Decompressive craniectomy (DC) is one of the most common neurosurgical procedures performed in a neurotraumatological setting, usually performed after disorders that cause significant increases in intracranial pressures, such as traumatic brain injury (TBI), but also vascular accidents (strokes), infections and other congenital abnormalities. DC, but also non-decompressive craniectomy, are usually followed by the reconstruction of the cranial vault, which is also known as a cranioplasty (CP) ^[1][2][1,2]. The need for CP is not only due to cosmetic reasons, but also because it has been shown that the reconstruction helps in the recovery not only of physiological blood and cerebrospinal fluid flow, but also in mental health status ^[3][4][5][3,4,5].

Currently, it is widely accepted that the first option treatment should be the autologous bone of the patient itself, since it maintains the biomimetic properties of the cranial vault and it is a cheaper option compared to other heterologous materials. However, this is not always a feasible option, since the graft could be lost during the decompressive surgery, in the case of traumatic patients, or during the storage phase [6]. Moreover, in the case of successful implantation, the autologous bone reported a high rate of postoperative complications, and, most importantly, symptomatic bone reabsorption that needed a revision surgery [3].

In order to overcome those limitations, in recent decades, several heterologous materials have been developed. The main ones used in cranioplasty are titanium, polyether-ether-ketone (PEEK), polymethyl-methacrylate (PMMA) and porous hydroxyapatite (PHA). Most of these materials have been used for several decades in the field of neurosurgery. However, they still present an important rate of postoperative complications and most importantly they do not allow effective integration of the device with the cranial vault since they are not “recognized” by the osteoblasts. More recently, PHA is the latest to be developed and caught the attention of the neurosurgical community for its biosimilarity with the autologous bone ^[3][4][6][7][3,4,6,7].

2. Molecular Characteristics and Physicochemical Properties

Modern medical sciences, among which neurosurgery, has recognized the importance of the concept of bio-mimetic materials and it is trying to apply it to all possible aspects of everyday practice, among which the creation of the new cranioplasty implants [8]. An effective example of such scientific efforts could be seen in the creation of porous hydroxyapatite cranial implants. Those are biomimetic devices that aim to resemble the human skull. Hydroxyapatite, a basic calcium phosphate, is one of the most present minerals in the human body, taking up to 50% by volume and 70% by weight of human bone, and today can be developed on a laboratory scale with characteristics similar to its natural counterpart. Because of its crystalline composition, it is accepted as a bioactive material. As a bioactive, it is meant that such material is able to support bone ingrowth and osteointegration, which will be further analyzed in the next section. This has been already widely proven in other medical specialties, such as orthopedic surgery ^{[9][10][11][12]}[9,10,11,12]. Over the years, hydroxyapatite has been produced and used in different forms, such as powders and pastes that can be quickly used in an intraoperative setting, but also more complex porous “blocks”, in order to cover cranial defects which are present from the previous craniectomy ^{[10][11][12][13]}[10,11,12,13]. In order to have an effective biomimetic action after the implantation of the device, the sole biochemical composition is not sufficient. In fact, there are other properties that neurosurgeons and manufacturers should take into consideration in the creation and application of such devices, such as the density of the material itself, the shape of the pore and the size of the pore to promote such osteointegration [14]. For what concerns the porosity, it has been shown in vivo studies that the porosity rate is fundamental in the process of osteointegration with the cranial vault since those elements influence the migration of the osteoblasts from the cranial vault to the implanted devices but also the proliferation of these cells that are involved in the process itself, such as the of osteoblasts and mesenchymal cells. Of similar importance is the shape of the pores, since a good integration is facilitated by a good ratio of matrix deposition and empty spaces ^[15][16][15,16]. The optimal size of the pores has been widely studied; there are studies that support an ideal dimension of 100–200 μm, since a lower dimension tends to allow the formation of fibroid tissue rather than a mineralization ^[15][16][15,16]. Studies have also shown the importance of the development of an interconnection pathway to achieve good integration. A structured vascularisation within the cranial implantation is the base of biological integration between the two structures. Further studies on this topic suggested that an incomplete or a minimal pore interconnection affect negatively the biomimetic and integrative process since it affects negatively the ability of the cranial blood vessels to invade the devices ^[17][18][17,18]. A strong vascularisation, not only in the skull but in all biological structures, is essential for the circulation not only of oxygen but also nutrients, allowing the tissue regrowth and the healing process [17]. From the physical point of view, it should be also highlighted that this grade of porosity reduces the mechanical strength of the device, increasing the risk of post-implantation fracture. As discussed below in the section about the custom-made cranioplasty, this risk is significantly reduced after the osteointegration with the cranial vault. From the clinical point of view, it has been recently also shown that PHA can prevent the formation of bacterial biofilms, resulting in greater resistance to infections [19]. A more recent study published by Amendola et al. that aimed to study the effectiveness of preoperative strategies to reduce the risk of postoperative complications. In their study, they suggested, based on the current evidence, that the hydrophilic nature of HA together with its porous structure and its rough surface are key factors in preventing early bacterial adhesion a proliferation, thus reducing risk of infection ^[20][21][22][20,21,22].

