Objectives. To explore the therapeutic potential of combining bone marrow-derived mesenchymal stem cells (BM-MSCs) and hydroxyapatite (HA) granules to treat nonunion of the long bone. Methods. Ten patients with an atrophic nonunion of a long bone fracture were selectively divided into two groups. Five subjects in the treatment group were treated with the combination of 15 million autologous BM-MSCs, 5g/cm. 3. (HA) granules and internal fixation. Control subjects were treated with iliac crest autograft, 5g/cm. 3. HA granules and internal fixation. The outcomes measured were post-operative pain (visual analogue scale), level of functionality (LEFS and DASH), and radiograph assessment. Results. Post-operative pain evaluation showed no significant differences between the two groups. The treatment group demonstrated faster initial radiographic and functional improvements. Statistically significant differences in functional scores were present during the first (p = 0.002), second (p = 0.005) and third (p = 0.01) month. Both groups achieved similar outcomes by the end of one-year follow-up. No immunologic or neoplastic side effects were reported. Conclusions. All cases of nonunion of a long bone presented in this study were successfully treated using autologous BM-MSCs. The combination of autologous BM-MSCs and HA granules is a safe method for treating nonunion. Patients treated with BM-MSCs had faster initial radiographic and functional improvements. By the end of 12 months, both groups had similar outcomes. Cite this article: H.D. Ismail, P. Phedy, E. Kholinne, Y. P. Djaja, Y. Kusnadi, M. Merlina, N. D. Yulisa. Mesenchymal stem cell implantation in atrophic nonunion of the long bones: A translational study. Bone Joint Res 2016;5:287–293. DOI: 10.1302/2046-3758.57.2000587

Introduction. We have investigated middle-term clinical results of total hip arthroplasty (THA) cemented socket with improved technique using hydroxyapatite (HA) granules. IBBC (interfacial bioactive bone cement method, Oonishi) (1) is an excellent technique for augmenting cement-bone fixation in the long term. However, the technique is difficult and there are concerns over some points, such as bleeding control, disturbance of cement intrusion to anchoring holes by granules, difficulty of the uniform granular dispersion to the acetabular bone. To improve the original technique, we have modified IBBC (M-IBBC), and investigated the middle-term clinical results and radiographic changes. Materials and Methods. K-MAX HS-3 THA (Kyocera, Japan), with tapered cemented stem with small collar and all polyethylene cemented socket, was used for THA implants (Fig.1). Basically the third generation cementing technique was used for THA using bone cement. The socket fixation was performed with bone cement (Endurance, DePuy) and HA granules (Ca10(PO4)6(OH)2, Boneceram P; G-2, 0.3–0.6mm in size, Olympus, Japan) (Fig.2). In original IBBC technique, HA granules were dispersed on reamed acetabulum before cementing. In M-IBBC technique, HA granules were attached to bone cement on plastic plate, then inserted to reamed acetabulum and pressurized (Fig.3). 112 hip joints (95 cases) were operated between June 2010 and March 2014, and followed. The average follow-up period was 6.5 years, and average age at operation was 66.5 years. The clinical results were evaluated by Japan Orthopaedic Association Hip Score (JOA score), and X-p findings were evaluated using antero-posterior radiographs. The locations of radiolucent lines were identified according to the zones described by Delee and Charnley for acetabular components, and Zone 1 was divided into two parts, outer Zone 1a and inner Zone 1b. Results and Discussion. Revision was not performed. JOA score improved from 47 to 88. Socket and stem loosening was not observed. X-p findings of sockets demonstrated radiolucent line in Zone 1a/1b/2/3 in 0.9/0/0/0% immediately after the operation, 6.3/1.8/0/0.9% at 2 years postoperatively. After 2 years there was no progressive change, however, improvement of radiolucent line in Zone 1a was observed in two cases after 3 years postoperatively. Accordingly, at 5 years radiolucent line in Zone 1a/1b was observed in 4.4/1.8%. Oonish has reported excellent clinical results of THA with IBBC (1). To easily perform IBBC, we have modified the technique, improving the problems of IBBC. In this study, radiolucent line was observed at the margin of the socket in a small number of cases, and there was no progressive change. In addition, improvement of radiolucent line was observed in M-IBBC in this study, which was not observed in conventional cementing technique. Conclusions. It is demonstrated that M-IBBC provides stable socket cement fixation for THA. The interesting finding in M-IBBC cases was the improvement of radiolucent line, suggesting osteoconductive property of hydroxyapatite granules at the interface after the operations. The promising long-term clinical results of M-IBBC method, were expected. For any figures or tables, please contact the authors directly

