Temperature-sensitive anti-adhesive poloxamer hydrogel decreases fascial adhesion in total knee arthroplasty: A prospective randomized controlled study

Abstract

A temperature sensitive anti-adhesive poloxamer (TAP) hydrogel has been developed to reduce post-operative adhesion. The purpose of this study was to evaluate the efficacy and safety of TAP hydrogel on fascial adhesion and clinical outcomes including range of motion, pain, and patient satisfaction after total knee arthroplasty. Sixty patients who underwent unilateral primary total knee arthroplasty for knee osteoarthritis were included and randomized to either TAP group or control group. After capsular closure, TAP hydrogel was applied on the fascial layer in 30 patients of the TAP hydrogel group, while normal saline was applied to 30 patients of the control group. The primary variable was range of motion at postoperative seven days, three months, and one year. As secondary outcomes, degree of skin fold, fascial thickness measured with ultra-sonography, postoperative pain visual analogue scale, total cumulative analgesics consumption, clinical scores, and degree of satisfaction were evaluated. There were no significant differences in range of motion after surgery between the two groups. However, the degree of suprapatellar skin folding in the TAP hydrogel group was less than that of the control group at six weeks after surgery (p = 0.041). There were no significant differences in postoperative fascial thickness, pain visual analogue scale, analgesics consumption, clinical scores, or degree of satisfaction. No surgical site complication was observed. The use of TAP hydrogel failed to enhance range of motion. However, application of TAP hydrogel on the fascial layer after capsular closure in total knee arthroplasty may decrease early postoperative fascial adhesion without any complications.

Keywords

Adhesion total knee arthroplasty temperature-sensitive anti-adhesive poloxamer hydrogel stiff knee range of motion

Introduction

Post-operative adhesion after total knee arthroplasty (TKA) is a disabling complication that can lead to knee stiffness with arthralgia.¹ According to a recent review, the incidence of stiffness is about 1.3% to 5.8% after TKA.² In another study analyzing revision TKA for aseptic failure, it was found that arthrofibrosis was one of the most common indications for revision surgery, suggesting that revision might be related to poor range of motion (ROM) caused by arthrofibrosis.³

A variety of methods have been developed to prevent adhesion of the knee joint in animal models and humans, including physical therapy or continuous passive motion after TKA, multimodal regimens to control postoperative pain, and manipulation under anesthesia.² Anti-adhesive agents have also been developed and used to prevent post-operative adhesion. Originally, anti-adhesive agents have been shown to be effective for decreasing postoperative adhesion in various fields of surgeries.^4–7 In the field of orthopaedic surgery, anti-adhesive agents have been introduced to deal with postoperative adhesion with many studies reporting favorable results.^8–16 However, studies about the efficacy of anti-adhesive agent use in the knee joint to prevent postoperative stiffness and enhance motion are limited.^8,12–14 One study on clinical outcomes after using periarticular injection of anti-adhesive hyaluronate gel in TKA has reported there was no beneficial effect on ROM or pain reduction during early postoperative period.⁸

Recently, temperature sensitive anti-adhesive poloxamer (TAP) hydrogel has been newly developed and introduced to the orthopaedic field. The major component of TAP hydrogel is poloxamer with thermo-reversible property transforming from a solution to a gel form at body temperature, thus elongating the acting time. Furthermore, chitosan and gelatin were added to TAP hydrogel providing antibiotic and anti-coagulant effects as well as biocompatibility compared to conventional anti-adhesive agents.¹⁷ Although some in vivo studies have shown the effectiveness of TAP hydrogel in spine surgery, studies about the clinical outcome after using TAP hydrogel in the knee joint especially in TKA have not been reported.^18,19 Therefore, the purpose of this study was to evaluate the efficacy and safety of TAP hydrogel on fascial adhesion and clinical outcomes including postoperative ROM, pain, and patient satisfaction after TKA.

Materials and methods

After obtaining approval from the Institutional Review Board of Korean Ministry of Food and Drug Safety, a prospective, randomized, single-blinded, placebo-controlled, single center comparative study was conducted. From March 2016 to September 2016, patients between 50 and 80 years old who were scheduled to receive unilateral primary TKA for knee osteoarthritis were enrolled. Exclusion criteria were: previous operative history of ipsilateral knee, severe deformity (pre-operative mechanical axis more than 20° or flexion contracture more than 20°), severe bone loss needing bone graft, metal augment, or stem fixation, current chronic anticoagulation therapy, history of bleeding disorder, history of deep vein thrombosis, thromboembolic complications or acute cardiac insufficiency, history of peripheral nerve disorder or numbness, psychiatric illness, and neuromuscular comorbidity such as parkinsonism, cerebral palsy, and cerebral infarct that could affect post-operative rehabilitation.

