With the technological advancements in material science, diverse types of polymers have been used for delivery of biopharmaceuticals. As compared with other types of bioengineered materials, there has been an increased interest in hydrogels over the past decades; their physical properties are close to the living tissue and their advantages include biocompatibility, biodegradability and non-toxicity [1,2]. Hydrogels are equipped with a 3-dimensional (3D) cross-linked configuration, which are composed of hydrophilic polymers that are able to captivate water without being dissolved [3]. Hydrogels are responsive to changes in the environment (e.g., temperature, pH, magnetic fields, enzymes and light); their 3D structure can be modified to obtain the desired functionality. This is the reason that they have been widely studied for their applicability as a drug delivery system (DDS) [4,5].

A temperature-responsive hydrogel (TRH) is equipped with both hydrophobic and hydrophilic components. It is therefore endowed with a thermal response arising from a delicate balance between the hydrophobic and hydrophilic components [6,7]. Such balance is altered by the temperature, which may cause changes in the solubility of the cross-linking network [8]. That is, a TRH shows a phase transition resulting in a sudden change in its solubility [9].

To date, TRHs have been widely developed because controlled release of bioactive agents is sensitive to the temperature change. As compared with traditional types of hydrogels, TRHs are advantageous in preventing the first pass metabolism and avoiding the burst release of the therapeutic agents by causing a rapid temperature-induced sol-to-gel transition that is both safe in the human body and appropriate for injectable systems. They are therefore equipped with the controlled release behavior [1].

PF-72 (TGel Bio Co. Ltd., Seoul, Korea) is a type of TRH; it was developed as a sustained drug delivery device for pain relief at the site of surgical incision for 72 h postoperatively [10,11]. Its mode of action is based on the mechanism that the hydrogel is soluble at low temperatures (2-8°C) and then converted into a gel at high temperature (>30°C). Moreover, its biocompatibility and preclinical feasibility have been verified on in vitro and in vivo tests. Furthermore, it deserves special attention that PF-72 mixed with ropivacaine was effective in inducing the extended pain relief in a rat experimental model of surgical wound [10]. A recent prospective trial showed that PF-72 mixed with 0.75% ropivacaine hydrochloride was an effective, safe medical device in the management of postoperative pain in patients undergoing single-level lumbar discectomy [12]. Along the continuum of previous literatures, we conducted this prospective, randomized controlled trial to assess the efficacy and safety of PF-72 mixed with 0.75% ropivacaine hydrochloride in the management of postoperative pain in patients undergoing elective arthroscopic shoulder surgery. This is an attempt to expand its indications to orthopedic surgery.

1. Trial design and setting

The current single-center, single-blind, randomized, confirmatory, controlled trial was conducted at Daejeon Woori Hospital in Daejeon, Korea between March 1 and September 30, 2023.

Inclusion criteria for the current study are as follows:

(1) Korean adult men or women aged between 19 and 70 years old

(2) The patients with (American Society of Anesthesiologists (ASA) scores 1-3

(3) The patients planned for elective arthroscopic shoulder surgery for rotator cuff tear, calcific tendinitis or a torn tendon or ligament.

Exclusion criteria for the current study are as follows:

(1) The patients with no preoperative 100 mm visual analogue scale (VAS) scores 0

(2) The patients with inflammation or acute intermittent porphyria, that may affect the results of the current trial, at the site of surgery or its adjacent regions

(3) The patients with cognitive dysfunction that may affect the subject pain assessment

(4) The patients with body weight <50 kg in men and <45 kg in women

(5) The patients with hypersensitivity reactions to sodium hyaluronate and those with a past history of it

(6) Women with confirmed pregnancy on urine human chorionic gonadotropin test

(7) The patients with preoperative estimated glomerular filtration rate <60 ml/min

(8) The patients with preoperative serum alanine aminotransferase levels >100 IU/L

(9) The patients who were currently participating in other clinical trials and those who participated in them within 30 days of baseline screening

(10) The patients who were deemed ineligible for study participation according to the investigators’ judgment.

