Table of Contents  
RESEARCH ARTICLE
Year : 2017  |  Volume : 2  |  Issue : 2  |  Page : 78-84

Platelet-rich plasma combined with conventional surgery in the treatment of atrophic nonunion of femoral shaft fractures: study protocol for a prospective, randomized, controlled clinical trial


Department of Trauma Orthopedics, Affiliated Hospital of Qinghai University, Xining, Qinghai Province, China

Date of Web Publication31-May-2017

Correspondence Address:
Zi-chun Zhao
Department of Trauma Orthopedics, Affiliated Hospital of Qinghai University, Xining, Qinghai Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2542-4157.207015

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  Abstract 

Background: Internal and external fixation combined with autologous bone graft for the treatment of atrophic nonunion has a long treatment cycle, and there remain cases where the nonunion cannot be cured. Platelet-rich plasma contains a variety of growth factors and a large number of white blood cells, and contributes to tissue healing. However, there have been no clinical studies on the effectiveness of platelet-rich plasma combined with conventional surgery in the treatment of atrophic nonunion.
Methods/Design: We conducted a prospective, open-label, randomized, controlled clinical trial at the Affiliated Hospital of Qinghai University, China. Ninety-two patients with atrophic nonunion of femoral shaft fractures were equally and randomly divided into a control group and an experimental group. The patients in the control group received conventional surgery, while the patients in the experimental group were injected with autologous platelet-rich plasma in addition to receiving conventional surgery. The primary outcome was fracture healing rate at 9 months postoperatively. The secondary outcomes were visual analogue scale scores for resting state and passive motion, healing time, treatment costs, and adverse reactions. Our partial results revealed that the visual analogue scale scores and complications were similar between the two groups on postoperative days 1–3. The healing rate was significantly higher in the experimental group compared with the control group. The healing time was significantly shorter in the experimental group compared with the control group.
Discussion: The present trial was designed in August 2014, and case recruitment was completed in September 2016. Data for the last case will be collected in June 2018, and the data analysis will be completed in December 2018. The trial will provide objective data on the clinical use of platelet-rich plasma combined with conventional surgery for the treatment of atrophic nonunion.
Trial registration: ClinicalTrials.gov identifier: NCT03129971.
Ethics: The study protocol has been approved by the Ethics Committee of Affiliated Hospital of Qinghai University of China (approval number: QHG0223A).
Informed consent: Written informed consent was obtained from all participants.

Keywords: clinical trial; atrophic nonunion; platelet-rich plasma; femoral shaft; effectiveness; fracture healing; pain; randomized controlled clinical trial


How to cite this article:
Zhao Zc, Li Zw, Yan Hx, Tang Bm, Li Cl, Zhang Qf, Ren R, Li P, Jia Sl. Platelet-rich plasma combined with conventional surgery in the treatment of atrophic nonunion of femoral shaft fractures: study protocol for a prospective, randomized, controlled clinical trial. Clin Trials Orthop Disord 2017;2:78-84

How to cite this URL:
Zhao Zc, Li Zw, Yan Hx, Tang Bm, Li Cl, Zhang Qf, Ren R, Li P, Jia Sl. Platelet-rich plasma combined with conventional surgery in the treatment of atrophic nonunion of femoral shaft fractures: study protocol for a prospective, randomized, controlled clinical trial. Clin Trials Orthop Disord [serial online] 2017 [cited 2024 Mar 28];2:78-84. Available from: https://www.clinicalto.com/text.asp?2017/2/2/78/207015


  Introduction Top


History and Current Related Studies

Fracture healing is a continuous process, and disturbance of any phase by unfavorable factors can block the healing process.[1],[2],[3] A clinical study found that the non-healing rate of long bone fractures was approximately 5%.[4] A certain site and type of fracture that has not healed within a particular time period (usually 3–6 months) is described as delayed union by the US Food and Drug Administration. In addition, a fracture that has not healed after 9 months and shows no tendency for further healing in the next 3 months is referred to as nonunion.[5],[6] Based on the fracture end activity, nonunion is further classified into hypertrophic nonunion and atrophic nonunion.[7],[8] Hypertrophic nonunion is mostly caused by unstable fixation of the fracture ends, and can be cured by strengthening the fracture site stability using conventional surgery. Atrophic nonunion is difficult to cure, because the lack of adequate blood supply and bone formation at the fracture ends leads to inability of periosteal callus formation.[7],[8] At present, atrophic nonunion is commonly treated by internal and external fixation combined with autologous bone graft, but this method has a long treatment cycle, and there remain cases where the nonunion cannot be cured.[9]