Between 1993 and 2003, 67 consecutive revision total hip arthroplasties were performed in 65 patients, including 52 women and 13 men, using hydroxyapatite (HA) granules supported by a Kerboull-type reinforcement acetabular device. The average age at the time of index surgery was 68.6 years. The Acetabular bone loss according to the American Academy of Orthopaedic Surgeons (AAOS) system was type II for 7 hips, type III for 58 hips, and type IV for one hip. The Kerboull-type acetabular reinforcement device used was Kerboull Cross Plate in 18 hips and KT Plate in 49 hips. HA granules of sizes 0.9 to1.2 mm (G4) and 3.0–5.0 mm (G6) were mixed in a ratio of 1:1. Autografts were used to reconstruct the major segmental defects in 7 hips. At the time of this study 30 hips were lost of follow-up. Among 30 hips 22 hips were lost of follow-up because of the death of the patients. The remaining 37 hips were examined clinically and radiologically. The mean follow-up period of the series was 12.8 years. Complications were examined and clinical evaluation was done using Japanese Orthopaedic Association (JOA) hip score. The criterion for loosening of the acetabular component was cup migration exceeding 3 mm or angular rotation exceeding 3 degrees or breakage of the device. Among the entire series of 67 hips postoperative complications included dislocation in 3 hips, infection in 2 hips and revision in 4 hips. Two hips were revised for loosening and the other two hips were revised for infection. The JOA hip score increased from a mean value of 48.0 preoperatively to 76.8 at the last follow-up. Radiologically 5 hips were loose. Two hips among them were revised. Survival rate of the acetabular component at 10 years was 97.1% using acetabular revision for loosening as the end point and 90.6% using radiological loosening as the end point. Acetabular reconstruction with HA granules and a Kerboull-type acetabular device provided satisfactory clinical and radiographic results at 12.8 post-operative years

We have used Interface Bioactive Bone Cement (IBBC) in all cases of total joint arthroplasties since 1987. The method is improved cement technique by interposing less than two layers of hydroxyapatite (HA) granules between bone and the polymethylmethacrylate (PMMA) bone cement. We report one patient who underwent revision surgery after total knee arthroplasty (TKA) using IBBC. The patient is a woman aged 70 years at the time of revision surgery. Right TKA was performed with the diagnosis of rheumatoid arthritis. An alumina ceramic total knee prosthesis was inserted using IBBC. Pain and walking ability were once improved after the primary TKA. However, the gait disturbance recurred after the patient fell on the ground. Radiographic findings showed severe genu varum, but neither radiolucent lines around the components nor migration of the components were seen. This was revised with semiconstrained prosthesis for the purpose of improving lateral instability at 31 months after the primary TKA. Avulsion of fibular attachment of collateral ligament was seen at the time of the revision surgery. As PMMA cement was strongly adhered to the bone, it was removed together with cancellous bone. Histologically, HA granules bound to the bone directly after bone ingrowth into the spaces around the HA granules. This is the reason we have described IBBC as a method having the both advantages of cementless HA coating and PMMA bone cement. After the revision surgery, the walking ability was improved. In conclusion, this case showed excellent characteristics of IBBC