2. Ethics statement

The current study was approved by the Internal Institutional Review Board (IRB) of National Bioethics Policy and then conducted in compliance with the relevant ethics guidelines. All the study treatments and procedures described herein were performed in accordance with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. All the patients submitted a written informed consent. The current study was conducted in compliance with the International Conference of Harmonization - Good Clinical Practice (ICH-GCP).

3. Rationale of sample size estimation

For the current trial, we estimated the sample size using G* Power (Heinrich-Heine-Universität, Düsseldorf, Germany). To do this, we performed a repeated-measures analysis of variance and used a type I error of 0.05, an effect size of 0.25, a statistical power of 0.9, and a drop-out rate of 10%. Moreover, we conservatively set the correlation between the repeated measures at 0. Therefore, we estimated the sample size to be a minimum of 80.

4. Trial methods

After submitting a written informed consent, all the eligible patients were randomized to either the trial group or the control group. According to the standard treatment protocol of our medical institution, they were hospitalized at least one day preoperatively and received a preoperative work-up, followed by elective arthroscopic shoulder surgery. The patients of the trial group received the application of PF-72 mixed with 0.75% ropivacaine hydrochloride to the surgical site. But the patients of the control group received patient-controlled anesthesia with no procedures at the surgical site. The patients of each group received rescue analgesics when they presented with pain based on numeric rating scale (NRS) pain scores ≥4, for which the dose of rescue analgesics was determined according to established principles of acute pain management [12].

5. Criteria for assessing trial outcomes

Baseline characteristics of the patients include age, sex, height, weight, ASA physical status and length of hospital stay (LHS).

For the assessment of the efficacy of PF-72 mixed with 0.75% ropivacaine hydrochloride, the patients were monitored at 3, 6, 24, 48 and 72 hours postoperatively. Then, the amount of used rescue analgesics was measured, and NRS pain scores were measured when the suture was compressed at 3, 6, 24, 48 and 72 hours postoperatively, for which the cumulative area under the curve (AUC_0-72) of NRS pain scores was plotted [12].

For the assessment of the safety of PF-72 mixed with 0.75% ropivacaine hydrochloride, any TEAEs and SAEs were categorized by the system organ class and then coded by preferred terms using the Medical Dictionary for Regulatory Activities (MedDRA) version 19. Then, incidences of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) were analyzed [12].

6. Analysis of survival of PF-72 mixed with 0.75% ropivacaine hydrochloride

In the current study, we analyzed pain-free survival; it is defined as survivorship of the patients presenting with no pain [13,14].

7. Statistical analysis of the patient data

All data was expressed as mean±standard deviation, mean±standard error with 95% confidence intervals (CIs) or the number of the patients with percentage, where appropriate. Kruskal-Wallis or Fisher’s exact test were used to compare outcome measures between the two groups. To estimate time-to-events (TTEs), we performed Kaplan-Meier survival analysis and provided 95% CIs accordingly. Then, we plotted Kaplan-Meier survival curve, as previously described [13,14]. Statistical analysis was performed using the Statistical Analysis Software Version 9.4 (SAS Institute Inc, Cary, North Carolina, USA). A P-value of <0.05 was considered statistically significant.

1. Baseline characteristics of the patients

A total of 80 patients (n = 80) were initially recruited for the current study, who were equally divided into the trial group (n = 40) and the control group (n = 40). Of these, however, five patients of the trial group and three of the control group dropped out of the study because of lack of compliance. Therefore, the remaining 72 patients (n = 72) were finally included in the assessment. They comprise 35 patients of the trial group (n = 35) and 37 of the control group (n = 37). There were no significant differences in age, sex, height, weight, ASA physical status and LHS between the two groups (P > 0.05) (Table 1).

Table 1 . Baseline characteristics of the patients (n = 72).

Variables	Values		P-value
	Trial group (n = 35)	Control group (n = 37)
Age (years old)	55.5 ± 3.8	57.1 ± 4.8	0.106
Sex			0.234
Men	17 (48.6)	24 (64.9)
Women	18 (51.4)	13 (35.1)
Height (cm)	163.6 ± 4.7	165.1 ± 4.5	0.176
Weight (kg)	63.4 ± 5.7	63.9 ± 4.0	0.683
ASA physical status			0.579
I	5 (14.3)	5 (13.5)
II	29 (82.9)	32 (86.5)
III	1 (2.8)	0 (0.0)
Length of hospital stay (days)	5.6 ± 0.6	5.4 ± 0.5	0.139

Values are mean ± standard deviation or the number of the patients with percentage, where appropriate..