Platelet-rich plasma (PRP) is blood plasma that has been enriched with platelets through centrifugation of autologous blood.[10] Activated platelets secrete platelet-derived growth factor, transforming growth factor beta, vascular endothelial growth factor, and epidermal growth factor. These growth factors promote cell proliferation, differentiation, matrix synthesis, and vascular regeneration, and accelerate tissue healing and bone repair.[11] PRP contains a large number of leukocytes, which locally phagocytize bacteria, scavenge necrotic tissue, inhibit inflammatory reaction, and resist infection.[12] In addition, PRP fibrin can locally build the three-dimensional structure required for tissue repair. Since Assoian et al.[13] first isolated PRP and used it for clinical purposes in 1984, PRP has received increasing attention in areas such as oral and maxillofacial surgery, orthopedics, plastic surgery, and neurosurgery.

Main Objective

This randomized controlled trial aims to objectively analyze the effectiveness of PRP combined with conventional surgery in the treatment of atrophic nonunion of femoral shaft fractures.

Distinguishing Features from Related Studies

In recent years, there have been a number of Chinese studies on the use of PRP in the treatment of nonunion [Table 1]. However, there have been no randomized controlled studies on the therapeutic effect of PRP combined with conventional surgery in the treatment of atrophic nonunion of femoral shaft fractures.
Table 1: Clinical studies on platelet-rich plasma in the treatment of nonunion

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  Methods/Design Top


Study design

This trial was designed in August 2014, and case recruitment was completed in September 2016. This is a prospective, open-label, randomized, controlled clinical trial at the Affiliated Hospital of Qinghai University, China.

After screening according to inclusion and exclusion criteria, 92 patients with atrophic nonunion of femoral shaft fractures were equally and randomly divided into a control group and an experimental group. The patients in the control group received conventional surgery, while the patients in the experimental group were injected with autologous PRP in addition to receiving conventional surgery.

The primary outcome was the fracture healing rate at 9 months postoperatively. The secondary outcomes were visual analogue scale scores in resting state and passive motion, healing time, treatment costs, and adverse reactions at 3, 6, 9, and 12 months postoperatively.

A flow chart of the study protocol is shown in [Figure 1].
Figure 1: Trial flow chart.

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Study Participants

We enrolled patients with atrophic nonunion of femoral shaft fractures who were treated at the Affiliated Hospital of Qinghai University, China.

Inclusion criteria

Patients meeting with all of the following criteria were considered for study inclusion:

  • Femoral shaft fractures
  • Fracture time of more than 9 months[5],[6]
  • X-rays revealing a gap and sclerosis at the fracture ends, medullary closure, and osteoporosis, with absence of trabecular bone formation in the callus, for more than 3 months[5],[6]
  • Magnetic resonance images revealing a widened gap and atrophic fracture ends, with a small amount of or even no callus formation[7]
  • Histological images revealing a gap at the fracture ends filled with fibrous tissue without osteogenic activity7
  • Age of 18–70 years


Exclusion criteria

Patients with one or more of the following conditions were excluded from the study:

  • Underlying disease affecting wound healing, such as diabetes, hematological system diseases, immune diseases, and connective tissue diseases
  • Pregnancy or lactation
  • Heart, lung, liver, and kidney dysfunction
  • Participation in other clinical trials


Withdrawal criteria

Patients with one or more of the following conditions were withdrawn from the study:

  • Development of a complication affecting the treatment efficacy and safety or a disease affecting the treatment outcome
  • Combined use of other therapies or drugs to speed up the treatment effect
  • Inability to complete the follow-up


Sample Size

The effectiveness of surgery alone in the treatment of atrophic nonunion was reported to exceed 75%.[20] In our experience, the effectiveness of PRP combined with conventional surgery for atrophic nonunion was approximately 90%. Considering a power of 1 – β = 0.9 with a significance level of α = 0.05 (two-sided), a sample size of n = 133 per group was required according to calculations performed with PASS 11.0 software (NSCC LLC, Kaysville, UT, USA). Assuming a patient loss rate of 20%, we required 160 patients per group. Owing to the limited time, 92 patients were recruited, and each group had a total of 46 cases.

Recruitment

Recruitment information was posted on the hospital bulletin boards. Patients were able to contact the project leader indirectly through their attending physician, or directly by telephone, email, and WeChat. After providing informed consent, participants who met the inclusion and exclusion criteria were enrolled.