Purpose. One of the drawbacks of cemented total hip arthroplasty (THA) is aseptic loosening after long period, major reason for which is bioinertness of PMMA bone cement. To improve longevity of THA, interface bioactive bone cement (IBBC) technique which is characterized with smearing hydroxyapatite (HA) granules just before cementation has been used in our institute. Objective. Smooth-surfaced triple-tapered Titanium-alloy stem (T) and Exeter stem (E) have been used consecutively in the different period. Objective of the present study was thoroughly comparing two stems clinically and radiologically. Method. The present study includes 38 hips of T and 40 hips of E. Mean postoperative follow up period was 7.7 years for T and 6.2 years for E. Radiolucent line (RL) was determined as clear line with sclerotic demarcation and cancellisation as without it. Results. Pre- and postoperative evaluation using Merle d'Aubigné score were 8.1 (2.2, 2.2, 3.7) and 16.0 (6.0, 5.2, 4.8) points for T and, 8.1 (2.2, 2.2, 3.7) and 16.4 (6.0, 5.6, 4.8) for E, respectively. Postoperative cementing grade using Barrack's classification was classified as A for 30 hips in T and 39 hips in E, and as B for 8 hips in T and 9 hips in E. Neither osteolysis nor loosening was observed in both groups. No RL at bone-cement interface, focal osteolysisã, cement fracture was observed. Cortical hypertrophy (CH) was observed in 7 hips of T and 5 hips of E (NS). Cortical hypertrophy (CH) localized beyond stem tip was observed in all hips of T (Figure 1) and in 1 hips of E (Figure 2) (p < 0.05). Cancellisation was observed in 17 hips of T and 16 hips in E (NS). Conclusion. The present study revealed excellent medium-term result was obtained using both stems fixed with IBBC technique. CH was observed more distally in T compared with E

Introduction. IBBC (interfacial bioactive bone cement method, Oonishi) (1) is an excellent technique for augmenting cement-bone fixation in the long term. However, the technique is difficult and there are concerns over some points, such as bleeding control, disturbance of cement intrusion to anchoring holes by granules, difficulty of the uniform granular dispersion to the acetabular bone (Zone 1 in particular). To improve this technique, we have modified IBBC (M-IBBC), and investigated the short-term clinical results and radiographic changes. Materials and Methods. K-MAX HS-3 THA (Kyocera Medical, Japan), with cemented stem and all polyethylene cemented socket, was used for THA implants. Basically the third generation cementing technique was used for THA using bone cement. The socket fixation was performed with bone cement (Endurance, DePuy) and hydroxyapatite (HA) granules (Ca10(PO4)6(OH)2, Boneceram P; G-2, Olympus, Japan). In original IBBC technique, HA granules were dispersed on reamed acetabulum before cementing. In M-IBBC technique, HA granules were attached to bone cement on plastic plate, then inserted to reamed acetabulum and pressurized. HA granules (G-2) are 0.3–0.6mm in size, with 35–38% porosity and sintered at 1150â��. 51 hip joints (49 cases) were operated between June 2010 and December 2011, and followed. The average follow-up was 3.9 years, and average age at operation was 66.5 years. The clinical results were evaluated by Japan Orthopaedic Association Hip Score (JOA score), and X-p findings were evaluated using antero-posterior radiographs. The locations of radiolucent lines were identified according to the zones described by Delee and Charnley for acetabular components, and Zone 1 was divided into two parts, outer Zone 1a and inner Zone 1b. Results and Discussion. Revision was not performed. Japanese orthopaedic association (JOA) score improved from 48 to 87. Socket and stem loosening was not observed. X-p findings of sockets demonstrated radiolucent line in Zone 1a/1b/2/3 in 2/0/0/0% immediately after the operation, 9.8/2/0/2% at 1 year postoperatively. After 1 year there was no progressive change, however, improvement of radiolucent line in Zone 1a was observed in two cases after 3 years postoperatively. Accordingly, after 3 years radiolucent line in Zone 1a/1b was observed in 5.9/2%. Oonish has reported excellent clinical results of THA with IBBC (1). To easily perform IBBC, we have modified the technique, improving the problems of IBBC. In our previous report, we reported improvement of radiolucent line in IBBC (2). In this report, the similar radiographic behavior was observed in M-IBBC, which was not observed in conventional cementing technique. This finding suggests osteoconductive property of hydroxyapatite granules at the interface after the operations. Conclusions. The interesting finding in M-IBBC cases was the improvement of radiolucent line, which was observed in IBBC cases. The promising long-term clinical results of M-IBBC method, similar to IBBC cases, were expected