A priori power analysis was performed based on results of a previous study.⁸ It was estimated that patients were needed in each group to potentially find an effect at compensated alpha level of 0.05 and a power of 80% using a two-sided test. To allow for 10% exclusions and dropouts, 60 patients (30 in each group) were enrolled in the present study.

A total of 60 patients were randomly assigned by using a computer-generated randomization table to either control or TAP hydrogel group. After capsular closure, 10 g of TAP hydrogel was applied on the fascial layer in 30 patients in the TAP hydrogel group, while normal saline was applied to 30 patients in the control group. During follow-up, one patient in TAP hydrogel group and two patients in control group dropped out (follow-up loss). Finally, a total of 57 patients (29 in TAP hydrogel group and 28 in control group) were analyzed (Figure 1). There were no significant differences in demographic characteristics between the two groups (Table 1).

Figure 1.

CONSORT ediagram of the randomized controlled trial.

Table 1.

Summary of demographic characteristics.

	Control (n = 28)	TAP hydrogel (n = 29)	p-value
Age at surgery (year)	68.7 ± 5.4 (54–77)	69.2 ± 4.9 (55–79)	n.s
Gender			n.s
Male	6 (20.0%)	4 (13.3%)
Female	24 (80.0%)	26 (86.7%)
BMI (kg/m²)	26.0 ± 3.9 (19.2–31.2)	26.8 ± 3.4 (21.3–30.8)	n.s

TAP: temperature-sensitive anti-adhesive poloxamer; BMI: body max index.

Thermo-sensitive sol–gel transition poloxamer hydrogel

The TAP hydrogel (Mediclore, CG Bio, Seoul, Korea) used in this study mainly consists of Poloxamer188/407 with a mixture of chitosan and gelatin. The concentration of chitosan and gelatin is less than about 1% to avoid a change of TAP hydrogel mechanical property. Low concentration chitosan shows an antibiotic effect and the gelatin is also well known natural polymer which shows biocompatibility, biodegradability, elasticity and adhesiveness even at low concentration.²⁰ This anti-adhesive agent is manufactured by heating sterile water for up to 60°C and dissolving chitosan (Biopolytech Inc., Korea), gelatin (Sammi, Korea), and Poloxamer188/407 (BASF, Germany). After that, the solution is stored at 0–4°C. This product is moved into a sterile syringe and packed in PET Tray and Tyvek Film. In the end, this solution is sterilized by electron beam (E-beam, GEV Co., Ltd Korea). The poloxamer188/407 allows TAP hydrogel can transform from a solution to a gel form at body temperature, thus enhancing its properties as a physical barrier, while chitosan and gelatin generate antibacterial effect and mucous membrane adherence¹⁷ (Figure 2).

Figure 2.

Transformation of thermo-sensitive anti-adhesive poloxamer hydrogel (TAP) from solution to gel. Solution form of TAP showed fluidity around 25°C (a, c). Gel form of TAP showed viscosity around 37°C (b, d). In specific, TAP flows down along the side of the syringe at 25.0°C (e) compared to the gel state of TAP at 37.4°C without flowing down (arrow) (f).

Surgical technique

A single surgeon performed all surgeries. All surgeries were performed with the same procedure using anterior midline skin incision and a standard mid-vastus arthrotomy with a tourniquet inflation. Posterior cruciate ligament was resected and a posterior stabilized knee prosthesis (Triathlon, Stryker, USA) with fixed bearing was implanted in all cases. Patella resurfacing was routinely done and cement ﬁxation was used for all components in every case. After tourniquet deflation and meticulous bleeding control, a suction drain was inserted and the capsule, vastus muscle fascia, and medial patellar retinaculum were closed. TAP hydrogel or normal saline was then applied onto the fascial layer (Figure 3). After wound closure with sterile dressing, tight Jones compression was performed in extension position.

Figure 3.

Method of anti-adhesive gel injection. Temperature sensitive anti-adhesive poloxamer gel was applied onto the fascial layer of vastus medialis.

