This study was a randomized, double-blinded parallel (1:1 ratio), clinical trial study that has been approved by the Research Ethics Committee at National Taiwan University Hospital (NTUH) from June 1st, 2014 to May 31st, 2017. The trial was registered at clinicaltrials.gov (NCT04103944). Written informed consent was obtained from all patients after the understanding of this research’s purpose and procedures explained at the beginning of each recruitment. Patients have the right to withdraw from this project for any reasons and their post-analysis will be excluded from this study.
A total of 20 cases were fulfilled in the inclusion criteria and has undergone the surgeries with 10 patients in the control group (core decompression surgery) and another 10 in the experimental group (osteonecrotic device) at NTUH. The patient’s eligibility consists of one) skeletally matured between the age of 20 to 70 (epiphyses of the femoral head is confirmed to be closed on the radiography, CT, or MRI scan, two) patients without any allergies or major systemic or organ diseases, and three) the patient’s affected hip was diagnosed as the third stage of ONFH by MRI, evaluated by specialized orthopedic surgeons. If patients have presented with either one) other lower limb fractures, two) pregnancy, three) extensive degenerative arthritis in the hip, four) severe osteoporosis in the head and/or neck of the femoral bone, five) rheumatoid immunity or metabolic arthritis that appears to have severe cartilage damage in the hip, six) stiffness in the hip due to other reasons or medical history with its range of motion clinically measured less than 20 degrees in the abduction, and less than 90 degrees flexion, or seven) diagnosed with either stage four, five, or six of ONFH classification by either radiography, MRI, or CT scan, they are excluded from this study.
MRI (Signa; GE Healthcare USA Inc, Milwaukee, WI) (Sonata; Siemens Medical Solutions USA Inc, Malvern, PA) and X-ray was used for all scans. This study evaluated the appropriate pulse wave sequence in evaluating the specific cartilage structure and quality in two parts. One, the use of proton density with T2-weighted fast spin-echo (no fat suppression because the subchondral bone was not involved) was used as the inspection time is short and is widely used in clinical practice. However, the quality of the image interpretation is not clear as the signals of the deep and soft cartilage and bones are blurred. So adding on to the second, T1-weight spoiled gradient echo (GRE) or 3D double echo steady state (3D-DESS) sequence was used as they have high-quality scans in discriminating diseased cartilage with normal cartilage (specifically at the edge at the junction with the articular surface). However, this sequence required a more experienced radiologist interpreter as well as longer inspection time. In addition to these scans, the endoscopic approach was also used for direct visual examination of the lesion site data collection.
Osteonecrotic Device Surgical Process
The patient was placed on the fracture table under anesthesia. The following protocol was followed in Figure 1. Under the C-arm fluoroscopic guide, a K-wire (2.0mm) was inserted into a small shin incision on the lateral femoral subtrochanteric region into the necrotic bone. The cylindrical bone drill of 8.0mm ((SUS420J2) was advanced along with the K-wire all the way only cutting through the femoral articular cartilage while the operated leg was pulled on the fracture table to distract the hip joint (Figure 1A through 1C ). Hip joint distraction was used to prevent the cutting injury to the acetabulum by the cylindrical bone drill. From Figure 1D through 1H, the cylindrical bone column was then retrieved from the cylinder bone drill. The articular cartilage was harvested and minced into small pieces, followed by an enzymatic digestion and a wash-out of the residual enzyme. The process of enzymatic digestion decomposition was broken down into enzyme digested cartilage (EDC) and biphasic cylindrical scaffold was made. The biphasic cylindrical scaffold was then put into a matrix cap. In Figure 1I, the necrotic part from the bone column was removed and sent for further histopathological examination. Then from Figure IJ to IM, the matrix cap was designed to be fitted onto the tip of the cylinder bone column, where the original necrotic bone was removed for the examination. The cylinder bone column was inserted back into the tunnel on the same lateral femoral subtrochanteric region under the C-arm fluoroscopic guide. The traction to the operated leg was released, allowing the femoral head to be in close contact with the acetabulum. The shortage of the bone tissue was filled with artificial bone substitution. The wound is then sutured and the operation is completed.