ASA: American Society of Anesthesiologists..

2. Efficacy outcomes

There was a significant difference in the amount of used analgesics between the two groups at 3, 6, 24, 48 and 72 hours postoperatively (P = 0.000) (Table 2) (Fig. 1). There were significant differences in NRS pain scores between the two groups at 3, 6, 24, 48 and 72 hours postoperatively (P = 0.000) (Fig. 2). Moreover, there were also significant differences in AUC_0-6, AUC_0-24, AUC_0-48 and AUC_0-72 between the two groups (P = 0.000) (Table 3) (Fig. 3). Furthermore, there was a significant difference in the proportion of the patients presenting with no pain (NRS pain scores ≤ 3) between the two groups at 3, 6 and 24 hours postoperatively (P = 0.000) (Fig. 4).

Table 2 . The amount of used analgesics (n = 72).

Variables	Values		P-value
	Trial group (n = 35)	Control group (n = 37)
Time points (postoperative hours)
3	2.16 ± 2.35	4.94 ± 1.87	0.000*
6	3.18 ± 3.47	9.91 ± 4.81	0.000*
24	6.12 ± 3.57	14.65 ± 6.53	0.000*
48	8.79 ± 3.62	18.02 ± 6.12	0.000*
72	12.26 ± 3.67	22.10 ± 6.34	0.000*

Values represent (the amount of rescue analgesics) × 0.01 in the trial group and (the amount of patient-controlled anesthesia) × 0.01 and (the amount of rescue analgesics) × 0.01 in the control group. The unit is mg..

*Statistical significance at P < 0.05..

Table 3 . The area under the curve of the numeric rating scale pain scores (n = 72).

Variables	Values		P-value
	Trial group (n = 35)	Control group (n = 37)
AUC0-6	18.3 ± 5.2	29.3 ± 8.2	0.000*
AUC0-24	59.9 ± 13.9	95.4 ± 24.0	0.000*
AUC0-48	111.3 ± 25.1	164.8 ± 41.2	0.000*
AUC0-72	141.5 ± 30.8	220.0 ± 56.0	0.000*

Values are mean ± standard deviation..

*Statistical significance at P < 0.05..

AUC: area under the curve..

Figure 1. The amount of used analgesics (n = 72). Values represent (the amount of rescue analgesics) × 0.01 in the trial group and (the amount of patient-controlled anesthesia) × 0.01 and (the amount of rescue analgesics) × 0.01 in the control group. The unit is mg. ***Statistical significance at P < 0.05.

Figure 2. Time-dependent changes in the numeric rating scale pain scores (n = 72). Values are mean ± standard deviation. ***Statistical significance at P < 0.05.

Figure 3. The area under the curve of the numeric rating scale pain scores (n = 72). Values are mean ± standard deviation. AUC: area under the curve.

Figure 4. The proportion of the patients presenting with no pain (numeric rating scale pain scores ≤ 3) (n = 72). ***Statistical significance at P < 0.05.

3. Safety outcomes

In both groups, TEAEs include mild nausea and vomiting, none of which had a causal relationship with PF-72 mixed with 0.75% ropivacaine hydrochloride. But there were no cases of SAEs. Moreover, there were no significant differences in the incidences of TEAEs and SAEs between the two groups (P > 0.05) (Fig. 5).

Figure 5. Incidences of treatment-emergent adverse events and serious adverse events (n = 72). TEAEs: treatment-emergent adverse events; SAEs: serious adverse events.

As shown in Fig. 6, TTEs are estimated at 7.486 ± 2.758 (95% CI 2.081 ± 12.890) hr in the trial group and 9.324 ± 2.488 (95% CI 4.448 ± 14.200) hr in the control group.

Figure 6. Kaplan-Meier survival. Time-to-events are estimated at 7.486 ± 2.758 (95% CI 2.081 ± 12.890) hr in the trial group and 9.324 ± 2.488 (95% CI 4.448 ± 14.200) hr in the control group.

