Osseointegrated oral implants are an integral part of modern reconstructive dentistry and are associated with favorable long-term therapeutic outcomes [1]. Osseointegration was originally defined as the direct contact between vital bone and a load-bearing implant observed at the light microscopic, i.e., histological, level [2]. Morphogenesis of implant osseointegration has been assessed in several preclinical in vivo and clinical histological studies [3-6], providing the basis for understanding the biological process.

The biological events during the early phase of osseointegration are directly influenced by the osseous microenvironment (i.e., cells, signaling molecules, and matrix) into which the implant is placed and have many similarities with general wound healing mechanisms [7]. Implant surgery induces trauma, resulting in bleeding and fibrin clot formation and an inflammatory reaction that dominate the events of the first post-operative week. The deposition of vital new bone on the implant surface by osteoblasts (osteogenesis), a fundamental requirement for osseointegration, occurs via secretion of a complex extracellular matrix (ECM) of proteins, which subsequently undergoes mineralization to form bone [8,9]. Primary (woven) bone lined by osteoblasts can indeed be observed on the implant surface already after 1 week [3,5]. In parallel, removal of the created bone debris and remodeling of necrotized bone (due to the pressure exerted by the implant) is underway. Replacement of woven bone by organized and mechanically superior lamellar bone can be observed from the second to fourth week (depending on the species) and progressively increases until woven bone is almost entirely replaced (8 to 12 weeks). These events, including the nutrition of the newly formed tissue, are sustained through concomitantly occurring angiogenesis, i.e., formation of new blood vessels from existing ones [10,11]. Thus, osseointegration is a dynamic process whereby bone formation and remodeling occur in parallel around the implant [4,6].

Morphogenesis of osseointegration and assessment of the degree of bone-to-implant contact is usually performed by means of histological evaluation [12], while the underlying molecular processes may be more precisely evaluated at genetic level [13,14]. Data from gene expression analyses of fracture healing provide the basis for understanding these processes [15]. These studies have identified the cells, signals, and interactions governing the key processes of bone regeneration. Bone-forming osteoblasts are primarily derived from marrow-resident multipotent progenitor cells (mesenchymal stem cells (MSCs)), which are recruited to the regeneration site. This process of MSC recruitment and differentiation along the osteogenic lineage is termed as osteoinduction and is controlled primarily by various pro/anti-inflammatory cytokines (CKs) and by growth factors (GFs) secreted by inflammatory cells and/or osteoblasts or by GF resident within the extracellular matrix (e.g., bone morphogenetic proteins (BMPs)) in response to injury [16-18]. Moreover, CKs and GFs act as signaling molecules via specific signaling pathways and guide the process of cell differentiation in the proper temporal sequence [19,20]. Intermediaries in this process are various bone-specific transcription factors (TFs), which act as ‘molecular switches’ during cell differentiation and are targets of CKs and GFs [21]. TFs facilitate bone-specific gene transcription and ultimately gene expression by which MSCs undergo differentiation and acquire the osteoblastic phenotype [22]. While GFs regulate mainly osteoinduction and osteogenesis, pro-inflammatory CKs regulate the antagonist process of bone resorption by inducing the differentiation of hematopoietic stem cells (HSCs) into osteoclasts and macrophages [23], contributing to the dynamic nature of bone regeneration and remodeling.