## 4 Discussion  
Various strategies have been developed to promote periodontal tissue regeneration using bioactive molecules, biomaterials, or their fabrication techniques [4,23,24]. In order to provide primary stability of dental implants or prosthetics after natural tooth extraction, the alveolar bone of periodontal tissues has been a major target tissue to regenerate or repair [25]. However, the tissue engineering paradigm has shifted to tissue regenerationand functioning restoration of tissue complexes for natural tooth preservation rather than tissue replacements with single bone formation [26; 27; 28]. In particular, digital design and manufacturing techniques of scaffolds have been rapidly developed in order to provide appropriate bioactive microenvironments and specific localization of tissue formation in sites defected by diseases or traumatic injuries [29; 30; 31]. Moreover, the investigations for local tissue regeneration could provide significant approaches to overcome limitations of systemic drug delivery systems; (1) the availability to affect other organs, (2) requirement of high concentrations and quantitative optimization of biologies, and (3) uncontrolled activities of factors with less effectiveness at distant wound sites [10; 32; 33]. Recently, periodontal tissues such as PDL or cement have been studied as multiple tissue neogenesis, with spatial compartmentalization of hierarchical structures and functioning restoration of regenerated tissues to support natural tooth constructs [20; 34]. Of periodontitis, fibrous connective tissues (PDL) have a specific orientation and are anchored to two different surfaces of mineralized tissues (alveolar bone and cement) with Sharpey's fibers [3; 35]. The natural PDLs with perpendicular or oblique orientations to tooth-root surfaces play a significant role in spatially distributing masticatory/oclusal stress [2; 6] or contributing to mineralized tissue remodeling [36]. Although some techniques have been developed to spatially provide the small dimension of PDL interspaces (approximately 250-300 \(\upmu\)m), it is still limited to predictably controlled specific angulations of PDL cells and fibrous tissue bundles using 3D engineering platforms [4; 37]. [PERSON] et al. demonstrated that surface artifacts (or stair-stepping errors) by the additive manufacturing technique could be reinterpreted as microgroove patterns on the scaffold surfaces, and it could be highly predictable and reproducible with specific angulations. Using angulated topographies, cell orientations and cytoskeletal polarities could be modulated for 7 and 21 days in vitro [21] and the follow-up study recently reported the optimization of microgroove intervals to regulate cell angulations [22]. Based on the achievement of organizing highly populated PDL cells following angular topographies, which were created during the slicing process of 3D printing [21; 22], this study investigated fibrous tissue formations and the tissue orientations in the interspace regions between PDL-guiding architectures in the scaffold, as well as cell alignments. After rat PDL cells were harvested from the incisors and primarily cultured by passage number three, rat PDL cells were seeded into scaffolds with three different topographies, and cell-scaffold constructs were subcutaneously transplanted into the immundodeficient nude mouse model (Figure 1). After 3 and 6 weeks, vasculature formations around scaffolds could be found clearly without any clinical signs such as inflammation or infection (Figure 2); histology images also showed that blood vessels infiltrated into the scaffolds (Figures 4 and 5). As vasculatures can promote and accelerate tissue differentiation or morphogenesis by supplying oxygen and nutrients to tissues [38; 39; 40], angiogenesis or vasculogenesis could be essential to regulating physiological tissue regeneration processes and facilitating pathological tissue maturation [41].