**1. Introduction**

Extensive bone defects can occur after severe trauma, infection, or bone tumor resection, and in some cases require bone tissue reconstruction. Therefore, auto/allografts and artificial materi‐ als are implanted. Materials currently used for bone tissue reconstruction include autologous bone tissue, such as the ilium and fibula, and allogeneic materials, such as cryopreserved bone, titanium alloys, and bioactive ceramics [1]. Each of these has distinct advantages, but they also have various disadvantages or problems that remain to be solved.

The autologous bone is the most effective material for small bone defects and is characterized by strong bone-forming ability, accompanied by the capability of bone union and remodeling capacity. However, it has disadvantages, including limitations in the collectable quantity and complications after collection, such as pain, infection, fracture, deformation, and risk of damage to major nerves or blood vessels. The use of allogeneic bone is associated with low bone-forming ability; potential transmission of infectious agents; and cost problems, including cleanliness management. Disadvantages of the heterologous bone include possible transmis‐ sion of animal infections and immunological rejection in addition to those listed for allogeneic bone [2–4].

Although artificial materials offer the advantages of easy access and processing, they are usually incapable of practical bone formation and thus are ineffective for bone regeneration in large bone defects. It is difficult to reconstruct relatively large bone defects in a shape that is anatomically similar to the normal structure.

Scaffolds, growth factors, and cells represent three key elements in regenerative medicine. An ideal approach for bone repair with regenerative medicine technology should have the abilities of osteogenesis, osteoconduction, osteoinduction, and osteointegration to resolve the disad‐ vantages of currently available graft materials. Biocompatible and biodegradable scaffolds include those made of biological materials, such as type 1 collagen and demineralized bone, and of synthetic (artificial) materials, such as porous metals, bioactive glass, synthetic poly‐ mers, and calcium phosphate ceramics [hydroxyapatite (HA) and tricalcium phosphate (TCP)] [5].

Among bone morphogenetic proteins (BMP), recombinant human BMP (rhBMP)-2 and -7 are potent osteoinductive cytokines and are clinically used as graft materials in spinal fusion, pseudarthrosis after long bone fractures, repeated posterolateral fusion, and treatment of open fractures of the tibia in some countries, such as European countries and the United States. We expect that they will find increasing application in bone-regenerating medicine because of their high rates of bone union and their simplicity and minimal invasiveness (i.e., bone harvesting is not required) [6–8].

Recent advances in computer-assisted techniques have led to computer-assisted preoperative planning, custom production of surgical implants using patient data, and use of navigation systems in orthopedics. Examples include three-dimensional (3D) printing-based preoperative planning, in which 3D printing of the relevant bone is performed before a trauma patient undergoes surgery and plates to be used are templated with the reference to the simulated bone so that no intraoperative plate bending maneuvers are required. Furthermore, the prebent plate itself serves as a reduction indicator, and accurate corrective osteotomy procedures for malunited fractures are prepared for each patient using osteotomy guides [9, 10]. In addition, the use of navigation systems has been reported to be useful in joint surgery, for example, for accurate installation of artificial joint components, safe and accurate insertion of pedicle screws in spinal fusion, and resection of musculoskeletal tumors [11–13].

These computer-assisted imaging technologies might be applicable for repair of large bone defects that result from wide resection of malignant musculoskeletal tumors. In those cases, the decision regarding optimal resection margins should be based on 3D computed tomogra‐ phy (CT) or/and magnetic resonance imaging (MRI) data to avoid exposure of the tumor tissue to the surgical field and late local recurrence of the tumor, and the image data would be applicable to surgical procedures using computer-assisted navigation surgery (CAS) system. Image data of the virtual bone defect in the computer-aided design (CAD) would be used to fabricate a porous HA block implant with computer-assisted manufacturing system (CAM) to fill the bone defect. To add osteoinductive capacity to the HA implant to accelerate bone defect repair, a cytokine rhBMP-2 with potent osteoinductive capacity retained in its dough-like delivery system is pasted on the HA surface during implantation.

In this study, we investigated the feasibility of computer-assisted technology (CAD, CAM, and CAS) for preoperative surgical planning and corrective surgical procedures to resect a virtual tumor and fabricate an HA implant. Another aim was to estimate the efficacy of rhBMP-2 and its delivery system to promote repair of a large bone defect without bone grafting in a beagle model.