3. Cement Hydroxyapatite

Hydroxyapatite cement is a set of pastes made of a calcium phosphate preparation. They are widely used in the surgical setting since they can be shaped intraoperatively by the attending surgeon ^[23][35]. The present scientific literature does not report noticeable toxic reactions, implants extruded, or wound infections. However, it has been suggested by some histologic examinations performed in those implants that there could be episodes of transient inflammatory response. In the study, it has been not reported any case of ì foreign body reaction ^[23][35]. Nowadays in neurosurgery, hydroxyapatite cement is especially used in for the reconstruction of the skull after skull base surgeries, in particular in the postoperative reconstruction after the translabyrinthine approaches (TLAs). TLAs are a series of skull base surgery approaches mainly used to resect skull base neoplasms. Recent evidence has suggested that the mix of such pastes with autologous fat grafts of the patients is responsible for the superior outcome in terms of postoperative complications. Concerning the clinical outcome, cement hydroxyapatite showed a postoperative complication rate similar to other reparative techniques ^[23][35]. Some studies supported the idea through the use of cement HA, there was a reduction in the length of stay (LOS) in the hospital and a reduction in episodes of CSF leaks. The satisfaction in using cement HA for the reconstruction after TLAs surgeries is not limited to the clinical outcome, but also to patients for the good cosmetic results ^[24][36]. such an option has resulted to be feasible also after other types of neurosurgical procedures, such as the suboccipital retrosigmoid ^[25][37]. Cement hydroxyapatite has been also used in pediatric patients. Despite the lack of large prospective studies, it seems as valid as in adult patients. It seems also that the use of computational simulations in the decision of the shape and size of the pore of the device implanted may alter the success of osteointegration ^[26][38].

4. Custom-Made Cranioplasty

In recent years, custom-made cranioplasties made of PHA have been widely used [7]. As per the name, these devices are prepared specifically for the patient. The cranioplasty is constructed based on a 3D CT-scan that the attending neurosurgeon gives to the manufacturer. With that, the company can construct a prototype that has to be analysed and accepted by the neurosurgeon before the production of the device that will be used. There has been also an increase in its use in recent years because of its well-known osteointegrative properties as well as not concerning risk of postoperative infection ^{[27][28][29][30]}[25,26,28,30]. A recent multicentric European retrospective study, with the largest clinical series of patients treated with PHA cranioplasty published (494 patients) showed that this material has a 7.9% rate of complications with an explantation rate of 4.3%. The most common complications were infection (4.86%), hematomas (1.2%), fractures (1.01%), mobilization (0.4%) and scar retraction (0.4%) [6]. Fractures are not only one of the most common postoperative complications for this material but also quite concerning and its management remains a topic of discussion (Figure 2). The authors, through their multicentric experience, have been able to show that despite its relatively important prevalence, especially in the first phase of implantation, when there is still no osteointegration, only, a smaller portion of patients with fractures needed a surgical revision.