Postoperative management and rehabilitation

All patients received the same multimodal perioperative pain management including periarticular cocktail injection, intravenous patient-controlled analgesia, oral analgesics, and rescue injection. Closed suction drain was removed on the next day of surgery, while compression dressing was maintained for two days after surgery.

Postoperatively, standardized rehabilitation programs were used for all patients. All patients were encouraged to have continuous passive motion and begin isometric quadriceps strengthening and straight-leg raise exercise on the ﬁrst post-operative day. Walking with aid of a walker was started on the first postoperative day.

Outcome assessment

ROMs at post-operative seven days, three months, and one year were measured as a primary outcome variable. Degree between the maximal extension and further flexion angle was measured with a goniometer by a blinded independent trained researcher. As secondary outcomes, degree of skin fold, fascial thickness measured with ultra-sonography, postoperative pain visual analogue scale (VAS), total cumulative consumption of analgesics, and postoperative clinical scores were evaluated. Skin fold was classified into three grades according to the presence or degree of folding in maximal extension and flexion of the knee at six weeks and one year after surgery (Figure 4). Fascial thicknesses in suprapatellar, para-patellar, and infrapatellar part of capsulotomy were measured with ultra-sonography at post-operative six weeks²¹ (Figure 5). Pain VAS (range 0–10) was measured at seven days, three months, and one year after surgery.²² Total dose of analgesics during seven-day hospitalization was calculated as morphine equivalents.²³ Clinical and functional status of patients was assessed before surgery and after surgery (three months and one year) using Hospital for Special Surgery (HSS) score, Knee Society Knee and Function score (KSKS and KSFS), and Western Ontario McMaster Universities Osteoarthritis Index score (WOMAC).^24–26 Patient’s satisfaction was measured with a satisfaction questionnaire surveyed at three months and one year postoperatively.²⁷ This study was registered at Cris.nih.go.kr (KCT0002185).

Figure 4.

Grade of skin folding. The degree of skin folding was classified to four groups according to the presence of folding in maximal extension and flexion of knee at six weeks and one year after surgery (a) Grade I: no skin folding, (b) Grade II: no folding in flexion, mild folding in extension, (c) no folding in flexion, moderate to severe folding in extension.

Figure 5.

Vastus medialis fascia thickness. The degree of adhesion was measured with ultra-sonography at six weeks after surgery by evaluating the thickness of fascia in vastus medialis suprapatellar, parapatellar and infrapatellar level.

Statistical analysis

Data were described as means and standard deviations (SDs). Categorical variables (sex, grade of skin fold) were analyzed using Pearson’s Chi-squared test or Fisher’s exact test with relative ratio, while continuous variables (age, weight, height, BMI, ROM, VAS total cumulative opioid consumption, thickness of operative site adhesion) were analyzed with Student’s t-test. Differences during the postoperative follow-up period between the two groups were evaluated with analysis of variance (ANOVA). All statistical analyses were performed with Statistical Package for the Social Sciences (SPSS) version 22 (IBM Corp.). A p-value of less than 0.05 was considered statistically significant.

Results

In both groups, ROMs were significantly improved after surgery compared to their preoperative levels (control group: from 114 to 127, p = 0.004; TAP hydrogel group: from 117 to 127, p = 0.003). However, there were no significant differences in ROMs between the two groups at seven days, three months, or one year after surgery (Figure 6).

Figure 6.

Comparison of range of motion between two groups. No significant difference between two groups was shown at seven days, three months, and one year after surgery (p-value > 0.05).

Data of secondary outcome variables are summarized in Figure 6 and Table 2. The degree of suprapatellar skin folding in the TAP hydrogel group was significantly lower than that in the control group at six weeks after surgery (p=0.041). However, it showed no significant difference between the two groups at one year after surgery (Figure 7). Postoperative fascial thickness value measured with US in TAP hydrogel group was smaller than that in the control group at six weeks after surgery, although the difference between the two groups was not statistically significant. There was no significant difference in pain VAS, analgesics consumption, clinical scores, or satisfaction score between the two groups. No surgical site complication was observed in either group (Table 2).

Table 2.

Summary of outcomes.

