An innovate strategy to treat large metaphyseal segmental femoral bone defect using customized design and 3D printed micro-porous prosthesis: a prospective clinical study

Background Large segmental bone defect at the metaphyseal area is still difficult to treat, nowadays, there is a tremendous level of interest in uses of 3D printing technology in orthopaedic surgery. This study was introduced to prospectively confirm the safety and effectiveness of 3D printed micro-porous prosthesis in clinical bone defect reconstruction application. Methods Patients with segmental irregular-shaped bone defect of the femur were recruited from 2017.12 to 2018.11. The first stage of the treatment involves radical debridement of all infected or non-viable bone and interposed fibrous tissue, and temporary fixation. Once the culture and biopsy results were negative, the PMMA spacer should remain in the defect approximately 6-8 weeks. This period is for the membrane formation, virtual surgery (computed tomography (CT) scan of the lesion area and the contra-lateral parts of the femur, and then design of the implant). The second stage involves reconstruction the defects with the 3D printed micro-porous prosthesis combined with intra-medullar nailwithout bone graft.Routine clinical follow-up and radiographic evaluation were done to assess bone incorporation and complications of internal fixation. The weight-bearing time and the joint function were recorded. Result 5 consecutive patients were included in the study. They were followed up for an average of 16.4 months. The average length of bone defect and the distal residual bone was 12 cm and 6.5 cm. The average time of partial weight-bearing and full weight-bearing was 12.7 days and 2.6 months. X-ray demonstrated good osseous integration of the implant/bone interface. No complications occurred such as implant loosening, subsidence, loss of correctionand infection. At the last follow-up, Harris score of hip joint was excellent in 2 cases, good in 2 cases, fair in 1 case; HSS score of knee joint was good in 4 cases, middle in 1 case.


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Conclusion Meticulous customized design 3D printed micro-porous prosthesis combined with intramedullary fixation may be a cost-effective and an alternative strategy to treat metaphyseal segmental irregular-shaped femoral bone defect without bone graft, especially for cases with massive juxta-articular bone loss.

Background
Trauma and infection are the main causes of clinical bone defect [1], large segmental bone defect of limb extremities is difficult to treat because of its large span, different shape and serious damage to local mechanical stability [2,3], especially at the metaphyseal area. There are many methods to treat bone defect of limb extremities, such as bone transport through distraction osteogenesis, Masquelet membrane induction, autogenous bone transplantation and artificial bone transplantation, but all these traditional methods have shortcomings such as long treatment cycle, unable to bear weight early, high medical cost and even unsatisfactory treatment effect.
Attias et al [4] reconstructed a long segmental defect with a cylindrical titanium mesh cage packed with bone graft and stabilized with limited contact dynamic compression plates. This metal inner support improved immediate stability, however it still needed massive bone graft. Nowadays, there is a tremendous level of interest in uses of 3D printing technology in orthopaedic surgery [5,6], especially in the realm of adult reconstructive surgery [7] and joint arthroplasty [8]. And it is rapidly permeating every aspect of orthopaedic surgery, such as trauma [9], spine [10], hand [11] and tumor [12].
These implants are custom designed by 3D printing technology with the cooperation of orthopaedic surgeons, orthopaedic engineers and biomedical engineers. The possibility of patient custom 3D printed implant has opened new alternative for complex post traumatic limb reconstruction. Such novel strategy may also be used to address the extremely difficult problem of segmental bone defect [13]. However, a composite of cancellous allograft and demineralized bone matrix putty may still be needed in most of the literature [14]. Xu and Liu et al [15] reported that application of 3D printing prosthesis in the treatment of defects caused by spinal tumors has achieved good results. These printed prostheses have achieved good bone ingrowth without any bone graft. Our animal experiments [16] also showed that good bone ingrowth around the prosthesis without any bone graft. So, we have innovatively improved this technique and assumed the 3D printing microporous titanium prosthesis combined membrane induction and intramedullary fixation could successfully treat large bone defect without bone graft.
This study was introduced to prospectively confirm the safety and effectiveness of 3D printed micro-porous prosthesis in clinical bone defect reconstruction application at the metaphyseal part of femur. This study is support by Beijing Municipal Science & Technology Commission. Several patients of distal femoral irregular-shaped bone defect have been treated successfully. And our cases showed that biomechanical and biological induction can stimulate local osteogenesis at the prosthetic-bone interface without bone grafting. We will address virtual surgical planning and implant design considerations, indicating how this strategy could be successfully introduced into clinical practice.