Conventional DDSs have been designed to physically entrap molecules in a polymer lattice; they induce a slow diffusion-dependent release of a drug. As a result, plasma levels of a drug reach an early peak followed by its steady, linear release [15].

Diverse types of polymers can be incorporated with medications and then dissolve completely after performing their functions. Polymeric networks, known as hydrogels, can absorb a considerable amount of liquid. Due to the high amount of water, hydrogels can mimic the soft and flexible texture of biological tissues [16]. Thanks to their similarity to living tissues and excellent biocompatibility, hydrogels display diverse biomedical and bioengineering actions, such as wound dressings, contact lenses and cosmetic products [16-20]. Moreover, biodegradable hydrogels are equipped with great biomedical potential such as controlled DDS [21-23]. Thus, polymers have been used as a controlled DDS; they are designed to maintain the concentration of a drug within the desired therapeutic range [15]. Drugs can be loaded into a hydrogel matrix in diverse ways, including physical entrapment, covalent attachment or adsorption. Hydrogels can be administered to patients via various routes, including injection, implantation and topical application. After entering the body, hydrogels protect the drug from being degraded. This enables hydrogels to gradually dispense the drug in a controlled manner. The rate of drug release is dependent on the physical and chemical properties of the hydrogel. Moreover, it can also be controlled when incorporated into stimuli-responsive components. Furthermore, hydrogels can be degraded in vivo and do not need to be removed after a useful lifespan [24].

Nevertheless, polymers reveal their limitations that they are insensitive to metabolic changes in the body, cannot alter the drug release and cannot accurately deliver the drug to the target site. Therefore, it has been imperative that a novel type of polymer be developed as a DDS. In this regard, temperature-responsive DDSs have been developed to release their payload in the environment above the physiological temperature [15]. According to the test for the temperature-responsive gelation behavior of hydrogel, the chilled solution undergoes transformation from a liquid to a semisolid gel when exposed to body temperature. In contrast to typical types of pharmaceutical solvents, including saline, hydrogel is designed to remain in the tissue after its percutaneous injection. Moreover, hydrogel may help to prevent drug leakage from the injection site [25].

The feasibility of TRH in the context of orthopedic surgery would be of interest. Although pain control at the surgical site is generally achieved by the local application of anesthetics loaded in saline, this analgesic method is generally short-lived and sometimes incomplete because saline as a carrier causes free diffusion and quick metabolism of the drug. Moreover, orthopedic surgeons are limited by recommended maximum bolus of the drug to avoid potential toxicity [25]. Thus, the application of PF-72 mixed with 0.75% ropivacaine hydrochloride to the surgical site deserves special attention in settings of elective arthroscopic shoulder surgery.

PF-72 was approved as a Class IV medical device by the Korean Ministry of Food and Drug Safety in 2021; it is a TRH that has been developed to release an anesthetic for three days for postoperative pain relief. Its manufacturing process complies with the Korean Good Manufacturing Practice guidelines [26]. Class IV medical devices are regulated under the Medical Devices Regulations (MDRs). The MDRs were also amended to provide that a medical device “that is manufactured from or that incorporates human or animal cells or tissues or their derivatives” or “that is manufactured from or that incorporates a product produced through the use of recombinant DNA technology” is a Class IV medical device (unless it is intended to come into contact with intact skin only). Class IV is the highest-risk classification and licensing requires the submission of more extensive information and documents, including detailed information on safety and effectiveness [27].

