate/severe postoperative swelling and pain increased at 3% and tations of extracellular matrix (ECM)-based technologies in 4%, respectively, for each minute of the surgical procedure.2 periodontal and peri-implant soft tissue augmentation. J Periodontol. 2020;91:17–25. wileyonlinelibrary.com/journal/jper © 2019 American Academy of Periodontology 17 18 TAVELLI ET AL. 2 NATURAL AND CADAVERIC biomechanical and biochemical properties of the allograft. It SCAFFOLDS has been suggested that several properties should be consid- ered when choosing the graft, including tissue origin, process- 2.1 Decellularized human dermis ing methods, cross-linking, and biomechanical properties,25 and that the different procedures to obtain human allografts Acellular dermal matrix (ADM) is a soft tissue graft obtained may influence scaffold characteristics, such as cell penetration from human skin that has undergone a decellularization and proliferation.26,27 Kuo et al. compared AlloDerm with process.4,5 Devoid of epithelium and cellular components, Allopatch as scaffolds supporting cellular ingrowth in fabri- the preserved ECM serves as a scaffold that promotes cellu- cating tissue-engineered grafts (TEGs).27 They observed dif- lar migration and revascularization from the surrounding host ferent properties between the allografts, suggesting that decel- tissues.4–7 lularization protocols can affect the scaffold’s biological and First introduced for the treatment of burn wounds,8 the physical characteristics.27 Increased vascular invasion into the ADM has been extensively used in several other indications, constructs were found for TEGs based on Allopatch compared such as facial augmentation, dural replacement, breast recon- with those including AlloDerm. However, AlloDerm-based struction, and esthetic plastic surgery.4,9,10 In dentistry, ADM TEGs showed more rapid cellular migration.27 was firstly evaluated for increasing attached and/or kera- tinized gingivae.11 However, the ADM clinical outcomes are inferior to the free gingival graft (FGG).12,13 In particular, 2.2 Human amniotic membrane the ADM seems to be more prone to shrinkage, which may Human amniotic membrane (HAM) is the innermost fetal also explain the reduced tissue thickness observed.5,13 His- membrane lining the amniotic cavity (0.02 to 0.05 mm in tological data of sites treated with ADM show a “scar” tissue thickness), which is derived from healthy maternal donors appearance,6 although better esthetic and color match with the during an elective caesarian section.28 All donors’ serum surrounding tissue has been described, when compared with samples are tested to ensure the absence of viruses and all a FGG.5,6,13 serologic tests are also repeated 6 months later.29 HAM Currently, the ADM is more routinely used for root cover- undergoes a process of preparation and preservation, such as age procedures (Fig. 1) and soft tissue augmentation at tooth cryopreservation and glycerol preservation or lyophilization or implant sites (Fig. 2),14–19 particularly when avoiding and gamma irradiation,30 resulting in the elimination of the a second surgical site and minimizing patient morbidity is cellular component while preserving the matrix.31,32 HAM is the primary concern.17,20,21 Although ADM is considered composed by a single epithelial layer, a thick basement mem- to be the graft substitute with the most similar outcomes to brane, and an avascular collagen layer.28,30 The avascular the connective tissue graft (CTG),22 a recent network meta- stroma contains several growth factors, including epidermal analysis evaluating the changes in root coverage outcomes growth factor, transforming growth factors alpha and beta over time showed that only CTG-treated sites had a trend (TGF-,TGF-), fibroblast growth factor-2, and keratinocyte towards the stability of the gingival margin among the other growth factor.29,33 These growth factors contribute to the root coverage techniques.19 Similarly, a 12-year follow-up anti-inflammatory, immunomodulatory, antimicrobial, study reported a significant relapse of the gingival margin in antiviral, anti-scarring, and analgesic properties.28,30,34,35 In multiple gingival recessions treated with ADM.17 A possible addition, it has been reported that HAM promotes epithelial mechanism may be that the ADM may not have the capability wound healing, angiogenesis, and ECM deposition.28,30,34,35 of inducing keratinization of the overlying epithelia,5,7,13 Because of these properties, HAM has been used in several which seems to be a positive predictor for the stability of fields for the promotion of wound repair and regeneration.30,36 the gingival margin.17,19,23,24 It can be suggested that with In periodontics, it has been investigated for application in the treatment of ADM, similar root coverage outcomes to guided tissue regeneration36 and in the treatment of gingival CTG can be obtained in the presence of a distinct amount of recession.28 In a randomized controlled study, it was con- keratinized tissue width at baseline (≥2mm17). firmed that cryopreserved amniotic membrane was effective Various human-derived ADMs are currently available, in enhancing cicatrization, wound healing, and reducing pain ∗ † ‡ including AlloDerm, Puros Dermis, and Allopatch . in patients undergoing implant placement.29 Disadvantages Allopatch is derived from the human fascia lata from the of this allograft includes difficulty in handling, rapid degra- American Association of Tissue Banks. This allograft dation, and the lack of adherence in full-thickness burns is minimally processed, which may better preserve the where HAM acts as a temporary wound dressing.37 HAM is commercially available as BioXclude.§ ∗ BioHorizons, Birmingham, AL. † Zimmer Dental, Carlsbad, CA. ‡ Musculoskeletal Transplant Foundation, Edison, NJ. § Snoasis Medical, Golden, CO. TAVELLI ET AL. 19 FIGURE 1 A through F) Coronally advanced flap and acellular dermal matrix for the treatment of an isolated gingival recession. A) Preoperative gingival recession on the left maxillary canine; B) flap design and elevation; C) acellular dermal matrix adapted and sutured over the root; D) flap coronally advanced and sutured; E) 6 month result; F) the complete root coverage is maintained also at the 10-year recall. G through L) Tunnel technique and acellular dermal matrix used for the treatment of multiple adjacent gingival recessions. G) clinical scenario at baseline; H) tunnel flap is performed; I) acellular dermal matrix is inserted in the flap; J) the flap is sutured together with