	Control (n = 28)	TAP hydrogel (n = 29)	p-value
Facial thickness (mm)
Suprapatellar	0.7 ± 0.1 (0.6–0.9)	0.7 ± 0.1 (0.6–0.9)	n.s
Parapatellar	0.8 ± 0.2 (0.5–0.8)	0.7 ± 0.2 (0.5–0.8)	n.s
Infrapatellar	0.8 ± 0.1 (0.5–0.9)	0.8 ± 0.1 (0.4–0.9)	n.s
Pain VAS
Preoperative	6.7 ± 2.1 (4–10)	7.0 ± 1.9 (4–10)	n.s
Postoperative 1 week	3.5 ± 0.8 (2–10)	3.3 ± 1.1 (1–9)	n.s
Postoperative 3 months	2.5 ± 0.4 (0–6)	2.3 ± 0.7 (0–5)	n.s
Postoperative 1 year	1.8 ± 0.3 (0–4)	1.8 ± 0.4 (0–4)	n.s
Analgesics consumption(mg)	7.1 ± 1.8 (2.4–11.5)	5.7 ± 2.9 (1.9–9.8)	n.s
Clinical scores
HSS score			n.s
Preoperative	46.3 ± 11.1 (28–83)	44.0 ± 13.2 (13–67)	n.s
Postoperative 3 months	90.9 ±8.9 (70–100)	90.8 ± 10.3 (68–100)	n.s
Postoperative 1year	91.4 ±6.8 (74–100)	87.8 ± 7.2 (78–100)	n.s
KS score
Preoperative	71.7 ± 6.8 (7–89)	69.4 ± 8.1 (3–82)	n.s
Postoperative 3 months	86.7 ± 7.8 (72–100)	83.4 ± 8.1 (70–100)	n.s
Postoperative 1 year	91.0 ± 6.4 (66–100)	92.5 ± 7.2 (64–100)	n.s
WOMAC score
Preoperative	59.7 ± 10.5 (22–89)	57.8 ± 12.3 (32–91)	n.s
Postoperative 3 months	22.3 ± 7.1 (0–42)	26.6 ± 5.6 (0–39)	n.s
Postoperative 1 year	23.0 ± 6.4 (0–38)	22.8 ± 4.9 (0–49)	n.s
Patient’s satisfaction score
Postoperative 3 months	3.5 ± 0.4 (2–6)	3.7 ± 0.8 (3–7)	n.s
Postoperative 1 year	3.6 ± 0.6 (3–7)	3.9 ± 0.4 (3–6)	n.s
Surgical site complication (n)	0	0

TAP: temperature-sensitive anti-adhesive poloxamer; VAS: visual analogue scale; HSS: hospital for special surgery; KS: knee society; WOMAC: Western Ontario and McMaster universities osteoarthritis index.

Figure 7.

Comparison of percentage of skin folding grade between two groups. When compared to the control group at six weeks after surgery, there was significant improvement in skin folding in anti-adhesive agent group (asterisk). There was significant improvement in skin folding in anti-adhesive agent group (p = 0.041). However, no significant difference was shown at one year after surgery.

Discussion

The most important finding of this study was that application of TAP hydrogel on the fascial layer after capsular closure in TKA decreased fascial adhesion in early postoperative period and that it was safe without any surgical site complication. However, local use of TAP hydrogel failed to enhance postoperative ROM, clinical scores, or the degree of patient satisfaction.

Postoperative ROM is considered as one of the most important factors in patients’ satisfaction after TKA.²⁸ Furthermore, limited motion of knee joint after operation is correlated with disabling clinical outcomes including arthralgia, restricted ambulation, implant loosening, and eventually surgical failure.¹ One of the most important reasons of limited ROM is soft tissue adhesion after surgery. Postoperative joint fibrosis and adhesion are normal consequences of the tissue healing process which is mediated by the inflammatory reaction cascade. However, characterized by excessive proliferation of scar tissue, an impaired wound healing response can cause severe adhesion that has strong correlations with postoperative pain and stiffness.^29,30 This unbalanced arthrofibrotic condition is characterized by a lack of fibroblast’s apoptosis during the pro-inflammatory phase, resulting in an imbalance between synthesis and degradation. Proteoglycans, collagens, and extracellular matrix components can aggressively accumulate in the intercellular space, creating a fibrotic state.³¹

