**2. Methodology**

*Clinical Implementation of Bone Regeneration and Maintenance*

protein 2 (BMP-2), attract host cells to a graft and encourage mesenchymal stem cells to differentiate into lineage-committed bone cells. Finally, osteogenicity describes the ability of a bone graft to form bone matrix directly, which can only happen when live cells capable of producing bone matrix are contained within the graft. Bone graft options may contain varying amounts of these properties and are chosen based on the characteristics that the patient needs in order to achieve bone fusion. There are several graft options available, including autograft, synthetic bone substitutes, and allografts. Autologous bone is harvested from the site of surgery in the patient or a second site, such as the iliac crest. It is still considered the gold standard by many surgeons because it can theoretically provide all three vital properties for bone formation, does not provoke an immune response, and has a long history of use. However, the use of autograft bone is associated with several disadvantages such as donor site morbidity, insufficient supply, and variable quality [2, 3]. Up to 30% of patients experience significant donor site morbidity as well as infection risk, increased operative time, blood loss, and the potential for arterial and nerve injury [4]. Additionally, autograft is limited, and the quality may be poor depending on the patient's health. For example, diabetes, low bone mass, and smoking can all increase

the risk of fusion failure as well as intraoperative complications [5].

natural bone, have continued to be a reliable source of grafting material.

Allograft bone is obtained from deceased human donors and has a long history of use. It is readily available in a variety of forms, shapes, and sizes providing surgeons with several graft options suitable for various procedures [12–14]. Allografts can provide up to all three properties necessary for bone formation. For example, mineralized bone allografts have similar osteoconductive properties to autograft while avoiding complications such as donor site morbidity [15]. Some mineralized grafts have been processed to increase desirable characteristics such as increased surface area on which cells can attach as well as increased coefficient of friction to prevent the graft from shifting once implanted. Other allografts, such as demineralized bone matrix (DBM) are both osteoconductive and osteoinductive. To produce DBMs, acid demineralization is used to remove a portion of the mineral component of bone, thus exposing the active signaling proteins necessary to induce new bone formation. The ability of DBMs to facilitate bone healing was demonstrated in clinical applications as early as 1889 when Dr. Nicholas Senn reported using demineralized bone as a vehicle for antiseptics to treat patients with osteomyelitis [16]. However, it was not until 1965, when Dr. Marshall Urist characterized specific proteins trapped within the bone matrix, that it was understood that bone morphogenetic proteins (BMPs) contributed to the osteoinductive property of DBMs [17]. Since the discovery of BMPs, other proteins, such as those associated with angiogenesis, have also been found to contribute to the process of bone healing

Synthetic bone substitutes are designed with the goal of mimicking the natural properties of human bone. They can be comprised of a variety of materials including but not limited to, ceramics, cements, and bioactive glass. These grafts are generally biocompatible, osteoconductive, and may be mechanically similar to bone [6, 7]. This category of graft has typically been manufactured to contain porosity similar to bone, but may lack other desirable surface properties, such as hydrophilicity or a rough surface on which cells can attach. Synthetic bone substitutes have gained popularity due to reduced cost and ready availability; however, they may have mismatched resorption rates compared to bone and generally lack osteogenic and osteoinductive properties [8]. Some synthetics, such as recombinant human BMP-2, depend almost solely upon osteoinductivity and often result in rapid bone formation. However, several studies indicate substantial side effects, including osteolysis, heterotopic bone formation, and swelling/edema [9–11]. While synthetics have improved over the last few decades, mimicking natural bone has proven difficult, and allografts, being

**34**
