Author(s): Maja Sabali aff1 , Alessandro Mangano aff2 , Georgios D Lianos aff3 aff4 , Luigi Boni aff5 , Gianlorenzo Dionigi aff5 , Alberto Mangano [*] aff5 aff6
bone regeneration; growth factors; mesenchymal stem cells; regenerative surgery; scaffolds; tissue engineering
There is a high demand for improved, less invasive bone regeneration approaches. New techniques and materials could improve the quality of life of patients with a wide spectrum of pathologies of the oral and maxillofacial regions, such as bone loss due to periodontal disease, periapical lesions, congenital malformations, tumors and trauma. Although associated with a number of minor and major postsurgical complications, bone grafting of autologous cancellous or cortical bone is still a treatment of choice for large bony defects. [1,2 ] The complexity of bone structure and function (loaded vs nonloaded bone) make its regeneration a challenging task; bone metabolic and mechanical competency, vascularization, immunogenicity and innate regeneration capacity are to be considered when developing new regeneration strategies. The following paragraphs discuss current challenges, recent developments in tissue engineering and the rationale for using mesenchymal stem cells (MSCs) in dental and regenerative surgery applications.
The three 'pillars' of tissue engineering & regenerative medicine
The fast developing field of tissue engineering, based on the paradigm of three 'pillars' - scaffolds, cells, signals (e.g., growth factors) offers some promising solutions for bone regeneration. The pillar sine qua non - a scaffold provides architecture to hold the components in the transplantation site. A number of scaffold designs have been tested in preclinical and clinical studies for requirements such as biocompatibility, high porosity to allow diffusion and vascularization, mixed porosity (different sizes of pores) support for the tissue but also biodegradability once tissue is formed in place. Notably, studies utilizing cell cultures provided insight into influence of microenvironment stiffness and mechanotransduction [3 ] and since it was shown that physical stimuli can foster regeneration of various nanostructured calcium phosphate biomaterials [4,5 ] mimicking bone matrix were developed.
Scaffolds resembling the natural extracellular matrix of intramembranous bone might be the key for successful craniofacial bone regeneration but satisfactory results cannot be achieved by scaffolds alone. The question that has recently emerged, however, is "Do we need to deliver all three 'pillars' to the transplantation site?" The paracrine effect of stem cells known from myocardium infarction studies [6 ] questions the need for adding growth factors, which are often expensive and can be rapidly degraded in big wounds. On the other hand, some papers are highlighting enhancement of endogenous stem cells by the use of conditioned media as a novel and alternative therapy [7,8 ]. It is not known whether secretomes from cell culture media can safely replace factors produced by cells in their in vivo microenvironment.
Importance of signals directing regeneration remains a focus of a number of current studies. A recent study [9 ] in mice, defining a lineage tree of a population of postnatal skeletal stem cell (SSC) and progenitors, identifies niche factors determining bone cells' fate. The SSCs and their progeny differentially express receptors involved in TGF and...