Purpose. We have compared the short-term clinical results of total hip arthroplasty (THA) using PMMA bone cement and hydroxyapatite (HA) granules (interfacial bioactive bone cement method; IBBC) with the results of conventional method using PMMA bone cement. Materials and Methods. K-MAX HS-3 THA (JMM, Japan), with cemented titanium alloy stem and all polyethylene cemented socket, was used for THA implants. The third generation cement technique was used for the conventional THA (Group C) using bone cement (Endurance, DePuy). In the IBBC group (Group BC), the socket fixation was performed by the third generation cement technique with HA granules (Boneceram P; G-2, Olympus, Japan) according to the Ohnishi's method. In both groups, the stems were fixed by conventional cementing technique using cement gun. 76 hip joins (69 cases) were operated between April 2005 and August 2007, and followed. The group C (22 hips, 19 cases, average follow-up; 5.6 years, average age at operation; 64 years) and the group BC (54 hips, 50 cases, 5.4 years, 65 years) were investigated. Results. One revision was performed in BC group due to late infection. Japanese orthopaedic association (JOA) score improved from 42/48 to 85/87 in Group C/BC. Socket loosening was not observed radiographically. X-p findings of Group C/BC demonstrated radiolucent line in the outer part of Zone 1 in 18%/16% immediately after operation, 24%/23% at 2 years postoperatively. After 2 years there was no change in Group C, however, improvement of radiolucent line (gap filling) with bone remodeling was observed in two cases in Group BC at 3 years postoperatively. Conclusions. The short-term clinical results of Group BC using IBBC method and Group C using conventional method were equally satisfactory. The interesting finding in Group BC case was the improvement of radiolucent line (gap filling), suggesting osteoconductive property of hydroxyapatite granules at the interface after the operations. The promising clinical results of IBBC method in the long term were expected

Improved cement technique by interposing less than two layers of hydroxyapatite (HA) granules between bone and bone cement at the cementing (Interface Bio-active Bone Cement : IBBC) have been performed in total knee arthroplasty (TKA) since 1987. We performed IBBC technique in 153 knees (130 patients) in TKA from 1987 to 1993. One hundred and forty knees (120 patients) could be followed up clinically and radiologically. Follow up rate was 91.5%. A mean follow-up period was 9.5 years (6 to 13 years) after surgery. As a control, clinical results of TKA with conventional cementing (Non-IBBC) which were operated in 44 knees (44 patients) in 1986 were used. In IBBC cases, radiolucent lines on the tibial components were seen 7.1%, 2.9%, 1.4%, 3.6%, 0%, 0% and 0% at Zone ‡T to ‡Z of the anteroposterior view, while in Non-IBBC cases, 40.9%, 13.6%, 9.1%, 27.3%, 11.4%, 4.5% and 13.6% at Zone ‡T to ‡Z, respectively. In IBBC cases peri-prosthetic osteolysis of the tibial components were seen in three knees (2.1%), while 29.5% in Non-IBBC cases. Aseptic loosening of the tibial component was only one case (0.7%) in IBBC cases, while 9.1% in Non-IBBC cases. In IBBC, bone cement bound to HA mechanically immediately after surgery and HA granules bound to the bone physicochemically after bone ingrowth into the spaces around the HA granules. In Non-IBBC, spaces will appear between bone and bone cement due to osteoporosis and/or atrophy after long years. However, in IBBC, bone and bone cement will contact by interposing HA forever due to osteoconductive effect of HA. In conclusion, the IBBC has significantly reduced the incidence of radiolucent lines and periprosthetic osteolysis in TKAs. IBBC is a method combining the advantage of cementless HA coating and bone cement

