## 1 Introduction  
In the last 50 years, remarkable advances have been made in the biomaterials field in general, including those for bone regeneration purposes [1]. In this respect, natural and synthetic materials [2] have evolved and are now able to properly replicate complex tissue structures, playing an active role in the repair and regeneration of bone defects [3, 4]. Different approaches have been developed to mimic native tissue function [5, 6]. One of the most successful one, is the use of porous scaffolds [7] that allow, initially, cell migration and nutrients diffusion, and afterwards provide structural support [8]. This way, cells can grow in the correct shape and location [9, 10]. In this respect, certainly the usage of trabecular bone itself (i.e., bone grafts [11, 12, 13, 14]) as a template, represent a major strategy, as its porous structure is already naturally suited for cell colonization [15, 16]. Moreover, ideal scaffolds, together with biocompatibility, osteocompatibility, osteoconduction, osteoinduction, and neovascularization profile [17] should be resorbed or replaced once new bone has formed and they are no longer needed [14]. Apart from bone grafts, other resorbable scaffold constructs are generally composed of a collagen matrix [18], hyaluron [19], and polymer-based [20, 21] materials. If properly formulated [22], they also ensure, together with resorption profile that can be tailored to desired timeframe [23, 24], adequate mechanical support [11, 16, 25] and promoted interactions between growth factors and progenitor cells allowing their proliferation and differentiation into various types [26, 27]. In our study, we used SmartBone(r) (SB), a xeno-hybrid heterologous bone scaffold proved to have osteoconductive abilities [28, 29, 30] available on the market since 2012 as a CE-marked class III medical device (according to Directive 93/42/EEC of the European Union). Initially used only in the oral field [31, 32, 33], its integration with natural bone resulted to be efficient enough (averagely about one millimeter per month in the complex microenvironment of the mouth, characterized by high concentration of bacteria, which theoretically could limit its osteointegration and cell differentiation [34]) to be successfully extended to other areas [35, 36]. As a matter of fact, nowadays, SB is used in the orthopedic field as well. Together with post-marketing surveillance, in general, advanced clinical and biological analysis are of utmost importance in evaluating an implantable medical device's performance (European Commission guideline Med.Dev 2.7.1, Rev.4, June 2016). This way, in the case of resorbable grafts, it is possible to track whether natural restructuring has allowed the creation of biological tissue with optimized microstructure, according to the physiological function [37, 38]. In this respect, certainly histological examinations represent a crucial analysis [39]. This technique involves tissue biopsy, which requires the collection of bone material from the patient [29, 31, 35]. As a consequence, it results to be an invasive practice and, although it can be carried out fairly smoothly in the oral field, it becomes rather difficult in the skull region or in the orthopedic one [40]. Another very important analysis is represented by in vitro studies that allow directly tracking the cell growth within the scaffold framework [30, 41]. On the other hand, they have the limitation of being only partially representative of the actual performance upon implantation into the patient body. Similar studies have already been performed on SB [29, 30, 41], providing a complete and detailed explanation of its integration mechanism over time on an averaged base, though not allowing the evaluation of each patient's specific situations. This was mostly due to the aforementioned difficulty in collecting tissue samples from the implantation site.