Baseline Analysis

Baseline data were collected at the time of enrollment. The detailed items are listed in [Table 2].
Table 2: Baseline data of the included patients

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Randomization and Blinding

According to the patient admission order, patients were equally randomized into a control group and an experimental group (n = 46 per group) by statisticians using SAS 9.4 software (SAS Institute Inc., Cary, NC, USA). The patients, physicians, and assessors were not blinded to the group information.

Interventions

Control group

After the fracture site was anesthetized, the skin was incised. The original fixator was removed. The nonunion site was exposed, and the scar tissue at the fracture ends was cleaned. The hardened bone was removed, and the medullary cavity was passed through. The periosteum was removed as little as possible during the operation. The fracture ends were reset and refixed using a plate, intramedullary nail, and screw. The fracture ends were pressurized, or an autologous, allogeneic, or artificial bone graft was used around the fracture ends.[21],[22],[23],[24],[25],[26],[27]

Experimental group

Together with the conventional surgery described above, PRP was injected into the affected site.

Preparation of PRP

PRP was prepared using the Landesberg method.[28] Briefly, approximately 30 mL of blood was collected from the elbow vein and treated with 3 mL of sodium citrate for anticoagulation. After shaking, the blood was centrifuged twice. After the first centrifugation at 200 × g for 10 minutes, the supernatant to 3 mm below the interface was obtained and moved to a new centrifuge tube. After balancing, the second centrifugation was conducted by the same method. The supernatant was moved to a sterile centrifuge tube, and an appropriate amount of the supernatant was used for a sterility test. The remaining supernatant (2.5 mL) was resuspended, and the obtained platelet fraction was defined as PRP. PRP (20 μL) was examined for the number of platelets. Activators (mixture of thrombin at final concentration of 100 U/mL and tranexamic acid at 25 mg/mL) were added before use.

Local injection of PRP

The fracture site was locally anesthetized. The puncture needle was precisely inserted into the nonunion site. After removal of the scar tissue at the nonunion site and with the needle maintained in place, 5 mL of PRP plus activators was injected into the injury site using a medicine mixer with double syringes. After local compression, the wound was bandaged. The affected limb was fixed.

Postoperative Rehabilitation

In both groups, a continuous passive motion device (Beijing Zhongxi Yuanda Technology Co. Ltd., Beijing, China) was used from postoperative day 2 for 30 minutes/time twice per day. At 2 weeks postoperatively, the patients were allowed to get out of bed with crutches, but were not allowed to bear heavy weight. X-ray films revealing growth of the callus determined the partial or full weight-bearing time.[21],[22],[23],[24],[25],[26],[27]

Outcome Measures

Primary Outcome Measure

Fracture healing rate at 9 months postoperatively: Disunion was identified if the fracture had not healed at 9 months postoperatively.[6] Fracture healing included clinical healing and bone healing.

Clinical healing criteria: 1) Absence of tenderness at the local site and no longitudinal percussion pain; 2) no abnormal activity at the local site; 3) X-ray films showing a blurred fracture line and continuous callus through the fracture line; 4) in cases with removal of external fixation, continuous walking for 3 minutes, not less than 30 steps; 5) fracture without any deformation for 2 weeks.[29]

Bone healing criteria: 1) Meeting clinical healing criteria; 2) X-ray films revealing trabecular bone passing through the fracture line.[29]

Secondary Outcome Measures

  • Visual analogue scale scores: A visual analogue scale is a method for assessing pain intensity. Using a ruler with 10 scales, the ends are set at 0 and 10, respectively, where 0 represents no pain and 10 represents the most unbearable severe pain. The side with the scales was at the back for the patient. The patient was allowed to mark the location of their pain on the ruler. The evaluator then selected the score according to the mark on the ruler.[30] The visual analogue scale scores in resting state and passive motion were recorded.
  • Healing time: Time for fracture healing.
  • Treatment costs: Costs from admission to fracture healing.
  • Adverse reactions: Postoperative fever, infection, leukocyte abnormality, unequal leg length, and paresthesia.


The schedule for the outcome measurement assessments is shown in [Table 3].
Table 3: Timing of outcome assessments

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Data Management

Clinical researchers filled in the clinical trial observation form to ensure that the data were accurate, complete, and collected in a timely manner. For the trial, all data would be input into a computer. After the data collection, the main clinical investigators and inspectors would monitor and check the integrity and accuracy of the data. Data processing statisticians would further verify and check the completeness and accuracy of the data after data entry. The anonymized trial data will be published at www.figshare.com.