INTRODUCTION. We have conducted interface bioactive bone cement method (IBBC) in total hip arthoplasty (THA) to prevent generation of connective tissue and osteolysis for the longevity of cemented THA since 1985, in which non-resorbable crystalline osteoconductive hydroxyapatite (HA) granules were interposed on the interface between bone and bone cement. To prevent the patients from infection, we use HA granules impregnated with antibiotics. However, there have been no reports on the loading and release of antibiotics from fine granules of HA. Here, we have investigated the loading of antibiotics on HA and their release in vitro. MATERIALS AND METHODS. HA was impregnated with antibiotics such as flomoxef sodium (F), vancomycin hydrochloride (V) cefotiam dihydrochloride (C) and cefozopran hydrochloride (CE) under normal or reduced pressure. After washing with PBS three times, HA loaded with the antibiotic was placed in PBS. An aliquot of solution was sampled at appropriate time intervals and the amount of the released antibiotic was estimated based on the anti-bacterial activity. RESULTS AND DISCUSSION. When drug loading was done by dropping antibiotic solution to HA granules, the amount of antibiotic released from 20 mg of HA was 16 μg for F, 0 μg for V, 13 μg for C and 65 μg for CE. The release of F continued for 48 hrs and that of V and CEcompleted within 24 hrs. On the other hand, when antibiotics loading were conducted under reduced pressure, the amount of released antibiotic was 14 μg for F, 0 μg for V, 0 μg for C and 1670 μg for CE. The burst release was observed for CE and F, and the release of them completed in 24 hrs. Then, the release of C and CE was observed in 0.025 M EDTA solution after the antibiotic was loaded under pressure. Observation was done for 19 days, at which one third of HA was dissolved. After 40 μg of burst release, the release of C continued for 19 days, at which the total amount of C released was 122 μg. Meanwhile, the release of CE continued over 19 days, during which 3350μg of CE was released after the burst release of 3280 μg. Thus, CE seemed the most suitable antibiotic for our purpose. The burst release of CE absorbed in HA following the issue of CE surrounding the HA granules on the interface of bone and bone cement is very effective for the protection of early infection after joint replacement

INTRODICTION. Since 1985, not resorbable crystalline osteoconductive hydroxyapatite (HA) granules were interposed on the interface between bone and bone cement at the cementation (Interface Bioactive Bone Cement: IBBC) of total hip arthoplasty (THA) to prevent generation of connective tissue and osteolysis for the longevity of cemented THA. To prevent the patients from infection, we are planning to use b-tricalcium phosphate (Beta-TCP) impregnated with antibiotics along with HA granules. However, there have been no reports on the loading and release of antibiotics from fine granules of Beta-TCP. Here, we have investigated the loading of antibiotics on Beta-TCP and their release in vivo. MATERIALS AND METHODS. Beta-TCP was impregnated with antibiotics such as flomoxef sodium (F), vancomycin hydrochloride (V) cefotiam dihydrochloride (C) and cefozopran hydrochloride (CE) under normal or reduced pressure. After washing with PBS three times, Beta-TCP loaded with the antibiotic was placed in PBS. An aliquot of solution was sampled at appropriate time intervals and the amount of the released antibiotic was estimated based on the anti-bacterial activity. RESULTS AND DISCUSSION. When drug loading was done by dropping the antibiotic solution to Beta-TCP granules, the amount of antibiotic released from 20 mg of HA was 8 μg forF, 0 μg for V, 6 μg for C and 520 μg for CE. Their release completed within 24 hrs. When the antibiotic loading was done under reduced pressure, 20 mg of Beta-TCP was loaded with 40 μg ofF, 130 μg of V and 25 μg of C, but the released amount was 16 μg for F, 8 μg for V and 0 μg forC. Each drug was released within 10 hrs. Meanwhile, 8000 μg of CE was loaded on 20 mg of Beta-TCP and its release continued for 6 days. When Beta-TCP loaded with C or CE was placed in 0.25 MEDTA to dissolve Beta-TCP gradually, the release of C and CE sustained over 14 days along with the dissolution of Beta-TCP. The release of C from Beta-TCP continued over 19 days in EDTA. The released amount of C and CE were 116 μg and 7100 μg, respectively. Thus, CE seemed the most suitable for our purpose in terms of the loaded amount and releasing behavior. However, CE as well as C showed the eminent sustained release in EDTA solution. Since Beta-TCP shows bioabsoption, it is expected to be efficient antibiotics carrier. It is worthy to use adequate sizes of Beta-TCP granules impregnated with antibiotics in combination with osteoconductive HA in IBBC for the protection of the infection after joint replacement, especially in revision surgery after infection