Patients
This was a prospective clinical study conducted at our hospital between 2017.12 and 2018.11. In this study, patients were recruited for 3D printed microporous titanium prosthesis combined with intramedullary fixation without bone graft based on the indications and contraindications as follows according to our limited experience, and few other reports in the literature [17].

First-stage Surgical procedure
The patients had undergone radiography of the leg pre-and post-operatively, a radionuclide scan is required if infection is suspected. The first stage involves radical debridement of all infected or non-viable bone and interposed fibrous tissue. The proximal bone/implant interface was cut smoothly, while deal with the distal bone/implant interface, we preserve the non-infected living bone as much as possible, not caring the contour profile. The femur is stabilized with external fixation, or if the defection is noninfectious, we would preserve the original internal fixation. The antibiotic cement spacer is used to fill the voids and the spacer should be configured to mimic the size and shape of the original bone that is to be reconstructed, following the principle of ''replace like with like''. The temporary construct must be rigid enough to facilitate early mobilization.
Adequate soft-tissue coverage could ensure wound healing. Vacuum wound drainage can be used to cover the wound in the early stage of debridement. Once the culture and biopsy results were negative, the wound was deemed clean and ready for reconstruction.
The PMMA spacer should remain in the defect approximately 6-8 weeks. This intervening period is for the membrane formation, virtual surgery and planning for secondary reconstruction.

Implant design
Each patient had consented for use of a custom-designed, patient specific 3D-printed titanium implant by Shandong Weigao Orthopaedic Device Company Limited. combined with additional internal fixation. The patients were sent for a computed tomography (CT) scan of the lesion area and the contra-lateral parts of the femur for preoperative planning after debridement. Once the CT images of the patient's irregular-shaped bone defect anatomy were available, the manufacturer initiated the design team through the medicalworker interaction platform. The surgeon is invited to provide recommendations for fixation desires. Each product is particular for its personalized design.
The design of the implant must take into consideration a number of critical factors include mechanical, anatomical and functional aspects that are unique to each case to allow the composite construct to successfully incorporate. The prosthesis adopts normal dodecahedron element micro-pore design, with porosity of about 70%, pore size of (625 ± 70) µm, elastic modulus of (1200 ± 48) MPa and compressive strength of (66 ± 0.5) MPa.
The micro-porous designed interface may provide not only torsional resistance, but also limits the potential for shear across the bone/implant interface. We usually use intramedullary (IM) nail to finish definitive fixation of the bone/implant composite, as it provides immediate stability. IM nails are highly constraining devices and require the bones to be positioned and aligned correctly during both the virtual and the actual procedure. So, the prosthesis is hollow to mimic the medullary cavity and its diameter is 1.0-1.5 mm larger than that of intramedullary nail for easy insertion of the nail, for our design is a fixation model of prosthesis combined with anterograde or retrograde intramedullary nail. The shape of the prosthesis must respect the original anatomy and configuration of bone. For long bone defects, juxta-articular sides have an irregularshaped metaphyseal side, and diaphyseal sides are more cylindrical. Doing so limits the potential for soft tissue impingement, retain more living bone, especially the supracondylar part of the femur. Also, the size of prosthesis should be just equal or smaller than that of residual proximal and distal bones, which do not affect bone tissue crawling. If the distal end of the prosthesis is too close to the knee joint or the distal residual bone quality is poor, it is necessary to print a lateral plate, which is 3.5-4 mm thick, and is connected with the prosthesis reinforcement to ensure strength, and 6.5 mm cancellous bone screw should be used for fixation, the design of screw hole should avoids interference with intramedullary nail locking screw. Furthermore, the 3-D configuration of the implant must be designed to allow it to be successfully implanted through the planned surgical exposure.
Once a design has been reached, a schematic is sent to the surgeon with hardware projections and dimensions. Supplemental hardware such as trial-sizing implants, trial implant replica, and directional guides are also designed at this time. The implant is manufactured after the surgeon has approved the implant. The prosthesis is printed by electron beam melting augmentation manufacturing equipment, and then support dispel, local polishing, clean, package, and then deliveded to the healthcare institution for inspection by the surgeon. Finally, the implant is sterilized before implantation.

Second-stage Surgical procedure
The second stage follows an interval of approximately 6-8 weeks, to allow the membrane to adequately develop. Of course, this will depend on the soft tissue, the physiologic quality of the patient. At this point the defect site is ready for definitive reconstruction with a custom mircro-porous implant placed into the induced membrane. The reconstruction must include intramedullar nail. The second stage is followed by physiotherapy including immediate unrestricted ROM exercises, and progression to full weight bearing (FWB) over 4-12 weeks.