Statistical Analysis

Al data were analyzed using SPSS 17.0 software (SPSS, Chicago, IL, USA). Measurement data were expressed as the mean ± SD. Count data were expressed as percentages.

A normality test and variance homogeneity test were conducted. Normally distributed data with homogeneity were compared by one-way analysis of variance. Non-normally distributed data were compared by Wilcoxon's two-sample rank-sum test.

The incidence of adverse reactions in the two groups was compared by the chi-square test.

A value of P < 0.05 was considered statistically significant. The results followed the intention-to-treat principle.

Confidentiality

The clinical trial observation forms and informed consent forms were password-protected. No persons other than authorized researchers were able to access these forms.

Ethical Requirements

The study protocol was approved by the Ethics Committee of the Affiliated Hospital of Qinghai University of China (approval number: QHG0223A). All protocols were performed in accordance with the Ethical Principles for Medical Research Involving Human Subjects in the Declaration of Helsinki. The writing and editing of the article were performed in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) (Additional file 1 [Additional file 1]). The trial was registered in ClinicalTrials.gov (identifier: NCT03129971). Written informed consent was provided by each patient and their family members after they indicated that they had fully understood the treatment plan.


  Trial Status Top


The trial began in August 2014. Ninety-two patients were enrolled and followed. The partial results are as follows:

Ninety-two patients will be followed for 8–26 months.

The visual analogue scale scores did not differ significantly between the experimental group and the control group on postoperative days 1–3 (P > 0.05; [Table 4].
Table 4: Effects of platelet-rich plasma on visual analogue scale scores in patients with atrophic nonunion of femoral shaft fractures

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The healing rate was higher in the experimental group compared with the control group (94% vs. 78%, P < 0.05; [Table 5].
Table 5: Healing of atrophic nonunion of femoral shaft fractures after treatment with platelet-rich plasma

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The healing time was significantly shorter in the experimental group compared with the control group (91.6 ± 6.9 vs. 115.2 ± 8.4, P < 0.05; [Table 6].
Table 6: Healing time (days) of atrophic nonunion of femoral shaft fractures after treatment with platelet-rich plasma

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Postoperative complications: Infection occurred in one case in the experimental group and two cases in the control group. Rejection was not found in either group [Table 7].
Table 7: Complications in patients with atrophic nonunion of femoral shaft fractures after treatment with platelet-rich plasma

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  Discussion Top


Significance of the Study

The key points for the treatment of nonunion are to maintain the stability of the fracture ends, restore the blood supply, fill the bone defect, and promote osteogenesis.[31] We considered the use of PRP combined with conventional surgery. PRP can promote cell proliferation, cell differentiation, and matrix synthesis, and has effects on vascular regeneration and anti-infection.[11],[12] PRP contributes to tissue healing and graft fusion, thus elevating the healing rate, shortening the treatment time, and mitigating the pain and costs.

Advantages and Limitations of the Study

The PRP used in the study was autologous, had no immunological rejection, was simply prepared, caused less damage to the body, released a large number of growth factors to promote fracture healing, and was limited to the fracture ends, thereby achieving the best synergistic effects.[11] The fibrin in PRP can provide support for tissue repair.[11] PRP contains a high concentration of leukocytes, which have local bacteriostatic and anti-inflammatory effects and can prevent infection.[12]

The Affiliated Hospital of Qinghai University of China is a third-class first-grade hospital, and has a good scientific research foundation. As a Qinghai First Aid Center, the Affiliated Hospital of Qinghai University has adequate traumatic cases and a good clinical basis for carrying out the trial. Our team has performed a study on PRP effectiveness in chronic osteomyelitis.[32] We have rich experience in the application of PRP and are skilled in the treatment of nonunion, both being conducive to smooth implementation of the study.

Evidence for Contribution to Future Studies

As fracture healing is a multifactorial process, a single treatment cannot achieve satisfactory results. This study uses a combined method for the treatment of fracture healing, and provides an experimental basis for the clinical use of PRP in the treatment of atrophic nonunion.

Additional File

Additional file 1: SPIRIT checklist (PDF 48.0 kb).

 
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Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Conflicts of interest
None declared.
Author contributions
Patient selection, surgery, PRP preparation and injection, and manuscript writing: ZCZ and ZWL. Equipment preparation, patient management during hospitalization and follow-up: HXY, BMT, CLL and QFZ. Data collection and analysis: RR, PL and SLJ.
Plagiarism check
This paper was screened twice using CrossCheck to verify originality before publication.
Peer review
This paper was double-blinded and stringently reviewed by international expert reviewers.


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]


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