In revision total hip arthroplasty (THA), it is essential to cope with the bone stock loss. The acetabular bone loss is reconstructed by bulk bone grafts, bone chips, bone cement or jumbo cup. The impaction bone-grafting (IBG) technique is a technique that can restore acetabular bone loss, while enough bone allografts are not easy to obtain and the quality is not always sufficient. Thus we mixed hydroxyapatite (HA) granules into bone chips to supplement the volume and the mechanical strength of allografts. To investigate the dynamic migration of cemented cup fixed with IBG, we made acetabular bone defect models and the migration of the cup was traced by a high-speed photography camera. Composite test blocks were used as synthetic acetabulum models. A hemisphere defect of 60mm in diameter was made. We tested 4 different bone/HA ratio; 100%/0%, 75%/25%, 50%/50% and 0%/100%. Each group consisted of 6 specimens. The grafted materials were impacted using impactors. Then, a 46 mm polyethylene cup was fixed with bone cement. The specimens were clamped to the MTS mechanical tester at an angle of 20 degrees. A dynamic load of 150 N to 1500 N with a frequency of 1 Hz was applied for 15 minutes, followed by a dynamic load of 300 N to 3000 N for the same time period. Then the load was released for 15 minutes. The cup migration was traced by the camera during loading and releasing. This camera captures 15 images per second thus it enables us to trace the migration of the cup during cyclic loading. The cup migration at the end of 3000N loading was measured. Elastic recoil was defined as the difference between the migration at the end of 3000N loading and that when the load reached to 0N. Visco-elastic recoil was defined as the difference between the migration at the release of loading and that after 15 minutes. Data were investigated by Pearson’s correlation coefficient test. A strong negative correlation (r = −0.71) was observed significantly between the amount of the migration and bone/HA ratio. In elastic recoil, statistically significant correlation was (r = −0.55) observed. In visco-elastic recoil, there is no correlation between the amounts of the visco-elastic recoil and bone/HA ratio. In the reconstruction of bone defects, initial stability of the cup is a first step to expect the long term survival. The initial stability depends on the mechanical properties of the grafted materials. To supplement the volume and mechanical strength of bone allografts, we added HA granules to the bone chips. In the current study, the cup migration was smaller by adding HA granules. Elastic recoil was affected, while visco-elastic recoil was not affected. These results indicated that the mixture of HA granules to bone chips stabilized the cup during loading period and load releasing period

Aims

The main aims were to identify risk factors predictive of a radiolucent line (RLL) around the acetabular component with an interface bioactive bone cement (IBBC) technique in the first year after THA, and evaluate whether these risk factors influence the development of RLLs at five and ten years after THA.