It would be mandatory to ensure the long-term safety of a medical device, which is essential for public health [28]. Postmarket data is considered an important source of evidence of patient safety and the performance of a medical device [29]. Nevertheless, manufacturer-sponsored postmarket clinical trials inherently lack an ability to assess long-term outcomes of a medical device or to predict the occurrence of rare adverse events. Moreover, they also lack an ability to completely confirm the safety profile of a medical device in a cohort of patients who are exposed to it although it was cleared through the US FDA 510(k) process [30,31]. It would therefore be mandatory to perform an analysis of RWD, defined as data obtained from diverse types of sources about patients’ health and use of healthcare resources, such as spontaneous reports, registries, administrative claims, mobile devices and electronic health records (EHRs) [32]. Real-world evidence (RWE) refers to an evidence derived from an analysis of the RWD. Both RWD and RWE constitute integral parts of global strategies for evidence generation. RWE includes clinical evidence derived from patient-reported outcomes and possible benefits or risks of a medical device. It plays a role in supporting the results of manufacturer-sponsored postmarket clinical trials, thus contributing to accumulating evidences of the efficacy and safety of a medical device in a cohort of patients [32]. In more detail, with the wide spread use of digital health data and EHRs, the efficacy and safety of a medical device has been assessed through an analysis of RWD using the health information technology system. This leads to the accumulation of RWE [33].

Of note, two recent retrospective studies have shown the efficacy and safety of PF-72 in other clinical settings; Cho J, et al. and Yun CW, et al. showed that the postoperative use of PF-72 was an effective, safe modality in relieving pain in patients undergoing breast augmentation and bimaxillary surgery, respectively [34,35]. Further studies are also warranted to expand the indications of PF-72 in the context of postoperative pain relief.

To summarize, our results are as follows:

There was a significant difference in the amount of used analgesics between the two groups at 3, 6, 24, 48 and 72 hours postoperatively (P = 0.000). There were significant differences in NRS pain scores between the two groups at 3, 6, 24, 48 and 72 hours postoperatively (P = 0.000). Moreover, there were also significant differences in AUC_0-6, AUC_0-24, AUC_0-48 and AUC_0-72 between the two groups (P = 0.000). Furthermore, there was a significant difference in the proportion of the patients presenting with no pain (NRS pain scores ≤ 3) between the two groups at 3, 6 and 24 hours postoperatively (P = 0.000).

In both groups, TEAEs include mild nausea and vomiting, none of which had a causal relationship with PF-72 mixed with 0.75% ropivacaine hydrochloride. But there were no cases of SAEs. Moreover, there were no significant differences in the incidences of TEAEs and SAEs between the two groups (P > 0.05).

TTEs are estimated at 7.486 ± 2.758 (95% CI 2.081 ± 12.890) hr in the trial group and 9.324 ± 2.488 (95% CI 4.448 ± 14.200) hr in the control group.

But our results cannot be generalized because there are two limitations of the current study as follows: First, we could not completely rule out the possibility of selection bias because this is a single-center study. Single-center studies are often followed by multicenter ones [36]. A collaborative, multicenter is equipped with key advantages, such as an ability to respond to questions requiring a larger sample size and those about the generalizability of outcomes across the centers and to compare the effects between the study centers [37,38]. Second, we failed to assess the quality of life (QoL) following the use of PF-72 mixed with 0.75% ropivacaine hydrochloride in the patients undergoing elective arthroscopic shoulder surgery. This warrants further studies using patient-reported outcome measures (PROMs). PROMs are a key important component in orthopedic registries. Their use in the context of orthopedic surgery enables orthopedic surgeons to better measure surgical outcomes through an objective assessment of patients’ subjective experience, including measurements of pain, function, range of motion and QoL [39]. This is beneficial to both patients and healthcare providers, thus contributing to value-based care models [40]. Further studies are therefore warranted to assess the effects of PF-72 in improving the QoL in the context of pain relief after orthopedic surgery with the use of the EuroQol 5 dimensions (EQ-5D) or the 36-Item Short Form Health Survey questionnaire (SF-36) [41,42]. Third, this is a single-blind study. A majority of clinical trials are conducted under the single-blind design, although double-, triple- or quadruple-blind ones raise the reliability of outcomes and their quality [43]. Further double-blind studies are therefore warranted to establish the results of the current study.

Based on the current results, it can be concluded that the use of PF-72 mixed with 0.75% ropivacaine hydrochloride is an effective, safe modality in the management of postoperative pain in the patients undergoing elective arthroscopic shoulder surgery. But further large-scale, multi-center studies are warranted to establish our results.

This study was sponsored by Reanzen Co., Ltd. (Anyang, Gyeonggi, Republic of Korea), the distributor of PF-72.

No potential conflict of interest relevant to this article was reported.