One way to prevent postoperative adhesion is using anti-adhesive agents. It has been reported that anti-adhesive agents can prevent fibrosis and scar formation in fetuses as well as in early phase of wound healing.^31–33 It can modulate cell proliferation, migration, and gene expression with anti-inflammatory effects. However, conventional anti-adhesive agents have limitations such as short activity, gel type form hindering application to a wide area, and low ability of attachment. These limitations were revealed in one clinical study reporting outcomes of using conventional anti-adhesive hyaluronate agent in TKA. The author used the anti-adhesive hyaluronate agent through both intra-articular and extra-articular injection and showed that there was no significant improvement in ROM or postoperative pain.⁸ These negative results regarding the efficacy of the anti-adhesive hyaluronate agent made surgeons hesitate to use such agent in knee joints and have doubt on its usefulness.

The newly developed TAP hydrogel used in this study is mainly consisted of poloxamer188/407 which allows solution-to-gel transition with a lower critical solution temperature of 28–30°C. Depending on its molecular mass, poloxamer can be liquid, paste, or waxy solid at room temperature.^34,35 Since polyethylene glycol has hydrophilic property, adherence to soft tissue around capsule is possible which is important for prolonged residence time. TAP hydrogel also contains chitosan and gelatin. The positively charged chitosan also facilitates adhesion to joint membrane which is consisted of negatively charged membrane cells. Chitosan and gelatin are also known to be biocompatible, biodegradable, non-toxic, and non-allergenic.^17,36–38 Owing to such properties, these components also play an important role as physical or biological barrier of membrane to cope with bleeding (anti-coagulant) and prevent invasion of bacteria (anti-bacterial).³⁹ Several in vivo studies have shown promising results of TAP hydrogel after spine surgery.^18,19 Poloxamer-based thermo-sensitive agent has shown superior efficacy over hyaluronate-based solution after laminectomy in a rabbit model.¹⁸ However, the present clinical study showed that there was no enhancement of postoperative ROM after TKA in the TAP hydrogel group compared to the control group, consistent with results of a previous study that used conventional (ex-, without poloxamer) anti-adhesive agent periarticularly during TKA.⁸ Although TAP hydrogel is a new generation of hydrogel expected to have favorable results, it failed to improve ROM compared to the control group. One possible reason might be that TAP hydrogel was only applied onto the fascial layer without intra-articular use. Fibrotic changes of soft tissue after TKA can occur in both intra- and extra-articular space.²⁹ However, intra-articular application of hydrogel can induce inflammatory response following degradation of hydrogel. In addition, according to the previous study, intra-articular use of anti-adhesive gel had no meaningful effect on postoperative ROM in TKA.⁸ For these reasons, we conducted this clinical trial study of extra-articular injection of TAP hydrogel.

This study demonstrated the efficacy and safety of TAP hydrogel on fascial adhesion in early postoperative period. This demonstrates that TAP hydrogel has anti-adhesive effect on the fascial layer. It induced less overlying skin adhesion and folding. However, such cosmetic advantage was valid for limited time, ranging at six weeks after surgery.

Although the application of TAP hydrogel had no meaningful effect on clinical scores or patient’s satisfaction in the present study, the safety of such anti-adhesive gel at knee joint was confirmed, similar to previous studies.^8,12 TAP hydrogel was used after capsular closure and showed no leakage without any surgical site infection or delayed wound healing. These results showed that TAP hydrogel also showed good ability of being held in the position where it was applied in early operative period, consistent with previous reports showing its excellent attachment ability after spine surgery based on histologic exam.^18,19 Since safety was secured, we can plan a future study of intra-articular administration of TAP hydrogel.

This study has several limitations. To the best of our knowledge, this was the first study to report correlation between anti-adhesive agent and fascial adhesion of the knee. However, the relevance between fascial adhesion and functional outcome has not been reported yet and not confirmed also in the present study. Skin folding can be considered only cosmetic problem. In addition, some data on skin folding at 1 year after TKA are missing and only 15 cases were analyzed. Second, the follow-up period was relatively short. Thus, with the effort to evaluate the concern of the short duration of the activity, a further long-term study is needed in the future.

Conclusions

The local use of TAP hydrogel failed to enhance postoperative ROM, clinical score, or patient’s satisfaction. However, application of temperature sensitive, anti-adhesive poloxamer hydrogel onto fascial layer after capsular closure in TKA may decrease fascial adhesion in early postoperative period. It was safe without causing surgical site complication.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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