**1. Introduction**

The management of large facial bone defects is a current challenge for clinicians and surgeons. Treatment success is frequently related to the size of the defect, the quality of the soft tissue covering the defect, the decision of reconstructive method and the choice of the grafted material [1–3].

Numerous bone grafts' regenerative procedures are currently available for having complete regenerative processes after bone trauma, or for favoring healing between two bones across a diseased joint, and also for obtaining new clinical function or aesthetic on site affected by disease, infection, or resection [2–5].

Facial bone augmentation procedure using autologous bone is a reliable technique, as confirmed by several studies; however, this treatment choice has integration advantages associated with several disadvantages. Autogenous bone harvested from the patient's extra oral or intra oral sites even considered the gold standard, at the same time is related with surgical intra and post operative complications, biological cost, and patient morbidity, pain and discomfort at the bone grafting area [1–7].

Recently, great interest has been directed towards the application of synthetic three-dimensional biomaterials scaffolds as bone substitutes used for facial large bone defect regeneration in order to have a substantial quantity of material and to avoid a second surgery site. Those synthetic bone substitutes materials should be non-toxic, compatible with the biological systems, and bio absorbable. The biomaterial has to be a macroscopic structure that is easy for surgeons to handle. Its microstructure should be able to promote cell adhesion, proliferation and new bone formation [4–8]. The fundamental key parameters for an excellent biomaterial are related to its capability on replacing the natural bone extracellular matrix. Secondly, it should be able to recall the osteo-genic cells in order to lay down the bone tissue matrix, and then the biomaterial should guarantee a sufficient vascularization to meet the growing tissue nutrient supply and clearance needs. Therefore, after being placed in situ, the microscopic features of the biomaterial should influence the host by releasing osteogenic and/or genic growth factors [5–10].

Nowadays, the tissue engineering approaches to the facial bone regeneration are connected with biomaterial matrices/scaffold that favorably interact with cells. The potential benefits of using recent tissue engineering findings is fundamental today in order to limit donor site morbidity, reducing operative time, and replacing the anatomical microstructure in an attempt to restore physiological craniofacial functions [8–11]. Currently, advances in computer-aided modeling and biomaterials manufacturing help the craniofacial surgery field, which is frequently confronted with the rebuilding of three-dimensional anatomic structures on function and aesthetics. Three-dimensional models of bone defects can be realized from patient computed tomography scans, creating a customized scaffold that interacts with the defect site and re-builds the complex anatomical features [4,5,8,12,13].

Recently, the use of bone substitutes obtained from marine origins is being considered high attractive by the industry as an alternative source. In this specific field, the marine collagen can be obtained from numerous sources. Type I collagen is obtained predominantly from skin, tendon, bone and muscle (epimysium), which is the most abundant type of collagen. Marine fish collagens find applications in numerous biomedical fields. Besides its mechanical elastic properties, marine collagen exhibited good absorption characteristics with interconnectivity between pores, which allowed human Mesenchymal Stem Cells (hMSCs) to adhere and proliferate, being a good base for osteogenic differentiation [3,7,12].

The aim of this review is to screen recent papers about biomaterials applied for facial bone reconstruction in order to give the clinicians' valuable suggestions about the possibility of replacing autologous bone graft for large reconstruction defects.

This systematic review also aimed to evaluate the potential of reconstructive marine biomaterials uses like scaffolds for growth factor in order to provide better results in comparison to others.

#### **2. Materials and Methods**

#### *2.1. Application Protocol and Website Recording Data*

A protocol including the investigation methods and the inclusion criteria for the current revision was submitted in advance and documented on the Center for Review and Dissemination (CRD) York website PROSPERO, an international prospective register of systematic reviews. The parameters and the analytic structure of the present work can be visualized relating the CRD id and code: Application number: CRD 74603.

The data of this systematic investigation observed the Preferred Reporting Items for Systematic Review accordingly with the (PRISMA) statement [14].