Observation index
Routine clinical review is conducted at intervals with plain radiographs to assess graft incorporation and to confirm restoration of skeletal continuity. The weight-bearing time of the patients was recorded, and the corresponding scoring system was used to evaluate the joint function after operation.

Results
All 5 patients were treated from 2017.12 to 2018.11. The patient demographic data are presented in the Table 1. The average age of the 5 patients was 52.6 years. There were 2 males and 3 females. 5 patients were followed up for an average of 16.4 months. The causes of bone defect were infection in 4 cases ( Figure 1) and trauma in 1 case (Figure 2). The length of bone defect was 8.5-15.5 cm (average 12 cm), the length of distal residual bone was 3.7-12 cm (average 6.5 cm). The average time of partial weight-bearing was 12.7 days. The average time of full weight-bearing was 2.6 months. All patients had good stability after operation.
No complications such as looseness and infection of internal fixation occurred. At the last follow-up, Harris score of hip joint was excellent in 2 cases, good in 2 cases, fair in 1 case, excellent and good rate was 80%; HSS score of knee joint was good in 4 cases, middle in 1 case, good rate was 80%.

Discussion
Segmental bone loss further complicates attempts at reconstruction after severe initial injury, it is often arduous for both surgeon and patient [18]. The distal metaphyseal part of femur is a cylindrical-like structure with gradually enlarged distal diameter and irregular shape. Segmental bone loss at this area is difficult to handle for the difficulty in reconstruction to its normal irregular shape, large demand of bone graft to achieve union and poor stability to allow weight bearing at the early stage, especially when there is less bone residual near the articular surface. Traditional methods such as bone lengthening, Masquelet membrane induction and autogenous bone graft, may need a long treatment period and unable to bear weight at early time. In recent years, the application of 3D printing technology in patient-specific orthopedics has developed rapidly. Introducing 3D printing technology into the treatment of irregular bone defect could rapidly realize anatomical reconstruction of bone defect, achieve mechanical conduction similar to original bone and promote bone/prosthesis osteogenesis, finally achieve relative stability fusion of bone/prosthesis interface. There are some key points of this innovative method to successfully treat segmental bone defect.

Reconstruction of mechanical stability and force conduction
We use the following methods to obtain the local early mechanical stability. of (1200 ± 48) MPa and compressive strength of (66 ± 0.5) MPa). 5) A lateral plate may be added at the distal end of the prosthesis according to the residual bone of the femoral condyle and can be fixed with screw to increase the stability of the prosthesis. Our structural design experience is shown in Fig. 3. All of the above factors may facilitate early weight-bearing and functional exercise, and help patients recover social function as soon as possible. Our case demonstrated a relative short weight-bearing time, which is 12.7 days for partial weight-bearing and 2.6 months for full weight-bearing, with good joints function nearby.

Factors promoting the osteogenesis of the defection region
Fracture healing depends on local mechanical stability and good biological environment [19], but for our study it is prosthesis-osseo-integration. Our previous experiments [20] have proved that bone tissue can grow well into the pore of 3D printed metal prosthesis From our cases observation, we found that osteogenesis occurred at the contact end of the bone and prosthesis, callus gradually increased, and crawled along the periphery of the prosthesis and around the contact surface of the prosthesis. Radiographies showed no complications such as implant loosening or subsidence, and our animal experiments [16] showed that osteogenesis was fully inserted into the prosthesis and crawled from both ends into the pore of the prosthesis.
There are limitations inherent in this approach. First of all, the number of patients is still small, more cases are needed to find the healing rules between prosthesis and bone.
Secondly, we are not sure whether the intramedullary nail can be removed to observe the settlement between the prosthesis and bone. Thirdly, Titanium printed prostheses may have limited osteo-inductive ability, filling the porous structure of the prostheses with inducible drugs and factors is likely to achieve the effect of controlling infection and accelerating bone healing. Finally, these devices are not biodegradable. Further research is still needed.

Conclusion
3D printing technology could help to reconstruct local anatomy rapid, restore local biomechanical strength to allow early weight-bearing and exercise, which is beneficial for social function recovery. Biomechanical stimulation combined with biological induction may stimulate osteogenesis, achieve bone growth and stability at the bone/prosthesis interface, and greatly reduce the need for bone graft. Form our study, meticulous custom designed 3D printing technique of micro-porous prosthesis combined membrane induction and intramedullary fixation may be a cost-effective strategy to treat large metaphyseal femoral irregular-shaped bone defect without bone graft. This may be an alternative treatment for metaphyseal segmental bone defects, especially for cases of massive juxtaarticular bone loss.