The biphasic cylindrical scaffold that was used, was a porous construction with two phases: a thin, spongy chondral phase of poly-lactic-co-glycolic acid (PLGA; PURAC 0809001002) served as the chondral phase, and a more rigid osseous phase of β -triCalcium phosphate (β – TCP; containing triCalcium phosphate; Fluka 21218) served as the osseous phase (Figure 2). All products were fabricated in a good manufacturing practice compliant laboratory and had passed all the necessary preclinical evaluations such as toxicology tests and animal experiments.
Core Decompression Surgical Process.
Core decompression is a common surgical procedure that aims to improve vascular inflow by decreasing intraosseous pressure in the femoral head. It is performed that involves removing a cylindrical core of bone from the proximal femur. The patient was placed on the fracture table under anesthesia. By using a C-arm fluoroscope as a guide, we made 2cm to 3cm longitudinal incision in the midlateral thigh at the level of the lesser trochanter, and split the fascia lata in the directions of its fibers. Using a cannulated drill, we created a 10 mm window in the lateral cortex of the femur at the level of the superior margin of the lesser trochanter. With the fluoroscopy guidance, we drove the 3.0 k-wire medially and proximally up the femoral heck towards the center of the lesion. Once the lesion has been reached, the 3.0 k-wire is withdrawn. This same procedure was repeated six times to decompressed the necrotic region. Once the procedure is completed, the wound is closed in layers, with one or two sutures used to close the skin incision.
Outcome tools included the use of one) Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC; primary outcome measures) and two) visual analogue scale (VAS; secondary outcome measures). The WOMAC consists of three categories including pain (five items), stiffness (two items), and physical function (17 items) which are scored on a scale of 0 (none), 1 (mild), 2 (moderate), 3 (severe), and 4 (extreme). Lower scores indicate a better patient condition while the higher scores indicate the severity of the patient’s condition.  VAS is a commonly used subjective assessment of current pain using a standard visual analogue scale, presenting as a 100-mm horizontal line, starting with “no pain” (score of 0) up to “worst imaginable pain” (score of 100).  Patients were instructed to mark down on the horizontal line the current pain they are in.
Testing Procedures and Follow Up
This was a randomized, double-blinded, parallel, study where both patients and third party evaluators to assess the postoperative outcomes were blinded to avoid subjective judgments and prevent bias in results. After the fulfillment of the inclusion criteria, baseline demographic data including age, gender, which affected side the surgery was performed, measurement of hip joint, WOMAC, VAS, MRI, and X-ray scans were collected. Simple randomization was used. Random numbers, numbering from one to 20, was used by a computer-generated randomization sequence by an independent statistician, assigning a number to each patient to decide their designated surgery procedure group. After the surgical procedures, each patient was asked to come back the following one to two weeks after to observe any complications from the surgery to assess by doctor’s assistants who were the evaluators. If there were no complications, the following postoperative data collection of WOMAC and VAS are then continued from six weeks, three months, six months, one year, and two years’ prior from the start of their surgery, in order to understand the new approach of the osteonecrotic device’s safety in comparison to the core decompression surgical procedure. The following image evaluation were also taken throughout each period.
All quantitative data were conducted using SPSS (version 20; SPSS Inc. Chicago, IL). Sample size calculation is based on the primary outcome WOMAC. A difference between two groups of 15% is considered clinically relevant. For a 5% significance level and 80% power and a 10% dropout, 20 patients were needed. Demographic data were expressed as mean ± standard deviation (SD). Independent samples t-test were used for continuous data while Mann-Whitney U test were used for non-parametric data. We assessed the change over time with VAS and WOMAC in both groups. They were followed by the use of Wilcoxon paired samples in order to compare the baseline data with the values obtained at six weeks, three months, six months, one year, and two years. If there are exclusion of patients in the postoperative analysis, a simple imputation method will be used to replace the values. Lastly, observation carried forward will be used to substitute the missing values where the data value will be taken as a representative value. Confidence intervals (CI) were presented at 95%.